Predisposition to cortical neurodegenerative changes in brains of hypertension prone rats.

BACKGROUND: Substantial evidence suggests that hypertension is a significant risk factor for cognitive decline. However, it is unclear whether the genetic predisposition to hypertension is also associated with cellular dysfunction that promotes neurodegeneration. METHODS: Changes in blood pressure were evaluated following dietary salt-loading or administration of a regular diet in Sabra Normotensive (SBN/y) and Sabra Hypertension-prone rats (SBH/y). We performed quantitative RT-PCR and immunofluorescence staining in brain cortical tissues before salt loading and 6 and 9 months after salt loading. To examine the expression of brain cortical proteins involved in the gene regulation (Histone Deacetylase-HDAC2; Histone Acetyltransferase 1-HAT1), stress response (Activating Transcription Factor 4-ATF4; Eukaryotic Initiation Factor 2- eIF2α), autophagy (Autophagy related 4A cysteine peptidase- Atg4a; light-chain 3-LC3A/B; mammalian target of rapamycin complex 1- mTORC1) and apoptosis (caspase-3). RESULTS: Prior to salt loading, SBH/y compared to SBN/y expressed a significantly higher level of cortical HAT1 (protein), Caspase-3 (mRNA/protein), LC3A, and ATF4 (mRNA), lower levels of ATG4A (mRNA/protein), LC3A/B, HDAC2 (protein), as well as a lower density of cortical neurons. Following dietary salt loading, SBH/y but not SBN/y developed high blood pressure. In hypertensive SBH/y, there was significant upregulation of cortical HAT1 (protein), Caspase-3 (protein), and eIF2α ~ P (protein) and downregulation of HDAC2 (protein) and mTORC1 (mRNA), and cortical neuronal loss. CONCLUSIONS: The present findings suggest that genetic predisposition to hypertension is associated in the brain cortex with disruption in autophagy, gene regulation, an abnormal response to cellular stress, and a high level of cortical apoptosis, and could therefore exacerbate cellular dysfunction and thereby promote neurodegeneration.

Healthcare Provider's Culture and Its Impact on End-Of-Life Discussions.

To examine the openness to communication in end-of-life care of three major ethno-cultural groups of healthcare providers (HCPs) (in Israel: Israeli Arabs (Arabs), Israeli Jews (Sabras), and Immigrants from the Soviet Union (Russians). An anonymized set of three questionnaires was distributed among 240 physicians and nurses (HCPs) from the three ethno-cultural groups, yielding a response rate of 91% (and 82% when including hospital division). Sabra ethno-cultural group was more open to communicating about and relating to end-of-life with terminally ill patients. While recent exposure to death and external locus of control decreased the effect of ethno-cultural background, the latter remained statistically significant. Gender, age, marital status, and specialty were not found to be influential factors.This research highlights the importance of increasing awareness and responses to the effects of HCPs' culture on end-of-life care as varied cultures and medico-legal requirements come into contact in society.

[DYNAMIC CHANGES OF D-DIMER FOLLOWING STROKE].

AIMS: To find the correlation between plasma D-dimer levels after stroke with different etiologies, severity of the stroke and to uncover whether plasma D-dimer levels may be used as a prognostic factor of stroke complication. BACKGROUND: D-dimer is a product of fibrin degradation and it is elevated in systemic vascular events. The association between plasma D-dimer levels and stroke remain uncertain. METHODS: A total of 96 acute stroke patients were enrolled in this study. Plasma levels of D-dimer were measured on admission, 24 hours, a week and 3 months after stroke onset. The clinical evaluation, type of event and severity of stroke were measured by using the NIHS Scale and brain CT on admission. RESULTS: Average levels of D-dimer were higher after stroke, returning to normal range after 3 months. D-dimer levels were highest at intracerebral hemorrhage (ICH) and lowest at normal brain CT on admission (P=0.021 on admission, P=0.002 after 24 hours, P=0.018 after a week). The percent of patients with high plasma D-dimer levels on admission was higher at ICH compared to brain infarction and to TIA. There is a correlation (p=0.039) between the severity of the stroke and the percent of patients with high plasma D-dimer levels and a correlation (P=0.017) between mortality and the percent of patients with high plasma D-dimer levels at admission. CONCLUSIONS: An association between plasma D-dimer levels and stroke etiology, size of the damaged area and severity of acute stroke was found. High levels of plasma D-dimer following acute stroke is associated with early complications and high mortality.

Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy.

Leukoencephalopathies are a group of white matter disorders related to abnormal formation, maintenance, and turnover of myelin in the central nervous system. These disorders of the brain are categorized according to neuroradiological and pathophysiological criteria. Herein, we have identified a unique form of leukoencephalopathy in seven patients presenting at ages 2 to 4 months with progressive microcephaly, spastic quadriparesis, and global developmental delay. Clinical, metabolic, and imaging characterization of seven patients followed by homozygosity mapping and linkage analysis were performed. Next generation sequencing, bioinformatics, and segregation analyses followed, to determine a loss of function sequence variation in the phospholipase A2-activating protein encoding gene (PLAA). Expression and functional studies of the encoded protein were performed and included measurement of prostaglandin E2 and cytosolic phospholipase A2 activity in membrane fractions of fibroblasts derived from patients and healthy controls. Plaa-null mice were generated and prostaglandin E2 levels were measured in different tissues. The novel phenotype of our patients segregated with a homozygous loss-of-function sequence variant, causing the substitution of leucine at position 752 to phenylalanine, in PLAA, which causes disruption of the protein's ability to induce prostaglandin E2 and cytosolic phospholipase A2 synthesis in patients' fibroblasts. Plaa-null mice were perinatal lethal with reduced brain levels of prostaglandin E2 The non-functional phospholipase A2-activating protein and the associated neurological phenotype, reported herein for the first time, join other complex phospholipid defects that cause leukoencephalopathies in humans, emphasizing the importance of this axis in white matter development and maintenance.

Cognitive Function of Patients with Crohn's Disease is Associated with Intestinal Disease Activity.

BACKGROUND: Systemic inflammation and nutritional deficiencies are characteristics of Crohn's disease (CD) and have been suggested to influence cognitive performance. This study assessed cognitive function in patients with CD. METHODS: Participants were adult patients with CD arriving at routine follow-up. Subjective cognitive complaints, depression, anxiety, fatigue, and sleep were evaluated by validated questionnaires. CD characteristics, blood tests, and Crohn's disease activity index were obtained. Nutritional risk index was derived from serum albumin and change in body weight. Montreal cognitive assessment was used for screening. Patients with either subjective cognitive complaints or Montreal cognitive assessment score ≤ 26 were tested by a computerized cognitive testing battery, with analysis of scores in 7 cognitive domains (CogDs) and an average of the CogD scores-global cognitive score (GCS). Impaired CogD was defined as scoring more than 1 SD below age and education adjusted average. RESULTS: A total of 105 patients were recruited and 61 were tested with computerized cognitive testing battery. Mean age was 39 ± 13 and mean education years were 14 ± 2. The most commonly impaired CogDs were information processing speed (33%) and verbal function (28%). Crohn's disease activity index, nutritional risk index, and hemoglobin were significantly correlated with GCS (r = -0.34, 0.39, 0.33; P = 0.007, 0.003, 0.01). Linear regression revealed significant correlations between Crohn's disease activity index, nutritional risk index, and GCS (ß = -0.3, 0.29; P = 0.03, 0.04), independent of depression. This model explained 24% of the variance in GCS. CONCLUSIONS: Cognitive performance is related to CD activity and nutritional status. The results provide insight into potential influence of nutrition and inflammation on cognitive function. Further studies on cognitive function of patients with CD are warranted.

A novel XPD mutation in a compound heterozygote; the mutation in the second allele is present in three homozygous patients with mild sun sensitivity.

The XPD protein plays a pivotal role in basal transcription and in nucleotide excision repair (NER) as one of the ten known components of the transcription factor TFIIH. Mutations in XPD can result in the DNA repair-deficient diseases xeroderma pigmentosum (XP), trichothiodystrophy (TTD), cerebro-oculo-facial-skeletal syndrome, and in combined phenotypes such as XP/Cockayne syndrome and XP/TTD. We describe here an 18-year-old individual with mild sun sensitivity, no neurological abnormalities and no tumors, who carries a p.R683Q mutation in one allele, and the novel p.R616Q mutation in the other allele of the XPD gene. We also describe four patients from one family, homozygous for the identical p.R683Q mutation in XPD, who exhibit mild skin pigmentation and loss of tendon reflexes. Three homozygous patients presented with late-onset skin tumors, and two with features of premature aging and moderate cognitive decline. Cells from the compound heterozygous individual and from one of the patients homozygous for p.R683Q exhibited similar responses to UV irradiation: reduced viability and defective overall removal of UV-induced cyclobutane pyrimidine dimers, implying deficient global genomic NER. Cells from the compound heterozygous subject also failed to recover RNA synthesis after UV, indicating defective transcription-coupled NER. Mutations affecting codon 616 in XPD generally result in functionally null proteins; we hypothesize that the phenotype of the heterozygous patient results solely from expression of the p.R683Q allele. This study illustrates the importance of detailed follow up with sun sensitive individuals, to ensure appropriate prophylaxis and to understand the mechanistic basis of the implicated hereditary disease.

A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis.

BACKGROUND: Members of two seemingly unrelated kindreds of Arab Moslem origin presented with pronounced early onset spastic paraparesis of upper and lower limbs, mild intellectual disability, kyphosis, pectus carinatum and hypertrichosis. METHODS: The authors performed neurological and developmental examinations on the affected individuals. The authors conducted whole genome linkage and haplotype analyses, followed by sequencing of candidate genes; RNA and protein expression studies; and finally proof of principle investigations on knockdown morpholino oligonucleotide injected zebrafish. RESULTS: The authors characterise a novel form of autosomal recessive complex hereditary spastic paraparesis (CHSP). MRI studies of brain and spinal cord were normal. Within a single significantly linked locus the authors ultimately identified a homozygous missense mutation c.1146A>T (p.K382N) in the vacuolar protein sorting 37A (Vps37A) gene, fully penetrant and segregating with the disease in both families. Mobility was significantly reduced in Vps37A knockdown morpholino oligonucleotide injected zebrafish, supporting the causal relationship between mutations in this gene and the phenotype described in the patients of this study. CONCLUSIONS: The authors provide evidence for the involvement of Vps37A, a member of the endosomal sorting complex required for transport (ESCRT) system, in upper motor neuron disease. The ESCRT system has been shown to play a central role in intracellular trafficking, in the maturation of multivesicular bodies and the sorting of ubiquitinated membrane proteins into internal luminal vesicles. Further investigation of mechanisms by which dysfunction of this gene causes CHSP will contribute to the understanding of intracellular trafficking of vesicles by the ESCRT machinery and its relevance to CHSP.

Chronic diarrhea and juvenile cataracts: think cerebrotendinous xanthomatosis and treat.

Cerebrotendinous xanthomatosis is an autosomal recessive disease of bile acid synthesis caused by 27-hydroxylase deficiency. Treatment with chenodeoxycholic acid normalizes cholestanol concentrations and abrogates progression of the disease. We present 4 patients with cerebrotendinous xanthomatosis within 1 family who were treated with chenodeoxycholic acid for 14 years. Two young sisters started treatment at the preclinical stage before the appearance of major symptoms. Their 2 older uncles, who had already developed the complete phenotypic form of cerebrotendinous xanthomatosis when diagnosed, commenced treatment at the same time as the sisters, thus establishing a natural control group. After 14 years of chenodeoxycholic acid therapy, the cholestanol levels of all 4 patients decreased to normal levels (<6 microg/mL). Both sisters remained asymptomatic. Only moderate improvement in symptoms was observed in their uncles. In this long-term study, prompt preclinical administration of chenodeoxycholic acid in early childhood completely prevented the cerebrotendinous xanthomatosis phenotype in 2 sisters. Pediatricians should be aware of this diagnostic possibility of cerebrotendinous xanthomatosis in children presenting with chronic diarrhea and juvenile cataracts. Prevention is particularly significant in light of the availability of early genetic diagnosis and the devastating effects of this illness if not treated.

[Guideliness for the management of stroke--2008 invasive measures for prevention of ischemic stroke].

Stroke is a major cause of morbidity and mortality in Israel and the main cause for neurological disability among adults. Continued efforts for its prevention and treatment began a long time ago and currently persist. During the last decade, these efforts have resulted in a number of significant breakthroughs. Consequently, several new guidelines and consensus statements from Europe and North America have been published. In Israel, up to date, guidelines have been published only for acute stroke treatment, as well as for its prevention by medical means. The present guideline is supplemental to the previous papers and focuses on the invasive options to treat specific risk factors and conditions, when appropriate, for primary and secondary stroke prevention.

[Expression of inflammatory mediators in meningitis].

BACKGROUND: Infectious diseases cause a systemic inflammatory reaction. In some cases of meningitis it is difficult to determine whether the disease is of bacterial, viral or non-infectious origin. In order to distinguish between bacterial and viral diseases the levels of various inflammatory markers are used to determine the severity of the disease and the clinical prognosis. OBJECTIVE: The purpose of this study was to determine whether the levels of different markers can be used to distinguish between bacterial or viral meningitis or non-infectious neurological disease. METHODS: Patients with bacterial meningitis (n= 8), viral meningitis (n= 17), non-infectious neurological diseases (n = 17) and healthy subjects (n = 15) were studied. The levels of soluble CD14 (sCD 14), interleukin-6 (IL-6), interleukin-1beta (IL-1beta) and soluble adhesion molecule-1 (sICAM-1) were determined in the blood of all participants and in spinal fluid only in patients who had clinical indication to perform lumbar puncture. RESULTS: All the patients showed significant differences in the levels of blood and CSF markers measured compared to healthy subjects. In the blood, although some differences were significant, there was overlapping between all values of the measured markers in patient blood samples excluding IL-6, for which levels were significantly different between the bacterial and viral meningitis. Interestingly, the levels of all markers showed significant differences among all groups of patients. CONCLUSIONS: Among the blood markers examined, IL-6 can be used to distinguish between bacterial and viral diseases. However, the levels of cytokines examined in CSF, can serve to distinguish between bacterial and viral meningitis and non-infectious diseases.

[Guidelines for the management of stroke--2007 prevention of ischemic stroke--general approach and medical treatment].

Stroke is a major cause of morbidity and mortality in Israel, the third most common cause of death and the main cause for neurological disability among adults. During the last decade several significant breakthroughs have occurred in the management of stroke and consequently several new guidelines and consensus statements from Europe and North America have been published. The new data necessitate a reappraisal of our approach to the management of stroke as well as to its primary prevention. The present guidelines focus on primary and secondary stroke prevention by medical means and provide detailed, updated, clinical guidelines for most specific risk factors and conditions, ways to investigate the underlying stroke mechanism and its preferred medical treatment. Invasive (surgical, stent insertion, correction of cardiac anomalies etc.) will be dealt with separately.

A new scale for assessing patients with vertebrobasilar stroke-the Israeli Vertebrobasilar Stroke Scale (IVBSS): inter-rater reliability and concurrent validity.

OBJECTIVES: Most of existing stroke scoring systems have limited ability to evaluate patients with cerebrovascular events in the vertebrobasilar territory. We devised a new scale, the Israeli Vertebrobasilar Stroke Scale (IVBSS) in order to directly and more accurately assess clinical deficits of patients with vertebrobasilar stroke. The present study measured the reliability and validity of the IVBSS. PATIENTS AND METHODS: Forty-three patients (mean age+/-S.D., 70.9+/-8.8 years, 27 males) with vertebrobasilar stroke were evaluated with the IVBSS (11 items), the NIH Stroke Scale (NIHSS) and the disability modified Rankin Scale (mRS) by independent examiners. Interobserver agreement was rated by weighted kappa statistics for each item and the total IVBSS score. Validity was examined with Spearman rank coefficients to compare the IVBSS with NIHSS and mRS. RESULTS: Excellent reliability was demonstrated between the examiners for almost each item and the total score of the IVBSS (kappa>0.75). The total IVBSS score was strongly associated with NIHSS and mRS results (r=0.80 and 0.76, respectively; P<0.0002). CONCLUSIONS: The IVBSS is a valid instrument that allows the assessment of patients with vertebrobasilar stroke with high reliability. Further observations are warranted to determine the predictive value of the IVBSS for stroke outcome.

[Guidelines for the management of acute stroke--2005].

Stroke is a major cause for morbidity and mortality in Israel, the third most common cause of death and the main cause for neurological disability among adults. Several significant breakthroughs occurred over recent years in the management of stroke, and acute stroke has increasingly been recognized as a medical emergency--a "brain attack" comparable to a "heart attack". Several new scientific publications, guidelines and consensus statements from Europe and North America necessitate a paradigm shift in the management of acute stroke. The guidelines focus on a number of issues: acute stroke as a medical emergency, dedicated stroke units, early reperfusion therapy for acute ischemic stroke, emergency management and general stroke treatment, use of diagnostic tests in the acute phase, and the prevention and treatment of complications.

Thromboembolic prophylaxis in nonrheumatic atrial fibrillation: utilization patterns, efficacy, and complications in a long-term follow-up of community patients.

OBJECTIVES: To define the incidence, contemporary utilization patterns, efficacy, and complications of thromboembolic prophylactic treatment in patients with chronic (CAF) and paroxysmal atrial fibrillation (PAF). BACKGROUND: Although recent randomized trials with antithrombotic therapy in nonrheumatic atrial fibrillation (AF) patients emphasized the benefits of warfarin in preventing stroke, warfarin treatment is still far from optimal. METHODS: A retrospective analysis of the medical records of 506 patients with nonrheumatic PAF or CAF from 23 clinics in the north of Israel, including an interview with the patients' family physician. RESULTS: (1) The most effective treatment for preventing thromboembolic events (a reduction of 75.9%) was warfarin at an international normalized ratio (INR) intensity of 2-3. (2) After diagnosis, 26.9% of the patients were treated with warfarin. (3) During the follow-up period (not following a thromboembolic event), an additional 26.9% of the patients began treatment with warfarin. (4) Elderly patients (p<0.001), patients with limited activity of daily living (ADL) (p<0.012) or instrumental activity of daily living (IADL) (p<0.001), and patients with PAF (p<0.0001) were less likely to be treated with warfarin. (5) Three new risk factors found for thromboembolic event were limited ADL (p<0.001), limited IADL (p<0.002), and extended duration of AF (p<0.006). CONCLUSIONS: Less than optimal utilization patterns of thromboembolic prophylactic treatment with anticoagulants were found, especially regarding elderly patients, patients with limited ADL and IADL, and patients with PAF, despite the fact that their thromboembolic risk is as high or higher than that of other patients with AF.

Treatment review and update for myasthenia gravis.

Myasthenia gravis (MG) is the best understood autoimmune disease, with well-characterized humoral and cellular effector mechanisms. It is not surprising, therefore, that immunotherapies play a key role in the management of MG. Significant progress has been made over the last few decades in the treatment of patients with MG, and the number of effective avenues of therapy continue to increase. In this review, we provide an update on management options in MG, highlighting recent literature on both traditional and more novel approaches.

Effect of erythropoietin therapy on polyneuropathy in predialytic patients.

BACKGROUND: Peripheral neuropathy commonly develops in patients with advanced chronic renal failure. The uremic neuropathy is often subclinical and detectable only by electrophysiological studies. Receptors to erythropoietin (EPO) have been described on non-hematopoietic cells including neuronal cells. METHODS: In order to evaluate the effect of five months' EPO therapy on polyneuropathy in predialytic patients, nerve conduction studies (NCS) were done in 46 anemic predialytic patients without neurological complaints. In 22 (twelve non-diabetic and ten diabetic) neuropathy was detected and these patients were included in the study. After five months of subcutaneous EPO therapy NCSs were repeated. RESULTS: Hemoglobin increased significantly (p=0.0001) with no significant increase in plasma creatinine. Motor nerve conduction velocity (MNCV) and compound muscle action potentials (CMAP) of the ulnar nerve were normal before EPO therapy and at the end of the study. MNCV of the median, peroneal and tibial nerves improved significantly (p<0.05). CMAP of the median nerve rose significantly, to the normal range (p=0.01). Sensory nerve conduction velocity (SNCV ) and sensory nerve action potentials (SNAP) were reduced in all sensory nerves and did not improve. The improvement in non-diabetic patients was better than in diabetic patients. No significant correlation was found between the increase in hemoglobin and the improvement in MNCV. CONCLUSIONS: Subcutaneous EPO therapy improved motor polyneuropathy in uremic patients, especially non-diabetic individuals. The improvement in MNCV may reflect remyelination. This non-hematopoietic effect may be related to some direct action through EPO receptors on peripheral neuronal cells.