bluuebunny/crossref_metadata_2025 huggingface dataset:
Estrogen replacement and skeletal muscle: mechanisms and population health
Authors: Tiidus Peter M. , Lowe Dawn A. , Brown Marybeth
Published: July 2013

There is a growing body of information supporting the beneficial effects of estrogen and estrogen-based hormone therapy (HT) on maintenance and enhancement of muscle mass, strength, and connective tissue. These effects are also evident in enhanced recovery from muscle atrophy or damage and have significant implications particularly for the muscular health of postmenopausal women. Evidence suggests that HT will also help maintain or increase muscle mass, improve postatrophy muscle recovery, and enhance muscle strength in aged females. This is important because this population, in particular, is at risk for a rapid onset of frailty. The potential benefits of estrogen and HT relative to skeletal muscle function and composition combined with other health-related enhancements associated with reduced risk of cardiovascular events, overall mortality, and metabolic dysfunction, as well as enhanced cognition and bone health cumulate in a strong argument for more widespread and prolonged consideration of HT if started proximal to menopausal onset in most women. Earlier reports of increased health risks with HT use in postmenopausal women has led to a decline in HT use. However, recent reevaluation regarding the health effects of HT indicates a general lack of risks and a number of significant health benefits of HT use when initiated at the onset of menopause. Although further research is still needed to fully delineate its mechanisms of action, the general use of HT by postmenopausal women, to enhance muscle mass and strength, as well as overall health, with initiation soon after the onset of menopause should be considered.
Central common drive to antagonistic ankle muscles in relation to short-term cocontraction training in nondancers and professional ballet dancers
Authors: Geertsen S. S. , Kjær M. , Pedersen K. K. , Petersen T. H. , Perez M. A. , Nielsen J. B.
Published: July 2013

Optimization of cocontraction of antagonistic muscles around the ankle joint has been shown to involve plastic changes in spinal and cortical neural circuitries. Such changes may explain the ability of elite ballet dancers to maintain a steady balance during various ballet postures. Here we investigated whether short-term cocontraction training in ballet dancers and nondancers leads to changes in the coupling between antagonistic ankle motor units. Eleven ballet dancers and 10 nondancers were recruited for the study. Prior to training, ballet dancers and nondancers showed an equal amount of coherence in the 15- to 35-Hz frequency band and short-term synchronization between antagonistic tibialis anterior and soleus motor units. The ballet dancers tended to be better at maintaining a stable cocontraction of the antagonistic muscles, but this difference was not significant ( P = 0.09). Following 27 min of cocontraction training, the nondancers improved their performance significantly, whereas no significant improvement was observed for the ballet dancers. The nondancers showed a significant increase in 15- to 35-Hz coherence following the training, whereas the ballet dancers did not show a significant change. A group of control subjects ( n = 4), who performed cocontraction of the antagonistic muscles for an equal amount of time, but without any requirement to improve their performance, showed no change in coherence. We suggest that improved ability to maintain a stable cocontraction around the ankle joint is accompanied by short-term plastic changes in the neural drive to the involved muscles, but that such changes are not necessary for maintained high-level performance.
Epimorphin Is a Novel Regulator of the Progesterone Receptor Isoform-A
Authors: Bascom Jamie L. , Radisky Derek C. , Koh Eileen , Fata Jimmie E. , Lo Alvin , Mori Hidetoshi , Roosta Neda , Hirai Yohei , Bissell Mina J.
Published: July 2013

Epimorphin/syntaxin-2 is a membrane-tethered protein localized extracellularly (Epim) and intracellularly (Stx-2). The extracellular form Epim stimulates morphogenic processes in a range of tissues, including in murine mammary glands where its overexpression in luminal epithelial cells is sufficient to drive hyperplasia and neoplasia. We analyzed WAP-Epim transgenic mice to gain insight into how Epim promotes malignancy. Ectopic overexpression of Epim during postnatal mammary gland development led to early side-branching onset, precocious bud formation, and increased proliferation of mammary epithelial cells. Conversely, peptide-based inhibition of Epim function reduced side branching. Because increased side branching and hyperplasia occurs similarly in mice upon overexpression of the progesterone receptor isoform-a (Pgr-a), we investigated whether Epim exhibits these phenotypes through Pgr modulation. Epim overexpression indeed led to a steep upregulation of both total Pgr mRNA and Pgr-a protein levels. Notably, the Pgr antagonist RU486 abrogated Epim-induced ductal side branching, mammary epithelial cell proliferation, and bud formation. Evaluation of Epim signaling in a three-dimensional ex vivo culture system showed that its action was dependent on binding to its extracellular receptor, integrin-αV, and on matrix metalloproteinase 3 activity downstream of Pgr-a. These findings elucidate a hitherto unknown transcriptional regulator of Pgr-a, and shed light on how overexpression of Epim leads to malignancy. Cancer Res; 73(18); 5719–29. ©2013 AACR.
Stem Cell Differentiation and Lumen Formation in Colorectal Cancer Cell Lines and Primary Tumors
Authors: Ashley Neil , Yeung Trevor M. , Bodmer Walter F.
Published: July 2013

Single cancer stem–like cells (CSC) from colorectal cancers can be functionally identified by their ability to form large lumen-containing colonies in three-dimensional Matrigel cultures. These colonies contain the three types of differentiated colorectal epithelial cells, and single cells obtained from them can reproduce themselves and form tumors efficiently in immunodeficient mice. In this study, we show how hypoxia affects these CSC-derived lumens to control differentiation of stem-like cells and enterocytes via the homeobox gene CDX1. Lumens were identified by F-actin staining and they expressed many characteristics associated with normal differentiated intestinal epithelium, including brush border enzymes, polarization, and tight junctions. RNA interference–mediated silencing of CDX1 reduced lumen formation. Inhibitory effects of hypoxia on lumen formation and stem cell differentiation, including suppression of CDX1 expression, could be mimicked by inhibiting prolyl-hydroxylases that activate HIF1, suggesting that HIF1 is a critical mediator of the effects of hypoxia in this setting. Cell line–derived lumens were phenotypically indistinguishable from colorectal tumor glandular structures used by pathologists to grade tumor differentiation. Parallel results to those obtained with established cell lines were seen with primary cultures from fresh tumors. This in vitro approach to functional characterization of CSCs and their differentiation offers a valid model to study colorectal tumor differentiation and differentiation of colorectal CSCs, with additional uses to enable high-throughput screening for novel anticancer compounds. Cancer Res; 73(18); 5798–809. ©2013 AACR.
Rapid Induction of Lung Adenocarcinoma by Fibroblast Growth Factor 9 Signaling through FGF Receptor 3
Authors: Yin Yongjun , Betsuyaku Tomoko , Garbow Joel R. , Miao Jinbai , Govindan Ramaswamy , Ornitz David M.
Published: July 2013

Fibroblast growth factors (FGF) are expressed in many non–small cell lung carcinoma (NSCLC) primary tumors and derived cell lines, and mutations in FGF receptor 3 (FGFR3) have been identified in human lung adenocarcinoma. FGF9 has been implicated in the pathogenesis of NSCLC by synergizing with EGFR pathways or by providing an escape pathway mediating resistance to EGFR inhibition. To model pathogenic mechanisms mediated by FGF signals, we have established a mouse model in which FGF9 expression can be induced in adult lung epithelium. Here, we show that induced expression of FGF9 in adult lung leads to the rapid proliferation of distal airway epithelial cells that express the stem cell marker, Sca-1, and the proximal and distal epithelial markers, Sftpc and CC10, the rapid formation of Sftpc-positive adenocarcinomas, and eventual metastasis in some mice. Furthermore, we have identified FGFR3 as the obligate receptor mediating the FGF9 oncogenic signal. These results identify an FGF9–FGFR3 signal as a primary oncogenic pathway for lung adenocarcinoma and suggest that this pathway could be exploited for customized therapeutic applications for both primary tumors and those that have acquired resistance to inhibition of other signaling pathways. Cancer Res; 73(18); 5730–41. ©2013 AACR.
A High-Throughput Functional Complementation Assay for Classification ofBRCA1Missense Variants
Authors: Bouwman Peter , van der Gulden Hanneke , van der Heijden Ingrid , Drost Rinske , Klijn Christiaan N. , Prasetyanti Pramudita , Pieterse Mark , Wientjens Ellen , Seibler Jost , Hogervorst Frans B.L. , Jonkers Jos
Published: July 2013

Mutations in BRCA1 and BRCA2 account for the majority of hereditary breast and ovarian cancers, and therefore sequence analysis of both genes is routinely conducted in patients with early-onset breast cancer. Besides mutations that clearly abolish protein function or are known to increase cancer risk, a large number of sequence variants of uncertain significance (VUS) have been identified. Although several functional assays for BRCA1 VUSs have been described, thus far it has not been possible to conduct a high-throughput analysis in the context of the full-length protein. We have developed a relatively fast and easy cDNA-based functional assay to classify BRCA1 VUSs based on their ability to functionally complement BRCA1-deficient mouse embryonic stem cells. Using this assay, we have analyzed 74 unclassified BRCA1 missense mutants for which all predicted pathogenic variants are confined to the BRCA1 RING and BRCT domains.

Significance: BRCA1 VUSs are frequently found in patients with hereditary breast or ovarian cancer and present a serious problem for clinical geneticists. This article describes the generation, validation, and application of a reliable high-throughput assay for the functional classification of BRCA1 sequence variants of uncertain significance. Cancer Discov; 3(10); 1142–55. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 1083
Lack of Association of Homocysteine Concentrations with Oxidative Stress, Alterations in Carotid Intima Media Thickness and Endothelial Reactivity in Prepubertal Children
Authors: Suano de Souza Fabíola Isabel , D'Almeida Vânia , Fonseca Fernando Luiz Affonso , Hix Sonia , Miranda Robson , Gomes de Torres Rossi Rosana , Ribeiro Renata , Saccardo Sarni Roseli Oselka
Published: July 2013

Background and Aims: Our purpose was to assess the presence of risk factors for cardiovascular diseases (alterations in the lipid profile, fasting glycaemia, high arterial pressure values, oxidative stress, increased intima media thickness and impaired endothelium-dependent vasodilation) in prepubertal children with elevated homocysteine (Hcy) levels. Methods: In a cross-sectional study, 35 children with Hcy levels ≥7.3 μmol/l were matched by gender and age with 29 children with Hcy levels ≤4.1 μmol/l. Our collected data included weight, height, waist circumference, systemic arterial pressure, lipid profile, fasting glycaemia and oxidative stress markers. A Doppler ultrasound was performed to measure the carotid intima media thickness and the endothelium-dependent vasodilation of the brachial artery. Results: There were no statistically significant differences between the groups regarding the lipid profile and fasting glycaemia, blood pressure or oxidative stress. Overweight and obesity (body mass index z-score > +1) were more frequent in the group with Hcy ≥7.3 μmol/l when compared to the group with Hcy ≤4.1 μmol/l [13/35 (37.1%) vs. 4/29 (13.8%); p = 0.035]. After adjusting for nutritional status, there were no differences in the intima media thickness and endothelium-dependent vasodilation between children with high and low Hcy levels. Conclusions: Among the cardiovascular risk factors investigated in the present study, which was based on prepubertal children, only overweight and obesity were associated with increased Hcy concentrations (≥7.3 μmol/l).
Safety and Efficacy of Modified FOLFOX6 plus High-Dose Bevacizumab in Second-Line or Later Treatment of Patients with Metastatic Colorectal Cancer
Authors: Takii Yasumasa , Maruyama Satoshi
Published: July 2013

Aim: The aim of this retrospective study was to show the efficacy and safety of modified FOLFOX6 plus high-dose bevacizumab (10 mg/kg/2 weeks) in the second-line or later treatment of metastatic colorectal cancer. Methods: A total of 24 consecutive patients treated between August 2007 and August 2009 were included in this retrospective study. None of the patients had received bevacizumab as part of prior treatment. Results: All 24 patients received modified FOLFOX6 plus high-dose bevacizumab and were followed for a median of 36.9 months. Overall response rate was 29%. Median progression-free survival was 7.5 months, and median overall survival was 17.3 months. Grade 3/4 adverse events were: neutropenia (54.2%), leukopenia (25.0%), neuropathy (12.5%), hypertension (12.5%), thrombocytopenia (8.3%), and decreased haemoglobin, gastrointestinal haemorrhage, wound complications, nausea, diarrhoea, mucositis and fatigue (each 4.2%). Conclusion: Modified FOLFOX6 plus high-dose bevacizumab may be useful in the second-line treatment of patients with metastatic colorectal cancer who have not received bevacizumab.
Neurological Soft Signs and Brainstem Morphology in First-Episode Schizophrenia
Authors: Hirjak Dusan , Wolf Robert Christian , Stieltjes Bram , Hauser Thomas , Seidl Ulrich , Thiemann Ulf , Schröder Johannes , Thomann Philipp Arthur
Published: July 2013

Background: Minor motor and sensory deficits or neurological soft signs (NSS) have frequently been reported in patients with schizophrenia at any stage of their illness. NSS have been demonstrated to correlate with neuroanatomical abnormalities in various brain regions. Despite its important role in the integration and coordination of automatic motor actions, the brainstem has so far rather been ignored in previous neuroimaging studies on NSS in schizophrenia. Method: We investigated 21 right-handed first-episode schizophrenia patients using high-resolution magnetic resonance imaging at 3 T. The severity of NSS was measured with the Heidelberg Scale. Associations between NSS and both brainstem volume and shape changes were examined. Results: Higher NSS scores were significantly associated with structural alterations in the brainstem. According to volume measurements higher NSS scores correlated with global changes of the brainstem. Using shape analyses these associations referred to regionally specific morphometric alterations predominantly in the midbrain and pons. Conclusion: The findings suggest that brainstem morphometric alterations are associated with the severity of NSS in patients with first-episode schizophrenia. They further indicate the involvement of the brainstem in the pathogenesis of schizophrenia.
Effects of Tiotropium and Salmeterol/Fluticasone Propionate on Airway Wall Thickness in Chronic Obstructive Pulmonary Disease
Authors: Hoshino Makoto , Ohtawa Junichi
Published: July 2013

Background: Triple inhalation therapy with tiotropium (Tio) and salmeterol/fluticasone propionate combination (SFC) is widely used in the treatment of chronic obstructive pulmonary disease (COPD). However, the effects of triple therapy on airway structural changes remain unknown. Objective: The aim of the study was to assess the effects of Tio, salmeterol (SM), SFC and Tio plus SFC on airway dimensions in COPD. Methods: A randomized, open-label, 4-way study (n = 60) was conducted comparing 16-week treatment periods of Tio (18 μg once daily), SM (50 μg twice daily), SFC (50/250 μg twice daily) and Tio (18 μg once daily) plus SFC (50/250 μg twice daily). Airway dimensions were assessed by a validated CT technique, and airway wall area (WA) corrected for body surface area (BSA), percentage WA (WA%), wall thickness/√BSA and luminal area (Ai)/BSA at the right apical segmental bronchus were measured. Pulmonary function and the St. George's Respiratory Questionnaire (SGRQ) were evaluated. Results: Tio plus SFC resulted in a significant decrease in WA corrected for BSA and WA% compared with Tio, SM and SFC (p < 0.05 for all). The changes in WA% and Ai/BSA were significantly correlated with changes in forced expiratory volume in 1 s (r = -0.86, p < 0.001, and r = 0.48, p < 0.05, respectively). There were more significant improvements in SGRQ scores after treatment with triple therapy than after the 3 other treatments. Conclusions: Tio plus SFC therapy is more effective than Tio, SM and SFC for reducing airway wall thickness in COPD.
Potential Interactions with Anticancer Agents: A Cross-Sectional Study
Authors: Mouzon A. , Kerger J. , D'Hondt L. , Spinewine A.
Published: July 2013

Background: Patients with cancer are particularly susceptible to drug interactions (DIs), but the extent of the problem has received limited attention. We aimed to evaluate the frequency of interactions with anticancer agents in a group of cancer patients. Methods: The study was performed in a Belgian teaching hospital. One hundred and twenty-two patients with solid malignancies were included. A comprehensive drug history was performed by a clinical pharmacist. Three renowned DI compendia were used to identify DIs. Results: Forty-one potential interactions involving an anticancer agent and considered to be clinically significant were identified among 25% of patients. The anticancer drugs mostly involved were cisplatin and methotrexate, and the most frequent co-medications involved were vitamin K antagonists, proton pump inhibitors and diuretics. In the majority of cases, the potential adverse consequence was increased toxicity of the anticancer agent and/or of the co-medication. Less than 10% of DIs were identified by the three compendia. Conclusions: Preventive measures should be taken to avoid increased toxicity or decreased efficacy of the drugs. Most of the time, this simply involves surveillance of biological or clinical parameters. Collaboration with a clinical pharmacist may be useful for the prescribing physician.
N-Terminal Pro-B-type Natriuretic Peptide and Its Correlation to Haemodialysis-Induced Myocardial Stunning
Authors: Breidthardt Tobias , Burton James O. , Odudu Aghogho , Eldehni Mohamed Tarek , Jefferies Helen , McIntyre Christopher W.
Published: July 2013

Background: Haemodialysis (HD) is able to induce recurrent myocardial ischemia and segmental left-ventricular dysfunction (myocardial stunning). The association of N-terminal Pro-B-type natriuretic peptide (NTpro-BNP) with HD-induced myocardial stunning is unclear. Methods: In 70 prevalent HD patients, HD-induced myocardial stunning was assessed echocardiographically at baseline and after 12 months. The extent to which pre-dialysis NTpro-BNP was associated with the occurrence of HD-induced myocardial stunning was assessed as the primary endpoint. Results: The median Ntpro-BNP concentration in this cohort was 2,154 pg/ml (IQR 1,224-3,014). Patients experiencing HD-induced myocardial stunning at either time point displayed elevated NTpro-BNP values (2,418 pg/ml, IQR, 1,583-3,474 vs. 1,751 pg/ml, IQR (536-2,029), p = 0.02). NTpro-BNP levels did not differ between patients showing HD-induced stunning at baseline and those developing stunning during the observational period (p = 0.8). NTpro-BNP levels drawn at the beginning of the dialysis session achieved a poor diagnostic accuracy for the detection of myocardial stunning (area under the ROC curve 0.61, 95% CI 0.45-0.77), but provided an accurate rule out for myocardial stunning during the subsequent year (AUC 0.85, 95% CI 0.70-0.99). The calculated cut-off of 1,570 pg/ml achieved a sensitivity of 66% and a specificity of 78% for the exclusion of myocardial stunning at any time point. In logistic regression analysis, only low NTpro-BNP levels (OR 0.92 for every additional 100 pg/ml, 95% CI 0.85-0.99, p = 0.03) were significantly associated with absence of myocardial stunning at any time point. Conclusion: Predialytic NTpro-BNP levels fail to adequately diagnose current dialysis-induced myocardial stunning, but help to identify patients with a propensity to develop dialysis-induced myocardial stunning at any time during the next 12 months.
On-Demand Proton Pump Inhibitory Treatment in Overweight/Obese Patients with Gastroesophageal Reflux Disease: Are There Pharmacodynamic Arguments for Using Higher Doses?
Authors: Bruley des Varannes Stanislas , Coudsy Bogdana , Waechter Sandra , DeLemos Byron , Xiang Jim , LoCoco John , Ducrotté Philippe
Published: July 2013

Background: Increased body mass index (BMI) is associated with a higher risk of gastroesophageal reflux disease (GORD). Aim: To investigate whether overweight/obesity affects proton pump inhibitor pharmacodynamics when used in a single dose in patients with GORD. Methods: Post hoc analyses by patient BMI were performed on data from two single-center, double-blind, single-dose, crossover studies comparing the pharmacodynamics of rabeprazole 20 mg and pantoprazole 40 mg in GORD patients with a history of nocturnal heartburn. The primary endpoint was the mean percentage of time with intragastric pH >4 between lean and overweight/obese patients (BMI <25 and ≥25). Results: 24 h baseline intragastric pH values were not different between BMI groups. The pharmacodynamic effects of both proton pump inhibitors were not significantly different between BMI groups, and no evidence was found for an interaction between BMI and treatment. As compared with pantoprazole, rabeprazole showed a significantly greater effect on the antisecretory response for both BMI groups. Conclusions: Overweight/obesity in GORD patients does not appear to affect the antisecretory efficacy of a single dose of rabeprazole and pantoprazole. These data do not support adapting the dosage of rabeprazole and pantoprazole according to BMI in GORD patients when administered as an on-demand therapy schedule.
Diffusion-Weighted Magnetic Resonance Imaging for Predicting and Detecting the Early Response to Chemoradiotherapy of Advanced Esophageal Squamous Cell Carcinoma
Authors: Imanishi Shunsuke , Shuto Kiyohiko , Aoyagi Tomoyoshi , Kono Tsuguaki , Saito Hiroshige , Matsubara Hisahiro
Published: July 2013

Background: The aim of this study was to investigate the utility of the apparent diffusion coefficient (ADC) value in diffusion-weighted magnetic resonance imaging (DWMRI) for prediction and early detection of treatment response in advanced esophageal squamous cell carcinoma. Method: DWMRI was performed in 27 patients with primary cT4 esophageal carcinoma that were undergoing chemoradiotherapy before treatment and after 20 and 40 Gy. We calculated tumor ADCs and association of the treatment effect between responders and nonresponders. Results: The ADC at the time of 20 Gy was significantly higher in responders compared to nonresponders (1.13 vs. 0.93; p = 0.005). The ADC cut-off value was set at 1.00 × 10-3 mm2/s and the ADC predicted the responders with a sensitivity, positive predictive value and accuracy of 79, 73 and 74%, respectively. The increased rate of the ADC at the time of 20 Gy (ΔADC20) was also significantly higher in responders compared to nonresponders (35.4 vs. 1.5%; p = 0.0007). An ADC cut-off value for ΔADC20 of 15% predicted the responders with a sensitivity, positive predictive value and accuracy of 71, 100 and 85%, respectively. Conclusion: The ADC values predicted the prognosis of patients with advanced esophageal squamous cell carcinoma as well as the treatment response.
Prevalence and Factors Associated with Neck and Jaw Muscle Modulation of Tinnitus
Authors: Won Jun Yeon , Yoo Shinyoung , Lee Seok Ki , Choi Hyun Kyung , Yakunina Natalia , Le Quang , Nam Eui-Cheol
Published: July 2013

Forceful contractions of neck and jaw muscles have consistently been shown to modulate tinnitus and can be used to screen patients who are responsive to somatic stimulation and, therefore, optimal candidates for somatosensory-based treatment. To identify the factors associated with somatic modulation of tinnitus, 163 patients underwent 19 neck and jaw maneuvers after an extensive physiological and audiological profile was compiled. Overall, tinnitus was modulated in 57.1% of ears tested. Unilateral tinnitus showed greater prevalence of modulation. Neck maneuvers generally decreased tinnitus loudness, whereas jaw maneuvers increased loudness. Female gender and buzzing tinnitus were associated with a high prevalence of modulation and a decrease in tinnitus loudness. Loud tinnitus and low-pitched tonal tinnitus were associated with exacerbation of the condition as a result of somatic testing. Use of these characteristics to select optimal candidates for somatosensory-based tinnitus therapies may be essential for the development of an effective approach for tinnitus treatment.
Dominant Form of Congenital Hyperinsulinism Maps to HK1 Region on 10q
Authors: Pinney Sara E. , Ganapathy Karthik , Bradfield Jonathan , Stokes David , Sasson Ariella , Mackiewicz Katarzyna , Boodhansingh Kara , Hughes Nkecha , Becker Susan , Givler Stephanie , Macmullen Courtney , Monos Dimitrios , Ganguly Arupa , Hakonarson Hakon , Stanley Charles A.
Published: July 2013

Background/Aims: In a family with congenital hyperinsulinism (HI), first described in the 1950s by McQuarrie, we examined the genetic locus and clinical phenotype of a novel form of dominant HI. Methods: We surveyed 25 affected individuals, 7 of whom participated in tests of insulin dysregulation (24-hour fasting, oral glucose and protein tolerance tests). To identify the disease locus and potential disease-associated mutations we performed linkage analysis, whole transcriptome sequencing, whole genome sequencing, gene capture, and next generation sequencing. Results: Most affecteds were diagnosed with HI before age one and 40% presented with a seizure. All affecteds responded well to diazoxide. Affecteds failed to adequately suppress insulin secretion following oral glucose tolerance test or prolonged fasting; none had protein-sensitive hypoglycemia. Linkage analysis mapped the HI locus to Chr10q21-22, a region containing 48 genes. Three novel noncoding variants were found in hexokinase 1 (HK1) and one missense variant in the coding region of DNA2. Conclusion: Dominant, diazoxide-responsive HI in this family maps to a novel locus on Chr10q21-22. HK1 is the more attractive disease gene candidate since a mutation interfering with the normal suppression of HK1 expression in beta-cells could readily explain the hypoglycemia phenotype of this pedigree.
Electroconvulsive Therapy Improves Clinical Manifestation with Plasma BDNF Levels Unchanged in Treatment-Resistant Depression Patients
Authors: Lin Ching-Hua , Chen Ming-Chao , Lee Wen-Kuei , Chen Cheng-Chung , Huang Chiung-Hsien , Lane Hsien-Yuan
Published: July 2013

Electroconvulsive therapy (ECT) is the most effective treatment in treatment-resistant depression; it may modulate intracellular processes in such patients. This study aimed to investigate the association between changes in plasma brain-derived neurotrophic factor (BDNF) levels and the clinical improvements after ECT for patients with treatment-resistant depression. Fifty-five inpatients with treatment-resistant depression were recruited. The severity of depression was measured using the 17-item Hamilton Rating Scale for Depression (HAMD-17) and the Clinical Global Impression-Severity (CGI-S) before ECT, after every 3 sessions of ECT, and at the end of ECT. Plasma BDNF levels were measured in all subjects before and after ECT. The severity of depression was significantly reduced on the HAMD-17 (p < 0.001) and the CGI-S (p < 0.001) after the end of ECT. There were no significant differences in plasma BDNF levels after ECT (p = 0.615). No significant correlation was found between changes in plasma BDNF levels and changes in HAMD-17 scores (r = 0.188, p = 0.169). Our results do not support the hypothesis that improvements in treatment-resistant depression patients after ECT are due to changes in BDNF levels.
The Pain Pathway in the Rat following Noxious Thermal Stimulation: Effect of Morphine on pERK1/2 and TRPV1 at the Dorsal Horn Level, and on Hyperalgesia
Authors: Donnerer Josef , Liebmann Ingrid
Published: July 2013

The aim of the present study was to investigate the phosphorylation of ERK1/2 in the lumbar dorsal horn of the rat by fluorescence immunohistochemistry following a noxious thermal stimulation of the hind paw. The protein level of TRPV1 in the dorsal spinal cord and the development of a heat hyperalgesia after the acute noxious thermal stimulation were also measured. The protein content of TRPV1 was determined by Western blot and heat hyperalgesia by the plantar test. At 2 and 10 min after the thermal stimulation a 4-fold increase in pERK1/2 immunoreactivity was observed in cells of lamina I/II of the L3-L5 dorsal horn. A pretreatment with the opioid analgesic morphine markedly attenuated ERK1/2 phosphorylation. The protein content of TRPV1 in the lumbar dorsal spinal cord was not significantly altered at 1 and 4 h after the thermal hind paw stimulation and by the morphine pretreatment. Heat hyperalgesia in the plantar test was observed at 8 h, but not at 24 h after the noxious stimulation. This temporary hyperalgesia was prevented by the morphine pretreatment. The present findings indicate that ERK1/2 activation in dorsal horn nociceptive neurons may be linked to the development of hyperalgesia, and that opioid analgesics are effective agents to prevent sensitization in the pain pathway at spinal level.
Association between Alanine Aminotransferase and Intracerebral Hemorrhage in East Asian Populations
Authors: Kim Hyeon Chang , Oh Sun Min , Pan Wen-Harn , Ueshima Hirotsugu , Gu Dongfeng , Chuang Shao-Yuan , Fujiyoshi Akira , Li Ying , Zhao Liancheng , Suh Il ,   on behalf of the East Asian Network for Stroke Prevention Study group
Published: July 2013

Background: Intracerebral hemorrhage (ICH) and chronic liver disease are relatively common in East Asian countries. However, the relationship between the two diseases is unclear. Thus, we investigated the association between serum alanine aminotransferase (ALT) levels and ICH risk in East Asian populations. Methods: The East Asian Network for Stroke Prevention enrolled 279,982 participants with ALT measurements from four cohort studies in Korea, Taiwan, Japan and mainland China. Among them, 1,324 ICH events and 493 ICH deaths were observed. Cox's proportional hazard regression analysis was performed in each cohort to estimate the hazard ratio (HR) after adjusting for age, blood pressure, diabetes, total cholesterol, smoking and alcohol intake. Combined HRs were then estimated using pooled analyses with fixed-effects models. Results: The multivariate-adjusted pooled HRs (with 95% confidence interval, CI) for ICH incidence per 10 IU/l increments of ALT were 1.04 (1.03-1.04) in men and 1.01 (0.98-1.04) in women. Corresponding HRs for ICH mortality were 1.04 (1.02-1.05) in men and 1.04 (1.00-1.08) in women. The pooled HRs for ICH incidence in participants with ALT levels greater than or equal to 50 IU/l compared to those with levels less than 20 IU/l were 1.74 (1.41-2.16) in men and 1.60 (1.06-2.40) in women. The corresponding HRs for ICH mortality were 1.72 (1.21-2.44) in men and 1.63 (0.79-3.36) in women. Conclusions: An elevated ALT level was independently and significantly associated with an increased risk of ICH in East Asian men, but the association was less prominent in women.
Insulin Resistance Is Associated With Significant Clinical Atherosclerosis in Nondiabetic Patients With Acute Myocardial Infarction
Authors: Karrowni Wassef , Li Yan , Jones Philip G. , Cresci Sharon , Abdallah Mouin S. , Lanfear David E. , Maddox Thomas M. , McGuire Darren K. , Spertus John A. , Horwitz Phillip A.
Published: July 2013

Objective—

The prevalence of insulin resistance (IR) is increasing worldwide because of increasing age, obesity, and physical inactivity. Emerging evidence supports a direct proatherogenic effect of IR on the coronary vasculature, but the relation between IR and angiographic atherosclerosis in a real-world clinical setting is uncertain. In this work, we assessed whether IR is independently associated with clinically significant angiographic atherosclerosis in nondiabetic individuals.

Approach and Results—

We examined the association between IR and the extent of coronary atherosclerosis determined by angiography in 1073 nondiabetic patients surviving acute myocardial infarction. Patients were divided into quartiles on the basis of the homeostasis model assessment grading of IR, and associations between IR and multivessel coronary artery disease, defined as ≥2 arteries with ≥70% stenosis (or ≥50% left main stenosis), were analyzed in bivariate and multivariable modeling. Overall, the cohort had a median age of 56 years; 28.9% women and 21.8% nonwhite. The crude prevalence of multivessel coronary artery disease was 37.8%, 42.3%, 47.2%, and 48.0% for homeostasis model assessment grading of IR quartiles 1, 2, 3, and 4, respectively (
P
trend
=0.009). In multivariable modeling, compared with quartile 1, both quartile 3 (relative risk [95% confidence interval], 1.31 [1.07–1.60]) and quartile 4 (1.29 [1.03–1.60]) were independently associated with multivessel coronary artery disease. Covariates in the model included patient demographic and clinical characteristics and metabolic factors (low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, triglyceride, glycosylated hemoglobin, and high-sensitivity C-reactive protein).

Conclusions—

We demonstrate an independent association between IR and multivessel coronary artery disease in nondiabetic postmyocardial infarction patients. Our findings strengthen the experimental evidence for a direct atherogenic effect of IR independent of glucose control and other components of the metabolic syndrome.
Pharmacological Inhibition of Phospholipase D Protects Mice From Occlusive Thrombus Formation and Ischemic Stroke—Brief Report
Authors: Stegner David , Thielmann Ina , Kraft Peter , Frohman Michael A. , Stoll Guido , Nieswandt Bernhard
Published: July 2013

Objective—

We recently showed that mice lacking the lipid signaling enzyme phospholipase (PL) D1 or both PLD isoforms (PLD1 and PLD2) were protected from pathological thrombus formation and ischemic stroke, whereas hemostasis was not impaired in these animals. We sought to assess whether pharmacological inhibition of PLD activity affects hemostasis, thrombosis, and thrombo-inflammatory brain infarction in mice.

Approach and Results—

Treatment of platelets with the reversible, small molecule PLD inhibitor, 5-fluoro-2-indolyl des-chlorohalopemide (FIPI), led to a specific blockade of PLD activity that was associated with reduced α-granule release and integrin activation. Mice that received FIPI at a dose of 3 mg/kg displayed reduced occlusive thrombus formation upon chemical injury of carotid arteries or mesenterial arterioles. Similarly, FIPI-treated mice had smaller infarct sizes and significantly better motor and neurological function 24 hours after transient middle cerebral artery occlusion. This protective effect was not associated with major intracerebral hemorrhage or prolonged tail bleeding times.

Conclusions—

These results provide the first evidence that pharmacological PLD inhibition might provide a safe therapeutic strategy to prevent arterial thrombosis and ischemic stroke.
Biomarkers of Dairy Fatty Acids and Risk of Cardiovascular Disease in the Multi‐Ethnic Study of Atherosclerosis
Authors: de Oliveira Otto Marcia C. , Nettleton Jennifer A. , Lemaitre Rozenn N. , M. Steffen Lyn , Kromhout Daan , Rich Stephen S. , Y. Tsai Michael , Jacobs David R. , Mozaffarian Dariush
Published: July 2013

Background

Evidence regarding the role of dairy fat intake in cardiovascular disease (
CVD
) has been mixed and inconclusive. Most earlier studies have used self‐reported measures of dietary intake and focused on relatively racially homogeneous populations. Circulating biomarkers of dairy fat in a multiethnic cohort provide objective measures of dairy fat intake and facilitate conclusions relevant to populations with different diets and susceptibility to
CVD
.

Methods and Results

In a multiethnic cohort of 2837
US
adults aged 45 to 84 years at baseline (2000–2002), phospholipid fatty acids including 15:0, 14:0, and
trans‐
16:1n7 were measured using standardized methods, and the incidence of
CVD
prospectively adjudicated. Self‐reported whole‐fat dairy and butter intakes had strongest associations with 15:0, rather than 14:0 or
trans‐
16:1n7. In multivariate models including demographics and lifestyle and dietary habits, each
SD
‐unit of 15:0 was associated with 19% lower
CVD
risk (hazard ratio [95%
CI
] 0.81 [0.68 to 0.98]) and 26% lower coronary heart disease (
CHD
) risk (0.74 [0.60 to 0.92]). Associations were strengthened after mutual adjustment for 14:0 and
trans
‐16:1n‐7 and were similar after adjustment for potential mediators. Plasma phospholipid 14:0 and
trans
‐16:1n‐7 were not significantly associated with incident
CVD
or
CHD
. All findings were similar in white, black,
H
ispanic, and
C
hinese American participants.

Conclusion

Plasma phospholipid 15:0, a biomarker of dairy fat, was inversely associated with incident
CVD
and
CHD
, while no association was found with phospholipid 14:0 and
trans‐
16:1n‐7. These findings support the need for further investigation of
CVD
effects of dairy fat, dairy‐specific fatty acids, and dairy products in general.
Intravenous Minocycline in Acute Stroke
Authors: Kohler Edith , Prentice David A. , Bates Timothy R. , Hankey Graeme J. , Claxton Anne , van Heerden Jolandi , Blacker David
Published: July 2013

Background and Purpose—

Minocycline, in animal models and 2 small randomized controlled human trials, is a promising neuroprotective agent in acute stroke. We analyzed the efficacy and safety of intravenous minocycline in acute ischemic and hemorrhagic stroke.

Methods—

A multicenter prospective randomized open-label blinded end point evaluation pilot study of minocycline 100 mg administered intravenously, commenced within 24 hours of onset of stroke, and continued 12 hourly for a total of 5 doses, versus no minocycline. All participants received routine stroke care. Primary end point was survival free of handicap (modified Rankin Scale, ≤2) at day 90.

Results—

Ninety-five participants were randomized; 47 to minocycline and 48 to no minocycline. In the intention-to-treat population, 29 of 47 (65.9%) allocated minocycline survived free of handicap compared with 33 of 48 (70.2%) allocated no minocycline (rate ratio, 0.94; 95% confidence interval, 0.71–1.25 and odds ratio, 0.73; 95% CI, 0.31–1.71). A meta-analysis of the 3 human trials suggests minocycline may increase the odds of handicap-free survival by 3-fold (odds ratio, 2.99; 95% CI, 1.74–5.16) but there was substantial heterogeneity among the trials.

Conclusions—

In this pilot study of a small sample of acute stroke patients, intravenous minocycline was safe but not efficacious. The study was not powered to identify reliably or exclude a modest but clinically important treatment effect of minocycline. Larger trials would improve the precision of the estimates of any treatment effect of minocycline.

Clinical Trial Registration—

URL:
http://www.anzctr.org.au
. Unique identifier: ACTRN12612000237886.
Inhibition of Calcium/Calmodulin-Dependent Protein Kinase Kinase β and Calcium/Calmodulin-Dependent Protein Kinase IV Is Detrimental in Cerebral Ischemia
Authors: McCullough Louise D. , Tarabishy Sami , Liu Lin , Benashski Sharon , Xu Yan , Ribar Thomas , Means Anthony , Li Jun
Published: July 2013

Background and Purpose—

Elevation of intracellular calcium was traditionally thought to be detrimental in stroke pathology. However, clinical trials testing treatments that block calcium signaling have failed to improve outcomes in ischemic stroke. Emerging data suggest that calcium may also trigger endogenous protective pathways after stroke. Calcium/calmodulin-dependent protein kinase kinase (CaMKK) is a major kinase activated by rising intracellular calcium. Compelling evidence has suggested that CaMKK and its downstream kinase CaMK IV are critical in neuronal survival when cells are under ischemic stress. We examined the functional role of CaMKK/CaMK IV signaling in stroke.

Methods—

We used a middle cerebral artery occlusion model in mice.

Results—

Our data demonstrated that pharmacological and genetic inhibition of CaMKK aggravated stroke injury. Additionally, deletion of CaMKK β, one of the 2 CaMKK isoforms, reduced CaMK IV activation, and CaMK IV deletion in mice worsened stroke outcome. Finally, CaMKK β or CaMK IV knockout mice had exacerbated blood–brain barrier disruption evidenced by increased hemorrhagic transformation and activation of matrix metalloproteinase. We observed transcriptional inactivation including reduced levels of histone deacetylase 4 phosphorylation in mice with CaMKK β or CaMK IV deletion after stroke.

Conclusions—

Our data have established that the CaMKK/CaMK IV pathway is a key endogenous protective mechanism in ischemia. Our results suggest that this pathway serves as an important regulator of blood–brain barrier integrity and transcriptional activation of neuroprotective molecules in stroke.
Retinal Microvascular Changes and Risk of Stroke
Authors: Cheung Carol Yim-lui , Tay Wan Ting , Ikram M. Kamran , Ong Yi Ting , De Silva Deidre A. , Chow Khuan Yew , Wong Tien Yin
Published: July 2013

Background and Purpose—

To examine the relationship between retinal microvascular measures and incident stroke in an Asian Malay population.

Methods—

We conducted a prospective, population-based cohort study of Asian Malay persons 40 to 80 years at baseline. Retinal microvascular signs were assessed from baseline retinal photographs including quantitative retinal microvascular parameters (caliber, branching angle, tortuosity, and fractal dimension) and qualitative retinopathy signs. Incident stroke cases were identified during the follow-up period. Cox proportional-hazards regression and incremental usefulness analysis (calibration, discrimination, and reclassification) were performed.

Results—

A total of 3189 participants were free of prevalent stroke at baseline. During the follow-up (median, 4.41 years), 51 (1.93%) participants had an incident stroke event. In Cox proportional-hazards models adjusting for established stroke predictors (age, sex, systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol, smoking, glycosylated hemoglobin, and antihypertensive medication), retinopathy (hazard ratio, 1.94; 95% confidence interval, 1.01–3.72) and larger retinal venular caliber (hazard ratio, 3.28; 95% confidence interval, 1.30–8.26, comparing fourth versus first quartiles) were associated with risk of stroke. Compared with the model with only established risk factors, the addition of retinal measures improved the prediction of stroke (C-Statistic 0.826 versus 0.792;
P
=0.017) and correctly reclassified 5.9% of participants with incident stroke and 3.4% of participants with no incident stroke.

Conclusions—

Retinal microvascular changes are related to an increased risk of stroke in Asian Malay, consistent with data from white populations. Retinal imaging improves the discrimination and stratification of stroke risk beyond that of established risk factors by a significant but small margin.
Age-Dependent Exacerbation of White Matter Stroke Outcomes
Authors: Rosenzweig Shira , Carmichael S. Thomas
Published: July 2013

Background and Purpose—

Subcortical white matter stroke (WMS) constitutes up to 30% of all stroke subtypes. Mechanisms of oligodendrocyte and axon injury and repair play a central role in the damage and recovery after this type of stroke, and a comprehensive study of these processes requires a specialized experimental model that is different from common large artery, gray matter stroke models. Diminished recovery from stroke in aged patients implies that damage and repair processes are affected by advanced age, but such effects have not been studied in WMS.

Methods—

WMS was produced with focal microinjection of the vasoconstrictor N5-(1-iminoethyl)-
L
-ornithine into the subcortical white matter ventral to the mouse forelimb motor cortex in young adult (2 months), middle-aged (15 months), and aged mice (24 months).

Results—

WMS produced localized oligodendrocyte cell death with higher numbers of apoptotic cells and greater oxidative damage in aged brains than in young-adult brains. Increased expression of monocyte chemotactic protein-1 and tumor necrosis factor-α in motor cortex neurons correlated with a more distributed microglial activation in aged brains 7 days after WMS. At 2 months, aged mice displayed increased white matter atrophy and greater loss of corticostriatal connections compared with young-adult mice. Behavioral testing revealed an age-dependent exacerbation of forelimb motor deficits caused by the stroke, with decreased long-term functional recovery in aged animals.

Conclusions—

Age has a profound effect on the outcome of WMS, with more prolonged cell death and oxidative damage, increased inflammation, greater secondary white matter atrophy, and a worse behavioral effect in aged versus young-adult mice.
Insular Strokes Cause No Vestibular Deficits
Authors: Baier Bernhard , Conrad Julian , zu Eulenburg Peter , Best Christoph , Müller-Forell Wibke , Birklein Frank , Dieterich Marianne
Published: July 2013

Background and Purpose—

In previous imaging studies, the posterior insular cortex (IC) was identified as an essential part for vestibular otolith perception and considered as a core region of a human vestibular cortical network. However, it is still unknown whether lesions exclusively restricted to the posterior IC suffice to provoke signs of vestibular otolith dysfunction. Thus, present data aimed to test whether patients with lesions restricted to the IC showed vestibular otolith dysfunction.

Methods—

We studied 10 acute unilateral stroke patients with lesions restricted to the IC which were tested for signs of vestibular otolith dysfunction, such as tilts of subjective visual vertical, out of 475 stroke patients.

Results—

None of the patients was with stroke exclusively affecting the IC-specified vertigo as a symptom. In addition, neither showed a deficit in the perception of verticality (subjective visual vertical tilts) nor showed any further vestibular otolith deficits, such as ocular torsion or skew deviation.

Conclusions—

It seems that lesions of the posterior IC might have to be combined with lesions of adjacent regions of the cortical and subcortical vestibular network to cause vestibular otolith deficits.
Palestinian Ṣulḥa and the Rule of Law
Authors: Kritz Brian A.
Published: July 2013

Abstract

Palestine’s alternative dispute resolution process, the ṣulḥa system, is utilized in the vast majority of civil and criminal disputes. Despite the popularity of the ṣulḥa process, there exists, to date, no international legal assessment of such proceedings. This article assesses Palestinian ṣulḥa’s adherence to international rule of law standards. Using rule of law theory to assess the fairness, equity, and accessibility of the ṣulḥa system, this article determines that Palestinian ṣulḥa proceedings satisfy the major requirements of international rule of law standards.