bluuebunny/crossref_metadata_2025 huggingface dataset:
Sexual dysfunction in people with prodromal or first-episode
psychosis
Authors: Marques Tiago Reis , Smith Shubulade , Bonaccorso Stefania , Gaughran Fiona , Kolliakou Anna , Dazzan Paola , Mondelli Valeria , Taylor Heather , DiForti Marta , McGuire Philip K. , Murray Robin M. , Howes Oliver D.
Published: June 2012

Background

Sexual dysfunction is common in psychotic disorder but it is not clear
whether it is intrinsic to the development of the illness or secondary to
other factors.

Aims

To compare sexual function in people at ultra-high risk (UHR) of a
psychotic disorder, patients with first-episode psychosis predominantly
taking antipsychotic drugs and healthy volunteers.

Method

Sexual function was assessed in a UHR group (n = 31), a
group with first-episode psychosis (n = 37) and a
matched control group of healthy volunteers (n = 56)
using the Sexual Function Questionnaire.

Results

There was a significant effect of group on sexual function
(P<0.001). Sexual dysfunction was evident in 50%
of the UHR group, 65% of first-episode patients and 21% of controls.
Within the UHR group, sexual dysfunction was more marked in those who
subsequently developed psychosis than in those who did not. Across all
groups the severity of sexual dysfunction was correlated with the
severity of psychotic symptoms (P<0.001). Within the
first-episode group there was no significant difference in sexual
dysfunction between patients taking prolactin-raising v.
prolactin-sparing antipsychotics.

Conclusions

Sexual dysfunction is present prior to onset of psychosis, suggesting it
is intrinsic to the development of illness unlikely to be related to the
prolactin-raising properties of antipsychotic medication.
Role of Estrogen Receptor Signaling Required for Endometriosis-Like Lesion Establishment in a Mouse Model
Authors: Burns Katherine A. , Rodriguez Karina F. , Hewitt Sylvia C. , Janardhan Kyathanahalli S. , Young Steven L. , Korach Kenneth S.
Published: June 2012

Endometriosis results from ectopic invasion of endometrial tissue within the peritoneal cavity. Aberrant levels of the estrogen receptor (ER), ERα and ERβ, and higher incidence of autoimmune disorders are observed in women with endometriosis. An immunocompetent mouse model of endometriosis was used in which minced uterine tissue from a donor was dispersed into the peritoneal cavity of a recipient. Wild-type (WT), ERα-knockout (αERKO), and βERKO mice were donors or recipients to investigate the roles of ERα, ERβ, and estradiol-mediated signaling on endometriosis-like disease. Mice were treated with vehicle or estradiol, and resulting location, number, and size of endometriosis-like lesions were assessed. In comparison with WT lesions in WT hosts, αERKO lesions in WT hosts were smaller and fewer in number. The effect of ER status and estradiol treatment on nuclear receptor status, proliferation, organization, and inflammation within lesions were examined. αERKO lesions in WT hosts did not form distal to the incision site, respond to estradiol, or proliferate but did have increased inflammation. WT lesions in αERKO hosts did respond to estradiol, proliferate, and show decreased inflammation with treatment, but surprisingly, progesterone receptor expression and localization remained unchanged. Only minor differences were observed between WT lesions in βERKO hosts and βERKO lesions in WT hosts, demonstrating the estradiol-mediated signaling responses are predominately through ERα. In sum, these results suggest ER in both endometriosis-like lesions and their environment influence lesion characteristics, and understanding these interactions may play a critical role in elucidating this enigmatic disease.
Phenotypic diversity in patients with lipodystrophy associated with LMNA mutations
Authors: Mory Patricia B , Crispim Felipe , Freire Maria Beatriz S , Salles João Eduardo N , Valério Cynthia M , Godoy-Matos Amelio F , Dib Sérgio A , Moisés Regina S
Published: June 2012

Objective

Mutations inLMNAhave been linked to diverse disorders called laminopathies, which display heterogeneous phenotypes and include diseases affecting muscles, axonal neurons, progeroid syndromes, and lipodystrophies. Among the lipodystrophies,LMNAmutations have been reported most frequently in patients with familial partial lipodystrophy (FPLD) of the Dunnigan variety; however, phenotypic heterogeneity in the pattern of body fat loss has been observed. In this study, we searched forLMNAmutations in patients with various forms of lipodystrophy.

Design and methods

We studied 21 unrelated individuals with lipodystrophy. Subjects underwent a complete clinical evaluation and were classified as typical FPLD (n=12), atypical partial lipodystrophy (n=7), or generalized lipodystrophy (n=2). Molecular analysis ofLMNAgene, analysis of body fat by dual-energy X-ray absorptiometry, and biochemical measurements were performed.

Results

All patients with typical FPLD were found to carryLMNAmutations: seven patients harbored the heterozygous p.R482W (c.1444C>T), two patients harbored the p.R482Q (c.1445G>A), and two individuals harbored the novel heterozygous variant p.N466D (c.1396A>G), all in exon 8. Also, a homozygous p.R584H (c.1751 G>A) mutation in exon 11 was found. Among patients with atypical partial lipodystrophy, two of them were found to haveLMNAmutations: a novel heterozygous p.R582C variation (c.1744 C>T) in exon 11 and a heterozygous substitution p.R349W (c.1045C>T) in exon 6. Among patients with generalized lipodystrophy, only one harboredLMNAmutation, a heterozygous p.T10I (c.29C>T) in exon 1.

Conclusions

We have identifiedLMNAmutations in phenotypically diverse lipodystrophies. Also, our study broadens the spectrum ofLMNAmutations in lipodystrophy.
Mice lacking AMP-activated protein kinase α1 catalytic subunit have increased bone remodelling and modified skeletal responses to hormonal challenges induced by ovariectomy and intermittent PTH treatment
Authors: Jeyabalan J , Shah M , Viollet B , Roux J P , Chavassieux P , Korbonits M , Chenu C
Published: June 2012

AMP-activated protein kinase (AMPK) is a key regulator of cellular and body energy homeostasis. We previously demonstrated that AMPK activation in osteoblasts increases in vitro bone formation while deletion of the Ampkα1 (Prkaa1) subunit, the dominant catalytic subunit expressed in bone, leads to decreased bone mass in vivo. To investigate the cause of low bone mass in the Ampkα1−/− mice, we analysed bone formation and resorption in the tibia of these mice by dynamic histomorphometry and determined whether bone turnover can be stimulated in the absence of the Ampkα1 subunit. We subjected 12-week-old Ampkα1+/+ and Ampkα1−/− mice to ovariectomy (OVX), intermittent PTH (iPTH) administration (80 μg/kg per day, 5 days/week) or both OVX and iPTH hormonal challenges. Tibiae were harvested from these mice and bone micro-architecture was determined by micro-computed tomography. We show for the first time that Ampkα1−/− mice have a high bone turnover at the basal level in favour of bone resorption. While both Ampkα1+/+ and Ampkα1−/− mice lost bone mass after OVX, the bone loss in Ampkα1−/− mice was lower compared with controls. iPTH increased trabecular and cortical bone indexes in both ovariectomised Ampkα1+/+ and Ampkα1−/− mice. However, ovariectomised Ampkα1−/− mice showed a smaller increase in bone parameters in response to iPTH compared with Ampkα1+/+ mice. By contrast, non-ovariectomised Ampkα1−/− mice responded better to iPTH treatment than non-ovariectomised Ampkα1+/+ mice. Overall, these data demonstrate that Ampkα1−/− mice are less affected by changes in bone turnover induced by OVX but respond better to the anabolic challenge induced by iPTH. These results suggest that AMPKα1 activation may play a role in the hormonal regulation of bone remodelling.
Nanosecond and picosecond laser structuring of electrode materials for lithium-ion batteries
Authors: Kohler Robert , Proell Johannes , Besser Heino , Torge Maika , Scholz Steffen , Dobrev Todor , Ulrich Sven , Pfleging Wilhelm
Published: June 2012

A comparative study for picosecond and nanosecond laser structuring was performed in order to identify structure geometries and dimensions that efficiently reduce the significant volume changes during electrochemical cycling of SnO2, a promising anode material. Line structures with widths of 20 μm could significantly improve cycling stability of 3 μm thick magnetron sputtered SnO2 thin films. A reduction of structure size led to further improvement of capacity retention. Free-standing conical micro-structures exhibited the best cycling behavior.
Bond of reinforcement in self-compacting steel-fibre-reinforced concrete
Authors: Jansson Anette , Lofgren Ingemar , Lundgren Karin , Gylltoft Kent
Published: June 2012

Crack control, one of the main benefits of using fibre reinforcement, depends to a large extent on the concrete–rebar bond. Pull-out tests of specimens with short embedment length were carried out and the results showed no effect from the fibres on the normalised bond–slip behaviour before peak load. After this, the fibre reinforcement provided extra confinement, changing the failure mode from splitting to pull-out failure. The test results were used to calibrate a finite-element bond model that considers both tangential stresses and stresses in the radial direction from the rebar. Splitting cracks may be thus considered in the finite-element analyses. The model proved to yield results in good agreement with the experimental results regarding failure mode, load–slip relation and splitting strains on the surfaces of the pull-out specimens. The analyses revealed that two types of action were active in the cracking process. In addition, the confinement effect of the fibre reinforcement was compared with the confinement of conventional stirrups using the bond model in CEB-FIP model code 2010.
How does economic risk aversion affect biodiversity?
Authors: Mouysset L. , Doyen L. , Jiguet F.
Published: June 2012

Significant decline of biodiversity in farmlands has been reported for several decades. To limit the negative impact of agriculture, many agro‐environmental schemes have been implemented, but their effectiveness remains controversial. In this context, the study of economic drivers is helpful to understand the role played by farming on biodiversity. The present paper analyzes the impact of risk aversion on farmland biodiversity. Here “risk aversion” means a cautious behavior of farmers facing uncertainty. We develop a bio‐economic model that articulates bird community dynamics and representative farmers selecting land uses within an uncertain macro‐economic context. It is specialized and calibrated at a regional scale for France through national databases. The influence of risk aversion is assessed on ecological, agricultural, and economic outputs through projections at the 2050 horizon. A high enough risk aversion appears sufficient to both manage economic risk and promote ecological performance. This occurs through a diversification mechanism on regional land uses. However, economic calibration leads to a weak risk‐aversion parameter, which is consistent with the current decline of farmland birds. Spatial disparities however suggest that public incentives could be necessary to reinforce the diversification and bio‐economic effectiveness.
Relationships between Levels of Urinary Podocalyxin, Number of Urinary Podocytes, and Histologic Injury in Adult Patients with IgA Nephropathy
Authors: Asao Rin , Asanuma Katsuhiko , Kodama Fumiko , Akiba-Takagi Miyuki , Nagai-Hosoe Yoshiko , Seki Takuto , Takeda Yukihiko , Ohsawa Isao , Mano Satoshi , Matsuoka Kiyoshi , Kurosawa Hiroyuki , Ogasawara Shinya , Hirayama Yoshiaki , Sekine Sakari , Horikoshi Satoshi , Hara Masanori , Tomino Yasuhiko
Published: June 2012

Background and objectives

Podocalyxin (PCX) is present on the apical cell membrane of podocytes and is shed in urine from injured podocytes. Urinary podocalyxin (u-PCX) is associated with severity of active glomerular injury in patients with glomerular diseases. This study examined the relationship between number of urinary podocytes, levels of u-PCX, and glomerular injury in adults with IgA nephropathy (IgAN).

Design, setting, participants, & measurements

Urine samples voided in the morning on the day of biopsy were obtained from 51 patients with IgAN (18 men and 33 women; mean age, 31 years). All renal biopsy specimens were analyzed histologically. Pathologic variables of IgAN were analyzed per Shigematsu classification, the Oxford classification of IgAN, and the Clinical Guidelines of IgAN in Japan. Levels of u-PCX were measured by sandwich ELISA.

Results

Histologic analysis based on Shigematsu classification revealed a significant correlation between levels of u-PCX and severity of acute extracapillary abnormalities (r=0.72; P<0.001), but levels of urinary protein excretion did not correlate with acute glomerular abnormalities. Levels of urinary protein excretion in patients with segmental sclerosis (n=19) were higher than in patients without (n=22) (0.49 [interquartile range (IQR), 0.20–0.88] g/g creatinine versus 0.20 [IQR, 0.10–0.33] g/g creatinine; P<0.01). The number of urinary podocytes in patients with segmental sclerosis was higher than in patients without (1.05 [IQR, 0.41–1.67] per mg creatinine versus 0.28 [IQR, 0.10–0.66] per mg creatinine; P<0.01).

Conclusions

Levels of u-PCX and the number of urinary podocytes are associated with histologic abnormalities in adults with IgAN.
Probing the Mechanisms of Intradialytic Hypertension
Authors: Inrig Jula K. , Van Buren Peter , Kim Catherine , Vongpatanasin Wanpen , Povsic Thomas J. , Toto Robert
Published: June 2012

Background and objectives

Intradialytic hypertension may be caused by an impaired endothelial cell response to hemodialysis. Carvedilol has been shown to improve endothelial cell function in vivo and to block endothelin-1 release in vitro. This study hypothesized that carvedilol would improve endothelial cell function and reduce the occurrence of intradialytic hypertension.

Design, setting, participants, & measurements

A prospective 12-week pilot study of carvedilol titrated to 50 mg twice daily was performed among 25 hemodialysis participants with intradialytic hypertension. Each patient served as his or her own control. Paired tests were used to analyze changes in BP and endothelial cell function—assessed by flow-mediated vasodilation, endothelial progenitor cells (aldehyde dehydrogenase bright activity and CD34+CD133+), asymmetric dimethylarginine, and endothelin-1—from baseline to study end.

Results

Flow-mediated vasodilation was significantly improved with carvedilol (from 1.03% to 1.40%, P=0.02). There was no significant change in endothelial progenitor cells, endothelin-1, or asymmetric dimethylarginine. Although prehemodialysis systolic BP was unchanged (144–146 mmHg, P=0.5), posthemodialysis systolic BP, 44-hour ambulatory systolic BP, and the frequency of intradialytic hypertension decreased with carvedilol (159–142 mmHg, P<0.001; 155–148 mmHg, P=0.05; and 77% [4.6 of 6] to 28% [1.7 of 6], P<0.001, respectively).

Conclusions

Among hemodialysis participants with intradialytic hypertension, targeting endothelial cell dysfunction with carvedilol was associated with modest improvements in endothelial function, improved intradialytic and interdialytic BP, and reduced frequency of intradialytic hypertension. Randomized controlled trials are required to confirm these findings.
Management Forecast Accuracy and CEO Turnover
Authors: Lee Sam (Sunghan) , Matsunaga Steven R. , Park Chul W.
Published: June 2012

We investigate whether management forecast accuracy provides a signal regarding CEOs' ability to anticipate and respond to future events by examining the relation between management forecast errors and CEO turnover. We find that the probability of CEO turnover is positively related to the magnitude of absolute forecast errors when firm performance is poor and that this positive relation holds for both positive and negative forecast errors. In addition, we find that the positive relation between CEO turnover and the absolute forecast errors is concentrated in the sample of less entrenched CEOs. Our findings indicate that boards of directors use management forecast accuracy as a signal of CEOs' managerial ability and that managers bear a cost for issuing inaccurate forecasts.
Polycystic Ovary Syndrome Is a Risk Factor for Type 2 Diabetes
Authors: Gambineri Alessandra , Patton Laura , Altieri Paola , Pagotto Uberto , Pizzi Carmine , Manzoli Lamberto , Pasquali Renato
Published: June 2012

Polycystic ovary syndrome (PCOS) recently has been identified as a risk factor associated with type 2 diabetes. However, the evidence derives from cross-sectional observational studies, retrospective studies, or short-term prospective studies. This long-term prospective study of a large cohort of women with PCOS, followed from youth to middle age, aimed at estimating, for the first time, the incidence and potential predictors of type 2 diabetes in this population. A total of 255 women with PCOS were followed for at least 10 years (mean follow-up 16.9 years). Six women were patients with diabetes at baseline, and another 42 women developed type 2 diabetes during the follow-up. The incidence rate of type 2 diabetes in the study population was 1.05 per 100 person-years. The age-standardized prevalence of diabetes at the end of follow-up was 39.3%, which is significantly higher with respect to that of the general Italian female population of a similar age (5.8%). The likelihood of developing type 2 diabetes significantly increased as BMI, fasting glucose, and glucose area under the curve at baseline increased and significantly decreased as sex hormone–binding globulin (SHBG) levels at follow-up increased. This study demonstrates that the risk of type 2 diabetes is markedly elevated in middle-aged women with PCOS and suggests including BMI, glucose, and SHBG-circulating levels in the risk stratification.
AttenuatedPik3r1Expression Prevents Insulin Resistance and Adipose Tissue Macrophage Accumulation in Diet-Induced Obese Mice
Authors: McCurdy Carrie E. , Schenk Simon , Holliday Michael J. , Philp Andrew , Houck Julie A. , Patsouris David , MacLean Paul S. , Majka Susan M. , Klemm Dwight J. , Friedman Jacob E.
Published: June 2012

Obese white adipose tissue (AT) is characterized by large-scale infiltration of proinflammatory macrophages, in parallel with systemic insulin resistance; however, the cellular stimulus that initiates this signaling cascade and chemokine release is still unknown. The objective of this study was to determine the role of the phosphoinositide 3-kinase (PI3K) regulatory subunits on AT macrophage (ATM) infiltration in obesity. Here, we find that the Pik3r1 regulatory subunits (i.e., p85α/p55α/p50α) are highly induced in AT from high-fat diet–fed obese mice, concurrent with insulin resistance. Global heterozygous deletion of the Pik3r1 regulatory subunits (αHZ), but not knockout of Pik3r2 (p85β), preserves whole-body, AT, and skeletal muscle insulin sensitivity, despite severe obesity. Moreover, ATM accumulation, proinflammatory gene expression, and ex vivo chemokine secretion in obese αHZ mice are markedly reduced despite endoplasmic reticulum (ER) stress, hypoxia, adipocyte hypertrophy, and Jun NH2-terminal kinase activation. Furthermore, bone marrow transplant studies reveal that these improvements in obese αHZ mice are independent of reduced Pik3r1 expression in the hematopoietic compartment. Taken together, these studies demonstrate that Pik3r1 expression plays a critical role in mediating AT insulin sensitivity and, more so, suggest that reduced PI3K activity is a key step in the initiation and propagation of the inflammatory response in obese AT.
B-Type Natriuretic Peptide Modulates Ghrelin, Hunger, and Satiety in Healthy Men
Authors: Vila Greisa , Grimm Gabriele , Resl Michael , Heinisch Birgit , Einwallner Elisa , Esterbauer Harald , Dieplinger Benjamin , Mueller Thomas , Luger Anton , Clodi Martin
Published: June 2012

Chronic heart failure is accompanied by anorexia and increased release of B-type natriuretic peptide (BNP) from ventricular cardiomyocytes. The pathophysiological mechanisms linking heart failure and appetite regulation remain unknown. In this study, we investigated the impact of intravenous BNP administration on appetite-regulating hormones and subjective ratings of hunger and satiety in 10 healthy volunteers. Participants received in a randomized, placebo-controlled, crossover, single-blinded study (subject) placebo once and 3.0 pmol/kg/min human BNP-32 once administered as a continuous infusion during 4 h. Circulating concentrations of appetite-regulating peptides were measured hourly. Subjective ratings of hunger and satiety were evaluated by visual analog scales. BNP inhibited the fasting-induced increase in total and acylated ghrelin concentrations over time (P = 0.043 and P = 0.038, respectively). In addition, BNP decreased the subjective rating of hunger (P = 0.009) and increased the feeling of satiety (P = 0.012) when compared with placebo. There were no significant changes in circulating peptide YY, glucagon-like peptide 1, oxyntomodulin, pancreatic polypeptide, leptin, and adiponectin concentrations. In summary, our results demonstrate that BNP exerts anorectic effects and reduces ghrelin concentrations in men. These data, taken together with the known cardiovascular properties of ghrelin, support the existence of a heart–gut–brain axis, which could be therapeutically targeted in patients with heart failure and obesity.
Hepatocyte-Specific Ptpn6 Deletion Protects From Obesity-Linked Hepatic Insulin Resistance
Authors: Xu Elaine , Charbonneau Alexandre , Rolland Yannève , Bellmann Kerstin , Pao Lily , Siminovitch Katherine A. , Neel Benjamin G. , Beauchemin Nicole , Marette André
Published: June 2012

The protein-tyrosine phosphatase Shp1 negatively regulates insulin action on glucose homeostasis in liver and muscle, but its potential role in obesity-linked insulin resistance has not been examined. To investigate the role of Shp1 in hepatic insulin resistance, we generated hepatocyte-specific Shp1 knockout mice (Ptpn6H-KO), which were subjected to extensive metabolic monitoring throughout an 8-week standard chow diet (SD) or high-fat diet (HFD) feeding. We report for the first time that Shp1 expression is upregulated in metabolic tissues of HFD-fed obese mice. When compared with their Shp1-expressing Ptpn6f/f littermates, Ptpn6H-KO mice exhibited significantly lowered fasting glycemia and heightened hepatic insulin sensitivity. After HFD feeding, Ptpn6H-KO mice developed comparable levels of obesity as Ptpn6f/f mice, but they were remarkably protected from liver insulin resistance, as revealed by euglycemic clamps and hepatic insulin signaling determinations. Although Ptpn6H-KO mice still acquired diet-induced peripheral insulin resistance, they were less hyperinsulinemic during a glucose tolerance test because of reduced insulin secretion. Ptpn6H-KO mice also exhibited increased insulin clearance in line with enhanced CC1 tyrosine phosphorylation in liver. These results show that hepatocyte Shp1 plays a critical role in the development of hepatic insulin resistance and represents a novel therapeutic target for obesity-linked diabetes.
Impact of Common Variation in Bone-Related Genes on Type 2 Diabetes and Related Traits
Authors: Billings Liana K. , Hsu Yi-Hsiang , Ackerman Rachel J. , Dupuis Josée , Voight Benjamin F. , Rasmussen-Torvik Laura J. , Hercberg Serge , Lathrop Mark , Barnes Daniel , Langenberg Claudia , Hui Jennie , Fu Mao , Bouatia-Naji Nabila , Lecoeur Cecile , An Ping , Magnusson Patrik K. , Surakka Ida , Ripatti Samuli , Christiansen Lene , Dalgård Christine , Folkersen Lasse , Grundberg Elin ,   the MAGIC Investigators,   the DIAGRAM + Consortium,   the MuTHER Consortium,   the ASCOT Investigators,   the GEFOS Consortium, Eriksson Per , Kaprio Jaakko , Ohm Kyvik Kirsten , Pedersen Nancy L. , Borecki Ingrid B. , Province Michael A. , Balkau Beverley , Froguel Philippe , Shuldiner Alan R. , Palmer Lyle J. , Wareham Nick , Meneton Pierre , Johnson Toby , Pankow James S. , Karasik David , Meigs James B. , Kiel Douglas P. , Florez Jose C.
Published: June 2012

Exploring genetic pleiotropy can provide clues to a mechanism underlying the observed epidemiological association between type 2 diabetes and heightened fracture risk. We examined genetic variants associated with bone mineral density (BMD) for association with type 2 diabetes and glycemic traits in large well-phenotyped and -genotyped consortia. We undertook follow-up analysis in ∼19,000 individuals and assessed gene expression. We queried single nucleotide polymorphisms (SNPs) associated with BMD at levels of genome-wide significance, variants in linkage disequilibrium (r2 > 0.5), and BMD candidate genes. SNP rs6867040, at the ITGA1 locus, was associated with a 0.0166 mmol/L (0.004) increase in fasting glucose per C allele in the combined analysis. Genetic variants in the ITGA1 locus were associated with its expression in the liver but not in adipose tissue. ITGA1 variants appeared among the top loci associated with type 2 diabetes, fasting insulin, β-cell function by homeostasis model assessment, and 2-h post–oral glucose tolerance test glucose and insulin levels. ITGA1 has demonstrated genetic pleiotropy in prior studies, and its suggested role in liver fibrosis, insulin secretion, and bone healing lends credence to its contribution to both osteoporosis and type 2 diabetes. These findings further underscore the link between skeletal and glucose metabolism and highlight a locus to direct future investigations.
Transgenic Control of Mitochondrial Fission Induces Mitochondrial Uncoupling and Relieves Diabetic Oxidative Stress
Authors: Galloway Chad A. , Lee Hakjoo , Nejjar Souad , Jhun Bong Sook , Yu Tianzheng , Hsu Wei , Yoon Yisang
Published: June 2012

Mitochondria are the essential eukaryotic organelles that produce most cellular energy. The energy production and supply by mitochondria appear closely associated with the continuous shape change of mitochondria mediated by fission and fusion, as evidenced not only by the hereditary diseases caused by mutations in fission/fusion genes but also by aberrant mitochondrial morphologies associated with numerous pathologic insults. However, how morphological change of mitochondria is linked to their energy-producing activity is poorly understood. In this study, we found that perturbation of mitochondrial fission induces a unique mitochondrial uncoupling phenomenon through a large-scale fluctuation of a mitochondrial inner membrane potential. Furthermore, by genetically controlling mitochondrial fission and thereby inducing mild proton leak in mice, we were able to relieve these mice from oxidative stress in a hyperglycemic model. These findings provide mechanistic insight into how mitochondrial fission participates in regulating mitochondrial activity. In addition, these results suggest a potential application of mitochondrial fission to control mitochondrial reactive oxygen species production and oxidative stress in many human diseases.
Metformin Inhibits Growth Hormone–Mediated Hepatic PDK4 Gene Expression Through Induction of Orphan Nuclear Receptor Small Heterodimer Partner
Authors: Kim Yong Deuk , Kim Yong-Hoon , Tadi Surendar , Yu Ji Hoon , Yim Yong-Hyeon , Jeoung Nam Ho , Shong Minho , Hennighausen Lothar , Harris Robert A. , Lee In-Kyu , Lee Chul-Ho , Choi Hueng-Sik
Published: June 2012

Growth hormone (GH) is a counter-regulatory hormone that plays an important role in preventing hypoglycemia during fasting. Because inhibition of the pyruvate dehydrogenase complex (PDC) by pyruvate dehydrogenase kinase 4 (PDK4) conserves substrates for gluconeogenesis, we tested whether GH increases PDK4 expression in liver by a signaling pathway sensitive to inhibition by metformin. The effects of GH and metformin were determined in the liver of wild-type, small heterodimer partner (SHP)-, PDK4-, and signal transducer and activator of transcription 5 (STAT5)-null mice. Administration of GH in vivo increased PDK4 expression via a pathway dependent on STAT5 phosphorylation. Metformin inhibited the induction of PDK4 expression by GH via a pathway dependent on AMP-activated protein kinase (AMPK) and SHP induction. The increase in PDK4 expression and PDC phosphorylation by GH was reduced in STAT5-null mice. Metformin decreased GH-mediated induction of PDK4 expression and metabolites in wild-type but not in SHP-null mice. In primary hepatocytes, dominant-negative mutant-AMPK and SHP knockdown prevented the inhibitory effect of metformin on GH-stimulated PDK4 expression. SHP directly inhibited STAT5 association on the PDK4 gene promoter. Metformin inhibits GH-induced PDK4 expression and metabolites via an AMPK-SHP–dependent pathway. The metformin-AMPK-SHP network may provide a novel therapeutic approach for the treatment of hepatic metabolic disorders induced by the GH-mediated pathway.
Autoantigen-Specific B-Cell Depletion Overcomes Failed Immune Tolerance in Type 1 Diabetes
Authors: Henry Rachel A. , Kendall Peggy L. , Thomas James W.
Published: June 2012

Eliminating autoantigen-specific B cells is an attractive alternative to global B-cell depletion for autoimmune disease treatment. To identify the potential for targeting a key autoimmune B-cell specificity in type 1 diabetes, insulin-binding B cells were tracked within a polyclonal repertoire using heavy chain B-cell receptor (BCR) transgenic (VH125Tg) mice. Insulin-specific B cells are rare in the periphery of nonautoimmune VH125Tg/C57BL/6 mice and WT/NOD autoimmune mice, whereas they clearly populate 1% of mature B-cell subsets in VH125Tg/NOD mice. Autoantigen upregulates CD86 in anti-insulin B cells, suggesting they are competent to interact with T cells. Endogenous insulin occupies anti-insulin BCR beginning with antigen commitment in bone marrow parenchyma, as identified by a second anti-insulin monoclonal antibody. Administration of this monoclonal antibody selectively eliminates insulin-reactive B cells in vivo and prevents disease in WT/NOD mice. Unexpectedly, developing B cells are less amenable to depletion, despite increased BCR sensitivity. These findings exemplify how a critical type 1 diabetes B-cell specificity escapes immune tolerance checkpoints. Disease liability is corrected by eliminating this B-cell specificity, providing proof of concept for a novel therapeutic approach for autoimmune disease.
Independent Effect of Ethnicity on Glycemia in South Asians and White Europeans
Authors: Mostafa Samiul A. , Davies Melanie J. , Webb David R. , Srinivasan Balasubramanian Thiagarajan , Gray Laura J. , Khunti Kamlesh
Published: June 2012

OBJECTIVE

HbA1c levels are higher in most ethnic groups compared with white Europeans (WEs) independent of glycemic control. This comparison has not been performed between South Asians (SAs) and WEs. We analyzed the independent effect of ethnicity on HbA1c and fasting and 2-h plasma glucose (FPG and 2hrPG, respectively) between these groups.

RESEARCH DESIGN AND METHODS

Analysis of the ADDITION-Leicester study, in which 4,688 WEs and 1,352 SAs underwent oral glucose tolerance testing, HbA1c, and other risk factor measurements.

RESULTS

Significant associations with HbA1c included ethnicity, FPG, 2hrPG, and homeostasis model assessment of β-cell function (P < 0.001); age and sex (P < 0.01); and fasting insulin and potassium (P < 0.05). After adjusting for these and other risk factors, SAs demonstrated higher HbA1c (6.22 and 6.02%, mean difference 0.20%, 0.10–0.30, P < 0.001), FPG (5.15 and 5.30 mmol/L, mean difference 0.15 mmol/L, 0.09–0.21, P < 0.001), and 2hrPG (5.82 and 6.57 mmol/L, mean difference 0.75 mmol/L, 0.59–0.92, P < 0.001) compared with WEs, respectively.

CONCLUSIONS

HbA1c, FPG, and 2hrPG levels were higher in SAs independent of factors affecting glycemic control.
Determinants of Insulin Resistance in Infants at Age 1 Year
Authors: Borgoño Carla A. , Hamilton Jill K. , Ye Chang , Hanley Anthony J. , Connelly Philip W. , Sermer Mathew , Zinman Bernard , Retnakaran Ravi
Published: June 2012

OBJECTIVE

The offspring of women with gestational diabetes mellitus (GDM) display a propensity for the early accrual of cardiometabolic risk factors, including insulin resistance, in childhood and adolescence. Thus, we sought to identify early life determinants of insulin resistance in infants of women with and without GDM.

RESEARCH DESIGN AND METHODS

In total, 104 full-term, singleton infants born to women with (n = 36) and without (n = 68) GDM were evaluated at age 1 year, with insulin resistance assessed by homeostasis model (HOMA-IR).

RESULTS

HOMA-IR at 1 year did not differ between infants born to mothers with and without GDM (P = 0.74). The sole independent predictor of infant HOMA-IR in the non-GDM group was birth weight (t = 3.33, P = 0.002). In contrast, weight gain in the 1st year was the only independent predictor of HOMA-IR in infants of women with GDM (t = 2.19, P = 0.039).

CONCLUSIONS

In the 1st year of life, weight gain in infants born to women with GDM is associated with insulin resistance, unlike in their peers.
Stress Management as an Adjunct to Physical Therapy for Chronic Neck Pain
Authors: Bruflat Angela K. , Balter Jaclyn E. , McGuire Denise , Fethke Nathan B. , Maluf Katrina S.
Published: June 2012

Background and Purpose

Chronic neck pain is prevalent in the workplace. Research suggests that psychosocial stress may contribute to the development of neck pain by causing excessive or prolonged muscle activity in some individuals. The purpose of this case report is to describe the rationale, development, and implementation of stress management as an adjunct to standard physical therapist management of chronic neck pain in a female office worker who responded to psychosocial stress with elevated muscle activity prior to treatment.

Case Description

A 44-year-old female office employee with an 8-year history of chronic neck pain participated in this case report. The patient was selected from a group of research participants who demonstrated elevated electromyographic (EMG) activity of the trapezius muscle in response to simulated occupational stressors. The multidisciplinary intervention consisted of 8 physical therapy sessions, supplemented by 8 stress management sessions that included EMG biofeedback and psychotherapy to facilitate muscle relaxation.

Outcomes

Neck disability decreased by 50%, trait anxiety decreased by 21%, and the duration of trapezius muscle rest in the workplace increased by 56% immediately after the 8-week intervention. These improvements were maintained 6 months after treatment, and the patient reported a complete absence of neck disability at the 2-year follow-up assessment.

Discussion

A sustained reduction in neck disability was observed for a patient with chronic neck pain after participating in a multidisciplinary intervention that combined physical therapy and stress management approaches to facilitate muscle relaxation in the workplace. Future clinical trials are needed to assess whether stress management is a useful adjunct therapy for patients with chronic neck pain who show elevated muscle activity in response to psychosocial stress.
Face Into the Storm
Authors: Jette Alan M.
Published: June 2012

America is about to experience a demographic shift of enormous magnitude: increasing longevity, declining fertility, and the aging of the baby boomers, which are triggering an enormous “age wave.” We are facing the challenge of limited access to health care services by millions of our citizens, and unsustainable cost escalation. In response, health care is changing fundamentally. In the 2012 McMillan Lecture, Jette discusses 3 critical “system skills” that physical therapists must develop to practice successfully in a changing health care environment. First, therapists must become interested in data. Second, they must become skilled in the ability to devise solutions for the system problems that data and experience uncover. Third, the physical therapy profession must develop the ability to implement at scale—the ability to get therapists along the entire chain of care functioning in concert, in collaboration. Jette discusses the American Physical Therapy Association's Vision 2020 as it relates to these challenges and the degree to which he believes physical therapists are equipped with the system skills needed to function within effective health care systems to identify what works in physical therapy, for what conditions, under what circumstances, and at what cost. Jette articulates a revised vision for physical therapy that includes being a leader in teaching systems skills to practice successfully in interconnected heath care teams; being a recognized national leader in implementing evidence-based strategies; using standardized collection, analysis, and dissemination of intervention and outcomes data as a regular part of practice to determine what interventions best improve the health of individuals and society; and being a profession that is a central player in devising, evaluating, and implementing cost-effective health care innovations for communities as well as for individuals.
Canadian Inequality: Recent Developments and Policy Options
Authors: Fortin Nicole , Green David A. , Lemieux Thomas , Milligan Kevin , Riddell W. Craig
Published: June 2012

Considerable concern has recently been expressed worldwide about growing income inequality. Much of the discussion, though, has been in general terms and focused on the US experience. To understand whether and how Canada ought to respond to this development, we need to be clear on the facts. This paper documents Canadian patterns in income inequality and investigates the top 1 percent of earners—the group receiving the most attention. We summarize what is known about the causes of growing income inequality, including the role of gender wage differences. Finally, we outline policy options for reducing—or slowing the growth of—inequality.
Evidence of the Association between Household Food Insecurity and Heating Cost Inflation in Canada, 1998–2001
Authors: Emery J. C. Herbert , Bartoo Aaron C. , Matheson Jesse , Ferrer Ana , Kirkpatrick Sharon I. , Tarasuk Valerie , McIntyre Lynn
Published: June 2012

We investigated the 5.3 percentage point increase in the prevalence of food insecurity in Canada between the National Population Health Survey of 1998–99 and the Canadian Community Health Survey of 2000–01. We found that the increase in food insecurity occurred disproportionately in households in the western provinces, particularly Alberta, and among homeowners rather than renters. Inter-provincial variation in heating cost inflation explained as much as 61 percent of the inter-provincial variation in food insecurity increases between 1998 and 2001.
Anaplastic medulloblastoma in a child with Duchenne muscular dystrophy
Authors: van den Akker Machiel , Northcott Paul , Taylor Michael D. , Halliday William , Bartels Ute , Bouffet Eric
Published: June 2012

A 9-year-old boy with known Duchenne type muscular dystrophy (DMD) presented with signs of increased intracranial pressure. Radiological investigations revealed a lesion in the midline of the posterior fossa. Subtotal resection was performed. Pathology findings were consistent with the diagnosis of anaplastic medulloblastoma. The postoperative lumbar CSF was positive for malignant cells. Postoperatively, the patient showed severe neurological deterioration and lost his capacity to walk. He was treated with craniospinal radiation followed by nonintensive chemotherapy. At 30 months postsurgery, he was still in complete remission but had not recovered his walking ability. This is the second report of a malignant brain tumor in a boy with DMD. The possible link between the 2 conditions is discussed, as are ethical considerations regarding the management of medulloblastoma in children with DMD.
Intradiploic hemangioma with repeated hemorrhage in a child with hemophilia
Authors: Zhong Weiying , Li Guoping , Huang Siqing , Chen Haifeng , You Chao
Published: June 2012

Intraosseous hemangioma is an uncommon benign vascular tumor, which is most frequently found in middle-aged female patients. The clinical course is usually insidious and the outcome excellent after total resection. The authors report a case of a calvarial hemangioma in a child with hemophilia who experienced a catastrophic postoperative hematoma and discuss the mechanism, clinical features, and treatment of this condition.
Cervical implantation of intrathecal baclofen pump catheter in children with severe scoliosis
Authors: Ughratdar Ismail , Muquit Samiul , Ingale Harshal , Moussa Ahmad , Ammar Amr , Vloeberghs Michael
Published: June 2012

Object

Intrathecal baclofen (ITB) pump catheter placement is traditionally performed through entry into the spinal sac at the lumbar spine. A minority of children with cerebral palsy have severe concomitant neuromuscular scoliosis. In these children, whether surgically treated or not, access to the intradural space via the lumbar spine may prove technically challenging. The authors report on a series of children in whom, for various reasons, an ITB catheter was implanted using a posterior cervical spine approach.

Methods

The records of 20 children in whom a baclofen catheter had been placed were retrospectively reviewed to assess the demographic details, indications, and outcome of this procedure.

Results

This approach was successful in all but one of the children in whom the procedure was abandoned given the presence of significant extradural scar tissue. Of the 20 children, 7 had previously undergone lumbar ITB catheter implantation, although the catheter was subsequently, iatrogenically transected during scoliosis surgery. Nine children had had corrective scoliosis surgery, and the fusion mass obviated access to the lumbar spinal sac. Four children had untreated scoliosis and corrective surgery was being contemplated. Complications included infection requiring explantation (2 patients), catheter migration (1 patient), intolerance to ITB (1 patient), and failure of implantation (1 patient). All patients who tolerated the ITB experienced improvement in spasticity. No complications were associated with the spinal level of catheter insertion.

Conclusions

Implantation of an ITB catheter via a cervical approach is safe and feasible and should be considered in children with severe corrected or uncorrected scoliosis, and thus avoiding the lumbar spinal sac.
Craniocerebral maduromycosis
Authors: Goel Ravishankar S. , Kataria Rashim , Sinha Virendra D. , Gupta Ashok , Singh Simran , Jain Ayushi
Published: June 2012

Craniocerebral maduromycetoma is extremely rare; only 2 cases have been reported so far. The authors report a case of maduromycetoma in a 17-year-old girl from a rural background in the state of Rajasthan, India, with involvement of the right parietal cortex, overlying bone, and subcutaneous tissue. The mass was totally excised, along with the involved dura mater, bone, and scalp. She was given antifungal drugs in the postoperative period. The patient responded very well to the treatment, and there were no signs of recurrence at the 6-month follow-up visit. The clinical features, imaging and histopathological investigations, and management of this rare entity are discussed, and the available literature is reviewed.
Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival
Authors: Knisely Jonathan P. S. , Yu James B. , Flanigan Jaclyn , Sznol Mario , Kluger Harriet M. , Chiang Veronica L. S.
Published: June 2012

Object

A prospectively collected cohort of 77 patients who underwent definitive radiosurgery between 2002 and 2010 for melanoma brain metastases was retrospectively reviewed to assess the impact of ipilimumab use and other clinical variables on survival.

Methods

The authors conducted an institutional review board–approved chart review to assess patient age at the time of brain metastasis diagnosis, sex, primary disease location, initial radiosurgery date, number of metastases treated, performance status, systemic therapy and ipilimumab history, whole-brain radiation therapy (WBRT) use, follow-up duration, and survival at the last follow-up. The Diagnosis-Specific Graded Prognostic Assessment (DSGPA) score was calculated for each patient based on performance status and the number of brain metastases treated.

Results

Thirty-five percent of the patients received ipilimumab. The median survival in this group was 21.3 months, as compared with 4.9 months in patients who did not receive ipilimumab. The 2-year survival rate was 47.2% in the ipilimumab group compared with 19.7% in the nonipilimumab group. The DS-GPA score was the most significant predictor of overall survival, and ipilimumab therapy was also independently associated with an improvement in the hazard for death (p = 0.03).

Conclusions

The survival of patients with melanoma brain metastases managed with ipilimumab and definitive radiosurgery can exceed the commonly anticipated 4–6 months. Using ipilimumab in a supportive treatment paradigm of radiosurgery for brain oligometastases was associated with an increased median survival from 4.9 to 21.3 months, with a 2-year survival rate of 19.7% versus 47.2%. This association between ipilimumab and prolonged survival remains significant even after adjustment for performance status without an increased need for salvage WBRT.
Long-term visual outcome after microsurgical removal of occipital lobe cavernomas
Authors: Kivelev Juri , Koskela Elina , Setälä Kirsi , Niemelä Mika , Hernesniemi Juha
Published: June 2012

Object

Cavernomas in the occipital lobe are relatively rare. Because of the proximity to the visual cortex and incoming subcortical tracts, microsurgical removal of occipital cavernomas may be associated with a risk of visual field defects. The goal of the study was to analyze long-term outcome after operative treatment of occipital cavernomas with special emphasis on visual outcome.

Methods

Of the 390 consecutive patients with cavernomas who were treated at Helsinki University Central Hospital between 1980 and 2011, 19 (5%) had occipital cavernomas. Sixteen patients (4%) were surgically treated and are included in this study. The median age was 39 years (range 3–59 years). Seven patients (56%) suffered from hemorrhage preoperatively, 5 (31%) presented with visual field deficits, 11 (69%) suffered from seizures, and 4 (25%) had multiple cavernomas. Surgery was indicated for progressive neurological deterioration. The median follow-up after surgery was 5.25 years (range 0.5–14 years).

Results

All patients underwent thorough neuroophthalmological assessment to determine visual outcome after surgery. Visual fields were classified as normal, mild homonymous visual field loss (not disturbing the patient, driving allowed), moderate homonymous visual field loss (disturbing the patient, driving prohibited), and severe visual field loss (total homonymous hemianopia or total homonymous quadrantanopia). At the last follow-up, 4 patients (25%) had normal visual fields, 6 (38%) had a mild visual field deficit, 1 (6%) complained of moderate visual field impairment, and 5 (31%) had severe homonymous visual field loss. Cavernomas seated deeper than 2 cm from the pial surface carried a 4.4-fold risk of postoperative visual field deficit relative to superficial ones (p = 0.034). Six (55%) of the 11 patients presenting with seizures were seizure-free postoperatively. Eleven (69%) of 16 patients had no disability during the long-term follow-up.

Conclusions

Surgical removal of occipital cavernomas may carry a significant risk of postoperative visual field deficit, and the risk is even higher for deeper lesions. Seizure outcome after removal of these cavernomas appeared to be worse than that after removal in other supratentorial locations. This should be taken into account during preoperative planning.