O-linked N-acetylglucosamine modification is essential for physiological adipose expansion induced by high-fat feeding.

Adipose tissues accumulate excess energy as fat and heavily influence metabolic homeostasis. O-linked N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation), which involves the addition of N-acetylglucosamine to proteins by O-GlcNAc transferase (Ogt), modulates multiple cellular processes. However, little is known about the role of O-GlcNAcylation in adipose tissues during body weight gain due to overnutrition. Here, we report on O-GlcNAcylation in mice with high-fat diet (HFD)-induced obesity. Mice with knockout of Ogt in adipose tissue achieved using adiponectin promoter-driven Cre recombinase (Ogt-FKO) gained less body weight than control mice under HFD. Surprisingly, Ogt-FKO mice exhibited glucose intolerance and insulin resistance, despite their reduced body weight gain, as well as decreased expression of de novo lipogenesis genes and increased expression of inflammatory genes, resulting in fibrosis at 24 weeks of age. Primary cultured adipocytes derived from Ogt-FKO mice showed decreased lipid accumulation. Both primary cultured adipocytes and 3T3-L1 adipocytes treated with OGT inhibitor showed increased secretion of free fatty acids. Medium derived from these adipocytes stimulated inflammatory genes in RAW 264.7 macrophages, suggesting that cell-to-cell communication via free fatty acids might be a cause of adipose inflammation in Ogt-FKO mice. In conclusion, O-GlcNAcylation is important for healthy adipose expansion in mice. Glucose flux into adipose tissues may be a signal to store excess energy as fat.NEW & NOTEWORTHY We evaluated the role of O-GlcNAcylation in adipose tissue in diet-induced obesity using adipose tissue-specific Ogt knockout mice. We found that O-GlcNAcylation in adipose tissue is essential for healthy fat expansion and that Ogt-FKO mice exhibit severe fibrosis upon long-term overnutrition. O-GlcNAcylation in adipose tissue may regulate de novo lipogenesis and free fatty acid efflux to the degree of overnutrition. We believe that these results provide new insights into adipose tissue physiology and obesity research.

Bilateral non-traumatic elbow luxation in a Yorkshire terrier puppy.

A 10-week-old Yorkshire terrier had lameness of the right forelimb with complete lateral radioulnar luxation at the humerus, consistent with Type III congenital elbow luxation; this is rarely treated in the presence of multiple skeletal deformities. Lateral subluxation of the radial head at the left elbow was diagnosed as Type I congenital elbow luxation. Procurvatum, distal valgus, and external torsion were present in both antebrachiae. Surgical stabilization of the right elbow was performed with temporary transarticular pins in the humeroulnar and radioulnar joints. A custom-made orthosis was applied to support the surgical reduction for 20 wk. Recurrent luxation was not observed. After complete right-sided function was established, the left forelimb showed noticeable instability in the antebrachium, and the puppy frequently fell while running. The lateral collateral ligament of the left elbow was augmented using screws and synthetic ligaments 22 wk after the right-side surgery. Congruity of the left elbow joint improved, and the puppy could bear full weight on the left forelimb, although slight deficits in movement and falling were observed. We demonstrate the effectiveness of combining a temporary transarticular pin and custom-made orthosis while treating Type III congenital elbow luxation and the inadequacy of collateral ligament augmentation alone for treating Type I congenital elbow luxation with antebrachium deformities. Key clinical message: Herein, we observed that a combination of a temporary transarticular pin and a custom-made orthosis was effective for the treatment of Type III congenital elbow luxations.

Luxation bilatérale non traumatique du coude chez un chiot Yorkshire terrier. Un Yorkshire terrier de 10 semaines présentait une boiterie du membre antérieur droit avec une luxation radio-ulnaire latérale complète au niveau de l'humérus, compatible avec une luxation congénitale du coude de type III; ceci est rarement traité en présence de multiples déformations squelettiques. La subluxation latérale de la tête radiale au niveau du coude gauche a été diagnostiquée comme une luxation congénitale du coude de type I. Procurvatum, valgus distal et torsion externe étaient présents dans les deux sections antébrachiales. La stabilisation chirurgicale du coude droit a été réalisée avec des broches trans-articulaires temporaires dans les articulations huméro-ulnaire et radio-ulnaire. Une orthèse sur mesure a été appliquée pour soutenir la réduction chirurgicale pendant 20 semaines. Aucune luxation récurrente n'a été observée. Une fois la fonction complète du côté droit établie, le membre antérieur gauche a montré une instabilité notable de la section antébrachiale et le chiot tombait fréquemment en courant. Le ligament collatéral latéral du coude gauche a été augmenté à l'aide de vis et de ligaments synthétiques 22 semaines après la chirurgie du côté droit. La congruence de l'articulation du coude gauche s'est améliorée et le chiot pouvait supporter tout son poids sur le membre antérieur gauche, bien que de légers déficits de mouvement et des chutes aient été observés. Nous démontrons l'efficacité de la combinaison d'une broche trans-articulaire temporaire et d'une orthèse sur mesure dans le traitement de la luxation congénitale du coude de type III et l'insuffisance de l'augmentation du ligament collatéral seule pour traiter la luxation congénitale du coude de type I avec des déformations de la section antébrachiale.Message clinique clé:Ici, nous avons observé qu'une combinaison d'une broche trans-articulaire temporaire et d'une orthèse sur mesure était efficace pour le traitement des luxations congénitales du coude de type III.(Traduit par Dr Serge Messier).

Molluscum contagiosum of the corneal limbus in an AIDS patient: a clinicopathological case report.

BACKGROUND: Molluscum contagiosum, a pox virus infection, is likely to occur in the eyelid skin; however, corneal involvements by molluscum lesions are extremely rare. We report a case of molluscum contagiosum arising in the corneal limbus in an untreated AIDS patient, together with anterior segment optical coherence tomography (OCT) findings and histopathology of the excised tumor. CASE PRESENTATION: A 46-year-old man with AIDS was referred to our department for the management of an ocular lesion. Blood tests revealed an extremely low CD4+ T-cell count of 11 cells/µL, being strongly positive for anti-HIV antibody (591.36 S/CO) with a high copy number of HIV RNA (8070.0 × 100 copy/mL). Slit-lamp examination of his right eye showed a white nodule at the lower limbus. Anterior segment OCT findings of the nodule revealed a highly reflective elevated lesion, which was considered to involve the Bowman layer. The nodular lesion was excised from the limbus including the superficial corneal stroma, and then processed for histologic examination. Histopathology of the excised lesion showed acanthotic corneal epithelium containing swollen cells with eosinophilic inclusions known as molluscum bodies. He was diagnosed with molluscum contagiosum. CONCLUSIONS: Anterior segment OCT findings provide useful information for morphological evaluations of and preoperative strategies against molluscum contagiosum.

Effect of durotomy in dogs with thoracolumbar disc herniation and without deep pain perception in the hind limbs.

OBJECTIVE: To determine the effectiveness of durotomy as an adjunct to surgical decompression in dogs with thoracolumbar intervertebral disc herniation (TL-IVDH) and loss of deep pain perception (DPP) in the hind limbs. STUDY DESIGN: Retrospective study. ANIMALS: Dogs (n = 116) with TL-IVDH and loss of DPP treated with hemilaminectomy. METHODS: Signalment, surgical site, recovery rate, incidence of progressive myelomalacia (PMM), time elapsed from onset of paraplegia of the hind limbs to surgery (TPS), and the length of area of hyperintensity of the spinal cord on magnetic resonance T2-weighted images compared with L2 vertebral body length (LHT2) were compared between dogs treated with hemilaminectomy alone and those treated with adjunct durotomy. Multivariate logistic regression analyses were used to test the association between outcomes and the external view of the spinal cord parenchyma after durotomy. RESULTS: The percentage of dogs regaining ambulation was greater when durotomy was performed (56.9%) than when dogs were treated with hemilaminectomy alone (38.5%; P = .04). In the hemilaminectomy group, 14 dogs died of suspected PMM, while no PMM was detected in the durotomy group. Durotomy, breed, surgical site, and LHT2 influenced recovery. No association was detected between age, sex, body weight, and TPS and recovery. CONCLUSION: Performing a durotomy in combination with decompression improved the return to function and prevented PMM in our clinical setting. CLINICAL SIGNIFICANCE: Surgeons should consider durotomy in dogs with TL-IVDH and loss of DPP in hind limbs to improve surgical outcome.

Combined Surgical, Radiation, and Medical Therapies for Osteochondrodysplasia in a Scottish Fold Cat.

Osteochondrodysplasia affects both homozygous and heterozygous Scottish Fold cats, and various treatments have been attempted to control chronic pain and improve mobility in these animals. However, to date, there is no single effective treatment that can be used to treat all cats with Scottish Fold osteochondrodysplasia (SFOCD). A 4 yr old castrated Scottish Fold cat presented with plantar exostoses in the right hindlimb, the largest of which was caudal to the tarsometatarsal joint and had stretched the overlying skin, causing ulceration and bleeding. There was right hindlimb lameness. The cat was diagnosed with SFOCD, and the skin lesions were treated by excision of the exostoses, removal of the damaged skin, and wound closure. All extremities were treated with radiotherapy and subcutaneous pentosan polysulfate for chronic pain. The cat's gait improved after surgery, and increased activity was noted after radiotherapy. There were no signs of excessive bone proliferation or adverse effects at 80 wk postoperatively. In conclusion, a combination of surgical, radiation, and medical therapies could be an effective treatment strategy for SFOCD with skin ulceration.

Microbiome potentiates endurance exercise through intestinal acetate production.

The intestinal microbiome produces short-chain fatty acids (SCFAs) from dietary fiber and has specific effects on other organs. During endurance exercise, fatty acids, glucose, and amino acids are major energy substrates. However, little is known about the role of SCFAs during exercise. To investigate this, mice were administered either multiple antibiotics or a low microbiome-accessible carbohydrate (LMC) diet, before endurance testing on a treadmill. Two-week antibiotic treatment significantly reduced endurance capacity versus the untreated group. In the cecum acetate, propionate, and butyrate became almost undetectable in the antibiotic-treated group, plasma SCFA concentrations were lower, and the microbiome was disrupted. Similarly, 6-wk LMC treatment significantly reduced exercise capacity, and fecal and plasma SCFA concentrations. Continuous acetate but not saline infusion in antibiotic-treated mice restored their exercise capacity (P < 0.05), suggesting that plasma acetate may be an important energy substrate during endurance exercise. In addition, running time was significantly improved in LMC-fed mice by fecal microbiome transplantation from others fed a high microbiome-accessible carbohydrate diet and administered a single portion of fermentable fiber (P < 0.05). In conclusion, the microbiome can contribute to endurance exercise by producing SCFAs. Our findings provide new insight into the effects of the microbiome on systemic metabolism.

Increment of plasma glucose by exogenous glucagon is associated with present and future renal function in type 2 diabetes:a retrospective study from glucagon stimulation test.

BACKGROUND: Glucagon stimulation test (GST) is often employed to assess the insulin reserve of the pancreatic beta cells in diabetic subjects. The clinical significance of the increment of plasma glucose (Δglucose) by exogenous glucagon during GST has not been elucidated. We investigated the relationship between Δglucose and clinical parameters including the liver and renal function in type 2 diabetic subjects, since we hypothesized that Δglucose is associated with the liver and renal function reflecting the capacity for gluconeogenesis in the organs. METHODS: A total of 209 subjects with type 2 diabetes who underwent GST during admission were included in this cross-sectional study. We defined the difference between plasma glucose at fasting and 6 min after intravenous injection of 1 mg glucagon as Δglucose. We assessed correlations between Δglucose and clinical parameters such as diabetic duration, BMI, HbA1c, beta cell function, serum free fatty acids (FFA) which is known to stimulate gluconeogenesis, liver function, the indices of liver function, renal function, and urinary albumin excretion (UAE). RESULTS: In correlation analysis, Δglucose positively correlated to FFA and estimated glomerular filtration rate (eGFR), but inversely to serum creatinine and cystatin C, although Δglucose showed no correlation with both liver function and the indices of residual liver function. Multiple regression analysis revealed that Δglucose was an independent determinant for the eGFR after 1 year, equally BMI, HbA1c, serum lipids, and UAE, which are known as the predictors for the development of chronic kidney disease. CONCLUSION: Our results suggest that Δglucose during GST might be related to gluconeogenesis in the kidney and could be the determinant of future renal function in type 2 diabetes.

Preserving ß-cell function is the major determinant of diabetes remission following laparoscopic sleeve gastrectomy in Japanese obese diabetic patients.

Laparoscopic sleeve gastrectomy has been proven effective in treating obesity-associated type 2 diabetes mellitus (T2DM). However, reports of the effect of laparoscopic sleeve gastrectomy on glucose metabolism in Japanese obese patients with T2DM are rare. The aim of this study was to evaluate the effects of laparoscopic sleeve gastrectomy on glucose tolerance in Japanese obese patients with T2DM, and to analyze factors influencing diabetes remission after surgery. This was a retrospective analysis of data for 24 consecutive patients with T2DM who underwent laparoscopic sleeve gastrectomy. We investigated weight loss and its impact on T2DM 1 year postoperatively. We also compared baseline characteristics and postoperative factors between patients who achieved diabetes remission and patients without remission. Mean body weight loss and percent total weight loss were 23.9 kg and 23.3%, respectively. Mean hemoglobin A1c levels dropped from 7.3 ± 0.3% to 6.1 ± 0.2%, and 18 patients (75%) achieved diabetes remission 1 year postoperatively. Patients achieving remission had significantly lower hemoglobin A1c levels (p = 0.026), higher fasting C-peptide values (p < 0.001), shorter diabetes duration (p < 0.001), lower insulin requirement (p = 0.002), and higher area under the insulin response curve (p < 0.001) and insulinogenic index (p < 0.001) during oral glucose tolerance testing. In conclusion, laparoscopic sleeve gastrectomy is an effective treatment for Japanese obese patients with T2DM. Preserving insulin secretion is the major determinant of diabetes remission.

Glucagon-like peptide-1: glucose homeostasis and beyond.

Glucagon-like peptide-1 (GLP-1), an incretin hormone secreted primarily from the intestinal L-cells in response to meals, modulates nutrient homeostasis via actions exerted in multiple tissues and cell types. GLP-1 and its analogs, as well as compounds that inhibit endogenous GLP-1 breakdown, have become an effective therapeutic strategy for many subjects with type 2 diabetes. Here we review the discovery of GLP-1; its synthesis, secretion, and elimination from the circulation; and its multiple pancreatic and extrapancreatic effects. Finally, we review current options for GLP-1-based diabetes therapy, including GLP-1 receptor agonism and inhibition of GLP-1 breakdown, as well as the benefits and drawbacks of different modes of therapy and the potential for new therapeutic avenues.

Short-term effects of arthrotomy with and without infrapatellar fat pad resection on the normal canine stifle.

OBJECTIVE: To investigate the short-term effects of infrapatellar fat pad (IFP) resection in normal dogs. STUDY DESIGN: Experimental in vivo study. ANIMALS: Five normal adult female beagle dogs. METHODS: The IFP was resected via arthrotomy in the left stifle joint (experimental side) while the right stifle underwent arthrotomy alone (sham side). An orthopedic examination was performed every week for 4 weeks and synovial fluid was analyzed before and 4 weeks after the procedure. The ratio of the length of the patellar ligament to the patellar length (L:P) was calculated on a lateral radiograph of the stifle before, 2 and 4 weeks after the procedure. Patellar depth (PD) and the contact area (CA) between the femur and patella were calculated from computed tomographic images taken at 3 different stifle angles (extended, flexed, hyperflexed) before, immediately after, and 4 weeks following the procedure. The dogs were euthanatized 4 weeks after the procedure for macroscopic and microscopic evaluation of the patellofemoral joint. RESULTS: No difference was found between treatment groups throughout the study. No evidence of postoperative osteoarthritis was detected in any of the dogs. Orthopedic examinations, radiographs, and synovial fluid analyses remained within normal limits. Most PD, but not CA measurements, increased with time in both joints and at all stifle angles. CONCLUSIONS: Excision of the IFP subsequent to medial arthrotomy did not result in any measurable changes in the canine patellofemoral joint when compared with medial arthrotomy alone after 4 weeks of follow-up.

Efficiency of medetomidine for epidural analgesia: Effects on isoflurane requirement and mean systemic arterial blood pressure in dogs.

Five healthy beagle dogs anesthetized with isoflurane were administered medetomidine (α-2 adrenoceptor agonist) by the epidural route. Mean arterial pressure (MAP) and end-tidal concentration of isoflurane (ISO) were measured 1, 2.5, and 4 h after administration. Epidural administration of medetomidine reduced the isoflurane dose required to prevent changes in vital parameters following mechanical stimulation and maintained the MAP at a higher level compared to the control.

Efficacité de la médétomidine pour l'analgésie épidurale : effets sur le besoin d'isoflurane et la tension artérielle systémique moyenne chez les chiens. De la médétomidine a été administrée à cinq chiens Beagle en santé anesthésiés à l'aide de l'isoflurane (agoniste adrénocepteur α-2) par voie épidurale. La tension artérielle moyenne (TAM) et la concentration de fin d'expiration de l'isoflurane (ISO) ont été mesurées 1 heure, 2,5 heures et 4 heures après l'administration. L'administration de médétomidine par épidurale a réduit la dose d'isoflurane requise pour prévenir des changements aux paramètres vitaux après la stimulation mécanique et a maintenu la TAM à un niveau supérieur comparativement au groupe témoin.(Traduit par Isabelle Vallières).

Pancreatic glucose-dependent insulinotropic polypeptide (GIP) (1-30) expression is upregulated in diabetes and PEGylated GIP(1-30) can suppress the progression of low-dose-STZ-induced hyperglycaemia in mice.

AIMS/HYPOTHESIS: Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone released from gut K cells. While the predominant form is GIP(1-42), a shorter form, GIP(1-30), is produced by pancreatic alpha cells and promotes insulin secretion in a paracrine manner. Here, we elucidated whether GIP(1-30) expression is modulated in mouse models of diabetes. We then investigated whether PEGylated GIP(1-30) can improve islet function and morphology as well as suppress the progression to hyperglycaemia in mice treated with low-dose streptozotocin (LD-STZ). METHODS: We examined pancreatic GIP immunoreactivity in rodent diabetic models. We synthesised [D-Ala(2)]GIP(1-30) and modified the C-terminus with polyethylene glycol (PEG) to produce a dipeptidyl peptidase-4 (DPP-4)-resistant long-acting GIP analogue, [D-Ala(2)]GIP(1-30)-PEG. We performed i.p.GTT and immunohistochemical analysis in non-diabetic and LD-STZ diabetic mice, with or without administration of [D-Ala(2)]GIP(1-30)-PEG. RESULTS: Pancreatic GIP expression was concomitantly enhanced with alpha cell expansion in rodent models of diabetes. Treatment with DPP-4 inhibitor decreased both the GIP- and glucagon-positive areas and preserved the insulin-positive area in LD-STZ diabetic mice. Body weight was not affected by [D-Ala(2)]GIP(1-30)-PEG in LD-STZ or non-diabetic mice. Treatment with GIP significantly ameliorated chronic hyperglycaemia and improved glucose excursions in LD-STZ mice. Treatment with GIP also reduced alpha cell expansion in the islets and suppressed plasma glucagon levels compared with non-treated LD-STZ mice. Additionally, [D-Ala(2)]GIP(1-30)-PEG preserved beta cell area via inhibition of apoptosis in LD-STZ mice. CONCLUSIONS/INTERPRETATION: Our data suggest that GIP(1-30) expression is upregulated in diabetes, and PEGylated GIP(1-30) can suppress the progression to STZ-induced hyperglycaemia by inhibiting beta cell apoptosis and alpha cell expansion.

Insulin-producing intestinal K cells protect nonobese diabetic mice from autoimmune diabetes.

BACKGROUND & AIMS: Type 1 diabetes is caused by an aberrant response against pancreatic ß cells. Intestinal K cells are glucose-responsive endocrine cells that might be engineered to secrete insulin. We generated diabetes-prone non-obese diabetic (NOD) mice that express insulin, via a transgene, in K cells. We assessed the effects on immunogenicity and diabetes development. METHODS: Diabetes incidence and glucose homeostasis were assessed in NOD mice that expressed mouse preproinsulin II from a transgene in K cells and nontransgenic NOD mice (controls); pancreas and duodenum tissues were collected and analyzed by histology. We evaluated T cell responses to insulin, levels of circulating autoantibodies against insulin, and the percentage of circulating antigen-specific T cells. Inflammation of mesenteric and pancreatic lymph node cells was also evaluated. RESULTS: The transgenic mice tended to have lower blood levels of glucose than control mice, associated with increased plasma levels of immunoreactive insulin and proinsulin. Fewer transgenic mice developed diabetes than controls. In analyses of pancreas and intestine tissues from the transgenic mice, insulin-producing K cells were not affected by the immune response and the mice had reduced destruction of endogenous ß cells. Fewer transgenic mice were positive for insulin autoantibodies compared with controls. Cells isolated from mesenteric lymph nodes of the transgenic mice had significantly lower rates of proliferation and T cells from transgenic mice tended to secrete lower levels of inflammatory cytokines than from controls. At 15 weeks, transgenic mice had fewer peripheral CD8(+) T cells specific for NRP-V7 than control mice. CONCLUSIONS: NOD mice with intestinal K cells engineered to express insulin have reduced blood levels of glucose, are less likely to develop diabetes, and have reduced immunity against pancreatic ß cells compared with control NOD mice. This approach might be developed to treat patients with type 1 diabetes.

Dipeptidyl peptidase-4 inhibitors in progressive kidney disease.

PURPOSE OF REVIEW: Dipeptidyl peptidase-4 (DPP-4) inhibitors are incretin-based drugs approved for the treatment of type 2 diabetes. The main action of DPP-4 inhibitors is to increase the level of incretin hormones such as glucagon-like peptide-1 (GLP-1), thereby stimulating insulin secretion from pancreatic ß cells. Recently emerging evidence suggests the pleiotropic extrapancreatic function of GLP-1 or DPP-4 inhibitors, including kidney and cardiovascular protection. Here, we review the effects of DPP-4 inhibitors on progressive kidney disease such as diabetic nephropathy from a therapeutic point of view. RECENT FINDINGS: A growing number of studies in animal models and human diseases have shown that DPP-4 inhibition ameliorates kidney disease by a process independent of glucose lowering. Possible mechanisms underlying such protective properties include the facilitation of natriuresis and reduction of blood pressure, and also local effects of the reduction of oxidative stress, inflammation and improvement of endothelial function in the kidney. DPP-4 inhibitors may also restore other DPP-4 substrates which have proven renal effects. SUMMARY: Treatment of diabetes with DPP-4 inhibitors is likely to involve a variety of extrapancreatic effects including renal protection. Such pleiotropic action of DPP-4 inhibitors might occur by both incretin-dependent and incretin-independent mechanisms. Conclusive evidence is needed to translate the favorable results from animal models to humans.

Bacteria hijack integrin-linked kinase to stabilize focal adhesions and block cell detachment.

The rapid turnover and exfoliation of mucosal epithelial cells provides an innate defence system against bacterial infection. Nevertheless, many pathogenic bacteria, including Shigella, are able to surmount exfoliation and colonize the epithelium efficiently. Here we show that the Shigella flexneri effector OspE (consisting of OspE1 and OspE2 proteins), which is highly conserved among enteropathogenic Escherichia coli, enterohaemorrhagic E. coli, Citrobacter rodentium and Salmonella strains, reinforces host cell adherence to the basement membrane by interacting with integrin-linked kinase (ILK). The number of focal adhesions was augmented along with membrane fraction ILK by ILK-OspE binding. The interaction between ILK and OspE increased cell surface levels of 1 integrin and suppressed phosphorylation of focal adhesion kinase and paxillin, which are required for rapid turnover of focal adhesion in cell motility. Nocodazole-washout-induced focal adhesion disassembly was blocked by expression of OspE. Polarized epithelial cells infected with a Shigella mutant lacking the ospE gene underwent more rapid cell detachment than cells infected with wild-type Shigella. Infection of guinea pig colons with Shigella corroborated the pivotal role of the OspE-ILK interaction in suppressing epithelial detachment, increasing bacterial cell-to-cell spreading, and promoting bacterial colonization. These results indicate that Shigella sustain their infectious foothold by using special tactics to prevent detachment of infected cells.

Intraoperative acridine orange photodynamic therapy and cribriform electron-beam irradiation for canine intranasal tumors: A pilot study.

Untreated canine intranasal tumors carry a poor prognosis. We retrospectively evaluated the efficacy of marginal tumor resection in combination with intraoperative acridine orange (AO) photodynamic therapy (PDT) and 1 fraction of 5 Gy megavoltage irradiation for canine intranasal malignant tumors. When cribriform plate invasion or turbinate destruction around the cribriform plate was present, an additional fraction of 20 Gy was delivered with an electron beam during surgery. The study included 6 dogs, 2 of which were classified as stage I, 1 as stage II, and 3 as stage IV. The median local disease-free survival time and overall survival after the treatment were 8.5 and 13 months, respectively. Recurrence was noted in 2 of the 6 dogs after 4 and 7 months. Adverse events were mild (subcutaneous emphysema in 1 case, and rhinitis in 3 cases). Combination AO therapy may increase the tumor control time of dogs with marginally resectable intranasal malignant tumors.

Pour des tumeurs intra-nasales malignes, une thérapie photodynamique administrant de l'acridine orange pendant l'opération et une irradiation par mégavoltage aux plaques cribriforms: l'etude préliminaire. Le pronostic des tumeurs intra-nasales canines non traitées est défavorable. Cette étude avait pour objectif d'évaluer rétrospectivement l'efficacité de la résection marginale d'une tumeur associée à une thérapie photodynamique (TPD) administrant de l'acridine orange (AO) pendant l'opération et à 1 fraction de 5 Gy d'irradiation par mégavoltage dans le traitement des tumeurs intra-nasales malignes. En cas d'invasion des plaques cribriformes et/ou de présence de cornets autour des lésions cribriformes, une fraction supplémentaire de 20 Gy a été administrée pendant l'opération par faisceaux d'électrons. Six chiens ont été inclus dans l'étude. Deux chiens présentaient des tumeurs de stade I, un de stade II et trois de stade IV. La durée moyenne de survie sans récidive locale et de survie globale après le traitement étaient respectivement de 8,5 et 13 mois. Une nouvelle tumeur est apparue chez deux des six chiens, respectivement 4 et 7 mois après le traitement. Les effets indésirables étaient bénins (un cas d'emphysème sous-cutané et trois cas de rhinite. L'association de la thérapie par AO améliorerait la durée de contrôle de la tumeur chez les chiens présentant des tumeurs intra-nasales malignes marginalement résécables.(Traduit par les auteurs).

Loss of HIF-1α impairs GLUT4 translocation and glucose uptake by the skeletal muscle cells.

Defects in glucose uptake by the skeletal muscle cause diseases linked to metabolic disturbance such as type 2 diabetes. The molecular mechanism determining glucose disposal in the skeletal muscle in response to cellular stimuli including insulin, however, remains largely unknown. The hypoxia-inducible factor-1α (HIF-1α) is a transcription factor operating in the cellular adaptive response to hypoxic conditions. Recent studies have uncovered pleiotropic actions of HIF-1α in the homeostatic response to various cellular stimuli, including insulin under normoxic conditions. Thus we hypothesized HIF-1α is involved in the regulation of glucose metabolism stimulated by insulin in the skeletal muscle. To this end, we generated C2C12 myocytes in which HIF-1α is knocked down by short-hairpin RNA and examined the intracellular signaling cascade and glucose uptake subsequent to insulin stimulation. Knockdown of HIF-1α expression in the skeletal muscle cells resulted in abrogation of insulin-stimulated glucose uptake associated with impaired mobilization of glucose transporter 4 (GLUT4) to the plasma membrane. Such defect seemed to be caused by reduced phosphorylation of the protein kinase B substrate of 160 kDa (AS160). AS160 phosphorylation and GLUT4 translocation by AMP-activated protein kinase activation were abrogated as well. In addition, expression of the constitutively active mutant of HIF-1α (CA-HIF-1α) or upregulation of endogenous HIF-1α in C2C12 cells shows AS160 phosphorylation comparable to the insulin-stimulated level even in the absence of insulin. Accordingly GLUT4 translocation was increased in the cells expressing CA-HIF1α. Taken together, HIF-1α is a determinant for GLUT4-mediated glucose uptake in the skeletal muscle cells thus as a possible target to alleviate impaired glucose metabolism in, e.g., type 2 diabetes.

Acetate derived from the intestinal tract has a critical role in maintaining skeletal muscle mass and strength in mice.

Acetate is a short-chain fatty acid (SCFA) that is produced by microbiota in the intestinal tract. It is an important nutrient for the intestinal epithelium, but also has a high plasma concentration and is used in the various tissues. Acetate is involved in endurance exercise, but its role in resistance exercise remains unclear. To investigate this, mice were administered either multiple antibiotics with and without oral acetate supplementation or fed a low-fiber diet. Antibiotic treatment for 2 weeks significantly reduced grip strength and the cross-sectional area (CSA) of muscle fiber compared with the control group. Intestinal concentrations of SCFAs were reduced in the antibiotic-treated group. Oral administration of acetate with antibiotics prevented antibiotic-induced weakness of skeletal muscle and reduced CSA of muscle fiber. Similarly, a low-fiber diet for 1 year significantly reduced the CSA of muscle fiber and fecal and plasma acetate concentrations. To investigate the role of acetate as an energy source, acetyl-CoA synthase 2 knockout mice were used. These mice had a shorter lifespan, reduced skeletal muscle mass and smaller CSA of muscle fiber than their wild type littermates. In conclusion, acetate derived from the intestinal microbiome can contribute to maintaining skeletal muscle performance.

Case report: Impact of hyperthyroidism on psychotic symptoms in schizophrenia comorbid with Graves' disease.

Introduction: Auditory hallucinations are the most common type of hallucinations observed in schizophrenia; however, visual hallucinations are not uncommon. In Graves' disease, depression, hypomania, and psychosis can occur. While the association between Graves' disease and psychosis has been explored, understanding of the specific impact of thyroid dysfunction severity on psychiatric symptom severity is limited. Here, we present a case report of a patient with schizophrenia comorbid with Graves' disease whose psychotic symptoms were impacted by hyperthyroidism. Case: The patient was a 32-year-old Japanese woman who presented with auditory and visual hallucinations, agitation, and pressured speech. The patient was diagnosed with schizophrenia comorbid with Graves' disease and thyroid storm. The patient's psychotic symptoms were found to be associated with fluctuations in thyroid hormone levels, and visual hallucinations were observed only during thyroid storms. Treatment involved dexamethasone, potassium iodide, bisoprolol fumarate, and methimazole for thyrotoxicosis, and a blonanserin transdermal patch, paliperidone, and paliperidone palmitate for psychotic symptoms. The patient's auditory and visual hallucinations improved with antipsychotic treatment and decreased thyroid hormone levels. Conclusion: This case highlights the importance of monitoring thyroid function in patients with schizophrenia, particularly those with comorbid Graves' disease. The correlation between psychiatric symptoms and thyroid hormone levels was demonstrated on an individual level over time, with symptoms worsening as thyroid hormone levels increased. Additionally, our case suggests that abnormally high thyroid hormone levels may trigger visual hallucinations in individuals with schizophrenia. Further studies are needed to elucidate the underlying mechanisms and potential treatment implications of this association.

A family with type A insulin resistance syndrome caused by a novel insulin receptor mutation.

Summary: A 17-year-old boy was referred to our endocrinology clinic for a clinical investigation of hyperinsulinemia. An oral glucose tolerance test showed plasma glucose concentrations in the normal range. However, insulin concentrations were considerably elevated (0 min: 71 µU/mL; 60 min: 953 µU/mL), suggesting severe insulin resistance. An insulin tolerance test confirmed that he had insulin resistance. There was no apparent hormonal or metabolic cause, including obesity. The patient had no outward features of hyperinsulinemia, including acanthosis nigricans or hirsutism. However, his mother and grandfather also had hyperinsulinemia. Genetic testing showed that the patient (proband), his mother, and his grandfather had a novel p.Val1086del heterozygous mutation in exon 17 of the insulin receptor gene (INSR). Although all three family members have the same mutation, their clinical courses have been different. The onset of the mother's diabetes was estimated at 50 years, whereas the grandfather developed diabetes at 77 years. Learning points: Type A insulin resistance syndrome is caused by mutations in the insulin receptor (INSR) gene and results in severe insulin resistance. Genetic evaluation should be considered in adolescents or young adults with dysglycemia when an atypical phenotype, such as severe insulin resistance, or a relevant family history is observed. Clinical courses may differ even if the same genetic mutation is found in a family.