Risk factors for persistent disability in children with obstetric brachial plexus palsy.

OBJECTIVE: Obstetric brachial plexus palsy (OBPP) at birth, is a serious neurologic injury that may lead to a long lasting disability. We aimed to examine the occurrence and risk factors associated with disability lasting >1 year. STUDY DESIGN: A retrospective cohort study conducted between 1993 and 2012 included individuals with diagnosis of OBPP at birth. Affected individual's motor function was evaluated by a direct physical exam based on a muscle grading system of the limb, shoulder, elbow and hand. When not feasible a telephone questionnaire was used. Participants reported on activities of daily living, disability duration and any type of intervention. Stepwise logistic regression model was used to identify demographic and obstetric risk factors for disability lasting >1 year. RESULTS: Of all 83 806 deliveries during this period, 144 OBPP cases were identified (1.7/1000). Of the 91 (63.2%) individuals located 42 (46.2%) were evaluated by a physical exam and 49 (53.8%) answered a telephone questionnaire. In 12 (13.2%) disability lasted >1 year. Significant predictors for disability lasting >1 year included birthweight >4 kg (P=0.02; odds ratio (OR) 6.17; 95% confidence interval (CI) 1.33-28.65) and younger maternal age (P=0.02; OR 0.84; 95% CI: 0.73-0.97). OBPP decreased 16% per 1 year increase in maternal age. CONCLUSIONS: OBPP is a transient injury in most cases. Birthweight over 4 kg and younger maternal age maybe associated with disability lasting >1 year.

Effects of Continuous Octreotide Infusion on Intraoperative Transfusion Requirements During Orthotopic Liver Transplantation.

Orthotopic liver transplantation (OLT) is often associated with major hemorrhage and a large red blood cell (RBC) transfusion requirement. Massive transfusion during OLT has been associated with decreased patient and graft survival. As a result, the anesthesiologist may use various techniques to decrease intraoperative blood loss and transfusion requirements, including maintenance of a low central venous pressure, antifibrinolytic drugs, cell salvage, and vasopressors. Due to its properties of splanchnic vasoconstriction and resultant decrease in portal venous blood flow, octreotide may decrease blood loss during the preanhepatic phase of OLT. We performed a retrospective review of 50 consecutive liver transplantations; a continuous octreotide infusion was used during the preanhepatic phase in 30 of these cases. We hypothesized that intraoperative transfusion requirements would be reduced in those patients treated with octreotide. Statistical analysis found that the number of RBCs transfused decreased from 20.4 U to 18.1 U when octreotide was used, although this result was not statistically significant (P = .5). Additional analysis found a significant positive correlation between the number of RBCs transfused and total operating room (OR) time, preoperative international normalized ratio (INR), and model for end-stage liver disease (MELD) and a negative correlation between the number of RBCs transfused and preoperative platelets and hemoglobin. Although our small study did not show a statistical difference in the number of units transfused, there was an absolute difference. A prospective, randomized trial would be useful in elucidating the true effect of octreotide on RBC transfusion requirements during OLT.

Steroid Sex Hormones, Sex Hormone-Binding Globulin, and Diabetes Incidence in the Diabetes Prevention Program.

CONTEXT: Steroid sex hormones and SHBG may modify metabolism and diabetes risk, with implications for sex-specific diabetes risk and effects of prevention interventions. OBJECTIVE: This study aimed to evaluate the relationships of steroid sex hormones, SHBG and SHBG single-nucleotide polymorphisms (SNPs) with diabetes risk factors and with progression to diabetes in the Diabetes Prevention Program (DPP). DESIGN AND SETTING: This was a secondary analysis of a multicenter randomized clinical trial involving 27 U.S. academic institutions. PARTICIPANTS: The study included 2898 DPP participants: 969 men, 948 premenopausal women not taking exogenous sex hormones, 550 postmenopausal women not taking exogenous sex hormones, and 431 postmenopausal women taking exogenous sex hormones. INTERVENTIONS: Participants were randomized to receive intensive lifestyle intervention, metformin, or placebo. MAIN OUTCOMES: Associations of steroid sex hormones, SHBG, and SHBG SNPs with glycemia and diabetes risk factors, and with incident diabetes over median 3.0 years (maximum, 5.0 y). RESULTS: T and DHT were inversely associated with fasting glucose in men, and estrone sulfate was directly associated with 2-hour post-challenge glucose in men and premenopausal women. SHBG was associated with fasting glucose in premenopausal women not taking exogenous sex hormones, and in postmenopausal women taking exogenous sex hormones, but not in the other groups. Diabetes incidence was directly associated with estrone and estradiol and inversely with T in men; the association with T was lost after adjustment for waist circumference. Sex steroids were not associated with diabetes outcomes in women. SHBG and SHBG SNPs did not predict incident diabetes in the DPP population. CONCLUSIONS: Estrogens and T predicted diabetes risk in men but not in women. SHBG and its polymorphisms did not predict risk in men or women. Diabetes risk is more potently determined by obesity and glycemia than by sex hormones.

The effect of lifestyle intervention and metformin on preventing or delaying diabetes among women with and without gestational diabetes: the Diabetes Prevention Program outcomes study 10-year follow-up.

CONTEXT: Gestational diabetes (GDM) confers a high risk of type 2 diabetes. In the Diabetes Prevention Program (DPP), intensive lifestyle (ILS) and metformin prevented or delayed diabetes in women with a history of GDM. OBJECTIVE: The objective of the study was to evaluate the impact of ILS and metformin intervention over 10 years in women with and without a history of GDM in the DPP/Diabetes Prevention Program Outcomes Study. DESIGN: This was a randomized controlled clinical trial with an observational follow-up. SETTING: The study was conducted at 27 clinical centers. PARTICIPANTS: Three hundred fifty women with a history of GDM and 1416 women with previous live births but no history of GDM participated in the study. The participants had an elevated body mass index and fasting glucose and impaired glucose tolerance at study entry. INTERVENTIONS: Interventions included placebo, ILS, or metformin. OUTCOMES MEASURE: Outcomes measure was diabetes mellitus. RESULTS: Over 10 years, women with a history of GDM assigned to placebo had a 48% higher risk of developing diabetes compared with women without a history of GDM. In women with a history of GDM, ILS and metformin reduced progression to diabetes compared with placebo by 35% and 40%, respectively. Among women without a history of GDM, ILS reduced the progression to diabetes by 30%, and metformin did not reduce the progression to diabetes. CONCLUSIONS: Women with a history of GDM are at an increased risk of developing diabetes. In women with a history of GDM in the DPP/Diabetes Prevention Program Outcomes Study, both lifestyle and metformin were highly effective in reducing progression to diabetes during a 10-year follow-up period. Among women without a history of GDM, lifestyle but not metformin reduced progression to diabetes.

Obesity and preference-weighted quality of life of ethnically diverse middle school children: the HEALTHY study.

To date, studies examining the relation between body mass index percentile (BMI%) categories and health-related quality of life (QOL) measurements have not reported preference-weighted scores among ethnically diverse children. We report the associations between BMI% categories and preference-weighted scores among a large cohort of ethnically diverse sixth grade children who participated in the HEALTHY school-based type 2 diabetes risk factor prevention study. Health Utility Index 2 (HUI2) and Health Utility Index 3 (HUI3) and the feeling thermometer (FT) were the preference-weighted QOL instruments used to measure student's preference scores. Of 6358 consented students, 4979 (78.3%) had complete QOL, height, weight, and covariate data. Mean (SD) preference scores were 0.846 (0.160), 0.796 (0.237), and 0.806 (0.161) for the HUI2, HUI3, and FT, respectively. After adjusting for age, sex, blood glucose and insulin, Tanner stage, race/ethnicity, family history of diabetes, and educational attainment, children with severe obesity (>99%) had significantly lower preference scores compared to normal weight on all three instruments (HUI2 P = 0.013; HUI3 P = 0.025; and FT P < 0.001). Obese and severe obese categories were significantly associated with lower HUI2 functional ratings in the mobility domain and with lower HUI3 functional ratings in the speech domain.

The effect of genetic variants in SERPING1 on the risk of neovascular age-related macular degeneration.

PURPOSE: Genetic factors influence an individual's risk for developing age-related macular degeneration (AMD), a leading cause of irreversible vision loss. Previous studies investigating the potential association between all AMD subtypes and the SERPING1 gene, which encodes a key regulator of the classic complement pathway, have yielded conflicting results. The purpose of this study is to determine whether variations in SERPING1 are associated with neovascular AMD. METHODS: A total of 556 patients with neovascular AMD and 256 ethnically matched controls were genotyped for polymorphisms in SERPING1. A tagging single nucleotide polymorphism (tSNP) approach was used to cover the SERPING1 gene plus 2 kb on each side, spanning the promoter and the 3' untranslated regions. Ten SNPs with a minor allele frequency of 0.10 were covered by three tSNPs (rs1005510, rs11603020, rs2511989). RESULTS: SERPING1 SNPs rs1005510 and rs2511989 were significantly associated with neovascular AMD in our cohort, with rs1005510 conferring an adverse risk effect (OR 1.49, 95% CI 1.18 to 1.88) and rs2511989 conferring a protective effect (OR 0.73, 95% CI 0.59 to 0.90). For both tSNPs, logistic regression of individual genotypes demonstrated statistically significant stepwise changes in the risk of developing AMD. Combined analysis of rs1005510 with variants in CFH and HTRA1 confirmed an independent risk effect. The rs11603020 variant had no effect on AMD susceptibility in this study (OR 0.98, 95% CI 0.78 to 1.24). CONCLUSIONS: The SERPING1 gene is comprehensively investigated in this study (using three tSNPs), and its genetic variants are evaluated in the largest neovascular AMD cohort to date. The hypothesis that SERPING1 has a modest effect on the risk of neovascular AMD is supported by our results.

Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to photodynamic therapy.

AIM: To determine whether there is an association between complement factor H (CFH) or LOC387715 genotypes and response to treatment with photodynamic therapy (PDT) for exudative age-related macular degeneration (AMD). METHODS: Sixty-nine patients being treated for neovascular AMD with PDT were genotyped for the CFH Y402H and LOC387715 A69S polymorphisms by allele-specific digestion of PCR products. AMD phenotypes were characterized by clinical examination, fundus photography, and fluorescein angiography. RESULTS: Adjusting for age, pre-PDT visual acuity (VA), and lesion type, mean VA after PDT was significantly worse for the CFH TT genotype than for the TC or CC genotypes (P=0.05). Post-PDT VA was significantly worse for the CFH TT genotype in the subgroup of patients with predominantly classic choroidal neovascular lesions (P=0.04), but not for the patients with occult lesions (P=0.22). For the LOC387715 A69S variant, there was no significant difference among the genotypes in response to PDT therapy. CONCLUSIONS: The CFH Y402H variant was associated with a response to PDT treatment in this study. Patients with the CFH TT genotype fared significantly worse with PDT than did those with the CFH TC and CC genotypes, suggesting a potential relationship between CFH genotype and response to PDT.

First versus repeat treatment with a lifestyle intervention program: attendance and weight loss outcomes.

OBJECTIVE: Following unblinding of the Diabetes Prevention Program (DPP) results, a 16-session lifestyle intervention program was offered to all study participants, including those who had initially been randomized to lifestyle treatment. This study compares the effects of the lifestyle program between participants who had previous exposure and those who had not. DESIGN: A 16-session behavioral intervention was conducted in groups at each of the 27 DPP sites during a transitional (bridge) period from the DPP trial to the DPP Outcomes Study (DPPOS). Session participation for this 6-month behavioral weight loss program was confirmed by originally randomized treatment groups. SUBJECTS AND MEASUREMENTS: Independently assessed weight measurements were available within a 7-month period before and after the program for 2808 ethnically diverse participants. RESULTS: Participants from the lifestyle group in the DPP were the least likely to attend a repeat offering of a 16-session behavioral weight loss program conducted in groups. Weight loss during the transitional lifestyle program was strongly related to the duration of attendance in the three groups that were participating in the program for the first time (metformin, placebo and troglitazone), but not related to amount of earlier weight loss. CONCLUSION: Individuals who were naive to the behavioral program lost a greater amount of weight and this was strongly related to their degree of participation. A second exposure to a behavioral weight loss program resulted in unsatisfactory low attendance rates and weight loss.

Improved outcome after intestinal transplantation at a single institution over 12 years.

PURPOSE: To evaluate the outcomes of patients undergoing intestinal transplantation (IT). METHODS: Retrospective review was undertaken using existing medical records and database. RESULTS: Between November 1991 and May 2003, 114 patients were referred for consideration for IT, of which 33 patients received 37 intestinal allografts. All patients had intestinal failure and all patients had significant complications from total parenteral nutrition (TPN). TPN was the predominant cause of liver failure (63%). Combined liver intestinal grafts were used in the majority of patients. Overall 1- and 3-year patient survival is 77% and 52% with patients transplanted since 1999 having a 1- and 3-year survival of 94% and 73%, respectively. The most common cause of death was sepsis. No graft or patient was lost to cytomegalovirus or Epstein-Barr virus disease. Twenty-seven percent of allografts were lost to rejection. Long-term TPN independence is 82% for grafts more than 30 days after IT. Statistical analysis revealed several important factors impacting outcome. CONCLUSIONS: Successful IT defined as prolonged patient and graft survival and TPN independence can be readily achieved in select patients with IF and complications related to TPN therapy. Outcomes have improved with experience gained and control of viral infections and rejection.

Application of combined liver-intestinal transplantation as a staged procedure.

Liver-intestinal transplantation is a complex surgical procedure that historically has required prolonged operative periods. This report is the first series where liver-intestinal transplantation was performed as a staged procedure. Specifically, allograft reperfusion was followed by resuscitation and stabilization in an intensive care unit before completion of the transplant procedure. Triage of recipients to the intensive care unit following allograft reperfusion was determined at the time of operation and was based upon the clinical condition of the recipient including hemodynamic stability, evidence of coagulopathy, and assessment of early liver function. Medical stabilization was followed by completion of the transplant procedure and definitive abdominal closure within 72 hours. The application of combined liver-intestinal transplantation as a staged procedure demonstrated no effect upon early graft function, incidence of complications, or ability to perform a definitive abdominal closure.

Induction therapy with interleukin-2 receptor antagonist after intestinal transplantation is associated with reduced acute cellular rejection and improved renal function.

PURPOSE: To determine the effectiveness of induction immunotherapy with interleukin-2 receptor antagonists (IL2RA) after intestinal transplantation (IT). METHODS: A single-center, retrospective study was undertaken of all patients undergoing IT using existing medical records and database. Immunotherapy was either triple (standard maintenance triple therapy [SMTT]) or IL2RA [induction IL2RA plus SMTTx] or OKT3 [induction antilymphocyte preparations plus SMTTx]). Data was collected for the first 175 postoperative days. Outcomes included pretransplant renal function, posttransplant serum creatinine normalized to age (nl-sCR), rejection (ACR), and survival. Standard statistical analysis was undertaken. RESULTS: There were no significant differences in the groups: triple (n = 10, median age 3.5 years, cGFR 106 +/- 44 mL/min), IL2RA (n = 13, median age 3.2 years, cGFR 101 +/- 61 mL/min), OKT3 (n = 4, median age 7.7 years, cGFR 104 +/- 27 mL/min). nl-sCR was significantly (P <.01) lower in IL2RA at most postoperative weeks. IL2RA had significantly fewer rejection and infectious episodes than the other two groups. Three-year patient survival was 92% in IL2RA versus 50% triple and OKT3. CONCLUSIONS: IL2RA immunotherapy after IT is associated with a lower incidence of renal dysfunction as compared with historical controls. Furthermore, IL2RA therapy resulted in a lower incidence of rejection and improved survival. IL2RA should be considered in select patients undergoing IT.

Infectious enteritis after intestinal transplantation: incidence, timing, and outcome.

AIM: To review the incidence, timing, and outcome of infectious enteritis after intestinal transplantation (IT). METHOD: A retrospective review of all patients undergoing IT at a single institution between 1991 and 2003 was analyze with standard statistical tools. RESULTS: Among 33 IT recipients, 13 (39%) developed 20 culture- or biopsy-proven episodes of infectious enteritis. The recipient demographics were 77% men and median age 2.6 years. Infections were diagnosed at a median of 76 days (32 to 1800) after IT. There were 14 viral (CMV one, rotavirus eight, adenovirus four, EBV one, three bacterial (Clostridium difficile), and three other infections (Giardia lamblia one, cryptosporidium two). Complete resolution was achieved in 17 (94%) infectious after appropriate antimicrobial or conservative therapy. Interestingly, there were six rejection episodes following infectious enteritis. Grafts were lost to rejection after rotaviral enteritis (n = 1) and adenoviral enteritis misdiagnosed as rejection (n = 1). Patient and graft survival were not adversely affected by infections. CONCLUSIONS: Infectious enteritis occurs frequently after IT. Viral agents are the cause in two-thirds of cases. With supportive care and appropriate treatment, resolution is possible in the majority of cases. Differentiating rejection and infection by histopathology can be difficult.

Somatostatin therapy ameliorates chronic and refractory gastrointestinal bleeding caused by diffuse angiodysplasia in a patient on anticoagulation therapy.

We present a patient receiving chronic anticoagulant treatment with recurrent and intractable gastrointestinal bleeding due to diffuse angiodysplasia. Following failure of previous medical and surgical treatment, and in light of the patient's need for chronic anticoagulation due to mechanical heart valve, she was treated with somatostatin analogue, octreotide s.c. 100 microg on alternate days for 28 months. Treatment significantly decreased the occurrence of bleeding episodes, the need for hospitalization and blood transfusion requirements despite continued anticoagulant therapy. Octreotide treatment should be considered in patients with refractory gastrointestinal bleeding due to angiodysplasia in particular in those who need anticoagulant treatment.

The neurokinin A receptor activates calcium and cAMP responses through distinct conformational states.

G protein-coupled receptors are thought to mediate agonist-evoked signal transduction by interconverting between discrete conformational states endowed with different pharmacological and functional properties. In order to address the question of multiple receptor states, we monitored rapid kinetics of fluorescent neurokinin A (NKA) binding to tachykinin NK2 receptors, in parallel with intracellular calcium, using rapid mixing equipment connected to real time fluorescence detection. Cyclic AMP accumulation responses were also monitored. The naturally truncated version of neurokinin A (NKA-(4-10)) binds to the receptor with a single rapid phase and evokes only calcium responses. In contrast, full-length NKA binding exhibits both a rapid phase that correlates with calcium responses and a slow phase that correlates with cAMP accumulation. Furthermore, activators (phorbol esters and forskolin) and inhibitors (Ro 31-8220 and H89) of protein kinase C or A, respectively, exhibit differential effects on NKA binding and associated responses; activated protein kinase C facilitates a switch between calcium and cAMP responses, whereas activation of protein kinase A diminishes cAMP responses. NK2 receptors thus adopt multiple activatable, active, and desensitized conformations with low, intermediate, or high affinities and with distinct signaling specificities.

Allosteric mechanisms in normal and pathological nicotinic acetylcholine receptors.

Recent chemical and advanced structural studies on site-directed and naturally occurring pathological mutants of individual members of the multigene family of nicotinic acetylcholine receptors have yielded structure-function relationships supporting indirect 'allosteric' interactions between the acetylcholine-binding sites and the ion channel in signal transduction.

Desensitization of neuronal nicotinic acetylcholine receptors conferred by N-terminal segments of the beta 2 subunit.

Desensitization is a general property of ligand-gated ion channels. Because of a wide array of available subunit combinations, it generates different time constants for channel closure, thereby modulating the processing of information in the brain. Within the family of neuronal nicotinic acetylcholine receptors (nAChRs), alpha 3 beta 2 and alpha 3 beta 4 receptors display contrasting properties of desensitization. When measured using two-electrode voltage-clamp in Xenopus oocytes, desensitization results in current decreases 2 s after initiation of acetylcholine application by 94% for alpha 3 beta 2 receptors, but only by 6% in the case of alpha 3 beta 4 receptors. Desensitization was analyzed by inserting different portions of the beta2 into the beta 4 subunit. Residues 1--212 of the beta2 subunit were able to confer 78% desensitization in 2 s, while smaller chimeras revealed desensitization in 2 s conferred by residues 1--42 alone to a level of 50%, by residues 72--89 to a level of 74%, and by residues 96--212 to a level of 77%. Some long-term (25 min) effects of desensitization driven by acetylcholine were found to rely partially on the same elements, including an enhancement mediated by residues 1--95 and 96--212 of the beta 2 subunit individually. Our results reveal that desensitization relies independently on diverse portions of the extracellular domain of the beta 2 subunit. Phenotype of alpha 3 beta 4 involves, in contrast, complex structural requirements involving residues dispersed throughout the entire N-terminal domain of the beta 4 subunit.

Helping foster parents cope with separation, loss, and grief.

Major changes in planning for children in foster care have resulted in significant changes in the roles of and expectations for foster parents, accompanied by even less attention to the issues of foster families' grief and loss. This article focuses on (1) the many ways foster parents encounter loss and grief on a continuous basis; (2) factors that affect the intensity of the loss and the healthy expression and resolution of grief; (3) problems that can result when the grief of foster parents is not adequately addressed; and (4) ways in which professionals can be helpful to these caregivers around loss and grief.