bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulation of γ-secretase by EVP-0015962 reduces amyloid deposition and behavioral deficits in Tg2576 mice
Authors: Rogers Kathryn , Felsenstein Kevin M , Hrdlicka Lori , Tu Zhiming , Albayya Faris , Lee Winnie , Hopp Sarah , Miller Mary-Jo , Spaulding Darcie , Yang Zhiyong , Hodgdon Hilliary , Nolan Scott , Wen Melody , Costa Don , Blain Jean-Francois , Freeman Emily , De Strooper Bart , Vulsteke Veerle , Scrocchi Louise , Zetterberg Henrik , Portelius Erik , Hutter-Paier Birgit , Havas Daniel , Ahlijanian Michael , Flood Dorothy , Leventhal Liza , Shapiro Gideon , Patzke Holger , Chesworth Richard , Koenig Gerhard
Published: December 2012

Background

A hallmark of Alzheimer’s disease is the presence of senile plaques in human brain primarily containing the amyloid peptides Aβ42 and Aβ40. Many drug discovery efforts have focused on decreasing the production of Aβ42 through γ-secretase inhibition. However, identification of γ-secretase inhibitors has also uncovered mechanism-based side effects. One approach to circumvent these side effects has been modulation of γ-secretase to shift Aβ production to favor shorter, less amyloidogenic peptides than Aβ42, without affecting the overall cleavage efficiency of the enzyme. This approach, frequently called γ-secretase modulation, appears more promising and has lead to the development of new therapeutic candidates for disease modification in Alzheimer’s disease.

Results

Here we describe EVP-0015962, a novel small molecule γ-secretase modulator. EVP-0015962 decreased Aβ42 in H4 cells (IC50 = 67 nM) and increased the shorter Aβ38 by 1.7 fold at the IC50 for lowering of Aβ42. AβTotal, as well as other carboxyl-terminal fragments of amyloid precursor protein, were not changed. EVP-0015962 did not cause the accumulation of other γ-secretase substrates, such as the Notch and ephrin A4 receptors, whereas a γ-secretase inhibitor reduced processing of both. A single oral dose of EVP-0015962 (30 mg/kg) decreased Aβ42 and did not alter AβTotal peptide levels in a dose-dependent manner in Tg2576 mouse brain at an age when overt Aβ deposition was not present. In Tg2576 mice, chronic treatment with EVP-0015962 (20 or 60 mg/kg/day in a food formulation) reduced Aβ aggregates, amyloid plaques, inflammatory markers, and cognitive deficits.

Conclusions

EVP-0015962 is orally bioavailable, detected in brain, and a potent, selective γ-secretase modulator in vitro and in vivo. Chronic treatment with EVP-0015962 was well tolerated in mice and lowered the production of Aβ42, attenuated memory deficits, and reduced Aβ plaque formation and inflammation in Tg2576 transgenic animals. In summary, these data suggest that γ-secretase modulation with EVP-0015962 represents a viable therapeutic alternative for disease modification in Alzheimer’s disease.
Lower short- and long-term mortality associated with overweight and obesity in a large cohort study of adult intensive care unit patients
Authors: Abhyankar Swapna , Leishear Kira , Callaghan Fiona M , Demner-Fushman Dina , McDonald Clement J
Published: December 2012

Introduction

Two thirds of United States adults are overweight or obese, which puts them at higher risk of developing chronic diseases and of death compared with normal-weight individuals. However, recent studies have found that overweight and obesity by themselves may be protective in some contexts, such as hospitalization in an intensive care unit (ICU). Our objective was to determine the relation between body mass index (BMI) and mortality at 30 days and 1 year after ICU admission.

Methods

We performed a cohort analysis of 16,812 adult patients from MIMIC-II, a large database of ICU patients at a tertiary care hospital in Boston, Massachusetts. The data were originally collected during the course of clinical care, and we subsequently extracted our dataset independent of the study outcome.

Results

Compared with normal-weight patients, obese patients had 26% and 43% lower mortality risk at 30 days and 1 year after ICU admission, respectively (odds ratio (OR), 0.74; 95% confidence interval (CI), 0.64 to 0.86) and 0.57 (95% CI, 0.49 to 0.67)); overweight patients had nearly 20% and 30% lower mortality risk (OR, 0.81; 95% CI, 0.70 to 0.93) and OR, 0.68 (95% CI, 0.59 to 0.79)). Severely obese patients (BMI ≥ 40 kg/m2) did not have a significant survival advantage at 30 days (OR, 0.94; 95% CI, 0.74 to 1.20), but did have 30% lower mortality risk at 1 year (OR, 0.70 (95% CI, 0.54 to 0.90)). No significant difference in admission acuity or ICU and hospital length of stay was found across BMI categories.

Conclusion

Our study supports the hypothesis that patients who are overweight or obese have improved survival both 30 days and 1 year after ICU admission.
Superior Long-Term Outcome With Idarubicin Compared With High-Dose Daunorubicin in Patients With Acute Myeloid Leukemia Age 50 Years and Older
Authors: Gardin Claude , Chevret Sylvie , Pautas Cécile , Turlure Pascal , Raffoux Emmanuel , Thomas Xavier , Quesnel Bruno , de Revel Thierry , de Botton Stéphane , Gachard Nathalie , Renneville Aline , Boissel Nicolas , Preudhomme Claude , Terré Christine , Fenaux Pierre , Bordessoule Dominique , Celli-Lebras Karine , Castaigne Sylvie , Dombret Hervé
Published: December 2012

Purpose

Although standard chemotherapy remains associated with a poor outcome in older patients with acute myeloid leukemia (AML), it is unclear which patients can survive long enough to be considered as cured. This study aimed to identify factors influencing the long-term outcome in these patients.

Patients and Methods

The study included 727 older patients with AML (median age, 67 years) treated in two idarubicin (IDA) versus daunorubicin (DNR) Acute Leukemia French Association trials. Prognostic analysis was based on standard univariate and multivariate models and also included a cure fraction model to focus on long-term outcome.

Results

Age, WBC count, secondary AML, Eastern Cooperative Oncology Group (ECOG) performance status (PS), and adverse-risk and favorable-risk AML subsets (European LeukemiaNet classification) all influenced complete remission (CR) rate and overall survival (OS). IDA random assignment was associated with higher CR rate, but not with longer OS (P = .13). The overall cure rate was 13.3%. Older age and ECOG-PS more than 1 negatively influenced cure rate, which was higher in patients with favorable-risk AML (39.1% v 8.0% in adverse-risk AML; P < .001) and those treated with IDA (16.6% v 9.8% with DNR; P = .018). The long-term impact of IDA was still observed in patients younger than age 65 years, although all of the younger patients in the DNR control arm received high DNR doses (cure rate, 27.4% for IDA v 15.9% for DNR; P = .049). In multivariate analysis, IDA random assignment remained associated with a higher cure rate (P = .04), together with younger age and favorable-risk AML, despite not influencing OS (P = .11).

Conclusion

In older patients with AML, younger age, favorable-risk AML, and IDA treatment predict a better long-term outcome.
Phase II Study of the MEK1/MEK2 Inhibitor Trametinib in Patients With Metastatic BRAF-Mutant Cutaneous Melanoma Previously Treated With or Without a BRAF Inhibitor
Authors: Kim Kevin B. , Kefford Richard , Pavlick Anna C. , Infante Jeffrey R. , Ribas Antoni , Sosman Jeffrey A. , Fecher Leslie A. , Millward Michael , McArthur Grant A. , Hwu Patrick , Gonzalez Rene , Ott Patrick A. , Long Georgina V. , Gardner Olivia S. , Ouellet Daniele , Xu Yanmei , DeMarini Douglas J. , Le Ngocdiep T. , Patel Kiran , Lewis Karl D.
Published: December 2012

Purpose

BRAF mutations promote melanoma cell proliferation and survival primarily through activation of MEK. The purpose of this study was to determine the response rate (RR) for the selective, allosteric MEK1/MEK2 inhibitor trametinib (GSK1120212), in patients with metastatic BRAF-mutant melanoma.

Patients and Methods

This was an open-label, two-stage, phase II study with two cohorts. Patients with metastatic BRAF-mutant melanoma previously treated with a BRAF inhibitor (cohort A) or treated with chemotherapy and/or immunotherapy (BRAF-inhibitor naive; cohort B) were enrolled. Patients received 2 mg of trametinib orally once daily.

Results

In cohort A (n = 40), there were no confirmed objective responses and 11 patients (28%) with stable disease (SD); the median progression-free survival (PFS) was 1.8 months. In cohort B (n = 57), there was one (2%) complete response, 13 (23%) partial responses (PRs), and 29 patients (51%) with SD (confirmed RR, 25%); the median PFS was 4.0 months. One patient each with BRAF K601E and BRAF V600R had prolonged PR. The most frequent treatment-related adverse events for all patients were skin-related toxicity, nausea, peripheral edema, diarrhea, pruritis, and fatigue. No cutaneous squamous cell carcinoma was observed.

Conclusion

Trametinib was well tolerated. Significant clinical activity was observed in BRAF-inhibitor–naive patients previously treated with chemotherapy and/or immunotherapy. Minimal clinical activity was observed as sequential therapy in patients previously treated with a BRAF inhibitor. Together, these data suggest that BRAF-inhibitor resistance mechanisms likely confer resistance to MEK-inhibitor monotherapy. These data support further evaluation of trametinib in BRAF-inhibitor–naive BRAF-mutant melanoma, including rarer forms of BRAF-mutant melanoma.
Adhesion in the stem cell niche: biological roles and regulation
Authors: Chen Shuyi , Lewallen Michelle , Xie Ting
Published: December 2012

Stem cell self-renewal is tightly controlled by the concerted action of stem cell-intrinsic factors and signals within the niche. Niche signals often function within a short range, allowing cells in the niche to self-renew while their daughters outside the niche differentiate. Thus, in order for stem cells to continuously self-renew, they are often anchored in the niche via adhesion molecules. In addition to niche anchoring, however, recent studies have revealed other important roles for adhesion molecules in the regulation of stem cell function, and it is clear that stem cell-niche adhesion is crucial for stem cell self-renewal and is dynamically regulated. Here, we highlight recent progress in understanding adhesion between stem cells and their niche and how this adhesion is regulated.
Racial Discrimination in the Labor Market: Theory and Empirics
Authors: Lang Kevin , Lehmann Jee-Yeon K
Published: December 2012

We review theories of race discrimination in the labor market. Taste-based models can generate wage and unemployment duration differentials when combined with either random or directed search even when strong prejudice is not widespread, but no existing model explains the unemployment rate differential. Models of statistical discrimination based on differential observability of productivity across races can explain the pattern and magnitudes of wage differentials but do not address employment and unemployment. At their current state of development, models of statistical discrimination based on rational stereotypes have little empirical content. It is plausible that models combining elements of the search models with statistical discrimination could fit the data. We suggest possible avenues to be pursued and comment briefly on the implication of existing theory for public policy. (JEL J15, J31, J64, J71)
Learners or participants? The pros and cons of ‘lifelong learning’
Authors: Mantie Roger
Published: December 2012

Whereas adult education used to be the preferred concept for those studying adult music-making, there is now an increasing trend away from this and towards lifelong learning. Uncritically adopting government lifelong learning discourses, however, blurs the line between educational ideals
and political ones. Although there may be merit in the claims for the benefits of learning throughout the lifespan, I suggest that the meaning and values of practice in community music activities far exceed that of learning for learning's sake. I argue in this article that there are compelling
reasons for reconsidering the use of the term 'lifelong learning' for community music activities.
Association of Nutrient-Dense Snack Combinations With Calories and Vegetable Intake
Authors: Wansink Brian , Shimizu Mitsuru , Brumberg Adam
Published: December 2012

BACKGROUND:

With other factors such as general diet and insufficient exercise, eating non–nutrient dense snack foods such as potato chips contributes to childhood obesity. We examined whether children consumed fewer calories when offered high-nutrient dense snacks consisting of cheese and vegetables than children who were offered non–nutrient dense snacks (ie, potato chips).

METHODS:

Two hundred one children (115 girls) entering the third to sixth grades were randomly assigned to 1 of 4 snacking conditions: (1) potato chips only, (2) cheese-only, (3) vegetables only, and (4) cheese and vegetables. Children were allowed to eat snacks freely provided while watching 45-minute TV programs. Satiety was measured before they started eating snacks, in the middle of the study, and 20 minutes after they finished eating the snacks. Parents completed a questionnaire regarding their family environment.

RESULTS:

Children consumed 72% fewer calories when eating a combined snack compared with when they were served potato chips, P < .001. Children who ate the combination snack needed significantly fewer calories to achieve satiety than those who ate potato chips, P < .001. The effects of the snack conditions on caloric intake were more pronounced among overweight or obese children (P = .02) and those from low-involvement families (P = .049)

CONCLUSIONS:

The combination snack of vegetables and cheese can be an effective means for children to reduce caloric intake while snacking. The effect was more pronounced among children who were overweight or obese and children from low-involvement families.
Detection of Kingella kingae Osteoarticular Infections in Children by Oropharyngeal Swab PCR
Authors: Ceroni Dimitri , Dubois-Ferriere Victor , Cherkaoui Abdessalam , Gesuele Renzi , Combescure Christophe , Lamah Léopold , Manzano Sergio , Hibbs Jonathan , Schrenzel Jacques
Published: December 2012

OBJECTIVE:

The purpose of this study was to investigate if oropharyngeal swab polymerase chain reaction (PCR) could predict osteoarticular infection (OAI) due to Kingella kingae in young children.

METHODS:

One hundred twenty-three consecutive children aged 6 to 48 months presenting with atraumatic osteoarticular complaints were prospectively studied. All had a clinical evaluation, imaging, and blood samples. Blood and oropharyngeal specimens were tested with a PCR assay specific for K kingae. OAI was defined as bone, joint, or blood detection of pathogenic bacteria, or MRI consistent with infection in the absence of positive microbiology. K kingae OAI was defined by blood, bone, or synovial fluid positivity for the organism by culture or PCR.

RESULTS:

Forty children met the OAI case definition; 30 had K kingae OAI, 1 had another organism, and 9 had no microbiologic diagnosis. All 30 oropharyngeal swabs from the K kingae case patients and 8 swabs from the 84 patients without OAI or with OAI caused by another organism were positive. The sensitivity and specificity of the oropharyngeal swab PCR assay for K kingae were 100% and 90.5%, respectively.

CONCLUSIONS:

Detection of K kingae DNA in oropharyngeal swabs of children with clinical findings of OAI is predictive of K kingae OAI. If these findings are replicated in other settings, detection of K kingae by oropharyngeal swab PCR could improve the recognition of OAI.
Chronic heart failure with impaired left ventricular function (systolic heart failure)
Authors: Hőgye Márta , Forster Tamás
Published: December 2012

Chronic heart failure is a common public health problem. The disease has a poor prognosis with high mortality rate and the incidence increases continuously. Prognosis of chronic systolic heart failure can be improved by several different medications as well as by special cardiac interventions based on the newly-published European and American guidelines. In case of severe systolic dysfunction, hospitalization and mortality can be reduced using angiotensin converting enzyme inhibitors, angiotensin receptor blocking drugs, beta-receptor blocking agents and aldosterone antagonists, as evidenced in multicentric studies. In selected cases different cardiac interventions, such as intracardial defibrillator and/or cardiac desynchronization device implantation can be used for supporting the failing left ventricle. In terminal stage, special devices (ventricular assist device, intra-aortic balloon pump, arteficial heart) and, finally, heart transplantation can be applied. In this paper, the authors highlight therapeutic options of chronic systolic heart failure referring to recommendations of the latest, 2012 guideline from the European Society of Cardiology. Orv. Hetil., 2012, 153, 2021–2029.
A three-phase model for predicting the effective chloride migration coefficient of ITZ in cement-based materials
Authors: Yang Chung-Chia , Weng Shih-Han
Published: December 2012

Specimens (water/cement ratio of 0·35) with various volume fractions (0, 0·1, 0·2, 0·3, 0·4 and 0·5) of fine aggregates were cast and tested to investigate the behaviour of the interfacial transition zone in mortar and the effect of the interfacial transition zone on the chloride migration coefficient. The double-inclusion method and Mori–Tanaka theory were used to predict the migration coefficient of three-phase composite materials, which are cement paste, interfacial transition zone and fine aggregate. There are two stages to calculate the overall migration coefficient of mortar. The first stage, the equivalent migration coefficient of fine aggregate and the interfacial transition zone, was calculated by Hori and Nemat-Nasser's double-inclusion model. The second stage, the equivalent migration coefficient, was used to calculate the overall migration coefficient of the mortar composite by Mori–Tanaka theory. A comparison was conducted between the theoretical and experimental data in this study. The results indicated that the migration coefficient of the interfacial transition zone is 1·5 to 10 times the migration coefficient of cement paste when an interfacial transition zone thickness of 20 to 30 μm is assumed.
Coadministration of Glucagon-Like Peptide-1 During Glucagon Infusion in Humans Results in Increased Energy Expenditure and Amelioration of Hyperglycemia
Authors: Tan Tricia M. , Field Benjamin C.T. , McCullough Katherine A. , Troke Rachel C. , Chambers Edward S. , Salem Victoria , Gonzalez Maffe Juan , Baynes Kevin C.R. , De Silva Akila , Viardot Alexander , Alsafi Ali , Frost Gary S. , Ghatei Mohammad A. , Bloom Stephen R.
Published: December 2012

Glucagon and glucagon-like peptide (GLP)-1 are the primary products of proglucagon processing from the pancreas and gut, respectively. Giving dual agonists with glucagon and GLP-1 activity to diabetic, obese mice causes enhanced weight loss and improves glucose tolerance by reduction of food intake and by increase in energy expenditure (EE). We aimed to observe the effect of a combination of glucagon and GLP-1 on resting EE and glycemia in healthy human volunteers. In a randomized, double-blinded crossover study, 10 overweight or obese volunteers without diabetes received placebo infusion, GLP-1 alone, glucagon alone, and GLP-1 plus glucagon simultaneously. Resting EE—measured using indirect calorimetry—was not affected by GLP-1 infusion but rose significantly with glucagon alone and to a similar degree with glucagon and GLP-1 together. Glucagon infusion was accompanied by a rise in plasma glucose levels, but addition of GLP-1 to glucagon rapidly reduced this excursion, due to a synergistic insulinotropic effect. The data indicate that drugs with glucagon and GLP-1 agonist activity may represent a useful treatment for type 2 diabetes and obesity. Long-term studies are required to demonstrate that this combination will reduce weight and improve glycemia in patients.
TGFβ Receptor Signaling Is Essential for Inflammation-Induced but Not β-Cell Workload–Induced β-Cell Proliferation
Authors: Xiao Xiangwei , Wiersch John , El-Gohary Yousef , Guo Ping , Prasadan Krishna , Paredes Jose , Welsh Carey , Shiota Chiyo , Gittes George K.
Published: December 2012

Protection and restoration of a functional β-cell mass are fundamental strategies for prevention and treatment of diabetes. Consequently, knowledge of signals that determine the functional β-cell mass is of immense clinical relevance. Transforming growth factor β (TGFβ) superfamily signaling pathways play a critical role in development and tissue specification. Nevertheless, the role of these pathways in adult β-cell homeostasis is not well defined. Here, we ablated TGFβ receptor I and II genes in mice undergoing two surgical β-cell replication models (partial pancreatectomy or partial duct ligation), representing two triggers for β-cell proliferation, increased β-cell workload and local inflammation, respectively. Our data suggest that TGFβ receptor signaling is necessary for baseline β-cell proliferation. By either provision of excess glucose or treatment with exogenous insulin, we further demonstrated that inflammation and increased β-cell workload are both stimulants for β-cell proliferation but are TGFβ receptor signaling dependent and independent, respectively. Collectively, by using a pancreas-specific TGFβ receptor–deleted mouse model, we have identified two distinct pathways that regulate adult β-cell proliferation. Our study thus provides important information for understanding β-cell proliferation during normal growth and in pancreatic diseases.
Duration of Abdominal Obesity Beginning in Young Adulthood and Incident Diabetes Through Middle Age
Authors: Reis Jared P. , Hankinson Arlene L. , Loria Catherine M. , Lewis Cora E. , Powell-Wiley Tiffany , Wei Gina S. , Liu Kiang
Published: December 2012

OBJECTIVE

To examine whether the duration of abdominal obesity determined prospectively using measured waist circumference (WC) is associated with the development of new-onset diabetes independent of the degree of abdominal adiposity.

RESEARCH DESIGN AND METHODS

The Coronary Artery Risk Development in Young Adults Study is a multicenter, community-based, longitudinal cohort study of 5,115 white and black adults aged 18–30 years in 1985 to 1986. Years spent abdominally obese were calculated for participants without abdominal obesity (WC >102 cm in men and >88 cm in women) or diabetes at baseline (n = 4,092) and was based upon repeat measurements conducted 2, 5, 7, 10, 15, 20, and 25 years later.

RESULTS

Over 25 years, 392 participants developed incident diabetes. Overall, following adjustment for demographics, family history of diabetes, study center, and time varying WC, energy intake, physical activity, smoking, and alcohol, each additional year of abdominal obesity was associated with a 4% higher risk of developing diabetes [hazard ratio (HR) 1.04 (95% CI 1.02–1.07)]. However, a quadratic model best represented the data. HRs for 0, 1–5, 6–10, 11–15, 16–20, and >20 years of abdominal obesity were 1.00 (referent), 2.06 (1.43–2.98), 3.45 (2.28–5.22), 3.43 (2.28–5.22), 2.80 (1.73–4.54), and 2.91 (1.60–5.29), respectively; P-quadratic < 0.001.

CONCLUSIONS

Longer duration of abdominal obesity was associated with substantially higher risk for diabetes independent of the degree of abdominal adiposity. Preventing or at least delaying the onset of abdominal obesity in young adulthood may lower the risk of developing diabetes through middle age.
Outcome of Modified Kidner Procedure with Subtalar Arthroereisis for Painful Accessory Navicular Associated with Planovalgus Deformity
Authors: Garras David N. , Hansen Patricia L. , Miller Adam G. , Raikin Steven Mark.
Published: December 2012

Background: Type II accessory naviculars are frequently associated with planovalgus deformity. Operative treatment for patients recalcitrant to nonoperative treatment involves resection, with or without takedown, and reattachment of the tibialis posterior tendon as described by Kidner. This does not address the planovalgus deformity. The authors hypothesized that adding a subtalar arthroereisis to the Kidner procedure would lead to improvement of pain and function and correction of the deformity. Methods: Institutional Review Board-approved, prospectively collected data were reviewed for 20 patients (23 feet), who underwent a combined modified Kidner and subtalar arthroereisis for painful type II accessory navicular with planovalgus deformity recalcitrant to nonoperative treatment. The average age at the time of surgery was 18 years. Patients were evaluated preoperatively and at final follow-up clinically, radiographically, and via the visual analog pain scale (VAPS), the American Orthopaedic Foot and Ankle Society (AOFAS) ankle hindfoot score, and a satisfaction rating. Mean follow-up was 53.9 months. Results: The mean AOFAS scores improved from 53 preoperatively to 95 at final follow-up and the mean VAPS score decreased from 7.4 preoperatively to 1.7 at final follow-up. Radiographically, the average Meary's angle improved from 18.5° apex plantar preoperatively to 3° apex plantar on weight-bearing lateral radiographs, and the average talar head uncoverage percentage on weight-bearing anteroposterior radiographs improved from 24% preoperatively to 3%. Nineteen of 20 patients reported good or excellent results. Three patients required implant removal because of pain; no recurrence of planovalgus deformity occurred after implant removal. No patients developed subtalar arthritis. Conclusion: The modified Kidner procedure combined with a subtalar arthroereisis resulted in significant pain and functional improvement. The deformity correction obtained at surgery was maintained even if the arthroereisis plug was removed. The extra-articular plug did not lead to subtalar arthritis.

Level of Evidence: IV, Case Series
Outcome of Medial Displacement Calcaneal Osteotomy for Correction of Adult-Acquired Flatfoot
Authors: Niki Hisateru , Hirano Takaaki , Okada Hirokazu , Beppu Moroe
Published: December 2012

Background: The results of medial displacement calcaneal osteotomy (MDCO) with flexor digitorum longus (FDL) tendon transfer were reviewed, as well as postoperative radiographic changes, to determine quantitative x-ray-based indications for MDCO with FDL tendon transfer in cases of adult-acquired flatfoot. Materials and Methods: Twenty-five patients, ages 42 to 71 years, underwent MDCO with FDL tendon transfer for stage II posterior tibial tendon dysfunction. Follow-up was 2.6 to 10.2 years. Preoperative and postoperative Japanese Society for Surgery of the Foot (JSSF), Foot Function Index, and SF-36 scores and physical and radiographic findings were compared. Eight measures of foot alignment were obtained from weight-bearing radiographs at 3, 6, 9, and 12 months after surgery and every 6 months thereafter. Differences in scores and values over time were analyzed statistically. Results: Average JSSF scores improved from 59 preoperatively to 91.3 postoperatively ( p < .001). The only x-ray parameters that improved significantly and showed maintenance of the surgical correction were the lateral talometatarsal (LTMT) and tibiocalcaneal (TBC) angles. With preoperative LTMT and TBC angles of >25° and >15°, respectively, correction was inadequate. Conclusions: It was concluded that indications for MDCO with FDL tendon transfer in cases of adult-acquired flatfoot are a preoperative LTMT angle of <25° and hindfoot coronal alignment (TBC angle) of <15°.

Level of Evidence: IV, Case Series
Two different volume of local anaesthetic in subarachnoid block for Minipercutaneous Nephrolithotomy in prone position
Authors: Shrestha BR , Khadgi S , Shrestha S , Thapa P
Published: December 2012

Aims: To see the maximum sensory level in supine and prone position after subarachnoid block in patients undergoing Minipercutaneous Nephrolithotomy with two different volumes of local anaesthetic. Methods: Prospective randomized comparative study in 500 patients undergoing Minipercutaneous Nephrolithotomy for finding out the extensiveness of sensory level spread after spinal anaesthesia using two different volumes of local anaesthetic before and after keeping patients in prone position. Patients were divided into two groups: Group A (three ml hyperbaric Bupivacaine) and Group B (four ml hyperbaric Bupivacaine) consisted of 250 patients each. Spinal block was performed in sitting position. Sensory level and hemodynamic measurements were carried out at different time points while patients were on supine and on prone position. Results: Patients attaining T4 sensory level at five minutes in Group B was significantly higher than in Group A (p=0.001). After 10-15 minutes of spinal block, greater number of patients in Group B reached T4 sensory level while being in supine position than those in Group A and the difference was statistically significant (p=0.000). After keeping the patients in prone position for in 10-15 minutes the number of patients reaching T4 level was found to be significantly higher in group A than in Group B (p=0.063). Decrease in heart rate and blood pressure in prone position were significant from baseline value and while during supine (p<0.05). Conclusion: Prone positioning extends the sensory level of subarachnoid block to higher level (T4) when three ml of hyperbaric solution is used. DOI: http://dx.doi.org/10.3126/jkmc.v1i1.7249 Journal of Kathmandu Medical College, Vol. 1, No. 1, Issue 1, Jul.-Sep., 2012 pp.10-15
Treatment of gingival recession with coronally advanced Flap - A case report
Authors: Singh R
Published: December 2012

Extensive gingival recession associated with cervical abrasions is common. Several different surgical and/or restorative therapies have been proposed to correct these lesions. This paper reports the treatment of multiple gingival recessions associated with shallow root caries. The procedure involved utilization of coronally advanced flap. At the postoperative follow-up visits, the success of the surgical approach was confirmed by the absence of tooth sensitivity and presence of gingival tissue with normal colour, texture and contour. After 12 months of follow-up, the clinical conditions were stable with satisfactory root coverage and periodontal health. An excellent aesthetical outcome was achieved and the patient was satisfied with the outcome. DOI: http://dx.doi.org/10.3126/jkmc.v1i1.7253 Journal of Kathmandu Medical College, Vol. 1, No. 1, Issue 1, Jul.-Sep., 2012 pp.29-32
Sclerosing haemangioma of the lung: A case report
Authors: Thapa R , Lakhey M , Shrestha U
Published: December 2012

Sclerosing haemangioma is a rare neoplasm of the lung which behaves in a clinically benign fashion. Herein, a case of sclerosing haemangioma of the lung in a 52 years old woman is reported. She presented with symptoms of cough and chest pain. Chest X-ray and CT scan showed a well-defined lesion in lower lobe of left lung. Bronchoscopic biopsy findings were suggestive of a carcinoid tumor. Later the tumor was removed by lobectomy. The distinctive constellation of histologic findings revealed it to be a sclerosing haemangioma. DOI: http://dx.doi.org/10.3126/jkmc.v1i1.7254 Journal of Kathmandu Medical College, Vol. 1, No. 1, Issue 1, Jul.-Sep., 2012 pp.33-36
History of Problem Based Learning in Nepal and Experiences at Kathmandu Medical College
Authors: Pradhan B , Ranjit E , Ghimire MR , Dixit Y
Published: December 2012

Problem Based Learning has been practised in Nepal for 30 years with some additional inputs every ten years as another medical institution of Nepal adopted it. The institution to introduce it in Nepal was the Institute of Medicine but its practise there is more as familiarisation about a method of learning medicine and making a diagnosis. As from 2012 the utilisation of Problem Based Learning in the MBBS medical education field is expected to increase as the two deemed and two full universities in Nepal are using this method to varying degrees. There are firm advocates for utilising PBL in the medical colleges of Nepal. There are many who would like to stick to the traditional methods saying that PBL is not in extensive use. The fact is that the traditional form of medical education and the PBL method have their positive and negative points and is the source of much debate. We in Nepal have not gone the full stretch with PBL. What we are practising here is mostly the hybrid form. DOI: http://dx.doi.org/10.3126/jkmc.v1i1.7255 Journal of Kathmandu Medical College, Vol. 1, No. 1, Issue 1, Jul.-Sep., 2012 pp.37-44
Avian Nests and Nest-Building as Signals
Authors: Moreno Juan
Published: December 2012

Birds may signal their condition, health or parental disposition to mates through large nests or intense or elaborate nest-building. The mass, number or elaborateness of nests may exceed their strict reproductive requirements. In several species, courtship rituals include exhibition of nesting materials to mates, and some nests are not used for breeding. Signalling through nests or nest construction may occur both before and after mating and may involve either males or females. Only males appear to be involved in pre-mating signalling, while both males and females may signal after mating. In several species, nest size and nest building activity has been associated with the condition of nest-building males, and females in some cases, while the evidence for parental disposition has been more mixed. Nest defence capacity has also been associated with nest size. In some species, males attract more mates through construction of multiple nests not related to breeding. The benefits obtained by males after pairing through differential allocation of their mates have been found in several species in terms of larger clutches, earlier hatching, biased sex ratios and increased parental investment. There is less evidence of this type of benefits for females. Measured responses of assumed receivers of the information provided by active nest construction may positively affect their fitness. Predators are probably attracted to bulky nests and so nest predation may have selected for concealed nests and for inconspicuous nest building activities, which has probably limited exaggeration of nest-building signals. There is also some evidence that ectoparasites and brood parasites may be attracted to bulky nests. Although signalling through nest construction appears as a plausible evolutionary scenario, much more empirical work needs to be done to demonstrate the relevance of nest-building signals.
Modeling Survival, Yield, Volume Partitioning and Their Response to Thinning for Longleaf Pine Plantations
Authors: Gonzalez-Benecke Carlos , Gezan Salvador , Leduc Daniel , Martin Timothy , Cropper Wendell , Samuelson Lisa
Published: December 2012

Longleaf pine (Pinus palustris Mill.) is an important tree species of the southeast U.S. Currently there is no comprehensive stand-level growth and yield model for the species. The model system described here estimates site index (SI) if dominant height (Hdom) and stand age are known (inversely, the model can project Hdom at any given age if SI is known). The survival (N) equation was dependent on stand age and Hdom, predicting greater mortality on stands with larger Hdom. The function that predicts stand basal area (BA) for unthinned stands was dependent on N and Hdom. For thinned stands BA was predicted with a competition index that was dependent on stand age. The function that best predicted stand stem volume (outside or inside bark) was dependent on BA and Hdom. All functions performed well for a wide range of stand ages and productivity, with coefficients of determination ranging between 0.946 (BA) and 0.998 (N). We also developed equations to estimate merchantable volume yield consisting of different combinations of threshold diameter at breast height and top diameter for longleaf pine stands. The equations presented in this study performed similarly or slightly better than other reported models to estimate future N, Hdom and BA. The system presented here provides important new tools for supporting future longleaf pine management and research.
Preparation, Characterization and Release of Urea from Wheat Gluten Electrospun Membranes
Authors: Castro-Enríquez Daniela , Rodríguez-Félix Francisco , Ramírez-Wong Benjamín , Torres-Chávez Patricia , Castillo-Ortega María , Rodríguez-Félix Dora , Armenta-Villegas Lorena , Ledesma-Osuna Ana
Published: December 2012

Homogeneous and thin porous membranes composed of oriented fibers were obtained from wheat gluten (WG) using the electrospinning technique. SEM micrographs showed an asymmetric structure and some porosity, which, in addition to a small thickness of 40 mm, are desirable characteristics for the membranes’ potential application in release systems. The membranes were loaded with urea to obtain pastilles. FT-IR and DSC studies confirmed the existence of interactions via hydrogen bonding between urea and WG proteins. The pastilles were studied as prolonged-released systems of urea in water. The release of urea during the first 10 min was very fast; then, the rate of release decreased as it reached equilibrium at 300 min, with a total of »98% urea released. TGA analysis showed that the release system obtained is thermally stable up to a temperature of 117 °C. It was concluded that a prolonged-release system of urea could be satisfactorily produced using WG fibers obtained by electrospinning for potential application in agricultural crops.
Optimization of the GaAs-on-Si Substrate for Microelectromechanical Systems (MEMS) Sensor Application
Authors: Shi Yunbo , Guo Hao , Ni Haiqiao , Xue Chenyang , Niu Zhichuan , Tang Jun , Liu Jun , Zhang Wendong , He Jifang , Li Mifeng , Yu Ying
Published: December 2012

Resonant Tunneling Diodes (RTD) and High Electron Mobility Transistor (HEMT) based on GaAs, as the piezoresistive sensing element, exhibit extremely high sensitivity in the MEMS sensors based on GaAs. To further expand their applications to the fields of MEMS sensors based on Si, we have studied the optimization of the GaAs epitaxy layers on Si wafers. Matching superlattice and strain superlattice were used, and the surface defect density can be improved by two orders of magnitude. Combing with the Raman spectrum, the residual stress was characterized, and it can be concluded from the experimental results that the residual stress can be reduced by 50%, in comparison with the original substrate. This method gives us a solution to optimize the epitaxy GaAs layers on Si substrate, which will also optimize our future process of integration RTD and HEMT based on GaAs on Si substrate for the MEMS sensor applications.
Induction of Apoptosis by Sinulariolide from Soft Coral through Mitochondrial-Related and p38MAPK Pathways on Human Bladder Carcinoma Cells
Authors: Neoh Choo-Aun , Wang Robert , Din Zhong-Hao , Su Jui-Hsin , Chen Yu-Kuei , Tsai Feng-Jen , Weng Shun-Hsiang , Wu Yu-Jen
Published: December 2012

Sinulariolide, an isolated compound from the soft coral Sinularia flexibilis, possesses the anti-proliferative, anti-migratory and apoptosis-inducing activities against the TSGH bladder carcinoma cell. The anti-tumor effects of sinulariolide were determined by 3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, cell migration assay and flow cytometry, respectively. Sinulariolide inhibited the growth and migration of bladder carcinoma cells in a dose-dependent manner, as well as induced both early and late apoptosis as determined by the flow cytometer. Also, the sinulariolide-induced apoptosis is related to the mitochondrial-mediated apoptosis via caspase-dependent pathways, elucidated by the loss of mitochondrial membrane potential, release of cytochrome C, activation of caspase-3/-9, Bax and Bad, as well as suppression of Bcl-2/Bcl-xL/Mcl-1. Detection of the PARP-1 cleaved product suggested the partial involvement of caspase-independent pathways. Moreover, inhibition of p38MAPK activity leads to the rescue of the cell cytotoxicity of sinulariolide-treated TSGH cells, indicating that the p38MAPK pathway is also involved in the sinulariolide-induced cell apoptosis. Altogether, these results suggest that sinulariolide induces apoptosis against bladder cancer cells through mitochondrial-related and p38MAPK pathways.
Changes in Primary and Secondary Metabolite Levels in Response to Gene Targeting-Mediated Site-Directed Mutagenesis of the Anthranilate Synthase Gene in Rice
Authors: Saika Hiroaki , Oikawa Akira , Nakabayashi Ryo , Matsuda Fumio , Saito Kazuki , Toki Seiichi
Published: December 2012

Gene targeting (GT) via homologous recombination allows precise modification of a target gene of interest. In a previous study, we successfully used GT to produce rice plants accumulating high levels of free tryptophan (Trp) in mature seeds and young leaves via targeted modification of a gene encoding anthranilate synthase—a key enzyme of Trp biosynthesis. Here, we performed metabolome analysis in the leaves and mature seeds of GT plants. Of 72 metabolites detected in both organs, a total of 13, including Trp, involved in amino acid metabolism, accumulated to levels >1.5-fold higher than controls in both leaves and mature seeds of GT plants. Surprisingly, the contents of certain metabolites valuable for both humans and livestock, such as γ-aminobutyric acid and vitamin B, were significantly increased in mature seeds of GT plants. Moreover, untargeted analysis using LC-MS revealed that secondary metabolites, including an indole alkaloid, 2-[2-hydroxy-3-β-d-glucopyranosyloxy-1-(1H-indol-3-yl)propyl] tryptophan, also accumulate to higher levels in GT plants. Some of these metabolite changes in plants produced via GT are similar to those observed in plants over expressing mutated genes, thus demonstrating that in vivo protein engineering via GT can be an effective approach to metabolic engineering in crops.
Accompagner plutôt qu'enseigner le business plan : bilan d'une expérimentation pédagogique
Authors: Verzat Caroline , Granger Benoît
Published: December 2012

Résumé Le business plan est un dispositif controversé dans l’enseignement de l’entrepreneuriat. Une expérimentation réalisée auprès d’étudiants de 3 e année de Bachelor à Novancia est ici présentée et discutée. Le dispositif mis en œuvre apparait comme un « entre-deux » original entre le monde académique et le monde professionnel, à la frontière du business plan et du business model. Il met en œuvre un processus d’accompagnement sur mesure dans un groupe bienveillant, qui autorise davantage le développement d’identités entrepreneuriales que la création d’entreprises par les étudiants.
Three-Dimensional Visualization of the Mouse Thymus Organization in Health and Immunodeficiency
Authors: Irla Magali , Guenot Jeanne , Sealy Gregg , Reith Walter , Imhof Beat A. , Sergé Arnauld
Published: December 2012

Lymphoid organs exhibit complex structures tightly related to their function. Surprisingly, although the thymic medulla constitutes a specialized microenvironment dedicated to the induction of T cell tolerance, its three-dimensional topology remains largely elusive because it has been studied mainly in two dimensions using thymic sections. To overcome this limitation, we have developed an automated method for full organ reconstruction in three dimensions, allowing visualization of intact mouse lymphoid organs from a collection of immunolabeled slices. We validated full organ reconstruction in three dimensions by reconstructing the well-characterized structure of skin-draining lymph nodes, before revisiting the complex and poorly described corticomedullary organization of the thymus. Wild-type thymi contain ∼200 small medullae that are connected to or separated from a major medullary compartment. In contrast, thymi of immunodeficient Rag2−/− mice exhibit only ∼20 small, unconnected medullary islets. Upon total body irradiation, medullary complexity was partially reduced and then recovered upon bone marrow transplantation. This intricate topology presents fractal properties, resulting in a considerable corticomedullary area. This feature ensures short distances between cortex and medulla, hence efficient thymocyte migration, as assessed by mathematical models. Remarkably, this junction is enriched, particularly in neonates, in medullary thymic epithelial cells expressing the autoimmune regulator. The emergence of a major medullary compartment is induced by CD4+ thymocytes via CD80/86 and lymphotoxin-α signals. This comprehensive three-dimensional view of the medulla emphasizes a complex topology favoring efficient interactions between developing T cells and autoimmune regulator–positive medullary thymic epithelial cells, a key process for central tolerance induction.
IL-33 Induces a Hyporesponsive Phenotype in Human and Mouse Mast Cells
Authors: Jung Mi-Yeon , Smrž Daniel , Desai Avanti , Bandara Geethani , Ito Tomonobu , Iwaki Shoko , Kang Jeong-Han , Andrade Marcus V. , Hilderbrand Susana C. , Brown Jared M. , Beaven Michael A. , Metcalfe Dean D. , Gilfillan Alasdair M.
Published: December 2012

IL-33 is elevated in afflicted tissues of patients with mast cell (MC)–dependent chronic allergic diseases. Based on its acute effects on mouse MCs, IL-33 is thought to play a role in the pathogenesis of allergic disease through MC activation. However, the manifestations of prolonged IL-33 exposure on human MC function, which best reflect the conditions associated with chronic allergic disease, are unknown. In this study, we found that long-term exposure of human and mouse MCs to IL-33 results in a substantial reduction of MC activation in response to Ag. This reduction required >72 h exposure to IL-33 for onset and 1–2 wk for reversion following IL-33 removal. This hyporesponsive phenotype was determined to be a consequence of MyD88-dependent attenuation of signaling processes necessary for MC activation, including Ag-mediated calcium mobilization and cytoskeletal reorganization, potentially as a consequence of downregulation of the expression of phospholipase Cγ1 and Hck. These findings suggest that IL-33 may play a protective, rather than a causative, role in MC activation under chronic conditions and, furthermore, reveal regulated plasticity in the MC activation phenotype. The ability to downregulate MC activation in this manner may provide alternative approaches for treatment of MC-driven disease.
Cutting Edge: Chronic Inflammatory Liver Disease in Mice Expressing a CD28-Specific Ligand
Authors: Corse Emily , Gottschalk Rachel A. , Park Joon Seok , Sepulveda Manuel A. , Loke P’ng , Sullivan Timothy J. , Johnson Linda K. , Allison James P.
Published: December 2012

Inflammation of the normally tolerant liver microenvironment precedes the development of chronic liver disease. Study of the pathogenesis of autoimmune liver diseases, such as autoimmune hepatitis (AIH), has been hampered by a lack of autochthonous chronic animal models. Through our studies of T cell costimulation, we generated transgenic mice expressing a ligand specific for the CD28 receptor, which normally shares ligands with the related inhibitory receptor CTLA-4. The mice spontaneously develop chronic inflammatory liver disease with several pathologies found in AIH, including elevated serum aminotransferases in the context of normal alkaline phosphatase and bilirubin levels, lymphocytic inflammation, focal necrosis, oval cell hyperplasia, and fibrosis. The prevalence of IFN-γ–producing CD8+ T cells in the livers of transgenic mice suggests a role for autoimmune cytotoxicity in the chronic disease state. The CD28 ligand–specific transgenic mice will facilitate evaluation of CD8+ T cell function in liver disease pathologies found in AIH.