Replication study of the association of SNPs in the LHX3-QSOX2 and IGF1 loci with adult height in the Japanese population; wide-ranging comparison of each SNP genotype distribution

Adult height is a highly heritable trait involving multiple genes. Recent genome-wide association studies have identified that SNP rs12338076 in the LHX3-QSOX2 locus, and rs1457595 and rs17032362 in the IGF1 locus are associated with human height in the Japanese population (Okada et al. (2010)). We performed a replication study to examine the associations between these three SNPs and adult height in the Japanese population based on autopsy cases. However, it was not possible to confirm that all these SNPs influenced adult height in the study population. We first conducted a wide-ranging survey of these three SNPs in the above genes using nine different populations including Asians, Africans and Caucasians, and demonstrated that the genotypes of rs12338076 and rs17032362 were distributed in an ethnicity-dependent manner; even within Asian populations, the genotype distributions of the SNPs differed widely. Although there are differences in height distribution between different populations, possibly due to genetic factors and/or gene-environmental interactions, the contradictory results of the association study and ethnic differences in genotype distribution allow us to assume that these height-related SNPs in the genes may contribute to adult height to a slight extent, at least in the Japanese population. It is anticipated that the present information will be useful for developing a reliable tool for personal identification through elucidation of the genetic basis of human height.     

Adult intussusception with cecal adenocarcinoma: Successful treatment by laparoscopy-assisted surgery following preoperative reduction

We report a case of adult intussusception caused by cecal adenocarcinoma that was treated by laparoscopyassisted ileocecal resection following reduction by contrast enema and preoperative colonoscopy.A 68-yearold male with cecal cancer was admitted to our hospital because of colicky abdominal pain after taking a laxative.His abdomen was distended,and a mass was palpable in the right upper quadrant,which appeared as a target-or sausage-shaped lesion by ultrasonograhpy and computed tomography.A contrast enema using water-soluble material showed a cup-shaped filling defect characterized by intussusception in the ascending colon.This round defect with a clear margin was pushed gradually back into the cecum by the enema pressure.Re-occurrence of the intussusception is easilyreleased by colonoscopy.We performed laparoscopyassisted ileocecal resection of a protruding tumor measuring 6.5 cm × 5.0 cm × 3.5 cm from the cecum,with D3 lymph node dissection.Histological examination revealed a well-differentiated adenocarcinoma that had invaded the serosa without permeating the lymphatic or venous capillaries,as well as lymph node metastasis.The postoperative course was uneventful,and the patient has been well without evidence of disease recurrence for 5 years following the operation.Preliminary reduction of adult colonic intussusception before surgical resection is therefore an option in cases of an early and correct diagnosis of intussusception.     

A Comparison of Indocyanine Green Fluorescence Imaging Plus Blue Dye and Blue Dye Alone for Sentinel Node Navigation Surgery in Breast Cancer Patients

Purpose

To evaluate two methods of sentinel node navigation surgery (SNNS) using blue dye with and without indocyanine green (ICG) fluorescence imaging (FI) to determine the usefulness of combined ICG and blue dye.

Methods

Between 2005 and 2010, a total of 501 patients underwent SNNS in our hospital. Detection of sentinel lymph node (SLN) was performed with sulfan blue (SB) alone until 2008 and with a combination of SB and ICG-FI since 2009. ICG 5?mg and SB 15?mg were injected in the subareolar region, and FI was obtained by a fluorescence imaging device.

Results

We attempted to identify SLNs in 393 patients by SB alone and in 108 patients by a combination of SB and FI. The mean number of SLNs detected was 1.6 (0?C5) for SB alone and 2.2 (1?C6) for the combination method. The SLN identification rate was 95.7?% for SB alone and 100?% for the combination method so that the combination was significantly superior to SB in terms of the identification rate (p?=?0.0037). In patients who received the combination method, detection of SLN was made through only SB in 1 patient, only ICG in 8 patients, and both in 99 patients. Lymph node metastasis was found in 56 patients with SB alone and in 16 patients with the combination method. Recurrence of an axillary node was observed in 3 patients (0.8?%) with SB alone and in no patients with the combination method.

Conclusions

ICG-FI is a useful method and is especially recommended in cases where no radiotracers are available.     

Regenerative repair of bone defects with osteoinductive hydroxyapatite fabricated to match the defect and implanted with combined use of computer-aided design, computer-aided manufacturing, and computer-assisted surgery systems: a feasibility study in a canine model

BackgroundCurrently, regenerative repair of large bone defects that result from bone tumor resection or severe trauma is a challenging issue because of the limited regenerative potential of bone and treatment modalities. The aim of this study was to achieve repair of large bone defects to the original three-dimensional (3D) anatomical state by combining computer-aided technologies and local delivery of bone morphogenetic protein (BMP) in a canine model.MethodsComputed tomography (CT) images of the pelvic bone of each dog were obtained, and an imaginary spherical malignant bone tumor of 15-mm diameter was placed in the left ilium of a canine on the 3D CT image. Resection of the whole tumor with a 10-mm margin of healthy bone was planned preoperatively by using computer-aided design (CAD) software. In addition, an image of the implant to be used to fill the resulting bone defect was constructed on the computer image. A porous hydroxyapatite (HA) implant identical to the imaged bone defect was made by shaving a tetragonal porous apatite block (40 × 20 × 10 mm) with a computer-aided manufacturing system operated by using the CT-image data of the bone defect obtained from the CAD system. To resect the iliac bone as planned preoperatively on the 3D CT image, computer-aided surgery was performed using the CT data. The defect was filled with the HA implant fabricated as described and coated with a putty carrier either with BMP-2 (BMP group, n = 6) or without BMP-2 (control group, n = 6).ResultsIn the BMP group, new bone formation was noted around each implant on CT images at 3 weeks after surgery and was remodeled to restore the original anatomy of the ilium on serial CT images. At 12 weeks, the implant was enclosed within new bone, and histological analysis revealed bone formation on and within the implant. Little bone formation was noted in the control group.ConclusionsThis new method may enable efficacious and precise regenerative repair of large bone defects without bone grafting.     

Adult ileoileal intussusception induced by an ileal lipoma diagnosed preoperatively: report of a case and review of the literature

We herein report a case of adult ileoileal intussusception induced by an ileal lipoma. A 68-year-old woman with a history of small intestinal tumors was admitted to our hospital with severe, colicky lower abdominal pain, similar to episodes experienced in the past. A barium meal enema at the initial admission demonstrated a small intestinal tumor in the ileum 30 cm proximal to the ileocecal valve. Abdominal ultrasound sonography and computed tomography showed a sausage-shaped mass presenting as a target sign in the right lower abdomen, suggestive of intussusception. There was also a round mass of fat attenuation representing a lipoma, which was considered the lead point of the intussusception. The patient underwent emergency surgery and partial resection of the ileum, including the ileal tumor, following reduction of the intussusception. The resected specimen contained a round tumor measuring 1.5 × 1.5 × 1.4 cm, which was diagnosed histopathologically as an intestinal lipoma. The patient made a satisfactory recovery and was discharged on postoperative day 10. The clinical characteristics of previously reported lipomas with intussusception are also discussed, including the relationships between the tumor size and symptoms or location.     

Hyperglycemia Causes Renal Cell Damage via CCN2-Induced Activation of the TrkA Receptor: Implications for Diabetic Nephropathy

CCN2, a secreted profibrotic protein, is highly expressed in diabetic nephropathy (DN) and implicated in its pathogenesis; however, the actions of CCN2 in DN remain elusive. We previously demonstrated that CCN2 triggers signaling via tropomyosin receptor kinase A (TrkA). Trace expression of TrkA is found in normal kidneys, but its expression is elevated in several nephropathies; yet its role in DN is unexplored. In this study we show de novo expression of TrkA in human and murine DN. We go on to study the molecular mechanisms leading to TrkA activation and show that it involves hypoxia, as demonstrated by ischemia-reperfusion injury and in vitro experiments mimicking hypoxia, implicating hypoxia as a common pathway leading to disease. We also expose renal cells to hyperglycemia, which led to TrkA phosphorylation in mesangial cells, tubular epithelial cells, and podocytes but not in glomerular endothelial cells and renal fibroblasts. In addition, we report that hyperglycemia caused an induction of phosphorylated extracellular signal-related kinase 1/2 and Snail1 that was abrogated by silencing of TrkA or CCN2 using small interfering RNA. In conclusion, we provide novel evidence that TrkA is activated in diabetic kidneys and suggest that anti-TrkA therapy may prove beneficial in DN.     

RB1 gene mutations are a distinct predictive factor in Merkel cell carcinoma

Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine carcinoma that tends to show local recurrence and metastasis. Typically, MCC is polyomavirus (MCPyV)-associated and cytokeratin 20 (CK20) positive. However, little is known about this tumor and its origins. Here, we aimed to determine the developmental origins of MCC and to identify prognostic clinicopathologic factors. Initial examinations revealed that CK20 and MCPyV expression (CK20+, MCPyV+ (60%); CK20+, MCPyV− (10%); CK20−, and MCPyV− (30%)) did not affect overall survival. With RB1 gene sequencing of FFPE specimens, which covered an entire exon, all RB1 mutation-positive cases showed positive regional lymph node and/or distant metastases (8/8 cases, 100%), whereas the frequency of the metastasis was statistically significantly lower in RB1 mutation-negative cases, (10/16 cases, 62%, P = 0.033). The results were also confirmed with immunohistochemistry, and either RB1 alterations, entire exon sequencing, or immunohistochemistry was associated with the metastasis (P = 0.007). RB1 alterations may be used to access the aggressive clinical course of MCC.     

Impaired Function is a Common Feature of Neuropathy‐Associated Glycyl‐tRNA Synthetase Mutations

Charcot–Marie–Tooth disease type 2D (CMT2D) is an autosomal‐dominant axonal peripheral neuropathy characterized by impaired motor and sensory function in the distal extremities. Mutations in the glycyl‐tRNA synthetase (GARS) gene cause CMT2D. GARS is a member of the ubiquitously expressed aminoacyl‐tRNA synthetase (ARS) family and is responsible for charging tRNA with glycine. To date, 13 GARS mutations have been identified in patients with CMT disease. While functional studies have revealed loss‐of‐function characteristics, only four GARS mutations have been rigorously studied. Here, we report the functional evaluation of nine CMT‐associated GARS mutations in tRNA charging, yeast complementation, and subcellular localization assays. Our results demonstrate that impaired function is a common characteristic of CMT‐associated GARS mutations. Additionally, one mutation previously associated with CMT disease (p.Ser581Leu) does not demonstrate impaired function, was identified in the general population, and failed to segregate with disease in two newly identified families with CMT disease. Thus, we propose that this variant is not a disease‐causing mutation. Together, our data indicate that impaired function is a key component of GARS‐mediated CMT disease and emphasize the need for careful genetic and functional evaluation before implicating a variant in disease onset.     

Living donor liver transplantation for pediatric patients with metabolic disorders: The Japanese multicenter registry

LDLT is indicated for a variety of metabolic disorders, primarily in Asian countries due to the absolute scarcity of deceased donor LT. We analyzed data for all pediatric LDLTs performed between November 1989 and December 2010, during which 2224 pediatric patients underwent LDLT in Japan. Of these patients, 194 (8.7%) underwent LDLT for metabolic disorders. Wilson's disease (n = 59; 30.4%) was the most common indication in the patients with metabolic disorders, followed by OTCD (n = 40; 20.6%), MMA (n = 20; 10.3%), and GSD (n = 15; 7.7%). The one‐, five‐, 10‐, and 15‐yr patient and graft survival rates were 91.2%, 87.9%, 87.0%, and 79.3%, and 91.2%, 87.9%, 86.1%, and 74.4%, respectively. Wilson's disease and urea cycle deficiency were associated with better patient survival. The use of heterozygous donors demonstrated no negative impact on either the donors or recipients. With regard to X‐linked OTCD, symptomatic heterozygote maternal donors should not be considered potential donor candidates. Improving the understanding of the long‐term suitability of this treatment modality will require the registration and ongoing evaluation of all patients with inherited metabolic disease considered for LT.