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.

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.

Results of treatment of malignant germ cell tumors in 93 children: a report from the Childrens Cancer Study Group.

We report treatment results in 93 children entered on study from 1978 to 1984 with malignant germ cell tumors (MGCTs), excluding dysgerminoma and tumors of the testis or brain. The estimated 4-year survival and event-free survival (EFS) for all 93 patients were 54% and 49%, respectively. For 30 children with ovarian tumors, the estimated 4-year survival was 67% and EFS was 63%. For 63 children with nongonadal tumors, survival and EFS were 48% and 42%, respectively. The comparison of EFS between ovarian and nongonadal tumors was significant at P = .03. The treatment plan included a second-look surgical procedure after 18 weeks of chemotherapy. Over half of 36 patients evaluated as having a residual mass present immediately before second-look surgery had no malignant tumor after review of surgical specimens. Age greater than 11 years at diagnosis, incomplete removal of tumor at first surgery, and more than one structure or organ involved at diagnosis increased the risk for adverse event. The histologic subtype of the primary tumor was not related to outcome. Diagnosis was verified by independent pathologic review, and treatment was uniform. Seventeen percent of all registered patients (21 of 127) were excluded because of ineligible pathologic diagnoses; sixty percent (13 of 21) were immature teratomas.

Solution structure of the GTPase activating domain of alpha s.

We have used heteronuclear three-dimensional NMR spectroscopy to determine the solution structure of a 141 residue protein containing the GTPase activating domain from the alpha chain of the heterotrimeric G protein Gs. The domain contains six alpha-helices and is stable and structured in solution despite having been excised from the intact Gs protein. The N-terminal ten and C-terminal 11 residues of the protein are unstructured in solution while the core is well determined by the 2483 distance and torsion restraints derived from the NMR spectra. The final ensemble of 14 structures, generated with a hybrid distance geometry/simulated annealing protocol, have an average to-the-mean backbone root-mean-square deviation of 0.39 A for the core residues 89 to 201. The majority of the structure is remarkably similar to that observed for the cognate domains in crystal structures of the homologous proteins alpha t and alpha i1. However, the orientations of the second helix and the subsequent interhelical loops differ markedly among the three proteins. This structural divergence, along with functional studies of chimeric proteins, suggests that this region of the domain interacts with either the downstream effector adenylyl cyclase or with some other intermediary protein.

Morphologic, immunologic, and cytogenetic classification of acute myeloid leukemia and myelodysplastic syndrome in childhood: a report from the Childrens Cancer Group.

The purposes of this report are to reaffirm concordance difficulties with the acute myeloid leukemia (AML) French-American-British (FAB) classification, to present the frequency of previously delineated AML syndromes in pediatric patients and to describe additional characteristic AML profiles utilizing composite morphologic, cytogenetic and immunophenotypic data. Profiles of 124 children with acute myeloid leukemia (AML) and 13 children with myelodysplastic syndrome entered on the Childrens Cancer Group (CCG) pilot study CCG-2861 were examined. Concordance between institutions and reviewers for FAB designation was 65%. Discordance was found principally between M1 and M2, M2 and M4, and M4 and M5. In 49% of marrow specimens, leukemic blasts expressed at least one T lineage-related antigen; 24% expressed the B lineage-related antigen CD19. CDw14 correlated with FAB M4 or M5 morphology and was the only surface antigen associated with a specific FAB subtype. Normal karyotypes were found for 15% of the 75 children with satisfactory karyotype preparations. Recurring aberrations, found in 76% of children, included t(15;17)(q22;q11), t(8;21)(q22;q22), inv(16)(p13q22), rearrangements of band 11q23, t(6;9) (p23;q34), trisomy 8 and monosomy 7. Results from this pilot study and from the current CCG randomized trial correlating morphology, immunophenotyping and cytogenetics, will help to classify AML into unique subgroups with differing clinical consequences or therapy requirements.

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.

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.

Aberrant cytoplasmic expression of proliferating cell nuclear antigen in Hodgkin's disease.

During a study using a monoclonal antibody directed against proliferating cell nuclear antigen (PCNA) to assess the proliferative activity of tumors, it was noted that the cytoplasm of Reed-Sternberg (RS) cells and variants of these cells in cases of Hodgkin's disease reacted very positively. This aberrant expression of PCNA has not been observed in any other tumor or in cells from normal tissues. The biological significance of this observation is currently unknown, but it may have diagnostic utility in detecting and identifying RS cells.

Relationship between epidemiologic risk factors and clinicopathologic findings in the sudden infant death syndrome.

The risk of sudden infant death syndrome (SIDS) is said to be enhanced by factors such as prematurity, low birth weight, and perinatal distress. The significance of risk factors for SIDS research was questioned because the majority of SIDS victims seem to lack them. Therefore, postmortem records of 1144 infants who died suddenly and unexpectedly in King County, Washington, over a 25-year period were studied. Deaths were classified as "explained" if a cause was apparent, "classic" SIDS if the history and autopsy were unrevealing or, where the diagnosis of SIDS was doubtful, as "probable" or "possible" SIDS. The infants' birth certificates were compared with those of 3647 infants born during a similar period. Seventy-nine deaths (7%) were explained. The 1065 previously certified as SIDS were reclassified classic SIDS (82%), probable SIDS (13%), and possible SIDS (5%). Low birth weight, small size for gestational age, prematurity, and low 5-minute Apgar scores each form a "continuum"; the possible-SIDS group had the highest proportion of such infants, followed by the probable- and classic-SIDS groups, which exhibit extensive overlap with the control population. A 5-minute Apgar score of less than 7 and delayed postnatal growth rate are not risk factors for classic SIDS. Risk factors are more prevalent in SIDS infants where the diagnosis may be doubtful. The great majority of SIDS victims possess fewer risk factors. To avoid the bias of confounding variables, SIDS research should focus on as "pure" a SIDS population as is possible.

Urinary tract anomalies associated with congenital diaphragmatic defects.

Anomalies of the urinary tract occur in some 13-27% of infants with congenital posterolateral diaphragmatic defect (CDD) and are often severe (renal agenesis, dysplasia, hypoplasia, or hydronephrosis). To test the hypothesis that urinary and diaphragmatic anomalies share elements of pathogenesis, we reviewed 60 autopsy cases of CDD studied at our institution. Sixteen patients (27%) manifested anomalies of the urinary tract: 12 had markedly altered kidneys, 8 of which were unilateral and ipsilateral to the diaphragmatic defect. Among 27 patients free of gross urinary tract anomalies, kidney weights formed a skewed distribution, with most values above published norms for body weight; by analysis of covariance, kidney weight (as a function of body weight) was significantly greater in CDD than in a control population of infants free of chronic illnesses and congenital anomalies who died suddenly and unexpectedly. Differences in glomerular number and diameter could not be identified between the latter groups. In 71% of patients with isolated left CDD, the left kidney was heavier than the right, a reversal of the usual condition in infancy. These findings demonstrate that both marked and subtle changes of the urinary tract in CDD are generally ipsilateral to the diaphragmatic defect and suggest that the pathogenetic mechanisms responsible for urinary and diaphragmatic anomalies may overlap topographically. Aberrant morphogenesis within a developmental field or fields is one explanation for this.

Multicystic pancreatic hamartoma: a distinctive lesion with immunohistochemical and ultrastructural study.

A multicystic pancreatic hamartoma is reported in a 20-month-old female who presented with abdominal pain and distention. This appears to be a distinctive lesion not previously characterized in the English language literature. The 9-cm mass consisted of large, irregular lobules of well-formed pancreatic acini admixed with fibrous tissue and fat. Cystically dilated ducts of variable caliber lined by benign epithelium were present. Endocrine cell islets were not evident. Immunohistochemistry and ultrastructural examination illustrated insulin-producing cells diffusely throughout the exocrine tissue as single cells or in small groups. Cells producing other pancreatic hormones were markedly decreased when compared with an age-matched control pancreas and were similarly dispersed. The patient was alive and well without tumor 9 months later. This entity may provide an unusual opportunity for insight into pancreatic organogenesis and pancreatic cellular differentiation.

EWS/FLI-1 fusion transcripts in three peripheral primitive neuroectodermal tumors of the kidney.

Although primitive neuroectodermal tumor (PNET) is a well-recognized entity, its renal localization as a primary site has not been appreciated. Only nine cases of renal PNET exist in the literature. The paucity of renal PNET could be explained by the lack of objective diagnostic techniques that would facilitate its distinction from other primitive round cell tumors of the kidney, such as the more widely recognized monophasic Wilms' tumor and clear-cell sarcoma of the kidney (CCSK), as well as renal carcinoid, or neuroblastoma invading the kidney from the adjacent adrenal gland. The recently identified specific fusion transcripts detectable by reverse transcription polymerase chain reaction (RT-PCR) have provided us with a valuable tool for the detection of renal PNET. This article reports three renal PNET that expressed EWS/FLI-1 fusion transcripts by RT-PCR, in addition to positive staining for MIC2 protein and neuron-specific enolase (NSE). One also exhibited dense core granules in cell processes by electron microscopy. Employment of such methodology will lead to a more accurate classification of renal tumors.

Hepatobiliary dysfunction in infants and children associated with long-term total parenteral nutrition. A clinico-pathologic study.

Hepatobiliary dysfunction is a well recognized complication in infants and children on long-term total parenteral nutrition. This clinical-pathological study of fifteen patients with this syndrome suggests that cholestasis is the primary pathogenetic mechanism. The cause of the cholestasis is not well understood, but does not appear to be primarily related to the type of intravenous fluids or the occurrence of sepsis. It is suggested that the prolonged fasting results in disruption of the normal gastro-intestinal mechanisms responsible for bile production and flow. This is supported by the pathological findings, the fact that hepatobiliary dysfunction develops late (usually around 2-3 months), the observation that elevated bile acids and direct hyperbilirubinemia occurs prior to any evidence of hepatocellular necrosis and the occurrence of cholelithiasis in some patients.

Bronchioloalveolar carcinoma of the lung and congenital cystic adenomatoid malformation.

A case of bronchioloalveolar carcinoma of the lung is described in a 19-year-old man who had had a lobectomy in infancy, for removal of a congenital cystic adenomatoid malformation. It is suggested that congenital cystic adenomatoid malformation may predispose a patient to development of epithelial malignancies of the lung, whereas mesenchymal hamartomas usually are associated with nonepithelial neoplasms.

Use of immunoperoxidase on brain tissue for the rapid diagnosis of herpes encephalitis.

An indirect immunoperoxidase method to detect herpes simplex viral antigen in brain cell suspensions from patients suspected to have herpes encephalitis is described. The method is rapid, reliable and specific, and successfully identified the herpes virus infected cells in four of five culture-proven cases. There was one false-negative reaction, but no false-positive. The immunoperoxidase technic offers a number of advantages over immunofluorescence for routine diagnosis.

Is C-reactive protein useful in the management of children with suspected bacterial meningitis?

C-reactive protein (CRP) was evaluated in both serum and cerebrospinal fluid in 119 patients to determine if either or both measurements were of clinical value in the diagnosis of bacterial meningitis. CSF C-reactive protein is too insensitive (sensitivity = 66%) to be useful, while serum CRP is too nonspecific for routine application. Serum CRP may have a role if used selectively in those patients with a low-grade CSF pleocytosis and a negative Gram's stain.

Eruptive keratoacanthoma with an internal malignant neoplasm.

A 65-year-old woman had hundreds of tumors on the sun-exposed portions of her body and similar lesions in her mouth. All biopsy specimens showed changes consistent with the diagnosis of keratoacanthoma. Further examination of this patient disclosed an asymptomatic ovarian carcinoma. To the best of our knowledge, this is the second case of the rare disorder of eruptive keratoacanthoma to occur in a patient with an internal malignant neoplasm.