Heterotrimeric Go protein links Wnt-Frizzled signaling with ankyrins to regulate the neuronal microtubule cytoskeleton.

Drosophila neuromuscular junctions (NMJs) represent a powerful model system with which to study glutamatergic synapse formation and remodeling. Several proteins have been implicated in these processes, including components of canonical Wingless (Drosophila Wnt1) signaling and the giant isoforms of the membrane-cytoskeleton linker Ankyrin 2, but possible interconnections and cooperation between these proteins were unknown. Here, we demonstrate that the heterotrimeric G protein Go functions as a transducer of Wingless-Frizzled 2 signaling in the synapse. We identify Ankyrin 2 as a target of Go signaling required for NMJ formation. Moreover, the Go-ankyrin interaction is conserved in the mammalian neurite outgrowth pathway. Without ankyrins, a major switch in the Go-induced neuronal cytoskeleton program is observed, from microtubule-dependent neurite outgrowth to actin-dependent lamellopodial induction. These findings describe a novel mechanism regulating the microtubule cytoskeleton in the nervous system. Our work in Drosophila and mammalian cells suggests that this mechanism might be generally applicable in nervous system development and function.

Reinitialization of evolutionary clocks during sublethal environmental stress in some invertebrates

This paper describes the influence of high environmental stress on evolutionary trends in some selected Mesozoic ammonite lineages and some protists. During extinction periods, many ammonoids are affected by drastic simplifications of their shell geometry, ornamentation and suture line. We observe that relatively tightly coiled ammonites can give rise to highly evolute forms or uncoiled heteromorphs with simple ornamentation and almost ceratitic suture line-a phenomenon called "proteromorphosis". Such simplifications often correspond to a reappearance of ancestral geometries (primitive ornamentation, evolute coiling or uncoiling) which suggest that the evolutionary clock of these organisms can be reinitialized by extreme, sublethal, environmental stress such as giant volcanism (including its consequences on diverse pollutions and on climatic changes) and major regressive events. (c) 2006 Elsevier B.V. All rights reserved.

The karyotype of Crocidura flavescens (Mammalia, Insectivora) in South Africa

Karyological results give evidence that the South African Crocidura flavescens (Geoffroy, 1827) is not conspecific with the West and East African giant shrews of the taxa spurrelli, manni, kivu and olivieri

Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts.

BACKGROUND: Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. METHODS AND FINDINGS: We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10⁻²⁷). The BMI allele score was associated both with BMI (p = 6.30×10⁻⁶²) and 25(OH)D (-0.06% [95% CI -0.10 to -0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10⁻⁵⁷ for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores). CONCLUSIONS: On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.

Le caryotype de Crocidura bolivari (Mammalia, Soricidae) Morales Agacino, 1934 (Mammalia, Soricidae)

The karyotype of Crocidura bolivari from Morocco is characterized by 2n = 50, NF = 66 and NFa = 62, and therefore corresponds to that of Crocidura occidentalis (Pucheran, 1855). Preliminary results on the standard genetic distances revealed by enzyme electrophoresis confirm the close relationship with the African giant shrews.

Diagnostic Performances of 18F-FDG Positron Emission Tomography in Large Vessels Vasculitis: Meta-analysis

Toperform a meta-analysis of FDG-PET performances in the diagnosis of largevessels vasculitis (Giant Cell Arteritis (GCA) associated or not withPolymyalgia Rheumatica(PMR), Takayasu). Materials and methods : The MEDLINE,Cochrane Library, Embase were searched for relevant original articlesdescribing FDG-PET for vasculitis assessment, using MesH terms ("GiantCell Arteritis or Vasculitis" AND "PET"). Criteria for inclusionwere:(1)FDG-PET for diagnosis of vasculitis(2)American College of Rheumatologycriteria as reference standard(3)control group. After data extraction, analyseswere performed using a random-effects model. Results : Of 184 citations(database search and references screening),70 articles were reviewed of which12 eligible studies were extracted (sensitivity range from 32% to 97%). 7studies fulfilled all inclusion criteria. Owing to overlapping population, 1study was excluded. Statistical heterogeneity justified the random-effectsmodel. Pooled 6 studies analysis(116 vasculitis,224 controls) showed a 81%sensitivity (95%CI:70-89%);a 89% specificity (95%CI:77-95%);a 85%PPV(95%CI:63-95%); a 90% NPV(95%CI:79-95%);a 7.1 positive LR(95%CI:3.4-14.9); a0.2 negative LR(95%CI:0.14-0.35) and 90.1 DOR(95%CI: 18.6-437). Conclusion :FDG-PET has good diagnostic performances in the detection of large vesselsvasculitis. Its promising role could be extended to follow up patients undertreatment, but further studies are needed to confirm this possibility.

Dramatic malignant progression of a pigmented villonodular synovitis of the knee after 27 years of multimodality treatment

Introduction: Pigmented villonodular synovitis (PVNS) is a rare benign tumour of the synovium, most commonly arising around the knee. Resection remains the treatment of choice. The diffuse variant of the disease is prone to local recurrence (30-50%). However distant dissemination is extremely rare. We report the case of a patient with massive loco-regional and late distant spread to the lungs of PVNS originating in the knee. Case report: A 69 yo women presented to our service 27 years ago with PVNS in her knee. Despite multible surgical resections, synoviorthesis and external beam radiotherapy, no local control was achieved. The disease spread in all thigh compartments. Due to the resistance to all convetional treatment modalities, isolated limb perfusion with TNFα and Melphalan was performed, without any effect on local control. After the disease was diagnosed in iliac lymph nodes, the patient was subjected to a systemic chemotherapy protocol with imitamib, which had to be abandoned, due to intolerance. Due to a giant lymphoedema of the entire limb, making up for a considerable part of the patient's body weight and in view of significant skin invasion, a hip disarticulation was performed. Finally, rapidly growing lung metastases appeared on CT scan, confirmed by core-needle biopsy. Palliative chemotherapy was initiated. Interestingly, histological analysis of the disease throughout the years remained consistent with classic benign PVNS. No sarcomatous dedifferentiation was observed, not even in the pulmonary lesions. Conclusion: PVNS is a benign tumour, with a high risk of local recurrence. Malignant behaviour, with loco-regional and distant metastases remains extremely rare. A histologically benign appearance does not exclude a clinically malignant behaviour with systemic spread.

Rupture of a concealed aneurysm after intravenous thrombolysis of a thrombus in the parent middle cerebral artery.

BACKGROUND: Management of ischemic stroke in the presence of aneurysmal brain disease is controversial. Recent retrospective evidence suggests that in selected patients, intravenous thrombolysis (IVT) remains a safe approach for reperfusion. METHODS: We document a case of post-thrombolysis aneurysmal rupture. Supported by additional scientific literature we postulate that acute aneurysmal thrombosis leading to stroke in the culprit artery may be an ominous sign of rupture and should be considered separately from fortuitously discovered distant aneurysmal disease. RESULTS: A 71-year-old female presented with an acute right middle cerebral artery stroke syndrome. IVT allowed vessel reperfusion and revealed a previously concealed, juxtaposed non-giant M1 segment saccular aneurysm. Secondary aneurysmal rupture ensued. The aneurysm was secured by surgical clipping. Postoperative course was uneventful. CONCLUSIONS: This case shows that despite reports of thrombolysis safety in the presence of brain aneurysms, thrombolysis remains potentially hazardous and hints toward an increased risk when the stroke arises on the parent vessel itself.

Forme pseudotumorale d'un chalazion [Chalazion mimicking an eyelid tumor].

A 3-year-old girl had a tumor growing for a month on the superior right eyelid, attached on the free margin of the eyelid and partially necrotic. A surgical excision was performed under general anesthesia. The histopathological study found an inflammatory lesion with epithelioid and giant cells, evidence of a granuloma, suggesting the diagnosis of chalazion. This case shows the various clinical presentations of this common and benign disease of the eyelid.

Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.

Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10(-8)) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT-assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits.

Novel Approach Identifies SNPs in SLC2A10 and KCNK9 with Evidence for Parent-of-Origin Effect on Body Mass Index.

The phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present a novel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. The method exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups. We applied the method to >56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six lead SNPs were carried forward for replication in five family-based studies (of ∼4,000 trios). Two SNPs replicated: the paternal rs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10 gene) increased BMI equally (beta = 0.11 (SD), P<0.0027) compared to the respective maternal alleles. Real-time PCR experiments of lymphoblastoid cell lines from the CEPH families showed that expression of both genes was dependent on parental origin of the SNPs alleles (P<0.01). Our scheme opens new opportunities to exploit GWAS data of unrelated individuals to identify POEs and demonstrates that they play an important role in adult obesity.

Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women.

Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1 × 10E-09), previously identified in association with waist-hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9 × 10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6 × 10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist-hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits.

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

Parésie trochléaire transitoire comme signe neurologique inaugural d'une panartérite noueuse [Transient trochlear nerve palsy as the presenting neurological sign of panarteritis nodosa]

INTRODUCTION: Panarteritis nodosa (PAN) is a systemic vasculitis affecting small and medium-sized arteries. Neuro-ophthalmological complications of PAN are rare but numerous, and may affect the eye, the visual and the oculomotor pathways. Such complications occur mainly in patients previously diagnosed with PAN. OBSERVATION: A 51-year-old woman presented with an isolated right trochlear (IV) palsy, in the setting of headaches and fluctuating fever of unknown etiology. Erythrocyte sedimentation rate was 13 mm and full blood cell count was normal. Previous chest X-ray and blood studies were negative for an infection or inflammation. Orbital and cerebral CT scan was normal. Spontaneous recovery of diplopia ensued over four days. Two days later, paresthesia and sensory paresis of the dorsal portion of the left foot were present. Lumbar puncture revealed 14 leucocytes (76 percent lymphocytes) with elevated proteins, but blood studies and serologies were negative. A diagnosis of undetermined meningo-myelo-radiculoneuritis was made. Because of a possible tick bite six weeks previously the patient was empirically treated with 2 g intravenous ceftriaxone for 3 weeks. Fever rapidly dropped. Six weeks after the onset of diplopia, acute onset of blindness in her right eye, diffuse arthralgias and fever motivated a new hospitalization. There was a central retinal artery occlusion of the right eye. Blood studies now revealed signs of systemic inflammation (ESR 30 mm, CRP 12 mg/L, ANA 1/80, pANCA 1/40, leucocytosis 12.4 G/L, Hb 111 g/L, Ht 33 percent). Biopsy of the left sural nerve revealed arterial fibrinoid necrosis. A diagnosis of PAN was made. CONCLUSIONS: Transient diplopia can be the heralding symptom of a systemic vasculitis such as PAN, giant cell arteritis and Wegener granulomatosis. In this patient the presence of accompanying systemic symptoms raised a suspicion of systemic inflammation, but the absence of serologic and imaging abnormalities precluded a specific diagnosis initially. A few weeks later, the presence of a second ischemic event (retinal) and positive blood studies led to a further diagnostic procedure. Oculomotor and abducens palsies have rarely been reported in association with PAN. We report the first case of trochlear nerve paresis as the inaugural neurological sign of PAN. This case highlights the importance of considering inflammatory systemic disorders in patients with acute diplopia particularly when they are young, lack vascular risk factors or cause, and complain of associated systemic symptoms.