Online repetitive transcranial magnetic stimulation (TMS) to the parietal operculum disrupts haptic memory for grasping

The parietal operculum (OP) contains haptic memory on the geometry of objects that is readily transferrable to the motor cortex but a causal role of OP in memory‐guided grasping is only speculative. We explored this issue by using online high‐frequency repetitive transcranial magnetic stimulation (rTMS). The experimental task was performed by blindfolded participants acting on objects of variable size. Trials consisted in three phases: haptic exploration of an object, delay, and reach‐grasp movement onto the explored object. Motor performance was evaluated by the kinematics of finger aperture. Online rTMS was applied to the left OP region separately in each of the three phases of the task. The results showed that rTMS altered grip aperture only when applied in the delay phase to the OP. In a second experiment a haptic discriminative (match‐to‐sample) task was carried out on objects similar to those used in the first experiment. Online rTMS was applied to the left OP. No psychophysical effects were induced by rTMS on the detection of explicit haptic object size. We conclude that neural activity in the OP region is necessary for proficient memory‐guided haptic grasping. The function of OP seems to be critical while maintaining the haptic memory trace and less so while encoding it or retrieving it. Hum Brain Mapp 36:4262–4271, 2015. © 2015 Wiley Periodicals, Inc .     

Identification of a geographic area characterized by extreme longevity in the Sardinia island: the AKEA study

High prevalence and low female/male ratio for validated centenarians are observed in Sardinia and these findings appear to be thus far unique to this island. Moreover a specific region on the island is characterized by exceptional male longevity. We calculated the extreme longevity index (ELI), defined as the percentage of persons born in Sardinia between 1880 and 1900, who became centenarians. A gaussian smoothing method was used in order to identify the so-called 'Blue Zone', where longevity is concentrated in the central-eastern part of the island and covers all the mountainous areas of central Sardinia. The estimated life expectancy in the 'Blue Zone' is longer than in the remaining territory of the island especially for men and the male to female ratio among centenarians born in this area is 1.35 compared to 2.43 in the rest of Sardinia. The specific mechanism by which persons living in this territory were more likely to reach extreme longevity remains unknown but it is interesting to note that most of the 'longevity hot spots' identified in various regions of the world over the years have been located in mountainous geographical areas even if none of these longevity regions have been fully validated. An alternative and interesting hypothesis is that the high rate of inbreeding determined by frequent marriages between consanguineous individuals and low immigration rates have progressively decreased the variability of the genetic pool and facilitated the emergence of genetic characteristics that protect individuals from diseases that are major causes of mortality particularly in older individuals. Given the exceptionally high prevalence of male centenarians in the 'Blue Zone', it is reasonable to assume that either the environmental characteristics or the genetic factors, or both, exert their favorable effect more strongly in men than in women. Thus, the mechanism involved may be modulated by the hormonal milieu, or may be associated with genes located in the sex chromosomes.     

Epstein‐Barr virus infection induces miR‐21 in terminally differentiated malignant B cells

The association of Epstein‐Barr virus (EBV) with plasmacytoid malignancies is now well established but how the virus influences microRNA expression in such cells is not known. We have used multiple myeloma (MM) cell lines to address this issue and find that an oncomiR, miR‐21 is induced after in vitro EBV infection. The PU.1 binding site in miR‐21 promoter was essential for its activation by the virus. In accordance with its noted oncogenic functions, miR‐21 induction in EBV infected MM cells caused downregulation of p21 and an increase in cyclin D3 expression. EBV infected MM cells were highly tumorigenic in SCID mice. Given the importance of miR‐21 in plasmacytoid malignancies, our findings that EBV could further exacerbate the disease by inducing miR‐21 has interesting implications both in terms of diagnosis and future miR based therapeutical approaches for the virus associated plasmacytoid tumors.     

Hyperpolarized [1,3‐13C2]ethyl acetoacetate is a novel diagnostic metabolic marker of liver cancer

An increased prevalence of liver diseases such as hepatitis C and nonalcoholic fatty liver results in an augmented incidence of the most common form of liver cancer, hepatocellular carcinoma (HCC). HCC is most often found in the cirrhotic liver and it can therefore be challenging to rely on anatomical information alone when diagnosing HCC. Valuable information on specific cellular metabolism can be obtained with high sensitivity thanks to an emerging magnetic resonance (MR) technique that uses ¹³C labeled hyperpolarized molecules. Our interest was to explore potential new high contrast metabolic markers of HCC using hyperpolarized ¹³C‐MR. This work led to the identification of a class of substrates, low molecular weight ethyl‐esters, which showed high specificity for carboxyl esterases and proved in many cases to possess good properties for signal enhancement. In particular, hyperpolarized [1,3‐¹³C₂]ethyl acetoacetate (EAA) was shown to provide a metabolic fingerprint of HCC. Using this substrate a liver cancer implanted in rats was diagnosed as a consequence of an ～4 times higher metabolic substrate‐to‐product ratio than in the surrounding healthy tissue, (p = 0.009). Unregulated cellular uptake as well as cosubstrate independent enzymatic conversion of EAA, made this substrate highly useful as a hyperpolarized ¹³C‐MR marker. This could be appreciated by the signal‐to‐noise (SNR) obtained from EAA, which was comparable to the SNR reported in a literature liver cancer study with state‐of‐the‐art hyperpolarized substrate, [1‐¹³C]pyruvate. Also, the contrast‐to‐noise (CNR) in the EAA based metabolic ratio images was significantly improved compared with the CNR in equivalent images reported using [1‐¹³C]pyruvate.     

A critical appraisal of daclizumab use as emerging therapy in multiple sclerosis

Introduction: Daclizumab (DAC) is a mAb that binds to CD25, a receptor on the surface of lymphocytes for IL-2, a chemical messenger in the immune system. This prevents activation and proliferation of lymphocytes, which are involved in the immune attack in multiple sclerosis (MS).

Areas covered: In this review, we will focus on newly emerging DAC-high-yield process (HYP) therapy for MS. Based on published original articles and citable meeting abstracts, we will discuss its mode of action as well as data on efficacy and safety.

Expert opinion: DAC has been observed to have multiple (biological) effects, which may contribute to beneficial effects in immune-related disease and particularly in relapsing-remitting MS. The positive results in the clinical studies represent achievement of an important milestone in the development of DAC-HYP as a potential new treatment option for MS patients. The benefit/risk ratios of this new biological agent in MS therapy are still being evaluated. Soon, DAC-HYP might qualify as MS therapy. A safety monitoring program is recommended in the clinical practice.     

Relationship between circulating syndecan-1 levels (CD138s) and serum free light chains in monoclonal gammopathies

Background

Monoclonal gammopathies encompass a wide range of diseases characterized by the monoclonal expansion of a B-cell clone. Despite emerging therapeutic strategies, chances of survival of patients who are affected are still scarce, which implies that new tools are necessary not only for the diagnosis but also for the follow-up of patients affected by such diseases. In this context, the use of free light chains (FLCs) has been incorporated into many guidelines.Likewise, tumor microenvironment is consistently gaining importance as role player in tumor pathogenesis. Specifically, Syndecan-1 (CD138), a heparan-sulfate proteoglycan is attracting interests as it is highly expressed and shed by myeloma plasma-cells.The aim of our study was to analyze CD138 levels in the serum of patients affected by multiple myeloma or light chain only disease, and to compare the values obtained with free light chain (FLC) kappa, lambda and FLC ratio in both groups of patients.

Methods

84 patients affected by Multiple Myeloma and Light Chain Myeloma were recruited for this study. Serum CD138 was assessed by ELISA (Diaclone Research, France) and FLC values were quantified by nephelometry (Freelite TM Human Kappa and Lambda Free Kits, The Binding Site, UK). Data was analyzed by GraphPad Prism software and Statgraph.

Results

We observed higher CD138 mean values in myeloma patients compared to the light chain only myeloma group. A positive linear regression of CD138 and FLC was observed in the light chain only cohort as opposed to myeloma patients which show an inverse trend.

Conclusions

The study highlighted an existing relationship between FLCs and CD138 and wishes to seek also a correlation in order to rapidly and efficiently perform diagnosis and different diagnostic schemes.     

The choice of amniotic fluid in metabolomics for the monitoring of fetus health

Amniotic fluid (AF) is a biological fluid in which metabolite transport is regulated by the placenta, the permeable skin, fetal lung egress and gastric fluid. During pregnancy, the composition of AF changes from similar to the interstitial fluid of the mother, to a more complex system, influenced by the fetus’s urine. Since AF reflects the mother’s and the fetus’s health status at the same time, it may be an important diagnostic tool for a wider spectrum of clinical conditions. Indeed, the metabolic characterization of AF in relation to pathological occurrences may lead to the discovery of new biomarkers for a better clinical practice. For this reason, metabolomics may be the most suitable strategy for this task. In this review, research works on metabolomic AF analysis are discussed according to the morbidity of interest, being preterm birth/labor, gestational age and diabetes and fetal malformations, along with a number of other important studies.     

Efficacy and safety of pregabalin in alcohol dependence

INTRODUCTION: Pregabalin is a new anxiolytic that selectively binds to the alpha2-delta subunit of voltage-gated calcium channels, inhibiting release of excessive levels of excitatory neurotransmitters. In this open-label trial we aimed to investigate the efficacy of pregabalin on alcoholism indices in detoxified alcohol-dependent subjects. Reduction of cravings, psychiatric symptom improvements, and the evaluation of safety parameters were the secondary endpoints. METHODS: Thirty-one alcohol-dependent patients were consecutively recruited and screened for the study. Twenty detoxified patients received pregabalin starting at 50 mg/day (orally) in the first week, gradually increasing to a flexible dose of 150-450 mg/day. Subjects were assessed at the beginning of the treatment, and after 2, 8 and 16 weeks. Craving (visual analogue scale, Obsessive and Compulsive Drinking Scale [OCDS]) and withdrawal (Clinical Institute Withdrawal Assessment for Alcohol [CIWA-Ar]) rating scales were applied; psychiatric symptoms were evaluated through the Symptom Check List-90-Revised (SCL-90-R). RESULTS: Out of the twenty patients who received the study drug, 15 completed the study procedures: 10 remained totally alcohol-free for the duration of the study, five relapsed. An additional four patients dropped out during the study, and one stopped taking medication due to adverse events. A significant progressive reduction of both craving and withdrawal symptomatology were observed. Safety parameters did not show any significant variation during treatment. CONCLUSION: Pregabalin shows promise as a treatment for alcohol dependence. Although limited by a low number of participants and by the open design, this is the first study concerning the efficacy and safety of pregabalin in current alcoholics. In these patients pregabalin was effective and well tolerated. Additional research is needed to explore the clinical relevance of these findings.