Loss of LDAH associated with prostate cancer and hearing loss.

Great strides in gene discovery have been made using a multitude of methods to associate phenotypes with genetic variants, but there still remains a substantial gap between observed symptoms and identified genetic defects. Herein, we use the convergence of various genetic and genomic techniques to investigate the underpinnings of a constellation of phenotypes that include prostate cancer (PCa) and sensorineural hearing loss (SNHL) in a human subject. Through interrogation of the subject's de novo, germline, balanced chromosomal translocation, we first identify a correlation between his disorders and a poorly annotated gene known as lipid droplet associated hydrolase (LDAH). Using data repositories of both germline and somatic variants, we identify convergent genomic evidence that substantiates a correlation between loss of LDAH and PCa. This correlation is validated through both in vitro and in vivo models that show loss of LDAH results in increased risk of PCa and, to a lesser extent, SNHL. By leveraging convergent evidence in emerging genomic data, we hypothesize that loss of LDAH is involved in PCa and other phenotypes observed in support of a genotype-phenotype association in an n-of-one human subject.

Small bowel tumors: pathology and management.

Despite comprising at least 75% of the length of the gastrointestinal tract, the small bowel only accounts for 3 to 6% of all its neoplasms. Forty different tumor subtypes arise from the small bowel; the commonest is adenoma, and malignant lesions include gastrointestinal stromal tumor neuroendocrine tumor lymphoma, and adenocarcinoma. Small bowel tumors typically cause either non-specific symptoms or none at all, which explains both the frequent delay in diagnosis and the wide range of potential investigations. The relative inaccessibility of the small bowel to endoscopic assessment is being challenged by the increased use of both capsule and double balloon endoscopy. Advances in endoscopic assessment are mirrored by improved sensitivity of radiological and nuclear imaging. Operative resection provides the mainstay of treatment for malignant disease (and symptomatic benign lesions), with oncological agents and somatostatin analogues providing useful adjuncts for inhibiting tumor growth and relieving symptoms. Survival reflects underlying tumor subtype, but is generally poor for malignant disease.

Extensive genetic diversity and substructuring among zebrafish strains revealed through copy number variant analysis.

Copy number variants (CNVs) represent a substantial source of genomic variation in vertebrates and have been associated with numerous human diseases. Despite this, the extent of CNVs in the zebrafish, an important model for human disease, remains unknown. Using 80 zebrafish genomes, representing three commonly used laboratory strains and one native population, we constructed a genome-wide, high-resolution CNV map for the zebrafish comprising 6,080 CNV elements and encompassing 14.6% of the zebrafish reference genome. This amount of copy number variation is four times that previously observed in other vertebrates, including humans. Moreover, 69% of the CNV elements exhibited strain specificity, with the highest number observed for Tubingen. This variation likely arose, in part, from Tubingen's large founding size and composite population origin. Additional population genetic studies also provided important insight into the origins and substructure of these commonly used laboratory strains. This extensive variation among and within zebrafish strains may have functional effects that impact phenotype and, if not properly addressed, such extensive levels of germ-line variation and population substructure in this commonly used model organism can potentially confound studies intended for translation to human diseases.

Non-occlusive small bowel necrosis in association with feeding jejunostomy after elective upper gastrointestinal surgery.

INTRODUCTION: Non-occlusive small bowel necrosis (NOSBN) has been associated with early postoperative enteral feeding. The purpose of this study was to determine the incidence of this complication in an elective upper gastrointestinal (GI) surgical patient population and the influence of both patient selection and type of feeding jejunostomy (FJ) inserted, based on the experience of two surgical units in affiliated hospitals. PATIENTS AND METHODS: The records were reviewed of 524 consecutive patients who underwent elective upper GI operations with insertion of a FJ for benign or malignant disease between 1997 and 2006. One unit routinely inserted needle catheter jejunostomies (NCJ), whilst the other selectively inserted tube jejunostomies (TJ). RESULTS: Six cases of NOSBN were identified over 120 months in 524 patients (1.15%), with no difference in incidence between routine NCJ (n = 5; 1.16%) and selective TJ (n = 1; 1.06%). Median rate of feeding at time of diagnosis was 105 ml/h (range, 75-125 ml/h), and diagnosis was made at a median of 6 days (range, 4-18 days) postoperatively. All patients developed abdominal distension, hypotension and tachycardia in the 24 h before re-exploratory laparotomy. Five patients died and one patient survived. CONCLUSIONS: The understanding of the pathophysiology of NOSBN is still rudimentary; nevertheless, its 1% incidence in the present study does call into question its routine postoperative use especially in those at high risk with an open abdomen, planned repeat laparotomies or marked bowel oedema. Patients should be fully resuscitated before initiating any enteral feeding, and feeding should be interrupted if there is any evidence of feed intolerance.

STrengthening the REporting of Genetic Association studies (STREGA)--an extension of the STROBE statement.

Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the STrengthening the Reporting of OBservational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modelling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed, but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct or analysis.

STrengthening the REporting of Genetic Association Studies (STREGA)--an extension of the STROBE statement.

Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the STrengthening the Reporting of OBservational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modelling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data, and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct, or analysis.

STrengthening the REporting of Genetic Association studies (STREGA): an extension of the STROBE Statement.

Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information into the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the STrengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modeling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data, and issues of data volume that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct, or analysis.

Strengthening the reporting of genetic association studies (STREGA): an extension of the strengthening the reporting of observational studies in epidemiology (STROBE) statement.

Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence, the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association (STREGA) studies initiative builds on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modeling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data, and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed, but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct, or analysis.

STrengthening the REporting of Genetic Association Studies (STREGA): an extension of the STROBE statement.

Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modelling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data, and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct, or analysis.

Strengthening the reporting of genetic association studies (STREGA): an extension of the STROBE Statement.

Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modeling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data, and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct, or analysis.

Strengthening the reporting of genetic association studies (STREGA): an extension of the STROBE statement.

Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modeling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data, and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct, or analysis.

Cancer-associated venous thrombosis in the surgical setting.

OBJECTIVE: Cancer patients are at a relatively high risk of venous thromboembolism (VTE), and this has implications for surgical outcome. DATA SOURCE: English literature search including the keywords cancer, surgery and VTE was undertaken to review the risk, etiology, prevention and treatment of VTE in surgical oncology patients. DATA SYNTHESIS: Malignant disease is highlighted as an important risk factor for VTE with an odds ratio of 6.5. The risk factors include higher age, previous VTE, advanced cancer, length of operation and immobility. CONCLUSIONS: Use of in-hospital thromboprophylaxis with low-molecular-weight heparin (LMWH) or low dose unfractionated heparin with graded stockings has been validated both in terms of safety and efficacy and should be considered for all patients. Subcutaneous LMWH has replaced unfractionated heparin for the initial treatment of VTE. The use of long-term LMWH instead of oral anticoagulants can substantially reduce the risk of recurrent VTE without increased bleeding. Recently, results of few trials have shown that LMWH may improve patient survival.

Management of delayed postoperative hemorrhage after pancreaticoduodenectomy: a meta-analysis.

OBJECTIVE: To determine whether interventional radiology (IR) or laparotomy (LAP) is the best management of delayed postoperative hemorrhage (DPH) after pancreaticoduodenectomy. Data Source We undertook an electronic search of MEDLINE and selected for analysis only original articles published between January 1, 1990, and December 31, 2007. STUDY SELECTION: Two of us independently selected studies reporting on clinical presentation and incidence of postoperative DPH and the following outcomes: complete hemostasis, morbidity, and mortality. DATA EXTRACTION: Two of us independently performed data extraction. Data were entered and analyzed by means of dedicated software from The Cochrane Collaboration. A random-effects meta-analytical technique was used for analysis. DATA SYNTHESIS: One hundred sixty-three cases of DPH after pancreaticoduodenectomy were identified from the literature. The incidence of DPH after pancreaticoduodenectomy was 3.9%. Seventy-seven patients (47.2%) underwent LAP; 73 (44.8%), IR; and 13 (8%), conservative treatment. On meta-analysis comparing LAP vs IR for DPH, no significant difference was found between the 2 treatment options for complete hemostasis (73% vs 76%; P = .23), mortality (43% vs 20%; P = .14), or morbidity (77% vs 35%; P = .06). CONCLUSIONS: This meta-analysis, although based on data from small case series, is unable to demonstrate any significant difference between LAP and IR in the management of DPH after pancreaticoduodenectomy. The management of this life-threatening complication is difficult, and the appropriate treatment pathway ultimately will be decided by the clinical status of the patient and the institution preference.

Lymphoplasmacytic sclerosing pancreatitis and retroperitoneal fibrosis.

Although cases of lymphoplasmacytic sclerosing pancreatitis (LSP) associated with idiopathic retroperitoneal fibrosis have been reported, the association is rare. We describe a 74-year-old man who presented with obstructive jaundice and weight loss. Nineteen months earlier, he had been diagnosed with idiopathic retroperitoneal fibrosis and treated with bilateral ureteric stents. Initial investigations were suggestive of a diagnosis of LSP, however, a malignant cause could not be ruled out. He underwent an exploratory laparotomy and frozen sections confirmed the diagnosis of LSP. An internal biliary bypass was performed using a Roux loop of jejunum, and the patient made an uneventful recovery. This case illustrates the difficulty in distinguishing LSP from pancreatic carcinoma preoperatively.

Characterization of apparently balanced chromosomal rearrangements from the developmental genome anatomy project.

Apparently balanced chromosomal rearrangements in individuals with major congenital anomalies represent natural experiments of gene disruption and dysregulation. These individuals can be studied to identify novel genes critical in human development and to annotate further the function of known genes. Identification and characterization of these genes is the goal of the Developmental Genome Anatomy Project (DGAP). DGAP is a multidisciplinary effort that leverages the recent advances resulting from the Human Genome Project to increase our understanding of birth defects and the process of human development. Clinically significant phenotypes of individuals enrolled in DGAP are varied and, in most cases, involve multiple organ systems. Study of these individuals' chromosomal rearrangements has resulted in the mapping of 77 breakpoints from 40 chromosomal rearrangements by FISH with BACs and fosmids, array CGH, Southern-blot hybridization, MLPA, RT-PCR, and suppression PCR. Eighteen chromosomal breakpoints have been cloned and sequenced. Unsuspected genomic imbalances and cryptic rearrangements were detected, but less frequently than has been reported previously. Chromosomal rearrangements, both balanced and unbalanced, in individuals with multiple congenital anomalies continue to be a valuable resource for gene discovery and annotation.

Management of delayed arterial hemorrhage after pancreaticoduodenectomy. A case series.

UNLABELLED: CONTEXT Delayed arterial hemorrhage is a rare complication after pancreaticoduodenectomy (frequency 2-4%) but carries a high mortality, with up to a third of patients dying as a consequence. Its ideal management remains unclear. CASE SERIES: Between 1993 and 2007, 317 head of pancreas resections were performed at our institution; there were 5 cases of delayed arterial hemorrhage (frequency 1.6%). CONCLUSION: This paper presents our experience in the management of delayed arterial haemorrhage post pancreaticoduodenecomy and discusses the role of angiograms, endoscopy and laparotomy in its management.

Expression studies of osteoglycin/mimecan (OGN) in the cochlea and auditory phenotype of Ogn-deficient mice.

Genes involved in the hearing process have been identified through both positional cloning efforts following genetic linkage studies of families with heritable deafness and by candidate gene approaches based on known functional properties or inner ear expression. The latter method of gene discovery may employ a tissue- or organ-specific approach. Through characterization of a human fetal cochlear cDNA library, we have identified transcripts that are preferentially and/or highly expressed in the cochlea. High expression in the cochlea may be suggestive of a fundamental role for a transcript in the auditory system. Herein we report the identification and characterization of a transcript from the cochlear cDNA library with abundant cochlear expression and unknown function that was subsequently determined to represent osteoglycin (OGN). Ogn-deficient mice, when analyzed by auditory brainstem response and distortion product otoacoustic emissions, have normal hearing thresholds.