Lower circulating kisspeptin and primary hypogonadism in men with type 2 diabetes.

INTRODUCTION: Kisspeptin influence on male androgens is partially understood. We aimed to evaluate serum concentrations of kisspeptin among Ghanaian men with type 2 diabetes and to identify related factors that may contribute to altering circulating kisspeptin. METHODS: A cross-sectional, observational study. Sixty persons with type 2 diabetes and 60 nondiabetic controls were included in this study. Blood pressure, body mass index (BMI), kisspeptin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone (T), glucose (FBG), glycated haemoglobin (HbA1c) and lipid levels were assessed. RESULTS: Type 2 diabetic men had lower kisspeptin and T concentrations than controls (P = 0.001 for both). Levels of LH and FSH were, respectively, higher in diabetic men compared with their control counterparts (P = 0.003; P = 0.017). There were negative associations within the diabetic group for kisspeptin vs age (r = -0.590, P = 0.0001) and kisspeptin vs BMI (r = -0.389, P = 0.002). Positive associations were also found within the diabetic group for kisspeptin vs T (r = 0.531, P = 0.001), kisspeptin vs LH (r = 0.423, P = 0.001) and kisspeptin vs FSH (r = 0.366, P = 0.004). Lower T (OR = 1.473, P = 0.003) and advancing age (OR = 0.890, P = 0.004) contributed to decreased kisspeptin levels among Ghanaian males with type 2 diabetes. CONCLUSION: Our data demonstrate that circulating kisspeptin and T concentrations are lower among men with type 2 diabetes and highlight the importance of considering kisspeptin concentrations in the management of hypogonadism and type 2 diabetes.

Engineered cysteine antibodies: an improved antibody-drug conjugate platform with a novel mechanism of drug-linker stability.

Antibody-drug conjugates (ADCs) are fulfilling the promise of targeted therapy with meaningful clinical success. An intense research effort is directed towards improving pharmacokinetic profiles, toxicity and chemical stability of ADCs. The majority of ADCs use amide and thioether chemistry to link potent cytotoxic agents to antibodies via endogenous lysine and cysteine residues. While maleimide-cysteine conjugation is used for many clinical stage ADC programs, maleimides have been shown to exhibit some degree of post-conjugation instability. Previous research with site-directed mutagenic incorporation of cysteine residues for conjugation revealed that the stability of the drug-antibody linkage depends on the site of conjugation. Here we report on a collection of engineered cysteine antibodies (S239C, E269C, K326C and A327C) that can be site-specifically conjugated to potent cytotoxic agents to produce homogenous 2-loaded ADCs. These ADCs confirm that site of conjugation impacts maleimide stability and present a novel mechanism of thioether stabilization, effectively unlinking stability from either local chemical environment or calculated solvent accessibility and expanding the current paradigm for ADC drug-linker stability. These ADCs show potent in vitro and in vivo activity while delivering half of the molar equivalent dose of drug per antibody when compared to an average 4-loaded ADC. In addition, our lead engineered site shields highly hydrophobic drugs, enabling conjugation, formulation and clinical use of otherwise intractable chemotypes.

Interaction between cannabis consumption and childhood abuse in psychotic disorders: preliminary findings on the role of different patterns of cannabis use.

AIM: Several studies have suggested that lifetime cannabis consumption and childhood abuse synergistically contribute to the risk for psychotic disorders. This study aimed to extend existing findings regarding an additive interaction between childhood abuse and lifetime cannabis use by investigating the moderating role of type and frequency of cannabis use. METHODS: Up to 231 individuals presenting for the first time to mental health services with psychotic disorders and 214 unaffected population controls from South London, United Kingdom, were recruited as part of the Genetics and Psychosis study. Information about history of cannabis use was collected using the Cannabis Experiences Questionnaire. Childhood physical and sexual abuse was assessed using the Childhood Experience of Care and Abuse Questionnaire. RESULTS: Neither lifetime cannabis use nor reported exposure to childhood abuse was associated with psychotic disorder when the other environmental variable was taken into account. Although the combination of the two risk factors raised the odds for psychosis by nearly three times (adjusted OR = 2.94, 95% CI: 1.44-6.02, P = 0.003), no evidence of interaction was found (adjusted OR = 1.46, 95% CI: -0.54 to 3.46, P = 0.152). Furthermore, the association of high-potency cannabis and daily consumption with psychosis was at least partially independent of the effect of childhood abuse. CONCLUSIONS: The heavy use of high-potency cannabis increases the risk of psychosis but, in addition, smoking of traditional resin (hash) and less than daily cannabis use may increase the risk for psychosis when combined with exposure to severe childhood abuse.

Measurement methods to assess diastasis of the rectus abdominis muscle (DRAM): A systematic review of their measurement properties and meta-analytic reliability generalisation.

STUDY DESIGN: Systematic literature review. BACKGROUND: Diastasis of the rectus abdominis muscle (DRAM) has been linked with low back pain, abdominal and pelvic dysfunction. Measurement is used to either screen or to monitor DRAM width. Determining which methods are suitable for screening and monitoring DRAM is of clinical value. OBJECTIVES: To identify the best methods to screen for DRAM presence and monitor DRAM width. METHODS: AMED, Embase, Medline, PubMed and CINAHL databases were searched for measurement property studies of DRAM measurement methods. Population characteristics, measurement methods/procedures and measurement information were extracted from included studies. Quality of all studies was evaluated using 'quality rating criteria'. When possible, reliability generalisation was conducted to provide combined reliability estimations. RESULTS: Thirteen studies evaluated measurement properties of the 'finger width'-method, tape measure, calipers, ultrasound, CT and MRI. Ultrasound was most evaluated. Methodological quality of these studies varied widely. Pearson's correlations of r = 0.66-0.79 were found between calipers and ultrasound measurements. Calipers and ultrasound had Intraclass Correlation Coefficients (ICC) of 0.78-0.97 for test-retest, inter- and intra-rater reliability. The 'finger width'-method had weighted Kappa's of 0.73-0.77 for test-retest reliability, but moderate agreement (63%; weighted Kappa = 0.53) between raters. Comparing calipers and ultrasound, low measurement error was found (above the umbilicus), and the methods had good agreement (83%; weighted Kappa = 0.66) for discriminative purposes. CONCLUSIONS: The available information support ultrasound and calipers as adequate methods to assess DRAM. For other methods limited measurement information of low to moderate quality is available and further evaluation of their measurement properties is required.

Jumping to conclusions, neuropsychological functioning, and delusional beliefs in first episode psychosis.

BACKGROUND: The "jumping to conclusions" (JTC) data-gathering bias is implicated in the development and maintenance of psychosis but has only recently been studied in first episode psychosis (FEP). In this study, we set out to establish the relationship of JTC in FEP with delusions and neuropsychological functioning. METHODS: One hundred and eight FEP patients and 101 age-matched controls completed assessments of delusions, general intelligence (IQ), working memory (WM), and JTC (the probabilistic reasoning "beads" task). RESULTS: Half the FEP participants jumped to conclusions on at least 1 task, compared with 25% of controls (OR range 2.1 to 3.9; 95% CI range 1.5 to 8.0, P values ≤ .02). JTC was associated with clinical, but not nonclinical delusion severity, and with neuropsychological functioning, irrespective of clinical status. Both IQ and delusion severity, but not WM, were independently associated with JTC in the FEP group. CONCLUSIONS: JTC is present in FEP. The specific association of JTC with clinical delusions supports a state, maintaining role for the bias. The associations of JTC with neuropsychological functioning indicate a separable, trait aspect to the bias, which may confer vulnerability to psychosis. The work has potential to inform emerging interventions targeting reasoning biases in early psychosis.

Effects of exercise on diastasis of the rectus abdominis muscle in the antenatal and postnatal periods: a systematic review.

BACKGROUND: Diastasis of the rectus abdominis muscle (DRAM) is common during and after pregnancy, and has been related to lumbopelvic instability and pelvic floor weakness. Women with DRAM are commonly referred to physiotherapists for conservative management, but little is known about the effectiveness of such strategies. OBJECTIVES: To determine if non-surgical interventions (such as exercise) prevent or reduce DRAM. DATA SOURCES: EMBASE, Medline, CINAHL, PUBMED, AMED and PEDro were searched. STUDY SELECTION/ELIGIBILITY: Studies of all designs that included any non-surgical interventions to manage DRAM during the ante- and postnatal periods were included. STUDY APPRAISAL AND SYNTHESIS METHODS: Methodological quality was assessed using a modified Downs and Black checklist. Meta-analysis was performed using a fixed effects model to calculate risk ratios (RR) and 95% confidence intervals (CI) where appropriate. RESULTS: Eight studies totalling 336 women during the ante- and/or postnatal period were included. The study design ranged from case study to randomised controlled trial. All interventions included some form of exercise, mainly targeted abdominal/core strengthening. The available evidence showed that exercise during the antenatal period reduced the presence of DRAM by 35% (RR 0.65, 95% CI 0.46 to 0.92), and suggested that DRAM width may be reduced by exercising during the ante- and postnatal periods. LIMITATIONS: The papers reviewed were of poor quality as there is very little high-quality literature on the subject. CONCLUSION AND IMPLICATIONS: Based on the available evidence and quality of this evidence, non-specific exercise may or may not help to prevent or reduce DRAM during the ante- and postnatal periods.

Do psychosis patients with poor insight show implicit awareness on the emotional stroop task?

BACKGROUND: The insight into psychosis can be assessed reliably by clinicians from interviews with patients. However, patients may retain implicit awareness of illness while lacking explicit awareness. SAMPLING AND METHODS: In a sample of first-episode psychosis patients, we used a test of processing of mental illness-related and other negative words as a measure of implicit awareness to see how this varied in relation to insight. An emotional-counting Stroop task tested reaction times to words of three types: psychosis-related (e.g. 'crazy'), general negative (e.g. 'cancer') and neutral (e.g. 'oyster'). Data were available from 43 patients and 23 healthy controls. Patients' insight was assessed using the Schedule for the Assessment of Insight (SAI-E). RESULTS: Patients reacted slower than controls to words across all conditions, and both patients and controls reacted slower to salient and negative words than neutral words. There was a near significant interaction between word type and group (Wilks' lambda = 0.53, p = 0.055); patients experienced greater interference from negative rather than psychosis-related words (p = 0.003), and controls experienced greater interference from salient rather than negative words (p = 0.01). Within the patient group, there was a correlation between insight and interference on salient words (r = 0.33, p = 0.05), such that those with less insight experienced less interference on psychosis-related words. CONCLUSIONS: Psychosis-related words were less threatening and less self-relevant to psychosis patients with less insight. This suggests that the lack of awareness such patients have of their illness is genuine and more likely to be mediated by lower-level information processing mechanisms than strategies such as conscious, motivated denial.

Cannabis users have higher premorbid IQ than other patients with first onset psychosis.

BACKGROUND: A number of studies have reported that patients with psychosis who use cannabis have better cognitive performance than those who do not. This is surprising as cannabis can impair cognition in healthy subjects. An obvious question is whether the better current performance of psychotic patients who have used cannabis is a reflection of their having a higher premorbid IQ than those psychotic patients who haven't used cannabis. AIM: In a sample of patients at their first episode of psychosis, we tested the hypothesis that patients who smoked cannabis would have a higher premorbid IQ than patients who did not. METHODOLOGY: 279 participants (119 patients and 160 healthy controls) were assessed in order to obtain current and premorbid IQ measures and detailed information on cannabis use. We examined the association between cannabis use and both premorbid and current IQ in patients and controls. RESULTS: Patients who had ever smoked cannabis had significantly higher current (p<.001) and premorbid IQ (p=.004) compared to patients who had never used cannabis. This difference was not found among controls. CONCLUSIONS: These findings suggest that the better cognitive performance of patients with their first episode of psychosis who have used cannabis compared with those who haven't is due to the better premorbid IQ of the former.

"I am sane but he is mad": Insight and illness attributions to self and others in psychosis.

We attempted to explore whether lack of insight in patients with psychosis is related to their genuine inability to recognise symptoms of mental illness as opposed to denial. We addressed this by examining participants' judgments of illness in vignettes in which they were either the protagonist or were commenting on others' behaviour. We recruited 44 first episode psychosis patients and 23 healthy controls to make judgements of specially constructed vignettes describing psychotic symptoms. Insight, Theory of Mind (ToM) and IQ was also measured. Patients' and controls' rating of vignettes overall did not differ significantly with respect to their attribution of mental illness. Patients and controls rated 2nd person vignettes similarly; patients were less likely to attribute mental illness to a character described in the 3rd person. This effect correlated with insight scores. Vignette judgments were significantly correlated with ToM performance but this was moderated by IQ. In conclusion, patients with lower insight tend to make the same attributions to others as to themselves, whilst healthy controls tend to think of mental illness as something seen in other people. There was no support for a 'denial' explanation for lack of insight in these patients.

Is deterioration of IQ a feature of first episode psychosis and how can we measure it?

Estimates of pre-morbid IQ are widely used to measure the trajectory of cognitive function and decline in people with schizophrenia. This study examined the usefulness of two indices of decline to identify cognitive subtypes in first episode psychosis, and to determine the specificity of non-IQ neuropsychological impairments in this population. Neuropsychological data were collected from 118 first episode psychosis patients and compared to 118 epidemiologically matched controls. The National Adult Reading Test (NART) and the Information subtest of the WAIS-III were compared as indicators of crystallised intelligence or 'pre-morbid IQ'. Measurement of NART minus current full scale IQ (FSIQ) (where 10 points discrepancy is the decline criterion) did not reveal a large group of individuals with 'deteriorating' IQ patterns. Using the Information subtest and the same decline criteria, a 'deteriorating' patient group emerged (36%) but was matched by a larger 'deteriorating' control group (45%). The 'deteriorating' patient group performed at a low IQ level for tasks that loaded highly on performance ability but a relatively high level for tasks measuring verbal skills. Verbal memory discriminated patients from controls better than IQ. Compared to controls, patients showed large selective impairments of verbal episodic memory (effect size, d=1.4) These data suggest that in first episode populations, caution should be exercised in inferring deterioration of IQ from discrepancies between reading-based and other IQ tests. Rather, sub-groups of patients and controls do show greater verbal aptitude in comparison to performance skills. Memory is generally impaired in first episode patients regardless of IQ.

Are there specific neuropsychological deficits underlying poor insight in first episode psychosis?

Insight in psychosis is a multi-dimensional phenomenon, and has been hypothesised to have some sort of neuropsychological basis. It is unclear to what extent specific neuropsychological abilities are able to predict insight beyond the effect of generalised cognitive ability. We aimed to test this association, alongside the relationship of insight with illness duration and diagnosis, in a sample of first episode psychosis patients. 110 first episode psychosis patients were recruited and a comprehensive assessment was administered, including insight, symptoms, diagnosis and neuropsychological function. Low insight was related to worse performance in a variety of neuropsychological tasks. Regression analysis tested whether any specific tasks were related to insight (or dimensions of insight) beyond the effect of IQ. Verbal memory had an effect on total insight and all dimensions of insight (except compliance) beyond the effect of IQ. Insight appeared to vary with diagnosis, with those diagnosed with depressive affective psychoses having better insight than those with manic affective psychoses. There was no relationship between insight and DUP, but there was a relationship between time spent in treatment before assessment and insight, even after controlling for severity of symptoms. These results suggest a model of insight in early psychosis with a significant neuropsychological component, particularly with verbal memory but also with generalised cognitive ability. There is likely to be a social component to insight affected by initial time spent in contact with treatment, helping patients to understand and come to terms with their illness.

Insight: demographic differences and associations with one-year outcome in schizophrenia and schizoaffective disorder.

BACKGROUND: Insight is increasingly seen as an important variable for study in psychotic illness, particularly in relation to treatment adherence. This study aims to quantify the association of insight with outcome, sociodemographic variables and diagnosis in a large stable patient sample. METHOD: Data are from a one-year, open-label, international, multicenter trial (n=670) of long-acting risperidone in adult symptomatically stable patients with schizophrenia or schizoaffective disorder. Psychopathology and insight were quantified using the Positive and Negative Syndrome Scale (PANSS). Patients were assessed at four time points over the year of the study. RESULTS: 31.2% of the sample showed clinically significant deficits in insight at baseline. There were no differences based on sex, but significant differences in age and diagnosis, with oldest patients and schizophrenia patients (cf., schizoaffective disorder) showing more deficits. Baseline insight impairment was correlated with change in PANSS score at one year (r=-0.243, p<0.001). Recursive partitioning showed that, of those whose symptoms improved, those whose insight also improved were more likely to complete the trial. CONCLUSIONS: Insight is important above and beyond the effects of symptoms for predicting continuation in drug trials. This may have implications for the design and analysis of such trials, as well as suggesting the importance of targeting insight in treatment to increase likelihood of adherence to treatment. There also appear to be small but significant differences in insight based on age and diagnosis within the schizophrenia spectrum.

Correlates, change and 'state or trait' properties of insight in schizophrenia.

BACKGROUND: The associations of insight into illness and clinical and socio-demographic variables in schizophrenia have been examined, yet little attention has been given to premorbid functioning, insight change and outcomes. OBJECTIVES: We examined these associations in a large cohort of recent onset schizophrenia spectrum disorder patients. METHODS: This was a prospective 6-month, open-label, multicentre, phase IV trial in 303 subjects with recent onset (

Prognostic variables in newly diagnosed children and adolescents with acute myeloid leukemia: Children's Cancer Group Study 213.

The objective of this study was to identify biologic parameters that were associated with either exceptionally good or poor outcome in childhood acute myeloid leukemia (AML). Among the children with AML who entered Children's Cancer Group trial 213, 498 patients without Down syndrome or acute promyelocytic leukemia (APL) comprise the basis for this report. Univariate comparisons of the proportion of patients attaining complete remission after induction (CR) indicate that, at diagnosis, male gender, low platelet count (< or =20 000/microl), hepatomegaly, myelodysplastic syndrome (MDS), French-American- British (FAB) category M5, high (>15%) bone marrow (BM) blasts on day 14 of the first course of induction, and +8 are associated with lower CR rates, while abnormal 16 is associated with a higher CR rate. Multivariate analysis suggests high platelet count at diagnosis (>20 000/microl), absence of hepatomegaly, < or =15% day 14 BM blast percentage, and abnormal 16 are independent prognostic factors associated with better CR. Univariate analysis demonstrated a significant favorable relationship between platelet count at diagnosis (>20 000/microl), absence of hepatomegaly, low percentage of BM blasts (< or =15%), and abnormal 16 with overall survival. Absence of hepatomegaly, < or =15% day 14 BM blast percentage, and abnormal 16 were determined to be independent prognostic factors associated with better survival.

Detection and selective dissociation of intact ribosomes in a mass spectrometer.

Intact Escherichia coli ribosomes have been projected into the gas phase of a mass spectrometer by means of nanoflow electrospray techniques. Species with mass/charge ratios in excess of 20,000 were detected at the level of individual ions by using time-of-flight analysis. Once in the gas phase the stability of intact ribosomes was investigated and found to increase as a result of cross-linking ribosomal proteins to the rRNA. By lowering the Mg(2+) concentration in solutions containing ribosomes the particles were found to dissociate into 30S and 50S subunits. The resolution of the charge states in the spectrum of the 30S subunit enabled its mass to be determined as 852,187 +/- 3,918 Da, a value within 0.6% of that calculated from the individual proteins and the 16S RNA. Further dissociation into smaller macromolecular complexes and then individual proteins could be induced by subjecting the particles to increasingly energetic gas phase collisions. The ease with which proteins dissociated from the intact species was found to be related to their known interactions in the ribosome particle. The results show that emerging mass spectrometric techniques can be used to characterize a fully functional biological assembly as well as its isolated components.

Solvent effects on the conformation of the transmembrane peptide gramicidin A: insights from electrospray ionization mass spectrometry.

The binding of sodium ions to the transmembrane channel peptide gramicidin A has permitted the use of electrospray ionization mass spectrometry to study its conformation in different solvent environments. The mass spectra of the peptide in the various solvents suggest that different conformations of gramicidin A differ in their ability to bind metal ions. The data are consistent with monomeric behavior of gramicidin A in trifluoroethanol and dimethyl sulfoxide solutions, but reveal the presence of noncovalent intermolecular interactions in ethanol solution through the observation of heterodimers formed between the naturally occurring variants of the peptide. The addition of 50% v/v of water to the ethanolic solution causes changes in the circular dichroism spectrum of the peptide, suggestive of a shift in the equilibrium mixture of conformers present toward monomeric species, a result supported by its mass spectrum. The structure of gramicidin A in trifluoroethanol has also been investigated by hydrogen exchange measurements monitored by mass spectrometry. The observation of significant protection against exchange suggests that the monomeric peptide is highly structured in trifluoroethanol. The results indicate that mass spectrometry has the potential to probe the conformational behavior of neutral hydrophobic peptides in environments that mimic their functional states.

Cholecystectomy is becoming an increasingly common operation in children.

PURPOSE: To determine the cause of a marked rise in cholecystectomy at a regional children's hospital. METHODS: Retrospective review of 185 patients undergoing cholecystectomy since 1984. The years 1984 to 1990 (group I) and 1991 to 1996 (group II) were compared. RESULTS: Cholecystectomy for gallbladder disease increased from 4.4/year (group I) to 16.3/ year (group II). Abdominal ultrasound examinations increased during this time. The ratio of children diagnosed with gallstones and then undergoing cholecystectomy also increased (P = 0.005). In group 11, 43% of children had no apparent etiology for gallstones, and more children developed complications of gallstones and evidence of choledocholithiasis. CONCLUSIONS: (1) The increased incidence of cholecystectomy is probably multifactorial. (2) Gallstone identification has increased owing to increased patient visits and more liberal use of ultrasonography in patients with abdominal pain. (3) More patients with cholelithiasis now undergo cholecystectomy perhaps because of a change in physician perception of the disease and an apparent increase in complications from gallstones.