Pilot Study of Low Dose Oral Methotrexate Treatment for Primary Biliary Cirrhosis

Objective: To assess the efficacy of low doses of oral methotrexate as therapy for primary biliary cirrhosis. Methods: Ten symptomatic patients with this disease were treated with methotrexate at a dose of 15 mg/wk in an open label trial. Results: Eight patients completed 1 yr of treatment and six completed 2. Pruritus and fatigue decreased in all patients treated for at least 1 yr. Mean levels of serum alkaline phosphatase, ALT, and IgM were less at 1 and 2 yr than corresponding baseline means. Total serum bilirubin increased in three patients during treatment. Serum aminotransferases and alkaline phosphatase became normal in one patient with stage I disease. Although liver biopsies at 1 and 2 yr revealed a decrease in the intensity of the Inflammatory infiltrate, they also showed an increase in fibrosis suggestive of disease progression. Methotrexate was discontinued in five patients: for disease progression in four (one at 4 months, one at 1 yr, and two at 2 yr) and for intractable pruritus in one (at 4 months). All patients experienced transient mucositis and intermittent dyspepsia. Conclusions: These findings suggest that methotrexate treatment in patients with primary biliary cirrhosis is not beneficial in patients with advanced disease; in patients with early disease, methotrexate may be associated with amelioration of symptoms, reduction in serum biochemical indices of liver disease, and reduction in hepatic inflammation. However, prospective, randomized, controlled trials will he necessary for definitive evaluation of the effects of methotrexate on the quality of life and survival of patients with primary biliary cirrhosis.     

Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis

Neurogenesis occurs within the adult dentate gyrus of the hippocampal formation and it has been proposed that the newly born neurons, recruited into the preexistent neuronal circuits, might be involved in hippocampal-dependent learning processes. Age-dependent spatial memory impairments have been related to an alteration in hippocampal plasticity. The aim of the current study was to examine whether cognitive functions in aged rats are quantitatively correlated with hippocampal neurogenesis. To this end, we took advantage of the existence of spontaneous individual differences observed in aged subjects in a hippocampal-dependent task, the water maze. We expected that the spatial memory capabilities of aged rats would be related to the levels of hippocampal neurogenesis. Old rats were trained in the water maze, and, 3 weeks after training, rats were injected with 5-bromo-2'-deoxyuridine (BrdUrd, 50 or 150 mg/kg) to label dividing cells. Cell proliferation was examined one day after the last BrdUrd injection, whereas cell survival and differentiation were determined 3 weeks later. It is shown that a quantitative relationship exists between learning and the number of newly generated neurons. Animals with preserved spatial memory, i.e., the aged-unimpaired rats, exhibited a higher level of cell proliferation and a higher number of new neurons in comparison with rats with spatial memory impairments, i.e., the aged-impaired rats. In conclusion, the extent of memory dysfunction in aged rats is quantitatively related to the hippocampal neurogenesis. These data reinforce the assumption that neurogenesis is involved in memory processes and aged-related cognitive alterations.     

A case of anti-Jo1 myositis with pleural effusions and pericardial tamponade developing after exposure to a fermented Kombucha beverage

The pathogenesis of the idiopathic inflammatory myopathies has been postulated to be an environmental trigger causing the expression of the disease in a genetically predisposed patient. We report a case of anti-Jo1 antibody-positive myositis which was associated with pleural effusions, pericardial effusion with tamponade, and mechanics hands, probably related to the consumption of a fermented Kombucha beverage. Kombucha mushroom, a symbiosis of yeast and bacteria, is postulated to be the trigger for our patients disease owing to the proximity of his symptoms to the consumption of the Kombucha beverage.Abbreviations ALT Alanine transferase - AST Aspartate aminotransferase - CPK Creatinine phosphokinase     

Attitudes of dental professional staff and auxiliaries in Riyadh,Saudi Arabia,toward disclosure of medical errors

Aim

To collect empirical data on the attitudes of dental professionals and dental auxiliaries in Riyadh, Saudi Arabia, regarding the disclosure of medical errors.

Right parietal cortex mediates recognition memory for melodies

Functional brain imaging studies have highlighted the significance of right‐lateralized temporal, frontal and parietal brain areas for memory for melodies. The present study investigated the involvement of bilateral posterior parietal cortices (PPCs) for the recognition memory of melodies using transcranial direct current stimulation (tDCS). Participants performed a recognition task before and after tDCS. The task included an encoding phase (12 melodies), a retention period, as well as a recognition phase (24 melodies). Experiment 1 revealed that anodal tDCS over the right PPC led to a deterioration of overall memory performance compared with sham. Experiment 2 confirmed the results of Experiment 1 and further showed that anodal tDCS over the left PPC did not show a modulatory effect on memory task performance, indicating a right lateralization for musical memory. Furthermore, both experiments revealed that the decline in memory for melodies can be traced back to an interference of anodal stimulation on the recollection process (remember judgements) rather than to familiarity judgements. Taken together, this study revealed a causal involvement of the right PPC for memory for melodies and demonstrated a key role for this brain region in the recollection process of the memory task.     

Antiretroviral therapy adherence measurement in non-clinical settings in South India

Optimal adherence to antiretroviral therapy (ART) is key to viral suppression, but may be impeded by psychosocial consequences of HIV-infection such as stigma and depression. Measures of adherence in India have been examined in clinic populations, but little is known about the performance of these measures outside clinical settings. We conducted a cross-sectional study of 151 Tamil-speaking people living with HIV/AIDS (PLHA) in India recruited through HIV support networks and compared single item measures from the Adult AIDS Clinical Trial Group (AACTG) scale, a visual analog scale (VAS), and a question on timing of last missed dose. Depression was measured using the Major Depression Inventory (MDI) and HIV-related stigma was measured using an adaptation of the Berger Stigma Scale. Mean age was 35.6 years (SD ± 5.9); 55.6% were male; mean MDI score was 11.9 (SD ± 9.1); and mean stigma score was 67.3 (SD ± 12.0). Self-reported perfect adherence (no missed doses) was 93.3% using the AACTG item, 87.1% using last missed dose, and 83.8% using the VAS. The measures had moderate agreement with each other (kappa 0.45–0.57). Depression was associated with lower adherence irrespective of adherence measure used, and remained significantly associated in multivariable analyses adjusting for age and marital status. Stigma was not associated with adherence irrespective of the measure used. The VAS captured the greatest number of potentially non-adherent individuals and may be useful for identifying PLHA in need of adherence support. Given the consistent and strong association between poorer adherence and depression, programs that jointly address adherence and mental health for PLHA in India may be more effective than programs targeting only one.     

Anesthetic Influence on Occurrence and Treatment of the Trigemino-Cardiac Reflex: A Systematic Literature Review

Trigeminocardiac reflex (TCR) is defined as sudden onset of parasympathetic dysrhythmia including hypotension, apnea, and gastric hypermotility during stimulation of any branches of the trigeminal nerve. Previous publications imply a relation between TCR and depth of anesthesia. To gain more detailed insights into this hypothesis, we performed a systematic literature review.Literature about occurrence of TCR was systematically identified through searching in Cochrane Central Register of Controlled Trials (CENTRAL), PubMed (MEDLINE), EMBASE (Ovid SP), and the Institute for Scientific Information (ISI Web of Sciences) databases until June 2013, as well as reference lists of articles for risk calculation. In this study, TCR was defined as drop in mean arterial blood pressure and heart rate, both >20% to baseline. We calculated intraoperative cerebral state index (CSI) of each TCR-case using a newly developed method. These data were further divided into 3 subgroups: CSI <40 (deep anesthesia), CSI 40–60 (regular anesthesia), and CSI >60 (slight anesthesia).Including 45 studies with 910 patients, 140 (15%) presented with TCR, and 770 (85%) without TCR during operation. TCR occurrence showed a 1.2-fold higher pooled risk slighter anesthesia (CSI <40: 13%, at CSI 40–60: 21%, and at CSI >60: 27%) compared with deeper anesthesia. In addition, we could discover a 1.3-fold higher pooled risk of higher MABP drop with a strong negative correlation (r = −0.935; r² = 0.89) and a 4.5-fold higher pooled risk of asystole during TCR under slight anesthesia compared with deeper anesthesia.Our work is the first systematic review about TCR and demonstrates clear evidence for TCR occurrence and a more severe course of the TCR in slight anesthesia underlying the importance of skills in anesthesia management during skull base surgery. Furthermore, we have introduced a new standard method to calculate the depth of anesthesia.     

Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer

Adenosine A_2A receptor (A_2AR)-dopamine D₂ receptor (D₂R) heteromers are key modulators of striatal neuronal function. It has been suggested that the psychostimulant effects of caffeine depend on its ability to block an allosteric modulation within the A_2AR-D₂R heteromer, by which adenosine decreases the affinity and intrinsic efficacy of dopamine at the D₂R. We describe novel unsuspected allosteric mechanisms within the heteromer by which not only A_2AR agonists, but also A_2AR antagonists, decrease the affinity and intrinsic efficacy of D₂R agonists and the affinity of D₂R antagonists. Strikingly, these allosteric modulations disappear on agonist and antagonist coadministration. This can be explained by a model that considers A_2AR-D₂R heteromers as heterotetramers, constituted by A_2AR and D₂R homodimers, as demonstrated by experiments with bioluminescence resonance energy transfer and bimolecular fluorescence and bioluminescence complementation. As predicted by the model, high concentrations of A_2AR antagonists behaved as A_2AR agonists and decreased D₂R function in the brain.Most evidence indicates that G protein-coupled receptors (GPCRs) form homodimers and heteromers. Homodimers seem to be a predominant species, and oligomeric entities can be viewed as multiples of dimers (1). It has been proposed that GPCR heteromers are constituted mainly by heteromers of homodimers (1, 2). Allosteric mechanisms determine a multiplicity of unique pharmacologic properties of GPCR homodimers and heteromers (1, 3). First, binding of a ligand to one of the receptors in the heteromer can modify the affinity of ligands for the other receptor (1, 3, 4). The most widely reproduced allosteric modulation of ligand-binding properties in a GPCR heteromer is the ability of adenosine A_2A receptor (A_2AR) agonists to decrease the affinity of dopamine D₂ receptor (D₂R) agonists in the A_2AR-D₂R heteromer (5). A_2AR-D₂R heteromers have been revealed both in transfected cells (6, 7), striatal neurons in culture (6, 8) and in situ, in mammalian striatum (9, 10), where they play an important role in the modulation of GABAergic striatopallidal neuronal function (9, 11).In addition to ligand-binding properties, unique properties for each GPCR oligomer emerge in relation to the varying intrinsic efficacy of ligands for different signaling pathways (1–3). Intrinsic efficacy refers to the power of the agonist to induce a functional response, independent of its affinity for the receptor. Thus, allosteric modulation of an agonist can potentially involve changes in affinity and/or intrinsic efficacy (1, 3). This principle can be observed in the A_2AR-D₂R heteromer, where a decrease in D₂R agonist affinity cannot alone explain the ability of an A_2AR agonist to abolish the decreased excitability of GABAergic striatopallidal neurons induced by high concentration of a D₂R agonist (9), which should overcome the decrease in affinity. Furthermore, a differential effect of allosteric modulations of different agonist-mediated signaling responses (i.e., functional selectivity) can occur within GPCR heteromers (1, 2, 8). Again, the A_2AR-D₂R heteromer provides a valuable example. A recent study has shown that different levels of intracellular Ca²⁺ exert different modulations of A_2AR-D₂R heteromer signaling (8). This depends on the ability of low and high Ca²⁺ to promote a selective interaction of the heteromer with different Ca²⁺-binding proteins, which differentially modulate allosteric interactions in the heteromer (8).It has been hypothesized that the allosteric interactions between A_2AR and D₂R agonists within the A_2AR-D₂R heteromer provide a mechanism responsible not only for the depressant effects of A_2AR agonists, but also for the psychostimulant effects of adenosine A_2AR antagonists and the nonselective adenosine receptor antagonist caffeine (9, 11, 12), with implications for several neuropsychiatric disorders (13). In fact, the same mechanism has provided the rationale for the use of A_2AR antagonists in patients with Parkinson’s disease (13, 14). The initial aim of the present study was to study in detail the ability of caffeine to counteract allosteric modulations between A_2AR and D₂R agonists (affinity and intrinsic efficacy) within the A_2AR-D₂R heteromer. Unexpectedly, when performing control radioligand-binding experiments, not only an A_2AR agonist, but also caffeine, significantly decreased D₂R agonist binding. However, when coadministered, the A_2AR agonist and caffeine co-counteracted their ability to modulate D₂R agonist binding. By exploring the molecular mechanisms behind these apparent inconsistencies, the present study provides new insight into the quaternary structure and function of A_2AR-D₂R heteromers.