Search

The purpose of this study was to describe the outcome after reversed Delta III shoulder prosthesis in patients with rheumatoid arthritis (RA) and irreparable rotator cuff tear. Fifteen patients (17 joints) were prospectively analysed using the Constant-Murley score (CS). Comprehensive outcome measure was carried out by means of four widely used questionnaires as well as clinical and radiographic examinations at an average of 24.3 months postoperatively. The CS improved significantly from 19 to 59.5 points. The mental (MSC) and physical (PCS) component summary score of the Short Form 36 (SF-36) reached 108% and 77%, respectively, while the DASH (Disabilities of the Arm, Shoulder, and Hand) was 58% of a comparative norm population. Remaining deficits were documented by SPADI (Shoulder Pain and Disability; 54.4 points) and ASES (clinical and patient-orientated American Shoulder and Elbow Surgeons; 84.3 and 61.3 points, respectively). No radiological signs of loosening were found, but scapular notching occurred in four cases. Reversed arthroplasty provides a substantial improvement of shoulder function in patients with RA. The high incidence of notching is of concern. [ABSTRACT FROM AUTHOR]

Background: Associations between ambient temperature exposure during pregnancy and stillbirth have been reviewed and described in the literature. However, there is no existing review of environmental and epidemiologic methods applied to measure stillbirths resulting from exposure to ambient temperatures during pregnancy. The objective of this study is to systematically review published methods, data sources, and data linkage practices to characterize associations between ambient temperature and stillbirth to inform stillbirth prevention and risk management strategies., Methods: A systematic review of published studies that assess the association between ambient temperature exposure during pregnancy using any measures or approach and stillbirth was undertaken in Cochrane Library, PubMed, Medline, Scopus, Embase, and Web of Science of studies (2000-2020, inclusive). Selection of studies were assessed by pre-specified eligibility criteria and documented using PRISMA. Citations were managed using EndNote X8 whilst selection, reviewing, and data extraction were performed using Covidence. The screening, selection, and data extraction process consisted of two blind, independent reviews followed by a tertiary independent review. An adapted Critical Appraisal Skills Program (CASP) checklist was used to assess quality and bias. The main findings and characteristics of all studies was extracted and summarized. Where appropriate, a meta-analysis will be performed for measures of association., Results: Among 538 original records, 12 eligible articles were identified that analysed associations between ambient temperature exposure and stillbirth for 42,848 stillbirths among 3.4 million births across seven countries. Varied definitions of stillbirth were reported based on gestational age, birthweight, both, or neither. The overall rate of stillbirth ranged from 1.9 to 38.4 per 1000 among six high-income countries and one low-middle-income country. All study designs were retrospective and included ten cohort studies, three case-crossover studies, and two additional case-control subgroup analysis. Exposure data for ambient temperature was mostly derived from standard municipal or country-level monitors based on weather stations (66.6%) or a forecasting model (16.7%); otherwise, not reported (16.7%). Results were not statistically pooled for a meta-analysis due to heterogeneity of methods and models among included studies. All studies reported associations of increased risk of stillbirth with ambient temperature exposures throughout pregnancy, particularly in late pregnancy. One study estimates 17-19% (PAR) of stillbirths are potentially attributable to chronic exposure to hot and cold ambient temperatures during pregnancy. Overall, risk of stillbirth was observed to increase below 15 °C and above 23.4 °C, where highest risk is above 29.4 °C., Conclusion: Exposure to hot and cold temperatures during pregnancy may increase the risk of stillbirth, although a clear causative mechanism remains unknown. Despite lack of causal evidence, existing evidence across diverse settings observed similar effects of increased risk of stillbirth using a variety of statistical and methodological approaches for exposure assessments, exposure windows, and data linkage. Managing exposure to ambient temperatures during pregnancy could potentially decrease risk of stillbirth, particularly among women in low-resource settings where access to safe antenatal and obstetric care is challenging. To fully understand the effects or dose-response relationship of maternal exposure to ambient temperatures and stillbirth, future studies should focus on biological mechanisms and contributing factors in addition to improving measurement of ambient temperature exposure., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Reduced expression of the plasma membrane citrate transporter INDY (acronym I'm Not Dead, Yet) extends life span in lower organisms. Deletion of the mammalian Indy (mIndy) gene in rodents improves metabolism via mechanisms akin to caloric restriction, known to lower blood pressure (BP) by sympathoadrenal inhibition. We hypothesized that mIndy deletion attenuates sympathoadrenal support of BP. Continuous arterial BP and heart rate (HR) were reduced in mINDY-KO mice. Concomitantly, urinary catecholamine content was lower, and the decreases in BP and HR by mIndy deletion were attenuated after autonomic ganglionic blockade. Catecholamine biosynthesis pathways were reduced in mINDY-KO adrenals using unbiased microarray analysis. Citrate, the main mINDY substrate, increased catecholamine content in pheochromocytoma cells, while pharmacological inhibition of citrate uptake blunted the effect. Our data suggest that deletion of mIndy reduces sympathoadrenal support of BP and HR by attenuating catecholamine biosynthesis. Deletion of mIndy recapitulates beneficial cardiovascular and metabolic responses to caloric restriction, making it an attractive therapeutic target.

Objective: After cross-cultural adaption for the German translation of the Ankle-Hindfoot Scale of the American Orthopaedic Foot and Ankle Society (AOFAS-AHS) and agreement analysis with the Foot Function Index (FFI-D), the following gait analysis study using the Oxford Foot Model (OFM) was carried out to show which of the two scores better correlates with objective gait dysfunction., Design and Participants: Results of the AOFAS-AHS and FFI-D, as well as data from three-dimensional gait analysis were collected from 20 patients with mild to severe ankle and hindfoot pathologies.Kinematic and kinetic gait data were correlated with the results of the total AOFAS scale and FFI-D as well as the results of those items representing hindfoot function in the AOFAS-AHS assessment. With respect to the foot disorders in our patients (osteoarthritis and prearthritic conditions), we correlated the total range of motion (ROM) in the ankle and subtalar joints as identified by the OFM with values identified during clinical examination 'translated' into score values. Furthermore, reduced walking speed, reduced step length and reduced maximum ankle power generation during push-off were taken into account and correlated to gait abnormalities described in the scores. An analysis of correlations with CIs between the FFI-D and the AOFAS-AHS items and the gait parameters was performed by means of the Jonckheere-Terpstra test; furthermore, exploratory factor analysis was applied to identify common information structures and thereby redundancy in the FFI-D and the AOFAS-AHS items., Results: Objective findings for hindfoot disorders, namely a reduced ROM, in the ankle and subtalar joints, respectively, as well as reduced ankle power generation during push-off, showed a better correlation with the AOFAS-AHS total score-as well as AOFAS-AHS items representing ROM in the ankle, subtalar joints and gait function-compared with the FFI-D score.Factor analysis, however, could not identify FFI-D items consistently related to these three indicator parameters (pain, disability and function) found in the AOFAS-AHS. Furthermore, factor analysis did not support stratification of the FFI-D into two subscales., Conclusions: The AOFAS-AHS showed a good agreement with objective gait parameters and is therefore better suited to evaluate disability and functional limitations of patients suffering from foot and ankle pathologies compared with the FFI-D., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Context: Depending on its lipolytic activity, glucagon plays a promising role in obesity treatment. Glucagon-induced growth hormone (GH) release can promote its effect on lipid metabolism, although the underlying mechanisms have not been well-defined., Objective: The present study highlights the glucagon effect on the GH/insulinlike growth factor 1 (IGF-1)/IGF-binding protein (IGFBP) axis in vivo and in vitro, taking into consideration insulin as a confounding factor., Materials and Methods: In a double-blind, placebo-controlled study, we investigated changes in GH, IGFBP, and IGF-1 bioactivity after intramuscular glucagon administration in 13 lean controls, 11 obese participants, and 13 patients with type 1 diabetes mellitus (T1DM). The effect of glucagon on the transcription factor forkhead box protein O1 (FOXO1) translocation, the transcription of GH/IGF-1 system members, and phosphorylation of protein kinase B (Akt) was further investigated in vitro., Results: Despite unchanged total IGF-1 and IGFBP-3 levels, glucagon decreased IGF-1 bioactivity in all study groups by increasing IGFBP-1 and IGFBP-2. The reduction in IGF-1 bioactivity occurred before the glucagon-induced surge in GH. In contrast to the transient increase in circulating insulin in obese and lean participants, no change was observed in those with T1DM. In vitro, glucagon dose dependently induced a substantial nuclear translocation of FOXO1 in human osteosarcoma cells and tended to increase IGFBP-1 and IGFBP-2 gene expression in mouse primary hepatocytes, despite absent Akt phosphorylation., Conclusions: Our data point to the glucagon-induced decrease in bioactive IGF-1 levels as a mechanism through which glucagon induces GH secretion. This insulin-independent reduction is related to increased IGFBP-1 and IGFBP-2 levels, which are most likely mediated via activation of the FOXO/mTOR (mechanistic target of rapamycin) pathway., (Copyright © 2017 Endocrine Society)

Reduced expression of the Indy ("I am Not Dead, Yet") gene in lower organisms promotes longevity in a manner akin to caloric restriction. Deletion of the mammalian homolog of Indy (mIndy, Slc13a5) encoding for a plasma membrane-associated citrate transporter expressed highly in the liver, protects mice from high-fat diet-induced and aging-induced obesity and hepatic fat accumulation through a mechanism resembling caloric restriction. We studied a possible role of mIndy in human hepatic fat metabolism. In obese, insulin-resistant patients with nonalcoholic fatty liver disease, hepatic mIndy expression was increased and mIndy expression was also independently associated with hepatic steatosis. In nonhuman primates, a 2-year high-fat, high-sucrose diet increased hepatic mIndy expression. Liver microarray analysis showed that high mIndy expression was associated with pathways involved in hepatic lipid metabolism and immunological processes. Interleukin-6 (IL-6) was identified as a regulator of mIndy by binding to its cognate receptor. Studies in human primary hepatocytes confirmed that IL-6 markedly induced mIndy transcription through the IL-6 receptor and activation of the transcription factor signal transducer and activator of transcription 3, and a putative start site of the human mIndy promoter was determined. Activation of the IL-6-signal transducer and activator of transcription 3 pathway stimulated mIndy expression, enhanced cytoplasmic citrate influx, and augmented hepatic lipogenesis in vivo. In contrast, deletion of mIndy completely prevented the stimulating effect of IL-6 on citrate uptake and reduced hepatic lipogenesis. These data show that mIndy is increased in liver of obese humans and nonhuman primates with NALFD. Moreover, our data identify mIndy as a target gene of IL-6 and determine novel functions of IL-6 through mINDY., Conclusion: Targeting human mINDY may have therapeutic potential in obese patients with nonalcoholic fatty liver disease. German Clinical Trials Register: DRKS00005450. (Hepatology 2017;66:616-630)., (© 2017 by the American Association for the Study of Liver Diseases.)

Aims: Molecular adaptations in human non-alcoholic fatty liver disease (NAFLD) are incompletely understood. This study investigated the main gene categories related to hepatic de novo lipogenesis and lipid oxidation capacity., Methods: Liver specimens of 48 subjects were histologically classified according to steatosis severity. In-depth analyses were undertaken using real-time polymerase chain reaction, immunoblotting, and immunohistochemistry. Lipid profiles were analyzed by gas chromatography/flame ionization detection, and effects of key fatty acids were studied in primary human hepatocytes., Results: Real-time polymerase chain reaction, immunoblotting, and immunohistochemistry indicated 5'AMP-activated protein kinase (AMPK) to be increased with steatosis score ≥ 2 (all P < 0.05), including various markers of de novo lipogenesis and lipid degradation (all P < 0.05). Regarding endoplasmic reticulum stress, X-Box binding protein-1 (XBP1) was upregulated in steatosis score ≥ 2 (P = 0.029) and correlated with plasma palmitate (r = 0.34; P = 0.035). Palmitate incubation of primary human hepatocytes increased XBP1 and downstream stearoyl CoA desaturase-1 mRNA expression (both P < 0.05). Moreover, plasma and liver tissue exposed a NAFLD-related lipid profile with reduced polyunsaturated/saturated fatty acid ratio, increased palmitate and palmitoleate, and elevated lipogenesis and desaturation indices with steatosis score ≥ 2 (all P < 0.05)., Conclusion: In humans with advanced fatty liver disease, hepatic AMPK protein is upregulated, potentially in a compensatory manner. Moreover, pathways of lipid synthesis and degradation are co-activated in subjects with advanced steatosis. Palmitate may drive lipogenesis by activating XBP1-mediated endoplasmic reticulum stress and represent a target for future dietary or pharmacological intervention., (© 2016 The Japan Society of Hepatology.)

Importance: Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant., Objective: To determine the relative effectiveness and safety of 3 common alternate treatments for MDD., Design, Setting, and Participants: From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks., Interventions: Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase)., Main Outcomes and Measures: The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects., Results: Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain., Conclusions and Relevance: Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach., Trial Registration: clinicaltrials.gov Identifier: NCT01421342.

Angiopoietin-like protein 8 (ANGPTL8)/betatrophin expression in visceral adipose tissue and associations with circulating fatty acid profile have not yet been investigated.Forty subjects were included in a cross-sectional study, 57 in a dietary weight reduction intervention. Circulating Angiopoietin-like protein 8/betatrophin was measured in all subjects. Liver and adipose tissue were sampled and plasma fatty acids and tissue Angiopoietin-like protein 8/betatrophin expression were evaluated in the cross-sectional study. In the intervention study oral glucose testing and liver magnetic resonance scanning at baseline and after 6 months were performed. Angiopoietin-like protein 8/betatrophin mRNA was increased in visceral compared to subcutaneous adipose tissue (p<0.001). Circulating ANGPTL8/betatrophin correlated with liver steatosis (r=0.42, p=0.047), triacylglycerols (r=0.34, p=0.046), saturated (r=0.43, p=0.022), monounsaturated (r=0.51, p=0.007), and polyunsaturated fatty acids (r=-0.53, p=0.004). In the intervention study, baseline Angiopoietin-like protein 8/betatrophin correlated with age (r=0.32, p=0.010) and triacylglycerols (r=0.30, p=0.02) and was increased with hepatic steatosis (p=0.033). Weight loss reduced liver fat by 45% and circulating Angiopoietin-like protein 8/betatrophin by 11% (288±17 vs. 258±17 pg/ml; p=0.015). Angiopoietin-like protein 8/betatrophin is related to liver steatosis, while visceral adipose tissue represents an additional site of expression in humans., (© Georg Thieme Verlag KG Stuttgart · New York.)

Non-alcoholic fatty liver disease is a growing problem in industrialized and developing countries. Hepatic lipid accumulation is the result of an imbalance between fatty acid uptake, fatty acid de novo synthesis, β-oxidation and secretion of triglyceride-rich lipoproteins from the hepatocyte. A central regulator of hepatic lipid metabolism is cytosolic citrate that can either be derived from the mitochondrium or be taken up from the blood via the plasma membrane sodium citrate transporter NaCT, the product of the mammalian INDY gene (SLC13A5). mINDY ablation protects against diet-induced steatosis whereas mINDY expression is increased in patients with hepatic steatosis. Diet-induced hepatic steatosis is also enhanced by activation of the arylhyrocarbon receptor (AhR) both in humans and animal models. Therefore, the hypothesis was tested whether the mINDY gene might be a target of the AhR. In accordance with such a hypothesis, the AhR activator benzo[a]pyrene induced the mINDY expression in primary cultures of rat hepatocytes in an AhR-dependent manner. This induction resulted in an increased citrate uptake and citrate incorporation into lipids which probably was further enhanced by the benzo[a]pyrene-dependent induction of key enzymes of fatty acid synthesis. A potential AhR binding site was identified in the mINDY promoter that appears to be conserved in the human promoter. Elimination or mutation of this site largely abolished the activation of the mINDY promoter by benzo[a]pyrene. This study thus identified the mINDY as an AhR target gene. AhR-dependent induction of the mINDY gene might contribute to the development of hepatic steatosis., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Despite its wide use in clinical outcome measurement, there is yet no validated German language version of the AOFAS-AHS available. After finishing cross-cultural adaption of the AOFAS-AHS according to the AAOS guidelines, an analysis of agreement was carried out., Methods: This was done by means of the 18-item Foot Function Index in its validated German translation by Naal et al. (FFI-D). The results of 91 orthopedic patients as well as healthy persons in both scores were then compared intraindividually. The cohort consisted of 46 individuals with hindfoot disorders and 45 persons without any hindfoot complaints. The FFI-D-Score was linearly transformed in the range 0-100 points of the AOFAS., Results: Encouraging correlation was then found for the patients with hindfoot disorders (Spearman's correlation 0.73 (95% CI 0.52-0.85); a median deviation of -2 points (interquartile range -13 points; +13 points) in patients with hindfoot disorders implied good median intraindividual score concordance. However, with 30 of these 46 patients showing score deviations beyond or below a pre-specified ±10 points range of clinically tolerable deviations, the scores cannot be considered exchangeable., Conclusion: Although the agreement analysis was performed for the German translation of the two questionnaires, analogous results can be expected also for other languages. It should be noted that the results do not allow for judging which of the scores is better suited to give a valid statement on patient outcome in treatment of hindfoot disorders. To verify which of these two scores is better suited to represent hindfoot-dysfunction a subsequent study using instrumental gait analysis and surface EMG is being carried out.

Reduced expression of the INDY (I'm not dead yet) tricarboxylate carrier increased the life span in different species by mechanisms akin to caloric restriction. Mammalian INDY homolog (mIndy, SLC13A5) gene expression seems to be regulated by hormonal and/or nutritional factors. The underlying mechanisms are still unknown. The current study revealed that mIndy expression and [(14)C]-citrate uptake was induced by physiological concentrations of glucagon via a cAMP-dependent and cAMP-responsive element-binding protein (CREB)-dependent mechanism in primary rat hepatocytes. The promoter sequence of mIndy located upstream of the most frequent transcription start site was determined by 5'-rapid amplification of cDNA ends. In silico analysis identified a CREB-binding site within this promoter fragment of mIndy. Functional relevance for the CREB-binding site was demonstrated with reporter gene constructs that were induced by CREB activation when under the control of a fragment of a wild-type promoter, whereas promoter activity was lost after site-directed mutagenesis of the CREB-binding site. Moreover, CREB binding to this promoter element was confirmed by chromatin immunoprecipitation in rat liver. In vivo studies revealed that mIndy was induced in livers of fasted as well as in high-fat-diet-streptozotocin diabetic rats, in which CREB is constitutively activated. mIndy induction was completely prevented when CREB was depleted in these rats by antisense oligonucleotides. Together, these data suggest that mIndy is a CREB-dependent glucagon target gene that is induced in fasting and in type 2 diabetes. Increased mIndy expression might contribute to the metabolic consequences of diabetes in the liver.

Cardiac natriuretic peptides (NP) are major activators of human fat cell lipolysis and have recently been shown to control brown fat thermogenesis. Here, we investigated the physiological role of NP on the oxidative metabolism of human skeletal muscle. NP receptor type A (NPRA) gene expression was positively correlated to mRNA levels of PPARγ coactivator-1α (PGC1A) and several oxidative phosphorylation (OXPHOS) genes in human skeletal muscle. Further, the expression of NPRA, PGC1A, and OXPHOS genes was coordinately upregulated in response to aerobic exercise training in human skeletal muscle. In human myotubes, NP induced PGC-1α and mitochondrial OXPHOS gene expression in a cyclic GMP-dependent manner. NP treatment increased OXPHOS protein expression, fat oxidation, and maximal respiration independent of substantial changes in mitochondrial proliferation and mass. Treatment of myotubes with NP recapitulated the effect of exercise training on muscle fat oxidative capacity in vivo. Collectively, these data show that activation of NP signaling in human skeletal muscle enhances mitochondrial oxidative metabolism and fat oxidation. We propose that NP could contribute to exercise training-induced improvement in skeletal muscle fat oxidative capacity in humans.

Recent studies have implicated endoplasmic reticulum (ER) stress in insulin resistance associated with caloric excess. In mice placed on a 3-day high fat diet, we find augmented eIF2α signaling, together with hepatic lipid accumulation and insulin resistance. To clarify the role of the liver ER stress-dependent phospho-eIF2α (eIF2α-P) pathway in response to acute caloric excess on liver and muscle glucose and lipid metabolism, we studied transgenic mice in which the hepatic ER stress-dependent eIF2α-P pathway was inhibited by overexpressing a constitutively active C-terminal fragment of GADD34/PPP1R15a, a regulatory subunit of phosphatase that terminates ER stress signaling by phospho-eIF2α. Inhibition of the eIF2α-P signaling in liver led to a decrease in hepatic glucose production in the basal and clamped state, which could be attributed to reduced gluconeogenic gene expression, resulting in reduced basal plasma glucose concentrations. Surprisingly, hepatic eIF2α inhibition also impaired insulin-stimulated muscle and adipose tissue insulin sensitivity. This latter effect could be attributed at least in part by an increase in circulating IGFBP-3 levels in the transgenic animals. In addition, infusion of insulin during a hyperinsulinemic-euglycemic clamp induced conspicuous ER stress in the 3-day high fat diet-fed mice, which was aggravated through continuous dephosphorylation of eIF2α. Together, these data imply that the hepatic ER stress eIF2α signaling pathway affects hepatic glucose production without altering hepatic insulin sensitivity. Moreover, hepatic ER stress-dependent eIF2α-P signaling is implicated in an unanticipated cross-talk between the liver and peripheral organs to influence insulin sensitivity, probably via IGFBP-3. Finally, eIF2α is crucial for proper resolution of insulin-induced ER stress.

Reduced expression of the Indy (I'm Not Dead, Yet) gene in D. melanogaster and its homolog in C. elegans prolongs life span and in D. melanogaster augments mitochondrial biogenesis in a manner akin to caloric restriction. However, the cellular mechanism by which Indy does this is unknown. Here, we report on the knockout mouse model of the mammalian Indy (mIndy) homolog, SLC13A5. Deletion of mIndy in mice (mINDY(-/-) mice) reduces hepatocellular ATP/ADP ratio, activates hepatic AMPK, induces PGC-1α, inhibits ACC-2, and reduces SREBP-1c levels. This signaling network promotes hepatic mitochondrial biogenesis, lipid oxidation, and energy expenditure and attenuates hepatic de novo lipogenesis. Together, these traits protect mINDY(-/-) mice from the adiposity and insulin resistance that evolve with high-fat feeding and aging. Our studies demonstrate a profound effect of mIndy on mammalian energy metabolism and suggest that mINDY might be a therapeutic target for the treatment of obesity and type 2 diabetes., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: The SALTO total ankle prosthesis is a noncemented mobile bearing anatomic design characterized by dual Ti-HA coating. This study reviews our results with this prosthesis., Materials and Methods: Between 2001 and 2007, 413 consecutive SALTO prostheses were implanted in our institution in 215 women and 198 men, aged 57.1 +/- 11.9 years. At the last visit, 401 implants (47% in the left ankle) were available with a mean followup of 29 (range, 1 to 84) months., Results: Based on the results of the 218 patients with at least 2 years of postoperative followup, the 5-year estimated survivorship, with the primary end-point being implant removal, was 86.6% and ranged from 85.1% in patients with post-traumatic osteoarthritis to 95.6% in those with rheumatoid arthritis. The AOFAS score increased from 50.9 +/- 16.8 points preoperatively to 82.2 +/- 14 points at followup (mean difference, 31.1 +/- 1.4, 95% confidence interval (C.I.) for the difference, 28.3 to 33.8, p < 0.001). Visual analog scale for pain decreased from 7.4 +/- 1.1 preoperatively to 2.0 +/- 2.0 postoperatively (mean difference, -5.4 +/- 0.7, 95% C.I. for the difference, -5.6 to -5.2, p < 0.001). Flexion/extension ROM increased from 25.2 +/- 14.1 degrees to 33.1 +/- 13.6 degrees at the last followup visit (mean difference, 7.9 +/- 0.5 degrees, 95% C.I. for the difference, 4.3 to 7.2, p < 0.001), while pronation/supination ROM increased from 23.8 +/- 13.7 degrees to 25.4 +/- 14.5 degrees (mean difference, 1.6 +/- 0.7 degrees, 95% C.I. for the difference, 0.9 to 2.2, p = 0.005)., Conclusion: The SALTO prosthesis provided good clinical and functional results and we believe helps validate the concept of anatomic replacement.

Objective: The aim of supramalleolar osteotomy of the tibia in the management of varus deformity of the upper ankle joint is to shift load bearing away from the severely degenerated medial part of the joint to the lateral part and thus restore physiological alignment of the hindfoot and a plantigrade foot. The intention is to reduce pain and to postpone the need for total endoprosthesis or arthrodesis., Indications: Painful degeneration of the ankle joint with varus deformity that has proven resistant to conservative treatment, i.e., > 15 degrees axial malalignment of the tibiotalar joint axis., Contraindications: Severe ankle joint degeneration that restricts movement. Florid infections. Extensive bone and soft-tissue defects. Osteonecrosis of the talus with necrotic regions > 50%., Surgical Technique: Anterior approach to the upper ankle joint and supramalleolar wedge-shaped resection of a predetermined bone wedge with lateral base. The desired correction is precisely calculated during preoperative planning. Subsequently, lateral approach over the distal fibula. Resection of a more proximal segment from the fibula. Closure of the tibial osteotomy (closed wedge) and osteosynthesis of the fibula., Results: A supramalleolar valgus osteotomy (closed wedge) was performed in 27 patients from 2002 to 2006. Preoperatively, there was an average varus deformity of 27 degrees , which was corrected to 6 degrees on average postoperatively. 21 patients were very satisfied at follow-up, three patients required joint replacement during the later course, and another three patients needed arthrodesis.