Identification of interactive loci linked to insulin and leptin in mice with genetic insulin resistance

Mice double heterozygous (DH) for deletion of insulin receptor and insulin receptor substrate-1 are lean, insulin resistant, and have a phenotype that strongly depends on the genetic background of the mouse. On the C57BL/6 (B6) background, DH mice develop marked hyperinsulinemia and diabetes, whereas on the 129S6 background, DH mice exhibit only mild elevations of insulin and remain free of diabetes. F2 male mice created by an intercross between these two strains exhibit a 60% incidence of diabetes and a bell-shaped distribution of insulin levels as related to glucose, reminiscent of that in humans with type 2 diabetes. These mice also exhibit a wide range of leptin levels as related to body weight. A genome-wide scan of F2 mice reveals a quantitative trait locus (QTL) related to hyperinsulinemia on chromosome 14 (D14Mit55) with a peak logarithm of odds (LOD) score of 5.6, accounting for up to 69% of this trait. A QTL with a LOD score of 3.7 related to hyperleptinemia is present on chromosome 7 at D12Mit38 (a marker previously assigned to chromosome 12) in the area of the uncoupling protein 2/3 gene cluster. This locus also interacts synergistically with D14Mit55 in development of hyperinsulinemia and with a QTL on chromosome 12 (D12Mit231) related to hyperglycemia. These data demonstrate how multiple genetic modifiers can interact and influence the development of diabetes and the phenotype of animals with genetically programmed insulin resistance and provide evidence as to the location and nature of these genes.     

APACHE-II scoring system in perforative peritonitis

BACKGROUND: Prospective assessment of the Acute Physiology and Chronic Health Evaluation-II (APACHE-II) scoring system of stratification of disease severity has been shown to provide objective discrimination between low-risk and high-risk groups of patients with intra-abdominal sepsis. The current study was undertaken to evaluate the performance of APACHE-II score in prediction of mortality risk in patients with peritonitis due to hollow viscus perforation. STUDY DESIGN: Fifty patients admitted to a teaching hospital with peritonitis due to hollow viscus perforation were prospectively studied over a 2-year period. APACHE-II points were assigned to all patients in order to calculate their individual risk of mortality before undergoing emergency surgery. The accuracy in outcome prediction of the APACHE-II system was assessed by means of receiver operating characteristic (ROC) curve and the Pearson correlation coefficient and its significance test. RESULTS: Of the 50 patients admitted during the study period, there were 42 (84%) survivors and 8 (16%) nonsurvivors. Mean APACHE-II score of the study population was 11.38 with a range of 1 to 23. The predicted death rate was 23% and the observed death rate was 16%. Mean APACHE-II score in survivors was 9.88, whereas in nonsurvivors it was 19.25. Using ROC analysis, the area under the curve was found to be .984. Correlation of APACHE-II score and predicted death rate showed perfect correlation, with r = .99 and P <.001 [R2 = .9993]. APACHE-II score between 11 and 15 showed a sensitivity and specificity of 100% and 73.8%, respectively, and APACHE-II score of 16 to 20 had a sensitivity and specificity of 87.5% and 100%, respectively. CONCLUSION: APACHE-II score between 11 and 20 was shown to be a better predictor of risk of mortality in patients with peritonitis due to hollow viscus perforation. Predicted mortality did not correlate with observed mortality in patients with APACHE-II scores of 1 to 10 and greater than 20. The APACHE-II scoring system can be used to assess group outcomes in patients with peritonitis due to hollow viscus perforation. However, it does not provide sufficient confidence for outcome prediction in individual patients.     

Impact of Common Variants of PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 on the Risk of Type 2 Diabetes in 5,164 Indians

OBJECTIVE

Common variants in PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 genes have been shown to be associated with type 2 diabetes in European populations by genome-wide association studies. We have studied the association of common variants in these eight genes with type 2 diabetes and related traits in Indians by combining the data from two independent case–control studies.

RESEARCH DESIGN AND METHODS

We genotyped eight single nucleotide polymorphisms (PPARG-rs1801282, KCNJ11-rs5219, TCF7L2-rs7903146, SLC30A8-rs13266634, HHEX-rs1111875, CDKN2A-rs10811661, IGF2BP2-rs4402960, and CDKAL1-rs10946398) in 5,164 unrelated Indians of Indo-European ethnicity, including 2,486 type 2 diabetic patients and 2,678 ethnically matched control subjects.

RESULTS

We confirmed the association of all eight loci with type 2 diabetes with odds ratio (OR) ranging from 1.18 to 1.89 (P = 1.6 × 10⁻³ to 4.6 × 10⁻³⁴). The strongest association with the highest effect size was observed for TCF7L2 (OR 1.89 [95% CI 1.71–2.09], P = 4.6 × 10⁻³⁴). We also found significant association of PPARG and TCF7L2 with homeostasis model assessment of β-cell function (P = 6.9 × 10⁻⁸ and 3 × 10⁻⁴, respectively), which looked consistent with recessive and under-dominant models, respectively.

CONCLUSIONS

Our study replicates the association of well-established common variants with type 2 diabetes in Indians and shows larger effect size for most of them than those reported in Europeans.Type 2 diabetes is a complex metabolic disorder with both genetic and environmental factors such as food habits and lifestyle contributing to its pathogenesis (1). Due to its complex etiology, the progress of discovery of genetic components for type 2 diabetes had been very slow until the advent of high throughput genome-wide association (GWA) studies (2). Until recently, only a few common variants in PPARG (3), KCNJ11 (4), and TCF7L2 (5) were shown to be associated with type 2 diabetes. With the advent of GWA studies, there are at least 20 loci identified today that are associated with the risk of type 2 diabetes (6). The first GWA study in the French population revealed SLC30A8 and HHEX as new loci for type 2 diabetes in addition to replicating the strong association with TCF7L2 (7). Further, GWA studies added several new genes including CDKAL1, CDKN2A, IGF2BP2, and FTO to the list of type 2 diabetes–associated loci and confirmed the associations for PPARG, KCNJ11, and TCF7L2 (8–12).India harbors the maximum number of diabetic patients, which is projected to double by the year 2030 (13). Indians are diagnosed with diabetes a decade earlier and at a lower BMI than Europeans, which may be partly explained by their excess central obesity (14,15). Hence, determination of genetic risk factors predicting the risk of type 2 diabetes in the Indian population is highly desirable. Recent evidence suggests that the genetic basis of several diseases in Indians might be different from that of Europeans (16,17), which could be due to differences in the risk allele frequency and pattern of linkage disequilibrium. A report from the Indian Genome Variation Consortium also suggested that most of the populations in the Indian subcontinent are distinct from HapMap populations (18). Hence, genes associated with a disease in other populations need to be assessed for their role in the Indian population. The present study evaluated the association of eight most replicated and well-established genetic variants of PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 with type 2 diabetes and related quantitative traits in Indians. We also performed allele dosage analysis of these variants and investigated their influence on quantitative metabolic traits related to type 2 diabetes.     

Treatment of Mammary Duct Fistula by Fistulectomy and Saucerization

This study was designed to assess the efficacy and long-term outcome of fistulectomy and saucerization for treatment of mammary duct fistulae. Mammary fistula is a chronic condition that represents the final step in what has been termed “mammary duct associated inflammatory disease sequence.” The treatment is primarily surgical and may include healing by secondary intention or primary closure with or without antibiotics. Reported series are small and often include variable surgical strategies applied without consistency. A consecutive series of 53 patients who had 59 mammary duct fistulae were treated by fistulectomy with saucerization. The median age was 32 years. Wounds were allowed to heal by secondary intention and antibiotics were not used. We reviewed the case records to establish the incidence of recurrent fistula and the time to complete healing. The long-term cosmetic outcome was determined by a postal survey. After a median follow-up of 6 years there had been no relapse in 92%. There was significant delay in healing in six cases (range: 10 to 30 weeks). Thirty-eight patients (83%) gave a definite history of regularly smoking between 10 and 20 cigarettes a day. Two thirds of the patients were either pleased or satisfied with the final cosmetic result of the surgery, but more than 90% said that it left them with some distortion of the nipple. Fistulectomy and saucerization achieves long-term cure in the majority of patients with mammary duct fistula, but it results in some degree of distortion of the nipple. The strong relationship between smoking and the occurrence of mammary duct fistulae is again demonstrated.     

Multidisciplinary treatment approach with one piece implants for congenitally missing maxillary lateral incisors: a case report

Congenitally missing lateral incisors are a common clinical occurrence. Dental Implants have become a primary treatment option for replacement of these teeth. Many times in prosthodontic treatment planning a multidisciplinary approach is needed for a comprehensive out come. Prosthodontic treatment planning is needed prior to the patient's consultation and following treatment acceptance; the prosthodontist may need to coordinate treatment needs with other specialists, including an orthodontist and an implant surgeon. This article describes multidisciplinary management of a case presenting with spaced maxillary anteriors due to the congenitally missing lateral incisors. Treatment consisted of initial orthodontic space management to obtain adequate space for missing lateral incisors. Single piece, narrow diameter implants were placed in edentulous spaces on both sides. Aesthetic crown lengthening procedure was performed with all anterior teeth along with tissues surrounding the implants. Metal-ceramic crowns were given as definitive restorations, resulting into an acceptable aesthetic outcome.     

Oral bone loss induced by mineral deficiency in a rat model: Effect of a synthetic bone mineral (SBM) preparation

Osteoporosis affects the craniofacial and oral structures and has been associated with periodontal bone loss, tooth loss and reduced jaw bone mass.ObjectiveThis study aimed to test the therapeutic efficacy of synthetic bone mineral (SBM) in minimizing alveolar bone loss induced by mineral deficiency in a rat model. SBM consists of a calcium carbonate apatite (similar to bone apatite) matrix incorporating magnesium, zinc, and fluoride ions.DesignThirty female Sprague Dawley rats (2 months old) were randomly distributed into 3 groups (10 rats per group): GA (control), on basic diet; GB, on mineral deficient (MD) diet; and GC, on MD + SBM. The rats were sacrificed after 3 months, the jawbones were isolated and the soft tissues removed. Bone density was determined using X-ray radiography (Faxitron); mandibular cortical width, panoramic mandibular index, and alveolar resorption degree (M/M ratio) using BioquantOsteo; and bone micro-architecture micro-computed tomography and scanning electron microscopy.ResultsCompared to control (GA), the rats on MD diet (GB) experienced significant mandibular bone loss while the rats on MD + SBM diet (GC) experienced significantly less bone loss compared to the GB group.ConclusionSBM, administered orally, may have the potential as an osteoporosis therapeutic agent in minimizing or preventing alveolar bone loss induced by mineral deficiency.     

Traumatic epidural hematoma of the cervical spine: diagnosis with magnetic resonance imaging. Case report

A traumatic epidural hematoma of the cervical spine is reported in a 13-year-old girl. The patient recovered spontaneously over several days without surgical intervention. The diagnosis was made on magnetic resonance (MR) imaging, which also demonstrated subsequent resolution of the hematoma. The etiological factors of spinal epidural hematomas are reviewed and the utility of MR imaging in differentiating other causes of acute spinal cord injury is emphasized.     

Ab externo technique for accurate haptic placement of transscleral sutured posterior chamber intraocular lenses.

A modified technique is presented for transscleral suture fixation of posterior chamber intraocular lenses for aphakic correction in cases with inadequate capsular support. An ab externo approach for suture externalization is described that minimizes intraocular manipulation and facilitates accurate placement of haptics in the ciliary sulcus, thereby reducing the risk of lens tilt and decentration. This technique eliminates intraocular suture knots and reduces the amount of time the globe is open during surgery by creating two intraocular suture loops in preparation for posterior chamber intraocular lens placement before creating a limbal incision.