Cartilage regeneration is related to superior mid-term patient-reported outcomes after open-wedge high tibial osteotomy.

PURPOSE: Medial open-wedge high tibial osteotomy (OWHTO) is related to cartilage improvement in the medial compartment. This study aimed to evaluate factors associated with cartilage improvement and patient-reported outcomes (PRO) after OWHTO. It was hypothesised that cartilage improvement is associated with favourable PRO. METHODS: This retrospective study included 94 patients who underwent OWHTO. The mean follow-up period was 5 years. The weight-bearing line ratio (WBLR) was defined as the ratio of the distance from the medial tibial edge to the tibial insertion of the weight-bearing line and the tibial width. The International Cartilage Research Society grade evaluated the medial femoral condyle (MFC) and medial tibial plateau (MTP) at initial and second-look arthroscopy, and cartilage improvement after OWHTO was assessed. Postoperative knee injury and osteoarthritis outcome scores (KOOS) were compared between the groups with improved and non-improved cartilage. Additionally, factors related to cartilage improvement and postoperative KOOS scores were analysed. RESULTS: Regarding the MFC, KOOS pain, symptoms, activities of daily living (ADL) and quality of life (QOL) were significantly higher in the cartilage-improved group than in the non-improved group (p = 0.012, 0.003, 0.001, 0.006), and cartilage improvement was significantly related to KOOS pain, ADL and QOL (p = 0.021, 0.039, 0.013). In addition, the postoperative WBLR was associated with cartilage improvement, with a cutoff value of 54.0% (p = 0.046). Regarding the MTP, KOOS ADL and QOL (p = 0.026, 0.022) were significantly higher in the cartilage-improved group than in the nonimproved group. Body mass index (BMI) was significantly related to the postoperative QOL (p = 0.018) and associated with cartilage improvement, with a cutoff value of 25.9 kg/m2 (p = 0.002). CONCLUSION: A postoperative WBLR greater than 54.0% and a preoperative BMI below 25.9 kg/m2 were associated with cartilage improvement, positively impacting PRO after OWHTO. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Patellofemoral Contact Pressure for Medial Patellofemoral Ligament Reconstruction Using Suture Tape Varies With the Knee Flexion Angle: A Biomechanical Evaluation.

PURPOSE: The purpose of this study was to evaluate the effect of the knee flexion angle during graft fixation on patellofemoral (PF) contact pressure in medial patellofemoral ligament (MPFL) reconstruction using polyester suture tape and knotless anchors. METHODS: Nine human knees (mean age 74.9 ± 14.1 years) were used in this study. Polyester suture tape was fixed at the medial edge of the patella with two 3.5-mm knotless anchors, and then to the femur with a 4.75-mm knotless anchor at 4 different knee flexion angles (0°, 30°, 60°, and 90°). A pressure sensor was used to measure the maximum contact pressure (MCP) of the medial and lateral PF joints in the intact knee and in postreconstruction knees at each knee flexion angle (0°, 30°, 60°, and 90°). Each MCP was normalized to that of the intact knee. A statistical comparison was made between MCP in the intact and reconstructed knees. RESULTS: The normalized MCP of the medial PF joint fixed at either 0° or 30° significantly increased at 60° of knee flexion (P = .036 and .042, respectively) and at 90° of knee flexion (P = .002 and .001, respectively). Conversely, the normalized MCP fixed at 60° and 90° remained at the same level as the intact knees at all angles of knee flexion. The normalized MCP of the lateral PF joint showed no significant difference at any fixation angle compared with intact knees. CONCLUSION: To avoid excessive PF joint contact pressure after MPFL reconstruction, it may be best to fix polyester suture tape between 60° and 90° of knee flexion. CLINICAL RELEVANCE: Fixation of the polyester suture tape with a knotless anchor for MPFL reconstruction should be at 60° to 90° of knee flexion to most closely restore PF joint contact pressures to that of the intact knee.

Effects of the tibial tunnel position on knee joint stability and meniscal contact pressure after double-bundle anterior cruciate ligament reconstruction.

BACKGROUND: To investigate the effect of the tibial tunnel position on knee stability and the maximum contact area and peak contact pressure on the menisci after double-bundle anterior cruciate ligament (ACL) reconstruction. METHODS: Ten human knee specimens (mean age: 74.1 ± 15.8 years) were used in this study. The anterior tibial loading test was conducted using a material testing machine at 30°, 60°, and 90° of knee flexion, with the anterior tibial translation (ATT) and the maximum contact area and peak contact pressure on the menisci measured. Outcome measures were compared between the following groups: 1) intact ACL (intact group); 2) anatomical tibial tunnel position (anatomical group) and 3) posterior tibial tunnel position (posterior group) with double-bundle reconstruction, and 4) ACL-deficient (deficient group). RESULTS: In response to a 100 N anterior tibial load, the ATT was greater for the posterior and ACL-deficient groups compared to that in the intact group. The normalized maximum contact area of the medial meniscus significantly decreased for the posterior group compared to that in the intact group. The normalized peak contact pressure on the medial meniscus increased in all groups compared to that in the intact group, but with no between-group differences in pressure applied to the lateral meniscus. CONCLUSIONS: ATT and contact pressure on the medial meniscus increased, concomitant with a decrease in contact area of the medial meniscus, as the position of the tibial tunnel position moved towards a posterior position.

Early total reconstruction for a Gustilo type IIIB open forearm fracture associated with avulsion injury of multiple extensor tendons: A case report.

Gustilo type IIIB open forearm fractures associated with avulsion injuries of multiple extensor tendons are difficult to reconstruct. Not only are bones, nerves, blood vessels, and soft tissues injured, but also tendons directly related to hand function. A 74-year-old man sustained an injury to his dominant right hand after being hit by a heavy pulley. The patient was diagnosed with a Gustilo type IIIB open forearm fracture, and multiple extensor tendons were avulsed from the musculotendinous junction. On the day of injury, the radius was fixed using a volar locking plate, and the ulnar head was fixed to the radius. On the fourth day, the avulsed extensor tendons were reconstructed using tendon transfer, and the exposed tendons and soft tissue defects were covered using a free anterolateral thigh flap on the seventh day. Three years after the injury, the patient had no difficulty in performing activities of daily living. Single-stage reconstruction allows for early rehabilitation. We believe that the more complex and severe the injury is, the more we should aim to repair the injured tissue as early as possible, that is, early total reconstruction.

Joint line convergence angle is the most associated alignment factor with the severity of medial knee osteoarthritis.

Purpose: The purpose of this study was to evaluate the relationship between the joint line convergence angle (JLCA) and the severity of medial knee osteoarthritis (OA). We hypothesise that JLCA is the most associated factor with the severity of medial knee OA. Methods: This retrospective study included a total of 202 knees that underwent either high tibial osteotomy or medial meniscus repair/partial resection. Kellgren-Lawrence grade and hip-knee-ankle angle (HKAA), mechanical lateral distal femoral angle (mLDFA), medial proximal tibial angle (MPTA) and JLCA were assessed from preoperative radiographs. Medial meniscus extrusion (MME) was measured using preoperative magnetic resonance imaging. The International Cartilage Research Society (ICRS) grade on the medial femoral condyle and medial tibial plateau were also assessed. The relationships between JLCA and Kellgren-Lawrence grades and MME and ICRS grades were analysed using Spearman's correlation test and regression analysis. Results: The JLCA was correlated with the Kellgren-Lawrence grade (R = 0.765, p < 0.001), MME (R = 0.638, p < 0.001), ICRS grade on the MFC (R = 0.586, p < 0.001) and the MTP (R = 0.586, p < 0.001). Regression analysis showed that age (p = 0.002) and JLCA (p < 0.001) were associated with Kellgren-Lawrence grade. Furthermore, JLCA was related to ICRS grade on the MFC (p < 0.001) and MTP (p < 0.001). Conclusion: The JLCA, reflecting radiological severity, meniscus status, and cartilage lesion, was the most associated alignment parameter in the severity of medial knee OA. The JLCA may be beneficial for quantitative assessment of medial knee OA. Level of Evidence: Level III, retrospective cohort study.

Mobile bearing shows larger rollback motion than fixed bearing in total knee arthroplasty using a medial stabilising technique with a navigation system.

Purpose: This study aimed to investigate the intraoperative knee kinematics of cruciate-retaining total knee arthroplasty with a medial stabilising technique (MST-TKA) and compare the kinematics between mobile- and fixed-bearing MST-TKAs. We hypothesised that mobile-bearing MST-TKA would result in greater physiological kinematic motion than fixed-bearing MST-TKA. Methods: Twenty-one and 20 knees underwent mobile- and fixed-bearing MST-TKAs using a navigation system (Orthopilot® ver. 6.0; B. Braun Aesculap), respectively. In the preoperative and postoperative kinematic analysis, the knee was moved manually from 0° to 120°, and femoral anteroposterior translations of the medial femoral condyle (MFC) and lateral femoral condyle (LFC) were recorded every 0.1 s from 0° to 120°. Data were subsequently extracted from the software every 10° of flexion and compared between the two groups, and the correlation coefficients between preoperative and postoperative kinematics were calculated. Results: In the postoperative analysis, the MFC in the mobile-bearing group showed significant posterior translation at 100°, 110° and 120° compared to the fixed-bearing group (p < 0.01). Similarly, the LFC in the mobile-bearing group showed significant posterior translation at 100°, 110° and 120° compared to the fixed-bearing group (p < 0.05, p < 0.01 and p < 0.05, respectively). In the mobile-bearing group, the preoperative and postoperative anteroposterior translations of the MFC and LFC were correlated (p < 0.01), while in the fixed-bearing group, there was no correlation. Conclusion: The femoral rollback motion in the mobile-bearing MST-TKA correlated with the preoperative kinematics and was larger than that in the fixed-bearing group. Level of Evidence: Level II, therapeutic prospective cohort study.

Identification of a novel mutation in the exon 2 splice donor site of the POU1F1/PIT-1 gene in Japanese identical twins with mild combined pituitary hormone deficiency.

CONTEXT: To date, approximately 35 different POU1F1 mutations have been described in patients with familial and sporadic combined pituitary hormone deficiency (CPHD) from different ethnic backgrounds. The majority are missense mutations clustered within the conserved POU-specific and POU-homeo domains, encoded by exons 4 and 6, respectively. OBJECTIVES: This study aimed to identify the molecular basis and clinical characteristics of a Japanese CPHD family with a novel POU1F1 mutation. DESIGN: The POU1F1 gene was sequenced in identical twin brothers with mild CPHD. The mutation identified was also evaluated in family members as well as 188 Japanese controls and then examined in functional studies. RESULTS: A novel heterozygous splice site mutation (Ex2 + 1G>T; c.214 + 1G>T) was detected. This mutation was also present in their undiagnosed mother, but not in any of the controls. In vitro splicing studies suggested this mutation to result in an in-frame skipping of exon 2, thus producing an internally deleted protein lacking most of the R2 transactivation subdomain (TAD-R2). Heterologous expression studies of the mutated POU1F1 protein showed only modest reductions in its transactivation activities in HEK293T cells, while acting as a dominant-negative inhibitor of the endogenous activities of POU1F1 in pituitary GH3 cells. CONCLUSIONS: This is the first report of a mutation at the exon 2 donor splice site of POU1F1, affecting TAD-R2. The addition of this mutation to the growing list of pathological POU1F1 mutations may provide deeper insights into clinical heterogeneity in the expressions of individual mutations and a better understanding of the structure-function relationships of POU1F1.

Posterior hip fracture-dislocation associated with posterior wall fracture of the acetabulum and ipsilateral comminuted trochanteric fracture of the femur: A case report.

INTRODUCTION AND IMPORTANCE: Traumatic posterior dislocation of the hip is often associated with fractures of the femoral head and posterior wall of the acetabulum. However, hip fracture-dislocation that includes the posterior wall of the acetabulum and the ipsilateral femoral trochanter is rare. There is no consensus on the bone that should be operated on first, the operative position, and the choice of implant for femoral fixation. CASE PRESENTATION: A 67-year-old man was brought to our emergency department after a 2-m fall. He was diagnosed with a hip fracture-dislocation associated with posterior wall acetabular fracture and ipsilateral femoral trochanteric fracture. Surgical reconstruction was performed with intramedullary nail (IMN) fixation of the femoral trochanteric lesion, followed by anatomically rigid acetabular fixation in the lateral decubitus position. At the 5-year follow-up after the injury, the patient showed good objective and subjective clinical outcomes. CLINICAL DISCUSSION: Fixing the femur first could allow an easier reduction and traction. The lateral decubitus position was useful, because fixation of the femur and the acetabulum could be performed without changing the position. When fixing the femoral trochanteric lesion, attention was paid to reduce the anteromedial cortex of the proximal fragment extramedullarly to the distal fragment to prevent complications such as cutout and implant breakage. CONCLUSION: Anatomically rigid fixation of the posterior wall of the acetabulum secondary to IMN fixation of the femur, with anteromedial cortical support in the lateral decubitus position, could achieve good objective and subjective clinical outcomes.

Helical plating for a re-nonunion and a peri-implant fracture after humeral intramedullary nailing: A report of two cases.

Introduction and importance: A re-nonunion after failed intramedullary nailing for a nonunion of the humeral shaft and a peri-implant distal humeral fracture with an ununited humeral shaft are rare cases. Therefore, no consensus has been established regarding the treatment strategies. Case presentation: Case 1: An 84-year-old woman presented with humeral shaft re-nonunion after intramedullary nailing. The images revealed callus formation and loosening of the implant, suggesting a lack of mechanical stability. Nail removal and helical plating were performed. One year postoperatively, bony union was achieved. Case 2: A 59-year-old woman presented with a peri-implant distal humeral fracture with an ununited humeral shaft after nailing. Nail removal and helical plating were performed using a minimally invasive plate osteosynthesis (MIPO) technique. The distal humeral fracture was fixed with plates. One year postoperatively, bony union was achieved. Clinical discussion: Imaging findings in Case 1 indicated that nonunion was caused by a lack of mechanical stability. In Case 2, stabilization of the ununited humeral shaft was also needed. Helical plating provides a mechanically strong fixation and prevents damage to the radial nerve and soft tissues. Conclusion: Evaluating the causative factors of nonunions is important. Helical plating provides mechanical stability and is associated with bony union without autologous bone grafting for a re-nonunion of humeral shaft lacking mechanical instability. For a peri-implant distal humeral fracture with an ununited humeral shaft, helical plating with the MIPO technique provides diaphyseal fracture union and enables the minimal length of distal humeral plate fixation.

γδ T cells play a protective role during infection with Nippostrongylus brasiliensis by promoting goblet cell function in the small intestine.

The intestinal epithelium is rich in γδ T cells and the gut is a site of residence for a wide variety of pathogens, including nematodes. Although CD4+ T-cell receptor (TCR) -αß+ T helper type 2 T cells are essential for the expulsion of intestinal nematodes, little information is available on the function of γδ T cells in this type of infection. Here, we demonstrate two major functions of γδ T cells as a potently protective T-cell population against Nippostrongylus brasiliensis infection using γδ T-cell-deficient (TCR-δ(-/-) ) mice. First, γδ T cells are required to initiate rapid expulsion of adult worms from the intestine and to limit egg production. Second, γδ T cells prevent the pathological intestinal damage associated with nematode infection, evident by increased clinical disease and more severe microscopic lesions in infected TCR-δ(-/-) mice. γδ T-cell deficiency led to delayed goblet cell hyperplasia in association with reduced expression of phosphorylated STAT6, MUC2, Trefoil factor-3 (TFF3) and T helper type 2 cytokines including interleukin-13 (IL-13). TCR-δ(-/-) mice also produced more interferon-γ than wild-type mice. Within the intraepithelial lymphocyte compartment, γδ T cells produced IL-13. Adoptive transfer of γδ T cells or administration of recombinant IL-13 to TCR-δ(-/-) mice successfully reduced the egg production by N. brasiliensis. Collectively, these data provide strong evidence that γδ T cells play an important role in controlling infection with intestinal nematodes and limiting infection-induced pathology.

Identification and functional analysis of novel human growth hormone-releasing hormone receptor (GHRHR) gene mutations in Japanese subjects with short stature.

CONTEXT: Growth hormone-releasing hormone receptor (GHRHR) gene mutations have been identified in patients of different ethnic origins with isolated GH deficiency (IGHD) type IB. However, the prevalence of these mutations in the Japanese population has yet to be fully determined. OBJECTIVES: This study aimed to evaluate the contributions of GHRHR mutations to the molecular mechanism underlying short stature in Japanese subjects. DESIGN: The GHRHR gene was sequenced in 127 unrelated Japanese patients with either IGHD (n = 14) or idiopathic short stature (ISS; n = 113). Sequence variants were evaluated in family members and 188 controls, and then examined in functional studies. RESULTS: A novel homozygous E382E (c.1146G>A) synonymous variant, at the last base of exon 12, was identified in an IGHD family with two affected sisters. In vitro splicing studies showed this mutation to result in skipping of exon 12. In one ISS patient, a heterozygous ATG-166T>C variant was found in the distal Pit-1 P2 binding element of the GHRHR promoter. In two control subjects, a close but distinct variant, ATG-164T>C, was detected. Functional studies showed that both promoter variants diminish promoter activity by altering Pit-1 binding ability. Four missense variants were also found in both patient and control groups but had no detectable functional consequences. CONCLUSIONS: The homozygous GHRHR mutation was rare, being detected in only one Japanese IGHD family. Future research is needed to clarify the genetic contributions of heterozygous functional promoter variants to GHD, ISS and normal-stature variations.

Walking Pattern in COPD Patients.

PURPOSE: To compare the activity and walking pattern of individuals with chronic obstructive pulmonary disease (COPD) and control subjects during a 24-hour period. DESIGN: Cross-sectional study in home and community. METHODS: The average walking velocity, time spent in sitting, standing, and lying, and numbers of steps per 24 hours were measured in nine individuals with COPD and eight healthy control subjects. FINDINGS: The average walking velocity in individuals with COPD was equivalent to that of the control subjects. Individuals with COPD walked significantly less than the control subjects. The total time spent sitting, standing, and walking was similar in the two groups. CONCLUSIONS: The results suggested that the walking velocity selected by individuals with COPD serves to minimize energy cost per distance. CLINICAL RELEVANCE: The study findings emphasize the need to maintain walking velocity in any exercise prescription for individuals with COPD.

Identification of a novel splice site mutation of the CSPG2 gene in a Japanese family with Wagner syndrome.

PURPOSE: To investigate the genetic basis and clinical variability of Wagner syndrome, a rare, dominantly inherited vitreoretinopathy. METHODS: Clinical examination, linkage analysis, and mutational screening were performed in a large, three-generation, consanguineous Japanese family with Wagner syndrome. The effect of splice site mutation was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis with lymphoblastoid cell total RNAs generated from affected individuals. RESULTS: Ocular phenotypes of affected members included an empty vitreous with fibrillary condensations, avascular membrane, perivascular sheathing, and progressive chorioretinal dystrophy and were similar to those of the original Wagner syndrome family. All affected eyes examined exhibited pseudoexotropia with ectopic fovea. No systemic manifestations were observed. Genetic linkage confirmed disease segregation with the previously identified WGN1 locus on 5q13-q14. A heterozygous A-->G transversion at the second base of the 3'-acceptor splice site of intron 7 (c.4004-2 A-->G) of the chondroitin sulfate proteoglycan 2 (CSPG2) gene that cosegregated with the disease was identified. Results of RT-PCR analysis indicated that the c.4004-2 A-->G mutation activates a cryptic splice site, located 39 bp downstream from the authentic 3' splice acceptor site. CONCLUSIONS: This linkage study confirmed the genetic homogeneity of the Wagner syndrome. CSPG2 encodes versican, a large chondroitin sulfate proteoglycan, which, in vitreous, binds to hyaluronan and link protein and forms large aggregates that are important for maintaining structural integrity. Although the CSPG2 gene has been excluded as a candidate for causing Wagner syndrome, these data emphasize the necessity of further mutational screening in new families and careful functional characterization.

The current status of parasitic diseases in Japan.

In Japan parasitic diseases have been considered to be successfully controlled in the last 30 years. However, some parasitic diseases, such as food-borne zoonoses and/or larva migrans, are emerging and/or re-emerging in Japan. Furthermore, imported parasitic diseases like malaria are also gradually increasing. Unfortunately accurate numbers of parasitic diseases other than echinococcosis, malaria, amebiasis, giardiasis, or cryptosporidiosis are obscure in Japan because of the lack of a legal registration system. Since symptoms and diagnostic imaging patterns of parasitic diseases are non-specific and have similarities with other infectious diseases or cancer, parasitic diseases are sometimes overlooked or left misdiagnosed. In this review, the current status of parasitic diseases in Japan is briefly summarized based on the analysis of the accumulated cases seen in our department. We also outline the clinical features, differential diagnosis and treatment of representative parasitic diseases for the better understanding and management of the parasitic diseases in Japan.

Identification and functional analysis of novel human growth hormone secretagogue receptor (GHSR) gene mutations in Japanese subjects with short stature.

CONTEXT: Short stature (SS) is a multifactorial developmental condition with a significant genetic component. Recent studies have revealed that rare deleterious mutations in the GH-secretagogue receptor type 1A (GHSR1A) gene could be a cause of familial SS or GH deficiency. OBJECTIVE: The aim of this study was to evaluate the contribution of GHSR1A mutations to the molecular mechanism underlying SS in Japanese subjects. METHODS: We performed mutational screening of the GHSR1A gene in 127 unrelated Japanese SS patients diagnosed with either isolated GH deficiency or idiopathic SS. Identified mutations were analyzed in 188 control subjects, and their functional properties were examined in a heterologous expression system. RESULTS: Four novel heterozygous GHSR1A mutations were identified (ΔQ36, P108L, C173R, and D246A). Expression studies demonstrated that these mutations had varying functional consequences: 1) all mutations showed a loss-of-function effect on the constitutive signaling activity of GHSR1A, but the degree of loss varied widely; 2) C173R caused intracellular retention of the mutated protein, resulting in total loss of receptor function; 3) P108L resulted in a large decrease in binding affinity to ghrelin, without affecting its surface expression; 4) D246A uniquely impaired agonist- and inverse agonist-stimulated receptor signaling; and 5) ΔQ36 showed only a subtle reduction in constitutive activity. The cumulative frequency of these putative functional mutations was significantly higher in the patient group than in controls (4.72 vs. 0.53%; P = 0.019; odds ratio = 9.28; 95% confidence interval, 1.10-78.0). CONCLUSIONS: Our results suggest that GHSR1A mutations contribute to the genetic etiology of SS in the Japanese population.

Analysis of expression and structure of the rat GH-secretagogue/ghrelin receptor (Ghsr) gene: roles of epigenetic modifications in transcriptional regulation.

In the current study, to elucidate the molecular basis of cell type-specific expression of the GH-secretagogue/ghrelin receptor type 1A (GHSR1A), we characterized the structure and putative promoter region of the rat Ghsr gene. We identified an alternative 5'-untranslated first exon that contains multiple transcription start sites, and confirmed a 200-bp sequence proximal to this exon to be sufficient for basal promoter activity. A promoter-associated CpG island conserved across different species was found to be hypomethylated in Ghsr1a-expressing cell lines, while being heavily methylated in non-expressing cells. In cells with low or absent Ghsr1a expression, treatment with demethylating agents activated Ghsr1a transcription. Chromatin immunoprecipitation assays demonstrated Ghsr1a-expressing cells to display active histone modifications, whereas repressive modifications were present exclusively in other cell types. These results suggest epigenetic modifications at GHSR to play important roles in determining GHSR1A expression and abundance, and therefore the consequent sensitivity of cells to ghrelin.

An outbreak of measles in Saitama City in 2007. What is the vaccination strategy to eliminate measles in Japan?

In the present study, to elucidate an outbreak of measles in Saitama City, Japan, we analyzed the data for all notified subjects with measles. According to an active surveillance program, a total of 464 subjects were notified in 2007. The clinical criteria for the diagnosis of measles were defined as at least 3 days of a generalized maculopapular rash; a fever of 38.0 degrees C or more; and cough, mucus, or pharyngitis. Two peaks according to age group were recognized: namely, children less than 2 years of age and adolescents from 15 to 19 years of age. The latter peak was associated with the period of time when the measles-mumps-rubella vaccine had become a social problem (40.9% of vaccinees and 41.6% of non-vaccinees in this group). Japan is said to be a developing country regarding its measles vaccination strategy. In addition, no national program against measles has yet been established. Continuous efforts to increase immunization coverage are needed to interrupt indigenous measles transmission. The Japanese Ministry of Health, Labor and Welfare should therefore plan and implement a nationwide program to eliminate measles in Japan.

Transgenic expression of a mutated cyclin-dependent kinase 4 (CDK4/R24C) in pancreatic beta-cells prevents progression of diabetes in db/db mice.

In an attempt to rectify the hyperglycemic state in obese insulin resistant db/db mice, a transgenic line was generated (db/db-CDK4(R24C)) that expresses a constitutively active form of cyclin-dependent kinase 4 (CDK4/R24C) under the control of the insulin promoter. Compared with non-transgenic db/db littermates, adult db/db-CDK4(R24C) mice show near-complete glycemic normalization and improved plasma lipid concentrations, but are also more susceptible to weight gain and have significantly lower plasma adiponection levels. They have striking islet hypertrophy and beta-cell hyperplasia, and retain an insulin secretory response during the glucose tolerance test. We examined the expression of several key regulatory transcription factor genes involved in lipid and glucose metabolism in insulin target tissues of db/db-CDK4(R24C) as well as db/db mice, and found that the expression levels of members of the peroxisome proliferator-activated receptor (PPAR) family are highly associated with metabolic alterations in a gene- and tissue-specific manner. We show for the first time that the Ppar-delta in skeletal muscle and white adipose tissues is transcriptionally down-regulated in db/db mice. The db/db-CDK4(R24C) mice present a novel model of leptin-resistant obesity with compensatory hyperinsulinemia and normalized blood glucose levels, and thus may be useful for future studies that aim to dissect relationships between insulin and leptin signaling.

Molecular characterization of GDD1/TMEM16E, the gene product responsible for autosomal dominant gnathodiaphyseal dysplasia.

The human GDD1/TMEM16E gene has been found to be mutated in gnathodiaphyseal dysplasia, an unusual skeletal syndrome with autosomal dominant inheritance. The molecular and biochemical function(s) of GDD1 protein has not yet been elucidated. In this study, we examined the murine GDD1 gene expression pattern during embryonic development, and characterized the cellular and tissue localizations of its gene product using a GDD1-specific antibody. In the developing embryos, GDD1 mRNA expression was principally associated with differentiating and developing somites, with a highly complex spatiotemporal pattern that involved the myotomal and sclerotomal lineages of somites. Biochemical studies indicated that GDD1 protein is an integral membrane glycoprotein that resides predominantly in intracellular vesicles. Immunohistochemical analysis showed a high level of murine GDD1 protein expression in cardiac and skeletal muscle tissues, and in growth-plate chondrocytes and osteoblasts in bone. These observations suggest diverse cellular role(s) of GDD1 in the development of musculoskeletal system.

SNPs in the KCNJ11-ABCC8 gene locus are associated with type 2 diabetes and blood pressure levels in the Japanese population.

Many genetic association studies support a contribution of genetic variants in the KCNJ11-ABCC8 gene locus to type 2 diabetes (T2D) susceptibility in Caucasians. In non-Caucasian populations, however, there have been only a few association studies, and discordant results were obtained. Herein, we selected a total of 31 SNPs covering a 211.3-kb region of the KCNJ11-ABCC8 locus, characterized the patterns of linkage disequilibrium (LD) and haplotype structure, and performed a case-control association study in a Japanese population consisting of 909 T2D patients and 893 control subjects. We found significant associations between eight SNPs, including the KCNJ11 E23K and ABCC8 S1369A variants, and T2D. These disease-associated SNPs were genetically indistinguishable because of the presence of strong LD, as found previously in Caucasians. For the KCNJ11 E23K variant, the most significant association was obtained under a dominant genetic model (OR 1.32, 95% CI 1.09-1.60, P = 0.004). A meta-analysis of East Asian studies, comprising a total of 3,357 T2D patients (77.4% Japanese) and 2,836 control subjects (77.8% Japanese), confirmed the significant role of the KCNJ11 E23K variant in T2D susceptibility. Furthermore, we found evidence suggesting that the KCNJ11 E23K genotype is independently associated with higher blood-pressure levels.