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.

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.

Ketone bodies: A double-edged sword for mammalian life span.

Accumulating evidence suggests health benefits of ketone bodies, and especially for longevity. However, the precise role of endogenous ketogenesis in mammalian life span, and the safety and efficacy of the long-term exogenous supplementation of ketone bodies remain unclear. In the present study, we show that a deficiency in endogenous ketogenesis, induced by whole-body Hmgcs2 deletion, shortens life span in mice, and that this is prevented by daily ketone body supplementation using a diet containing 1,3-butanediol, a precursor of ß-hydroxybutyrate. Furthermore, feeding the 1,3-butanediol-containing diet from early in life increases midlife mortality in normal mice, but in aged mice it extends life span and prevents the high mortality associated with atherosclerosis in ApoE-deficient mice. By contrast, an ad libitum low-carbohydrate ketogenic diet markedly increases mortality. In conclusion, endogenous ketogenesis affects mammalian survival, and ketone body supplementation may represent a double-edged sword with respect to survival, depending on the method of administration and health status.

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.

Coexistence of Pheochromocytoma and Primary Aldosteronism due to Multiple Aldosterone-producing Micronodules in the Ipsilateral Adrenal Gland.

A 46-year-old woman was referred for hypertension and a right adrenal tumor. Primary aldosteronism (PA) was suspected because of the high plasma aldosterone concentration-to-plasma renin activity ratio. However, a subsequent evaluation revealed coexistent PA and pheochromocytoma. We performed laparoscopic right adrenalectomy. Histology of the resected adrenal gland confirmed pheochromocytoma and multiple aldosterone-producing adrenocortical micronodules. Following adrenalectomy, the urinary catecholamine levels normalized, and hyperaldosteronism improved but persisted. Hypertension also improved but persisted and was normalized with spironolactone. The clinical course indicated that the PA lesions were likely bilateral. This was a histologically proven case of coexistent pheochromocytoma and PA due to multiple aldosterone-producing micronodules.

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).

Force plate analysis of ground reaction forces in relation to gait velocity of healthy Beagles.

OBJECTIVE: To evaluate changes in ground reaction forces (GRFs) in relation to gait velocity using 2 force plates (FPs) for healthy Beagles. ANIMALS: 18 healthy Beagles were included (body weight, 10.45 ± 1.28 kg; age, 26 ± 11 months). PROCEDURES: Ten GRF parameters were measured at three gait velocities (walk, 0.9 to 1.2 m/s; trot 1, 1.6 to 2.0 m/s; and trot 2, 2.1 to 2.5 m/s): peak lateral force (PLF), peak medial force (PMF), lateral impulse (LI), medial impulse (MI), peak propulsive force (PPF), peak braking force (PBF), propulsive impulse (PI), braking impulse (BI), peak vertical force (PVF), and vertical impulse (VI). RESULTS: As velocity increased, the PVF of all limbs increased, the VI of all limbs decreased, and the PPF of the forelimbs increased. At all velocities, PBF and BI were significantly higher than the PPF and PI in forelimbs; however, PBF and BI were significantly lower than the PPF and PI in hindlimbs. There were no significant differences in the PLF, PMF, LI, and MI of the forelimbs and hindlimbs among all velocities. The PLF was significantly higher than the PMF of forelimbs during trot 1 and trot 2. CLINICAL RELEVANCE: These results may be useful when comparing healthy Beagles with diseased ones when premorbid data are not available. Because the forelimbs are mainly responsible for the braking force, it is suggested that weight bearing is more stable in the forelimbs than in the hindlimbs, which are mainly responsible for the propulsive force, and that a greater force is generated laterally than medially during trot.

Clinical practice of diabetic foot, nephropathy, and retinopathy in Japan: cross-sectional study using local and nationwide questionnaire surveys.

Aims/introduction: It is a reality that there are still many diabetic subjects who suffer from serious complications, but there are few statistics of severe eye complications such as vitrectomy or blindness and diabetic foot including amputations in Japan. Materials and methods: To determine the status of medical examination, consultation, and the actual practice for diabetic foot, retinopathy, and nephropathy, we conducted two surveys on diabetic subjects under treatment by the local physicians in Asahikawa area or in the nationwide diabetes-specialized facilities, respectively. Results: A total of 3649 diabetic subjects responded to the questionnaire from 35 clinics/hospitals in Asahikawa area. Sixty-five percent of the subjects had a routine eye examination at least once a year, but 29% of them interrupted or never attended eye examination. Besides, only 37.2% of subjects had received ankle-brachial index (ABI) test as a useful screening for diabetic foot. The nationwide survey found that 1,273,103 diabetic subjects were undergoing treatment in 472 diabetes-specialized facilities. There, lower extremity amputations accounted for 0.23% and revascularization accounted for 0.64% of the subjects. However, outpatient foot care and dialysis preventive outpatient services were offered only in 77.3% and 66.5% of the facilities, respectively. Furthermore, we found a lower availability of ophthalmologic treatments even in some of the specialized facilities. Conclusion: We considered that interruption and non-attendance of eye examinations were a barrier to prevent severe retinopathy. Our results also suggested that some of the specialized facilities may be inadequate in their efforts to detect and prevent these complications.

Effect of diabetes and prediabetes on the development of disability and mortality among middle-aged Japanese adults: A 22-year follow up of NIPPON DATA90.

AIMS/INTRODUCTION: To examine the association between diabetes and prediabetes at baseline, and disability, mortality over a 22-year period among middle-aged Japanese adults. MATERIALS AND METHODS: Participants consisted of 1,788 adults aged 45-64 years at baseline from the cohort study National Integrated Project for Prospective Observation of Non-communicable Disease and its Trends in the Aged 1990 (NIPPON DATA90). Disability, defined as having a decline in activities of daily living (ADL), was assessed by a modified Katz questionnaire at four time points. Disability and death without disability for 22-year follow up were used as outcomes to test the association with a diagnosis of diabetes or prediabetes at baseline, using multinomial logistic regression. Adjusted odds ratios (ORs) were obtained from four models that contained appropriate adjustment factors, such as age, sex, smoking status, drinking status, body mass index and cardiovascular risk factors (hypertension, hypercholesterolemia, triglycerides, low serum high-density lipoprotein), at baseline. RESULTS: In the present study, 334 participants (18.7%) reported at least one disability, and 350 (19.6%) were reported dead without observation of disability during follow up. Adjusting sex and other risk factors, participants with diabetes and prediabetes had a higher risk for disability (OR 1.43, 95% confidence interval [CI] 1.07-1.91 and OR 1.66, 95% CI 1.10-2.50, respectively) and for mortality (OR 1.56, 95% CI 1.16-2.08 and OR 1.77, 95% CI 1.18-2.65, respectively) than individuals with normal glucose tolerance. CONCLUSIONS: In middle-aged Japanese adults, individuals with diabetes and prediabetes were more likely to be associated with disability and mortality. Our findings suggest that prediabetes and diabetes in middle-aged adults should be paid more attention, and requires more intervention to prevent disability and mortality in later life.

Glycaemia and body weight are regulated by sodium-glucose cotransporter 1 (SGLT1) expression via O-GlcNAcylation in the intestine.

OBJECTIVE: The intestine is an important organ for nutrient metabolism via absorption and endocrine systems. Nutrients regulate O-GlcNAcylation, a post-translational modification of various proteins by O-GlcNAc transferase (OGT). We have previously shown that general OGT knockout induced severe weight loss and hypoglycaemia in mice, but little is known about how O-GlcNAcylation in the intestine modulates nutrient metabolism, especially glucose metabolism, through absorption. We aimed to reveal the roles of O-GlcNAcylation in glucose absorption by the small intestine and elucidate the mechanism by which O-GlcNAcylation regulates sodium-glucose cotransporter 1 (SGLT1) expression. METHODS: First, we fasted normal mice and examined the changes in glucose transporters and O-GlcNAcylation in the intestine. Then, we generated two lines of small intestine-specific OGT-deficient mice (congenital: Ogt-VKO, tamoxifen-inducible: Ogt-iVKO) and observed the changes in body weight and in glucose and lipid metabolism. Finally, we investigated Sglt1 gene regulation by O-GlcNAcylation using enteroendocrine STC-1 cells. RESULTS: Fasting decreased O-GlcNAcylation in the intestinal epithelium of normal mice. The Ogt-VKO mice showed significantly lower non-fasted blood glucose levels and were underweight compared with litter matched controls. Glycaemic excursion in the Ogt-VKO mice was significantly lower during the oral glucose tolerance test but comparable during the intraperitoneal glucose tolerance test. Furthermore, the Ogt-VKO mice exhibited lower Sglt1 expression in the small intestine compared with the control mice. We obtained similar results using the Ogt-iVKO mice only after tamoxifen administration. The oral d-xylose administration test revealed that the intestinal sugar absorption was diminished in the Ogt-iVKO mice and that GLP-1 secretion did not sufficiently increase after glucose gavage in the Ogt-iVKO mice. When using STC-1 cells, O-GlcNAcylation increased Sglt1 mRNA via a PKA/CREB-dependent pathway. CONCLUSION: Collectively, loss of O-GlcNAcylation in the intestine reduced glucose absorption via suppression of SGLT1 expression; this may lead to new treatments for malabsorption, obesity and diabetes.

Metabolic changes induced by dapagliflozin, an SGLT2 inhibitor, in Japanese patients with type 2 diabetes treated by oral anti-diabetic agents: A randomized, clinical trial.

AIM: We aimed to determine whether SGLT2 inhibitor dapagliflozin treatment affects body composition and amino acid (AA) metabolism. METHODS: Fifty-two overweight patients treated by oral antidiabetic agents were randomly assigned to dapagliflozin (Dapa) or a standard treatment (Con) and followed for 24 weeks. The primary outcome was the change in body mass (BM) between baseline and week 24. Body composition, intrahepatic triglyceride (IHTG) content, and plasma AA concentrations were examined as secondary outcomes. RESULTS: The change in BM was significantly larger in the Dapa than in the Con group, with a difference in the mean change of -1.72 kg (95 %CI: -2.85, -0.59; P = 0.004) between the groups. Total fat mass was reduced by dapagliflozin treatment, but fat-free mass was maintained. IHTG content was significantly reduced in the Dapa than in the Con (P = 0.033). Changes in AAs showed small differences between the groups, but only serine concentrations were significantly reduced in the Dapa. Intra-group analysis showed that positive associations were observed between changes in branched chain AA concentrations and body composition only in the Dapa. CONCLUSIONS: Dapagliflozin treatment causes a reduction in BM mainly by reducing fat mass. AA metabolism shows subtle changes with dapagliflozin treatment.

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.

Determining the Variation in the Tibial Tuberosity Transposition Distance That Is Required to Correct the Quadriceps Angle With the Severity of Medial Patellar Luxation of the Canine Stifle Joint.

The aim of this study was to evaluate the transposition distance in in vitro canine medial patellar luxation (MPL) models of different severity grades using a single radiograph of the stifle joint. Each MPL grade model was generated with manipulation and evaluated by palpating the stability of the patella. An anterior-posterior radiograph of the entire hind limb with extended hip and stifle joints, including the iliopubic eminence, was used for all measurements. The quadriceps angles and the percentage of the transposition distance to the maximum width of the proximal tibia were measured. Our results demonstrated that when the tibial tuberosity transposition procedure is performed in a clinical setting, the required distance to correct the abnormal direction of the extensor mechanism in the canine stifle joint was greater in severe grade MPL than in mild grade MPL.

Determination of the insertion position of implants for the cross-pin fixation of distal femoral physis fractures.

The cross-pin technique for the treatment of distal femoral physis fractures (specifically, Salter-Harris Type I fractures) was investigated using femurs collected from beagle cadavers. The pin was inserted from the medial surface of the femur at an inclination of approximately 30 to 45° relative to the long axis of the femur in the anteroposterior direction; the pin exit was set proximal to the origin of the long digital extensor tendon. Digital and radiographic images of the femur in the anteroposterior and lateral directions were obtained. In both types of images, the insertion angle of the pin relative to the long axis was measured. Results suggest that when inserting a pin proximal to the fracture line, the ideal position can be achieved by inclining the pin approximately 20° cranially relative to the long axis of the lateral direction of the femur, in addition to the previously described criteria.

La technique des tiges croisées pour le traitement des fractures de la physe fémorale distale (en particulier, les fractures de Salter-Harris de type I) a été étudiée à l'aide de fémurs prélevés sur des cadavres de beagle. La tige a été insérée à partir de la surface médiale du fémur à une inclinaison d'environ 30 à 45° par rapport au grand axe du fémur dans la direction antéropostérieure; la sortie de la tige était localisée en amont de l'origine du tendon extenseur digital long. Des images numériques et radiographiques du fémur dans les directions antéropostérieure et latérale ont été obtenues. Dans les deux types d'images, l'angle d'insertion de la tige par rapport au grand axe a été mesuré. Les résultats suggèrent que lors de l'insertion d'une tige proximale au trait de fracture, la position idéale peut être obtenue en inclinant la tige d'environ 20° crânialement par rapport au grand axe de la direction latérale du fémur, en plus des critères décrits précédemment.(Traduit par Docteur Serge Messier).

Acromegaly Cases Exhibiting Increased Growth Hormone Levels during Oral Glucose Loading with Preadministration of Dipeptidyl Peptidase-4 Inhibitor.

Objective Glucose-dependent insulinotropic polypeptide (GIP) is speculated to worsen growth hormone (GH) hypersecretion in acromegaly and to be a cause of paradoxical increases in GH (PI-GH) during 75-g oral glucose tolerance testing (75-g OGTT). Dipeptidyl peptidase-4 inhibitors (DPP4is), which increase the circulating concentration of active GIP, are frequently administered to diabetic patients, including those with acromegaly. We aimed to determine whether or not the administration of a DPP4i increases GH concentration, especially in patients demonstrating PI-GH during a DPP4i-OGTT, in which a DPP4i was administered immediately before 75-g OGTT. Methods This prospective cross-sectional study was carried out on acromegalic patients admitted to Hokkaido University hospital between June 2011 and May 2018. The participants underwent both 75-g OGTT and DPP4i-OGTT. For those who underwent surgery, immunohistochemical staining and quantitative polymerase chain reaction (PCR) for the GIP receptor (GIPR) were performed on the resected pituitary adenomas. Results Twenty-five percent of the participants had PI-GH confirmed (3 of 12 cases). Two of the three participants who demonstrated PI-GH exhibited higher circulating GH concentrations during DPP4i-OGTT than during OGTT. The increase in plasma glucose was reduced during DPP4i-OGTT compared to during 75-g OGTT, suggesting that the increase in GH during DPP4i-OGTT was due not to high glucose concentrations but instead increased GIP caused by the administration of DPP4i. The adenoma from one participant with PI-GH displayed positive immunostaining for GIPR and a higher GIPR messenger ribonucleic acid (mRNA) expression than the others. Conclusion DPP4i may enhance the GH secretion response during glucose loading, especially in individuals with PI-GH.

Investigation of the effects of excessive tibial plateau angle and changes in load on ligament tensile forces in the stifle joints of dogs.

OBJECTIVE: To investigate the effect of an excessive tibial plateau angle (TPA) and change in compressive load on tensile forces experienced by the cranial cruciate, medial collateral, and lateral collateral ligaments (CCL, MCL, and LCL, respectively) of canine stifle joints. SAMPLE: 16 cadaveric stifle joints from 16 orthopedically normal Beagles. PROCEDURES: Stifle joints were categorized into unchanged (mean TPA, 30.4°) and excessive (mean TPA before and after modification, 31.2° and 41.1°, respectively) TPA groups. The excessive TPA group underwent a TPA-increasing procedure (curvilinear osteotomy of the proximal aspect of the tibia) to achieve the desired TPA. A robotic system was used to apply a 30- and 60-N compressive load to specimens. The craniomedial band of the CCL, caudolateral band of the CCL, MCL, and LCL were sequentially transected; load application was repeated after each transection. Orthogonal force components were measured in situ. Forces on ligaments were calculated after repeated output force measurements as the contribution of each component was eliminated. RESULTS: Increasing the compressive load increased tensile forces on the craniomedial and caudolateral bands of the CCL, but not on the MCL or LCL, in specimens of both groups. At the 60-N load, tensile force on the craniomedial band, but not other ligaments, was greater for the excessive TPA group than for the unchanged TPA group. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that stress on the CCL may increase when the compressive load increases. The TPA-increasing procedure resulted in increased tensile force on the CCL at a 60-N compressive load without affecting forces on the MCL or LCL.

A Low-Carbohydrate Diet Improves Glucose Metabolism in Lean Insulinopenic Akita Mice Along With Sodium-Glucose Cotransporter 2 Inhibitor.

Objective: A low-carbohydrate diet (LC) can be beneficial to obese subjects with type2 diabetes mellitus (T2DM). Sodium-glucose cotransporter 2 inhibitor (SGLT2i) presents prompt glucose-lowering effects in subjects with T2DM. We investigated how LC and SGLT2i could similarly or differently influence on the metabolic changes, including glucose, lipid, and ketone metabolism in lean insulinopenic Akita mice. We also examined the impacts of the combination. Methods: Male Akita mice were fed ad libitum normal-carbohydrate diet (NC) as a control or low-carbohydrate diet (LC) as an intervention for 8 weeks with or without SGLT2i treatment. Body weight and casual bold glucose levels were monitored during the study, in addition to measuring TG, NEFA, and ketone levels. We quantified gene expressions involved in gluconeogenesis, lipid metabolism and ketogenesis in the liver and the kidney. We also investigated the immunostaining analysis of pancreatic islets to assess the effect of islet protection. Results: Both LC and SGLT2i treatment reduced chronic hyperglycemia. Moreover, the combination therapy additionally ameliorated glycemic levels and preserved the islet morphology in part. LC but not SGLT2i increased body weight accompanied by epididymal fat accumulation. In contrast, SGLT2i, not LC potentiated four-fold ketone production with higher ketogenic gene expression, in comparison with the non-treated Akita mice. Besides, the combination did not enhance further ketone production compared to the SGLT2i alone. Conclusions: Our results indicated that both LC and SGLT2i reduced chronic hyperglycemia, and the combination presented synergistic favorable effects concomitantly with amelioration of islet morphology, while the combination did not enhance further ketosis in Akita mice.

Receptor-Mediated Bioassay Reflects Dynamic Change of Glucose-Dependent Insulinotropic Polypeptide by Dipeptidyl Peptidase 4 Inhibitor Treatment in Subjects With Type 2 Diabetes.

Objective: We recently observed a greater increase in plasma levels of bioactive glucose-dependent insulinotropic polypeptide (GIP) than glucagon-like peptide 1 (GLP-1) using the receptor-mediated bioassays in the subjects with normal glycemic tolerance (NGT) treated with dipeptidyl peptidase 4 (DPP-4) inhibitors, which may be unappreciated using conventional enzyme-linked immunosorbent assays (ELISAs) during oral glucose tolerance test. Thus, we determined incretin levels in addition to glucagon level using the bioassays in type 2 diabetes mellitus (T2DM) subjects with or without treatment of DPP-4 inhibitor, to evaluate whether these assays can accurately measure bioactivity of these peptides. Methods: We performed single meal tolerance test (MTT) by using a cookie meal (carbohydrate 75.0 g, protein 8.0 g, fat 28.5 g) in the subjects with NGT (n = 9), the subjects with T2DM treated without DPP-4 inhibitor (n = 7) and the subjects with T2DM treated with DPP-4 inhibitor (n = 10). All subjects fasted for 10-12 h before the MTT, and blood samples were collected at 0, 30, 60, and 120 min. We used the cell lines stably cotransfected with human-form GIP, GLP-1 or glucagon receptor, and a cyclic adenosine monophosphate-inducible luciferase expression construct for the bioassays. We measured active GIP, active GLP-1, and glucagon by the bioassays. To evaluate the efficacy of bioassay, we measured identical samples via ELISA kits. Results: During the single MTT study, postprandial active GIP bioassay levels of T2DM with DPP-4 inhibitor treatment were drastically higher than those of NGT and T2DM without DPP-4 inhibitor, although the DPP-4 inhibitor-treated group showed moderate increase of active GIPELISA and active GLP-1 bioassay , while active GLP-1 bioassay levels of T2DM subjects without DPP-4 inhibitor were comparable to those of NGT subjects. During the serial MTT, administration of DPP-4 inhibitor significantly increased active GIP bioassay levels, but not active GLP-1 bioassay . Conclusions: In comparison to conventional ELISA, receptor-mediated bioassay reflects dynamic change of GIP polypeptide by DPP-4 inhibitor treatment in subjects with type 2 diabetes.

Establishment of novel specific assay for short-form glucose-dependent insulinotropic polypeptide and evaluation of its secretion in nondiabetic subjects.

The short-form glucose-dependent insulinotropic polypeptide (GIP) (1-30) is released from islet alpha cells and promotes insulin secretion in a paracrine manner in vitro. However, it is not well elucidated how GIP (1-30) is involved in glucose metabolism in vivo, since a specific assay system for GIP (1-30) has not yet been established. We first developed a sandwich enzyme-linked immunosorbent assay (ELISA) specific for GIP (1-30) by combining a novel antibody specific to the GIP (1-30) C terminus with the common antibody against GIP N terminus. Then, we explored cross-reactivities with incretins and glucagon-related peptides in this ELISA. GIP (1-30) amide, but not GIP (1-42), GLP-1, or glucagon increased absorbance in a dose-dependent manner. We next measured plasma GIP (1-30) concentrations in nondiabetic participants (ND) during a 75-g oral glucose tolerance test or cookie meal test (carbohydrates 75 g, lipids 28.5 g, proteins 8.5 g). Both glucose and cookie load increased GIP (1-30) concentrations in ND, but the increases were much lower than those of GIP (1-42). Furthermore, the DPP-4 inhibitor significantly increased GIP (1-30) concentrations similarly to GIP (1-42) in ND. In conclusion, we for the first time developed an ELISA specific for GIP (1-30) and revealed its secretion in ND.

Contrast medium-induced severe thrombocytopenia in patient on maintenance hemodialysis: a case report and literature review.

A 43-year-old male patient on maintenance hemodialysis had an enhanced computed tomography scan examination with iohexol for the first time 10 min before regular hemodialysis therapy. At the start of hemodialysis, no symptoms were observed, and the platelet count was 148,000/µl. Approximately 1 h after starting hemodialysis, dyspnea and chest discomfort appeared. Since oxygen saturation of the peripheral artery decreased to 87%, oxygen administration was immediately started while continuing hemodialysis therapy. Furthermore, gingival hemorrhage was observed, and the platelet count decreased to 5000/µl. We were carefully monitoring his conditions while continuing hemodialysis and oxygen administration, but no further deterioration was observed. Thereafter, these symptoms and severe thrombocytopenia gradually improved without additional treatment. At the end of hemodialysis, these symptoms completely disappeared. As well, the platelet count recovered to 35,000/µl at the end of hemodialysis and increased to 92,000/µl the next morning. From the clinical course, we diagnosed with contrast medium-induced thrombocytopenia. Acute thrombocytopenia is a rare complication induced by the contrast medium. Until now, 16 cases on contrast medium-induced thrombocytopenia have been reported. Our case spontaneously recovered from severe thrombocytopenia relatively earlier than previous reports. Our patient started hemodialysis therapy 10 min after an enhanced computed tomography examination. Early removal of contrast medium by hemodialysis might be associated with early improvement. We should acknowledge that contrast media have potential to induce severe thrombocytopenia, even in patients on maintenance hemodialysis.