Common variant in the HMGA2 gene increases susceptibility to nephropathy in patients with type 2 diabetes.

AIMS/HYPOTHESIS: Type 2 diabetes is a chronic metabolic disorder associated with devastating microvascular complications. Genome-wide association studies have identified more than 60 genetic variants associated with type 2 diabetes and/or glucose and insulin traits, but their role in the progression of diabetes is not established. The aim of this study was to explore whether these variants were also associated with the development of nephropathy in patients with type 2 diabetes. METHODS: We studied 28 genetic variants in 2,229 patients with type 2 diabetes from the local Malmö Scania Diabetes Registry (SDR) published during 2007-2010. Diabetic nephropathy (DN) was defined as micro- or macroalbuminuria and/or end-stage renal disease. Estimated glomerular filtration rate (eGFR) was assessed using the MDRD-4 formula. Replication genotyping of rs1531343 was performed in diabetic (Steno type 2 diabetes [n = 345], Genetics of Diabetes Audit and Research in Tayside Scotland [Go-DARTS] [n = 784]) and non-diabetic (Malmö Preventive Project [n = 2,523], Botnia study [n = 2,247]) cohorts. RESULTS: In the SDR, HMGA2 single-nucleotide polymorphism rs1531343 was associated with DN (OR 1.50, 95% CI 1.20, 1.87, p = 0.00035). In the combined analysis totalling 3,358 patients with type 2 diabetes (n = 1,233 cases, n = 2,125 controls), carriers of the C-allele had a 1.45-fold increased risk of developing nephropathy (95% CI 1.20, 1.75, p = 0.00010). Furthermore, the risk C-allele was associated with lower eGFR in patients with type 2 diabetes (n = 2,499, ß ± SEM, -3.7 ± 1.2 ml/min, p = 0.002) and also in non-diabetic individuals (n = 17,602, ß ± SEM, -0.008 ± 0.003 ml/min (log( e )), p = 0.006). CONCLUSIONS/INTERPRETATION: These data demonstrate that the HMGA2 variant seems to be associated with increased risk of developing nephropathy in patients with type 2 diabetes and lower eGFR in both diabetic and non-diabetic individuals and could thus be a common denominator in the pathogenesis of type 2 diabetes and kidney complications.

Investigation of known estimated glomerular filtration rate loci in patients with type 2 diabetes.

AIMS: To replicate the association of genetic variants with estimated glomerular filtration rate (GFR) and albuminuria, which has been found in recent genome-wide studies in patients with Type 2 diabetes. METHODS: We evaluated 16 candidate single nucleotide polymorphisms for estimated GFR in 3028 patients with Type 2 diabetes sampled from clinics across Tayside, Scotland, UK, who were included in the Genetics of Diabetes Audit and Research Tayside (GoDARTs) study. These single nucleotide polymorphisms were tested for their association with estimated GFR at entry to the study, with albuminuria, and with time to stage 3B chronic kidney disease (estimated GFR<45 ml/min/1.73 m(2)). We also stratified the effects on estimated GFR in patients with (n = 2096) and without albuminuria (n = 613). RESULTS: rs1260326 in GCKR (ß=1.30, P = 3.23E-03), rs17319721 in SHROOM3 (ß = -1.28, P-value = 3.18E-03) and rs12917707 in UMOD (ß = 2.0, P-value = 8.84E-04) were significantly associated with baseline estimated GFR. Analysis of effects on estimated GFR, stratified by albuminuria status, showed that in those without albuminuria (normoalbuminura; n = 613), UMOD had a significantly stronger effect on estimated GFR (ß(normo) = 4.03 ± 1.23 vs ß(albuminuria) = 1.72 ± 0.76, P = 0.002) compared with those with albuminuria, while GCKR (ß(normo) = 0.45 ± 0.89 vs ß(albuminuria) = 1.12 ± 0.55, P = 0.08) and SHROOM3 (ß(normo) = -0.07 ± 0.89 vs ß(albuminuria) = -1.43 ± 0.53, P = 0.003) had a stronger effect on estimated GFR in those with albuminuria. UMOD was also associated with a lower rate of transition to stage 3B chronic kidney disease (hazard ratio = 0.83[0.70, 0.99], P = 0.03). CONCLUSION: The genetic variants that regulate estimated GFR in the general population tend to have similar effects in patients with Type 2 diabetes and in this latter population, it is important to adjust for albuminuria status while investigating the genetic determinants of renal function.

A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts.

AIMS/HYPOTHESIS: In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (ATM) gene in multiple additional populations. METHODS: Incident users of metformin selected from the Diabetes Care System West-Friesland (DCS, n = 929) and the Rotterdam Study (n = 182) from the Netherlands, and the CARDS Trial (n = 254) from the UK were genotyped for rs11212617 and tested for an association with both HbA(1c) reduction and treatment success, defined as the ability to reach the treatment target of an HbA(1c) ≤ 7 % (53 mmol/mol). Finally, a meta-analysis including data from literature was performed. RESULTS: In the DCS cohort, we observed an association between rs11212617 genotype and treatment success on metformin (OR 1.27, 95% CI 1.03, 1.58, p = 0.028); in the smaller Rotterdam Study cohort, a numerically similar but non-significant trend was observed (OR 1.45, 95% CI 0.87, 2.39, p = 0.15); while in the CARDS cohort there was no significant association. In meta-analyses of these three cohorts separately or combined with the previously published cohorts, rs11212617 genotype is associated with metformin treatment success (OR 1.24, 95% CI 1.04, 1.49, p = 0.016 and OR 1.25, 95% CI 1.33, 1.38, p = 7.8 × 10(-6), respectively). CONCLUSIONS/INTERPRETATION: A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetic patients from the Netherlands and the UK. This is the first robustly replicated common susceptibility locus found to be associated with metformin treatment response.

Admixture in Hispanic Americans: its impact on ITGAM association and implications for admixture mapping in SLE.

Systemic Lupus Erythematosus (SLE) disproportionately affects minorities, such as Hispanic Americans (HA). Prevalence of SLE is 3-5 times higher in HA than in European-derived populations and have more active disease at the time of diagnosis, with more serious organ system involvement. HA is an admixed population, it is possible that there is an effect of admixture on the relative risk of the disease. This admixture can create substantial increase of linkage disequilibrium (LD) in both magnitude and range, which can provide a unique opportunity for admixture mapping. The main objectives of this study are to (a) estimate hidden population structure in HA individuals; (b) estimate individual ancestry proportions and its impact on SLE risk; (c) assess impact of admixture on ITGAM association, a recently identified SLE susceptibility gene; and (d) estimate power of admixture mapping in HA. Our dataset contained 1125 individuals, of whom 884 (657 SLE cases and 227 controls) were self-classified as HA. Using 107 unlinked ancestry informative markers (AIMs), we estimated hidden population structure and individual ancestry in HA. Out of 5671 possible pairwise LD, 54% were statistically significant, indicating recent population admixture. The best-fitted model for HA was a four-population model with average ancestry of European (48%), American-Indian (AI) (40%), African (8%) and a fourth population (4%) with unknown ancestry. We also identified significant higher risk associated with AI ancestry (odds ratio (OR)=4.84, P=0.0001, 95% CI (confidence interval)=2.14-10.95) on overall SLE. We showed that ITGAM is associated as a risk factor for SLE (OR=2.06, P=8.74 x 10(-5), 95% CI=1.44-2.97). This association is not affected by population substructure or admixture. We have shown that HA have great potential and are an appropriate population for admixture mapping. As expected, the case-only design is more powerful than case-control design, for any given admixture proportion or ancestry risk ratio.

Replication of the BANK1 genetic association with systemic lupus erythematosus in a European-derived population.

Systemic lupus erythematosus (SLE) is an autoimmune disease with highly variable clinical presentation. Patients suffer from immunological abnormalities that target T-cell, B-cell and accessory cell functions. B cells are hyperactive in SLE patients. An adapter protein expressed in B cells called BANK1 (B-cell scaffold protein with ankyrin repeats) was reported in a previous study to be associated with SLE in a European population. The objective of this study was to assess the BANK1 genotype-phenotype association in an independent replication sample. We genotyped 38 single nucleotide polymorphisms (SNPs) in BANK1 on 1892 European-derived SLE patients and 2652 European-derived controls. The strongest associations with SLE and BANK1 were at rs17266594 (corrected P-value=1.97 x 10(-5), odds ratio (OR)=1.22, 95% CI 1.12-1.34) and rs10516487 (corrected P-value=2.59 x 10(-5), OR=1.22, 95% CI 1.11-1.34). Our findings suggest that the association is explained by these two SNPs, confirming previous reports that these polymorphisms contribute to the risk of developing lupus. Analysis of patient subsets enriched for hematological, immunological and renal ACR criteria or the levels of autoantibodies, such as anti-RNP A and anti-SmRNP, uncovers additional BANK1 associations. Our results suggest that BANK1 polymorphisms alter immune system development and function to increase the risk for developing lupus.

Stenotrophomonas maltophilia endogenous endophthalmitis: clinical presentation, sensitivity spectrum and management.

Stenotrophomonas maltophilia is gaining importance as a community-acquired pathogen, after becoming firmly established as a nosocomial pathogen. Here we report a case of endogenous endophthalmitis due to S. maltophilia. Antibiotic-susceptibility testing of the isolate was performed by the Kirby-Bauer disc diffusion method. The organism was resistant to aminoglycosides, imipenem, ticarcillin and cotrimoxazole and was sensitive to ceftazidime and chloramphenicol. The patient was successfully treated with a sensitivity-based intravitreal antibiotic regimen.

Transjugular liver biopsy using Tru-cut biopsy needle: KEM experience.

BACKGROUND AND AIM: Transjugular liver biopsy is accepted procedure in patients in whom percutaneous liver biopsy is contraindicated. We report our experience with this procedure, its indications, efficacy and safety in Indian population over 5 years. MATERIAL & METHODS: A retrospective study of 145 consecutive patients who had undergone transjugular liver biopsy from May 2002 to Nov. 2007 was done from the database maintained in our department. We evaluated the indications, technical success, complication and impact of histological diagnosis on the management of those patients. RESULTS: 145 Transjugular liver biopsies were performed of which 74 were males and 71 were females aged between 5 and 74 years. Two procedures were abandoned due to failed hepatic vein cannulation because of venous occlusion. Out of 143 biopsies, 4 were inadequate while 139 yielded adequate tissue for histopathological diagnosis. Histopathological examination in our study showed cirrhotic changes in 56, hepatitis including both acute and chronic in 48, periportal fibrosis in 9, Wilson's disease in 5 and obstructive cholangiopathy in 2 patients. The remaining 19 were normal. Minor complications occurred in 2 patients. CONCLUSION: Transjugular liver biopsy is a safe procedure in the trained hands and provides adequate tissue for diagnosis when percutaneous liver biopsy is contraindicated.

Safety and effectiveness of transjugular renal biopsy: A single center study.

Although percutaneous renal biopsy remains the preferred method, there are several scenarios where transjugular approach is more suitable. We hereby describe our technique of transjugular renal biopsy (TJRB) and evaluate its safety and efficacy. We retrospectively collected data regarding indication for the transjugular route of biopsy, its complications, clinical and laboratory data, and adequacy of samples from patients' records. TJRB was performed when the patients were at a high risk for bleeding from percutaneous renal biopsy. Tissue samples were assessed by a pathologist for adequacy. All patients were followed up with ultrasonographic scan 3 h after the procedure and on day 3. Nine patients (age 41.5 ± 15.4 years; 8 men) underwent 9 TJRB procedures. The procedure was technically successful in all patients. Six patients (66.67%) had a platelet count of <50,000/mcL, 2 (33.3%) had an elevated International Normalized Ratio of more than 1.4, and 1 had both. 3.2 ± 0.4 cores were obtained, with median (range) number of glomeruli being ten (7-11). Adequate renal tissue sample was obtained in all the patients. Though capsular perforation developed in 5 patients, none had major complication requiring management (endovascular treatment or blood transfusion). TJRB is a safe and effective in patients with contraindications to percutaneous biopsy.

A genome-wide association study suggests an association of Chr8p21.3 (GFRA2) with diabetic neuropathic pain.

BACKGROUND: Neuropathic pain, caused by a lesion or a disease affecting the somatosensory system, is one of the most common complications in diabetic patients. The purpose of this study is to identify genetic factors contributing to this type of pain in a general diabetic population. METHOD: We accessed the Genetics of Diabetes Audit and Research Tayside (GoDARTS) datasets that contain prescription information and monofilament test results for 9439 diabetic patients, among which 6927 diabetic individuals were genotyped by Affymetrix SNP6.0 or Illumina OmniExpress chips. Cases of neuropathic pain were defined as diabetic patients with a prescription history of at least one of five drugs specifically indicated for the treatment of neuropathic pain and in whom monofilament test result was positive for sensory neuropathy in at least one foot. Controls were individuals who did not have a record of receiving any opioid analgesics. Imputation of non-genotyped SNPs was performed by IMPUTE2, with reference files from 1000 Genomes Phase I datasets. RESULTS: After data cleaning and relevant exclusions, imputed genotypes of 572 diabetic neuropathic pain cases and 2491 diabetic controls were used in the Fisher's exact test. We identified a cluster in the Chr8p21.3, next to GFRA2 with a lowest p-value of 1.77 × 10(-7) at rs17428041. The narrow-sense heritability of this phenotype was 11.00%. CONCLUSION: This genome-wide association study on diabetic neuropathic pain suggests new evidence for the involvement of variants near GFRA2 with the disorder, which needs to be verified in an independent cohort and at the molecular level.

The predictive value of myocardial perfusion scintigraphy after stress in patients without previous myocardial infarction.

Seventy-five patients who had chest pain but no history or ECG evidence of myocardial infarction (MI) underwent myocardial-stress perfusion scintigraphy (MSPS) with thallium-201, treadmill-stress testing (TST), and coronary cineangiography (CA). The sensitivities of MSPS and TST for coronary stenosis greater than or equal to 75% were 68% and 71%, respectively; their specificities were 97% and 79%, respectively (0.1 greater than p greater than 0.05). When the character of a patient's chest pain is considered, Bayesian analysis leads to the following conclusions: (a) MSPS can be useful in pre-CA screening of patients with chest pain but no MI if their pain is thought to be of uncertain or nonischemic origin: (b) the sensitivity of Tl-201 MSPS is not sufficient for pre-CA screening of patients without MI who have typical or atypical angina pectoris; (c) the sensitivity of MSPS would have to be approximately 95% in order for the test to be useful in pre-CA screening of patients who have atypical angina pectoris; (d) MSPS may be superior to TST in these applications; and (e) it is not clear that there is any advantage in combining MSPS and TST into a single screening test rather than using MSPS alone.

Mechanism of blood flow generated by precordial compression during CPR. I. Studies on closed chest precordial compression.

The mechanism of forward flow produced by precordial compression during CPR was investigated with the aid of echocardiographic and hemodynamic measurements in anesthetized, mechanically ventilated domestic pigs. Both mitral and tricuspid valves opened during compression diastole and closed during compression systole. Valve motion persisted throughout resuscitation in 17 of 22 animals which were hemodynamically resuscitated. There was a 25 percent reduction in left ventricular area during compression systole. Maximum pressure generated during compression systole in the aorta exceeded that of the right atrium throughout the 12-min interval of precordial compression in successfully resuscitated animals. These observations provide evidence of direct cardiac compression as the mechanism accounting for effective forward blood flow during CPR. The persistence of valve function, chamber compression, and pressure gradients during precordial compression was predictive of successful resuscitation. The absence of these factors prognosticates failure of resuscitation and explains, in part, the inconsistency of prior reports.

Increases in coronary vein CO2 during cardiac resuscitation.

We investigated the aortic, mixed venous, and great cardiac vein acid-base changes in eight domestic pigs during cardiac arrest produced by ventricular fibrillation and during cardiopulmonary resuscitation (CPR). The great cardiac vein PCO2 increased from a control value of 52 +/- 2 to 132 +/- 28 (SD) Torr during CPR, whereas the arterial PCO2 was unchanged (39 +/- 4 vs. 38 +/- 4). The coronary venoarterial PCO2 gradient, therefore, increased remarkably from 13 +/- 2 to 94 +/- 29 Torr. The simultaneously measured great cardiac vein lactate concentrations increased from 0.24 +/- 0.06 to 7.3 +/- 2.34 mmol/l. Much more moderate increases in the lactate content of aortic blood from 0.64 +/- 0.25 to 2.56 +/- 0.27 mmol/l were observed. Increases in great cardiac vein PCO2 and lactate were highly correlated during CPR (r = 0.91). After successful CPR, the coronary venoarterial PCO2 gradient returned to normal levels within 2 min after restoration of spontaneous circulation. Lactate content was rapidly reduced and lactate extraction was reestablished within 30 min after CPR. These studies demonstrate marked but reversible acidosis predominantly as the result of myocardial CO2 production during CPR.

Extensive portal and splenic vein thrombosis: differences in hemodynamics and management.

BACKGROUND/AIMS: To assess the incidence of extensive portal and splenic vein thrombosis in patients with extrahepatic portal vein obstruction and determine the differences in presentation, portal hemodynamics and management as compared to patients with portal vein thrombosis alone. METHODOLOGY: 118 patients of extrahepatic portal vein obstruction presenting with variceal hemorrhage, having received no definitive treatment prior to presentation were divided into two groups--with portal and splenic vein thrombosis and with portal vein thrombosis, based on ultrasonography and splenoportography. Collateralization patterns on splenoportography were studied. Results of endoscopic variceal sclerotherapy were compared. RESULTS: Portal and splenic vein thrombosis was seen in 39 patients. Collateralization in case of portal and splenic vein thrombosis, in contrast to portal vein thrombosis, was predominantly left sided (74% vs. 9%, p < 0.0001). Fundal gastric varices were seen more often in patients with portal and splenic vein thrombosis (28% vs. 11%, p = 0.02), developing even after variceal obliteration, though obliteration was achieved in fewer sessions. Surgery for control of variceal bleed was performed more in the portal and splenic vein thrombosis group (33% vs. 15%, p = 0.02), especially for gastric varices (28% vs. 9%, p = 0.006). CONCLUSIONS: Portal and splenic vein thrombosis is present in 33% of patients with extrahepatic portal vein obstruction. Hemodynamic patterns differ, accounting for the preponderance of gastric varices on presentation in patients with portal and splenic vein thrombosis and an increased need for surgery.

Internal mammary artery pseudoaneurysms complicating chest wall infection in children: diagnosis and endovascular therapy.

Mycotic internal mammary artery (IMA) pseudoaneurysms are sparsely reported in medical literature. We report imaging findings of IMA pseudoaneurysms secondary to chest wall abscesses (staphylococcal and tuberculous) in two children. Both children were successfully treated by endovascular method thus obviating the need for surgery.

Obstructive jaundice--an unusual complication of duodenal tuberculosis: treatment with transhepatic balloon dilatation.

This is a report of a patient on treatment for duodenal tuberculosis, who developed obstructive jaundice due to a benign stricture of the terminal common bile duct. This complication of duodenal tuberculosis, to our knowledge, has not been reported before. Percutaneous, transhepatic balloon dilatation of the stricture alleviated the jaundice.

Effect of sublingual isosorbide dinitrate in portal hypertension.

Nitrates decrease portal pressure by decreasing portal venous inflow and resistance. We studied over 20 minutes the effect of 10 mg isosorbide dinitrate sublingual on intrasplenic pulp pressure, mean arterial pressure and heart rate, in 13 patients with cirrhotic or non-cirrhotic portal hypertension. The pulp pressure fell progressively over 20 minutes, from mean 43.6 +/- 2.4 (SEM) to 35.6 +/- 1.8 cm H2O (p less than 0.001). This was accompanied initially by a significant fall in mean arterial pressure (85.8 +/- 1.9 to 80.4 +/- 2.7 mmHg at 4 minutes; p less than 0.01) and rise in heart rate (92.5 +/- 5.0 to 102.6 +/- 5.9 per minute at 6 minutes; p less than 0.02), following which these parameters remained stable. One patient developed giddiness due to hypotension at 15 minutes. We conclude that sublingual isosorbide dinitrate decreases pulp pressure in cirrhotic and non-cirrhotic portal hypertensives, but this is initially accompanied by significant hemodynamic changes.

Endoscopic removal of retained bile duct calculi via T-tube tract.

A simple and safe technique for removal of retained bile duct calculi using a flexible fibreoptic choledochoscope and rigid nephroscope via the T-tube tract has been described. The technique allowed removal of large impacted calculi under direct vision without damage to the bile duct.

Massive rectal bleeding due to jejunal and colonic tuberculosis.

A case of massive rectal bleeding due to colonic tuberculosis in advanced pregnancy with intrauterine foetal death is reported. Patient was treated with resection of the left colon and left transverse end colostomy with closure of the rectal stump. Hysterotomy for the removal of the dead foetus was performed. The patient improved in health with antitubercular treatment. The colorectal anastomosis was performed after 4 months. Massive rectal bleeding in intestinal tuberculosis, though rare should be kept in mind.

High resolution array comparative genomic hybridization identifies copy number alterations in diffuse large B-cell lymphoma that predict response to immuno-chemotherapy.

Despite recent attempts at sub-categorization, including gene expression profiling into prognostically different groups of "germinal center B-cell type" and "activated B-cell type," diffuse large B-cell lymphoma (DLBCL) remains a biologically heterogenous tumor with no clear prognostic biomarkers to guide therapy. Whole genome, high resolution array comparative genomic hybridization (aCGH) was performed on four cases of chemoresistant DLBCL and four cases of chemo-responsive DLBCL to identify genetic differences that may correlate with response to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Array CGH analysis identified seven DNA copy number alteration (CNA) regions exclusive to the chemoresistant group, consisting of amplifications at 1p36.13, 1q42.3, 3p21.31, 7q11.23, and 16p13.3, as well as loss at 9p21.3 and 14p21.31. Copy number loss of the tumor suppressor genes CDKN2A (p16, p14) and CDKN2B (p15) at 9p21.3 was validated by fluorescence in situ hybridization and immunohistochemistry as independent techniques. In the chemo-sensitive group, 12 CNAs were detected consisting of segment gains on 1p36.11, 1p36.22, 2q11.2, 8q24.3, 12p13.33, and 22q13.2, as well as segment loss on 6p21.32. RUNX3, a tumor suppressor gene located on 1p36.11 and MTHFR, which encodes for the enzyme methylenetetrahydrofolate reductase, located on 1p36.22, are the only known genes in this group associated with lymphoma. Whole genome aCGH analysis has detected copy number alterations exclusive to either chemoresistant or chemoresponsive DLBCL that may represent consistent clonal changes predictive for prognosis and outcome of chemotherapy.