Impaired trafficking of mutants of lysosomal glucocerebrosidase in Gaucher's disease

Gaucher's disease is the most inherited lysosomal storage disorder. Except for a few cases, the broad phenotypic heterogeneity of Gaucher's disease can be neither predicted from defined mutations nor from differences in residual enzyme activity. Here, we analyse the intracellular trafficking of glucocerebrosidase as an underlying mechanism for the expression of the clinical phenotype. Biosynthetic labeling studies combined with immunofluorescence analyses with fibroblasts from patients with the defined mutations N370S, L444P, D409H and G202R unequivocally demonstrate a retarded transport of glucocerebrosidase carrying the mutation N370S and a transport block in the ER of the enzyme with the mutations G202R, L444P and D409H. We asked whether cellular components in the patients' fibroblasts other than glucocerebrosidase are implicated in the onset of the disease. For this, mutant cDNA's corresponding to the phenotypes N370S, G202R and L444P were expressed in the mouse fibroblasts NIH3T3. Essentially similar biochemical and cellular features were revealed as compared to the patients' fibroblasts strongly suggesting that these mutations are exclusively responsible for the characterized phenotypes. Interestingly, the immunoglobulin binding protein (BiP) binds wild type and the mutant N370S but not the G202R and L444P variants suggesting a discriminatory role played by this chaperone associated with the severity of the disease.     

Atorvastatin Added to Interferon Beta for Relapsing Multiple Sclerosis: 12-Month Treatment Extension of the Randomized Multicenter SWABIMS Trial

Background

Statins have anti-inflammatory and immunomodulatory properties in addition to lipid-lowering effects.

Objectives

To report the 12-month extension of a phase II trial evaluating the efficacy, safety and tolerability of atorvastatin 40 mg/d added to interferon beta-1b (IFNB-1b) in relapsing-remitting multiple sclerosis (RRMS).

Methods

In the randomized, multicenter, parallel-group, rater-blinded core study, 77 RRMS patients started IFNB-1b. At month three they were randomized 1∶1 to receive atorvastatin 40 mg/d or not in addition to IFNB-1b until month 15. In the subsequent extension study, patients continued with unchanged medication for another 12 months. Data at study end were compared to data at month three of the core study.

Results

27 of 72 patients that finished the core study entered the extension study. 45 patients were lost mainly due to a safety analysis during the core study including a recruitment stop for the extension study. The primary end point, the proportion of patients with new lesions on T2-weighted images was equal in both groups (odds ratio 1.926; 95% CI 0.265–14.0007; p = 0.51). All secondary endpoints including number of new lesions and total lesion volume on T2-weighted images, total number of Gd-enhancing lesions on T1-weighted images, volume of grey and white matter, EDSS, MSFC, relapse rate, number of relapse-free patients and neutralizing antibodies did not show significant differences either. The combination therapy was well tolerated.

Conclusions

Atorvastatin 40 mg/day in addition to IFNB-1b did not have any beneficial effects on RRMS compared to IFNB-1b monotherapy over a period of 24 months.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01111656","term_id":"NCT01111656"}}NCT01111656     

Safety of mapping in the sinus of valsalva region under intracardiac echocardiography guidance without angiography

BackgroundRadiofrequency ablation at the region of the sinus of Valsalva carries a risk to the ostia of the coronary arteries. Coronary angiography is usually utilized to document a safe distance for mapping and ablation.ObjectiveTo show that catheter ablation in the aortic root could be guided by phased-array intra cardiac echocardiography (ICE) and electro anatomic mapping without the need for coronary angiography.MethodsWe reviewed all patients referred to our lab that underwent mapping and/or ablation in the sinus of Valsalva region. Procedures were carried out by operators that are skilled in the use of ICE. The need for angiography was documented, also the rate of success along with the immediate and 30-day complications rate.ResultsSeventy patients (average age 48.7 ± 13.8 years; 64.3% males) were referred for ablation of ventricular and atrial arrhythmias. PVC constituted 95.7% of the cases. All patients underwent mapping and/or ablation at the sinus of Valsalva region without the need for coronary angiography to visualize the coronary ostia. Acute and effective ablation was achieved in 57 out of 70 (81.4%) patients partially effective ablation was achieved in 10 (14.3%) patients, and failure to ablate in the remaining 3 patients (4.3%). There was no occurrence of any adverse events, neither immediately or at day 30 after the procedure.ConclusionIn the hands of experienced operators, mapping and radiofrequency ablation in the sinus of Valsalva can be safely and reliably performed using intracardiac echocardiography alone without the need for supplementary catheter coronary angiography.     

Characterizing asymmetry across the whole sit to stand movement in healthy participants

Sit-to-stand transfer (STS) is a common yet critical prerequisite for many daily tasks. Literature conducted on healthy STS often assume the body to behave symmetrically across the left and right side; yet only a few studies have been conducted to investigate this supposition. These studies have focused on a single numerical indicator such as peak joint moment (JM) values to describe symmetricity; however, STS is a dynamic and time dependent movement. This study addresses the validity of peak value analyses through the introduction of a time based peak-offset measure and proposes two time-dependent techniques to further characterize asymmetry and assesses their feasibility in ten (10) healthy male participants. JM and joint power (JP) over the whole STS movement was determined using motion capture and inverse dynamics. Using a paired one-tailed t-test differences were found in the time at which the left and right side reached peak values in all lower extremity joints (p<0.05) with exception of the hip JM. Using a measure of JM and JP straight-difference it was determined that the ankle joint displayed the largest number of JM and JP development strategies of all the lower extremity joints. Finally, through numerical integration of the JM and JP data with respect to time, it was found that the longer one side spends dominating the movement, the larger the excess angular impulse and work that can be expected from that side. The results suggest that when analyzing STS movements, one must be aware of the potential asymmetry present even in healthy movements. Furthermore, a simple peak JM or JP analysis may not fully describe the extent of these asymmetries.     

Reduced Levels of Brain Derived Neurotrophic Factor (BDNF) in the Serum of Diabetic Retinopathy Patients and in the Retina of Diabetic Rats

Diabetic retinopathy (DR) is widely recognized as a neurovascular disease. Retina, being a neuronal tissue of the eye, produces neurotrophic factors for its maintenance. However, diabetes dysregulates their levels and thereby may damage the retina. Among neurotrophins, brain derived neurotrophic factor (BDNF) is the most abundant in the retina. In this study, we investigated the level of BDNF in the serum of patients with DR and also in the serum and retina of streptozotocin-induced diabetic rats. The level of BDNF was significantly decreased in the serum of proliferative diabetic retinopathy patients as compared to that of non-diabetic healthy controls (25.5 ± 8.5–10.0 ± 8.1 ng/ml, p < 0.001) as well as compared to that of diabetic patients with no retinopathy (21.8 ± 4.7–10.0 ± 8.1 ng/ml, p < 0.001), as measured by ELISA techniques. The levels of BDNF in the serum and retina of diabetic rats were also significantly reduced compared to that of non-diabetic controls (p < 0.05). In addition, the expression level of tropomyosin-related kinase B (TrkB) was significantly decreased in diabetic rat retina compared to that of non-diabetic controls as determined by Western blotting technique. Caspase-3 activity was increased in diabetic rat retina after 3 weeks of diabetes and remained elevated until 10 weeks, which negatively correlated with the level of BDNF (r = ?0.544, p = 0.013). Our results indicate that reduced levels of BDNF in diabetes may cause apoptosis and neurodegeneration early in diabetic retina, which may lead to neuro-vascular damage later in DR.     

A Combination of Chemosensory and Mechanosensory Stimuli Triggers the Male Mating Response in the Giant Rotifer Asplanchna sieboldi

The rotifer Asplanchna sieboldi performs several well-defined behavioural responses to external stimuli. Contact of male and female occasionally elicits a mating response in the male. The mating response is composed of a series of distinct behavioural elements. After the initial contact, the male stretches out its body wall outgrowths, arcs into a characteristic mating posture and glides along the surface of the female until the penis becomes attached to the female's body wall, through which the spermatozoa are injected. Under experimental conditions, the mating response could be evoked by stimulation with agar spheres that were impregnated with extracts prepared from females, while agar spheres prepared from buffer only did not cause any mating response. If the active substance was added directly to the suspending medium in the observation chamber, mating could be triggered just by mechanical stimulation. It is concluded that the mating response is triggered by a combination of chemical and mechanical stimuli. During the time course of the experiment there was no adaptation to the chemical stimulus. The receptor cells involved in the perception of the two stimuli remain to be identified. The mating response suppressed other behavioural responses that are usually triggered by tactile stimulation of the apical mechanosensors, suggesting that signal processing by the nervous system occurs.     

Two novel RAD21 mutations in patients with mild Cornelia de Lange syndrome-like presentation and report of the first familial case

Cornelia de Lange syndrome (CdLS) is a developmental disorder characterized by limb reduction defects, characteristic facial features and impaired cognitive development. Mutations in the NIPBL gene predominate; however, mutations in other cohesin complex genes have also been implicated, particularly in atypical and mild CdLS cases. Missense mutations and whole gene deletions in RAD21 have been identified in children with growth retardation, minor skeletal anomalies and facial features that overlap findings in individuals with CdLS. We report the first intragenic deletion and frameshift mutations identified in RAD21 in two patients presenting with atypical CdLS. One patient had an in-frame deletion of exon 13, while the second patient had a c.592_593dup frameshift mutation. The first patient presented with developmental delay, hypospadias, inguinal hernia and dysmorphic features while, the second patient presented with developmental delay, characteristic facial features, hirsutism, and hand and feet anomalies, with the first patient being milder than the second. The in-frame deletion mutation was found to be inherited from the mother who had a history of melanoma and other unspecified medical problems.     

The Psychosocial Function Of Reincarnation Among Druze In Israel

To gain an understanding of the psychosocial function of reincarnation among Druze, interviews were conducted with nine male subjects who had experienced reincarnation (Notq) and with one or two of their family members. Analysis of these interviews revealed that the onset of Notq typically occurs at between two and five years of age. Five of the subjects had displayed psychological distress in their childhood that was alleviated after the Notq. Once the child has displayed initial indications of reincarnation, such as mentioning names that the family construes as being from a past life, the family takes an active role in constructing the past-life story and matching it to a known real story involving a tragic death. This match creates a new order in the life of the child, the family, and the past-life family. All parties benefit from this new order: the child receives new special attention and love and becomes able to control and manipulate the parents; the parents are relieved because they see the child happy, and benefit from the social attention and regard they receive; and the grieving of the bereaved past-life family is alleviated by the realization that the soul of their lost son still lives. The findings support the sociocognitive notion of the constructing of past memories by the social environment. Additional research that should include data collection from the past-life family and examination of the affinity of reincarnation with dissociation and child abuse is recommended.