Low ALT Levels Independently Associated with 22-Year All-Cause Mortality Among Coronary Heart Disease Patients.

BACKGROUND: Low alanine aminotransferase (ALT) blood levels are known to be associated with frailty and increased risk of long-term mortality in certain populations. However, the contribution of this marker to long-term outcome has not been assessed in patients with chronic coronary heart disease. OBJECTIVE: The aim of the current study was to assess the association between low ALT values and long-term, 22.8-year, all-cause mortality in this population. PARTICIPANTS: We examined the association of low ALT (<17 IU/l) with long-term all-cause mortality in the Bezafibrate Infarction Prevention (BIP) Registry population. KEY RESULTS: Appropriate laboratory and survival data were available for 6,575 patients, without known liver pathology, included in the BIP registry, with a median follow-up period of 22.8 years. The cumulative probability of all-cause mortality was significantly higher in the low ALT group compared with patients with higher ALT levels (65.6 % vs. 58.4 %; log-rank p < 0.001). Consistently, multivariate analysis, adjusted for multiple established predictors of mortality in this population, demonstrated that low ALT is independently associated with 11 % greater long-term (22.8 years) mortality risk [HR 1.11 (95 % confidence interval: 1.03-1.19; adjusted p < 0.01)]. CONCLUSIONS: Low ALT levels are associated with increased long-term mortality among middle-aged patients with stable coronary heart disease. This association remained statistically significant after adjustment for other well-established risk factors for mortality in this population.

Low ALT blood levels predict long-term all-cause mortality among adults. A historical prospective cohort study.

BACKGROUND: Increased blood levels of alanine amino transferase (ALT, also known as SGPT; serum glutamic pyruvic transaminase) serve as a marker of liver injury by various mechanisms. Less is known about the clinical implications associated with low-normal ALT levels. Previous studies showed low ALT levels to be associated with poor long-term outcomes among elderlies, serving as a biomarker for increased incidence of frailty and subsequent risk of mortality. However, it has not been determined yet whether low-normal ALT values might be predictive of frailty and mortality in younger, middle-aged adults. METHODS: We conducted a historical prospective cohort analysis. RESULTS: A total of 23,506 adults with ALT levels within the normal range, at the mean age of 48 ± 11 years, participating in an annual screening program for preventive medicine, were followed-up for a median period of 8.5 years during which 638 died. Low-normal ALT values (serum ALT activity <17IU/L) were found to be predictive for increased risk of all-cause mortality (HR=1.6; 95% CI 1.34-1.92; p<0.001). Statistically significant correlation was demonstrated even after applying a multifactorial model correction for age, gender, eGFR, low albumin, arterial hypertension, diabetes mellitus and ischemic heart disease. CONCLUSIONS: We suggest that low-normal ALT values may serve as an independent predictive marker for increased long-term mortality in middle-aged adults.

Homocysteine levels in adolescent schizophrenia patients.

Homocysteine is a sulfur containing amino acid that has been widely investigated for its putative role in cardiovascular and neuropsychiatric disorders. It has been suggested that homocysteine has implications especially in young, male schizophrenia patients. In this prospective case-control study, we compared plasma homocysteine levels in a group of adolescent schizophrenia inpatients (aged 14-21 years; n=23) to normal healthy controls (n=51). Mean plasma homocysteine levels were significantly higher in the patient group than in the control group (15.40+/-2.00 and 9.78+/-0.33 micromol/L, respectively, p<0.032). The difference was almost entirely attributable to the male schizophrenia subgroup (18.18+/-5.65 in male patients vs. 10.31+/-5.33 micromol/L in female patients). The group x sex interaction was statistically significant (p=0.0035). These data indicate that a subgroup of male adolescent schizophrenia patients has high homocysteine blood levels. The role of homocysteine in the pathophysiology of adolescent-onset schizophrenia merits further investigation.

[ADMA (asymmetric dimethylarginine)--the inhibitor of nitric oxide (NO) synthesis: a new marker for vascular pathology].

Ample evidence is accumulating to suggest that asymmetric dimethylarginine (ADMA), an endogenous competitive inhibitor of nitric oxide synthase, is significantly elevated during phases of endothelial dysfunction. ADMA inhibits NO synthesis, hence its arterial infusion induces local arterial constriction. ADMA is generated ubiquitously in numerous tissues, by proteolysis of methylated proteins, while its degeneration is carried out mainly by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). Administration of L-arginine can override partially NO synthesis by ADMA, yet it cannot eliminate the primary factors involved in the endothelial dysfunction. ADMA measurements might add valuable information about this new risk factor or at least a marker for adverse endothelial events.

CSF homocysteine is not elevated in schizophrenia.

Homocysteine is a neurotoxic amino acid originally found to be an independent risk factor for cardiovascular and cerebral vascular disease and more recently suggested to be a risk factor for Alzheimer's disease. Several authors have observed high plasma homocysteine levels among schizophrenia patients. We reported that such high levels characterize young male schizophrenia patients. We now studied two groups of schizophrenia patients (N=41) and controls (N=29) for CSF homocysteine levels. No difference was found for CSF homocysteine levels between schizophrenia patients and controls (p=.041 for Study A and p=.52 for Study B).

Thrombophilic factors are not the leading cause of thrombosis in Behçet's disease.

BACKGROUND: Venous and arterial thromboses occur in patients with Behçet's disease and are associated with significant morbidity and mortality. Studies on a possible association between the occurrence of thrombosis and thrombophilia in patients with this disease have been controversial. OBJECTIVE: To determine the prevalence of the most common thrombophilias and dyslipidaemia in patients with Behçet's disease with and without thrombosis. METHODS: Blood samples from 107 patients with Behçet's disease who had or did not have thrombosis were analysed for factor V Leiden, prothrombin G20210A polymorphism, methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, factor VIII level, homocysteine and C reactive protein concentrations, dyslipidaemia, and plasma glucosylceramide. RESULTS: There was no difference between patients with and without thrombosis in the prevalence of prothrombin G20210A polymorphism, factor V Leiden, homozygous MTHFR C677T, or plasma concentrations of homocysteine, C reactive protein, or glucosylceramide. In contrast, patients with thrombosis were found to have significantly higher mean levels of factor VIII, total cholesterol, triglycerides, VLDL cholesterol, and apolipoproteins B-100, C-II, and C-III than those without thrombosis. Multistepwise logistic regression analysis showed that triglyceride concentration was the best marker associated with thrombosis (p = 0.008), with an estimated odds ratio of 1.58 (95% confidence interval, 1.09 to 2.30) for a difference of 40 mg/dl. CONCLUSIONS: Thrombophilia does not seem to play a major role in the tendency to thrombosis in Behçet's disease. However, dyslipidaemia, predominantly hypertriglyceridaemia, might be a risk factor.

Assessment of the coagulation profile in hemato-oncological patients receiving ATG-based conditioning treatment for allogeneic stem cell transplantation.

Antithymocyte globulin (ATG) is increasingly used in pre-allogeneic stem cell transplantation (allo-SCT) conditioning regimens to prevent graft rejection and graft-versus-host disease. However, ATG was also found to be associated with increased incidence of thrombosis during organ transplantation. In the present study, we tested the coagulation status of 21 patients with hematologic malignancies undergoing allo-SCT who received ATG-based (11 patients) or non-ATG-based (10) conditioning treatment. We assessed several thrombophilia markers as well as circulating total and endothelial microparticles (TMP/EMP) and soluble CD40 ligand (CD40L). No significant difference in the mean values of prothrombin time, partial thromboplastin time, fibrinogen, antithrombin, protein C, protein S, thrombin-antithrombin III complex, homocysteine levels, prevalence of genetic thrombophilia markers and levels of EMP, TMP or CD40L was observed between the ATG-treated and ATG-untreated patients, as well as before and after conditioning in each group separately. Platelet counts decreased significantly in ATG-treated patients; however, this decrease was not associated with clinical or laboratory evidence of disseminated intravascular coagulation. No patient developed thromboembolic event or veno-occlusive liver disease. Our results suggest that allo-SCT is not associated with increased hypercoagulability and addition of ATG to conditioning regimen has no significant procoagulant effect.

Hyperhomocysteinemia in patients with diabetes mellitus with and without diabetic retinopathy.

OBJECTIVE: To evaluate the prevalence of hyperhomocysteinaemia in diabetic patients with no diabetic retinopathy (no DR), with non-proliferative diabetic retinopathy (NPDR) and with proliferative diabetic retinopathy (PDR). RESEARCH DESIGN AND METHODS: This prospective, case-control study, included 179 diabetic patients and 156 age-matched controls with no diabetes and no history of ocular disease, who were undergoing routine physical checkups. Plasma homocysteine levels of all study participants were measured using high-performance liquid chromatography (HPLC). Hyperhomocysteinaemia was defined when homocysteine levels were higher than 15 micromol/l. RESULTS: The mean plasma homocysteine level was 11.75+-0.24 in the control group,13.46+0.74 in the no DR group, 14.56 + 0.64 in the NPDR group and 15.86 + 1.34 in the PDR group. Mean homocysteine levels were significantly elevated in the NPDR and PDR groups compared to the control group(P = 0.001 and <0.0001, respectively). The prevalence of hyperhomocysteinaemia was also higher in the NPDR and PDR groups compared to the control group (P = 0.032 and 0.011, respectively). No statistically significant difference was found between the no DR and the control group. CONCLUSIONS: Our findings suggest that hyperhomocysteinaemia may be associated with diabetic retinopathy and partially explain the increased risk of microvascular angiopathy occurring in these patients.

[Dermatological manifestations of smoking].

Heavy smokers are at risk of aggravating several cutaneous diseases. The main adverse effects of cigarette smoking on the skin are associated with psoriasis, with squamous cell carcinoma and with the poorer outcome of malignant melanoma. One of the main concerns to smokers is the well-documented effect of smoking on premature face aging due to excessive wrinkling, which may follow enhanced elastase activity, and the degradation of elastin in the dermis. Recently, evidence has emerged indicating that smoking induces in the skin the activity of the metallo-proteinase MMP-1 that specifically degrades collagen, the most abundant protein in the cutaneous matrix.

Cerebrovascular events in patients with significant stenosis of the carotid artery are associated with hyperhomocysteinemia and platelet antigen-1 (Leu33Pro) polymorphism.

BACKGROUND AND PURPOSE: Although risk factors for carotid artery stenosis caused by atherosclerosis are known, it is unclear what triggers "activation" of the atherosclerotic plaques and the ensuing thromboembolic cerebral events. The aim of this study was to evaluate whether thrombophilic factors, platelet glycoprotein (GP) polymorphisms, and homocysteine are associated with a risk of ischemic events in patients with significant carotid stenosis. METHODS: Consecutive patients with >/=50% carotid stenosis, whether symptomatic (with ipsilateral ischemic events) or asymptomatic, who were evaluated and followed in a neurovascular clinic were tested for plasma levels of homocysteine, C677T mutation in methylenetetrahydrofolate reductase, G20210A mutation of factor II, factor V Leiden, antiphospholipid antibodies, and polymorphisms of platelet membrane GP: human platelet antigen (HPA)-1, GP Ia (C807T), and GP Ib (variable number of tandem repeats, Kozak, and HPA-2). RESULTS: Eighty-six asymptomatic and 67 symptomatic patients were evaluated. The former group was older (73.7+/-6.9 versus 69.5+/-9.1 years, P=0.02). Major risk factors for stroke were similar in both groups. In symptomatic patients versus asymptomatic patients, hyperhomocysteinemia was 3-fold more frequent (34.3% versus 12.8%, respectively; P=0.002) and HPA-1a/b was almost 2-fold more common (38.8% versus 20.9%, respectively; P=0.01). All other thrombophilic factors and platelet polymorphisms studied did not differ significantly between the 2 groups. Multivariate analysis revealed that hyperhomocysteinemia and the HPA-1a/b genotype conferred a significant risk of cerebral ischemic events, with odds ratios (95% CI) of 4.07 (1.7 to 9.7) and 3.4 (1.5 to 7.8), respectively. CONCLUSIONS: Hyperhomocysteinemia and HPA-1a/b are independent risk factors for ischemic events in patients with significant carotid stenosis.

Homocysteine elevation with fibrates: is it a class effect?

BACKGROUND: Case-control and prospective studies indicate that an elevated plasma homocysteine level is a powerful risk factor for atherosclerotic vascular diseases. Certain medications can induce hyperhomocystinemia, such as methotrexate, trimethoprim and anti-epileptic drugs. There are few reports indicating an interaction between lipid-lowering drugs (cholestyramine and niacin) and homocysteine. Recently, an interaction was shown between fenofibrate and benzafibrates (a fibric acid derivative) and homocysteine plasma levels. OBJECTIVES: To evaluate the effects of different fibrates on plasma homocysteine levels and to measure the reversibility of this effect. METHODS AND RESULTS: We investigated the effects of ciprofibrate and bezafibrate on homocysteine levels in patients with type IV hyperlipidemia and/or low high density lipoprotein levels. While a 57% increase in homocysteine was detected in the ciprofibrate-treated group (n = 26), a 17% reduction in homocysteine was detected in the group treated with bezafibrate (n = 12). The increase in homocysteine in the ciprofibrate-treated group was sustained for the 12 weeks of treatment and was partially reversible after 6 weeks of discontinuing the ciprofibrate therapy. CONCLUSIONS: These results indicate that an increase in plasma homocysteine levels following administration of fibrates is not a class effect, at least in its magnitude. Moreover, it is reversible upon discontinuation of the treatment.

Salivary flow dynamics after parotid surgery: a preliminary report.

BACKGROUND: Tumors in the parotid gland may affect salivary flow. The effects of tumor on glandular function and postoperative changes in both resected gland and contralateral gland were not formerly reported. We prospectively evaluated salivary flow rates and composition in patients undergoing parotidectomy preoperatively and postoperatively. METHOD: Stimulated parotid saliva from 17 patients undergoing parotidectomy was collected bilaterally preoperatively and postoperatively by using a parotid cup. Subjective complaints were recorded. Salivary flow rates, sodium, potassium, and amylase levels were evaluated. RESULTS: None of the patients complained of "dry mouth" before or after surgery. Analysis of the individual results revealed 3 patterns of preoperative and postoperative response, compatible with either a preoperative or postoperative compensatory mechanism in the contralateral gland. The postoperative decrease in flow rate corresponds with the amount of gland removed. Salivary electrolyte composition was unchanged. CONCLUSION: This study is the first to demonstrate the effects of parotid tumors and their surgery on salivary flow and a compensatory response and its different patterns in human parotid glands after their excision.

Hypercoagulable thrombophilic defects and hyperhomocysteinemia in patients with recurrent pregnancy loss.

PROBLEM: Placental perfusion may be compromised by increased thrombosis that leads to pregnancy complications and recurrent pregnancy loss (RPL). Since heritable thrombophilic defects and hyperhomocysteinemia are associated with increased thrombosis, their prevalence was evaluated in RPL patients with special emphasis on combinations of the above pathologies. METHODS OF STUDY: Evaluation of the prevalence of heritable thrombophilic defects (protein S, protein C, anti-thrombin III deficiency, and the mutations for factor V Leiden, methylenetetrahydrofolate reductase [MTHFR], and prothrombin gene), hyperhomocysteinemia. and combinations of these pathologies in 36 non-pregnant recurrent aborters compared with 40 parous women. RESULTS: We found a relatively high prevalence of deficiencies of plasma coagulation proteins in RPL patients compared with the controls. A non-significant different increase in factor V Leiden mutation was detected (6/36 [16%] compared with 2/40 [5%] in the control group, P = 0.14]. Hyperhomocysteinemia was found in 31% of the RPL patients. MTHFR mutation homozygosity was found in 6/36 (16%) of the aborting patients. Combinations of hyperhomocysteinemia and MTHFR mutation were found in three patients, with folate deficiency in two patients, and with B12 deficiency in three. CONCLUSIONS: Combinations of gene mutations, plasma protein deficiencies, and hyperhomocysteinemia, which are associated with an increased thrombotic risk, are more common in RPL patients compared with controls. Large-scale prevalence studies are needed in order to draw conclusions as to the causative relation of such a condition and RPL.

Analysis of cell-free human alpha1 integrin with a monoclonal antibody to the I-domain: detection in ocular fluid and function as an adhesion substrate.

The alpha1 beta1 integrin, an inserted (1) domain containing collagen receptor, is expressed in the cell surface membrane of normal and malignant cells, and may play a role in their migration through tissues or in metastatic spread. Here we report that a functional anti-human alpha1beta1 integrin monoclonal antibody (mAb) (1B3.1) directly and specifically binds plastic bound recombinant human alpha1 I-domain protein containing the collagen binding site. Detection was diminished by acidification of the I-domain protein but was enhanced by increasing concentrations of Mg2+ cation. Furthermore, we detected binding of the mAb to proteins from the ocular fluids of 6 patients, with the highest concentration, corresponding to 22.1 ng/ml of I-domain, found in a sample from the eye of a patient with metastatic lung adenocarcinoma. Interestingly, we found that both SKNSH neuroblastoma cells and virally transformed human T cells adhered specifically to plastic wells coated with either immobilized collagen IV or alpha1 I-domain. MAb I B3.1 inhibited adhesion to collagen IV but not to immobilized I-domain. These results suggest a novel function for cell free alpha1 I-domain as a substrate for cellular adhesion, which may have relevance in tumor spread in vivo.

[Can we apply gene therapy in the treatment of Parkinson patients?].

Problems associated with a long-term application of L-dopa to treat Parkinsons disease, have prompted interest in developing alternative therapeutic strategies. Parkinsons disease is a suitable candidate for neurological gene therapy, given our knowledge of the functional anatomy of the striato-nigral system. Recently, much effort was devoted to the administration of trophic factors to injured neurons, especially using glial cell line-derived factor (DGNF). Various aspects of this approach are discussed in this study.

[What's new in the hippocampus? Neurons regenerate in the adult brain].

Since the late 1960's, the production of new neurons was known to occur in the brains of adult rodents however, only recently, neurogenesis was documented in the hippocampus of adult mammals. This region in the brain is related to the function of learning and memory. Hence, the finding that in response to training on associative learning tasks that require the hippocampus the number of newly generated neurons increases, could be highly significant.

Thrombophilia as a cause for central and branch retinal artery occlusion in patients without an apparent embolic source.

PURPOSE: To assess the prevalence of vascular risk factors and thrombophilias in central and branch retinal artery occlusion in patients in whom an embolic source is not apparent. METHODS: The study group consisted of 21 consecutive patients with retinal artery occlusion (RAO) in whom Doppler ultrasonography of the carotid arteries and transthoracic or transoesophageal echocardiography were normal. Laboratory methods included polymerase chain reaction for detection of factor V G1691A, factor II G20210A and methylentetrahydrofolate reductase C677T mutations, assays of plasma levels of protein C, free protein S, antithrombin, fibrinogen and homocysteine; and tests for the presence of lupus anticoagulant and anticardiolipin antibodies. Controls for the laboratory tests were 243 healthy subjects. RESULTS: Nine of the 21 (43%) patients had at least one thrombophilic marker: 4 were homozygous for MTHFR C677T, 1 was heterozygous for factor V G1691A, 1 had a high titre of IgM anticardiolipin, 2 were heterozygous for factor V G1691A and homozygous for MTHFR C677T, and 1 had lupus anticoagulant, a high titre of IgM anticardiolipin, homozygosity for MTHFR C677T and hyperhomocysteinaemia. An interaction between vascular risk factors and thrombophilias seemed important since out of 14 patients with hypertension, diabetes and/or hypercholesterolaemia 7 (50%) had a thrombophilia. Homozygous MTHFR C677T was a significant risk factor with odds ratio of 3.18 (95% CI 1.20-8.47). The prevalence of factor V G1691A was also higher in the RAO patients versus controls with an odds ratio of 2.36 (95% CI 0.63-8.88), but this value did not reach significance, probably due to the small sample size. CONCLUSION: A search for thrombophilia in RAO is advisable in patients without evident source of emboli even when vascular risk factors are identified.

Oral contraceptives can cause falsely low vitamin B(12) levels.

Serum vitamin B(12) radioimmunoassays may give falsely low results in patients with folate deficiency, multiple myeloma, megadose of vitamin C and following radioisotope organ scan. We evaluated 10 consecutive healthy women on oral contraceptives (OC) who had falsely low vitamin B(12) levels, as reflected by normal urine methylmalonic acid and plasma homocysteine. After 1-month cessation of OCs, vitamin B(12) returned to the normal range in all women. Transcobalamin I (TCI) blood level was decreased in 60% of patients. OCs may cause temporary low vitamin B(12) blood levels of no clinical significance that can be associated with low TCI levels