Participatory identification of breeding objective traits and selection criteria for indigenous goat of the pastoral communities in Ethiopia.

A structured questionnaire, own-flock ranking experiment, and group discussions were undertaken to assess goat breeding practices and to identify traits of interest for genetic improvement of indigenous goats. Four pastoral villages in Ethiopia, namely, Jarso, Mesoya, Eleweya, and Dharito were selected based on their goat production potential, accessibility, and suitability to implement community-based breeding programs. A survey and flock ranking experiment involving 70 households and 199 goats were used. In flock ranking experiment, goat owners were asked to choose the first three superior and the worst doe within their own flock. They were also asked to provide their reason for ranking the animals. In addition, data on size traits, kid growth, kid survival, reproduction traits, and milk yield were recorded for each doe. Data obtained from questionnaire, flock ranking, and measurements were subjected to both qualitative and quantitative analysis. Large variation was observed between top and last ranked does in most of the traits and price, for example, in body weight (33.6 ± 0.88 vs. 25.2 ± 0.93 kg), doe's kid survival (92.1 ± 4.01 vs. 59.6 ± 4.48%) and doe's price (1367 ± 46.5 vs. 833 ± 46.9 (US$1 = 28.4 Ethiopian Birr) Ethiopian Birr). Mobility is practiced with a defined and known pattern; therefore, recruitment of mobile enumerators for data recording would assist in implementation of breeding programs. Breeding objective should emphasize mothering ability (kid growth and survival), milk yield of does, and coat color in all areas. Due to its good correlation with other traits like kid growth and pre-weaning kid survival, considering milk yield alone as selection criteria or giving more weight for milk yield in the breeding program could generate better genetic benefit. Setting-up breeding program should be based on full participation and context of pastoralists.

HMGCR is a genetic modifier for risk, age of onset and MCI conversion to Alzheimer's disease in a three cohorts study.

Several retrospective epidemiological studies report that utilization of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibitors called statins at mid-life can reduce the risk of developing sporadic Alzheimer's disease (AD) by as much as 70%. Conversely, the administration of these inhibitors in clinically diagnosed subjects with AD confers little or no benefits over time. Here, we investigated the association between AD and HMGCR rs3846662, a polymorphism known to be involved in the regulation of HMGCR exon 13 skipping, in a founder population and in two distinct mixed North American populations of converting mild cognitively impaired (MCI) subjects (Alzheimer's disease Cooperative study (ADCS) and Alzheimer's disease Neuroimaging Initiative (ADNI) cohorts). Targeting more specifically women, the G allele negative (G-) AD subjects exhibit delayed age of onset of AD (P=0.017) and significantly reduced risk of AD (OR: 0.521; P=0.0028), matching the effect size reported by the apolipoprotein E type 2 variant. Stratification for APOE4 in a large sample of MCI patients from the ADCS cohort revealed a significant protective effect of G negative carriers on AD conversion 3 years after MCI diagnosis (odds ratio (OR): 0.554; P=0.041). Conversion rate among APOE4 carriers with the HMGCR's G negative allele was markedly reduced (from 76% to 27%) to levels similar to APOE4 non-carriers (27.14%), which strongly indicate protection. Conversion data from the independent ADNI cohort also showed significantly reduced MCI or AD conversion among APOE4 carriers with the protective A allele (P=0.005). In conclusion, HMGCR rs3846662 acts as a potent genetic modifier for AD risk, age of onset and conversion.

The MPTP neurotoxic lesion model of Parkinson's disease activates the apolipoprotein E cascade in the mouse brain.

Apolipoprotein E (apoE) is recognized as a key actor in brain remodeling. It has been shown to increase after peripheral and central injury, to modulate reparative capacity in neurodegenerative conditions like Alzheimer's disease (AD) and to be associated with a number of other neurodegenerative diseases. This particular function of apoE has been postulated to underlie the robust association with risk and age at onset of AD. ApoE associations studies with Parkinson's disease (PD), the second most prevalent neurodegenerative disease, have generated contradictory results but associations with age at onset and dementia in PD stand out. We investigate here whether apoE is involved in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced degeneration that models PD-like deafferentation of the striatum in the mouse and participates in compensatory reinnervation mechanisms. We examined the modifications in gene expression and protein levels of apoE and its key receptors, the low density lipoprotein receptor (LDLR) and the LDLR-related protein (LRP), as well as the reactive astrocyte marker glial fibrillary acidic protein (GFAP) in different brain structures throughout the degenerative and reactive regenerative period. In the striatum, upregulations of GFAP, apoE and LRP mRNAs at 1 day post-treatment were associated with marked decreases in dopamine (DA) levels, loss in tyrosine hydroxylase protein content, as well as to a compensatory increase in dopaminergic metabolism. Subsequent return to near control levels coincided with indications of reinnervation in the striatum: all consistent with a role of apoE during the degenerative process and regenerative period. We also found that this cascade was activated in the hippocampus and more so than in the striatum, with a particular contribution of LDLR expression. The hippocampal activation did not correlate with substantial neurochemical reductions but appears to reflect local subtle alteration of DA metabolism and the regulation of plasticity-related event in this structure. This study provides first evidence of an activation of the apoE/apoE receptors cascade in a mouse model of PD, specifically in the MPTP-induced deafferentation of the striatum. Results are also quite consistent with the postulated role of apoE in brain repair but, raise the issue of possible lesion- and region-specific alterations in gene expression.

Retrofitting houses with insulation: a cost-benefit analysis of a randomised community trial.

BACKGROUND: Housing is an important environmental influence on population health, and there is growing evidence of health effects from indoor environment characteristics such as low indoor temperatures. However, there is relatively little research, and thus little firm guidance, on the cost-effectiveness of public policies to retrospectively improve the standards of houses. The purpose of this study was to value the health, energy and environmental benefits of retrofitting insulation, through assessing a number of forms of possible benefit: a reduced number of visits to GPs, hospitalisations, days off school, days off work, energy savings and CO(2) savings. METHODS: All these metrics are used in a cluster randomised trial--the "Housing, Insulation and Health Study"--of retrofitting insulation in 1350 houses, in which at least one person had symptoms of respiratory disease, in predominantly low-income communities in New Zealand. RESULTS: Valuing the health gains, and energy and CO(2) emissions savings, suggests that total benefits in "present value" (discounted) terms are one and a half to two times the magnitude of the cost of retrofitting insulation. CONCLUSION: This study points to the need to consider as wide a range of benefits as possible, including health and environmental benefits, when assessing the value for money of an intervention to improve housing quality. From an environmental, energy and health perspective, the value for money of improving housing quality by retrofitting insulation is compelling.

After the smoke has cleared: evaluation of the impact of a new national smoke-free law in New Zealand.

BACKGROUND: The New Zealand 2003 Smoke-free Environments Amendment Act (SEAA) extended existing restrictions on smoking in office and retail workplaces by introducing smoking bans in bars, casinos, members' clubs, restaurants and nearly all other workplaces from 10 December 2004. OBJECTIVE: To evaluate the implementation and outcomes of aspects of the SEAA relating to smoke-free indoor workplaces and public places, excluding schools and early learning centres. METHODS: Data were gathered on public and stakeholder attitudes and support for smoke-free policies; dissemination of information, enforcement activities and compliance; exposure to secondhand smoke (SHS) in the workplace; changes in health outcomes linked to SHS exposure; exposure to SHS in homes; smoking prevalence and smoking related behaviours; and economic impacts. RESULTS: Surveys suggested growing majority support for the SEAA and its underlying principles among the public and bar managers. There was evidence of high compliance in bars and pubs, where most enforcement problems were expected. Self reported data suggested that SHS exposure in the workplace, the primary objective of the SEAA, decreased significantly from around 20% in 2003, to 8% in 2006. Air quality improved greatly in hospitality venues. Reported SHS exposure in homes also reduced significantly. There was no clear evidence of a short term effect on health or on adult smoking prevalence, although calls to the smoking cessation quitline increased despite reduced expenditure on smoking cessation advertising. Available data suggested a broadly neutral economic impact, including in the tourist and hospitality sectors. CONCLUSION: The effects of the legislation change were favourable from a public health perspective. Areas for further investigation and possible regulation were identified such as SHS related pollution in semi-enclosed outdoor areas. The study adds to a growing body of literature documenting the positive impact of comprehensive smoke-free legislation. The scientific and public health case for introducing comprehensive smoke-free legislation that covers all indoor public places and workplaces is now overwhelming, and should be a public health priority for legislators across the world as part of the globalization of effective public health policy to control the tobacco epidemic.

Cellular distribution of insulin-like growth factor-II/mannose-6-phosphate receptor in normal human brain and its alteration in Alzheimer's disease pathology.

The insulin-like growth factor-II/mannose-6-phosphate (IGF-II/M6P) receptor is a multifunctional membrane glycoprotein, which binds different classes of ligands including IGF-II and M6P-bearing lysosomal enzymes. Besides participating in the process of endocytosis this receptor functions in the trafficking of lysosomal enzymes from the trans-Glogi network (TGN) or the cell surface to lysosomes. In Alzheimer's disease (AD) brain, marked overexpression of certain lysosomal enzymes in vulnerable neuronal populations and their association to beta-amyloid (Abeta) containing neuritic plaques has been correlated to altered metabolic functions. In the present study, we measured the levels of IGF-II/M6P receptor and characterized its distribution profile in selected regions of AD and age-matched normal postmortem brains. Western blot analysis revealed no significant alteration in the levels of IGF-II/M6P receptor either in the hippocampus, frontal cortex or cerebellum between AD and age-matched control brains. However, a significant gene dose effect of apolipoprotein E (APOE) epsilon4 allele on IGF-II/M6P receptor levels was evident in the hippocampus of the AD brain. At the cellular level, immunoreactive IGF-II/M6P receptors were localized in the neurons of the frontal cortex, hippocampus and cerebellum of control brains. In AD brains, the labeling of the neurons was less intense in the frontal cortex and hippocampus than in the age-matched control brains. Additionally, IGF-II/M6P receptor immunoreactivity was observed in association with a subpopulation of Abeta-containing neuritic plaques as well as tau-positive neurofibrillary tangles both in the frontal cortex and the hippocampus. Reactive glial cells localized adjacent to the plaques also occasionally exhibited IGF-II/M6P receptor immunoreactivity. These results, when analyzed in context of the established role of the IGF-II/M6P receptor in the regulation of the intracellular trafficking of lysosomal enzymes, suggest that alterations in IGF-II/M6P receptor levels/distribution are possibly associated with altered functioning of the lysosomal enzymes and/or loss of neurons observed in AD brains, especially in patients carrying APOE epsilon4 alleles.

Retrofitting houses with insulation to reduce health inequalities: aims and methods of a clustered, randomised community-based trial.

This paper describes the purpose and methods of a single-blinded, clustered and randomised trial of the health impacts of insulating existing houses. The key research question was whether this intervention increased the indoor temperature and lowered the relative humidity, energy consumption and mould growth in the houses, as well as improved the health and well-being of the occupants and thereby lowered their utilisation of health care. Households in which at least one person had symptoms of respiratory disease were recruited from seven predominantly low-income communities in New Zealand. These households were then randomised within communities to receive retrofitted insulation either during or after the study. Measures at baseline (2001) and follow-up (2002) included subjective measures of health, comfort and well-being and objective measures of house condition, temperature, relative humidity, mould (speciation and mass), endotoxin, beta glucans, house dust mite allergens, general practitioner and hospital visits, and energy or fuel usage. All measurements referred to the three coldest winter months, June, July and August. From the 1352 households that were initially recruited, baseline information was obtained from 1310 households and 4413 people. At follow-up, 3312 people and 1110 households remained, an 84% household retention rate and a 75% individual retention rate. Final outcome results will be reported in a subsequent paper. The study showed that large trials of complex environmental interventions can be conducted in a robust manner with high participation rates. Critical success factors are effective community involvement and an intervention that is valued by the participants.

The cholesterol-lowering drug probucol increases apolipoprotein E production in the hippocampus of aged rats: implications for Alzheimer's disease.

Several recent epidemiological studies have proposed that cholesterol-lowering drug Statin may provide protection against Alzheimer's disease (AD). Probucol is a non-Statin cholesterol-lowering drug and a potent inducer of apolipoprotein E (apoE) production in peripheral circulation. A recent clinical study using Probucol in elderly AD subjects revealed a concomitant stabilisation of cognitive symptoms and significant increases in apoE levels in the cerebral spinal fluid in these patients. To gain insight into the mechanisms underlying these effects, we treated a cohort of aged male rats (26-month-old) with oral dose of Probucol for 30 days. Specifically, we examined the effects of Probucol on apoE production and its receptors (low density lipoprotein receptor [LDLr] and low density lipoprotein receptor-related protein [LRP]), astroglial marker of cell damage (glial fibrillary acidic protein [GFAP]), markers of neuronal synaptic plasticity and integrity (synaptosomal associated protein of 25 kDa [SNAP-25] and synaptophysin) as well as cholesterol biosynthesis (3-hydroxy-3-methylglutaryl coenzyme A reductase [HMGCoAr]) in the hippocampus. We report that Probucol induces the production of apoE and one of its main receptors, LRP, increases HMGCoAr (rate-limiting enzyme in cholesterol synthesis), substantially attenuates age-related increases in glial activation, and induces production of synaptic marker SNAP-25, a molecule commonly associated with synaptogenesis and dendritic remodeling. These findings suggest that Probucol could promote neural and synaptic plasticity to counteract the synaptic deterioration associated with brain aging through an apoE/LRP-mediated system. Consistent with the beneficial effects of other cholesterol-lowering drugs such as the Statin, Probucol could also offers additional benefits based on apoE neurobiology.

No association of income inequality with adult mortality within New Zealand: a multi-level study of 1.4 million 25-64 year olds.

STUDY OBJECTIVE: To determine the association of regional income inequality within New Zealand with mortality among 25-64 year olds. DESIGN: Individual census and mortality records were linked over the 1991-94 period. Income inequality (Gini coefficients) and average household income variables were calculated for 35 regions. "Individual level" variables were sex, age, ethnicity, household income, rurality, and small area socioeconomic deprivation. Logistic regression was used for the analyses. Sensitivity analyses for the level of regional aggregation were conducted. PARTICIPANTS: 1.4 million New Zealand census respondents aged 25-64 years followed up for mortality for three years. MAIN RESULTS: Controlling for age, ethnicity, rurality, household income, and regional mean income, there was no association of income inequality with all cause mortality for either men (OR=1.007 for a 0.01 increase in the Gini, 95% confidence intervals 0.989 to 1.024) or women (OR=1.004, 0. 983 to 1.026). By cause of death (cancer, cardiovascular disease, unintentional injury, and suicide) there was some suggestion of a positive association for female unintentional injury (OR=1.068, 0.952 to 1.198) and suicide (OR=1.087, 0.957 to 1.234) but the 95% confidence intervals all included 1.0. Failure to control for ethnicity at the individual level resulted in some association of increasing regional income inequality with increasing mortality risk. Using fewer (n=14) or more (n=73) regional divisions did not substantially change the findings. CONCLUSION: There is no convincing evidence of an association of income inequality within New Zealand with adult mortality. Previous ecological analyses within New Zealand suggesting an association of income inequality with mortality were confounded by ethnicity at the individual level. However, this study does not refute the possibility that income inequality at the national level affects health.

Tobacco spending and children in low income households.

OBJECTIVE: To examine the role of tobacco use in creating financial hardship for New Zealand (NZ) low income households with children. DATA: The 1996 NZ census (smoking prevalence by household types), Statistics NZ (household spending surveys 1988-98), and NZ Customs (tobacco released from bond 1988-98). MAIN OUTCOME MEASURES: Proportion of children in households with smokers and < or = 15,000 NZ dollars gross income per adult. Proportion of spending on tobacco of second lowest equivalised household disposable income decile and of solo parent households. RESULTS: In < or = 15,000 NZ dollars gross income per adult households with both children and smokers, there were over 90,000 children, or 11% of the total population aged less than 15 years. Enabling second lowest income decile households with smokers to be smoker-free would on average allow an estimated 14% of the non-housing budgets of those households to be reallocated. CONCLUSIONS: The children in low income households with smokers need to be protected from the financial hardship caused by tobacco use. This protection could take the form of more comprehensive government support for such households and stronger tobacco control programmes. A reliance on tobacco price policy alone to deter smokers is likely to have mixed outcomes-for example, increased hardship among some of these households. The challenge for tobacco control is to move from a sole focus on "doing good" towards incorporating the principle of "doing no harm".

Apolipoprotein C-I expression in the brain in Alzheimer's disease.

The H2 allele of apolipoprotein (apo) C-I is associated with Alzheimer's disease (AD). However, this association is potentially confounded by the linkage disequilibrium of H2 with the epsilon2 and epsilon4 alleles of apoE and of H1 with the epsilon3 allele. To establish plausibility for a direct role for apoC-I in AD, we compared apoC-I and apoE protein and mRNA levels in postmortem specimens of frontal cortex and hippocampus from AD patients with levels in nondemented controls. In H2-allelic individuals (usually also epsilon4 carriers), apoC-I mRNA levels were strikingly lower with AD (by 65%, P < 0.05), but apoC-I protein levels in AD were significantly higher (by 34%, P < 0.05). The opposite direction of the apoC-I mRNA and apoC-I protein level changes in AD in the epsilon4/H2 genotype may reflect decreased clearance of CNS lipoproteins associated with apoE4. In H1/H1 (usually epsilon3/epsilon3) individuals, both apoC-I protein and mRNA were lower in AD. ApoC-I protein levels in hippocampus were nearly twice those in frontal cortex. Immunohistochemistry of hippocampus revealed colocalization of apoC-I protein with the astrocytic marker GFAP. In addition, cultured human astrocytes expressed the mRNA for apoC-I. This study confirms apoC-I expression in the CNS and identifies astrocytes as the source of apoC-I. In addition, it has revealed differences in apoC-I expression based on site, genotype, and disease status that may reflect a role for apoC-I in the pathogenesis of AD.

Apolipoprotein E isoform-specific reduction of extracellular amyloid in neuronal cultures.

Both apolipoprotein E (apoE) and amyloid peptides are associated with Alzheimer's disease (AD). Using primary hippocampal neurons, we demonstrate that apoE is capable of reducing potentially toxic extracellular amyloid peptides, likely through a receptor mediated mechanism. We hypothesize that isoform-specific differences in apoE-mediated amyloid clearance and intracellular accumulation may be responsible, at least in part, for the increased number of amyloid plaques observed in apoE epsilon4 allele AD individuals.

Higher risk for renal failure in first-degree relatives of white patients with end-stage renal disease: a population-based study.

To explore the possibility that hereditary factors increase the risk for end-stage renal disease (ESRD), 669 patients with ESRD in the province of Newfoundland, Canada from 1987 to 1993 were studied. Detailed family histories were obtained from 584 (87%) consecutive probands and 499 spousal control subjects. Diseases with a Mendelian pattern of inheritance accounted for 8.4% of the cases; 4.5% of the cases were caused by autosomal dominant polycystic kidney disease (ADPKD). Glomerulonephritis was the original cause of renal failure in 25% of the probands, diabetes mellitus (DM) in 20%, unknown in 14%, interstitial kidney disease in 11%, other disease in 12%, multifactorial in 4%, and hypertension in 5%. In the group without a Mendelian pattern of inheritance, 28% of the probands had a first-, second-, or third-degree relative with renal failure associated with death or dialysis versus 15% of the controls. Compared with 0.4% of the control group, 1.2% of the first-degree relatives of probands developed renal failure (odds ratio [OR]=3.0; 95% confidence interval [CI], 1.7 to 5.2). No difference was observed when risks were compared for second-degree relatives, but a highly significant increased risk was observed for third-degree relatives (OR=2.1; 95% CI, 1.2 to 3.4). The highest rates of affected first-degree relatives occurred in probands with hypertensive renal failure (2.3%), DM (1.6%), and interstitial kidney disease (1.6%). The annual provincial incidence of ESRD, registered with the Canadian Organ Replacement Registry (CORR) from 1981 to 1993 was 79 per million, excluding the 8% of patients with Mendelian inherited disease. The similar rate of ESRD in first-degree relatives of probands without Mendelian inherited disease was 297 per million. We conclude that not only is the contribution of Mendelian inherited diseases to ESRD high, but there is also an increased risk for renal failure in first-degree relatives of probands without a Mendelian inherited renal disease in a white population.

Beta-amyloid peptides increase the binding and internalization of apolipoprotein E to hippocampal neurons.

The frequency of the epsilon4 allele of apolipoprotein E (apoE) is increased in late-onset and sporadic forms of Alzheimer's disease (AD). ApoE also binds to beta-amyloid (A beta) and both proteins are found in AD plaques. To further investigate the potential interaction of apoE and A beta in the pathogenesis of AD, we have determined the binding, internalization, and degradation of human apoE isoforms in the presence and absence of A beta peptides to rat primary hippocampal neurons. We demonstrate that the lipophilic A beta peptides, in particular A beta(1-42), A beta(1-40), and A beta(25-35), increase significantly apoE-liposome binding to hippocampal neurons. For each A beta peptide, the increase was significantly greater for the apoE4 isoform than for the apoE3 isoform. The most effective of the A beta peptides to increase apoE binding, A beta(25-35), was further shown to increase significantly the internalization of both apoE3- and apoE4-liposomes, without affecting apoE degradation. Conversely, A beta(1-40) uptake by hippocampal neurons was shown to be increased in the presence of apoE-liposomes, more so in the presence of the apoE4 than the apoE3 isoform. These results provide evidence that A beta peptides interact directly with apoE lipoproteins, which may then be transported together into neuronal cells through apoE receptors.

Apolipoprotein E and low-density lipoprotein binding and internalization in primary cultures of rat astrocytes: isoform-specific alterations.

Apolipoprotein (apo) E is likely involved in redistributing cholesterol and phospholipids during compensatory synaptogenesis in the injured CNS. Three common isoforms of apoE exist in human (E2, E3, and E4). The apoE4 allele frequency is markedly increased in both late-onset sporadic and familial Alzheimer's disease (AD). ApoE concentration in the brain of AD subjects follows a gradient: ApoE levels decrease as a function of E2 > E3 >> E4. It has been proposed that the poor reinnervation capacity reported in AD may be caused by impairment of the apoE/low-density lipoprotein (LDL) receptor activity. To understand further the role of this particular axis in lipid homeostasis in the CNS, we have characterized binding, internalization, and degradation of human 125I-LDL to primary cultures of rat astrocytes. Specific binding was saturable, with a KD of 1.8 nM and a Bmax of 0.14 pmol/mg of proteins. Excess unlabeled human LDL or very LDL (VLDL) displaced 70% of total binding. Studies at 37 degrees C confirmed that astrocytes bind, internalize, and degrade 125I-LDL by a specific, saturable mechanism. Reconstituted apoE (E2, E3, and E4)-liposomes were labeled with 125I and incubated with primary cultures of rat astrocytes and hippocampal neurons to examine specific binding. Human LDL and VLDL displaced binding and internalization of all apoE isoforms similarly in both astrocytes and neurons. 125I-ApoE2 binding was significantly lower than that of the other 125I-apoE isoforms in both cell types. 125I-ApoE4 binding was similar to that of 125I-apoE3 in both astrocytes and neurons. On the other hand, 125I-apoE3 binding was significantly higher in neurons than in astrocytes. These isoform-specific alterations in apoE-lipoprotein pathway could explain some of the differences reported in the pathophysiology of AD subjects carrying different apoE alleles.

The importance of renal impairment in the natural history of Bardet-Biedl syndrome.

Bardet-Biedl syndrome is a rare autosomal recessive disease characterized by dysphormic extremities, retinal dystrophy, obesity, hypogenitalism in males, and renal structural abnormalities. Because the clinical outcome of these patients is not well known, 21 families with Bardet-Biedl syndrome (BBS) were studied to determine the natural history of the disease. In a prospective cohort study, 38 patients with the syndrome and 58 unaffected siblings were identified. Patients were studied in 1987 and again in 1993. Age of onset of blindness, hypertension, diabetes, renal impairment, and death was determined. The prevalence of obesity, gonadal dysfunction, and renal structural abnormalities was assessed. All but 5 BBS patients (86%) were legally blind, 26% being blind by the age of 13 years and 50% by 18 years. Eighty-eight percent were above the 90th percentile for height and weight. Twenty-five (66%) patients had hypertension, 25% of BBS patients by age 26 years, and 50% by age 34 years, whereas in the unaffected group, 25% had hypertension by age 49 years (P < 0.0001). Twelve (32%) BBS patients developed diabetes mellitus, compared with none of the unaffected group. Only 2 patients were insulin dependent. Twenty-five percent of BBS patients had diabetes by the age of 35 years. In 12 women of reproductive age, 1 (8%) had primary gonadal failure. In 10 men, 4 had primary testicular failure. Nine (25%) patients developed renal impairment, with 25% of the BBS group affected by the age of 48 years. Imaging procedures of the kidney were performed in 25 patients with normal renal function. Whereas fetal lobulation and calyceal cysts/diverticula/clubbing were characteristic, occurring in 96% of patients, 20% (n = 5) had diffuse and 4% (n = 1) focal cortical loss. Eight patients with BBS died, 3 with end-stage renal failure and 3 with chronic renal failure. On life-table analysis, 25% of BBS patients had died by 44 years, whereas at that age 98% of unaffected siblings were still alive (P < 0.0001). Bardet-Biedl syndrome has an adverse prognosis, with early onset of blindness, obesity, hypertension, and diabetes mellitus. Renal impairment is frequent and an important cause of death. Survival is substantially reduced.

Increased levels of statin, a marker of cell cycle arrest, in response to hippocampal neuronal injury.

Injured neurons in the CNS are known to synthesize high levels of proliferation related oncogene products and heat shock proteins without dividing. Statin is a cell cycle regulated nuclear phosphoprotein, selectively associated with the non-proliferative state in a wide variety of cell types. In the present study, neuronal statin was examined following lethal or sublethal neuronal injuries in the hippocampus of Alzheimer's disease patients, in rats receiving kainate lesions to the dorsal hippocampus and in entorhinal cortex lesioned rats. Immunolabelling of nuclear statin showed that statin immunoreactivity increased preferentially in CA1 pyramidal neurons of the hippocampus in Alzheimer's disease. In kainate lesioned rats, statin immunoreactivity was markedly induced in the CA3 hippocampal region in association with neuronal loss. Entorhinal cortex lesioned rats showed a transient induction of statin between 2 and 6 days post lesion in CA1 neurons. However, cell counts in entorhinal cortex lesioned rats remained unaltered in the CA1 and granule cell layers during the entire 30 day time course, indicating that increased statin levels are not secondary to neuronal degeneration and are not necessarily accompanied by irreversible neuronal death. It is concluded that, in addition to proliferation related gene products, neuronal injury induces an increase in levels of statin, a nuclear marker of cell cycle arrest. Furthermore, statin may be a potentially useful marker of injurious neuronal stress, even under conditions that do not necessarily lead to irreversible cell death.