<Emphasis Type="Italic">MED13L</Emphasis>-related intellectual disability: involvement of missense variants and delineation of the phenotype

Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to “MED13L haploinsufficiency syndrome.” Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15–17 and 25–31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition.     

Antipsychotic Dose in Acute Schizophrenia: A Meta-analysis

Little is known regarding optimal antipsychotic doses in the acute phase of schizophrenia. The aim of the present study was to employ the concept of minimum effective dose (MED) in examining efficacy and tolerability within this population. MED was identified for each antipsychotic through a previous systematic review. We then identified double-blind placebo-controlled randomized trials that involved fixed-dose antipsychotic monotherapy in acute schizophrenia and compared the identified MED vs higher doses of the same oral antipsychotic. Studies were selected from a recent meta-analysis examining dose–response relationship of second-generation antipsychotics and haloperidol. We extracted the data on study discontinuation, psychopathology, extrapyramidal symptoms, and treatment-emergent adverse events. For each antipsychotic, we conducted a meta-analysis to compare outcomes between MED and 2-fold MED, and MED and 3-fold MED. A total of 26 studies involving 5618 patients were included in the meta-analysis. In terms of study discontinuation, significant differences were found in study discontinuation due to lack of efficacy between MED and higher doses, in favor of 2-fold and 3-fold MEDs. Regarding psychopathology, both 2-fold and 3-fold MEDs were superior to MED for total and positive symptom scores. As for side effects, 2-fold MED proved inferior to MED for parkinsonism scores and diarrhea, whereas 3-fold MED was inferior for akathisia, somnolence, and vomiting. Findings suggest that clinicians can dose an antipsychotic at 2-fold or 3-fold MED for patients with acute schizophrenia but should closely monitor side effects.     

Nerve transplantation shows that motor end-plate disease is not a primary Schwann cell defect

Motor end-plate diseased (MED) mice have altered nerve impulse conduction velocities and refractory periods. To test whether these pathological properties are caused by a primary Schwann cell defect, nerves were transplanted from MED and wildtype (WT) animals onto WT recipients. The donor origin of cells in the regenerated nerve was assessed by prelabeling with [3H]thymidine and by electrophoretic analysis of glucose phosphate isomerase allotypes. Nerve fiber regeneration through MED and WT implants was equally efficient. No difference was found in nerve conductivities of MED and WT grafts. Therefore a primary defect in the Schwann cells of the MED mouse is unlikely.     

Dialectical behavior therapy for depressed older adults: a randomized pilot study.

OBJECTIVE: Although there is evidence for the efficacy of antidepressants and for some individual and group psychotherapy interventions for depressed older adults, a significant number of these do not respond to treatment. Authors assessed the benefits of augmenting medication with group psychotherapy. METHODS: They randomly assigned 34 (largely chronically) depressed individuals age 60 and older to receive 28 weeks of antidepressant medication plus clinical management, either alone (MED) or with the addition of dialectical behavior therapy skills-training and scheduled telephone coaching sessions (MED+DBT). RESULTS: Only MED+DBT showed significant decreases on mean self-rated depression scores, and both treatment groups demonstrated significant and roughly equivalent decreases on interviewer-rated depression scores. However, on interviewer-rated depression, 71% of MED+DBT patients were in remission at post-treatment, in contrast to 47% of MED patients. At a 6-month follow-up, 75% of MED+DBT patients were in remission, compared with only 31% of MED patients, a significant difference. Only patients receiving MED+DBT showed significant improvements from pre- to post-treatment on dependency and adaptive coping that are proposed to create vulnerability to depression. CONCLUSION: Results from this pilot study suggest that DBT skills training and telephone coaching may offer promise to effectively augment the effects of antidepressant medication in depressed older adults.     

Treatment of older adults with co-morbid personality disorder and depression: a dialectical behavior therapy approach

BACKGROUND AND SIGNIFICANCE: The treatment of personality disorders in older adults, particularly those co-morbid with other Axis I disorders (e.g., Major Depressive Disorder), is an understudied clinical phenomenon. It has also been demonstrated that personality disorders in older adults complicate treatment of other psychopathology, as well as result in heightened interpersonal disturbance and emotional distress. METHODS: Two studies utilizing standard Dialectical Behavior Therapy (DBT) to treat depression and personality disorders in older adults are reviewed. Study 1 examined 34 chronically depressed individuals aged 60 and older who were randomly assigned to receive 28 weeks of antidepressant medication plus clinical management, either alone (MED) or with the addition of DBT skills-training and scheduled telephone coaching sessions (MED + DBT). Study 2 had two phases of treatment: Phase I: 8-week open-trial of antidepressant medication (n = 65); Phase II: 24-week randomized trial of DBT + MED versus MED alone for those who prospectively failed to respond to the Phase I medication trial (n = 37). RESULTS: Study 1 demonstrated that 71% of MED + DBT patients were in remission at post-treatment, in contrast to 47% of MED patients. This became a significant difference at the 6-month follow-up; where 75% of MED + DBT-D patients were in remission compared with only 31% of MED patients. Study 2 showed that after 8 weeks of treatment with antidepressant medication alone (Phase 1) only 14% of the sample had at least a 50% reduction in HAM-D scores. Phase II results showed on average, the DBT + MED group reached depression remission by the post-group assessment and maintained these gains while the MED group did not reach remission, until the follow-up assessment. Results demonstrated superiority of DBT + MED compared to MED alone on Interpersonal Sensitivity and Interpersonal Aggression at post-treatment and 6-month follow-up. CONCLUSION: Results from these two treatment development studies indicate that applying standard DBT for the treatment of co-morbid MDD or MDD + PD in older adults is feasible, acceptable, and has clinical promise. Modifications to standard DBT and an overview of a new treatment manual for this population are summarized.     

A new planar multielectrode array for extracellular recording: application to hippocampal acute slice

The present paper describes a new planar multielectrode array (the MED probe) and its electronics (the MED system) which perform electrophysiological studies on acute hippocampal slices. The MED probe has 64 planar microelectrodes, is covered with a non-toxic, uniform insulation layer, and is further coated with polyethylenimine and serum. The MED probe is shown to be appropriate for both stimulation and recording. In particular, multi-channel recordings of field EPSPs obtained by stimulating with a pair of planar microelectrodes were established for rat hippocampal acute slices. The recordings were stable for 6 h. Finally a spatial distribution of long-term potentiation was studied using the MED system.     

Neurocognitive deficits in medulloblastoma survivors and white matter loss

Although previous studies have documented a significant risk of intellectual loss after treatment for childhood medulloblastoma (MED), the pathophysiology underlying this process is poorly understood. The purpose of this study was to test the hypotheses that (1) patients treated for MED in childhood have reduced volumes of normal white matter (NWM) related to their treatment with craniospinal irradiation with or without chemotherapy, and (2) deficits in NWM among patients surviving MED can at least partially explain deficits in their intellectual performance. Eighteen pediatric patients previously treated for MED were matched on the basis of age at the time of evaluation to 18 patients previously treated for low-grade posterior fossa tumors with surgery alone (mean difference, 3.7 months). Evaluations were conducted with age-appropriate neurocognitive testing and quantitative magnetic resonance imaging by using a novel automated segmentation and classification algorithm constructed from a hybrid neural network. Patients treated for MED had significantly less NWM (p < 0.01) and significantly lower Full-Scale IQ values than those treated for low-grade tumors (mean, 82.1 vs 92.9). In addition, NWM had a positive and statistically significant association with Full-Scale IQ among the patients treated for MED. We conclude that irradiation- or chemotherapy-induced destruction of NWM can at least partially explain intellectual and academic achievement deficits among MED survivors.     

Charcot-Marie-Tooth disorders with an autosomal recessive mode of inheritance

In recent years, 13 loci and 10 genes have been identified in Charcot-Marie-Tooth disorders with a recessive mode of inheritance (AR-CMT). Accordingly, the entity of AR-CMT has been divided into subgroups on the basis of genetic linkage. Mutations in the MTMR2, MTMR13, GDAP1, PRX, CTDPI, KIAA1985 and NDRG1 genes have been shown to be associated with specific CMT phenotypes. In AR-CMT disorders associated with mutations in the LMNA and MED25 genes the number of patients is still too low to achieve reliable phenotype-genotype correlations. In the present review, we summarize molecular, electrophysiological, neuropathological and clinical aspects of AR-CMT disorders.     

Microendoscopic discectomy (MED) for lumbar disc prolapse.

Microendoscopic discectomy (MED), which combines traditional lumbar microsurgical techniques with endoscopy, is being used as a minimally invasive procedure for lumbar disc herniation. We reviewed 30 patients who underwent MED at our institution and compared their outcome with that of patients subjected to the conventional method. Laboratory data suggested that MED was less invasive surgery. Moreover, MED allowed an early return to work. However, the difficulties of this endoscopic procedure were evident, because of the limited exposure and two-dimensional video display. The potential injury of the nerve root and prolonged surgical time remain as matters of serious concern. To overcome this problem, we used an operative magnifying glass during surgery and this helped us to accomplish the procedure comfortably. We recommend the use of an operative magnifying glass in the early stage of the introduction of MED, for it is quite useful to identify the three-dimensional relationships of the structures.     

Locomotor projections from the pedunculopontine nucleus to the medioventral medulla

Retrograde tracers were injected into the rat medioventral medulla (MED) and the injection site was identified as a locomotion- inducing area by electrical stimulation in the decerebrate preparation. Histological reconstructions showed that about 10% of cholinergic pedunculopontine (PPN) and laterodorsal tegmental (LDT) neurons project to the MED. Also, large numbers of non-cholinergic cells in and around the PPN and LDT were found to project to the MED.     

Motor end-plate disease is expressed in congenitally athymic mice

To test a possible interaction between a neuromuscular disease and thymus function in the mouse, the homozygous condition $\text{med}\text{med}$ for motor end-plate disease (MED) was combined with that for the nude gene ($\text{nu}\text{nu}$). Five nude MED animals (expectation 11 animals) were observed among 181 F2 progeny. Their weight was severely reduced already at 9 to 10 postnatal days, and they died earlier than their nonnude MED littermates. Thus a thymogenic etiology of the MED phenotype is excluded.     

Erection induced hallucinations

Eclectic treatment approaches to male erectile disorder (MED) may be neglected. A case report of treating a man with schizophrenia and multi-aetiological MED with intra-cavernous injections of prostaglandin E, is presented. Restoration of erectile capacity precipitated psychological and psychiatric reactions which were considered deleterious to the patient. It is concluded that consideration must be given to both psychological and physical aspects of treatment in MED.     

Medioventral medulla-induced locomotion

Previous anatomical studies demonstrated the presence of descending projections from the physiologically identified mesencephalic locomotor region (MLR) to the medioventral medulla (MED) in the cat. The present experiments were designed to determine if a similar low threshold locomotion-inducing area is present in the rat medulla. In addition, the nature of the neurochemical control of this area of the brain was explored using localized injections of neurochemical agents in the decerebrate rat during locomotion on a treadmill. A region virtually identical to that reported in the cat was found to lead to controlled locomotion on a treadmill following stimulation at low amplitude currents (less than or equal to 60 microA). Injections of cholinergic agonists into the MED of the rat induced locomotion which could be blocked by injections of cholinergic antagonists. In addition, injections of GABA antagonists were found to induce stepping which could be blocked by injections of GABA or GABA agonists. Substance P (SP) also was found to induce walking following injection into the MED of the rat. Injections of an excitatory amino acid agonist (NMDA) also were found to induce locomotion in the rat. These effects were blocked by injections of an excitatory amino acid antagonist (APV). Since these results had not been reported for the cat MED, a short series of experiments revealed that the MED in the cat also responded to NMDA.     

Serotonergic involvement in methamphetamine-induced locomotor activity: a detailed pharmacological study

The mechanism by which the psychostimulant methamphetamine (METH) increases locomotor activity may be attributable to indirect activation of serotonin (5-HT) and dopamine (DA) receptors. In the present study, the ability of the serotonin reuptake inhibitor fluvoxamine, 5-HT(1A), 5-HT(1B), 5-HT(2A) and 5-HT(2C) receptor antagonists WAY100635, GR127935, M100907 and SB242084, and the 5-HT(2C) receptor agonists WAY163909 and Ro 60-0175 or the 5-HT synthesis inhibitor para-chlorophenylalanine (pCPA) to alter METH-induced hyperactivity was analysed. Further, for comparative purposes, the involvement of the DA D(1) and D(2) receptor antagonists SCH23390 and haloperidol, D(2) partial agonists terguride, (-)3PPP and aripiprazole and finally clozapine were assessed. Doses of pCPA that attenuated 5-HT levels reduced METH activity. The 5-HT(1B) antagonist GR127935 had no effect on METH-induced locomotor activity but blocked that induced by MDMA. The 5-HT(1A) antagonist WAY100635 reduced activity but this did not reach significance. In contrast, M100907 (minimal effective dose; MED=0.125 mg/kg), WAY163909 (MED=3mg/kg), Ro 60-0175 (MED=3mg/kg), haloperidol (MED=0.1mg/kg), clozapine (MED=5mg/kg), aripiprazole (MED=1mg/kg), (-)3PPP (MED=3mg/kg), terguride (MED=0.2mg/kg) and SCH23390 (MED=0.001325 mg/kg) attenuated METH-induced locomotor activity. Administration of 20mg/kg fluvoxamine attenuated, while SB242084 (MED=0.25mg/kg) potentiated METH-induced activity. These results contribute significantly to the understanding of the mechanism of action of this psychostimulant and suggest for the first time, that METH-induced locomotor stimulation is modulated by 5-HT(2A) and 5-HT(2C) receptors, but demonstrate that 5-HT(1B) receptors are not directly involved. The involvement of the dopaminergic system was also demonstrated.     

Diagnostic moléculaire des formes axonales de la maladie de Charcot-Marie-Tooth

Charcot-Marie-Tooth (CMT) disease is the most common cause of inherited peripheral neuropathies with a frequency estimated at 1/2500. Electroneuromyographic examination distinguishes a myelinic form (CMT1) and an axonal form of the disease (CMT2). Significant genetic heterogeneity is found in CMT, with 15 genes or loci for CMT2. To date, a molecular diagnosis has not been established for most CMT2 patients and the distribution of identified mutations is wide spreading over nearly all genes. Simple guidelines for daily practice are difficult to establish from compilation of mutation reports or consultation of databases; little simplification can be expected from future findings. We present our results of molecular diagnosis for 251 CMT2 index cases characterized by their mode of inheritance (217 dominant and 34 recessive cases), and a motor conduction velocity in median nerve equal to or above to 38 m/s. For each case, at least one of the genes known to date for CMT2 (MFN2, RAB7, GARS, NF-L, HSPB1, GDAP1, MPZ, HSPB8, GJB1, DNM2, YARS, LMNA, and MED25) was studied. Around 22% of diagnoses were established and efficiency was comparable for dominant or recessive cases. For dominant cases, the first objective was to search for mutations of proteins connexin32, mitofusin2 and P0. For recessive cases, GDAP1 provided the key to molecular diagnosis; lamin A/C mutations were only found for patients with an ethnic background from North Africa. Heat shock proteins HSPB1 and HSPB8 were implicated in a significant proportion of “spinal” (or pure motor) CMT2. NF-L or RAB7 mutations were rare. We did not identify any deleterious mutations in GARS, DNM2, YARS orMED2. We propose a simple decision tree for molecular diagnosis of CMT2.     

Microendoscopic discectomy for prolapsed lumbar intervertebral disc

BACKGROUND: Lumbar disc prolapse is a common problem and the current surgical standard for its treatment is a microsurgical discectomy. Microendoscopic discectomy (MED) is a minimally invasive spinal procedure being done successfully for prolapsed intervertebral disc disease. AIMS: We report the technique, outcome and complications seen in 107 cases of prolapsed lumbar intervertebral disc who underwent MED. SETTING AND DESIGN: The study was carried out at the Department of Neurosurgery, at a tertiary hospital in South India and the data was collected prospectively. MATERIALS AND METHODS: 107 patients with prolapsed lumbar intervertebral disc who were seen at our institution between November 2002 and January 2006 were included in the study. Data was collected prospectively. The METRx system (Medtronic Sofamor Danek, Memphis,TN) was used to perform MED. Outcome assessment was done by the modified Macnab criteria. RESULTS: 107 patients (67 males, 40 females) underwent MED for prolapsed lumbar intervertebral disc. Follow up ranged from 2 to 40 months with a mean follow up 12.9 months. Seventy six patients had an excellent outcome, 22 patients had a good outcome, 5 patients had a fair outcome and 3 patients had a poor outcome. One patient with a long dural tear required conversion to a standard microdiscectomy and was excluded from outcome assessment. Complications included dural puncture with K-wire (1), dural tear (2), superficial wound infection (1), discitis (1) and recurrent disc prolapse (2). CONCLUSIONS: Microendoscopic Discectomy (MED) is a safe and effective procedure for the treatment of prolapsed lumbar intervertebral disc.     

Regulation of rat brain angiotensin II (AII) receptors by intravenous AII and low dietary Na

Previous studies have shown the presence of specific AII receptors at several areas of the brain. The purpose of this study was to examine by radioreceptor assay the effect of intravenous AII infusion (5 or 25 ng/kg/min) and low dietary Na+ (less than 8 mmol/100 g) on AII receptors in five brain regions: the olfactory lobes (OLF), hypothalamus/thalamus/septum (HTS), midbrain (MID), cerebellum (CER) and medulla (MED). Scatchard analysis of binding data from control rats showed significant (P less than 0.01 ANOVA) differences between brain areas in both Ka (1.54 OLF, 1.87 HTS, 1.25 MID, 1.33 MED, 0.77 CER x 10(9) M-1) and Ro (321 OLF, 224 HTS, 203 MID, 145 MED, 41 CER fmol/g tissue). Following the i.v. infusion of AII for 4-7 days, marked changes were observed in the areas with a porous BBB, the HTS and MED. Both the Ka [3.20 (HTS) and 0.67 (MED) x 10(9) M-1] and Ro [116 (HTS) and 249 (MED) fmol/g tissue] changed. In addition, decreases in Ro were also observed in the OLF (241 fmol/g tissue) and CER (21 fmol/g tissue), areas which have not been considered as being accessible to blood-borne AII. A low Na+ diet for 21-30 days changed the Ka and Ro in all five regions but not in similar directions. Furthermore, with the exception of the OLF the direction of change was not similar to that caused by i.v. infusion of AII. It was concluded that AII receptor sites in the rat brain differ from each other in both receptor properties in their response to such regulatory factors as AII Na+ depletion.(ABSTRACT TRUNCATED AT 250 WORDS)     

腰椎间盘镜手术和显微手术治疗腰椎间盘突出症的系统评价

目的 系统评价腰椎间盘镜手术和显微手术治疗腰椎间盘突出症的疗效和安全性.方法 分别以椎间盘镜、显微镜、腰椎间盘突出等相关中英文关键词作为检索词,计算机检索PubMed、EMbase、Cochrane图书馆临床对照试验资料库、中国知网中国期刊全文数据库和万方数据知识服务平台学术期刊库,并对部分杂志进行手工检索,收集椎间盘镜手术和显微手术治疗腰椎间盘突出症的随机对照临床试验.采用Jadad 量表进行文献质量评价,数据提取和文献质量评价由两名评价员独立进行,RevMan 5.0.24 统计软件行Meta分析.结果 共纳入4 项临床研究计1069 例患者.Meta分析结果显示,术后Oswestry 功能障碍指数比较,两种术式间差异无统计学意义(MD = - 0.170,95%CI:- 3.590 ~ 3.260;P = 0.920).椎间盘镜手术患者术中硬脊膜撕裂(RR = 3.040,95%CI:1.170 ~ 7.890;P = 0.020)、神经根损伤(RR = 5.130,95%CI:0.890 ~ 29.420;P = 0.070)等并发症发生率和术后复发率(RR = 2.320,95%CI:0.970 ~ 5.520;P = 0.060)均高于显微手术;两种手术所用时间(MD = 10.780,95%CI:7.180 ~ 14.370;P =0.000)、手术切口长度(MD = - 0.950,95%CI:- 1.840 ~ 0.070;P = 0.030)和术后住院时间(MD = 0.210,95%CI:- 0.080 ~ 0.340;P = 0.002)具有统计学差异,但术中出血量比较差异无统计学意义(MD = 27.420,95%CI:- 8.840 ~ 63.680;P = 0.140).结论 椎间盘镜手术和显微手术治疗腰椎间盘突出症疗效相当,但椎间盘镜手术术后复发率和手术并发症发生率均高于显微手术.鉴于所纳入临床研究的整体质量较低且数量较少,应谨慎引用本研究结果,上述结论尚需更多高质量的随机对照临床试验加以验证.     

Nonlinear measures of heart rate time series: influence of posture and controlled breathing

In this study, we investigated measures of nonlinear dynamics and chaos theory in regards to heart rate variability in 27 normal control subjects in supine and standing postures, and 14 subjects in spontaneous and controlled breathing conditions. We examined minimum embedding dimension (MED), largest Lyapunov exponent (LLE) and measures of nonlinearity (NL) of heart rate time series. MED quantifies the system's complexity, LLE predictability and NL, a measure of deviation from linear processes. There was a significant decrease in complexity (P < 0.00001), a decrease in predictability (P < 0.00001) and an increase in nonlinearity (P = 0.00001) during the change from supine to standing posture. Decrease in MED, and increases in NL score and LLE in standing posture appear to be partly due to an increase in sympathetic activity of the autonomous nervous system in standing posture. An improvement in predictability during controlled breathing appears to be due to the introduction of a periodic component.