Bovine prion protein gene (PRNP) promoter polymorphisms modulate PRNP expression and may be responsible for differences in bovine spongiform encephalopathy susceptibility

The susceptibility of humans to the variant Creutzfeldt-Jakob disease is greatly influenced by polymorphisms within the human prion protein gene (PRNP). Similar genetic differences exist in sheep, in which PRNP polymorphisms modify the susceptibility to scrapie. However, the known coding polymorphisms within the bovine PRNP gene have little or no effect on bovine spongiform encephalopathy (BSE) susceptibility in cattle. We have recently found a tentative association between PRNP promoter polymorphisms and BSE susceptibility in German cattle (Sander, P., Hamann, H., Pfeiffer, I., Wemheuer, W., Brenig, B., Groschup, M., Ziegler, U., Distl, O., and Leeb, T. (2004) Neurogenetics 5, 19-25). A plausible hypothesis explaining this observation could be that the bovine PRNP promoter polymorphisms cause changes in PRNP expression that might be responsible for differences in BSE incubation time and/or BSE susceptibility. To test this hypothesis, we performed a functional promoter analysis of the different bovine PRNP promoter alleles by reporter gene assays in vitro and by measuring PRNP mRNA levels in calves with different PRNP genotypes in vivo. Two variable sites, a 23-bp insertion/deletion (indel) polymorphism containing a RP58-binding site and a 12-bp indel polymorphism containing an SP1-binding site, were investigated. Band shift assays indicated differences in transcription factor binding to the different alleles at the two polymorphisms. Reporter gene assays demonstrated an interaction between the two postulated transcription factors and lower expression levels of the ins/ins allele compared with the del/del allele. The in vivo data revealed substantial individual variation of PRNP expression in different tissues. In intestinal lymph nodes, expression levels differed between the different PRNP genotypes.

Further Concerns About Glutamine: A Case Report on Hyperammonemic Encephalopathy.

OBJECTIVE We report a case of a woman with hyperammonemic encephalopathy following glutamine supplementation. DESIGN Case report. INTERVENTIONS Plasma amino acid analysis suggestive of a urea cycle defect and initiation of a treatment with lactulose and the two ammonia scavenger drugs sodium benzoate and phenylacetate. Together with a restricted protein intake ammonia and glutamine plasma levels decreased with subsequent improvement of the neurological status. MEASUREMENTS AND MAIN RESULTS Massive catabolism and exogenous glutamine administration may have contributed to hyperammonemia and hyperglutaminemia in this patient. CONCLUSION This case adds further concerns regarding glutamine administration to critically ill patients and implies the importance of monitoring ammonia and glutamine serum levels in such patients.

Capillary growth, ultrastructure remodelling and exercise training in skeletal muscle of essential hypertensive patients

AIM The aim was to elucidate whether essential hypertension is associated with altered capillary morphology and density and to what extent exercise training can normalize these parameters. METHODS To investigate angiogenesis and capillary morphology in essential hypertension, muscle biopsies were obtained from m. vastus lateralis in subjects with essential hypertension (n = 10) and normotensive controls (n = 11) before and after 8 weeks of aerobic exercise training. Morphometry was performed after transmission electron microscopy, and protein levels of several angioregulatory factors were determined. RESULTS At baseline, capillary density and capillary-to-fibre ratio were not different between the two groups. However, the hypertensive subjects had 9% lower capillary area (12.7 ± 0.4 vs. 13.9 ± 0.2 μm(2)) and tended to have thicker capillary basement membranes (399 ± 16 vs. 358 ± 13 nm; P = 0.094) than controls. Protein expression of vascular endothelial growth factor (VEGF), VEGF receptor-2 and thrombospondin-1 were similar in normotensive and hypertensive subjects, but tissue inhibitor of matrix metalloproteinase was 69% lower in the hypertensive group. After training, angiogenesis was evident by 15% increased capillary-to-fibre ratio in the hypertensive subjects only. Capillary area and capillary lumen area were increased by 7 and 15% in the hypertensive patients, whereas capillary basement membrane thickness was decreased by 17% (P < 0.05). VEGF expression after training was increased in both groups, whereas VEGF receptor-2 was decreased by 25% in the hypertensive patients(P < 0.05). CONCLUSION Essential hypertension is associated with decreased lumen area and a tendency for increased basement membrane thickening in capillaries of skeletal muscle. Exercise training may improve the diffusion conditions in essential hypertension by altering capillary structure and capillary number.

Efficacy and safety of calcium channel blocker/diuretics combination therapy in hypertensive patients: a meta-analysis.

Although recent guidelines recommend the combination of calcium channel blockers (CCBs) and thiazide (-like) diuretics, this combination is not widely used in clinical practice. The aim of this meta-analysis was to assess the efficacy and safety of this combination regarding the following endpoints: all-cause and cardiovascular mortality, myocardial infarction, and stroke. Four studies with a total of 30,791 of patients met the inclusion criteria. The combination CCB/thiazide (-like) diuretic was associated with a significant risk reduction for myocardial infarction (risk ratio [RR], 0.83; 95% confidence interval [CI], 0.73-0.95) and stroke (RR, 0.77; CI, 0.64-0.92) compared with other combinations, whereas it was similarly effective compared with other combinations in reducing the risk of all-cause (RR, 0.89; CI, 0.75-1.06) and cardiovascular (RR, 0.89; CI 0.71-1.10) mortality. Elderly patients with isolated systolic hypertension may particularly benefit from such a combination, since both drug classes have been shown to confer cerebrovascular protection.

Wernicke Encephalopathy: a Future Problem Even After Sleeve Gastrectomy? A Systematic Literature Review.

Wernicke encephalopathy (WE) is a serious complication of bariatric surgery with significant morbidity and mortality. A few cases have been reported in the literature, mainly in patients after a Roux-en-Y gastric bypass. Since sleeve gastrectomy (SG) has become a more established and popular bariatric procedure, WE is expected to appear more frequently after SG. We performed a literature review on WE after SG, and 13 cases have been found to be sufficiently documented. The risk of WE needs to be considered in patients with a prolonged vomiting episode and any type of neurological symptoms, independent of the presence of any surgical complications.

STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy

OBJECTIVE To give a comprehensive overview of the phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E) by systematically reviewing newly diagnosed and previously reported patients. METHODS We recruited newly diagnosed patients with STXBP1 mutations through an international network of clinicians and geneticists. Furthermore, we performed a systematic literature search to review the phenotypes of all previously reported patients. RESULTS We describe the phenotypic features of 147 patients with STXBP1-E including 45 previously unreported patients with 33 novel STXBP1 mutations. All patients have intellectual disability (ID), which is mostly severe to profound (88%). Ninety-five percent of patients have epilepsy. While one-third of patients presented with Ohtahara syndrome (21%) or West syndrome (9.5%), the majority has a nonsyndromic early-onset epilepsy and encephalopathy (53%) with epileptic spasms or tonic seizures as main seizure type. We found no correlation between severity of seizures and severity of ID or between mutation type and seizure characteristics or cognitive outcome. Neurologic comorbidities including autistic features and movement disorders are frequent. We also report 2 previously unreported adult patients with prominent extrapyramidal features. CONCLUSION De novo STXBP1 mutations are among the most frequent causes of epilepsy and encephalopathy. Most patients have severe to profound ID with little correlation among seizure onset, seizure severity, and the degree of ID. Accordingly, we hypothesize that seizure severity and ID present 2 independent dimensions of the STXBP1-E phenotype. STXBP1-E may be conceptualized as a complex neurodevelopmental disorder rather than a primary epileptic encephalopathy.

Atypical variants of bovine spongiform encephalopathy: rare diseases with consequences for BSE surveillance and control

Occurring for the first time in 1986 in the United Kingdom, bovine spongiform encephalopathy (BSE), the so-called “mad-cow disease”, has had unprecedented consequences in veterinary public health. The implementation of drastic measures, including the ban of meat-and-bone-meal from livestock feed and the removal of specified risk materials from the food chain has eventually resulted in a significant decline of the epidemic. The disease was long thought to be caused by a single agent, but since the introduction of immunochemical diagnostic techniques, evidence of a phenotypic variation of BSE has emerged. Reviewing the literature available on the subject, this paper briefly summarizes the current knowledge about these atypical forms of BSE and discusses the consequences of their occurrence for disease control measures.

Resting and reactive blood pressure as predictors of ambulatory blood pressure in older hypertensive adults

Background. A review of the literature suggests that Hypertension (HTN) in older adults is associated with sympathetic stimulation that results in increasing blood pressure (BP) reactivity. If clinical assessment of BP captured sympathetic stimulation, it would be valuable for hypertension management. ^ Objectives. The study examined whether reactive change scores from a short BPR protocol, resting blood pressure (BP), or resting pulse pressure (PP) is a better predictor of 24 hour ambulatory BP and BP load in cardiac patients. ^ Method. The study used a single-group design, with both an experimental clinical component and an observational field component. Both components used repeated measurement methods. The study population consisted of 45 adult patients with a mean age of 64.6 ± 8.5 years who were diagnosed with cardiac disease and who were taking anti-hypertensive medication. Blood pressure reactivity was operationalized with a speech protocol. During the speech protocol, BP was measured with an automatic device (Dinamap 825XT) while subjects talked about their health and about their usual day. Twenty-four hour ambulatory BP measurement (Spacelabs 90207 monitor) followed the speech protocol. ^ Results. Resting SBP and resting PP were significant predictors of 24-hour SBP, and resting SBP was a significant predictor of SBP load. No predictors were significant of 24-hour DBP or DBP load. ^ Conclusions. Initial resting BP and PP may be used in clinical settings to assess hypertension management. Future studies are necessary to confirm the ability of resting BP to predict ABP and BP load in older, medicated hypertensives. ^

Incident hypertension among pre-hypertensive adolescents: Evaluation of pre-hypertension as an independent risk factor among secondary school students in the Houston area

Cardiovascular disease has been the leading cause of death in the United States for over fifty years. While multiple risk factors for cardiovascular disease have been identified, hypertension is one of the most commonly recognized and treatable. Recent studies indicate that the prevalence of hypertension among children and adolescents is between 3-5%, much higher than originally estimated and likely rising due to the epidemic of obesity in the U.S. In 2004, the National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents published new guidelines for the diagnosis and treatment of hypertension in this population. Included in these recommendations was the creation of a new diagnosis, pre-hypertension, aimed at identifying children at-risk for hypertension to provide early lifestyle interventions in an effort to prevent its ultimate development. In order to determine the risk associated with pre-hypertension for the development of incident HTN, a secondary analysis of a repeated cross-sectional study measuring blood pressure in Houston area adolescents from 2000 to 2007 was performed. Of 1006 students participating in the blood pressure screening on more than one occasion not diagnosed with hypertension at initial encounter, eleven were later found to have hypertension providing an overall incident rate of 0.5% per year. Incidence rates were higher among overweight adolescents–1.9% per year [IRR 8.6 (1.97, 51.63)]; students “at-risk for hypertension” (pre-hypertensive or initial blood pressure in the hypertensive range but falling on subsequent measures)–1.4% per year [IRR 4.77 (1.21, 19.78)]; and those with blood pressure ≥90th percentile on three occasions–6.6% per year [IRR 21.87 (3.40, 112.40)]. Students with pre-hypertension as currently defined by the Task Force did have an increased rate of hypertension (1.1% per year) but it did not reach statistical significance [IRR 2.44 (0.42, 10.18)]. Further research is needed to determine the morbidity and mortality associated with pre-hypertension in this age group as well as the effectiveness of various interventions for preventing the development of hypertensive disease among these at-risk individuals. ^

Disparities in medical expenditure and utilization among hypertensive men and women in the U.S.: Cross-section and lifetime analysis

Objectives. To investigate procedural gender equity by assessing predisposing, enabling and need predictors of gender differences in annual medical expenditures and utilization among hypertensive individuals in the U.S. Also, to estimate and compare lifetime medical expenditures among hypertensive men and women in the U.S. ^ Data source. 2001-2004 the Medical Expenditure Panel Survey (MEPS);1986-2000 National Health Interview Survey (NHIS) and National Health Interview Survey linked to mortality in the National Death Index through 2002 (2002 NHIS-NDI). ^ Study design. We estimated total medical expenditure using four equations regression model, specific medical expenditures using two equations regression model and utilization using negative binomial regression model. Procedural equity was assessed by applying the Aday et al. theoretical framework. Expenditures were estimated in 2004 dollars. We estimated hypertension-attributable medical expenditure and utilization among men and women. ^ To estimate lifetime expenditures from ages 20 to 85+, we estimated medical expenditures with cross-sectional data and survival with prospective data. The four equations regression model were used to estimate average annual medical expenditures defined as sum of inpatient stay, emergency room visits, outpatient visits, office based visits, and prescription drugs expenditures. Life tables were used to estimate the distribution of life time medical expenditures for hypertensive men and women at different age and factors such as disease incidence, medical technology and health care cost were assumed to be fixed. Both total and hypertension attributable expenditures among men and women were estimated. ^ Data collection. We used the 2001-2004 MEPS household component and medical condition files; the NHIS person and condition files from 1986-1996 and 1997-2000 sample adult files were used; and the 1986-2000 NHIS that were linked to mortality in the 2002 NHIS-NDI. ^ Principal findings. Hypertensive men had significantly less utilization for most measures after controlling predisposing, enabling and need factors than hypertensive women. Similarly, hypertensive men had less prescription drug (-9.3%), office based (-7.2%) and total medical (-4.5%) expenditures than hypertensive women. However, men had more hypertension-attributable medical expenditures and utilization than women. ^ Expected total lifetime expenditure for average life table individuals at age 20, was $188,300 for hypertensive men and $254,910 for hypertensive women. But the lifetime expenditure that could be attributed to hypertension was $88,033 for men and $40,960 for women. ^ Conclusion. Hypertensive women had more utilization and expenditure for most measures than hypertensive men, possibly indicating procedural inequity. However, relatively higher hypertension-attributable health care of men shows more utilization of resources to treat hypertension related diseases among men than women. Similar results were reported in lifetime analyses.^ Key words: gender, medical expenditures, utilization, hypertension-attributable, lifetime expenditure ^

The impact of social support networks on compliance with hypertensive therapeutic regimens among noninstitutionalized black adults

A conceptual framework based on the Health Belief Model was proposed which identified those factors most significant in the prediction of compliance behavior. The hypothesized model was applied to analyze the effects of sociodemographic characteristics, self-assessed health status, and social support networks on compliance with antihypertensive regimens, focusing on black adults.^ The study population was selected from the National Health and Examination Survey II (NHANES II) which produced a sample of 3,957 eligible persons 35-74 years of age.^ The study addressed the following research questions: (a) what is the relationship between demographic variables and self-assessed health status, (b) what is the relationship between social support network and self-assessed health status, (c) what is the compliance, (d) what factors, e.g., demographic characteristics, social support network, self-assessed health status, are most related to compliance, and (e) does the effect of these factors on compliance differ between black and white adults?^ The results of the study found that blacks: (a) had poorer health than whites, and education and income were significantly related to self-assessed health status, (b) the stronger social support networks of blacks, the better their health status, and (c) older blacks and those in poorer health were more likely to comply with recommended treatment. The hypothesized conceptual model for the prediction of compliance behavior was partially substantiated for both blacks and whites.^ Implications for the application of the conceptual model are also discussed. ^

THE EFFECT OF CAFFEINE CONSUMPTION ON MORTALITY IN HYPERTENSIVE INDIVIDUALS

The effect of caffeine consumption on mortality was evaluated in a historical cohort study of 10064 hypertensive individuals participating in the Hypertension Detection and Follow-Up Program (HDFP) from 1973 to 1979. The study cohort was stratified into caffeine consumption groups (none, low, medium and high) based on their total level of caffeine intake from beverages (coffee and tea) and certain medications at the One-year follow-up home visit. Stratification was also made by sex, race, type of care and age. The total relative risks (RRs) when computed across strata for each caffeine consumer group (low, medium and high) were not significantly different when compared to the noncaffeine consumer group for all-cause or cause-specific mortality rates. The point estimates and 95 per cent confidence intervals for relative risks of all-cause mortality when compared to nonconsumers were as follows: Low = 0.82 (0.65-1.03), Medium: = 0.82 (0.62-1.82) and High = 0.90 (0.63-1.28). For all sex, race combinations there was an increase in the per cent of current smokers within each caffeine consumer group as the level of caffeine consumption increased. Cigarette smoking was an important confounder correlated with caffeine consumption and associated with mortality in this cohort. When confounding by cigarette smoking was adjusted for in the analysis, no association was found between the level of caffeine consumption and all-cause or cause-specific mortality. ^

Natural and experimental oral infection of nonhuman primates by bovine spongiform encephalopathy agents

Experimental lemurs either were infected orally with the agent of bovine spongiform encephalopathy (BSE) or were maintained as uninfected control animals. Immunohistochemical examination for proteinase-resistant protein (prion protein or PrP) was performed on tissues from two infected but still asymptomatic lemurs, killed 5 months after infection, and from three uninfected control lemurs. Control tissues showed no staining, whereas PrP was detected in the infected animals in tonsil, gastrointestinal tract and associated lymphatic tissues, and spleen. In addition, PrP was detected in ventral and dorsal roots of the cervical spinal cord, and within the spinal cord PrP could be traced in nerve tracts as far as the cerebral cortex. Similar patterns of PrP immunoreactivity were seen in two symptomatic and 18 apparently healthy lemurs in three different French primate centers, all of which had been fed diets supplemented with a beef protein product manufactured by a British company that has since ceased to include beef in its veterinary nutritional products. This study of BSE-infected lemurs early in their incubation period extends previous pathogenesis studies of the distribution of infectivity and PrP in natural and experimental scrapie. The similarity of neuropathology and PrP immunostaining patterns in experimentally infected animals to those observed in both symptomatic and asymptomatic animals in primate centers suggests that BSE contamination of zoo animals may have been more widespread than is generally appreciated.

Xanthine oxidase activity associated with arterial blood pressure in spontaneously hypertensive rats

Recent evidence in vivo indicates that spontaneously hypertensive rats (SHR) exhibit an increase in oxyradical production in and around microvascular endothelium. This study is aimed to examine whether xanthine oxidase plays a role in overproduction of oxidants and thereby may contribute to hypertensive states as a consequence of the increasing microvascular tone. The xanthine oxidase activity in SHR was inhibited by dietary supplement of tungsten (0.7 g/kg) that depletes molybdenum as a cofactor for the enzyme activity as well as by administration of (−)BOF4272 [(−)-8-(3-methoxy-4-phenylsulfinylphenyl)pyrazolo(1,5-α)-1,3,5-triazine-4-monohydrate], a synthetic inhibitor of the enzyme. The characteristic elevation of mean arterial pressure in SHR was normalized by the tungsten diet, whereas Wistar Koto (WKY) rats displayed no significant alteration in the pressure. Multifunctional intravital videomicroscopy in mesentery microvessels with hydroethidine, an oxidant-sensitive fluoroprobe, showed that SHR endothelium exhibited overproduction of oxyradicals that coincided with the elevated arteriolar tone as compared with WKY rats. The tungsten diet significantly repressed these changes toward the levels observed in WKY rats. The activity of oxyradical-producing form of xanthine oxidase in the mesenteric tissue of SHR was ≈3-fold greater than that of WKY rats, and pretreatment with the tungsten diet eliminated detectable levels of the enzyme activity. The inhibitory effects of the tungsten diet on the increasing blood pressure and arteriolar tone in SHR were also reproducible by administration of (−)BOF4272. These results suggest that xanthine oxidase accounts for a putative source of oxyradical generation that is associated with an increasing arteriolar tone in this form of hypertension.

Compelling transgenetic evidence for transmission of bovine spongiform encephalopathy prions to humans

There is growing concern that bovine spongiform encephalopathy (BSE) may have passed from cattle to humans. We report here that transgenic (Tg) mice expressing bovine (Bo) prion protein (PrP) serially propagate BSE prions and that there is no species barrier for transmission from cattle to Tg(BoPrP) mice. These same mice were also highly susceptible to a new variant of Creutzfeldt–Jakob disease (nvCJD) and natural sheep scrapie. The incubation times (≈250 days), neuropathology, and disease-causing PrP isoforms in Tg(BoPrP)Prnp0/0 mice inoculated with nvCJD and BSE brain extracts were indistinguishable and differed dramatically from those seen in these mice injected with natural scrapie prions. Our findings provide the most compelling evidence to date that prions from cattle with BSE have infected humans and caused fatal neurodegeneration.