Association of IQ Changes and Progressive Brain Changes in Patients With Schizophrenia.

IMPORTANCE: Although schizophrenia is characterized by impairments in intelligence and the loss of brain volume, the relationship between changes in IQ and brain measures is not clear. OBJECTIVE: To investigate the association between IQ and brain measures in patients with schizophrenia across time. DESIGN, SETTING, AND PARTICIPANTS: Case-control longitudinal study at the Department of Psychiatry at the University Medical Center Utrecht, Utrecht, the Netherlands, comparing patients with schizophrenia and healthy control participants between September 22, 2004, and April 17, 2008. Magnetic resonance imaging of the brain and IQ scores were obtained at baseline and the 3-year follow-up. Participants included 84 patients with schizophrenia (mean illness duration, 4.35 years) and 116 age-matched healthy control participants. MAIN OUTCOMES AND MEASURES: Associations between changes in IQ and the total brain, cerebral gray matter, cerebral white matter, lateral ventricular, third ventricles, cortical, and subcortical volumes; cortical thickness; and cortical surface area. RESULTS: Cerebral gray matter volume (P = .006) and cortical volume (P = .03) and thickness (P = .02) decreased more in patients with schizophrenia across time compared with control participants. Patients showed additional loss in cortical volume and thickness of the right supramarginal, posterior superior temporal, left supramarginal, left postcentral, and occipital regions (P values were between <.001 and .03 after clusterwise correction). Although IQ increased similarly in patients with schizophrenia and control participants, changes in IQ were negatively correlated with changes in lateral ventricular volume (P = .05) and positively correlated with changes in cortical volume (P = .007) and thickness (P = .004) only in patients with schizophrenia. Positive correlations between changes in IQ and cortical volume and thickness were found globally and in widespread regions across frontal, temporal, and parietal cortices (P values were between <.001 and .03 after clusterwise correction). These findings were independent of symptom severity at follow-up, cannabis use, and the use of cumulative antipsychotic medications during the 3 years of follow-up. CONCLUSIONS AND RELEVANCE: Progressive brain tissue loss in schizophrenia is related to relative cognitive decline during the early course of illness.

[Vascular anomaly in the midcheek region of an infant--review of the diagnostic procedure]. / Gefäßanomalie in der Wangenregion eines Säuglings - Diagnostischer Prozess anhand einer Kasuistik.

Clinical history, physical examination, evolution and imaging findings (Colour Doppler sonography, MRI if available) are of pivotal importance in the diagnostic pathway of an infantile vascular anomaly. Histopathology with specific stains and markers is contributive in difficult cases. Differentiation between vascular tumors (hemangioma) and vascular malformations is now well known and integrated into the ISSVA classification. We report here a 6-months-old boy, who presented with a localized cutaneous and expansive vascular birthmark in the left cheek and developed bleedings at the age of 18 months. Diagnostic features of a hemangioma were not evident, and the final diagnosis of a venous malformation was confirmed by histopathology.

Brain volumes in schizophrenia: a meta-analysis in over 18 000 subjects.

Although structural brain alterations in schizophrenia have been demonstrated extensively, their quantitative distribution has not been studied over the last 14 years despite advances in neuroimaging. Moreover, a volumetric meta-analysis has not been conducted in antipsychotic-naive patients. Therefore, meta-analysis on cross-sectional volumetric brain alterations in both medicated and antipsychotic-naive patients was conducted. Three hundred seventeen studies published from September 1, 1998 to January 1, 2012 comprising over 9000 patients were selected for meta-analysis, including 33 studies in antipsychotic-naive patients. In addition to effect sizes, potential modifying factors such as duration of illness, sex composition, current antipsychotic dose, and intelligence quotient matching status of participants were extracted where available. In the sample of medicated schizophrenia patients (n = 8327), intracranial and total brain volume was significantly decreased by 2.0% (effect size d = -0.17) and 2.6% (d = -0.30), respectively. Largest effect sizes were observed for gray matter structures, with effect sizes ranging from -0.22 to -0.58. In the sample of antipsychotic-naive patients (n = 771), volume reductions in caudate nucleus (d = -0.38) and thalamus (d = -0.68) were more pronounced than in medicated patients. White matter volume was decreased to a similar extent in both groups, while gray matter loss was less extensive in antipsychotic-naive patients. Gray matter reduction was associated with longer duration of illness and higher dose of antipsychotic medication at time of scanning. Therefore, brain loss in schizophrenia is related to a combination of (early) neurodevelopmental processes-reflected in intracranial volume reduction-as well as illness progression.

TRPM7 is required for breast tumor cell metastasis.

TRPM7 encodes a Ca2+-permeable nonselective cation channel with kinase activity. TRPM7 has been implicated in control of cell adhesion and migration, but whether TRPM7 activity contributes to cancer progression has not been established. Here we report that high levels of TRPM7 expression independently predict poor outcome in breast cancer patients and that it is functionally required for metastasis formation in a mouse xenograft model of human breast cancer. Mechanistic investigation revealed that TRPM7 regulated myosin II-based cellular tension, thereby modifying focal adhesion number, cell-cell adhesion and polarized cell movement. Our findings therefore suggest that TRPM7 is part of a mechanosensory complex adopted by cancer cells to drive metastasis formation.

Impaired cerebellar functional connectivity in schizophrenia patients and their healthy siblings.

The long-standing notion of schizophrenia as a disorder of connectivity is supported by emerging evidence from recent neuroimaging studies, suggesting impairments of both structural and functional connectivity in schizophrenia. However, investigations are generally restricted to supratentorial brain regions, thereby excluding the cerebellum. As increasing evidence suggests that the cerebellum contributes to cognitive and affective processing, aberrant connectivity in schizophrenia may include cerebellar dysconnectivity. Moreover, as schizophrenia is highly heritable, unaffected family members of schizophrenia patients may exhibit similar connectivity profiles. The present study applies resting-state functional magnetic resonance imaging to determine cerebellar functional connectivity profiles, and the familial component of cerebellar connectivity profiles, in 62 schizophrenia patients and 67 siblings of schizophrenia patients. Compared to healthy control subjects, schizophrenia patients showed impaired functional connectivity between the cerebellum and several left-sided cerebral regions, including the hippocampus, thalamus, middle cingulate gyrus, triangular part of the inferior frontal gyrus, supplementary motor area, and lingual gyrus (all p < 0.0025, whole-brain significant). Importantly, siblings of schizophrenia patients showed several similarities to patients in cerebellar functional connectivity, suggesting that cerebellar dysconnectivity in schizophrenia might be related to familial factors. In conclusion, our findings suggest that dysconnectivity in schizophrenia involves the cerebellum and that this defect may be related to the risk to develop the illness.

Association of the germline TP53 R72P and MDM2 SNP309 variants with breast cancer survival in specific breast tumor subgroups.

The tumor suppressor gene TP53 and its regulator MDM2 are both important players in the DNA-damage repair "TP53 response pathway". Common germline polymorphisms in these genes may affect outcome in patients with tumors characterized by additional somatic changes in the same or a related pathway. To evaluate this hypothesis, we determined the effect of the common germline TP53 R72P and MDM2 SNP309 polymorphisms on breast cancer survival in a consecutive cohort of breast cancer patients (age at diagnosis <53 years, n = 295) with gene expression data available. Patients were classified in subgroups according to their tumor TP53 mutation status and three gene expression profiles; a TP53 mutation status expression signature, a PTEN/PI3K pathway signature and the 70-gene prognosis profile. Survival analyses were performed using Cox regression models adjusting for clinico-pathological characteristics and treatment. An increase in breast cancer-specific mortality was observed for carriers of the germline MDM2 SNP309 rare GG-genotype (range hazard ratios: 2-3) or TP53 R72P heterozygous GC-genotype (range hazard ratios: 1-2) compared to those having the common genotypes within subgroups of tumors displaying a "more aggressive phenotype" gene expression profile. There was no evidence of such an effect on survival within the TP53-mutated tumor group for TP53 R72P carriers but a suggestion of an effect for MDM2 SNP309 carriers (GG vs. TT-genotype HR 2.99, P = 0.06). These results indicate that common polymorphisms in specific pathways may add to the worse prognosis of patients with tumors in which these pathways are affected by somatic alterations.

Dehydroepiandrosterone and metformin regulate proliferation of murine T lymphocytes.

The aim of the present study was to assess the effect of dehydroepiandrosterone (DHEA: 10 microM) and metformin (10 microM and 100 microM) in regulating proliferation of cultured T lymphocytes. T cells were isolated from lymph nodes of prepuberal BALB/c mice. We found that DHEA, metformin and DHEA + metformin added to the incubation media diminished proliferation of T cells. The inhibition by DHEA was higher than that produced by metformin, while the combined treatment showed a synergistic action that allowed us to speculate distinct regulatory pathways. This was supported later by other findings in which the addition of DHEA to the incubation media did not modify T lymphocyte viability, while treatment with metformin and DHEA + metformin diminished cellular viability and increased both early and late apoptosis. Moreover, DHEA diminished the content of the anti-oxidant molecule glutathione (GSH), whereas M and DHEA + metformin increased GSH levels and diminished lipid peroxidation. We conclude that DHEA and metformin diminish proliferation of T cells through different pathways and that not only the increase, but also the decrease of oxidative stress inhibited proliferation of T cells, i.e. a minimal status of oxidative stress, is necessary to trigger cellular response.

The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus.

OBJECTIVES: A globally acceptable definition and classification of gastroesophageal reflux disease (GERD) is desirable for research and clinical practice. The aim of this initiative was to develop a consensus definition and classification that would be useful for patients, physicians, and regulatory agencies. METHODS: A modified Delphi process was employed to reach consensus using repeated iterative voting. A series of statements was developed by a working group of five experts after a systematic review of the literature in three databases (Embase, Cochrane trials register, Medline). Over a period of 2 yr, the statements were developed, modified, and approved through four rounds of voting. The voting group consisted of 44 experts from 18 countries. The final vote was conducted on a 6-point scale and consensus was defined a priori as agreement by two-thirds of the participants. RESULTS: The level of agreement strengthened throughout the process with two-thirds of the participants agreeing with 86%, 88%, 94%, and 100% of statements at each vote, respectively. At the final vote, 94% of the final 51 statements were approved by 90% of the Consensus Group, and 90% of statements were accepted with strong agreement or minor reservation. GERD was defined as a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications. The disease was subclassified into esophageal and extraesophageal syndromes. Novel aspects of the new definition include a patient-centered approach that is independent of endoscopic findings, subclassification of the disease into discrete syndromes, and the recognition of laryngitis, cough, asthma, and dental erosions as possible GERD syndromes. It also proposes a new definition for suspected and proven Barrett's esophagus. CONCLUSIONS: Evidence-based global consensus definitions are possible despite differences in terminology and language, prevalence, and manifestations of the disease in different countries. A global consensus definition for GERD may simplify disease management, allow collaborative research, and make studies more generalizable, assisting patients, physicians, and regulatory agencies.

The mechanisms involved in the action of metformin in regulating ovarian function in hyperandrogenized mice.

The aim of this study was to investigate the mechanisms by which N,N'-dimethylbiguanide metformin (50 mg/100 g body weight (BW) in 0.05 ml of water, given orally with a cannula) prevents the ovarian disorders provoked by the hyperandrogenization with dehydroepiandrosterone (DHEA) in prepuberal BALB/c mice. The injection of DHEA (6 mg/100 g BW in 0.1 ml of oil) for 20 consecutive days re-creates a mouse model that resembles some aspects of the human polycystic ovary syndrome (PCOS). The treatment with DHEA increased ovarian oxidative stress because it enhanced lipid peroxidation (LPO) and diminished both catalase (CAT) activity and glutathione (GSH) content. Therefore, the treatment with DHEA diminished both ovarian nitric oxide synthase (NOS) activity and prostaglandin E (PGE) production. When metformin was administered together with DHEA, the ovarian GSH content, NOS activity and PGE production did not differ when compared with controls. However, metformin was not able to prevent the effect of DHEA on ovarian LPO or CAT activity. Finally, DHEA increased the ovarian protein expressions of inducible NOS (iNOS), inducible cyclooxygenase (COX2) and the phosphorylated AMP-dependent kinase alpha (AMPK-alpha) (Thr172). Metformin administered together with DHEA was able to prevent the increase of ovarian iNOS and COX2 expressions and to enhance the activation of phosphorylated AMPK-alpha expression.

Metformin prevents embryonic resorption induced by hyperandrogenisation with dehydroepiandrosterone in mice.

The present study examined the mechanism by which metformin prevents dehydroepiandrosterone (DHEA)-induced embryonic resorption in mice. Treatment with DHEA (6 mg/100 g bodyweight, 24 and 48 h post implantation) induced 88 +/- 1 % embryonic resorption and the diminution of both serum oestradiol (E) and progesterone (P) levels. However, when metformin (50 mg/kg bodyweight) was given together with DHEA, embryo resorption (43 +/- 3% v. 35 +/- 5% in controls) and both serum E and P levels were not significantly different from controls. Glucose and insulin levels were increased in the DHEA-treated mice but when metformin was administered together with DHEA these parameters were similar to control values. Treatment with DHEA increased ovarian oxidative stress and diminished uterine nitric oxide synthase (NOS) activity; however, when metformin was administered together with DHEA, both ovarian oxidative stress and uterine NOS activity were not different from controls. Metformin treatment did not modify the percentage of CD4(+) and CD8(+) T cells from both axillar and retroperitoneal lymph nodes but prevented the increase of serum tumour necrosis factor +/- produced in DHEA-treated mice. These results show that metformin acts in DHEA-induced embryonic resorption in mice by modulating endocrine parameters, ovarian oxidative stress and uterine NOS activity.

The GHRH/GHRP-6 test for the diagnosis of GH deficiency in elderly or severely obese men.

OBJECTIVE AND DESIGN: Ageing and obesity result in decreased activity of the GH/IGF-I axis and concomitant impaired GH responses to secretory stimuli. We therefore determined the validity of the GH cut-off value of 15.0 microg/l in the GH-releasing hormone (GHRH)/GH releasing peptide-6 (GHRP-6) test for the diagnosis of GH deficiency in elderly or severely obese men. METHODS: We performed a combined GHRH/GHRP-6 test in ten elderly men (mean age 74 years; mean body mass index (BMI) 24.6 kg/m(2)), nine obese men (mean age 47 years; mean BMI 40.6 kg/m(2)) and seven healthy male controls (mean age 51 years, mean BMI 24.3 kg/m(2)). After assessment of fasting plasma GH, IGF-I and IGF-binding protein-3 (IGFBP-3), GHRH (100 microg) and GHRP-6 (93 microg) were given intravenously as a bolus injection. Repeated GH measurements were performed for two hours. RESULTS: Both peak GH levels and areas under the curve (AUC) were significantly lower in the obese than in the controls (peak 13.2 vs 53.4 microg/l, P = 0.001; AUC 707 vs 3250 microg/l x 120 min; P = 0.001). Mean GH response in the elderly was lower than in the controls (peak 35.0 microg/l; AUC 2274 microg/l x 120 min), but this was not statistically significant. In contrast, GH peak levels in seven obese men remained below the cut-off level of 15.0 microg/l associated with severe GH deficiency. All others had GH peak levels exceeding this threshold. IGFBP-3 levels were significantly lower in the elderly than in the controls (1.35 vs 2.05 mg/l, P = 0.001). Baseline GH or IGF-I did not differ significantly between groups. CONCLUSIONS: GH responses following GHRH/GHRP-6 administration were significantly reduced in severely obese men, but were not significantly reduced in elderly men, despite a negative trend. Our data indicate that the cut-off GH level of 15.0 microg/l after GHRH + GHRP-6 administration for the diagnosis of severe GH deficiency cannot be used in severely obese men.

Sequence of interleukin 1beta actions on corpus luteum regression: relationship with inducible cyclooxygenase and nitric oxide synthase expression.

Corpus luteum regression has been described in terms of: (i) functional luteolysis - a reversible decline in serum progesterone concentration; and (ii) structural luteolysis - irreversible morphological changes and tissue remodelling events within the cellular membrane. In rats, PGF(2alpha) and interleukin 1beta (IL-1beta) are involved in structural luteolysis, PGF(2alpha) by increasing ovarian lipid peroxidation, and IL-1beta by reducing progesterone and increasing PGF(2alpha) concentrations. The aim of the present report was to determine whether by an early action IL-1beta is able to regulate functional luteolysis. Thus, ovarian explants from rats at the mid-stage of corpus luteum development were incubated during short periods with either 15 or 25 ng IL-1beta ml(-1). At 15 ng ml(-1), IL-1beta inhibited progesterone after 4 and 8 h of culture without affecting PGF(2alpha) production, and a longer incubation (21 h) was needed to increase PGF(2alpha) production. In contrast, IL-1beta enhanced PGF(2alpha) concentrations at 8 h only at the higher dose (25 ng ml(-1)). The observed reduction in progesterone synthesis at the lower dose of IL-1beta before the increase in PGF(2alpha) concentrations led to the hypothesis that IL-1beta regulates functional luteolysis (progesterone diminution) before it affects structural luteolysis (PGF(2alpha) increase). The fact that the early IL-1beta action was described at 4 h but no effects on inducible nitric oxide synthase and inducible cyclooxygenase expression were found before this time led to the suggestion that these inductions were not necessary for the early IL-1beta action described.

Relationship between endothelin 1 and nitric oxide system in the corpus luteum regression.

The present study was designed to investigate the relationship between the nitric oxide (NO) system and endothelin 1 (ET-1) in the mechanism of corpus luteum (CL) development and consequently regression in rats. We first evaluated basal ET-1 levels in ovarian tissue from rats with different stages of CL development. An increased ovarian ET-1 content was found during CL regression. In a dose-department response, ET-1 decreased progesterone (P4) and increased prostaglandin (PG) PGF2alpha production. By means of a competitive nitric oxide synthase (NOS) inhibitor: L-nitro arginine methyl ester (L-NAME) and a slow NO releasing: diethyl-aminetriamine (DETA-NONOate), we demonstrated that NO system could be the intermediary in the ET-1 diminishing P4 production. The Western blot analysis revealed an increase on iNOS while eNOS protein expression was diminished. We also found a diminution of total NOS activity after ET-1 treatment. These data suggest the existence of a functional relationship between ET-1 and NOS isoforms leading the regulation of CL functionally.

Lymphocyte count and mortality risk in older persons. The Leiden 85-Plus Study.

OBJECTIVES: To investigate whether a low peripheral blood lymphocyte count is associated with increased mortality risk in older persons and to determine whether this association could be ascribed to ill health. DESIGN: A cohort study with a total follow-up period of 1,602 person years. SETTING: Leiden, the Netherlands. PARTICIPANTS: Four hundred thirty-six community-dwelling residents aged 85 and older. MEASUREMENTS: Health status and leukocyte total and differential counts were assessed at baseline. Lymphocyte subsets were measured with a fluorescence-activated cell sorter. Age- and sex-adjusted mortality risks were estimated using Cox proportional hazard regression analysis. RESULTS: There was no association between lymphocyte count and mortality in persons with ill health (mortality risk lowest vs highest quartile=1.16; 95% confidence interval (CI)=0.85-1.58, P=.35), but mortality was dependent on lymphocyte count if disease was excluded (mortality risk lowest vs highest quartile=2.14; 95% CI=1.08-4.23, P=.03). A similar increase in mortality risk was found when the cluster designation (CD)4+, CD8+, and CD16+ lymphocyte subsets were analyzed. Within individuals, low values of the lymphocyte subsets were related and there was no compensatory increase in CD16+ lymphocyte counts. A low lymphocyte count was not associated with specific causes of death. CONCLUSION: A low lymphocyte count was associated with an increased mortality risk in older persons without apparent disease. This association was not only found for the total lymphocyte count but also for the CD4+, CD8+, and CD16+ lymphocyte subset counts.

Interleukin-1beta in the functional and structural luteolysis. Relationship with the nitric oxide system.

The aim of the present report was to investigate the in vitro effect of interleukin-1beta(IL-1beta) on corpus luteum (CL) function and some aspects of this mechanism involved. Ovarian rat dispersates from mid-luteal phase were exposed to different doses of IL-1beta (1, 10, 20 ng/ml). Meanwhile 1, 10 and 20 ng/ml of IL-1beta decreased progesterone (P4) production, only the highest doses of IL-1beta increased prostaglandin F2alpha (PGF2alpha) levels. To investigate the possible relationship between PGs production and P4 synthesis, we incubated together IL-1beta (20 ng/ml) and indomethacin (0.1 mM) a potent inhibitor of cyclooxygenase pathway. We found that P4 inhibition induced by IL-1beta was completely prevented by addition of indomethacin. On the other hand, when ovarian rat tissue were exposed at 20 ng/ml of IL-1beta (doses that affected both PGF2alpha and P4 production) the nitric oxide synthase (NOS) activity was augmented. Moreover, IL-1beta effects on PGF2alpha and P4 levels were impaired when a NOS inhibitor N(W)-nitro- L -arginine methyl ester (L-NAME, 600 microM) was added to the incubation media. These data demonstrate that: (i) at the tested doses (1-20 ng/ml), IL-1beta is involved in CL function through the diminution of P4 production of whole ovarian dispersate culture; (ii) at the highest doses assayed (20 ng/ml) IL-1beta increased PGF2alpha production; (iii) at these doses, IL-1beta decreased P4 production by means of a cyclooxygenase pathway and (iv) the NO system would be a key intermediary second messenger in the IL-1beta actions.

Xenopus brevican is expressed in the notochord and the brain during early embryogenesis.

A complete cDNA encoding the Xenopus laevis homologue of the aggrecan/versican family member, brevican (Xbcan) was cloned from an embryonic stage 42 cDNA library. In the deduced amino acid sequence, 1152 in length, similarity to the hyaluronan-binding (link) domains of brevicans from other species were present in the N-terminal region as well as EGF-, lectin- and complement regulatory protein-like domains in the C-terminal part, the latter three being characteristic for brevican found within the extracellular matrix (J. Biol. Chem. 269 (1994) 10119). Indeed, Xbcan was secreted into the extracellular space as a soluble protein when expressed in oocytes. No cDNAs encoding a GPI-anchored bcan variant could be isolated from that cDNA library. During embryonic development, the expression of this gene was first observed in the notochord of neurula stage embryos. In addition to this, in tailbuds, Xbcan was also found to be expressed within the fifth and sixth rhombomere of the hindbrain. In tadpole stage embryos, expression was furthermore observed in periventricular regions of the developing brain and the rostral part of the spinal cord.

Duchenne and Becker muscular dystrophies: an Estonian experience.

The clinical and molecular features of 25 Duchenne (DMD), two intermediate (D/BMD) and three Becker (BMD) muscular dystrophy patients from 26 unrelated families were evaluated. Early psychomotor development was normal in patients with D/BMD and BMD. Learning to walk independently after 15 months of age was a risk sign of DMD in nine (36%) patients. Abnormality in crawling was seen in 13 (54%) patients with DMD. These boys demonstrated initial symptoms earlier than those who learned to crawl normally. Mental retardation was established in five (20%) patients with DMD. Deletions in the dystrophin gene were found in 11 families (48%). They were accumulated (9/11, 82%) in the distal region of the gene.

School and the in-center pediatric hemodialysis patient.

Life "on the machine" can significantly disrupt the social and academic school experience of preadolescent and adolescent renal failure patients because of their frequent absences. When hemodialysis patients were offered treatments after school and on Saturday mornings, patients, families, and staff reported significant improvement in the patients' social integration and academic performance.