Neuropathology of Parkinson's disease with the R1441G mutation in LRRK2

We report the neuropathological findings in a patient with Parkinson's disease (PD) associated with Basque R1441G‐LRRK2/dardarin mutation. The patient was a man with disease onset at 68 years of age, with unilateral rest tremor; the Parkinsonism was well controlled with medication for 15 years. He died at the age of 86, after 18 years of evolution. The neuropathological examination disclosed mild neuronal loss in the substantia nigra pars compacta without α‐synuclein, tau, LRRK2, or ubiquitin cytoplasmic inclusions. Lewy bodies and Lewy neurites were absent. This is the first neuropathological study of PD associated with brain with the R1441G mutation in LRRK2. © 2009 Movement Disorder Society     

Blood pressure and cardiovascular involvement in children with neurofibromatosis type1

We evaluated blood pressure in a sample of patients with neurofibromatosis type 1 (NF1), using ambulatory blood pressure monitoring (ABPM), to determine whether ABPM, when compared with casual BP recordings, allowed the detection of a higher risk for hypertension. We also evaluated the correlation between BP and vascular abnormalities. We studied 69 NF1 patients (36 males and 33 females) with a mean age of 11±4 years, divided into group A, with 24-h mean systolic blood pressure (SBP) or diastolic blood pressure (DBP) <95th percentile, and group B, with mean SBP or DBP >95th percentile. Standard electrocardiography and M-mode, two-dimensional echocardiography were performed and all patients were in sinus rhythm. ABPM identified 11 hypertensive patients (16%); 5 had a mean SBP >95th percentile, 3 mean SBP–DBP >95th percentile, and 3 a mean DBP >95th percentile. Laboratory and other investigations to exclude secondary hypertension were normal. Cardiac abnormalities were found in 13 of the 69 patients (18.8%) with NF1. There were no significant clinical and cardiac differences between the normotensive and hypertensive group. Our data emphasize the importance of periodic ABPM in NF1 patients to diagnose hypertension early and avoid target organ damage and increased mortality.     

Analysis of renal function in the immediate postoperative period after partial liver transplantation.

Although renal dysfunction is common after liver transplantation, postoperative renal function after split liver transplantation (SLT) has not been well studied. Renal function immediately after surgery was analyzed retrospectively in 16 patients that received a SLT (SLT group). The results were compared with corresponding data from 31 matched patients that received a full-size liver transplant (FSLT group) during the same period. Serum creatinine (SCr) was measured before surgery, and, after transplantation, daily during the first week and at days 14, 21, and 28. Renal dysfunction (RD) was defined as the requirement for renal replacement therapy (RRT) or a 100% increase in SCr if the basal value had been <1.0 mg/dL or a 50% increase in SCr if the basal value had been >1.0 mg/dL. SCr had to be at least 1.5 mg/dL for a diagnosis of RD to be considered. The classification of RD was: mild, SCr 1.5-2.4 mg/dL; moderate, SCr 2.5-4.0 mg/dL; or severe, SCr >4.0 mg/dL (the requirement for RRT). Both donor and recipient age and cold ischemia time were lower in the SLT group than in the FSLT group (P < 0.05). Length of surgery was longer in the SLT group (P < 0.05). There were no significant differences between groups with respect to Model for End-Stage Liver Disease scores, the need for transfusions, the length of admission to the intensive care unit (ICU), survival rate, individual severity index, or sepsis-related organ failure assessment scores at the time of diagnosing RD. Immunosuppression regimens were similar in both groups. RD developed in 82% of SLT patients, but in only 58% of FSLT patients (P = not significant [NS]). Among SLT patients, RD (23.0% mild, 15.5% moderate, and 61.5% severe) was more severe (P = 0.007) than in FSLT patients (63.1% mild, 15.8% moderate, and 24.1% severe). The requirement for RRT in the SLT group (43.7%) was significantly greater (P < 0.05) than that in the FSLT group (12.9%). This finding may be due to the different incidence of sepsis in the 2 groups (SLT 37.5% vs. FSLT 9.7%; P < 0.05). In conclusion, although the number of patients studied was small, our data suggest a higher incidence of RD and a greater requirement for RRT in patients that receive a split liver graft than in those that receive a full size liver graft.     

Polymerization of α-olefins in the presence of δ-TiCl3/Al(CH3)3: Chain propagation rate constants for ethylene and propene

The chain propagation rate constants for the polymerization of ethylene and propene in the presence of δ-TiCl₃/Al(CH₃)₃ at 22 °C are determined by means of a ¹³C NMR analysis of suitable block copolymers. The numerical values of the rate constants are compared with those previously reported.     

Concurrent hiatal hernia repair and bariatric surgery: outcomes after sleeve gastrectomy and Roux-en-Y gastric bypass

BackgroundHiatal hernias are often repaired concurrently with bariatric surgery to reduce risk of gastroesophageal reflux disease–related complications.ObjectivesTo examine the association between concurrent hiatal hernia repair (HHR) and bariatric outcomes.SettingA 2010–2017 U.S. commercial insurance claims data set.MethodsWe conducted a retrospective cohort study. We identified adults who underwent sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) alone or had bariatric surgery concurrently with HHR. We matched patients with and without HHR and followed patients up to 3 years for incident abdominal operative interventions, bariatric revisions/conversions, and endoscopy. Time to first event for each outcome was compared using multivariable Cox proportional hazards modeling.ResultsWe matched 1546 SG patients with HHR to 3170 SG patients without HHR, and we matched 457 RYGB patients with HHR to 1156 RYGB patients without HHR. A total of 73% had a full year of postoperative enrollment. Patients who underwent concurrent SG and HHR were more likely to have additional abdominal operations (adjusted hazard ratio [aHR], 2.1; 95% CI, 1.5–3.1) and endoscopies (aHR, 1.5; 95% CI, 1.2–1.8) but not bariatric revisions/conversions (aHR, 1.7; 95% CI, .6–4.6) by 1 year after surgery, a pattern maintained at 3 years of follow-up. Among RYGB patients, concurrent HHR was associated only with an increased risk of endoscopy (aHR, 1.4; 95% CI, 1.1–1.8)) at 1 year of follow-up, persisting at 3 years.ConclusionsConcurrent SG/HHR was associated with increased risk of some subsequent operative and nonoperative interventions, a pattern that was not consistently observed for RYGB. Additional studies could examine whether changes to concurrent HHR technique could reduce risk.     

Disruption of hepatocyte growth factor/c-Met signaling enhances pancreatic beta-cell death and accelerates the onset of diabetes

OBJECTIVE

To determine the role of hepatocyte growth factor (HGF)/c-Met on β-cell survival in diabetogenic conditions in vivo and in response to cytokines in vitro.

RESEARCH DESIGN AND METHODS

We generated pancreas-specific c-Met-null (PancMet KO) mice and characterized their response to diabetes induced by multiple low-dose streptozotocin (MLDS) administration. We also analyzed the effect of HGF/c-Met signaling in vitro on cytokine-induced β-cell death in mouse and human islets, specifically examining the role of nuclear factor (NF)-κB.

RESULTS

Islets exposed in vitro to cytokines or from MLDS-treated mice displayed significantly increased HGF and c-Met levels, suggesting a potential role for HGF/c-Met in β-cell survival against diabetogenic agents. Adult PancMet KO mice displayed normal glucose and β-cell homeostasis, indicating that pancreatic c-Met loss is not detrimental for β-cell growth and function under basal conditions. However, PancMet KO mice were more susceptible to MLDS-induced diabetes. They displayed higher blood glucose levels, marked hypoinsulinemia, and reduced β-cell mass compared with wild-type littermates. PancMet KO mice showed enhanced intraislet infiltration, islet nitric oxide (NO) and chemokine production, and β-cell apoptosis. c-Met-null β-cells were more sensitive to cytokine-induced cell death in vitro, an effect mediated by NF-κB activation and NO production. Conversely, HGF treatment decreased p65/NF-κB activation and fully protected mouse and, more important, human β-cells against cytokines.

CONCLUSIONS

These results show that HGF/c-Met is critical for β-cell survival by attenuating NF-κB signaling and suggest that activation of the HGF/c-Met signaling pathway represents a novel strategy for enhancing β-cell protection.Type I diabetes is an autoimmune disease that results from cellular cytotoxicity leading to selective and progressive destruction of insulin-secreting cells (1–3). Many growth factors known to control cell growth and survival in physiologic and pathologic conditions are expressed in the pancreas and could potentially participate in an autocrine/paracrine fashion in the final fate of β-cells in an autoimmune environment. Overexpression of IGF-1, transforming growth factor-β, or granulocyte macrophage-colony stimulating factor ameliorates islet infiltration and β-cell death in mouse models of increased islet inflammation and diabetes (4–6). However, the role of endogenous pancreatic growth factors in type I diabetes has not been examined. Because growth factors can locally affect β-cell survival, neogenesis, and regeneration, and modulate chemokine production and immune responses, alterations in the level/activation of growth factor signaling pathways might contribute to the delay/acceleration of the onset of diabetes.Hepatocyte growth factor (HGF)/c-Met signaling pathway participates in the control of multiple biological functions, including development, proliferation, survival, regeneration, and branching morphogenesis (7). HGF binds with high affinity to, and induces the dimerization of, c-Met, its transmembrane tyrosine kinase receptor (8). Deletion of exon 16 of the c-Met gene, which encodes Lys¹¹⁰⁸ (ATP binding site), essential for the kinase activity of this receptor, in knockout mice results in embryonic lethality (9). These mice display a phenotype identical to HGF knockout mice (10). Both HGF and c-Met are expressed in the pancreas; HGF localizes to endothelial, islet, and mesenchymal cells, and c-Met is expressed in islet, ductal, and pancreatic progenitor cells (11–14). Conditional ablation of the c-Met gene in mouse β-cells using RIP-Cre and lox-c-Met mice leads to deficient insulin secretion without alteration of β-cell mass (12,13). On the other hand, HGF overexpression in the β-cell of transgenic mice increases β-cell replication, mass, and function (15,16). Furthermore, HGF improves islet graft survival in animal models of diabetes (17–19). HGF positively influences autoimmune responses, reducing the severity of autoimmune myocarditis and arthritis (20,21). HGF also downregulates airway and kidney inflammation, and inflammatory bowel disease (22–24). Whether HGF plays a role in autoimmune diabetes is unknown.To address the function of c-Met in the development, growth, and maintenance of β-cells under physiologic conditions, as well as its role in β-cell survival and response to injury in vivo, we generated pancreas-specific c-Met-null (PancMet KO) mice. We report that although c-Met is dispensable for normal β-cell growth and function under basal conditions, it is critically important for β-cell survival in diabetogenic conditions. β-Cell survival is dramatically worsened in the absence of HGF/c-Met signaling, resulting in accelerated diabetes onset. These observations also apply to human β-cells, underscoring a therapeutic opportunity for the HGF/c-Met signaling pathway in human diabetes.     

Predicting fractures in an international cohort using risk factor algorithms without BMD

Clinical risk factors are associated with increased probability of fracture in postmenopausal women. We sought to compare prediction models using self‐reported clinical risk factors, excluding BMD, to predict incident fracture among postmenopausal women. The GLOW study enrolled women aged 55 years or older from 723 primary‐care practices in 10 countries. The population comprised 19,586 women aged 60 years or older who were not receiving antiosteoporosis medication and were followed annually for 2 years. Self‐administered questionnaires were used to collect data on characteristics, fracture risk factors, previous fractures, and health status. The main outcome measure compares the C index for models using the WHO Fracture Risk (FRAX), the Garvan Fracture Risk Calculator (FRC), and a simple model using age and prior fracture. Over 2 years, 880 women reported incident fractures including 69 hip fractures, 468 “major fractures” (as defined by FRAX), and 583 “osteoporotic fractures” (as defined by FRC). Using baseline clinical risk factors, both FRAX and FRC showed a moderate ability to correctly order hip fracture times (C index for hip fracture 0.78 and 0.76, respectively). C indices for “major” and “osteoporotic” fractures showed lower values, at 0.61 and 0.64. Neither algorithm was better than the model based on age + fracture history alone (C index for hip fracture 0.78). In conclusion, estimation of fracture risk in an international primary‐care population of postmenopausal women can be made using clinical risk factors alone without BMD. However, more sophisticated models incorporating multiple clinical risk factors including falls were not superior to more parsimonious models in predicting future fracture in this population. © 2011 American Society for Bone and Mineral Research     

A Meta‐Analysis of the Association of Fracture Risk and Body Mass Index in Women

Several recent studies suggest that obesity may be a risk factor for fracture. The aim of this study was to investigate the association between body mass index (BMI) and future fracture risk at different skeletal sites. In prospective cohorts from more than 25 countries, baseline data on BMI were available in 398,610 women with an average age of 63 (range, 20–105) years and follow up of 2.2 million person‐years during which 30,280 osteoporotic fractures (6457 hip fractures) occurred. Femoral neck BMD was measured in 108,267 of these women. Obesity (BMI ≥ 30 kg/m²) was present in 22%. A majority of osteoporotic fractures (81%) and hip fractures (87%) arose in non‐obese women. Compared to a BMI of 25 kg/m², the hazard ratio (HR) for osteoporotic fracture at a BMI of 35 kg/m² was 0.87 (95% confidence interval [CI], 0.85–0.90). When adjusted for bone mineral density (BMD), however, the same comparison showed that the HR for osteoporotic fracture was increased (HR, 1.16; 95% CI, 1.09–1.23). Low BMI is a risk factor for hip and all osteoporotic fracture, but is a protective factor for lower leg fracture, whereas high BMI is a risk factor for upper arm (humerus and elbow) fracture. When adjusted for BMD, low BMI remained a risk factor for hip fracture but was protective for osteoporotic fracture, tibia and fibula fracture, distal forearm fracture, and upper arm fracture. When adjusted for BMD, high BMI remained a risk factor for upper arm fracture but was also a risk factor for all osteoporotic fractures. The association between BMI and fracture risk is complex, differs across skeletal sites, and is modified by the interaction between BMI and BMD. At a population level, high BMI remains a protective factor for most sites of fragility fracture. The contribution of increasing population rates of obesity to apparent decreases in fracture rates should be explored. © 2014 American Society for Bone and Mineral Research.