Long-term effects of cannabis on brain structure.

The dose-dependent toxicity of the main psychoactive component of cannabis in brain regions rich in cannabinoid CB1 receptors is well known in animal studies. However, research in humans does not show common findings across studies regarding the brain regions that are affected after long-term exposure to cannabis. In the present study, we investigate (using Voxel-based Morphometry) gray matter changes in a group of regular cannabis smokers in comparison with a group of occasional smokers matched by the years of cannabis use. We provide evidence that regular cannabis use is associated with gray matter volume reduction in the medial temporal cortex, temporal pole, parahippocampal gyrus, insula, and orbitofrontal cortex; these regions are rich in cannabinoid CB1 receptors and functionally associated with motivational, emotional, and affective processing. Furthermore, these changes correlate with the frequency of cannabis use in the 3 months before inclusion in the study. The age of onset of drug use also influences the magnitude of these changes. Significant gray matter volume reduction could result either from heavy consumption unrelated to the age of onset or instead from recreational cannabis use initiated at an adolescent age. In contrast, the larger gray matter volume detected in the cerebellum of regular smokers without any correlation with the monthly consumption of cannabis may be related to developmental (ontogenic) processes that occur in adolescence.

Reduced fronto-temporal and limbic connectivity in the 22q11.2 deletion syndrome: vulnerability markers for developing schizophrenia?

The 22q11.2 deletion syndrome (22q11DS) is a widely recognized genetic model allowing the study of neuroanatomical biomarkers that underlie the risk for developing schizophrenia. Recent advances in magnetic resonance image analyses enable the examination of structural connectivity integrity, scarcely used in the 22q11DS field. This framework potentially provides evidence for the disconnectivity hypothesis of schizophrenia in this high-risk population. In the present study, we quantify the whole brain white matter connections in 22q11DS using deterministic tractography. Diffusion Tensor Imaging was acquired in 30 affected patients and 30 age- and gender-matched healthy participants. The Human Connectome technique was applied to register white matter streamlines with cortical anatomy. The number of fibers (streamlines) was used as a measure of connectivity for comparison between groups at the global, lobar and regional level. All statistics were corrected for age and gender. Results showed a 10% reduction of the total number of fibers in patients compared to controls. After correcting for this global reduction, preserved connectivity was found within the right frontal and right parietal lobes. The relative increase in the number of fibers was located mainly in the right hemisphere. Conversely, an excessive reduction of connectivity was observed within and between limbic structures. Finally, a disproportionate reduction was shown at the level of fibers connecting the left fronto-temporal regions. We could therefore speculate that the observed disruption to fronto-temporal connectivity in individuals at risk of schizophrenia implies that fronto-temporal disconnectivity, frequently implicated in the pathogenesis of schizophrenia, could precede the onset of symptoms and, as such, constitutes a biomarker of the vulnerability to develop psychosis. On the contrary, connectivity alterations in the limbic lobe play a role in a wide range of psychiatric disorders and therefore seem to be less specific in defining schizophrenia.

Beyond splitting: observer-rated defense mechanisms in borderline personality disorder

Defense mechanism is a key concept in the psychoanalytic psychopathology of borderline personality disorder (BPD). Theoretical and empirical elaborations on this question are briefly reviewed and discussed with respect to process assessment of defense mechanisms; we put forward observer-rater methodology as an accurate means of assessing unconscious in-session processes. A sample of 25 patients presenting with BPD were interviewed, as were subjects from a matched control group without psychiatric symptoms (n = 25), using a psychodynamic interview paradigm. These interviews were transcribed and rated using the Defense Mechanisms Rating Scales. The results indicate that, compared to controls, patients with BPD used higher percentages of a action, borderline, disavowal, narcissistic, and hysteric defenses, along with lower levels of mature and obsessional defenses. Overall defensive functioning was significantly lower in the patients with BPD, compared to controls. Narcissistic defenses were related with symptom level. These results are discussed in light of previous studies on defensive functioning of BPD and the literature on psychoanalytic psychopathology. These results have several important clinical implications.

Short-course thymoglobulin induction and steroid-free immunosuppressive regimen in renal transplantation

Purpose: Optimal induction and maintenance immunosuppressive therapies in renal transplantation are still a matter of debate.Chronic corticosteroid usage is a major cause of morbidity but steroid-free immunosuppression (SF) can result in unacceptably high rates of acute rejection and even graft loss. Methods and materials: We have conducted a prospective openlabelled clinical trial in the Geneva-Lausanne Transplant Network from March 2005 to May 2008. 20 low immunological risk (<20% PRA, no DSA) adult recipients of a primary kidney allograft received a 4-day course of thymoglobulin (1.5 mg/kg/d) with methylprednisolone and maintenance based immunosuppression of tacrolimus and entericcoated mycophenolic acid (MPA). The control arm consisted of 16 matched recipients treated with basiliximab induction, tacrolimus, mycophenolate mofetil and corticosteroids. Primary endpoints were the percentage of recipients not taking steroids and the percentage of rejection-free recipients at 12 months.Secondary end points were allograft survival at 12 months and significant thymoglobulin and/or other drugs side effects. Results: In the SF group, 85% of the kidney recipients remained steroid-free at 12 months. The 3 cases of steroids introduction were due to one acute tubulo-interstitial rejection occurring at day 11, one tacrolimus withdrawal due to thrombotic microangiopathy and one MPA withdrawal because of multiple sinusitis and CMV reactivations. No BK viremia was detected nor CMV disease. The 6 CMV negative patients who received a positive CMV allograft had a symptomatic primoinfection after their 6-month course valgancyclovir prophylaxis. In the steroid-based group, 3 acute rejection episodes (acute humoral rejection, acute tubulointerstitial Banff IA and vascular Banff IIA) occurred in 2 recipients, 3 BK virus nephropathies were diagnosed between 45 and 135 days post transplant No side effects were associated with thymoglobulin infusion.In the SF group, 4 recipients presented severe leukopenia or agranulocytosis and one recipient had febrile hepatitis leading to transient MPA withdrawal. Discontinuation of MPA was needed in 2 patients for recurrent sinusitis and CMV reactivations. Patient and graft survival was 100% in both groups at 12 month follow-up. Conclusion: Steroid-free with short-course thymoglobulin induction therapy was a safe protocol in low-risk renal transplant recipients. Lower rates of acute rejection and BK virus infections episodes were seen compared to the steroid-based control group. A longer follow-up will be needed to determine whether this SF immunosuppressive regimen will result in higher graft and patient survival.

Understanding the low-temperature limitations to forest growth through calibration of a forest dynamics model with tree-ring data

The sensitivity of altitudinal and latitudinal tree-line ecotones to climate change, particularly that of temperature, has received much attention. To improve our understanding of the factors affecting tree-line position, we used the spatially explicit dynamic forest model TreeMig. Although well-suited because of its landscape dynamics functions, TreeMig features a parabolic temperature growth response curve, which has recently been questioned. and the species parameters are not specifically calibrated for cold temperatures. Our main goals were to improve the theoretical basis of the temperature growth response curve in the model and develop a method for deriving that curve's parameters from tree-ring data. We replaced the parabola with an asymptotic curve, calibrated for the main species at the subalpine (Swiss Alps: Pinus cembra, Larix decidua, Picea abies) and boreal (Fennoscandia: Pinus sylvestris, Betula pubescens, P. abies) tree-lines. After fitting new parameters, the growth curve matched observed tree-ring widths better. For the subalpine species, the minimum degree-day sum allowing, growth (kDDMin) was lowered by around 100 degree-days; in the case of Larix, the maximum potential ring-width was increased to 5.19 mm. At the boreal tree-line, the kDDMin for P. sylvestris was lowered by 210 degree-days and its maximum ring-width increased to 2.943 mm; for Betula (new in the model) kDDMin was set to 325 degree-days and the maximum ring-width to 2.51 mm; the values from the only boreal sample site for Picea were similar to the subalpine ones, so the same parameters were used. However, adjusting the growth response alone did not improve the model's output concerning species' distributions and their relative importance at tree-line. Minimum winter temperature (MinWiT, mean of the coldest winter month), which controls seedling establishment in TreeMig, proved more important for determining distribution. Picea, P. sylvestris and Betula did not previously have minimum winter temperature limits, so these values were set to the 95th percentile of each species' coldest MinWiT site (respectively -7, -11, -13). In a case study for the Alps, the original and newly calibrated versions of TreeMig were compared with biomass data from the National Forest Inventor), (NFI). Both models gave similar, reasonably realistic results. In conclusion, this method of deriving temperature responses from tree-rings works well. However, regeneration and its underlying factors seem more important for controlling species' distributions than previously thought. More research on regeneration ecology, especially at the upper limit of forests. is needed to improve predictions of tree-line responses to climate change further.

Low-grade and high-grade mammary carcinomas in WAP-T transgenic mice are independent entities distinguished by Met expression.

Mammary carcinomas developing in SV40 transgenic WAP-T mice arise in two distinct histological phenotypes: as differentiated low-grade and undifferentiated high-grade tumors. We integrated different types of information such as histological grading, analysis of aCGH-based gene copy number and gene expression profiling to provide a comprehensive molecular description of mammary tumors in WAP-T mice. Applying a novel procedure for the correlation of gene copy number with gene expression on a global scale, we observed in tumor samples a global coherence between genotype and transcription. This coherence can be interpreted as a matched transcriptional regulation inherited from the cells of tumor origin and determined by the activity of cancer driver genes. Despite common recurrent genomic aberrations, e.g. gain of chr. 15 in most WAP-T tumors, loss of chr. 19 frequently occurs only in low-grade tumors. These tumors show features of "basal-like" epithelial differentiation, particularly expression of keratin 14. The high-grade tumors are clearly separated from the low-grade tumors by strong expression of the Met gene and by coexpression of epithelial (e.g. keratin 18) and mesenchymal (e.g. vimentin) markers. In high-grade tumors, the expression of the nonmutated Met protein is associated with Met-locus amplification and Met activity. The role of Met as a cancer driver gene is supported by the contribution of active Met signaling to motility and growth of mammary tumor-derived cells. Finally, we discuss the independent origin of low- and high-grade tumors from distinct cells of tumor origin, possibly luminal progenitors, distinguished by Met gene expression and Met signaling.

Transmission disequilibrium of small CNVs in simplex autism.

We searched for disruptive, genic rare copy-number variants (CNVs) among 411 families affected by sporadic autism spectrum disorder (ASD) from the Simons Simplex Collection by using available exome sequence data and CoNIFER (Copy Number Inference from Exome Reads). Compared to high-density SNP microarrays, our approach yielded ∼2× more smaller genic rare CNVs. We found that affected probands inherited more CNVs than did their siblings (453 versus 394, p = 0.004; odds ratio [OR] = 1.19) and that the probands' CNVs affected more genes (921 versus 726, p = 0.02; OR = 1.30). These smaller CNVs (median size 18 kb) were transmitted preferentially from the mother (136 maternal versus 100 paternal, p = 0.02), although this bias occurred irrespective of affected status. The excess burden of inherited CNVs among probands was driven primarily by sibling pairs with discordant social-behavior phenotypes (p < 0.0002, measured by Social Responsiveness Scale [SRS] score), which contrasts with families where the phenotypes were more closely matched or less extreme (p > 0.5). Finally, we found enrichment of brain-expressed genes unique to probands, especially in the SRS-discordant group (p = 0.0035). In a combined model, our inherited CNVs, de novo CNVs, and de novo single-nucleotide variants all independently contributed to the risk of autism (p < 0.05). Taken together, these results suggest that small transmitted rare CNVs play a role in the etiology of simplex autism. Importantly, the small size of these variants aids in the identification of specific genes as additional risk factors associated with ASD.

Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis.

OBJECTIVE: Familial cold urticaria (FCU) and Muckle-Wells syndrome (MWS) are dominantly inherited autoinflammatory disorders that cause rashes, fever, arthralgia, and in some subjects, AA amyloidosis, and have been mapped to chromosome 1q44. Sensorineural deafness in MWS, and provocation of symptoms by cold in FCU, are distinctive features. This study was undertaken to characterize the genetic basis of FCU, MWS, and an overlapping disorder in French Canadian, British, and Indian families, respectively. METHODS: Mutations in the candidate gene NALP3, which has also been named CIAS1 and PYPAF1, were sought in the study families, in a British/Spanish patient with apparent sporadic MWS, and in matched population controls. Identified variants were sought in 50 European subjects with uncharacterized, apparently sporadic periodic fever syndromes, 48 subjects with rheumatoid arthritis (RA), and 19 subjects with juvenile idiopathic arthritis (JIA). RESULTS: Point mutations, encoding putative protein variants R262W and L307P, were present in all affected members of the Indian and French Canadian families, respectively, but not in controls. The R262W variant was also present in the subject with sporadic MWS. The V200M variant was present in all affected members of the British family with MWS, in 2 of the 50 subjects with uncharacterized periodic fevers, and in 1 of 130 Caucasian and 2 of 48 Indian healthy controls. No mutations were identified among the subjects with RA or JIA. CONCLUSION: These findings confirm that mutations in the NALP3/CIAS1/PYPAF1 gene are associated with FCU and MWS, and that disease severity and clinical features may differ substantially within and between families. Analysis of this gene will improve classification of patients with inherited or apparently sporadic periodic fever syndromes.

Marginal adaptation in vitro and clinical outcome of Class V restorations

OBJECTIVES: We examined the correlation between the quantitative margin analysis of two laboratory test methods (Berlin, Zurich) and the clinical outcome in Class V restorations. METHODS: Prospective clinical studies with an observation period of at least 18 months were searched in the literature, for which laboratory data were also available. The clinical outcome variables were retention loss, marginal discoloration, detectable margins and secondary caries. Forty-four clinical studies matched the inclusion criteria, including 34 adhesive systems for which laboratory data were also present. For both laboratory test methods and the clinical studies, an index was formulated to better compare the in vitro and in vivo results. Linear mixed models which included a random study effect were calculated. As most clinical data were available for 12 and 24 months, the main analysis was restricted to these recall intervals. RESULTS: The comparative analysis revealed a weak correlation between the clinical index and both in vitro indices. The correlation was statistically significant for the Berlin method but not for the Zurich method and only present if studies were compared which used the same composite in the in vitro and in vivo study. When defining specific cut-off values, the prognosis for the good clinical performance of an adhesive system based on in vitro results was 78% (Berlin) or 100% (Zurich). For poor performance it was 67% and 60%, respectively. No correlation was found between both in vitro methods. SIGNIFICANCE: The surrogate parameter "marginal adaptation" of restorations placed in extracted teeth has a mediocre value to predict the clinical performance of an adhesive system in cervical cavities. The composite is an important factor for a successful prediction. The comparison between in vitro/in vivo is sometimes hampered by the great variability of clinical results on the same adhesive system.

Selected polymorphisms in sex hormone-related genes, circulating sex hormones and risk of endometrial cancer.

BACKGROUND: The role of estrogen and progesterone in the development of endometrial cancer is well documented. Few studies have examined the association of genetic variants in sex hormone-related genes with endometrial cancer risk. METHODS: We conducted a case-control study nested within three cohorts to examine the association of endometrial cancer risk with polymorphisms in hormone-related genes among 391 cases (92% postmenopausal at diagnosis) and 712 individually-matched controls. We also examined the association of these polymorphisms with circulating levels of sex hormones and SHBG in a cross-sectional analysis including 596 healthy postmenopausal women at blood donation (controls from this nested case-control study and from a nested case-control study of breast cancer in one of the three cohorts). RESULTS: Adjusting for endometrial cancer risk factors, the A allele of rs4775936 in CYP19 was significantly associated (OR(per allele)=1.22, 95% CI=1.01-1.47, p(trend)=0.04), while the T allele of rs10046 was marginally associated with increased risk of endometrial cancer (OR(per allele)=1.20, 95% CI=0.99-1.45, p(trend)=0.06). PGR rs1042838 was also marginally associated with risk (OR(per allele)=1.25, 95% CI=0.96-1.61, p(trend)=0.09). No significant association was found for the other polymorphisms, i.e. CYP1B1 rs1800440 and rs1056836, UGT1A1 rs8175347, SHBG rs6259 and ESR1 rs2234693. Rs8175347 was significantly associated with postmenopausal levels of estradiol, free estradiol and estrone and rs6259 with SHBG and estradiol. CONCLUSION: Our findings support an association between genetic variants in CYP19, and possibly PGR, and risk of endometrial cancer.

Serum-Mediane von Placentaprotein-Markern: Relevanz der Unterschiede zwischen spontanen und nach-in-vitro-Fertilisation eingetretenen Schwangerschaften für das fetale Trisomie-Screening.

Trisomy-21 (Down syndrome) is the most frequent chromosomal abnorm- ality but only one third of cases would be detected by amniocentesis based on maternal age alone. Serum screening tests in the early second trimester increase the detec- tion rate to 60-65%, and more recently it was found that such screening was also possible in the first trimester by quantifying a diffe- rent panel of markers. The concen- trations of these placental proteins are strongly dependent on gestatio- nal age; thus control medians must be established and precise dating is essential. Serum chorionic gonado- trophin (HCG) levels were recently found to be increased in IVF preg- nancies compared to spontaneous gestations, leading to a falsely ele- vated trisomy screening risk. The aim of this preliminary study was to find out whether, in the first-trime- ster screening, the markers similarly differed between IVF and spontane- ous pregnancies which would call for the establishment of separate normal medians for IVF patients. We compared 24 pregnancies ob- tained after ovarian stimulation and IVF with six women after thawed embryo transfer (unstimulated cycle) and 63 gestation- and maternal-age matched spontaneously pregnant controls. A single serum was ob- tained between 6 and 16 weeks of gestation and various placental protein levels determined by im- munometric assays. Serum levels of pregnancy-associated plasma protein A (PAPP-A), which is the major marker in the first-trimes- ter screening test, were reduced in IVF pregnancies: after 9 weeks of gestation, multiples of median (MoMs) ranged between 0.23 and 3.58 (logarithmic mean 0.743). For the frozen/thawed transfers, this value was 1.08. In the 9-12 week group containing 6 cases of IVF, three thawed transfers and 25 con- trols, PAPP-A was significantly redu- ced in the stimulated compared to the nonstimulated cycles. In the late first and early second trimester the difference was not significant in our small group but the trend persisted. Pregnancies after IVF will thus show an increased incidence of false positive results in fetal trisomy-21 screening, and special medians should be established for these pati- ents.

Whole body protein metabolism and resting energy expenditure in pregnant Gambian women.

Whole body protein metabolism and resting energy expenditure (REE) were measured at 11, 23, and 33 wk of pregnancy in nine pregnant (not malnourished) Gambian women and in eight matched nonpregnant nonlactating (NPNL) matched controls. Rates of whole body nitrogen flux, protein synthesis, and protein breakdown were determined in the fed state from the level of isotope enrichment of urinary urea and ammonia during a period of 9 h after a single oral dose of [15N]glycine. At regular intervals, REE was measured by indirect calorimetry (hood system). Based on the arithmetic end-product average of values obtained with urea and ammonia, a significant increase in whole body protein synthesis was observed during the second trimester (5.8 +/- 0.4 g.kg-1.day-1) relative to values obtained both for the NPNL controls (4.5 +/- 0.3 g.kg-1.day-1) and those during the first trimester (4.7 +/- 0.3 g.kg-1.day-1). There was a significant rise in REE during the third trimester both in the preprandial and postprandial states. No correlation was found between REE after meal ingestion and the rate of whole body protein synthesis.

Spatio-temporal gait analysis in children with cerebral palsy using, foot-worn inertial sensors.

A child's natural gait pattern may be affected by the gait laboratory environment. Wearable devices using body-worn sensors have been developed for gait analysis. The purpose of this study was to validate and explore the use of foot-worn inertial sensors for the measurement of selected spatio-temporal parameters, based on the 3D foot trajectory, in independently walking children with cerebral palsy (CP). We performed a case control study with 14 children with CP aged 6-15 years old and 15 age-matched controls. Accuracy and precision of the foot-worn device were measured using an optical motion capture system as the reference system. Mean accuracy±precision for both groups was 3.4±4.6cm for stride length, 4.3±4.2cm/s for speed and 0.5±2.9° for strike angle. Longer stance and shorter swing phases with an increase in double support were observed in children with CP (p=0.001). Stride length, speed and peak angular velocity during swing were decreased in paretic limbs, with significant differences in strike and lift-off angles. Children with cerebral palsy showed significantly higher inter-stride variability (measured by their coefficient of variation) for speed, stride length, swing and stance. During turning trajectories speed and stride length decreased significantly (p<0.01) for both groups, whereas stance increased significantly (p<0.01) in CP children only. Foot-worn inertial sensors allowed us to analyze gait spatiotemporal data outside a laboratory environment with good accuracy and precision and congruent results with what is known of gait variations during linear walking in children with CP.

Encoding dysfunctions in a dynamic-static paradigm for visuospatial working memory in first-episode psychosis patients: a 2-year follow-up study.

Aim: To investigate static and dynamic visuospatial working memory (VSWM) processes in first-episode psychosis (FEP) patients and explore the validity of such measures as specific trait markers of schizophrenia. Methods: Twenty FEP patients and 20 age-, sex-, laterality- and education-matched controls carried out a dynamic and static VSWM paradigm. At 2-year follow up 13 patients met Diagnostic and Statistical Manual (of Mental Health Disorders) - Fourth Edition (DSM-IV) criteria for schizophrenia, 1 for bipolar disorder, 1 for brief psychotic episode and 5 for schizotypal personality disorder. Results: Compared with controls, the 20 FEP patients showed severe impairment in the dynamic VSWM condition but much less impairment in the static condition. No specific bias in stimulus selection was detected in the two tasks. Two-year follow-up evaluations suggested poorer baseline scores on the dynamic task clearly differentiated the 13 FEP patients who developed schizophrenia from the seven who did not. Conclusions: Results suggest deficits in VSWM in FEP patients. Specific exploratory analyses further suggest that deficit in monitoring-manipulation VSWM processes, especially involved in our dynamic VSWM task, can be a reliable marker of schizophrenia.

Pain: a common symptom in human immunodeficiency virus-infected Thai children.

AIM: To determine the prevalence and characteristics of pain in Thai human immunodeficiency virus-infected children. METHODS: A cross-sectional study was performed at the HIV/AIDS outpatient clinic at the Queen Sirikit National Institute of Child Health, Bangkok, Thailand from November 2002 to January 2003. Sixty-one human immunodeficiency virus-infected patients aged 4 to 15 y, an equal number of age-matched children with no chronic disease and their caregivers participated. We interviewed children and their caregivers using a structured questionnaire on pain. The main outcome measure was the percentage of human immunodeficiency virus-infected children reporting pain. RESULTS: Forty-four percent of the human immunodeficiency virus-infected children reported pain compared to 13% of the children with no chronic disease (odds ratio, OR = 5.3; 95% CI: 2.0-14.3). Seven percent of the infected children experienced chronic pain. Children in human immunodeficiency virus clinical categories B and C reported more pain than children in categories N and A (OR = 4.0, 95% CI: 1.1-14.7). Pain in infected children tended to occur in the abdomen, lower limbs or head. Only 44 percent of the infected children experiencing pain received analgesic medication. CONCLUSION: Despite being a common experience, pain is insufficiently taken into account and treated in Thai children with HIV/AIDS. Therefore, adequate pain identification, assessment and management should be systemically considered in their routine care.