A pilot double-blind sham-controlled trial of repetitive transcranial magnetic stimulation for patients with refractory schizophrenia treated with clozapine

Schizophrenia is a complex and heterogeneous psychiatric disorder. Auditory verbal hallucinations occur in 50-70% of patients with schizophrenia and are associated with significant distress, decreased quality of life and impaired social functioning. This study aimed to investigate the effects of active compared with sham 1-Hz repetitive transcranial magnetic stimulation (rTMS) applied to the left temporal-parietal cortex in patients with schizophrenia treated with clozapine. Symptom dimensions that were evaluated included general psychopathology, severity of auditory hallucinations, quality of life and functionality. Seventeen right-handed patients with refractory schizophrenia experiencing auditory verbal hallucinations and treated with clozapine were randomly allocated to receive either active rTMS or sham stimulation. A total of 384 min of rTMS was administered over 20 days using a double-masked, sham-controlled, parallel design. There was a significant reduction in Brief Psychiatric Rating Scale (BPRS) scores in the active group compared with the sham group. There was no significant difference between active and sham rTMS on Quality of Life Scale (QLS), Auditory Hallucinations Rating Scale (AHRS), Clinical Global Impressions (CGI) and functional assessment staging ( FAST) scores. Compared with sham stimulation, active rTMS of the left temporoparietal cortex in clozapine-treated patients showed a positive effect on general psychopathology. However, there was no effect on refractory auditory hallucinations. Further studies with larger sample sizes are needed to confirm these findings. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Characterization of inflammatory responses to eccentric exercise in humans

Eccentric exercise commonly results in muscle damage. The primary sequence of events leading to exercise-induced muscle damage is believed to involve initial mechanical disruption of sarcomeres, followed by impaired excitation-contraction coupling and calcium signaling, and finally, activation of calcium-sensitive degradation pathways. Muscle damage is characterized by ultrastructural changes to muscle architecture, increased muscle proteins and enzymes in the bloodstream, loss of muscular strength and range of motion and muscle soreness. The inflammatory response to exercise-induced muscle damage is characterized by leukocyte infiltration and production of pro-inflammatory cytokines within damaged muscle tissue, systemic release of leukocytes and cytokines, in addition to alterations in leukocyte receptor expression and functional activity. Current evidence suggests that inflammatory responses to muscle damage are dependent on the type of eccentric exercise, previous eccentric loading (repeated bouts), age and gender. Circulating neutrophil counts and systemic cytokine responses are greater after eccentric exercise using a large muscle mass (e.g. downhill running, eccentric cycling) than after other types of eccentric exercise involving a smaller muscle mass. After an initial bout of eccentric exercise, circulating leukocyte counts and cell surface receptor expression are attenuated. Leukocyte and cytokine responses to eccentric exercise are impaired in elderly individuals, while cellular infiltration into skeletal muscle is greater in human females than males after eccentric exercise. Whether alterations in intracellular calcium homeostasis influence inflammatory responses to muscle damage is uncertain. Furthermore, the effects of antioxidant supplements are variable, and the limited data available indicates that anti-inflammatory drugs largely have no influence on inflammatory responses to eccentric exercise. In this review, we compare local versus systemic inflammatory responses, and discuss some of the possible mechanisms regulating the inflammatory responses to exercise-induced muscle damage in humans.

Episodic and semantic memory in children with mesial temporal sclerosis

The aim of this study was to analyze semantic and episodic memory deficits in children with mesial temporal sclerosis (MTS) and their correlation with clinical epilepsy variables. For this purpose, 19 consecutive children and adolescents with MTS (8 to 16 years old) were evaluated and their performance on five episodic memory tests (short- and long-term memory and learning) and four semantic memory tests was compared with that of 28 healthy volunteers. Patients performed worse on tests of immediate and delayed verbal episodic memory, visual episodic memory, verbal and visual learning, mental scanning for semantic clues, object naming, word definition, and repetition of sentences. Clinical variables such as early age at seizure onset, severity of epilepsy, and polytherapy impaired distinct types of memory. These data confirm that children with MTS have episodic memory deficits and add new information on semantic memory. The data also demonstrate that clinical variables contribute differently to episodic and semantic memory performance. (C) 2011 Elsevier Inc. All rights reserved.

Functional MR Imaging of visuo-spatial network in Autism Spectrum Disorder

Individuals with Autism Spectrum Disorder (ASD) are generally thought to have impaired attentional and executive function upon which all their cognitive and behaviour functions are based. Mental Rotation is a recognized visuo-spatial task, involving spatial working memory, known to involve activation in the fronto-parietal networks. To elucidate the functioning of fronto-parietal networks in ASD, the aim of this study was to use fMRI techniques with a mental rotation task, to characterize the underlying functional neural system. Sixteen male participants (seven highfunctioning autism or Asperger's syndrome; nine ageand performance IQ-matched controls) underwent fMRI. Participants were presented with 18 baseline and 18 rotation trials, with stimuli rotated 3- dimensionaUy (45°-180°). Data were acquired on a 3- Tesla scanner. The most widely accepted area reported to be involved in processing of visuo-spatial information. Posterior Parietal Cortex, was found to be activated in both groups, however, the ASD group showed decreased activation in cortical and subcortical frontal structures that are highly interconnected, including lateral and medial Brodmann area 6, frontal eye fields, caudate, dorsolateral prefrontal cortex and anterior cingulate. The suggested connectivity between these regions indicates that one or more circuits are impaired as a result of the disorder. In future it is hoped that we are able to identify the possible point of origin of this dysfunction, or indeed if the entire network is dysfunctional.

Measurement of anxiety symptoms in older adults: The geriatric anxiety inventory

A measure of dimensional anxiety specifically designed for use in older people is urgently needed. Such a measure could be used in a variety of settings to screen for anxiety disorders and to measure response to treatment in older people with established anxiety disorders. We have developed a new instrument to measure generalized anxiety symptoms in older people, the Geriatric Anxiety Inventory (GAI). This new instrument uses plain language, minimises somatic items and has a dichotomous response scale. Although it is a self-report measure, it may readily be administered to frail and mildly cognitively impaired older people by nursing staff. The development and initial validation of the GAI will be described. The scale was administered to community samples as well as patients with anxiety, depression, and mild cognitive impairment. Reliability was high and validity sound when compared to a range of standard anxiety instruments, and the instrument was well-tolerated among these cohorts. Sensitivity, specificity and cut-off scores for community and impatient samples will be presented.

Mucociliary clearance in patients with chronic asthma: Effects of beta(2) agonists

Chronic asthma is characterized by airway inflammation, mucus hypersecretion and impaired mucociliary clearance (MCC). We investigated baseline MCC and the acute effect of terbutaline in chronic asthmatics with sputum production while on long-term treatment with salmeterol in combination with inhaled corticosteroids (ICS). MCC was measured at baseline and in response to 1 mg terbutaline (or placebo) on three visits over 80 min in 16 asthmatics (52 +/- 13 years of age). Subjects who had greater than 10% absolute increase in MCC above baseline and placebo, after terbutaline, were categorized in group A and subjects who had less than 10% in group B. In group A subjects (n = 6), MCC increased from 23.7 +/- 4.0% at baseline to 43.7 +/- 4.9% with terbutaline (P < 0.0001) and to 34.4 +/- 5.7% with placebo (P < 0.01). In group B subjects (n = 10), MCC remained similar: 11.3 +/- 3.2% at initial baseline, 12.0 +/- 3.2% with terbutaline and 7.3 +/- 3.0% with placebo (P > 0.05). Group B subjects withdrew from all beta(2) agonists for a week and MCC was remeasured. After withdrawal, baseline MCC (7.0 +/- 1.8%) was similar to the initial baseline value (P > 0.1) and MCC with terbutaline (15.8 +/- 4.9%) was greater than baseline (P < 0.005) but remained abnormal in most subjects. Baseline percentage predicted FEV1 and FEF25-75% were 77.3 +/- 7.2 and 41.7 +/- 5.6 in group A and 59.9 +/- 8.1 and 29.5 +/- 8.4 in group B subjects, respectively. MCC was impaired in most of these asthmatics with persistent airway obstruction and sputum production, despite regular treatment with ICS and salmeterol. In addition, there was little or no stimulation of MCC acutely after terbutaline in most of these asthmatics.

The common p450 oxidoreductase variant A503V is not a modifier gene for 21-hydroxylase deficiency

Context: 21-hydroxylase deficiency (21OHD) is a common genetic disorder caused by mutations in the CYP21A2 gene, which encodes the adrenal 21-hydroxylase, microsomal P450c21. CYP21A2 gene mutations generally correlate well with impaired P450c21 enzymatic activity and the clinical findings in 21OHD, but occasional discrepancies between genotype and phenotype suggest the effects of modifier genes. Mutations in P450 oxidoreductase (POR), the protein that transfers electrons from reduced nicotinamide adenine dinucleotide phosphate to all microsomal P450s, can ameliorate the 21OHD phenotype and, therefore, could be a modifier gene. Objectives: We sought to identify POR variants in patients with 21OHD having discordant phenotype and genotype, and to evaluate their effect on 21-hydroxylase activity. Patients and Methods: We determined the CYP21A2 genotypes of 313 Brazilian patients with 21OHD and correlated the genotype and phenotype. The POR gene was sequenced in 17 patients with discordant genotype and phenotype. Wild-type and A503V POR, and P450c21 were expressed in bacteria and reconstituted in vitro. Activities were assayed by conversion of [C-14] progesterone to deoxycorticosterone and [H-3]17-hydroxyprogesterone to 11-deoxycortisol, and assessed by thin layer chromatography and phosphorimaging. Results: The A503V POR variant was found in 10 of 30 alleles, the same ratio as in the normal population. There were no significant differences in Michaelis constant, maximum velocity and maximum velocity/Michaelis constant of 21-hydroxylase activity supported by wild-type and A503V POR. Conclusion: The only POR missense polymorphism found in atypical 21OHD patients was A503V. Although A503V reduces P450c17 enzymatic activity, it does not influence P450c21 activity, indicating that POR A503V does not modify the 21OHD phenotype.

Visuospatial processing and the function of prefrontal-parietal networks in autism spectrum disorders: a functional MRI study

Objective: Individuals with autism spectrum disorders typically have normal visuospatial abilities but impaired executive functioning, particularly in abilities related to working memory and attention. The aim of this study was to elucidate the functioning of frontoparietal networks underlying spatial working memory processes during mental rotation in persons with autism spectrum disorders. Method: Seven adolescent males with normal IQ with an autism spectrum disorder and nine age- and IQ-matched male comparison subjects underwent functional magnetic resonance imaging scans while performing a mental rotation task. Results: The autism spectrum disorders group showed less activation in lateral and medial premotor cortex, dorsolateral prefrontal cortex, anterior cingulate gyrus, and caudate nucleus. Conclusions: The finding of less activation in prefrontal regions but not in parietal regions supports a model of dysfunction of frontostriatal networks in autism spectrum disorders.

An examination of movement kinematics in young people with high-functioning autism and Asperger's disorder: Further evidence for a motor planning deficit

This paper examines upper-body movement kinematics in individuals with high-functioning autism (HFA) and Asperger's disorder (AD). In general, the results indicate that HFA is more consistently associated with impaired motoric preparation/initiation than AD. The data further suggest that this quantitative difference in motor impairment is not necessarily underpinned by greater executive dysfunction vulnerability in autism relative to AD. Quantitative motoric dissociation between autism and AD may have down-stream effects on later stages of movement resulting in qualitative differences between these disorder groups, e.g. motor clumsiness in AD versus abnormal posturing in autism. It will be important for future research to map the developmental trajectory of motor abnormalities in these disorder groups.

Laparoscopic treatment of type 2 diabetes mellitus for patients with a body mass index less than 35

Background Type 2 diabetes mellitus (T2DM) is a common disease with numerous complications. Bariatric surgery is an efficient procedure for controlling T2DM in morbidly obese patients. In T2DM, the incretin effect is either greatly impaired or absent. This study aimed to evaluate the preliminary results from interposing a segment of ileum into the proximal jejunum associated with a sleeve or diverted sleeve gastrectomy to control T2DM in patients with a body mass index (BMI) less than 35 kg/m(2). Methods For this study, 39 patients (16 women and 23 men) underwent two laparoscopic procedures comprising different combinations of ileal interposition into the proximal jejunum via a sleeve or diverted sleeve gastrectomy. The mean age of these patients was 50.3 years (range, 36-66 years). The mean BMI was 30.1 kg/m(2) (range, 23.4-34.9 kg/m(2)). All the patients had a diagnosis of T2DM that had persisted for at least 3 years and evidence of stable treatment with oral hypoglycemic agents or insulin for at least 12 months. The mean duration of T2DM was 9.3 years (range, 3-22 years). Results The mean operative time was 185 min, and the median hospital stay was 4.3 days. Four major complications occurred in the short term (30-days), and the mortality rate was 2.6%. The mean postoperative follow-up period was 7 months (range, 4-16 months), and the mean percentage of weight loss was 22%. The mean postoperative BMI was 24.9 kg/m(2) (range, 18.9-31.7 kg/m2). An adequate glycemic control was achieved for 86.9% of the patients, and 13.1% had important improvement. The patients whose glycemia was not normalized were using a single oral hypoglycemic agent. No patient needed insulin therapy postoperatively. All the patients except experienced normalization of their cholesterol levels. Targeted triglycerides levels were achieved by 71% of the patients, and hypertension was controlled for 95.8%. Conclusions The laparoscopic ileal interposition via either a sleeve gastrectomy or diverted sleeve gastrectomy seems to be a promising procedure for the control of T2DM and the metabolic syndrome. A longer follow-up period is needed.

Two distinct regions in 2q24.2-q24.3 associated with idiopathic epilepsy

P>Approximately 50% of all carriers of 2q21-q31 deletions present epileptic seizures. The band 2q24 constitutes the smallest commonly deleted segment in these patients, and contains the voltage-gated sodium channel genes SCN1A and SCN2A, associated with Dravet syndrome and benign familial neonatal-infantile seizures, respectively. A further putative locus involving epilepsy in the region was previously identified through disruption of the SLC4A10 gene by translocation. In the course of performing high-resolution DNA copy number analyses on syndromic mentally impaired individuals, we encountered three patients with overlapping deletions in chromosome region 2q24. Two of these patients exhibited epileptic seizures in addition to mental deficiency. The deletion in one of the epileptic patients did not include the SCN cluster, demonstrating that a less severe form of epilepsy maps to an adjacent genomic region. This second region comprises about 3 Mb and contains the candidate gene SLC4A10, providing further support for the potential role of this gene in epilepsy.

A comparison of computer-based methods for the determination of onset of muscle contraction using electromyography

Little consensus exists in the literature regarding methods for determination of the onset of electromyographic (EMG) activity. The aim of this study was to compare the relative accuracy of a range of computer-based techniques with respect to EMG onset determined visually by an experienced examiner. Twenty-seven methods were compared which varied in terms of EMG processing (low pass filtering at 10, 50 and 500 Hz), threshold value (1, 2 and 3 SD beyond mean of baseline activity) and the number of samples for which the mean must exceed the defined threshold (20, 50 and 100 ms). Three hundred randomly selected trials of a postural task were evaluated using each technique. The visual determination of EMG onset was found to be highly repeatable between days. Linear regression equations were calculated for the values selected by each computer method which indicated that the onset values selected by the majority of the parameter combinations deviated significantly from the visually derived onset values. Several methods accurately selected the time of onset of EMG activity and are recommended for future use. Copyright (C) 1996 Elsevier Science Ireland Ltd.

A prospective study evaluating the efficacy of the artificial sphincter AMS 800 for the treatment of postradical prostatectomy urinary incontinence and the correlation between preoperative urodynamic and surgical outcomes

OBJECTIVES We have evaluated prospectively the long-term efficacy of the artificial urinary sphincter (AUS) AMS 800 for the treatment postradical prostatectomy urinary incontinence (PRPUI) patients. We also evaluated the correlation between preoperative urodynamic findings and surgical outcomes. METHODS From May 1997 to April 2003, 40 consecutive patients with PRPUI caused by intrinsic sphincter deficiency (ISD) were treated with the AMS 800. Mean age was 68.3 +/- 6.3 years. Continence status was evaluated on the basis of pad count, impact of urinary incontinence on the quality of life, complications, and surgical revisions. Preoperative urodynamic findings were correlated with surgical outcomes. RESULTS Follow-up ranged from 27 to 132 months (mean = 53.4 +/- 21.4 months). There was a significant reduction in pad count from 4.0 +/- 0.9 to 0.62 +/- 1.07 diapers per day (P <0.001) leading to continence in 90%. There was a significant reduction on the impact of incontinence decreasing from 5.0 +/- 0.7 to 1.4 +/- 0.93 (P <0.001) in a visual analogue scale (VAS). Surgical revision rate was 20%. Preoperative urodynamics was useful to identify sphincter deficiency. Except by a tendency of worse results in patients with reduced bladder compliance (RBC), other urodynamic parameters did not correlate with a worse surgical outcome. CONCLUSIONS The AMS 800 offers good long-term continence to most PRPUI patients. Preoperative findings like detrusor hyperactivity (DH), impaired detrusor contraction (IDC), low Valsalva leak point pressure, bladder outlet obstruction (BOO), and mild RBC were not associated with worse surgical outcomes.

The Role of Membranous Urethral Afferent Autonomic Innervation in the Continence Mechanism After Nerve Sparing Radical Prostatectomy: A Clinical and Prospective Study

Purpose: We evaluated the somatic and autonomic innervation of the pelvic floor and rhabdosphincter before and after nerve sparing radical retropubic prostatectomy using neurophysiological tests and correlated findings with clinical parameters and urinary continence. Materials and Methods: From February 2003 to October 2005, 46 patients with prostate cancer were enrolled in a controlled, prospective study. Patients were evaluated before and 6 months after nerve sparing radical retropubic prostatectomy using the UCLA-PCI urinary function domain and neurophysiological tests, including somatosensory evoked potential, and the pudendo-urethral, pudendo-anal and urethro-anal reflexes. Clinical parameters and urinary continence were correlated with afferent and efferent innervation of the membranous urethra and pelvic floor. We used strict criteria to define urinary continence as complete dryness with no leakage at all, not requiring any pads or diapers and with a UCLA-PCI score of 500. Patients with a sporadic drop of leakage, requiring up to 1 pad daily, were defined as having occasional urinary leakage. Results: Two patients were excluded from study due to urethral stricture postoperatively. We evaluated 44 patients within 6 months after surgery. The pudendo-anal and pudendo-urethral reflexes were unchanged postoperatively (p = 0.93 and 0.09, respectively), demonstrating that afferent and efferent pudendal innervation to this pelvic region was not affected by the surgery. Autonomic afferent denervation of the membranous urethral mucosa was found in 34 patients (77.3%), as demonstrated by a postoperative increase in the urethro-anal reflex sensory threshold and urethro-anal reflex latency (p<0.001 and 0.0007, respectively). Six of the 44 patients used pads. One patient with more severe leakage required 3 pads daily and 23 showed urinary leakage, including 5 who needed 1 pad per day and 18 who did not wear pads. Afferent autonomic denervation at the membranous urethral mucosa was found in 91.7% of patients with urinary leakage. Of 10 patients with preserved urethro-anal reflex latency 80% were continent. Conclusions: Sensory and motor pudendal innervation to this specific pelvic region did not change after nerve sparing radical retropubic prostatectomy. Significant autonomic afferent denervation of the membranous urethral mucosa was present in most patients postoperatively. Impaired membranous urethral sensitivity seemed to be associated with urinary incontinence, particularly in patients with occasional urinary leakage. Damage to the afferent autonomic innervation may have a role in the continence mechanism after nerve sparing radical retropubic prostatectomy.

The p.A2215D Thyroglobulin Gene Mutation Leads to Deficient Synthesis and Secretion of the Mutated Protein and Congenital Hypothyroidism with Wide Phenotype Variation

Context: Thyroglobulin (TG) is a large glycoprotein and functions as a matrix for thyroid hormone synthesis. TG gene mutations give rise to goitrous congenital hypothyroidism (CH) with considerable phenotype variation. Objectives: The aim of the study was to report the genetic screening of 15 patients with CH due to TG gene mutations and to perform functional analysis of the p. A2215D mutation. Design: Clinical evaluation and DNA sequencing of the TG gene were performed in all patients. TG expression was analyzed in the goitrous tissue of one patient. Human cells were transfected with expression vectors containing mutated and wild-type human TG cDNA. Results: All patients had an absent rise of serum TG after stimulation with recombinant human TSH. Sequence analysis revealed three previously described mutations (p. A2215D, p. R277X, and g. IVS30 + 1G > T), and two novel mutations (p. Q2142X and g. IVS46-1G > A). Two known (g. IVS30 + 1G/p. A2215D and p. A2215D/p. R277X) and one novel (p. R277X/g. IVS46-1G > A) compound heterozygous constellations were also identified. Functional analysis indicated deficiency in TG synthesis, reduction of TG secretion, and retention of the mutant TG within the cell, leading to an endoplasmic reticulum storage disease, whereas small amounts of mutant TG were still secreted within the cell system. Conclusion: All studied patients were either homozygous or heterozygous for TG gene mutations. Two novel mutations have been detected, and we show that TG mutation p. A2215D promotes the retention of TG within the endoplasmic reticulum and reduces TG synthesis and secretion, causing mild hypothyroidism. In the presence of sufficient iodine supply, some patients with TG mutations are able to compensate the impaired hormonogenesis and generate thyroid hormone. (J Clin Endocrinol Metab 94: 2938-2944, 2009)