The characteristics of patients with possible familial hypercholesterolemia-screening a large payer/provider healthcare delivery system.

BACKGROUND: Familial hypercholesterolemia (FH) is an under-diagnosed condition. AIM: We applied standard laboratory criteria across a large longitudinal electronic medical record database to describe cross-sectional population with possible FH. METHODS: A cross-sectional study of Clalit Health Services members. Subjects who met the General Population MED-PED laboratory criteria, excluding: age <10 years, documentation of thyroid, liver, biliary or autoimmune diseases, a history of chronic kidney disease stage 3 or greater, the presence of urine protein >300 mg/l, HDL-C>80 mg/dl, active malignancy or pregnancy at the time of testing were considered possible FH. Demographic and clinical characteristics are described at time of diagnosis and at a single index date following diagnosis to estimate the burden on the healthcare system. The patient population is also compared to the general population. RESULTS: The study cohort included 12 494 subjects with out of over 4.5 million members of Clalit Health Services. The estimated prevalence of FH in Israel was found to be 1:285. These patients are notably positive for, and have a family history of, cardiovascular disease and risk factors. For most of them the LDL-C levels are not controlled, and only a quarter of them are medically treated. CONCLUSIONS: By using the modified MED-PED criteria in a large electronic database, patients with possible FH can be identified enabling early intervention and treatment.

Glycaemic control and cardiovascular disease: is there a light at the end of the tunnel?

Patients with type 2 diabetes mellitus (T2DM) have been shown by numerous studies to have a substantially increased risk of cardiovascular disease (CVD), including coronary artery disease, ischemic stroke and heart failure, even after adjusting for other known risk factors.1,2 First reported in the Framingham studies and followed by additional data including a meta-analysis of 102 prospective studies, diabetes confers about a two-fold excess risk for coronary heart disease and ischemic stroke in both men and women, and about a 2-fold and 5-fold excess risk of heart failure in diabetic men and women.1-3 However, there is still a debate as to whether improved glycaemic control reduces the excessive CVD risk of T2DM patients. Large randomised controlled trials (RCTs), aimed at determining the effect of anti-hyperglycaemic agents on CVD, provide a handful of important data, albeit not consistent answers. Nevertheless, looking further into these RCTs provides new perspective on the complex interplay between diabetes treatment and CVD.

Hepatitis C core protein impairs insulin downstream signalling and regulatory role of IGFBP-1 expression.

Chronic infection with hepatitis C virus (HCV), mainly genotype 1, has been shown to be associated with insulin resistance and type 2 diabetes. The mechanisms underlying this association are partly understood. Increased levels of tumor necrosis factor (TNF)-α occurring in HCV infection have an important role in HCV-mediated insulin resistance; however, other direct effects of HCV core protein on disrupting insulin signalling have been suggested. The insulin receptor substrate (IRS) proteins are key players in insulin signal transduction and are the major substrates of the insulin receptor. To further elucidate the direct effect of HCV core protein on insulin signalling. We studied the direct effects of HCV core protein in two cell lines transfected with HCV core protein. We found several impairments in the insulin signalling cascade which could be attributed to a significant proteasomal degradation of IRS-1 protein, in a dose-dependent way. In addition, our data show that liver cells transfected by HCV core protein show a marked attenuation of the regulatory inhibitory role of insulin on insulin growth factor binding protein-1 (IGFBP-1) expression. Since IGFBP-1 may have a role in glucose regulation and hepatic insulin sensitivity, this effect of HCV core protein can contribute to insulin resistance in chronic HCV infection. Our data suggest that the degradation of IRS-1 by HCV core protein translates to impaired ability of insulin to inhibit the expression of the target gene IGFBP-1 in the liver and may serve as a novel mechanism for insulin resistance and hyperglycaemia.

Diabetes, but not the metabolic syndrome, predicts the severity and extent of coronary artery disease in women.

BACKGROUND: Previous studies have suggested that diabetes and metabolic syndrome are significant risk factors for coronary artery disease (CAD). However, in women, their relative importance remains controversial. AIM: To evaluate risk factors for CAD in women and their association with the severity and extent of coronary angiographic findings. METHODS: We clinically evaluated 243 consecutive female patients with chest pain who underwent coronary angiography. The location and extent of coronary artery occlusions were assessed using the modified Gensini index. RESULTS: Compared with women with normal coronary arteries (n = 90), those with CAD (n = 153) reported less physical activity (p = 0.001), and had higher prevalences of diabetes (p = 0.046), hypertension (p = 0.002), and the metabolic syndrome (p = 0.001). They also had lower HDL cholesterol levels (p = 0.017), higher levels of triglycerides (p = 0.005), and higher fasting plasma glucose (FPG) (p < 0.001). Physical activity, FPG, serum triglycerides and HDL-cholesterol, but not the metabolic syndrome, were independent predictors of CAD. A score combining the extent and severity of angiographic findings was significantly higher in women with diabetes (p = 0.007), hypertension (p = 0.010) and FPG >or=100 mg/dl (p = 0.031), but showed no association with the metabolic syndrome. In a multivariate linear regression analysis, diabetes was an independent predictor of the extent and severity of angiographic score (p = 0.013). DISCUSSION: Diabetes, fasting plasma glucose and hypertension, but not the metabolic syndrome, were associated with severity of coronary angiographic findings in these women.

Hypophosphataemia in old patients is associated with the refeeding syndrome and reduced survival.

OBJECTIVES: Previous studies found that hypophosphataemia (HP) a common finding in hospitalised patients associated with unfavourable outcome, but they did not focus on old patients. The aim of the current study was to determine the prevalence, associated risk factors and potential clinical consequences of HP detected during hospitalisation in a geriatric medical centre. DESIGN: Case-control study. SETTING: A total of 312-bed geriatric division. SUBJECTS: We compared 325 patients aged >or=65 years with at least one episode of HP-group defined by serum phosphate

TNF-{alpha}, chronic hepatitis C and diabetes: a novel triad.

Patients with chronic hepatitis C virus (HCV) infection have a significantly increased prevalence of type 2 DM compared to controls or HBV-infected patients, independent of the presence of cirrhosis. Moreover, antecedent HCV infection markedly increases the risk of developing DM in susceptible subjects. Even non-diabetic HCV patients have insulin resistance and specific defects in the insulin-signalling pathway. Activation of the tumour necrosis factor (TNF)-alpha system has a pivotal role in the inflammatory process of chronic hepatitis C, and TNF-alpha levels correlate with the degree of inflammation. TNF-alpha is known to cause insulin resistance, with similar defects in the insulin signalling pathway to those described in HCV infection. A model of mice transgenic for the HCV core protein demonstrated insulin resistance, glucose intolerance, and elevated intrahepatic TNF-alpha mRNA; all of which were ameliorated by anti-TNF-alpha antibodies. In addition, diabetic HCV patients have significantly higher levels of soluble TNF-alpha receptors, compared to non-diabetic HCV patients and controls. TNF-alpha may be the link between HCV infection and diabetes, suggesting an additional mechanism of diabetes with important implications for prognosis and therapy.

Cognitive performance of male adolescents is lower than controls across psychiatric disorders: a population-based study.

OBJECTIVE: Psychiatric patients, as well as humans or experimental animals with brain lesions, often concurrently manifest behavioral deviations and subtle cognitive impairments. This study tested the hypothesis that as a group, adolescents suffering from psychiatric disorders score worse on cognitive tests compared with controls. METHOD: As part of the assessment for eligibility to serve in the military, the entire, unselected population of 16-17-year old male Israelis undergo cognitive testing and screening for psychopathology by the Draft Board. We retrieved the cognitive test scores of 19 075 adolescents who were assigned any psychiatric diagnosis, and compared them with the scores of 243 507 adolescents without psychiatric diagnoses. RESULTS: Mean test scores of cases were significantly poorer then controls for all diagnostic groups, except for eating disorders. Effect sizes ranged from 0.3 to 1.6. CONCLUSION: As group, adolescent males with psychiatric disorders manifest at least subtle impairments in cognitive functioning.

Suicidality and second generation antipsychotics in schizophrenia patients: a case-controlled retrospective study during a 5-year period.

RATIONALE: Rates of attempted suicide for individuals with schizophrenia are approaching 30%. Attempted suicide is among the most potent predictors of subsequent suicide. Several studies suggest that suicide is more likely to occur in patients who are not being adequately treated or not being treated at all. An effort was made in the last decade to evaluate the antisuicide effects of pharmacological treatment in schizophrenia with emphasis on the role of the newer second-generation antipsychotics (SGA). OBJECTIVE: The aim of the present study was to assess in a large cohort of schizophrenia patients the effects of exposure to SGA on suicidality of patients suffering from schizophrenia or schizoaffective disorder. The study is a retrospective case-controlled evaluation over a 5-year period undertaken in a large university affiliated tertiary care psychiatric hospital. METHODS: Between January 1998 and December 2002, all records of admissions of schizophrenia or schizoaffective disorder patients (ICD-10) were assessed. Data as to age, gender, diagnosis, suicide attempt prior to admission, treatment with antipsychotic medication, dose and duration of treatment (mg daily, duration) with SGA was extracted from patients' files. All patients who had attempted suicide prior to admission were defined as the index group. The case-controlled group was comprised of the next admission of a patient suffering from schizophrenia (or schizoaffective disorder), matched for gender and age, who did not attempt suicide. RESULTS: Records of 756 patients (4486 admissions for said period) were analyzed (56.6% male, mean age 39.1+/-13.5 years). Amongst 378 patients who attempted suicide (index group), 16.1% were exposed to SGA while 37% were exposed in the control group (P=0.0001). The protective effect (odds ratio) of treatment by SGA was 3.54 (95%CI: 2.4-5.3). Risperidone was more frequently prescribed in the control group (54.3%) and had a larger effect-size than olanzapine (3.16 versus 1.76), although not statistically significant. Clozapine was prescribed only to a few patients. CONCLUSIONS: Schizophrenia patients exposed to both risperidone and olanzapine may gain protection from suicidality. The antisuicide effects seem to differ between SGAs. The long duration and large sample size support this finding, despite the retrospective nature of this study.

Generalized cognitive impairment in male adolescents with schizotypal personality disorder.

Schizotypal Personality Disorder (SPD) shares common genetic and biological substrates with schizophrenia, and patients with SPD have been reported to suffer both from specific cognitive impairments, and from a generalized cognitive dysfunction, similar to those found in schizophrenia. The aim of this cross-sectional, population-based study was to assess general cognitive functioning in adolescents with SPD. The Israeli Draft Board systematically assesses cognitive functioning and administers psychiatric screening in all 16-17-year-old males in the population. Of 341,511 males assessed, the cognitive test scores of adolescents with SPD (N = 326) were retrieved, and compared to the scores of adolescents diagnosed as suffering from schizophrenia (N = 901), and adolescents with no neurological or psychiatric diagnosis (controls, N = 293,820). Male adolescents with SPD or with schizophrenia scored lower on all measures compared to healthy individuals (effect sizes ranging from 0.6-0.88, all P < 0.001). The SPD patients scored significantly higher than the schizophrenia patients on the sub-tests of similarities and Ravens Progressive Matrices, tests that reflect abstract reasoning. On the sub-tests of arithmetic and instruction comprehension, tests that rely on concentration, SPD and schizophrenia patients' scores did not differ significantly from each other. These results might be interpreted to imply that a generalized cognitive impairment, in the presence of schizotypal personality traits and in the absence of psychosis, might be conceptualized as being the core of the schizotaxia syndrome. The greater impairment in abstract reasoning in the schizophrenia patients might be correlated with the psychotic symptoms that differentiate schizophrenia from SPD.

Time zone change and major psychiatric morbidity: the results of a 6-year study in Jerusalem.

Psychiatric morbidity among foreign tourists is usually connected to external factors such as unfamiliar surroundings, language problems, and special religious experiences, as well as biological factors such as dyschronism of circadian rhythms. Long-range flights through several time zones are typically followed by symptoms of jet lag such as fatigue, severe sleep schedule disturbance, impairment of cognitive functions, and even mild depression. Jet lag is generally attributed to a conflict between external time cues and internal biological rhythms. This study examined the possible association between jet lag and psychiatric morbidity among long-distance travelers hospitalized in the Jerusalem Mental Health Center, Kfar Shaul Hospital between 1993 and 1998. This was a prospective open-label study. Patients (n = 152) were divided into two groups based on the number of time zones crossed in the flight to Israel: group I, seven time zones or more (n = 81); and group II, three time zones or less (n = 71). The direction of flight was mainly eastbound. After controlling the two groups for demographic and religious background, past psychiatric history, and diagnosis on admission (P > 0.1, Fisher's exact test), the possible association between jet lag and psychotic or major affective disorder was evaluated according to the following criteria: (1) absence of major mental problems before the flight or good remission of an existing disorder 1 year or more before flight; and (2) the appearance of psychotic or major affective syndromes during the first 7 days after landing. The number of first psychotic/major affective episodes in both groups presumed as associated with jet lag was found similar (P =.5), whereas the number of relapses conjoint with jet lag in the seven or more time zone group was significantly higher (P =.04). The results suggest that the dyschronism of circadian rhythms and jet lag possibly play a role in the exacerbation of major psychiatric disorders.

Cholesterol lowering in the older population: time for reassessment?

Hypercholesterolaemia is an established major risk factor for coronary heart disease (CHD) in the general population. In the vast majority of studies that focused on this particular age group and carefully eliminated other confounding factors such as co-morbid conditions, hypercholesterolaemia was a risk factor for CHD in the older population. Because the prevalence of CHD increases with advancing age, studies that consider not only the relative risk attributed to cholesterol but also the absolute numbers of people affected, show hypercholesterolaemia to be an even stronger risk factor in the elderly. Large primary and secondary prevention studies of HMG-CoA reductase inhibitors (statins) in the elderly have shown a reduction in major coronary events similar to that observed in the younger age group. The role of hypercholesterolaemia as a risk factor for stroke is less clear, and a major limitation is the heterogeneous nature of the disease. Nevertheless, most studies that evaluated non-haemorrhagic strokes separately showed a positive association with cholesterol levels, and statin therapy is effective in preventing stroke. These data provide a rationale for treating older hypercholesterolaemic people with statins, not only to prevent CHD, but also to prevent stroke.

The role of hyperglycemia in acute stroke.

BACKGROUND: Ischemic stroke is a leading cause of death and long-term disability, and hyperglycemia is believed to aggravate cerebral ischemia. OBJECTIVES: To review animal and human studies on the relationship between hyperglycemia and brain ischemia that elucidate some of the mechanisms for the deleterious effect of hyperglycemia. To discuss present and future clinical recommendations for glucose control. METHODS: Computerized data sources and published indexes and articles from 1976 through 2000 were searched for human studies that evaluated the association between stroke and hyperglycemia, and studies focused on experimental models of hyperglycemic animals with focal and global brain ischemia. RESULTS: Most human studies have shown that in acute stroke, admission hyperglycemia in patients with or without diabetes is associated with a worse clinical outcome than in patients without hyperglycemia. This association is more consistent in the nonlacunar type of stroke. Animal studies support these findings by showing both in global and in focal postischemic models that hyperglycemia exaggerates the following damaging processes: intracellular acidosis, accumulation of extracellular glutamate, brain edema formation, blood-brain barrier disruption, and tendency for hemorrhagic transformation. Insulin treatment of hyperglycemic animals was found to have a beneficial effect in focal and global brain ischemia, which may be mediated by the glucose-reduction effect or by a direct neuroprotection. CONCLUSIONS: Most studies show the deleterious effect of early hyperglycemia, especially in patients with nonlacunar focal or global ischemia. Clinical trials of intensive insulin treatment are needed. Meanwhile simple measures to avoid excessive hyperglycemia are recommended.

The fitness of the mental patient to be a witness.

The determination of whether a patient has criminal responsibility or is able to stand trial is routine psychiatric work. Cases in which we- psychiatrists- are asked to express our opinion on whether a patient can testify, however, are quite rare. We shall attempt to clarify some of the issues relating to the testimony of mentally ill patients through a case presentation. In this case, the Court agreed to consider our patient's testimony, only after receiving our expert opinion. We find that the Court's reversal of its original decision and its willingness to consider the testimony of a mental patient in the same trial in which he was initially found unable to stand trial, marks an important precedent. The question of the credibility of the mental patient as a witness has significance beyond this case concerning mental patients' rights in regard to the judicial system. We believe there is a need for further discussion between psychiatrists andjurists regarding the fitness of the mental patient to testify as a witness.

Psychiatric aspects of jet lag: review and hypothesis.

Jet lag is a travel-induced circadian rhythm phenomenon that afflicts healthy individuals following long- distance flights through several time zones. The typical jet-lag manifestations - insomnia during local sleep time, day fatigue, reduced concentration, irritability, and exhaustion with mild depression - are attributed to transient desynchronization in the circadian rhythm until the internal biological clock is rephased to the new environmental conditions. There is strong evidence relating affective disorders with circadian rhythm abnormalities. Less convincing suggestions relate jet lag to psychosis. It can be hypothesized that in predisposed individuals jet lag may play a role in triggering exacerbation or even de novo affective disorders. Furthermore, we propose the possibility that psychosis and even schizophrenia can be elicited by jet lag. This outlook gains its support from case studies and some common underlying phase-advanced biological denominators involved in both jet lag sufferers and psychotic patients.

[Drug abuse among patients requiring psychiatric hospitalization].

We assessed the incidence of drug abuse among patients requiring psychiatric hospitalization, and characterized the population at risk. The data on drug abuse were obtained from self-reports and urine tests in 103 patients, aged 18-65, hospitalized in the Kfar Shaul Psychiatric Hospital (autumn 1998). There was close correspondence between the self-reports and the results obtained from urine tests. 1/3 admitted to having used illegal drugs and signs of drug abuse were found in about 1/4 of the urine tests. The most prevalent drugs were cannabis products (hashish and/or marijuana) and in 15 patients opiates. Drug users were younger than non-users. With regard to psychiatric symptomatology, fewer negative symptoms were recorded among cannabis abusers with schizophrenia, compared to schizophrenic patients with no history, past or present, of cannabis abuse. The present findings confirm the clinical impression that there has been an increase in drug abuse among mental patients, parallel to that found in society at large. Confirmatory surveys are necessary. Our findings clearly suggest that a change in attitude has occurred in Israel to what has been considered a marginal problem. Hospitalized mentally-ill patients, the younger in particular, should be considered at risk for drug abuse.