Showing papers by "Casa Sollievo della Sofferenza published in 2007"
TL;DR: ERCP remains the endoscopic procedure that carries a high risk for morbidity and mortality, and complications continue to occur at a relatively consistent rate.
937 citations
TL;DR: In patients with HCV‐related, histologically proven cirrhosis, achievement of a SVR after IFNα therapy was associated with a reduction of liver‐related mortality lowering both the risk of complications and HCC development.
605 citations
TL;DR: The present report expands the spectrum of knowledge showing that MS has frequent monoblastic/myelomonocytic differentiation, displays distinctive phenotypic profile, carries chromosomal aberrations other than t(8;21), and requires supra-maximal therapy.
Abstract: Myeloid sarcoma (MS) is a rare neoplasm whose knowledge is largely based on case reports and/or technically dated contributions. Ninety-two MSs in adulthood with clinical data available were evaluated both morphologically and immunohistochemically. Seventy-four cases were also studied by fluorescent in situ hybridization on tissue sections and/or conventional karyotyping on bone marrow or peripheral blood. Histologically, 50% of the tumors were of the blastic type, 43.5% either monoblastic or myelomonocytic and 6.5% corresponded to different histotypes. CD68/KP1 was the most commonly expressed marker (100%), followed by myeloperoxidase (83.6%), CD117 (80.4%), CD99 (54.3%), CD68/PG-M1 (51%), CD34 (43.4%), terminal-deoxy-nucleotidyl-transferase (31.5%), CD56 (13%), CD61/linker for activation of T cells (2.2%), CD30 (2.2%) and CD4 (1.1%). Foci of plasmacytoid monocyte differentiation were observed in intestinal cases carrying inv16. Chromosomal aberrations were detected in about 54% of cases: monosomy 7(10.8%), trisomy 8(10.4%) and mixed lineage leukemia-splitting (8.5%) were the commonest abnormalities, whereas t(8;21) was rare (2.2%). The behavior was dramatic irrespective of presentation, age, sex, phenotype and cytogenetics. Most if not all, long survivors received bone-marrow transplantation. The present report expands the spectrum of our knowledge showing that MS has frequent monoblastic/myelomonocytic differentiation, displays distinctive phenotypic profile, carries chromosomal aberrations other than t(8;21), and requires supra-maximal therapy.
556 citations
Istituto Superiore di Sanità1, United States Department of Energy2, Lawrence Berkeley National Laboratory3, New York University4, Sapienza University of Rome5, Casa Sollievo della Sofferenza6, Icahn School of Medicine at Mount Sinai7, Catholic University of the Sacred Heart8, Royal Children's Hospital9
TL;DR: In this paper, the authors reported that 22 of 129 NoNoonan syndrome (NS) patients without PTPN11 or KRAS mutation (17 percent) have missense mutations in SOS1, which encodesa RAS-specific guanine nucleotide exchange factor (GEF).
Abstract: Noonan syndrome (NS) is a developmental disordercharacterized by short stature, facial dysmorphia, congenital heartdefects and skeletal anomalies1. Increased RAS-mitogenactivated proteinkinase (MAPK) signaling due to PTPN11 and KRAS mutations cause 50 percentof NS2-6. Here, we report that 22 of 129 NS patients without PTPN11 orKRAS mutation (17 percent) have missense mutations in SOS1, which encodesa RAS-specific guanine nucleotide exchange factor (GEF). SOS1 mutationscluster at residues implicated in the maintenance of SOS1 in itsautoinhibited form and ectopic expression of two NS-associated mutantsinduced enhanced RAS activation. The phenotype associated with SOS1defects is distinctive, although within NS spectrum, with a highprevalence of ectodermal abnormalities but generally normal developmentand linear growth. Our findings implicate for the first timegain-of-function mutations in a RAS GEF in inherited disease and define anew mechanism by which upregulation of the RAS pathway can profoundlychange human development.
510 citations
BC Cancer Agency1, Health Sciences Centre2, University of British Columbia3, Casa Sollievo della Sofferenza4, Stanford University5, University of Porto6, McGill University7, Queen's University8, University of Texas Health Science Center at San Antonio9, University of Connecticut10, Université de Montréal11, University of Vermont12, Memorial University of Newfoundland13, Memorial Sloan Kettering Cancer Center14, Harvard University15, Hospital Italiano de Buenos Aires16, University Health Network17, University of Cambridge18
TL;DR: Recurrent CDH1 mutations in families with hereditary diffuse gastric cancer are due to both independent mutational events and common ancestry, and the presence of a founder mutation from Newfoundland is strongly supported.
Abstract: ContextHereditary diffuse gastric cancer is caused by germline mutations in the epithelial cadherin (CDH1) gene and is characterized by an increased risk for diffuse gastric cancer and lobular breast cancer.ObjectiveTo determine whether recurring germline CDH1 mutations occurred due to independent mutational events or common ancestry.Design, Setting, and PatientsThirty-eight families diagnosed clinically with hereditary diffuse gastric cancer were accrued between November 2004 and January 2006 and were analyzed for CDH1 mutations as part of an ongoing study at the British Columbia Cancer Agency. Twenty-six families had at least 2 gastric cancer cases with 1 case of diffuse gastric cancer in a person younger than 50 years; 12 families had either a single case of diffuse gastric cancer diagnosed in a person younger than 35 years or multiple cases of diffuse gastric cancer diagnosed in persons older than 50 years.Main Outcome MeasuresClassification of family members as carriers or noncarriers of CDH1 mutations. Haplotype analysis to assess recurring mutations for common ancestry was performed on 7 families from this study and 7 previously reported families with the same mutations.ResultsThirteen mutations (6 novel) were identified in 15 of the 38 families (40% detection rate). The 1137G>A splicing mutation and the 1901C>T (A634V) missense/splicing mutation occurred on common haplotypes in 2 families but on different haplotypes in a third family. The 2195G>A (R732Q) missense/splicing mutation occurred in 2 families on different haplotypes. The 2064-2065delTG mutation occurred on a common haplotype in 2 families. Two families from this study plus 2 additional families carrying the novel 2398delC mutation shared a common haplotype, suggesting a founder effect. All 4 families originate from the southeast coast of Newfoundland. Due to concentrations of lobular breast cancer cases, 2 branches of this family had been diagnosed as having hereditary breast cancer and were tested for BRCA mutations. Within these 4 families, the cumulative risk by age 75 years in mutation carriers for clinically detected gastric cancer was 40% (95% confidence interval [CI], 12%-91%) for males and 63% (95% CI, 19%-99%) for females and the risk for breast cancer in female mutation carriers was 52% (95% CI, 29%-94%).ConclusionsRecurrent CDH1 mutations in families with hereditary diffuse gastric cancer are due to both independent mutational events and common ancestry. The presence of a founder mutation from Newfoundland is strongly supported.Published online June 3, 2007 (doi:10.1001/jama.297.21.2360).
381 citations
TL;DR: CT screening of thyroid nodules is a highly sensitive test for early diagnosis of MTC, but confirmatory stimulation testing is necessary in most cases to identify true positive increases.
Abstract: Results: Fifteen cases of MTC and seven of C cell hyperplasia (CCH) were identified. MTCs were diagnosed in all patients with basal CT more than 100 pg/ml. The four patients with basal CT more than or equal to 50 and less than 100 pg/ml included two diagnosed with MTC andtwowithCCH.In10patientswithbasallevelsmorethanorequal to 20 and less than 50 pg/ml, histology confirmed the presence of MTC in four, four others had CCH, and the remaining two were negative for thyroid malignancy. Positive predictive values for basal CT levels in the preoperative diagnosis of MTC were: 23.1% for values more than or equal to 20 pg/ml, 100% for values more than 100 pg/ml, 25% for levels more than or equal to 50 and less than 100 pg/ml, and 8.3% for values more than or equal to 20 and less than 50 pg/ml. Positive predictive values for the pentagastrin test (100 pg/ml) were 40% in the entire series. Conclusions: CT screening of thyroid nodules is a highly sensitive test for early diagnosis of MTC, but confirmatory stimulation testing is necessary in most cases to identify true positive increases. (J Clin Endocrinol Metab 92: 450–455, 2007)
322 citations
TL;DR: Oral MPR therapy is a promising first-line treatment for elderly myeloma patients and aspirin appears to provide adequate antithrombosis prophylaxis.
Abstract: Purpose Lenalidomide has shown significant antimyeloma activity in clinical studies. Oral melphalan, prednisone, and thalidomide have been regarded as the standard of care in elderly multiple myeloma patients. We assessed dosing, efficacy, and safety of melphalan, prednisone, and lenalidomide (MPR) in newly diagnosed elderly myeloma patients. Patients and Methods Oral melphalan was administered in doses ranging from 0.18 to 0.25 mg/kg on days 1 to 4, prednisone at a 2-mg/kg dose on days 1 to 4, and lenalidomide at doses ranging from 5 to 10 mg on days 1 to 21, every 28 days for nine cycles, followed by maintenance therapy with lenalidomide alone. Aspirin was given as a prophylaxis for thrombosis. Results Fifty-four patients were enrolled and evaluated after completing the assigned treatment schedule. The maximum tolerated dose was defined as 0.18 mg/kg melphalan and 10 mg lenalidomide. With these doses, 81% of patients achieved at least a partial response, 47.6% achieved a very good partial response, and ...
312 citations
TL;DR: Polymorphisms at the adiponectin locus are indeed predictors of circulating adip onectin levels, insulin sensitivity, and atherosclerosis, highlighting the pivotal role of this adipokine in the modulation of metabolism and atherogenesis.
Abstract: Recent evidence points to molecules secreted by the adipose tissue, or adipokines, as possible links between increased adipose mass and metabolic abnormalities. Among these molecules, adiponectin has drawn much attention because of its insulin-sensitizing and antiatherogenic actions, suggesting that genetic deficits in its production or action may contribute to insulin resistance and coronary artery disease (CAD). A meta-analysis of the data published to date supports this hypothesis. Two independent effects, corresponding to the two linkage disequilibrium blocks that can be identified at the adiponectin locus, appear to be present. In the 5′ block, the g.−11391G→A variant has a modest but significant effect on adiponectinemia, with a mean difference between genotypes of 1.64 ng/ml (95% CI 0.88–2.41). In the 3′ block, the g.+276G→T variant is a strong determinant of insulin resistance and CAD, with minor allele homozygotes having a lower homeostasis model assessment of insulin resistance (HOMAIR) index (−0.36 units, 95% CI 0.24–0.47) and a lower cardiovascular risk (odds ratio 0.55, 95% CI 0.38–0.80) than carriers of other genotypes. No consistent effect on BMI or risk of type 2 diabetes is evident. Polymorphisms in the genes coding for the adiponectin receptors may also influence the risk of insulin resistance and CAD, but data on these genes are still too sparse to draw firm conclusions. In summary, the studies published to date indicate that polymorphisms at the adiponectin locus are indeed predictors of circulating adiponectin levels, insulin sensitivity, and atherosclerosis, highlighting the pivotal role of this adipokine in the modulation of metabolism and atherogenesis.
281 citations
University of Pavia1, University of Siena2, University of Turin3, University of Zurich4, University of Bari5, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico6, Casa Sollievo della Sofferenza7, University of Catania8, Vita-Salute San Raffaele University9, University of Ferrara10, Agilent Technologies11, Katholieke Universiteit Leuven12
TL;DR: The results show that the phenotypic abnormalities of apparently balanced de novo CCRs are mainly due to cryptic deletions and that spermatogenesis is more prone to generate multiple chaotic chromosome imbalances and reciprocal translocations than oogenesis.
Abstract: Using array comparative genome hybridisation (CGH) 41 de novo reciprocal translocations and 18 de novo complex chromosome rearrangements (CCRs) were screened. All cases had been interpreted as "balanced" by conventional cytogenetics. In all, 27 cases of reciprocal translocations were detected in patients with an abnormal phenotype, and after array CGH analysis, 11 were found to be unbalanced. Thus 40% (11 of 27) of patients with a "chromosomal phenotype" and an apparently balanced translocation were in fact unbalanced, and 18% (5 of 27) of the reciprocal translocations were instead complex rearrangements with >3 breakpoints. Fourteen fetuses with de novo, apparently balanced translocations, all but two with normal ultrasound findings, were also analysed and all were found to be normal using array CGH. Thirteen CCRs were detected in patients with abnormal phenotypes, two in women who had experienced repeated spontaneous abortions and three in fetuses. Sixteen patients were found to have unbalanced mutations, with up to 4 deletions. These results suggest that genome-wide array CGH may be advisable in all carriers of "balanced" CCRs. The parental origin of the deletions was investigated in 5 reciprocal translocations and 11 CCRs; all were found to be paternal. Using customized platforms in seven cases of CCRs, the deletion breakpoints were narrowed down to regions of a few hundred base pairs in length. No susceptibility motifs were associated with the imbalances. These results show that the phenotypic abnormalities of apparently balanced de novo CCRs are mainly due to cryptic deletions and that spermatogenesis is more prone to generate multiple chaotic chromosome imbalances and reciprocal translocations than oogenesis.
267 citations
TL;DR: Variable treatment duration ensures SVR rates similar to those of standard treatment duration, sparing unnecessary side effects and costs, according to HEPATOLOGY 2007.
257 citations
TL;DR: An overview of the current concepts of vertebral instability is provided, focusing on degenerative lumbar intervertebral instability, and the different imaging modalities most indicated in diagnosing vertebra instability are reviewed.
Abstract: Intervertebral instability of the lumbar spine is thought to be a possible pathomechanical mechanism underlying low back pain and sciatica and is often an important factor in determining surgical indication for spinal fusion and decompression. Instability of the lumbar spine, however, remains a controversial and poorly understood topic. At present, much controversy exists regarding the proper definition of the condition, the best diagnostic methods, and the most efficacious treatment approaches. Clinical presentation is not specific, and the relationship between radiologic evidence of instability and its symptoms is controversial. Because of its simplicity, low expense, and pervasive availability, functional flexion-extension radiography is the most thoroughly studied and the most widely used method in the imaging diagnosis of lumbar intervertebral instability. In this article, we provide an overview of the current concepts of vertebral instability, focusing on degenerative lumbar intervertebral instabili...
TL;DR: Anticoagulant therapy was effective to obtain recanalization of acute SVT in 45.4% of patients and preserved patients from recurrent thrombosis when given lifelong, according to preestablished criteria.
TL;DR: The data highlight the key role played by the T cell compartment in the pathogenesis of CVID, pointing to the need to consider this aspect for classification of this disease.
Abstract: We investigated several phenotypic and functional parameters of T cell-mediated immunity in a large series of common variable immunodeficiency (CVID) patients. We demonstrated that the vast majority of CVID patients presented multiple T cell abnormalities intimately related among them, the severity of which was reflected in a parallel loss of CD4+ naive T cells. A strong correlation between the number of CD4+ naive T cells and clinical features was observed, supporting the subgrouping of patients according to their number of naive CD4+ T lymphocytes. A reduced thymic output and disrupted CD4+ and CD8+ TCR repertoires paralleled the contraction of CD4+ naive T cell pools. The evaluation of activation markers and cytokine production indicated a strong T cell activation that was significantly related to the increased levels of T cell turnover and apoptosis. Finally, discrete genetic profiles could be demonstrated in groups of patients showing extremely diverse T cell subset composition and function. Naive CD4+ T cell levels were significantly associated with the switched memory B cell-based classification, although the concordance between the respective subgroups did not exceed 58.8%. In conclusion, our data highlight the key role played by the T cell compartment in the pathogenesis of CVID, pointing to the need to consider this aspect for classification of this disease.
TL;DR: Despite the small sequence divergence of the HCV core proteins of genotypes 3a and 1b, the 2 proteins appear to interfere with the insulin signaling pathway using genotype‐specific mechanisms.
TL;DR: It is suggested a strict adherence to criteria of allocation based on the virological characteristics of both recipients and donors in the general setting of transplants and in liver transplantation the universal prophylaxis with nucleos(t)ides analogues (frequently combined with specific anti-HBV immunoglobulins) in HBsAg positive candidates and inHBsAg negative recipients of anti- HBc positive grafts.
TL;DR: In type 2 diabetic subjects, hypothalmic-pituitary-adrenal activity is enhanced in patients with diabetes complications and the degree of cortisol secretion is related to the presence and number of diabetes complications.
Abstract: OBJECTIVE —The presence of an enhanced cortisol secretion in patients with type 2 diabetes is debated. In type 2 diabetic subjects, cortisol secretion was found to be associated with the complications and metabolic control of diabetes. We evaluated cortisol secretion in 170 type 2 diabetic subjects and in 71 sex-, age-, and BMI-matched nondiabetic subjects. RESEARCH DESIGN AND METHODS —In all subjects, we evaluated ACTH at 8:00 a.m. in basal conditions and serum cortisol levels at 12:00 p.m. (F24) and at 9:00 a.m. after a 1-mg overnight dexamethasone suppression test and 24-h urinary free cortisol (UFC). In diabetic patients, we evaluated the presence of chronic complications (incipient nephropathy, asymptomatic neuropathy, background retinopathy, and silent macroangiopathy). Patients were subdivided according to the absence (group 1, n = 53) or presence (group 2, n = 117) of diabetes complications. RESULTS —In group 2, UFC (125.2 ± 4.6 nmol/24 h) and F24 (120.6 ± 4.1 nmol/l) were higher than in group 1 (109.2 ± 6.8 nmol/24 h, P = 0.057, and 99.7 ± 6.1 nmol/l, P = 0.005, respectively) and in nondiabetic patients (101.7 ± 5.9 nmol/24 h, P = 0.002, and 100.3 ± 5.3 nmol/l, P = 0.003, respectively). In diabetic patients, the number of complications was associated with F24 ( R = 0.345; P R = 0.39; P CONCLUSIONS —In type 2 diabetic subjects, hypothalmic-pituitary-adrenal activity is enhanced in patients with diabetes complications and the degree of cortisol secretion is related to the presence and number of diabetes complications.
TL;DR: In decompensated cirrhotics, HCV clearance by therapy is life-saving and reduces disease progression and early separation of SVR patients from both non-responders and controls at approximately 6 months.
TL;DR: This study provides the first extensive data set on HSA21 gene-expression variation in DS and underscores its role in modulating the outcome of gene-dosage imbalance.
Abstract: Down syndrome (DS) is characterized by extensive phenotypic variability, with most traits occurring in only a fraction of affected individuals. Substantial gene-expression variation is present among unaffected individuals, and this variation has a strong genetic component. Since DS is caused by genomic-dosage imbalance, we hypothesize that gene-expression variation of human chromosome 21 (HSA21) genes in individuals with DS has an impact on the phenotypic variability among affected individuals. We studied gene-expression variation in 14 lymphoblastoid and 17 fibroblast cell lines from individuals with DS and an equal number of controls. Gene expression was assayed using quantitative real-time polymerase chain reaction on 100 and 106 HSA21 genes and 23 and 26 non-HSA21 genes in lymphoblastoid and fibroblast cell lines, respectively. Surprisingly, only 39% and 62% of HSA21 genes in lymphoblastoid and fibroblast cells, respectively, showed a statistically significant difference between DS and normal samples, although the average up-regulation of HSA21 genes was close to the expected 1.5-fold in both cell types. Gene-expression variation in DS and normal samples was evaluated using the Kolmogorov-Smirnov test. According to the degree of overlap in expression levels, we classified all genes into 3 groups: (A) nonoverlapping, (B) partially overlapping, and (C) extensively overlapping expression distributions between normal and DS samples. We hypothesize that, in each cell type, group A genes are the most dosage sensitive and are most likely involved in the constant DS traits, group B genes might be involved in variable DS traits, and group C genes are not dosage sensitive and are least likely to participate in DS pathological phenotypes. This study provides the first extensive data set on HSA21 gene-expression variation in DS and underscores its role in modulating the outcome of gene-dosage imbalance.
TL;DR: This study indicates that TMPRSS2:ERG gene rearrangements in CaP may be used as a diagnostic tool to identify prognostically relevant sub-classifications of these cancers.
Abstract: Background: Recent reports indicate that prostate cancers (CaP) frequently over-express the potential oncogenes, ERG or ETV1. Many cases have chromosomal rearrangements leading to the fusion of the 5’ end of the androgen-regulated serine protease TMPRSS2 (21q22.2) to the 3’ end of either ERG (21q22.3) or ETV1 (7p21.3). The consequence of these rearrangements is aberrant androgen receptor-driven expression of the potential oncogenes, ETV1 or ERG. Aim: To determine the frequency of rearrangements involving TMPRSS2, ERG, or ETV1 genes in CaP of varying Gleason grades through fluorescent in situ hybridization (FISH) on CaP tissue microarrays (TMAs). Methods: Two independent assays, a TMPRSS2 break-apart assay and a three-colour gene fusion FISH assay were applied to TMAs. FISH positive cases were confirmed by reverse transcriptase - polymerase chain reaction (RT-PCR) and DNA sequence analysis. Results: 106/196 (54.1%) cases were analyzed by FISH. None of the five benign prostatic hyperplasia cases analyzed exhibited these gene rearrangements. TMPRSS2:ERG fusion was found more frequently in moderate to poorly differentiated tumours (35/86, 40.7%) than in well-differentiated tumours (1/15, 6.7%, p = 0.017). TMPRSS2:ETV1 gene rearrangement was not detected in all of the cases tested. TMPRSS2:ERG fusion product was verified by RT-PCR followed by DNAsequencing in 7/7 randomly selected positive cases analysed. Conclusion: This study indicates that TMPRSS2:ERG gene rearrangements in CaP may be used as a diagnostic tool to identify prognostically relevant sub-classifications of these cancers.
TL;DR: Using an assay with a lower functional sensitivity may give an earlier indication of the presence of Tg in the serum on L-T4 treatment and may be used to study the trend in serum Tg without performing any TSH stimulation.
Abstract: Background: Serum thyroglobulin (Tg) is the marker of differentiated thyroid cancer after initial treatment and TSH stimulation increases its sensitivity for the diagnosis of recurrent disease. Aim: The goal of the study is to compare the diagnostic values of seven methods for serum Tg measurement for detecting recurrent disease both during L-T4 treatment and after TSH stimulation. Methods: Thyroid cancer patients who had no evidence of persistent disease after initial treatment (total thyroidectomy and radioiodine ablation) were studied at 3 months on L-T4 treatment (Tg1) and then at 9–12 months after withdrawal or recombinant human TSH stimulation (Tg2). Sera with anti-Tg antibodies or with an abnormal recovery test result were excluded from Tg analysis with the corresponding assay. The results of serum Tg determination were compared to the clinical status of the patient at the end of follow-up. Results: Thirty recurrences were detected among 944 patients. A control 131I total body scan had a low sensit...
TL;DR: Hp infection is associated with promoter methylation of genes which are relevant in the initiation and progression of gastric carcinogenesis, while CDH 1 methylation seems to be an early event in Hp gastritis, MLH1 methylation occurs late along with IM.
TL;DR: Determination of the JAK2 V617F mutation may contribute to the search for genetic determinants of PMVT and may be useful to recognize patients who should be carefully observed for the subsequent development of overt MPDs.
TL;DR: Severe ulcerative colitis is a life‐threatening disorder, despite i.v. glucocorticoids treatment, and infliximab has been proposed as a safe rescue therapy.
Abstract: Background Severe ulcerative colitis is a life-threatening disorder, despite i.v. glucocorticoids treatment. Infliximab has been proposed as a safe rescue therapy. Aim To evaluate short- and long-term effectiveness and safety of infliximab in severe refractory ulcerative colitis. Methods Eighty-three patients with severe ulcerative colitis (i.v. glucocorticoids treatment-refractory) were treated with infliximab in 10 Italian Gastroenterology Units. Patients underwent one or more infusions according to the choice of treating physicians. Short-term outcome was colectomy/death 2 months after the first infusion. Long-term outcome was survival free from colectomy. Safety data were recorded. Results Twelve patients (15%) underwent colectomy within 2 months. One died of Legionella pneumophila infection 12 days after infliximab. Early colectomy rates were higher in patients receiving one infusion (9/26), compared with those receiving two/more infusions (3/57, P = 0.001, OR = 9.53). Seventy patients who survived colectomy and did not experience any fatal complications were followed-up for a median time of 23 months; 58 patients avoided colectomy during the follow-up. Forty-two patients were maintained on immunosuppressive drugs. No clinical features were associated with outcomes. Conclusions Infliximab is an effective and relatively safe therapy to avoid colectomy and maintain long-term remission for patients with severe refractory ulcerative colitis. In the short term, two or more infusions seem to be more effective than one single infusion.
TL;DR: The prevalence of subclinical hypercortisolism among patients with T-scores of 2.5 or less and vertebral fractures was 10.8%, which may be more common than is generally recognized in patients with osteoporosis.
Abstract: The Cushing syndrome is a well-recognized secondary cause of osteoporosis. Chiodini and associates looked for hypercortisolism in 219 patients who were referred for osteoporosis testing and did not...
TL;DR: CYP2C9 genotyping may identify subgroups of persons who potentially are at increased risk of gastroduodenal bleeding when treated with NSAIDs metabolized by CYP2C8, and further studies that evaluate the effectiveness of a strategy using CYP 2C9genotyping in NSAID users are needed.
University of Paris1, Australian National University2, University of California, Los Angeles3, Katholieke Universiteit Leuven4, University of Helsinki5, University of Kiel6, Casa Sollievo della Sofferenza7, Royal Brisbane and Women's Hospital8, Johns Hopkins University9, University of Toronto10, University of Chicago11, Broad Institute12, Université de Montréal13, University of Edinburgh14, Cambridge University Hospitals NHS Foundation Trust15
TL;DR: Data confirm that CARD15/NOD2 acts in interaction with other unknown risk cofactors in Caucasians, and provide strong evidence that the penetrances of the most at-risk genotypes are low.
TL;DR: By analyzing the genomic region flanking the HRAS mutations, it is demonstrated that de novo mutations were inherited from the father in all cases and an advanced age at conception in unaffected fathers transmitting the mutation is noted.
Abstract: Activating mutations in v-Ha-ras Harvey rat sarcoma viral oncogene homolog (HRAS) have recently been identified as the molecular cause underlying Costello syndrome (CS). To further investigate the phenotypic spectrum associated with germline HRAS mutations and characterize their molecular diversity, subjects with a diagnosis of CS (N = 9), Noonan syndrome (NS; N = 36), cardiofaciocutaneous syndrome (CFCS; N = 4), or with a phenotype suggestive of these conditions but without a definitive diagnosis (N = 12) were screened for the entire coding sequence of the gene. A de novo heterozygous HRAS change was detected in all the subjects diagnosed with CS, while no lesion was observed with any of the other phenotypes. While eight cases shared the recurrent c.34G>A change, a novel c.436G>A transition was observed in one individual. The latter affected residue, p.Ala146, which contributes to guanosine triphosphate (GTP)/guanosine diphosphate (GDP) binding, defining a novel class of activating HRAS lesions that perturb development. Clinical characterization indicated that p.Gly12Ser was associated with a homogeneous phenotype. By analyzing the genomic region flanking the HRAS mutations, we traced the parental origin of lesions in nine informative families and demonstrated that de novo mutations were inherited from the father in all cases. We noted an advanced age at conception in unaffected fathers transmitting the mutation.
TL;DR: In Joubert syndrome, the fibers of the pyramidal tract and the superior cerebellar peduncles do not cross, irrespective of the underlying mutation.
Abstract: BACKGROUND AND PURPOSE: Neuropathologic findings and preliminary imaging studies demonstrated the absence of pyramidal tract and superior cerebellar peduncular decussation in individual patients with Joubert syndrome (JS). We hypothesized that functional-structural neuroimaging findings do not differ between the genetic forms of JS. MATERIALS AND METHODS: MR imaging was performed with a 3T MR imaging-unit. Multiplanar T2- and T1-weighted imaging was followed by diffusion tensor imaging (DTI). Isotropic diffusion-weighted images, apparent diffusion coefficient maps, and color-coded fractional anisotropy maps, including tractography, were subsequently calculated. RESULTS: In all 6 patients studied, DTI showed that the fibers of the superior cerebellar peduncles did not decussate in the mesencephalon and the corticospinal tract failed to cross in the caudal medulla. The patients represented various genetic forms of JS. CONCLUSION: In JS, the fibers of the pyramidal tract and the superior cerebellar peduncles do not cross, irrespective of the underlying mutation.
TL;DR: Ca2+ imaging of vestibular hair cells showed that the dissipation of stereociliary Ca2+ transients induced by Ca2- uncaging was compromised in the dfw and PMCA2 knockout mice, as was the sensitivity of the mechanoelectrical transduction channels to hair bundle displacement in cochlear hair cells.
Abstract: Ca2+ enters the stereocilia of hair cells through mechanoelectrical transduction channels opened by the deflection of the hair bundle and is exported back to endolymph by an unusual splicing isoform (w/a) of plasma-membrane calcium-pump isoform 2 (PMCA2). Ablation or missense mutations of the pump cause deafness, as described for the G283S mutation in the deafwaddler (dfw) mouse. A deafness-inducing missense mutation of PMCA2 (G293S) has been identified in a human family. The family also was screened for mutations in cadherin 23, which accentuated hearing loss in a previously described human family with a PMCA2 mutation. A T1999S substitution was detected in the cadherin 23 gene of the healthy father and affected son but not in that of the unaffected mother, who presented instead the PMCA2 mutation. The w/a isoform was overexpressed in CHO cells. At variance with the other PMCA2 isoforms, it became activated only marginally when exposed to a Ca2+ pulse. The G293S and G283S mutations delayed the dissipation of Ca2+ transients induced in CHO cells by InsP3. In organotypic cultures, Ca2+ imaging of vestibular hair cells showed that the dissipation of stereociliary Ca2+ transients induced by Ca2+ uncaging was compromised in the dfw and PMCA2 knockout mice, as was the sensitivity of the mechanoelectrical transduction channels to hair bundle displacement in cochlear hair cells.
TL;DR: Incidence and prevalence rates of CIDP in Italy were higher than those observed in most previous studies, indicating either a good response to immunomodulating therapy or a tendency of CIDs to have a mild course in most cases.
Abstract: Aim: The clinical and epidemiological characteristics of chronic inflammatory demyelinating polyneuropathy (CIDP) in an Italian population were assessed. Subjects and methods: All subjects with a diagnosis of demyelinating neuropathy after 1990 in Piemonte and Valle d’Aosta (4 334 225 inhabitants) were considered. The diagnosis of CIDP was based on the research criteria of the American Academy of Neurology. 165 of 294 patients met the diagnostic criteria. Results: The crude prevalence rate was 3.58/100 000 population (95% CI 3.02 to 4.20). At the prevalence day, 76 (49.0%) cases had definite, 67 (43.2%) probable and 12 (7.7%) possible CIDP; disability was mild in 105 (67.7%) cases, moderate in 32 (20.6%) and severe in 18 (11.6%). The course was remitting–relapsing in 40 cases (25.8%), chronic progressive in 96 (61.9%) and monophasic in 19 (12.3%). Considering the 95 patients whose disorder presented in the period 1995–2001, the mean annual crude incidence rate was 0.36/100 000 population (95% CI 0.29 to 0.44), with a male to female ratio of 2.3:1. 14 cases were affected by diabetes mellitus. In multivariate analysis, factors related to severe disability at the prevalence day were: age>60 years; failure of immunomodulating therapies at the time of diagnosis; worse disability at nadir; and chronic course. Conclusion: Incidence and prevalence rates of CIDP in Italy were higher than those observed in most previous studies. At the prevalence day, more than 80% of cases had a mild or moderate disability, indicating either a good response to immunomodulating therapy or a tendency of CIDP to have a mild course in most cases.