Equivalence of cell survival data for radiation dose and thermal dose in ablative treatments: analysis applied to essential tremor thalamotomy by focused ultrasound and gamma knife.

Thermal dose and absorbed radiation dose have historically been difficult to compare because different biological mechanisms are at work. Thermal dose denatures proteins and the radiation dose causes DNA damage in order to achieve ablation. The purpose of this paper is to use the proportion of cell survival as a potential common unit by which to measure the biological effect of each procedure. Survival curves for both thermal and radiation doses have been extracted from previously published data for three different cell types. Fits of these curves were used to convert both thermal and radiation dose into the same quantified biological effect: fraction of surviving cells. They have also been used to generate and compare survival profiles from the only indication for which clinical data are available for both focused ultrasound (FUS) thermal ablation and radiation ablation: essential tremor thalamotomy. All cell types could be fitted with coefficients of determination greater than 0.992. As an illustration, survival profiles of clinical thalamotomies performed by radiosurgery and FUS are plotted on a same graph for the same metric: fraction of surviving cells. FUS and Gamma Knife have the potential to be used in combination to deliver a more effective treatment (for example, FUS may be used to debulk the main tumour mass, and radiation to treat the surrounding tumour bed). In this case, a model which compares thermal and radiation treatments is valuable in order to adjust the dose between the two.

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.

Plasma levels of amino acids in elderly long term care residents with oropharyngeal dysphagia: comparison of hand-oral with tube-enteral-fed patients.

BACKGROUND: Dysphagia and eating difficulties are highly prevalent in long term care patients. Evaluation of their nutritional status is complicated by comorbidity, frailty and individual patterns of feeding. In previous studies we found vitamin deficiencies (folic acid B6 and B12) in orally fed elderly in early stages of oropharyngeal dysphagia despite satisfactory nutritional parameters (BMI, albumin and hemoglobin). The aim of this study is to evaluate the plasma amino acids levels in these hand-oral fed elderly patients with dysphagia. METHODS: Plasma amino acids were measured in 15 orally fed elderly patients in early functional outcome swallowing scale (FOSS), stage 2, and compared with those of 15 matched nasogastric-tube-fed counterparts. RESULTS: The plasma levels of all measured amino acids, ratio of essential to nonessential, levels of conditionally essential and the immune-enhancing amino acids were similar in both groups and within the normal range of our laboratory. The traditional nutritional parameters were also similar in both groups and within the normal range. CONCLUSIONS: Plasma levels of amino acids in elderly patients in early stage of FOSS are satisfactory, supporting the view that their protein intake is adequate. Further studies should concentrate on patients in advanced stages of FOSS.

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).

[On the relevance of protein kinase C to lithium therapy in bipolar disorder].

The discovery of lithium's efficacy as a mood-stabilizing agent revolutionized the treatment of patients with bipolar disorder and after 5 decades this drug continues to be the mainstay of treatment of this disorder. Valproate, which is dissimilar structurally to lithium, shares most of the effects of lithium at the level of protein kinase C (PKC). Both drugs reduce the activity of PKC, though via different mechanisms. In comparison to patients with major depressive disorder, schizophrenia, or healthy controls, PKC activity is significantly elevated in manic patients, suggesting that changes of PKC activity may be a central pathological trait of the illness. The precise physiological role of PKC activity in the regulation of mood is unclear. The enzyme modulates cellular responses via phosphorylation of numerous substrate proteins. Such substrates of PKC include cytoskeletal proteins, neurotransmitter and hormone receptors, G proteins, GAP-43, MARCKS etc. Further studies are required to clarify any causal role of CPK changes in bipolar-disorder.

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.

[The identification of the immunodominant gliadin epitope].

Recent efforts have piri-pointed a relevant sequence on gliadin, that may act as the immunodominant epitope in celiac disease. Independent reports from several leading laboratories identify a 33 amino acid segment spanning through residues 57-89, and excessively rich in proline and glutamine, as the putative epitope. A glutamine residue in position 65 is the site of deamidation by transglutaminase, promoting its recognition by DQ2-HLA. In addition, another gluten protein, glutenin, may be relevant to the pathogenesis in celiac disease.

[Monitoring heart failure with brain natriuretic peptide].

Brain natriuretic peptide (BNP), is a 32 amino acid containing cardiac hormone released from the ventricles due to increased filling pressure and left ventricle wall stretch. For over a decade since its discovery, information is mounting to suggest its superiority over the other natriureic peptide, ANP, as a reliable measure of left ventricular systolic dysfunction. Measurement of BNP concentration in blood emerges as a sensitive and specific test for the identification of patients with congestive heart failure in the urgent-care setting. It is a potent, cost-effective addition to the diagnostic armamentarium and helps in the titration of following therapy and prognosis evaluation.

[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.

[Survivin: anti-apoptosis protein and a prognostic marker for tumor progression and recurrence].

The recently discovered 16.5 kDa protein survivin was found to inhibit the two early apoptotic enzymes caspase-3 and caspase-7, thus preventing programmed cell death. Survivin may act simultaneously with the bel-2 family proteins, but has a different apoptosis inhibitory mechanism. Numerous reports have demonstrated the expression of survivin in various tumors such as neuroblastoma, melanoma, bladder carcinoma, breast and lung non-small cell tumors, esophegeal and colo-rectal carcinomas and leukemic cells. In contrast, this protein was not traced in adjacent normal tissues by either immunohistochemical staining or by PCR analysis of the expression of survivin mRNA. Importantly, there seems to be a positive correlation between survivin expression and tumor grading, as well as an indication of tumor recurrence after resection or chemotherapy. Potentially, this protein could add to the repertory of diagnostic and prognostic markers in monitoring oncologic patients.

[New approaches to immune against hepatitis C virus].

Hepatitis C virus represents a global health problem as some 170 million individuals are infected worldwide. Studies on virus replication and pathogenesis are hampered by the lack of a reliable cell culture system. In addition, the high rate of mutations reflected in viral antigen variability complicates attempts to prepare an efficient vaccine against HCV. Recently some significant strides were made towards resolving some of the above-mentioned difficulties. The importance of several structural antigens i.e. HVR1 and CD81 was demonstrated with regard to the infection mechanism and as structures that may serve to immunize against the virus. A promising new approach of using recombinant DNA vaccines instead of protein vaccines is discussed.

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.

Is blood homocysteine elevated in migraine?

OBJECTIVE: To determine total serum homocysteine levels in a large group of patients with migraine with and without aura. BACKGROUND: Hypercoagulable state is a known risk factor for stroke in the young. The existence of a hypercoagulable state has been postulated in migraine and homocysteinemia with young-onset stroke. To the best of our knowledge, blood homocysteine has not been studied in a significant number of patients with various forms of migraine. METHODS: Total serum homocysteine was measured with high-performance liquid chromatography in 78 patients with migraine and in 126 age- and sex-matched healthy volunteers. RESULTS: Seventy-eight patients aged 18 to 65 years were studied: 22 with migraine with aura and 56 with migraine without aura. Only 1 man had significantly elevated blood homocysteine (38.6 micromol/L), while another had a borderline elevation (15.8 micromol/L) (reference value for both sexes in our laboratory is 4 to 14 micromol/L). Both patients suffered from migraine without aura. CONCLUSIONS: Blood homocysteine is not elevated in migraine.