FH
Fumarate hydratase, mitochondrial precursor (EC 4.2.1.2) (Fumarase) (HsFH)
Publications[править]
Fluid intelligence (FI) involves abstract problem-solving without prior knowledge. Greater age-related FI decline increases Alzheimer's disease (AD) risk, and recent studies suggest that certain dietary regimens may influence rates of decline. However, it is uncertain how long-term food consumption affects FI among adults with or without familial history of AD (FH) or APOE4 (ɛ4). Observe how the total diet is associated with long-term cognition among mid- to late-life populations at-risk and not-at-risk for AD. Among 1,787 mid-to-late-aged adult UK Biobank participants, 10-year FI trajectories were modeled and regressed onto the total diet based on self-reported intake of 49 whole foods from a Food Frequency Questionnaire (FFQ). Daily cheese intake strongly predicted better FIT scores over time (FH-: β= 0.207, p < 0.001; ɛ4-: β= 0.073, p = 0.008; ɛ4 : β= 0.162, p = 0.001). Alcohol of any type daily also appeared beneficial (ɛ4 : β= 0.101, p = 0.022) and red wine was sometimes additionally protective (FH : β= 0.100, p = 0.014; ɛ4-: β= 0.59, p = 0.039). Consuming lamb weekly was associated with improved outcomes (FH-: β= 0.066, p = 0.008; ɛ4 : β= 0.097, p = 0.044). Among at risk groups, added salt correlated with decreased performance (FH : β= -0.114, p = 0.004; ɛ4 : β= -0.121, p = 0.009). Modifying meal plans may help minimize cognitive decline. We observed that added salt may put at-risk individuals at greater risk, but did not observe similar interactions among FH- and AD- individuals. Observations further suggest in risk status-dependent manners that adding cheese and red wine to the diet daily, and lamb on a weekly basis, may also improve long-term cognitive outcomes.
Keywords
- APOE4
- Aging
- Mediterranean diet
- cognitive decline
- functional food
- lamb
- nutrition policy
- preventive medicine
- red wine
- salt
APOE-ε4 is a major genetic risk factor for late-onset Alzheimer's disease that interacts with other risk factors, but the nature of such combined effects remains poorly understood. We quantified the impact of APOE-ε4, family history (FH) of dementia, and obesity on white matter (WM) microstructure in 165 asymptomatic adults (38-71 years old) using quantitative magnetization transfer and neurite orientation dispersion and density imaging. Microstructural properties of the fornix, parahippocampal cingulum, and uncinate fasciculus were compared with those in motor and whole-brain WM regions. Widespread interaction effects between APOE, FH, and waist-hip ratio were found in the myelin-sensitive macromolecular proton fraction from quantitative magnetization transfer. Among individuals with the highest genetic risk (FH and APOE-ε4), obesity was associated with reduced macromolecular proton fraction in the right parahippocampal cingulum, whereas no effects were present for those without FH. Risk effects on apparent myelin were moderated by hypertension and inflammation-related markers. These findings suggest that genetic risk modifies the impact of obesity on WM myelin consistent with neuroglia models of aging and late-onset Alzheimer's disease.
Keywords
- APOE
- Aging
- Alzheimer’s disease
- Central obesity
- Family history of dementia
- Hypertension
- Inflammation
- Myelin
- Parahippocampal cingulum
The hippocampus is one of the first regions to demonstrate atrophy during the prodromal stage of Alzheimer's disease. Volumetric analysis of its individual subfields could provide biomarkers with higher sensitivity than whole hippocampal volume during an earlier disease stage. We quantified the hippocampal subfields volume in a large cohort comprising healthy participants (aged 40-59) with dementia family history (FH) and controls (without FH), examined at 2 time points across 2 years. Subfield volumes were quantified using both a T1-weighted and a high-resolution T2 hippocampal magnetic resonance imaging acquisition with Freesurfer. The participants were stratified based on dementia FH, APOE genotype, and CAIDE (Cardiovascular Risk Factors, Aging and Dementia) risk score. Whole hippocampal volume did not differ between the groups. The volume of the molecular layer was lower in participants with an APOE ε4 genotype, but there were no differences between subjects with and without dementia FH or with an increasing CAIDE score. The molecular layer may be the first hippocampal region to demonstrate volumetric alterations in subjects at risk of dementia.
MeSH Terms
- Adult
- Aging
- Alzheimer Disease
- Apolipoproteins E
- Atrophy
- Dementia
- Diffusion Magnetic Resonance Imaging
- Educational Status
- Female
- Genotype
- Hippocampus
- Humans
- Male
- Middle Aged
- Organ Size
- Risk
Keywords
- Alzheimer's disease
- Dementia
- Hippocampal subfields
- Hippocampus
- Preclinical dementia
Ageing people with hemophilia (PWH) have a higher prevalence of hypertension than the general population. This study aimed to determine whether macroscopic hematuria was associated with hypertension in PWH in a post hoc analysis using data from a cross-sectional study conducted by the ADVANCE Working Group (the H3 study), which included PWH ≥ 40 years of age. Data from 16 contributing centers, located in 13 European countries and Israel, were analyzed using logistic regression models. Of 532 recruited PWH in the H3 study, 117 had hypertension and a positive family history of hypertension (hypertension FH ), 75 had hypertension and a negative family history of hypertension (hypertension FH-), 290 had no diagnosis of hypertension, and the remaining 50 had missing hypertension data. Logistic regressions showed that macroscopic hematuria was associated with hypertension FH , both in the univariate (OR = 1.84 [1.17-2.90], P = .01) and in the multivariate model (OR = 1.80 [1.03-3.16], P = .04). Macroscopic hematuria was not associated with hypertension FH-. Moreover, in a multivariate logistic regression the odds of hypertension FH were increased with the number of macroscopic hematuria episodes. The association between macroscopic hematuria and hypertension was significant for PWH with a family history of hypertension.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Cross-Sectional Studies
- Female
- Hematuria
- Hemophilia A
- Humans
- Hypertension
- Israel
- Logistic Models
- Male
- Middle Aged
- Risk Factors
Familial hypercholesterolemia (FH) is a genetic disorder caused by dysfunction of low density lipoprotein receptors (LDLr), resulting in elevated plasma cholesterol levels. FH patients frequently exhibit cognitive impairment, a finding recapitulated in LDLr deficient mice (LDLr-/-), an animal model of FH. In addition, LDLr-/- mice are more vulnerable to the deleterious memory impact of amyloid-β (Aβ), a peptide linked to Alzheimer's disease. Here, we investigated whether the expression of proteins involved in Aβ metabolism are altered in the brains of adult or middle-aged LDLr-/- mice. After spatial memory assessment, Aβ levels and gene expression of LDLr related-protein 1, proteins involved in Aβ synthesis, and apoptosis-related proteins were evaluated in prefrontal cortex and hippocampus. Moreover, the location and cell-specificity of apoptosis signals were evaluated. LDLr-/- mice presented memory impairment, which was more severe in middle-aged animals. Memory deficit in LDLr-/- mice was not associated with altered expression of proteins involved in Aβ processing or changes in Aβ levels in either hippocampus or prefrontal cortex. We further found that the expression of Bcl-2 was reduced while the expression of Bax was increased in both prefrontal cortex and hippocampus in 3- and 14-month-old LDLr-/-mice Finally, LDLr-/- mice presented increased immunoreactivity for activated caspase-3 in the prefrontal cortex and hippocampus. The activation of caspase 3 was predominantly associated with neurons in LDLr-/- mice. Cognitive impairment in LDLr-/- mice is thus accompanied by an exacerbation of neuronal apoptosis in brain regions related to memory formation, but not by changes in Aβ processing or levels.
MeSH Terms
- Aging
- Amyloid beta-Protein Precursor
- Animals
- Apoptosis
- Brain Chemistry
- Caspase 3
- Cholesterol
- Gene Expression
- Hippocampus
- Male
- Maze Learning
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Prefrontal Cortex
- Receptors, LDL
Keywords
- Familial hypercholesterolemia
- LDLr-/- mice
- amyloid-β
- apoptosis
- memory impairment
The increased risk of cardiovascular disease in familial hypercholesterolemia (FH) is caused by increased cholesterol burden from birth. Even small elevation in cholesterol level accumulates over time and aggravates atherosclerosis. The aim of the present study was to describe the lipid profile across sex and age in a large cohort of untreated children and adolescents with FH, as this have not clearly been described. FH children (438 girls, 452 boys) not receiving lipid-lowering therapy, aged 0 to 19 years were included and divided into 4 age groups (<5, 5-9, 10-14, and 15-19 years). Information was retrieved from the medical records. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and non-HDL cholesterol (non-HDL-C) were studied in relation to sex and age by multiple linear regression analysis. Girls with FH as compared to boys had significantly higher TC, LDL-C, and non-HDL-C (P < .001 for all) levels with mean (95% confidence interval) differences of 0.48 mmol/L (0.28, 0.68) (18.6 g/dL), 0.39 mmol/L (0.19, 0.59) (15.08 mg/dL), and 0.42 mmol/L (0.22, 0.63) (16.24 mg/dL), respectively. These estimates did not change after adjustment for age. We also observed sex differences for HDL-C; girls had higher HDL-C in the youngest (<5 years, P = .05) and oldest age groups (15-19 years, P < .001). FH girls have higher levels of TC, LDL-C, and non-HDL-C levels than boys from birth up to 19 years of age. This may contribute significantly to the total lifelong cholesterol burden in FH women.
MeSH Terms
- Adolescent
- Aging
- Child
- Child, Preschool
- Cholesterol
- Female
- Humans
- Hyperlipoproteinemia Type II
- Infant
- Infant, Newborn
- Male
- Mutation
- Sex Characteristics
- Young Adult
Keywords
- Age
- Children
- Cholesterol
- Familial hypercholesterolemia
- Sex
Recent data have suggested an important role of lipoprotein (a) [Lp(a)] and proprotein convertase substilisin/kexin type 9 (PCSK9) in the development of atherosclerotic cardiovascular disease (ASCVD) in both general population and family hypercholesterolemia (FH), while the relation of Lp(a) to PCSK9 has not been examined. The aim of the present study was to investigate the association between plasma PCSK9 and Lp(a)in patients with heterozygous FH (HeFH). Two hundred and fifty-five molecularly confirmed patients with HeFH were compared to 255 age- and gender-matched non-FH controls. Plasma PCSK9 and Lp(a) concentrations were measured using ELISA and immunoturbidimetric method respectively, and finally their association was assessed. Both plasma PCSK9 and Lp(a) levels were significantly higher in patients with HeFH compared to control group (p<0.001). Besides, the Lp(a) concentration and percentage of Lp(a)≥300mg/L were increased by PCSK9 tertiles in HeFH group (both p<0.05) while not in control group. In partial correlation analysis, Lp(a) was associated with PCSK9 (r=0.254, p<0.001) in HeFH group but not in control, which were further confirmed by multivariable linear regression analysis. Furthermore, significant associations between Lp(a) and PCSK9 were also found in subgroups of HeFH group irrespective of definite or probable FH, with and without coronary artery disease (CAD), and with statin or not. Plasma Lp(a) level was associated with PCSK9 in patients with HeFH alone, suggesting that much about the interaction of PCSK9 with Lp(a) in FH need further explorations.
MeSH Terms
- Adult
- Aged
- Aging
- Case-Control Studies
- Coronary Artery Disease
- DNA
- Female
- Humans
- Hyperlipoproteinemia Type II
- Lipids
- Lipoprotein(a)
- Male
- Middle Aged
- Proprotein Convertase 9
- Risk Factors
Keywords
- Atherosclerosis
- Familial hypercholesterolemia
- Lipoprotein (a)
- Proprotein convertase subtilisin/kexin type 9
The purpose of this study was to investigate the longitudinal trajectory of self- and informant-subjective cognitive complaints (SCC), and to determine if SCC predict longitudinal changes in objective measures (OM) of cognitive function. The study included healthy and cognitively normal late middle-aged adults enriched with a family history of AD who were evaluated at up to three visits over a 4-year period. At each visit (Visit 1-3), self- and informant-SCC and OM were evaluated. Linear mixed models were used to determine if the longitudinal rate of change of self- and informant-SCC were associated with demographic variables, depressive symptoms, family history (FH), and apolipoprotein epsilon 4 (APOE4) status. The same modeling approach was used to examine the effect of Visit 1 SCC on longitudinal cognitive change after controlling for the same variables. At Visit 1, more self-SCC were associated with fewer years of education and more depressive symptoms. SCC were also associated with poorer performance on cognitive measures, such that more self-SCC at Visit 1 were associated with poorer performance on memory and executive functioning measures at Visit 1, while more informant-SCC were associated with faster rate of longitudinal decline on a measure of episodic learning and memory. FH and APOE4 status were not associated with SCC. Self- and informant-SCC showed an association with OM, albeit over different time frames in our late middle-aged sample. Additional longitudinal follow-up will likely assist in further clarifying these relationships as our sample ages and more pronounced cognitive changes eventually emerge. (JINS, 2017, 23, 617-626).
MeSH Terms
- Aging
- Alzheimer Disease
- Cognitive Dysfunction
- Diagnostic Self Evaluation
- Female
- Genetic Predisposition to Disease
- Humans
- Longitudinal Studies
- Male
- Middle Aged
Keywords
- Aging
- Dementia
- Executive function
- Memory
- Neuropsychology
- Self-report
White matter (WM) integrity within the mesial temporal lobe (MTL) is important for episodic memory (EM) functioning. The current study investigated the ability of diffusion tensor imaging (DTI) in MTL WM tracts to predict 3-year changes in EM performance in healthy elders at disproportionately higher genetic risk for Alzheimer's disease (AD). Fifty-one cognitively intact elders (52% with family history (FH) of dementia and 33% possessing an Apolipoprotein E ε4 allelle) were administered the Rey Auditory Verbal Learning Test (RAVLT) at study entry and at 3-year follow-up. DTI scanning, conducted at study entry, examined fractional anisotropy and mean, radial and axial diffusion within three MTL WM tracts: uncinate fasciculus (UNC), cingulate-hippocampal (CHG), and fornix-stria terminalis (FxS). Correlations were performed between residualized change scores computed from RAVLT trials 1-5, immediate recall, and delayed recall scores and baseline DTI measures; MTL gray matter (GM) and WM volumes; demographics; and AD genetic and metabolic risk factors. Higher MTL mean and axial diffusivity at baseline significantly predicted 3-year changes in EM, whereas baseline MTL GM and WM volumes, FH, and metabolic risk factors did not. Both ε4 status and DTI correlated with change in immediate recall. Longitudinal EM changes in cognitively intact, healthy elders can be predicted by disruption of the MTL WM microstructure. These results are derived from a sample with a disproportionately higher genetic risk for AD, suggesting that the observed WM disruption in MTL pathways may be related to early neuropathological changes associated with the preclinical stage of AD. (JINS, 2016, 22, 1005-1015).
MeSH Terms
- Aftercare
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Apolipoprotein E4
- Diffusion Tensor Imaging
- Female
- Humans
- Male
- Memory, Episodic
- Prognosis
- Risk
- Temporal Lobe
- White Matter
Keywords
- Alzheimer’s disease
- Anatomical MRI
- Apolipoprotein E
- Diffusion tensor imaging
- Episodic memory
- Mesial temporal lobe
Familial hypercholesterolaemia (FH) is the most common monogenic disorder associated with premature cardiovascular disease. If untreated, life expectancy in heterozygous FH patients is shortened by 20-30 years compared with the general population. Nevertheless, treatment goals are only met in approximately 50% of patients. This comparative study examined the quality of life (QoL) impact of FH in patients who had and had not reached the target of treatment. Two qualitative focus group interviews were carried out with a total of ten FH patients. A semi-structured interview guide included questions identified in a preceding literature study. The data were analysed using a medical anthropological approach. While having FH did not have much impact on well-treated patients' QoL, patients who had not reached the treatment target had markedly more concerns. They had experienced severe side-effects and worried about their own and their relatives' health. They were concerned about the long-term impact of not being effectively treated including the risk that coronary heart disease could cause their premature death or disability and inability to care for their children, in particular. The women had issues with stigma and self-efficacy. The QoL impact of FH is related to treatment efficacy. These findings need to be addressed in the management of FH patients. Particular attention should be paid to those who are not presently reaching the target of treatment. The study was funded by a research grant from Amgen. not relevant.
MeSH Terms
- Adolescent
- Adult
- Aged
- Cardiovascular Diseases
- Child
- Early Diagnosis
- Female
- Focus Groups
- Humans
- Hyperlipoproteinemia Type II
- Life Expectancy
- Male
- Medication Adherence
- Middle Aged
- Patient Acceptance of Health Care
- Qualitative Research
- Quality of Life
- Risk Factors
- Young Adult
Aging is associated with increased prevalence of cardiovascular disease. Thyroid hormone deficiency during fetal life decreases myocardial tolerance to ischemia-reperfusion (IR) injury in later life. The long-term effects of fetal hypothyroidism (FH) on response to IR injury in aged rats have not been well documented. The aim of this study was therefore to compare the effect of FH on tolerance to IR injury in young and aged male rats and to determine contribution of iNOS (inducible nitric oxide synthase), Bax, and Bcl-2. Pregnant female rats were divided into two groups: The FH group received water containing 0.025% 6-propyl-2-thiouracil during gestation and the controls consumed tap water. Isolated perfused hearts from young (3 months) and aged (12 months) rats were subjected to IR. Hemodynamic parameters, infarct size, and heart NOx (nitrite nitrate) levels were measured; in addition, mRNA expression of iNOS, Bax, and Bcl-2 and their protein levels in heart were measured. Recovery of post-ischemic LVDP and ±dp/dt were lower and infarct sizes were higher than controls in aged FH rats (68.38 ± 6.7% vs. 50.5 ± 1.7%; P < 0.05). Aged FH rats had higher heart NOx values than controls (74.3 ± 2.6 vs. 47.6 ± 2.5 μmol/L, P < 0.05). After IR, in FH rats, mRNA expression of iNOS and Bax were higher and Bcl-2 was lower in both the young (350 and 240% for iNOS and Bax, respectively and 51% for Bcl-2) and aged rats (504 and 567% for iNOS and Bax, respectively and 67% for Bcl-2). Compared to controls, in FH rats protein levels of iNOS (37% for young and 45% for aged rats) and Bax (94% for young and 118% for aged rats) were higher while for Bcl-2 (36% for young and 62% for aged rats) were lower. After IR, in FH rats, aminoguanidine, a selective iNOS inhibitor, decreased mRNA expression of iNOS and Bax and increased expression of Bcl-2 in both young (65% and 58% for iNOS and Bax, respectively and 152% for Bcl-2) and aged rats (76% and 64% for iNOS and Bax, respectively and 222% for Bcl-2). In addition, in the heart of FH rats, aminoguanidine decreased protein levels of iNOS (47% for young and 60% for aged rats) and Bax (57% for young and 80% for aged rats) and increased protein levels of Bcl-2 (124% for young and 180% for aged rats). In conclusion, thyroid hormone deficiency during fetal life decreases tolerance to IR injury in aged rats; this effect is at least in part, due to increased expression of iNOS and Bax-to-Bcl-2 ratio in the heart and is restored by iNOS inhibition.
MeSH Terms
- Aging
- Animals
- Congenital Hypothyroidism
- Creatine Kinase
- L-Lactate Dehydrogenase
- Male
- Myocardial Reperfusion Injury
- Myocardium
- Nitrates
- Nitric Oxide
- Nitric Oxide Synthase Type II
- Nitrites
- Proto-Oncogene Proteins c-bcl-2
- RNA
- Rats, Wistar
- Up-Regulation
- bcl-2-Associated X Protein
Keywords
- Aging
- Fetal hypothyroidism
- Ischemia-reperfusion injury
- Nitric oxide
- Rat
Familial hypercholesterolaemia (FH) is a common genetic cause of premature coronary heart disease (CHD). Globally, one baby is born with FH every minute. If diagnosed and treated early in childhood, individuals with FH can have normal life expectancy. This consensus paper aims to improve awareness of the need for early detection and management of FH children. Familial hypercholesterolaemia is diagnosed either on phenotypic criteria, i.e. an elevated low-density lipoprotein cholesterol (LDL-C) level plus a family history of elevated LDL-C, premature coronary artery disease and/or genetic diagnosis, or positive genetic testing. Childhood is the optimal period for discrimination between FH and non-FH using LDL-C screening. An LDL-C ≥5 mmol/L (190 mg/dL), or an LDL-C ≥4 mmol/L (160 mg/dL) with family history of premature CHD and/or high baseline cholesterol in one parent, make the phenotypic diagnosis. If a parent has a genetic defect, the LDL-C cut-off for the child is ≥3.5 mmol/L (130 mg/dL). We recommend cascade screening of families using a combined phenotypic and genotypic strategy. In children, testing is recommended from age 5 years, or earlier if homozygous FH is suspected. A healthy lifestyle and statin treatment (from age 8 to 10 years) are the cornerstones of management of heterozygous FH. Target LDL-C is <3.5 mmol/L (130 mg/dL) if >10 years, or ideally 50% reduction from baseline if 8-10 years, especially with very high LDL-C, elevated lipoprotein(a), a family history of premature CHD or other cardiovascular risk factors, balanced against the long-term risk of treatment side effects. Identifying FH early and optimally lowering LDL-C over the lifespan reduces cumulative LDL-C burden and offers health and socioeconomic benefits. To drive policy change for timely detection and management, we call for further studies in the young. Increased awareness, early identification, and optimal treatment from childhood are critical to adding decades of healthy life for children and adolescents with FH.
MeSH Terms
- Adolescent
- Adult
- Atherosclerosis
- Carotid Intima-Media Thickness
- Child
- Clinical Laboratory Techniques
- Cost of Illness
- Counseling
- Diet
- Dietary Supplements
- Early Diagnosis
- Economics, Medical
- Evidence-Based Medicine
- Female
- Genetic Testing
- Heterozygote
- Homozygote
- Humans
- Hyperlipoproteinemia Type II
- Life Expectancy
- Medication Adherence
- Middle Aged
- Pregnancy
- Pregnancy Complications
- Risk Factors
- Young Adult
Keywords
- Adolescents
- Children
- Consensus statement
- Diagnosis
- Ezetimibe
- Familial hypercholesterolaemia
- LDL cholesterol
- PCSK9 inhibitor
- Statin
- Treatment
Neuroimaging studies of individuals with family histories of alcoholism provide evidence suggesting neurobiological risk factors for alcoholism. Youth family history positive (FH ) for alcoholism exhibit increased impulsivity compared to family history negative (FH-) peers in conjunction with altered functional activation in prefrontal cortex, including anterior cingulate cortex (ACC). This study examined glutamate (Glu) and glutamine (Gln), amino acids vital to protein synthesis, cellular metabolism and neurotransmission, acquired from ACC and parieto-occipital cortex (POC) using magnetic resonance spectroscopy (MRS) at 4T. Participants were 28 adolescents (13 male, 12-14 yrs) and 31 emerging adults (16 male, 18-25 yrs), stratified into FH- and FH groups. Significantly higher ACC Gln/Glu was observed in emerging adults versus adolescents in FH- but not FH groups. In FH- adolescents, higher impulsivity was significantly associated with higher ACC Gln/Glu. In FH emerging adults, higher impulsivity was negatively associated with ACC Gln/Glu. No differences or associations were observed for POC. These findings provide preliminary evidence that family history of alcoholism is associated with a neurochemical profile that may influence normative age differences in glutamatergic metabolites and their association with impulse control, which together could confer greater genetic risk of addiction later in life.
MeSH Terms
- Adolescent
- Aging
- Alcoholism
- Brain Chemistry
- Child
- Female
- Glutamic Acid
- Glutamine
- Gyrus Cinguli
- Humans
- Impulsive Behavior
- Magnetic Resonance Imaging
- Magnetic Resonance Spectroscopy
- Male
- Young Adult
Keywords
- Adolescence
- Alcoholism
- Family history
- Glutamate
- Impulsivity
- MRS
Glucose homeostasis is a trait of healthy ageing and is crucial to the elderly, but less consideration has been given to the age composition in most studies involving genetics and hyperglycemia. Seven variants in FOXO3 were genotyped in three cohorts (n = 2037; LLI, MI_S and MI_N; mean age: 92.5 ± 3.6, 45.9 ± 8.2 and 46.8 ± 10.3, respectively) to compare the contribution of FOXO3 to fasting hyperglycemia (FH) between long-lived individuals (LLI, aged over 90 years) and middle-aged subjects (aged from 35-65 years). A different genetic predisposition of FOXO3 alleles to FH was observed between LLI and both of two middle-aged cohorts. In the LLI cohort, the longevity beneficial alleles of three variants with the haplotype "AGGC" in block 1 were significantly protective to FH, fasting glucose, hemoglobin A1C and HOMA-IR. Notably, combining multifactor dimensionality reduction and logistic regression, we identified a significant 3-factor interaction model (rs2802288, rs2802292 and moderate physical activity) associated with lower FH risk. However, not all of the findings were replicated in the two middle-aged cohorts. Our data provides a novel insight into the inconsistent genetic determinants between middle-aged and LLI subjects. FOXO3 might act as a shared genetic predisposition to hyperglycemia and lifespan.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Blood Glucose
- Cross-Sectional Studies
- Fasting
- Female
- Forkhead Box Protein O3
- Forkhead Transcription Factors
- Gene Expression
- Genetic Predisposition to Disease
- Glycated Hemoglobin A
- Humans
- Hyperglycemia
- Insulin
- Insulin Resistance
- Logistic Models
- Longevity
- Male
- Middle Aged
- Multifactor Dimensionality Reduction
Having a parent affected by late-onset Alzheimer's disease (AD) is a major risk factor for cognitively normal (NL) individuals. This study explores the potential of PET with F-FDG and the amyloid- [i]β[/i] (A[i]β[/i]) tracer C-Pittsburgh Compound B (PiB) for detection of individual risk in NL adults with AD-parents. FDG- and PiB-PET was performed in 119 young to late-middle aged NL individuals including 80 NL with positive family history of AD (FH ) and 39 NL with negative family history of any dementia (FH-). The FH group included 50 subjects with maternal (FHm) and 30 with paternal family history (FHp). Individual FDG and PiB scans were Z scored on a voxel-wise basis relative to modality-specific reference databases using automated procedures and rated as positive or negative ( /-) for AD-typical abnormalities using predefined criteria. To determine the effect of age, the cohort was separated into younger (49 ± 9 y) and older (68 ± 5 y) groups relative to the median age (60 y). Among individuals of age >60 y, as compared to controls, NL FH showed a higher frequency of FDG scans vs. FH- (53% vs. 6% p < 0.003), and a trend for PiB scans (27% vs. 11%; p = 0.19). This effect was observed for both FHm and FHp groups. Among individuals of age ≤60 y, NL FHm showed a higher frequency of FDG scans (29%) compared to FH- (5%, p = 0.04) and a trend compared to FHp (11%) (p = 0.07), while the distribution of PiB scans was not different between groups. In both age cohorts, FDG scans were more frequent than PiB scans among NL FH , especially FHm (p < 0.03). FDG-PET was a significant predictor of FH status. Classification according to PiB status was significantly less successful. Automated analysis of FDG- and PiB-PET demonstrates higher rates of abnormalities in at-risk FH vs FH- subjects, indicating potentially ongoing early AD-pathology in this population. The frequency of metabolic abnormalities was higher than that of A[i]β[/i] pathology in the younger cohort, suggesting that neuronal dysfunction may precede major aggregated A[i]β[/i] burden in young NL FH . Longitudinal follow-up is required to determine if the observed abnormalities predict future AD.
Keywords
- Alzheimer’s Disease
- Amyloid Imaging
- Early Detection
- Glucose Metabolism
- Normal Aging
- Positron Emission Tomography
To evaluate the effects of a home-monitoring device with tele-monitoring compared with standard care in detection of progression to choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD), the leading cause of blindness in the US. Participants, aged 55 to 90 years, at high risk of developing CNV associated with AMD were recruited to the HOme Monitoring of Eye (HOME) Study, an unmasked, multi-center, randomized trial of the ForeseeHome (FH) device plus standard care vs. standard care alone. The FH device utilizes preferential hyperacuity perimetry and tele-monitoring to detect changes in vision function associated with development of CNV, potentially prior to symptom and visual acuity loss. After establishing baseline measurements, subsequent changes on follow-up are detected by the device, causing the monitoring center to alert the clinical center to recall participants for an exam. Standard care consists of instructions for self-monitoring visual changes with subsequent self-report to the clinical center. The primary objective of this study is to determine whether home monitoring plus standard care in comparison with standard care alone, results in earlier detection of incident CNV with better present visual acuity. The primary outcome is the decline in visual acuity at CNV diagnosis from baseline. Detection of CNV prior to substantial vision loss is critical as vision outcome following anti-angiogenic therapy is dependent on the visual acuity at initiation of treatment. HOME Study is the first large scale study to test the use of home tele-monitoring system in the management of AMD patients.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Choroidal Neovascularization
- Female
- Humans
- Macular Degeneration
- Male
- Middle Aged
- Prospective Studies
- Research Design
- Risk Factors
- Telemedicine
- Visual Acuity
- Visual Field Tests
Keywords
- Age-related macular degeneration
- Best-corrected visual acuity
- Choroidal neovascularization
- Controlled clinical trial
- Home-monitoring
Mutations in the FH gene cause the deficiency of the enzyme fumarase (fumarate hydratase, EC 4.2.1.2) which result in autosomal recessive fumaric aciduria in early childhood with failure to thrive, seizures, developmental delay, mental retardation, hypotonia and sometimes with polycythemia, leukopenia, and neutropenia. Many children with fumarate hydratase deficiency do not survive infancy or childhood; those surviving beyond childhood have severe psychomotor retardation. Recently, FH gene was also identified as a "non-classical" tumor suppressor gene and heterozygous mutations were shown to cause multiple cutaneous and uterine leiomyomas as well as hereditary leiomyomatosis and renal cell cancer. A male patient who was referred to investigate the etiology of psychomotor retardation was later diagnosed to have fumaric aciduria due to the combination of a previously known (c.1431_1433dupAAA) and a novel (c.782G>T) mutation. The patient had an unusually mild clinical course without acidotic attacks. Interestingly his father who was heterozygous for the c.1431_1433dupAAA mutation in the FH gene had cutaneous leiomyoma.
MeSH Terms
- Amino Acid Sequence
- Child
- Child, Preschool
- Fumarate Hydratase
- Genetic Predisposition to Disease
- Heterozygote
- Humans
- Infant
- Leiomyoma
- Life Expectancy
- Male
- Metabolism, Inborn Errors
- Molecular Sequence Data
- Muscle Hypotonia
- Mutation
- Psychomotor Disorders
- Survival Analysis
Following identification of peak height velocity (PHV) by a recent study as a possible prognostic factor for curve progression in patients with idiopathic scoliosis (IS), the aim of this study was to investigate PHV curves in Japanese female patients with IS. The study subjects were 20 skeletally immature IS patients who were followed until maturity. The mean age and the mean pubertal status at the initial visit were 9.8 years and 24 months before menarche, respectively, with a follow-up period of 5.2 years. Height measurements were recorded at each visit, and HV was calculated as the change in height (cm) divided by the time interval (yr.) between visits of 6 to 12 months. The PHV, age at PHV (APHV), height at PHV (HPHV), and final height (FH) were determined. Patient HV curves were plotted using their HV data, and growth periods (GPs) were calculated from the curves. PHVs and GPs of study patients were compared to standard data from unaffected girls. The median values and interquartile ranges in PHV, APHV, HPHV, and FH were 8.5 cm/yr. (7.9-9.7), 11.8 yr. (11.2-12.1), 153.2 cm (150.1-155.8), and 160.1 cm (157.4-162.4), respectively. The median GP was 27 months. The PHV and GP values in IS female patients were higher and shorter than those in unaffected girls. These findings indicate that the patterns of height velocity curves in IS patients are different from those in unaffected girls, suggesting that curve progression in IS patients is associated with the magnitude of PHV and duration of GP. Recently, we have developed an HV reader to easily and quickly identify the present HV in patients with scoliosis, applicable for the clinical setting or school screening. We conclude that risk assessments of curve progression in patients with IS should include HV along with measures of skeletal maturity such as the Risser sign and/or digital skeletal age using hand X-rays.
MeSH Terms
- Adolescent
- Aging
- Body Height
- Child
- Female
- Humans
- Models, Biological
- Reproducibility of Results
- Scoliosis
- Sensitivity and Specificity
- Statistics as Topic
Patients with familial hypercholesterolemia (FH) due mutations in the low-density lipoprotein receptor (LDLR) suffer premature aortic calcification, an effect that is age- and gene dosage-dependent and cholesterol level independent later in life. To better understand this process, we examined a murine model. We compared chow fed Ldlr(-/-) mice to controls at 6, 12 and 18 months and on a Western diet (WD) at 6 months. Additionally, we compared controls to Ldlr(-/-) mice and transgenic mice Tg(Pcsk9) overexpressing PCSK9, which promotes LDLR degradation. Aortas were perfused-fixed, embedded in paraffin, and sections were stained with alizarin red. Micro-computerized tomography (micro-CT) was used to quantify vascular calcification. Ldlr(-/-) mice develop calcification in the ascending, transverse aorta and neck vessels with a distribution similar to that of human. Calcification was most prominent in 18-month-old Ldlr(-/-) mice fed a chow diet and in 6-month-old Ldlr(-/-) mice fed a WD. Interestingly, Tg(Pcsk9) mice fed a WD develop aortic calcifications as well. Histology confirmed that the calcification were predominantly sub-intimal. Marked expression of LRP5 and WNT was observed in the Ldlr(-/-) and Tg(Pcsk9) models, but not in age-matched controls. The two mouse models develop aortic calcification in an age- and diet-dependent manner. Abnormal regulation of the LRP5/Wnt pathway may play a role in the calcification process. Further analysis of these aortic calcification models using this micro-CT imaging technique may provide a better understanding of the link between FH and arterial calcification.
MeSH Terms
- Age Factors
- Aging
- Animals
- Aortic Diseases
- Aortography
- Biomarkers
- Cholesterol
- Diet, High-Fat
- Disease Models, Animal
- Disease Progression
- Low Density Lipoprotein Receptor-Related Protein-5
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Transgenic
- Paraffin Embedding
- Proprotein Convertase 9
- Proprotein Convertases
- Receptors, LDL
- Serine Endopeptidases
- Severity of Illness Index
- Staining and Labeling
- Vascular Calcification
- Wnt Proteins
- X-Ray Microtomography
In the developing fetus, cerebral arteries (CA) show striking differences in signal transduction mechanisms compared with the adult, and these differences are magnified in response to high-altitude long-term hypoxia (LTH). In addition, in the mature organism, cerebrovascular acclimatization to LTH may be associated with several clinical problems, the mechanisms of which are unknown. Because PKC plays a key role in regulating CA contractility, in fetal and adult cerebral arteries, we tested the hypothesis that LTH differentially regulates the PKC-mediated Ca(2 ) sensitization pathways and contractility. In four groups of sheep [fetal normoxic (FN), fetal hypoxic (FH), adult normoxic (AN), and adult hypoxic (AH)], we examined, simultaneously, responses of CA tension and intracellular Ca(2 ) concentration and measured CA levels of PKC, ERK1/2, RhoA, 20-kDa myosin light chain, and the 17-kDa PKC-potentiated myosin phosphatase inhibitor CPI-17. The PKC activator phorbol 12,13-dibutyrate (PDBu) produced robust contractions in all four groups. However, PDBu-induced contractions were significantly greater in AH CA than in the other groups. In all CA groups except AH, in the presence of MEK inhibitor (U-0126), the PDBu-induced contractions were increased a further 20-30%. Furthermore, in adult CA, PDBu led to increased phosphorylation of ERK1, but not ERK2; in fetal CA, the reverse was the case. PDBu-stimulated ERK2 phosphorylation also was significantly greater in FH than FN CA. Also, although RhoA/Rho kinase played a significant role in PDBu-mediated contractions of FN CA, this was not the case in FH or either adult group. Also, whereas CPI-17 had a significant role in adult CA contractility, this was not the case for the fetus. Overall, in ovine CA, the present study demonstrates several important maturational and LTH acclimatization changes in PKC-induced contractile responses and downstream pathways. The latter may play a key role in the pathophysiologic disorders associated with acclimatization to high altitude.
MeSH Terms
- Acclimatization
- Age Factors
- Aging
- Animals
- Calcium Signaling
- Cerebral Arteries
- Disease Models, Animal
- Enzyme Activation
- Enzyme Activators
- Fetal Hypoxia
- Gestational Age
- Hypoxia
- MAP Kinase Kinase Kinases
- Mitogen-Activated Protein Kinase 1
- Mitogen-Activated Protein Kinase 3
- Myosin Light Chains
- Phosphoprotein Phosphatases
- Phosphorylation
- Protein Kinase C
- Protein Kinase Inhibitors
- Sheep
- Time Factors
- Vasoconstriction
- rho-Associated Kinases
- rhoA GTP-Binding Protein
The cognitive status of aged familial hypercholesterolemia (FH) patients treated with long-term statin therapy was compared with that of population controls. A comprehensive cohort of 43 elderly (age > or = 65 years) patients all with the same FH North Karelia mutation living in North Karelia (eastern Finland) was identified, 37 of whom (aged 65 to 84 years) agreed to participate. All but one of these FH patients had been using statins for approximately 15 years. Population-based controls (aged 65 to 84 years, n= 309) were the participants of the Health 2000 Survey living in eastern Finland. The cognitive assessment was conducted with tests for verbal fluency, Word List Learning (WLL) and Word List Delayed Recall (WLDR) subtests in the Consortium to Establish a Registry for Alzheimer's disease test battery. After adjustment for age, gender, education, diabetes mellitus, and coronary heart disease, FH patients were more likely to be in the top tertile of the WLDR (Odds ratio (OR) 3.40, 95% confidence interval (CI) 1.52-7.63) and WLL3 (OR 2.83, 95% CI 1.28-6.25) subtests. When the FH patients were subdivided according to the median length of their statin therapy, the ORs to be in the top tertile in the WLDR subtest were 1.65 (95% CI 0.52-5.25) for those with less and 5.40 (95% CI 1.74-17.72) in those individuals with more than median length of statin therapy. In conclusion, aged FH patients receiving long-term statin therapy exhibited better episodic memory than population controls, and this association became even more pronounced with longer statin therapy.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Cognition
- Family Health
- Female
- Finland
- Health Surveys
- Humans
- Hydroxymethylglutaryl-CoA Reductase Inhibitors
- Hypercholesterolemia
- Logistic Models
- Male
- Mental Recall
- Time Factors
It is unknown whether generalized vascular dysfunction precedes the development of kidney disease. Therefore, we studied myogenic constriction and endothelium-mediated dilatory responses in two inbred Fawn-Hooded (FH) rat strains, one of which spontaneously develops hypertension, proteinuria, and glomerulosclerosis (FHH), whereas the other (FHL) does not. Small renal, mesenteric resistance arteries and thoracic aorta isolated from FH rats before (7 wk old) and after the development of mild proteinuria (12 wks old) were mounted in perfused and isometric set-ups, respectively. Myogenic response, endothelium-dependent relaxation, and the contribution of endothelium-mediated dilatory compounds were studied using their respective inhibitors. Myogenic reactivity was assessed constructing pressure-diameter curves in the presence and absence of calcium. At the age of 7 wk, renal arteries isolated from kidneys of FHH rats developed significantly lower myogenic tone compared with FHL, most likely because of excessive cyclo-oxygenase 1-mediated production of constrictive prostaglandins. Consequently, young FHH demonstrated reduced maximal myogenic tone (22 /- 4.8 vs. 10.8 /- 2.0%, P = 0.03) and the peak myogenic index (-6.9 /- 4.8 vs. 0.6 /- 0.8%/mmHg, P = 0.07 for FHL vs. FHH, respectively). Active myogenic curves obtained in mesenteric arteries isolated from 7-wk-old rats did not differ between either strain, demonstrating a similar level of systemic myogenic tone in FHL and FHH rats. Therefore, before any renal end-organ damage is present, myogenic response seems selectively impaired in renal vasculature of FHH rats. Aortic reactivity did not differ between FHL and FHH at the time points studied. The present study shows that vascular dysfunction in both small renal and systemic arteries precedes renal end-organ damage in a spontaneous model of hypertension-associated renal damage. These early vascular changes might be potentially involved in the increased susceptibility of FHH rats to renal injury.
MeSH Terms
- Age Factors
- Aging
- Animals
- Aorta, Thoracic
- Biological Factors
- Blood Pressure
- Cyclooxygenase 1
- Disease Models, Animal
- Disease Progression
- Dose-Response Relationship, Drug
- Endothelium, Vascular
- Hypertension
- Kidney
- Kidney Diseases
- Male
- Membrane Proteins
- Nitric Oxide
- Prostaglandins
- Proteinuria
- Rats
- Rats, Inbred Strains
- Renal Artery
- Renal Circulation
- Vasoconstriction
- Vasoconstrictor Agents
- Vasodilation
- Vasodilator Agents
Previous research has shown that an early onset of drinking is associated with a range of problematic drinking outcomes in adulthood. However, earlier drinking is also linked to additional characteristics that themselves predict alcohol problems including male gender, a family history (FH) of alcoholism, age, race, parental alcoholism, depression symptoms, prior drug use, and conduct problems. This study tested the relationship between the age of first drink (AFD) and a range of risk factors that predict the onset of alcohol use. Participants were offspring from the San Diego Prospective Study (SDPS) who were at least 15 years old at the time of their most recent interview (n=147). Discrete-time survival analysis (DTSA) was used to relate multiple characteristics to the hazard function of alcohol onset across a relevant age range. The results demonstrated the predicted relationships to AFD for conduct problems, male gender, prior marijuana use, and a FH of alcoholism, even when these characteristics were estimated together. Furthermore, an interaction occurred such that offspring with both conduct problems and marijuana use were at substantially higher risk for alcohol use onset during this time period than would be predicted from the effect of these two risk factors alone. However, age at interview, ethnicity, parent education, and depressive symptoms did not predict the pattern of onset of drinking. Implications for future research and prevention efforts are discussed.
MeSH Terms
- Adolescent
- Adolescent Behavior
- Adult
- Age of Onset
- Aging
- Alcohol Drinking
- California
- Conduct Disorder
- Family
- Fathers
- Follow-Up Studies
- Humans
- Interview, Psychological
- Male
- Marijuana Abuse
- Parent-Child Relations
- Prospective Studies
- Risk Factors
- Risk-Taking
- Sex Factors
- Survival Analysis
- Young Adult
At cross-section, cognitively normal individuals (NL) with a maternal history of late-onset Alzheimer disease (AD) have reduced glucose metabolism (CMRglc) on FDG-PET in the same brain regions as patients with clinical AD as compared to those with a paternal and a negative family history (FH) of AD. This longitudinal FDG-PET study examines whether CMRglc reductions in NL subjects with a maternal history of AD are progressive. Seventy-five 50- to 82-year-old NL received 2-year follow-up clinical, neuropsychological, and FDG-PET examinations. These included 37 subjects with negative family history of AD (FH-), 9 with paternal (FHp), and 20 with maternal AD (FHm). Two subjects had parents with postmortem confirmed AD. Statistical parametric mapping was used to compare CMRglc across FH groups at baseline, follow-up, and longitudinally. At both time points, the FH groups were comparable for demographic and neuropsychological characteristics. At baseline and at follow-up, FHm subjects showed CMRglc reductions in the parieto-temporal, posterior cingulate, and medial temporal cortices as compared to FH- and FHp (p < 0.001). Longitudinally, FHm had significant CMRglc declines in these regions, which were significantly greater than those in FH- and FHp (p < 0.05). A maternal history of Alzheimer disease (AD) predisposes normal individuals to progressive CMRglc reductions in AD-vulnerable brain regions, which may be related to a higher risk for developing AD.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Brain
- Female
- Genetic Predisposition to Disease
- Glucose
- Heterozygote
- Humans
- Male
- Middle Aged
- Mothers
Nearly 50 million people worldwide suffer from age-related macular degeneration (AMD), which causes severe loss of central vision. A single-nucleotide polymorphism in the gene for the complement regulator factor H (FH), which causes a Tyr-to-His substitution at position 402, is linked to approximately 50% of attributable risks for AMD. We present the crystal structure of the region of FH containing the polymorphic amino acid His402 in complex with an analogue of the glycosaminoglycans (GAGs) that localize the complement regulator on the cell surface. The structure demonstrates direct coordination of ligand by the disease-associated polymorphic residue, providing a molecular explanation of the genetic observation. This glycan-binding site occupies the center of an extended interaction groove on the regulator's surface, implying multivalent binding of sulfated GAGs. This finding is confirmed by structure-based site-directed mutagenesis, nuclear magnetic resonance-monitored binding experiments performed for both H402 and Y402 variants with this and another model GAG, and analysis of an extended GAG-FH complex.
MeSH Terms
- Aging
- Binding Sites
- Complement Factor H
- Crystallography, X-Ray
- Gene Products, gag
- Ligands
- Models, Molecular
- Mutation
- Polysaccharides
- Protein Structure, Quaternary
- Protein Structure, Tertiary
- Sucrose
- Surface Properties
We retrospectively evaluated the frequency and identified the factors associated with the development of aortic stenosis (AS) in 96 patients with heterozygous familial hypercholesterolemia (FH). The frequency of AS was 31% (4/13) and that of critical stenosis was 15% (2/13) in older patients over the age of 70 years. All 4 patients with AS were female aged more than 70 years who were diagnosed with FH when aged more than 60 years. There were no significant differences in conventional coronary risk factors; however, the age at cardiac catheterization, age at diagnosis of FH and the cholesterol-years score (CYS) with AS were significantly higher than those without AS (p=0.006, p=0.017, p=0.021, respectively). In multiple regression analysis, CYS was a significant independent predictor for the development of AS (p=0.037) in 13 older patients over the age of 70 years. These results suggest that physicians should be aware that AS needs attention in older patients with heterozygous FH, especially women who have been diagnosed late in life and those who have been inadequately treated.
MeSH Terms
- Adult
- Aged
- Aging
- Aortic Valve Stenosis
- Cholesterol
- Female
- Heterozygote
- Humans
- Hyperlipoproteinemia Type II
- Male
- Middle Aged
- Regression Analysis
- Retrospective Studies
- Time Factors
According to FDA-approved guidelines, boys whose height predictions fall to 160 cm or less are considered for treatment with recombinant growth hormone (rGH). The aim of this study was to analyze the value of different height prediction methods by accurately identifying those boys with constitutional delay of growth and puberty (CDGP) in whom final height (FH) prognosis was poor (<or=160 cm) and who might therefore be candidates for this treatment modality. In 69 boys with CDGP diagnosed at a mean age of 14.9 /-1.2 years, FH prediction was calculated by means of Bayley-Pinneau (BP), Roche-Wainer-Tissen (RWT), Tanner-Whitehouse II (TWII) and target height (TH) methods. At the age of 22.6 /- 3.5 years their height was remeasured and the accuracy of height prediction was analyzed. In 6 men (8.7%) measured FH was <or=160 cm. Depending on the prediction method, different individual patients within the 14- to 16-year age range would have been candidates for rGH treatment. The BP method would have recruited 8 subjects of whom only 3 had FH <or=160 cm (sensitivity 50%, specificity 92%). The RWT and TW II methods identified only one recruit, and this patient did achieve FH <or=160 cm (sensitivity 17%, specificity 100%). None of the 8 subjects with FH <or=160 cm would have qualified for GH treatment using the TH method. In three boys none of the four methods predicted their final height <or=160 cm. Although some boys with CDGP may be considered the candidates for rGH treatment according to FDA recommendations, none of the available methods of prediction are sufficiently sensitive to reliably recruit 14- to 16-year-old boys whose final height will fall at or below 160 cm.
MeSH Terms
- Adolescent
- Adult
- Aging
- Body Height
- Bone and Bones
- Data Interpretation, Statistical
- Growth Disorders
- Growth Hormone
- Guidelines as Topic
- Humans
- Male
- Predictive Value of Tests
- Prognosis
- Puberty, Delayed
- Retrospective Studies
- Sensitivity and Specificity
- United States
- United States Food and Drug Administration
The aim of this study was to examine the influences of genetic predisposition to hypertension and of age on the sympathetic nervous system response to the cold pressor test (CPT). A total of 32 young subjects (aged 27 /- 2 years) were studied: 11 normotensive subjects without a family history of hypertension (FH), 14 normotensive subjects with a strong family history of hypertension (FH ), and eight hypertensive subjects. In addition, 21 older subjects (aged 53 /- 2 years) were studied: 13 hypertensive and eight normotensive subjects. Blood pressure (BP), heart rate (HR), and muscle sympathetic nerve activity (MSNA) were recorded at rest and during a 2-min period of a CPT. Both young and older hypertensive subjects had higher resting MSNA than did the normotensive ones (47 /- 7 v 29 /- 4 bursts per 100 heartbeats (P < .05) and 66 /- 4 v 40 /- 7 bursts per 100 heartbeats (P < .01), respectively). The CPT resulted in HR increases of similar magnitude in all groups of patients. The FH group displayed slightly less increase in systolic BP than that of the FH- group (P < .05). The MSNA increased to a far greater degree in FH- (103%) than in FH (32%) and in young hypertensive patients (12%) (P < .05). Similarly, MSNA change with the CPT was greater in older normotensive subjects than in older hypertensive patients (61% v 12%, P < .05). Our results show that a CPT induces sympathetic responses that are subnormal in hypertensive patients and those with a family history of hypertension, highlighting the importance of genetic factors in determining the sympathetic nervous reactivity to CPT.
MeSH Terms
- Adult
- Aging
- Blood Pressure
- Case-Control Studies
- Cold Temperature
- Female
- Genetic Predisposition to Disease
- Heart Rate
- Humans
- Hypertension
- Male
- Middle Aged
- Muscle, Skeletal
- Sympathetic Nervous System
The starting point of this study was the statement made in the literature that the angle between the two reference planes Frankfort horizontal (FH) and sella-nasion line (SN) changes relatively little during growth. The growth-induced relocation of the orbitale (Or; anterior reference point of the FH) in relation to SN is known from implant studies, whereas the relocation of the porion (Po; posterior reference point of the FH) has been the subject of only little research. The present study was aimed at analyzing the factors contributing to the almost constant angle between FH and SN. The study material consisted of two groups of macerated skulls and the relevant lateral cephalograms. The first group comprised 32 skulls of individuals aged 2.5 to 5 years, and the second group ten skulls of individuals aged 18 to 20 years. A diagram showing the growth-dependent changes was prepared with reference to the mean values for the two groups. The cephalograms were superimposed on the anterior cranial base line at sella point (S). A 3.1 degrees increase in the angle between FH and SN during growth was recorded in our investigations. The distance between Or and SN increased by 3.9 mm while Po remained vertically almost constant with respect to SN. In sagittal direction the distance between Or and S also increased, while Po was displaced to almost the same extent in the opposite direction. The increasing vertical distance between the anterior and posterior reference points of FH and SN was largely compensated by the sagittal developments of the reference points Po and Or, so that the angle between these two planes changed very little. The relatively stable angle between FH and SN thus showed by no means a constant relationship of the four reference points to one another.
MeSH Terms
- Adolescent
- Adult
- Aging
- Cadaver
- Cephalometry
- Child, Preschool
- Face
- Female
- Humans
- Image Interpretation, Computer-Assisted
- Male
- Maxillofacial Development
- Nasal Bone
- Orbit
- Reference Values
- Reproducibility of Results
- Sella Turcica
- Sensitivity and Specificity
- Skull
In a retrospective study we evaluated long-term growth, pubertal developmental patterns to final height (FH), and medication in 55 patients (35 females) affected by 21-hydroxylase deficiency. The patients were classified into 3 groups according to predicted mutation severity: group A (11 women and 9 men), homozygous or compound heterozygous for null or In2 splice mutations [residual enzymatic activity (RA), <1%]; group B (11 women and 4 men), homozygous for I172N or R341P or R426H mutations (RA, approximately 2-3%) or compound heterozygous with any of the group A or B mutations; and group C (13 women and 7 men), homozygous for P30L or V281L or P453S mutations (RA, >30%) or compound heterozygous with any of the group A, B, or C mutations. Three patients showed unclassifiable genotypes. FH was similar in the female groups, whereas male patients in group B were shorter than males in groups A and C. Fifty-five percent of patients in group A, 33% in group B, and 40% in group C reached an FH within 0.5 SD of target height. Four of the 7 patients diagnosed via neonatal screening achieved an FH equal to or above the target height. In the entire group, early diagnosis (<1 yr) improved height outcome. Early diagnosed CAH patients who received lower cortisol equivalent doses during the first year of life reached a better FH. Our results underline the importance of mineralocorticoid therapy, as CAH subjects in groups A and B who did not receive this treatment showed reduced FH. Early diagnosis, the use of more physiological cortisol equivalent dosages during the first year of life, and the extension of mineralocorticoid therapy to all classical patients are shown to improve the auxological outcome. Genotypic analysis helped to interpret the height results of our cases and prospectively may represent a useful tool for improving the therapeutic choice and the height outcome.
MeSH Terms
- Adrenal Hyperplasia, Congenital
- Aging
- Body Height
- Child
- Child, Preschool
- Female
- Fertility
- Genotype
- Humans
- Infant
- Infant, Newborn
- Male
- Mineralocorticoids
- Prognosis
- Puberty
- Retrospective Studies
- Steroid 21-Hydroxylase
Although it has been well established that GH treatment increases final height (FH) in girls with Turner syndrome (TS), the optimal ages to start GH therapy and introduce estrogens for pubertal induction have not been defined. We evaluated retrospectively the influence of the age at onset of GH treatment and age at onset of puberty on FH of 186 adult TS women treated during childhood with GH. Puberty started spontaneously in 38 patients, and it was induced in 148 girls with ethinyl estradiol (mean /- SD starting dose, 66 /- 32 ng/kg.d). Patients with spontaneous or induced puberty were divided into quartiles on the basis of age at initiation of GH treatment (3-10, 10-12, 12-14, and 14-19 yr). FH was 151.7 /- 6.0 cm; there were no FH differences between patients with induced or spontaneous puberty, nor were there differences between the age quartiles. Puberty started earlier in the girls with spontaneous puberty than in those with induced puberty (12.4 /- 1.3 yr vs. 14.5 /- 1.9 yr; P < 0.0001). The age at onset of puberty was not related to FH. Pubertal growth was 15.4 /- 4.6 cm in the girls with spontaneous puberty and 8.6 /- 4.3 cm in the girls with induced puberty (P < 0.0001). We conclude that GH treatment results in a significant increase in FH in most TS girls. Under the conditions of GH treatment and induction of puberty that we have used, the age at start of GH treatment was not related to FH; in addition, late or delayed induced or spontaneous puberty did not affect FH.
MeSH Terms
- Adolescent
- Aging
- Birth Weight
- Body Height
- Ethinyl Estradiol
- Growth
- Growth Hormone
- Humans
- Male
- Puberty
- Puberty, Delayed
- Regression Analysis
- Retrospective Studies
- Turner Syndrome
We compared the structures of the femoral head (FH) of neonates between normal and operated legs with restrained fetal movement using an exo utero technique. At embryonic day (E) 16.5, one hind limb was sutured onto the embryonic membrane and the fetuses were allowed to develop exo utero until the term (E22.5). There was no significant difference in the largest diameter of the FH between the non-operated and operated side FH in the operated neonates and the FH of the non-operated neonates. By scanning electron microscopy, roughness and collagen fiber bundles, which were detected on the surface of the operated side FH at E18.5, disappeared at E22.5. However, the operated side FH was deformed and the surface cell arrangement was more irregular than that of the controls at E22.5 by light microscopy. These results suggest that the abnormality of cell arrangement caused by the restraint of fetal movement may induce the deformity and irregularity of the FH surface, although this operation may not disturb the basic cellular activities such as cell proliferation as well as the secretion of cartilage ma-trix and collagen fibers. To further investigate the recovery process in the operated newborns after releasing the restraint, we bred them artificially for a considerable period after birth. The operated side FH surface of the neonate bred for 45 hours was smoother than that at E22.5 and similar to that of the non-operated side FH. This result suggests that the proper movement of the extremities after birth may recover the deformity caused by restrained fetal joint movement.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Disease Models, Animal
- Embryo, Mammalian
- Female
- Femur
- Fetus
- Gestational Age
- Hip Dislocation, Congenital
- Hip Joint
- Microscopy, Electron, Scanning
- Pregnancy
- Rats
- Rats, Wistar
- Restraint, Physical
There is now ample evidence to demonstrate that atherosclerosis begins in childhood and is significantly accelerated in certain genetic disorders, most notably familial hypercholesterolemia (FH). Untreated FH, both the homozygous and heterozygous forms, carry a substantial burden of morbidity and mortality if left untreated or inadequately treated. Males with FH are at earlier and greater risk than females and thus should begin therapy earlier, preferably at about 10. While bile acid sequestrants have long been considered the drug of choice in children, they have never been approved for pediatric use by FDA, are poorly tolerated, marginally effective at lowering low-density lipoprotein cholesterol and have minimal well controlled studies in children upon which to adequately assess safety. Over the last decade statins have been studied extensively in children and adolescents, although many of these studies have also been poorly controlled, of short duration, too small and lack detailed assessment. However there has been at least one large, randomized, placebo-controlled and comprehensive study with lovastatin in adolescent males that indicated efficacy similar to that anticipated in adults and no apparent safety concerns. While additional well-controlled studies are needed, especially those focusing on surrogates of atherosclerosis to determine clinical benefit, it is opportune for re-evaluation of current treatment guidelines.
MeSH Terms
- Age Factors
- Aging
- Anticholesteremic Agents
- Arteriosclerosis
- Child
- Female
- Humans
- Hyperlipoproteinemia Type II
- Lovastatin
- Male
- Safety
- Sex Factors
- Treatment Outcome
To quantify the prevalence and growth of the postglenoid tubercle in a skull sample and in children. a) ninety skulls ranging in age from between 2 years and adulthood, b) sixtyfour corrected lateral tomograms of left and right temporomandibular joints of 32 boys and girls. Their age range was between 9 and 11 years. Impressions of the temporal fossae of the skull material were taken with a silicone type impression material, using a face-bow for leveling the base of the impression parallel to the FH plane. Each impression was divided into two halves along a paramedian plane from the tip of the postglenoid tubercle through the middle of the articular eminence and the surface was photocopied to a 200% scale. Height was measured with an electronic caliper. The presence or absence of a postglenoid tubercle was established on the corrected tomograms. Seventy-nine percent of the skulls had a postglenoid tubercle. It steadily enlarged and reached almost its final dimension by the age of 13 years. On corrected tomograms, 66% of the children showed a postglenoid tubercle. a) the postglenoid tubercle exists in a high percentage of human temporomandibular joints b) growth is almost completed by the age of 13, and c) there exists a right-left symmetry.
MeSH Terms
- Adolescent
- Adult
- Aging
- Child
- Child, Preschool
- Cranial Fossa, Posterior
- Humans
- Infant
- Skull
- Temporal Bone
Final adult height following renal transplantation was assessed in 237 recipients enrolled in NAPRTCS before the ages of 11 (girls) and 12 (boys) years and followed for at least 6 months with a functioning graft at or after 18 years of age. The overall change in standardized height (SDS) from baseline to final adult height (FH) was 0.0; however, delta SDS was significantly better for the youngest recipients (6-8 years) than for the older age group. Retarded FH was associated with higher average prednisone dosage and better FH was associated with good graft function. Low baseline SDS was also predictive of retarded FH. Final adult height continues to be suboptimal in the cyclosporine A era.
MeSH Terms
- Aging
- Body Height
- Child
- Creatinine
- Dose-Response Relationship, Drug
- Female
- Glucocorticoids
- Humans
- Kidney
- Kidney Transplantation
- Male
- Prednisone
- Risk Factors
Differentiating FH from other causes of hypercholesterolemia has important clinical and therapeutic implications but is often not possible by standard clinical criteria. As accumulation of cholesterol in tendon is generally considered as pathognomonic of FH, we evaluated the sensitivity and specificity of clinical and ultrasonographic tendon characteristics using the data of 127 genetically ascertained FH and 160 controls with various lipid profiles. Upon clinical examination, none of the controls and 29% of FH individuals (17% FH women and 38% FH men) presented with xanthomata in Achilles tendons, but no female and only 6% of male FH patients also showed xanthomata in the extensor tendon of the hand. Amongst all possible quantitative parameters (thickness, breadth, section and roundness) of Achilles tendon (AT) measured by ultrasonography, the thickness presented the best receiver operating curves. AT thickness above 5.8 mm was the most useful threshold for diagnosis of FH, procuring sensitivity of 75% and specificity of 85%. Analysis of variation of AT thickness with age and sex indicated that this clinical criterion performed better in females older than 45 and in males under 45. In patients carrying the APOB-R3500Q mutation, AT-thickness appeared significantly less important compared with those carrying LDLR mutations. In conclusion, this study recommends identification of possible FH individuals amongst hypercholesterolemic patients using a criteria of AT-thickness over 5.8 mm eventually associated with a specific genetic test for APOB-R3500Q mutation.
MeSH Terms
- Achilles Tendon
- Adult
- Aging
- Apolipoproteins B
- Female
- Hand
- Humans
- Hyperlipoproteinemia Type II
- Male
- Middle Aged
- Muscular Diseases
- Mutation
- ROC Curve
- Receptors, LDL
- Sensitivity and Specificity
- Tendons
- Ultrasonography
- Xanthomatosis
There is still controversy about the auxological outcome of GnRH agonist treatment in patients with CPP and about the favorable age and auxological characteristics at start of treatment for achieving a normal final height (FH) or for preserving height potential. We analyzed the FH data of 52 young women from a prospective multicentric trial which was started in 1985. The aim of this analysis was to determine factors that may predict a favorable FH or a good height gain. Chronological age (CA) was 5.2 /- 2.1 yr ( /- SD) at start of puberty, 6.2 /- 2.0 yr at start of triptorelin depot treatment, 11.1 /- 1.1 yr at end of treatment, and 16.7 /- 2.6 yr at FH evaluation. After 4.8 /- 2.2 yr (1.1-9.9 yr) of treatment duration, FH was 160.6 /- 8.0 cm (vs 154.9 /- 9.6 cm of initial height prediction [[[PAH]]], p<0.05). A FH within TH range or in excess of mean TH was achieved by 78% or 41% of patients. FH was above the 3rd percentile of the normal German population in 29% of patients (63% had an initial PAH < 156 cm). The group of patients with start of puberty at age < or = 6 yr (Group 1) showed a significantly higher height gain (FH - initial PAH) and lower height deficit compared to TH than older patients (Group 2). Furthermore, the percentage of patients from Group 1 reaching TH range or mean TH showed a significant increase with GnRH agonist treatment whereas this was not the case in Group 2. Stepwise regression analysis showed that height SDS at end of treatment, age at menarche, bone age (BA) at start of treatment, and BA advancement at end of treatment were determinants of FH (r2=0.923). Initial BA advancement and treatment duration were the factors that explained 68% of the variability of height gain. Although BA advancement at initiation of treatment was negatively associated with FH it was a positive predictor of height gain. In addition, height gain correlated significantly with CA and BA at start of treatment (r= -0.430, p=0.004 and r=0.359, p=0.018). Growth after interruption of treatment had no significant predictive effect on FH. It is concluded that a higher percentage of patients below 6 yr of age at start of puberty do profit from GnRH agonist treatment with respect to achieving a normal FH. BA, BA advancement, and height SDS at treatment start are important factors for determining outcome.
MeSH Terms
- Aging
- Body Height
- Brain Diseases
- Child
- Child, Preschool
- Delayed-Action Preparations
- Female
- Gonadotropin-Releasing Hormone
- Humans
- Infant
- Menarche
- Prospective Studies
- Puberty, Precocious
- Time Factors
- Treatment Outcome
- Triptorelin Pamoate
Premature corneal arcus may identify individuals with hyperlipidaemia and increased cardiovascular risk. We have attempted to quantitate relationships through determination of graded prevalence of corneal arcus with age for 81 males and 73 females suffering from heterozygous familial hypercholesterolaemia (HFH) at presentation, and for 280 male and 353 female unselected patients (age range 16-76 years) attending a country general practice. Some degree of arcus affected 50% of HFH patients by age 31-35 years, and 50% of practice patients by age 41-45 years. Complete full ring arcus affected 50% of the familial hypercholesterolaemia (FH) group by age 50 years, with only 5% similarly affected in the non-FH group. Arcus grade with age was advanced by some 5 years in males versus females. Premature arcus potentially alerting to HFH can be broadly defined for males and females combined, as heavy full ring by age 50 years, or any degree of arcus by age 30-35 years. Arcus grade was not related to the presence of coronary disease. Accelerated development of corneal arcus with age is an indicator of HFH, but premature arcus is not an additional marker of premature coronary disease for individual cases of HFH.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aging
- Arcus Senilis
- Coronary Disease
- Female
- Heterozygote
- Humans
- Hyperlipoproteinemia Type II
- Male
- Middle Aged
- Prevalence
- Risk Factors
Many factors play important roles in the development of atherosclerotic lesions. The leading risk factor for atherosclerosis is familial hypercholesterolaemia (FH). FH is a genetic disease characterized by a deficiency of receptors for low density lipoprotein (LDL) on the plasmalemma of endothelial cells, a high level of serum LDL, and early development of atherosclerosis and skin xanthoma. Watanabe and colleagues have developed a line of rabbits with unprovoked hypercholesterolaemia, increased blood level of LDL, pronounced atherosclerosis and skin xanthoma. These Watanabe Heritable Hyperlipidaemic (WHHL) rabbits possess an inheritable mutation of one gene, similar to that in human FH. The morphogenesis of atherosclerosis in patients with FH is characterized by multifocal deposit of lipids in the stromal cells of thymus, spleen, skin, interstitial and parenchymatous cells of kidneys and the presence of some single foam cells in aorta. The manifestation of atherosclerotic lesions in WHHL rabbits increases progressively with age but the presence of atherosclerotic lesions in newborn WHHL rabbits suggest that the process may commence in utero. Moreover, the main mass of plasma cholesterol in WHHL rabbits is first found in LDL and to a lesser degree in lipoproteins of intermediate density. This is contrary to diet-induced atherosclerosis in rabbits where the main mass of serum cholesterol is found in very low density beta-lipoproteins. Thus the distribution of cholesterol among lipoprotein fractions differs from that in WHHL rabbits. Atherosclerotic damage of arteries in WHHL rabbits goes through several stages. During the progression of intimal damage, lipid and foam cell deposits are found in the internal surface together with developing plaques and increased content of lipids in the tunica media. Calcification often follows this process. The main factors initiating atherosclerosis in WHHL rabbits are adhesion of leukocytes and platelets to endothelial cells and the accumulation of lipids in the aortic wall. The deposits of lipids in macrophages and intimal smooth muscle cells in WHHL rabbits occurs mostly at the expense of cytoplasmic neutral lipid particles with some accumulation in lysosomes. Hypertension as a risk factor increases the area of atherosclerotic damage in all arterial vessels in WHHL rabbits, particularly in the thoracic and abdominal aorta. Morphogenesis of the development of atherosclerosis in WHHL and diet-induced atherosclerosis in rabbits was similar, but differs from rats with heritable hypercholesterolaemia. Damage or loss of endothelial cells can predispose the atherosclerotic vessels to vasospasm and can leave vessels unprotected against vasoconstrictor stimuli. The development of the WHHL model has not only given insight into the mechanisms of development of familial hypercholesterolaemia but has also provided a model for assessing various therapeutic approaches for the prevention and treatment of atherosclerosis.
MeSH Terms
- Aging
- Animals
- Arteriosclerosis
- Disease Models, Animal
- Hemodynamics
- Humans
- Hyperlipoproteinemia Type II
- Lipid Metabolism
- Rabbits
- Rats
A group of six girls with slowly progressive idiopathic precocious puberty (IPP) and a good initial height prognosis was followed without treatment. At first observation the girls had a bone age advance over chronological age of no more than 18 months, a delta height age (delta HA): delta bone age (delta BA) ratio higher than 0.9 and height prognosis was unimpaired after 6 months. During the first two years of follow-up the girls maintained an acceptable height potential. The delta HA:delta BA ratio remained constant at greater than 0.9. Predicted height showed a slight increase or decrease ( /- 4 cm). The girls were reevaluated after the age of 14 years and followed-up until they reached their final height (FH). The mean FH (155.4 /- 2.8 cm) was below the mean target height (159.3 /- 4.2 cm) by 3.9 cm (range -2.1 to -6.7 cm); this difference was not statistically significant. The FH was more than 5 cm below the target height in only one case; this girl had the most precocious onset of puberty, at 6 years of age. In three cases FH was between the 3rd and 10th centiles. These three girls had a target height below 158 cm (< 25th centile). Girls with slowly progressive IPP and a good initial height prognosis preserved height potential with an acceptable final height without therapy.
MeSH Terms
- Age Determination by Skeleton
- Aging
- Body Height
- Child
- Female
- Follicle Stimulating Hormone
- Humans
- Luteinizing Hormone
- Ovary
- Prognosis
- Puberty, Precocious
- Ultrasonography
- Uterus
The aim of this study was to compare the age at first elective coronary angiogram and the age at first revascularization (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) in 102 patients without familial hypercholesterolaemia (FH), who were matched for age and sex with 76 heterozygous FH patients carrying a defective allele at the low-density lipoprotein (LDL) receptor gene (LDL-R) and 26 heterozygous FH patients bearing a null mutation at the LDL-R. The prevalence of diabetes was significantly higher in the non-FH group than in the two FH groups (P < 0.05). Furthermore, mean body mass index (BMI) and waist circumference values were also higher in the non-FH group than in the two FH heterozygous groups (P < 0.005). However, FH patients who were null allele carriers had the highest plasma total and LDL-cholesterol levels and the highest cholesterol/HDL-cholesterol ratio, whereas the defective allele carriers group had intermediate levels between null allele carriers and non-FH patients. Comparison of the age at first coronary angiography revealed that the null allele carriers group were younger at first angiogram than the non-FH patients (P < 0.005). In addition, a trend was observed for a younger age at first angiogram in FH heterozygotes bearing a null allele than in carriers of a defective allele (P = 0.06). Moreover, null allele carriers were younger at first revascularization than defective allele carriers (P < 0.005) or non-FH patients (P < 0.005). Finally, the mean number of diseased vessels with > 50% stenosis was higher in null allele carriers than in non-FH patients and tended to be higher than among defective allele carriers (P < 0.01). Although no difference in plasma Lp(a) levels were noted between null allele carrier and non-FH patients, plasma Lp(a) concentrations were higher in the defective allele group than in the other two groups. In summary, the development of coronary artery disease as estimated by the age at first elective coronary angiography or at first revascularization is premature in FH patients carrying a null mutation compared with defective allele carriers or with non-FH patients. Moreover, the higher number of stenosed vessels among null allele carriers suggests that coronary artery disease was more severe in FH subjects with a null allele at the LDL-R locus.
MeSH Terms
- Adult
- Aging
- Angioplasty, Balloon, Coronary
- Body Constitution
- Body Mass Index
- Coronary Angiography
- Coronary Artery Bypass
- Coronary Disease
- Female
- Heterozygote
- Humans
- Hyperlipoproteinemia Type II
- Lipoprotein(a)
- Male
- Middle Aged
- Mutation
- Quebec
- Receptors, LDL
Familial defective apolipoprotein B-100 (FDB) is a dominantly inherited genetic disorder resulting from a point mutation in the apolipoprotein (apo) B gene and is associated with significantly elevated plasma total and LDL cholesterol levels. Despite numerous descriptions outlining the phenotype of children with familial hypercholesterolemia (FH), no study has described the biochemical and clinical phenotype in a cohort of children with FDB. The phenotypes of FH and FDB, therefore, have not been compared in children. We have studied a cohort of 38 Dutch children (all <20 years old) with FDB from 21 different families. Lipid and lipoprotein levels and the clinical phenotype were compared with 97 age-matched FH heterozygotes, as defined by molecular analysis, and with age-matched non-FDB, non-FH control subjects. Female FDB carriers (n=23) had significantly lower total cholesterol (P<.001), LDL cholesterol (P=.001), total cholesterol:HDL ratio (P<.001), and apoB levels (P=.001) than age-matched female FH heterozygotes (n=50). Similar results were noted in male FDB carriers (n=15) compared with male FH heterozygotes (n=47; P=.005, P=.007, P=.014, and P=.074, respectively). Within the FDB group, female FDB heterozygotes had higher LDL cholesterol (P=.038) and a trend to higher total cholesterol levels (P=.165) than age-matched males. Both male and female FDB carriers had significantly higher total cholesterol, LDL cholesterol, and total cholesterol:HDL ratio than age- and sex-matched control subjects, which was evident even in children <10 years of age, providing additional evidence that this mutation is penetrant in early life. These results provide evidence for a milder biochemical phenotype in children with FDB than in children with FH. The phenotype observed is intermediate between that of control subjects and FH heterozygotes matched for age and sex. As the incidence of coronary artery disease is related to both the extent and duration of cholesterol elevation, our findings might explain in part the lower incidence of clinical atherosclerosis seen in adults with this condition than in adults with FH.
MeSH Terms
- Adolescent
- Adult
- Aging
- Apolipoprotein B-100
- Apolipoproteins B
- Child
- Child, Preschool
- Cholesterol
- Cholesterol, HDL
- Cholesterol, LDL
- Female
- Heterozygote
- Humans
- Hyperlipoproteinemia Type II
- Male
- Netherlands
- Phenotype
- Point Mutation
- Reference Values
The present retrospective study is based on a historical follow-up of 49 boys with constitutional delay of growth and puberty (CDGP) who went into puberty spontaneously (27 cases) or induced by depotestosterone treatment, 50 mg/ month for 6 months (22 cases). At the time of puberty the two groups of boys were similar in bone age, height deficiency, target height (TH) and had similar predicted final heights (FH). Their FH was measured and compared with TH calculated from measured parents' heights. FH did not significantly differ between the untreated boys and those treated. In the two groups of patients FH was similar and corresponded to both TH and height predicted at puberty onset. This study confirms that most boys with CDGP spontaneously attain a FH within the target range (24/27 cases). A short-term and low dose course of depotestosterone can be used without adverse effects on FH. The Bayley-Pinneau method can be generally considered accurate for predicting FH in CDGP, although significant discrepancies between FH and predicted height have been recorded in a fair number of both untreated and treated boys.
MeSH Terms
- Adolescent
- Age Determination by Skeleton
- Aging
- Body Height
- Bone Development
- Humans
- Male
- Puberty
- Puberty, Delayed
- Retrospective Studies
- Testosterone
Influence of feeding level and temperature on posture and posture-related heat production was studied in preruminant calves. Twenty-four young calves were assigned in a 2 x 2 factorial design to one of two feeding levels [high (FH) or low (FL)] and to one of two temperature (7.5 degrees C or 19 degrees C). Heat production (HP) and posture were measured per calf every 9 min, during 3 days. HP was dependent on feeding level and temperature. Energy expenditure related to standing was higher at 7.5 degrees C than at 19 degrees C. Time spent standing was higher at FL than at FH, and at 7.5 degrees C than at 19 degrees C. On the contrary, the number of standing periods was lower at 7.5 degrees C than at 19 degrees C. Consequently, the duration of a standing period was higher at 7.5 degrees C than at 19 degrees C. Within a standing period, HP decreased with time. This decline was largest at 7.5 degrees C. Thus, energy cost of standing was lower in treatments with a longer duration of a standing period. These results demonstrated that the effect of temperature on energy cost of standing is influenced by the number of standing periods.
MeSH Terms
- Acclimatization
- Aging
- Animals
- Body Temperature Regulation
- Cattle
- Energy Intake
- Energy Metabolism
- Male
- Motor Activity
- Posture
- Weaning
Two common founder-related gene mutations that affect the low-density lipoprotein receptor (LDLR) are responsible for approximately 80% of familial hypercholesterolemia (FH) in South African Afrikaners. The FH Afrikaner-1 (FH1) mutation (Asp206-->Glu) in exon 4 results in defective receptors with approximately 20% of normal activity, whereas the FH Afrikaner-2 (FH2) mutation (Val408-->Met) in exon 9 completely abolishes LDLR activity (< 2% normal activity). We analyzed the contribution of these mutations and other factors on the variation of hypercholesterolemia and clinical features in Afrikaner FH heterozygotes. The type of FH mutation, plasma triglyceride levels, and age of patients each contributed significantly to the variation in hypercholesterolemia, whereas smoking status, high-density lipoprotein cholesterol levels, and gender had no influence. Although all FH heterozygotes had frank hypercholesterolemia, patients with the FH1 mutation had significantly lower cholesterol levels than those with the FH2 mutation. FH1 heterozygotes also tended to have milder clinical features. The differences between the two FH groups could not be explained by a difference in the common apolipoprotein E variants. This study demonstrates that mutational heterogeneity in the LDLR gene influences the phenotypic expression of heterozygous FH.
MeSH Terms
- Adult
- Aged
- Aging
- Apolipoproteins E
- European Continental Ancestry Group
- Female
- Heterozygote
- Humans
- Hyperlipoproteinemia Type II
- Lipids
- Lipoproteins
- Male
- Middle Aged
- Mutation
- Phenotype
- Polymorphism, Genetic
- Receptors, LDL
- Sex Characteristics
- South Africa
An association between the activity of the renin-angiotensin system and the development of spontaneous focal glomerular sclerosis (FGS) in rats has been observed: the onset is preceded by a decrease in plasma renin activity (PRA). This observation was facilitated by the use of Fawn-hooded rats, which develop spontaneous FGS at an early age. Male Fawn-hooded rats develop severe FGS as early as 3 months of age. Male Wistar rats do not develop similar lesions until after 1 year of age. Correspondingly the PRA drops much sooner in Fawn-hooded than in Wistar rats. The low PRA appears to be due to low plasma renin rather than a limitation of the renin substrate, angiotensinogen, which appears to be present in the Fawn-hooded plasma in nonlimiting quantities. In the FH male rats renin content of the kidney drops only after severe glomerular pathology is evident, implying that the low PRA may be due to a decrease in renin secretion by the chromaffin cells of the juxtaglomerular apparatus.
MeSH Terms
- Aging
- Angiotensinogen
- Animals
- Female
- Glomerulonephritis
- Glomerulosclerosis, Focal Segmental
- Juxtaglomerular Apparatus
- Male
- Rats
- Rats, Inbred Strains
- Renin
- Renin-Angiotensin System
Fawn-hooded (FH) rats, primarily males, develop spontaneous low-renin hypertension associated with reduced urinary excretion of kallikrein as early as 2 months of age, followed by progressive glomerular sclerosis and proteinuria as early as 3 months of age. In the present study we determined the effects of early (5-7 weeks) or late (5 months) orchiectomy on the blood pressure and nephropathy of FH rats, compared to sham-operated (control) FH males. Early orchiectomy reduced significantly the progression of glomerular sclerosis and of proteinuria and ameliorated the hypertension but had no significant effect on excretion of urinary kallikrein. Late orchiectomy, in contrast, had no significant effect on the progression of glomerular sclerosis or proteinuria but did significantly reduce the blood pressure and marginally increase the excretion of urine kallikrein. These results suggest that (a) male sex hormones may play a role in the pathogenesis of hypertension and nephropathy in the FH rats and (b) renal disease in this strain progresses in spite of improvement in blood pressure.
MeSH Terms
- Aging
- Androgens
- Animals
- Hypertension
- Kallikreins
- Kidney
- Kidney Diseases
- Male
- Orchiectomy
- Proteinuria
- Rats
- Rats, Inbred Strains
- Sex Characteristics
The fawn-hooded rat (FH rat) develops hypertension accompanied with focal and segmental glomerulosclerosis and proteinuria, resulting in premature death. In a first experiment the relationship between renal lesions and blood pressure at various ages was investigated. In a second experiment blood pressure was measured weekly from 10 to 38 weeks of age in a number of male FH rats, followed by examination of renal tissues at 40 weeks of age. Plasma renin activity (PRA) had also been determined in individual FH rats. FH rats aged 4.5 weeks had no renal morphological abnormalities. The severity of the glomerulosclerosis increased with age and showed a positive relationship with blood pressure. The scores of the proteinaceous tubular casts also increased with age and they, too, showed a positive correlation with blood pressure. The severity of glomerulosclerosis and proteinaceous casts at 40 weeks of age was related positively to the course of blood pressure throughout life. The final blood pressure level showed a positive correlation with final PRA values. Only FH rats with malignant nephrosclerosis had high PRA values. The renal glomerular and vascular lesions in the FH rat, most likely caused by the hypertension, progressively deteriorate to malignant nephrosclerosis. At that stage PRA values are increased and may be contributing to the development of renal vascular lesions and acceleration of the hypertension.
MeSH Terms
- Aging
- Animals
- Blood Pressure
- Glomerulonephritis
- Hypertension, Renal
- Kidney
- Male
- Proteinuria
- Rats
- Rats, Inbred SHR
- Renal Artery
- Renin
There is concern that whole cow's milk feedings may be associated with intestinal abnormalities in infants. We studied this issue by measuring random fecal samples for alpha 1-antitrypsin (FA1AT) and hemoglobin (FH) concentrations in 820 healthy infants up to 12 months of age. Subjects were fed either human milk, formula, or fresh whole cow's milk. Solid foods were given ad libitum. Fecal samples were also tested for occult blood with Hematest reagent tablets. None of the infants younger than 6 months of age were receiving fresh whole cow's milk. We found small but statistically significant differences in mean FA1AT between the three feeding groups (P less than .0001): human milk (n = 354) greater than formula (n = 320) greater than cow's milk (n = 146). The younger subjects fed either formula or human milk tended to have higher FA1AT concentrations than did the age-matched subjects who were not consuming solid foods (P less than or equal to .005). Daily FA1AT excretion, FA1AT concentration, and daily stool output were subsequently determined on a separate group of 40 infants 8 to 12 months of age to ascertain whether differences in total daily FA1AT excretion occur in children fed different types of milk. Total daily FA1AT excretion was similar in the three milk feeding groups. An inverse correlation between FA1AT concentration and daily stool output was also found (P less than .001). The overall rate of detectable FH in 792 stool smears was 2.1% and unrelated to type of milk feeding. Of 705 stool smears, 3.5% had positive Hematest reactions.(ABSTRACT TRUNCATED AT 250 WORDS)
MeSH Terms
- Aging
- Animals
- Cattle
- Ethnic Groups
- Feces
- Female
- Hemoglobins
- Humans
- Immunodiffusion
- Infant
- Infant Food
- Infant, Newborn
- Male
- Milk
- Milk, Human
- Occult Blood
- Protein-Losing Enteropathies
- alpha 1-Antitrypsin
Abnormalities in baroreflex control of heart rate may be important in the pathogenesis of essential hypertension. To investigate the influence of heredity on baroreflex function, we measured baroreflex sensitivity in 40 untreated patients with essential hypertension grouped by the presence (FH ) or absence (FH-) of a family history of hypertension and in 24 normotensive counterparts. Baroreflex sensitivity was assessed by both high-pressure (phenylephrine bolus) and low-pressure (amyl nitrite inhalation) stimuli. Subject groups were matched for age, blood pressure, body weight, and race. Baroreflex sensitivity (in milliseconds per millimeter of mercury) assessed by amyl nitrite inhalation was 24.3 /- 2.8 in FH- normotensives, 12.3 /- 1.7 in FH normotensives, 15.4 /- 3.3 in FH- hypertensives, and 8.1 /- 1.2 in FH hypertensives. Baroreflex sensitivity assessed by phenylephrine bolus was 28.8 /- 5.6 in FH- normotensives, 19.3 /- 2.8 in FH normotensives, 19.1 /- 2.0 in FH- hypertensives, and 13.6 /- 1.3 in FH hypertensives. Two-factor analysis of variance showed significant effects on baroreflex sensitivity for blood pressure status (normotensive versus hypertensive) and for family history of hypertension. After control line (controlling) for the effects of several variables, including age, mean arterial pressure, body weight, and race through multiple linear regression analysis, the effect of family history of hypertension on baroreflex sensitivity was still highly significant. Indeed, of all variables investigated, family history of hypertension was the strongest unique baroreflex sensitivity predictor. These data suggest that the impairment in baroreflex sensitivity in hypertension is in part genetically determined and may be an important hereditary component in the pathogenesis of essential hypertension.
MeSH Terms
- Administration, Inhalation
- Adult
- Aging
- Forecasting
- Humans
- Hypertension
- Male
- Middle Aged
- Nitrates
- Pentanols
- Phenylephrine
- Pressoreceptors
- Reflex
- Regression Analysis