An analysis of osteoporosis in patients with hereditary multiple exostoses.

We analyzed osteoporosis in 20 HME patients. According to the T-score of BMD, 30% and 67.5% of the patients fell in the range of osteopenia in the lumbar spine and femoral neck. Our results indicate HME patients have low bone mass. They do not have abnormal bone metabolism. INTRODUCTION: There are few reports of osteoporosis in hereditary multiple exostoses (HME) patients. Therefore, the purpose of this study was to analyze osteoporosis in HME patients. METHODS: This retrospective cohort study included 20 patients diagnosed with HME. Patients underwent bone mineral density (BMD) measurement of the lumbar spine (n = 20) and femoral neck (n = 40). Bone metabolic parameters, including serum osteocalcin and urinary cross-linked N-telopeptide of type 1 collagen (NTx), were analyzed in all subjects. EXT1 and EXT2 genes were sequenced using genomic DNA. We also examined the correlation between genotype and BMD Z-score and T-score. RESULTS: The mean BMD values of the lumbar spine were 1.085 ± 0.116 g/cm2 (n = 11) in male and 1.108 ± 0.088 g/cm2 (n = 9) in female. The mean BMD values of the femoral neck area were 0.759 ± 0.125 g/cm2 (n = 22) in male and 0.749 ± 0.115 g/cm2 (n = 18) in female. Z-score of most HME patients show < 0, indicating that these patients tend to have low bone mass compared with the age-matched population. According to the T-score of BMD, 30% (6 of 20) and 67.5% (27 of 40) of the patients fell in the range of osteopenia in the lumbar spine and femoral neck areas, respectively. Serum osteocalcin and urinary NTx were in the normal range in most patients. There was no significant correlation between genotypes and Z-score. CONCLUSION: HME patients have low bone mass, especially in the femoral neck area. They do not have abnormal bone metabolism, and there was no correlation between genotypes and Z-score.

A ten-color tube with dried antibody reagents for the screening of hematological malignancies.

INTRODUCTION: The workflow in clinical flow cytometry laboratories must constantly be reviewed to develop technical procedures that improve quality and productivity and reduce costs. Using the Beckman Coulter dry coating technology, we customized a ten-color tube with dried antibody reagents, designated the Duraclone screening tube (DST), for screening hematological malignancies. Here, we compared the applicability, clinical and numerical equivalence, and cost and time required for the technical procedures between the liquid reagents and the DST. METHODS: The DST contains CD4 + Kappa-FITC, CD8 + Lambda-PE, CD3 + CD14-ECD, CD33-PE-Cy5.5, CD20 + CD56-PE-Cy7, CD34-APC, CD19-APC-AlexaFluor700, CD10-APC-AlexaFluor750, CD5-Pacific Blue, and CD45-Krome Orange. We evaluated 20 bone marrow samples, 13 peripheral blood samples, 6 lymph node biopsy samples, 5 fine-needle aspirate samples, 5 cerebrospinal fluid samples, and 1 pleural fluid sample. RESULTS: The DST was useful for more than 60% of our samples. It was able to enumerate the majority of the populations in all types of samples with a statistically acceptable correlation with the liquid reagents. The use of the DST translated into significant time and cost savings of 15.8% and 12.3%, respectively, compared with the use of the liquid reagent. The cost was reduced by $14.36 per sample. CONCLUSIONS: The DST is an efficient solution for screening hematological malignancies with improved quality, productivity, standardization, and sustainability. These improvements could benefit patients by providing faster diagnoses using a higher quality and lower cost reagent.

Sodium temperature/wind lidar based on laser-diode-pumped Nd:YAG lasers deployed at Tromsø, Norway (69.6°N, 19.2°E).

An Nd:YAG laser-based sodium temperature/wind lidar was developed for the measurement of the northern polar mesosphere and lower thermosphere at Tromsø (69.6N, 19.2E), Norway. Coherent light at 589 nm is produced by sum frequency generation of 1064 nm and 1319 nm from two diode laser end-pumped pulsed Nd:YAG lasers. The output power is as high as 4W, with 4 mJ/pulse at 1000 Hz repetition rate. Five tilting Cassegrain telescopes enable us to make five-direction (zenith, north, south, east, west) observation for temperature and wind simultaneously. This highly stable laser system is first of its kind to operate virtually maintenance-free during the observation season (from late September to March) since 2010.

A pre-operative clinical model to predict microvascular invasion and long-term outcome after resection of hepatocellular cancer: The Australian experience.

BACKGROUND: Hepatocellular cancer (HCC) is a leading cause of mortality worldwide. Liver resection or transplantation offer the best chance of long-term survival. The aim of this study was to perform a survival and prognostic factor analysis on patients who underwent resection of HCC at two major tertiary referral hospitals, and to investigate a pre-operative prediction model for microvascular invasion (MVI). METHODS: Clinico-pathological and survival data were collected from all patients who underwent liver resection for HCC at two tertiary referral centres (Royal North Shore/North Shore Private Hospitals and Westmead Hospital) from 1998 to 2012. An overall and disease-free survival analysis was performed and a predictive model for MVI identified. RESULTS: The total number of patients in this series was 125 and the 5-year overall and disease-free survival rates were 56% and 37%, respectively. MVI was the only factor to be independently associated with a poor prognosis on both overall and disease-free survival. Age ≥64 years, a serum alpha-fetoprotein (AFP) ≥400 ng/ml (×40 above normal) and tumor size ≥50 mm were independently associated with MVI. An MVI prediction model using these three pre-operative factors provides a good assessment of the risk of MVI. CONCLUSION: MVI in the resected specimen of patients with HCC is associated with a poor prognosis. A preoperative MVI prediction model offers a useful way to identify patients at risk of relapse. However, more precise predictive models using molecular and genetic variables are needed to improve selection of patients most suitable for radical surgical treatment.

Y chromosome haplogroup D2a1 is significantly associated with high levels of luteinizing hormone in Japanese men.

The association between the Y chromosome haplogroup D2 and risk of azoospermia and low sperm motility has been previously studied, and it was indicated that haplogroups DE (YAP lineage) are associated with prostate cancer risk in Japanese males. Our assumption had been that Y chromosome haplogroups may be associated with sex hormone levels, because sex hormones have been deemed responsible for spermatogenesis and carcinogenesis. In this study, we assessed the association between Y chromosome haplogroups and sex hormone levels, including those of testosterone, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), luteinizing hormone (LH), inhibin-B, and calculated free testosterone (cFT), in 901 young men from the general Japanese population (cohort 1) and 786 Japanese men of proven fertility (cohort 2). We found that the haplogroup D2a1 was significantly associated with high LH levels in a combined analysis involving two cohorts (ß = 0.068, SE = 0.025, p = 0.0075), following correction for multiple testing. To date, this result is the first evidence that implicates Y chromosome haplogroups in an association with sex hormone levels.

Pyrethroid insecticide exposure and reproductive hormone levels in healthy Japanese male subjects.

The associations between serum levels of reproductive hormones (follicle-stimulating hormone, luteinizing hormone, testosterone, sex hormone-binding globulin, inhibin B and calculated free testosterone) and urinary metabolite concentration of pyrethroid insecticides [3-phenoxybenzoic acid (3-PBA)] were explored in 322 male university students in suburban Tokyo. The subjects constituted part of a large cross-sectional survey on the reference value of semen quality of Japanese men. Urinary 3-PBA was detectable in 91% of the subjects demonstrating ubiquitous exposure among the general population. However, there were no associations between urinary 3-PBA and serum hormone levels. This result was inconsistent with those reported in China and the USA for subjects who had similar levels of urinary 3-PBA to the present subjects. One of the possible reasons of the inconsistency might be different composition of pyrethroid insecticides to which the subjects were exposed; 3-PBA is a common metabolite of a number of pyrethroids and thus lacks specificity to compounds that may have different potentials of reproductive toxicity. Another reason might be related to the fact that our subjects were university students who were not aware of their own fertility, whereas the previous study subjects were infertility patients. However, the multiple regression models could explain only a limited fraction of total variance in serum levels of hormones. Identification of other contributors is warranted.

The value of T1-weighted coronal MRI scans in diagnosing occult fracture of the hip.

A delay in establishing the diagnosis of an occult fracture of the hip that remains unrecognised after plain radiography can result in more complex treatment such as an arthroplasty being required. This might be avoided by earlier diagnosis using MRI. The aim of this study was to investigate the best MR imaging sequence for diagnosing such fractures. From a consecutive cohort of 771 patients admitted between 2003 and 2011 with a clinically suspected fracture of the hip, we retrospectively reviewed the MRI scans of the 35 patients who had no evidence of a fracture on their plain radiographs. In eight of these patients MR scanning excluded a fracture but the remaining 27 patients had an abnormal scan: one with a fracture of the pubic ramus, and in the other 26 a T(1)-weighted coronal MRI showed a hip fracture with 100% sensitivity. T(2)-weighted imaging was undertaken in 25 patients, in whom the diagnosis could not be established with this scanning sequence alone, giving a sensitivity of 84.0% for T(2)-weighted imaging. If there is a clinical suspicion of a hip fracture with normal radiographs, T(1)-weighted coronal MRI is the best sequence of images for identifying a fracture.

Improper waste disposal of silver-mercury amalgam.

The objective of this work was to estimate the quantity of mercury residue present in dental amalgam that is generated and discarded in the city of Manaus (Amazon-Brazil). For this purpose, the locations of amalgam usage (10 public and 31 private dental clinics), the method by which the residue is discarded (14 clinics improper disposal), and the analysis of total mercury in the sediment of the controlled landfill (2.68-3 µgHg/g), were described. It was concluded that: there are dental clinics in the city that discard mercury residue into the common waste disposal system, which contravenes health safety standards.

Time-action profiles of insulin detemir in normal and diabetic dogs.

Insulin detemir is the first member of a new class of long-acting soluble insulin analogues capable of maintaining the basal level of insulin in humans. In this preliminary study, we investigated the time-action profiles of insulin detemir in normal and diabetic dogs since the use of insulin detemir in canines has yet to be determined. Eight animals were used in our study (three normal and five insulin dependent diabetic dogs). Time-action profiles of insulin detemir were monitored in normal dogs using an artificial pancreas apparatus under euglycemic condition. Blood sampling was performed at 2h intervals post feeding, with insulin administration, in insulin dependent diabetic dogs. Time-action profiles of insulin detemir, in normal dogs, demonstrated that insulin detemir is a long-lasting preparation similar to what has been observed in humans. A pronounced peak was detected at 8-10h while the glucose-lowering effect lasted for over 24h after insulin injection, thus illustrating its longer prolonged peak activity time. Furthermore, intensive glycemic control was achieved with insulin detemir in insulin dependent diabetic dogs, using a lower dosage than NPH insulin and insulin glargine therapeutic doses. Our results indicate that insulin detemir has a greater effect than either NPH insulin or insulin glargine in canines, requiring a lower dose than either insulin preparation. However, using insulin detemir also carries a higher risk of inducing hypoglycemia as compared to either NPH insulin or insulin glargine.

Xenografting of testicular tissue from an infant human donor results in accelerated testicular maturation.

BACKGROUND: Grafting of testicular tissue into immunodeficient mice has been used to differentiate the neonatal testes from different animal species up to the level of complete spermatogenesis; however, this approach has not been successful for human testicular tissue. The aim of this study was to evaluate the capacity for differentiation of infant human testicular tissue grafts. METHODS AND RESULTS: Testicular tissue from a 3-month-old patient with testicular cancer was grafted into immunodeficient nude mice. At the time of grafting, A spermatogonia were the only germ cells present in the testicular tissue. B spermatogonia and first spermatocytes were observed at 7 months and 1 year after grafting, respectively. Positive immunostaining with antibodies against BOULE and CDC25A suggested that spermatocytes in the graft were not arrested but in meiosis. Furthermore, ultrastructural and immunohistochemical analyses showed that the onset of both Sertoli cell maturation and partial differentiation of Leydig cells preceded the appearance of spermatocytes. Differentiation of testicular cells was accelerated compared with in vivo development. CONCLUSIONS: Spermatogenesis in the xenograft of infant human testicular tissues proceeded successfully from the stage of spermatogonial stem cells until pachytene spermatocyte formation. The differentiation of Sertoli cells and Leydig cells was reproduced in a manner similar to that in normal testicular development. Grafting of infant human testicular tissue may be a powerful tool to examine the early period of human spermatogenesis and may pave the way for fertility preservation among infant patients.

100 ps time-resolved solution scattering utilizing a wide-bandwidth X-ray beam from multilayer optics.

100 ps time-resolved X-ray solution-scattering capabilities have been developed using multilayer optics at the beamline NW14A, Photon Factory Advanced Ring, KEK. X-ray pulses with an energy bandwidth of DeltaE/E = 1-5% are generated by reflecting X-ray pulses (DeltaE/E = 15%) through multilayer optics, made of W/B(4)C or depth-graded Ru/C on silicon substrate. This tailor-made wide-bandwidth X-ray pulse provides high-quality solution-scattering data for obtaining photo-induced molecular reaction dynamics. The time-resolved solution scattering of CH(2)I(2) in methanol is demonstrated as a typical example.

Polybrominated diphenyl ethers in human serum and sperm quality.

Polybrominated diphenyl ethers (PBDEs) are widely used flame retardants; currently, they are identified as ubiquitous environmental contaminants. Several studies indicate that PBDEs might affect male fertility. We present the results of a pilot study on the relationship between human serum PBDEs and sperm quality. The PBDE levels in Japan are comparable to those found in European countries. Strong inverse correlations were observed between the serum concentration of 2,2',4,4',5,5'-hexabromodiphenyl ether and sperm concentration (r = -0.841, p = 0.002) and testis size (r = -0.764, p = 0.01). Extensive studies on the relationship between PBDEs and sperm quality are required.

Effect of prenatal exposure to bisphenol A on the serum testosterone concentration of rats at birth.

In the rat, testosterone (T) in the neonatal period plays an important role in sexual differentiation and there is a serum T surge in male rats 2 hours after birth. Pregnant female rats were exposed to various doses of bisphenol A (BPA) from gestational day 1 (GD1) through 2 hours after parturition. About half of the BPA-exposed and control dams were subjected to cesarean section on GD22. The male fetuses on GD22 were immediately sacrificed and blood was collected. The other half of the BPA-treated and control dams delivered at GD23 (parturition day). The male pups were sacrificed 2 hours after birth. Serum T concentration was determined by radioimmunoassay (RIA). The BPA concentration in the fetal serum on GD22 increased inversely to the T levels in the serum. The T concentration in the pups' serum 2 hours after birth decreased inversely to the BPA concentration in the serum. However, there were no differences in the serum T concentration among the various doses of BPA. These results suggest that exposure to BPA in utero inhibits the T surge in the neonatal period and we speculate that exposure to BPA in utero disrupts the endocrine environment in the neonatal male.

Analysis of clinicopathologic factors predicting para-aortic lymph node metastasis in endometrial cancer.

The purposes of this study were to compare the relationships between para-aortic lymph node metastasis and various clinicopathologic factors to evaluate whether para-aortic lymph node dissection is necessary when treating endometrial cancer. A retrospective study was performed on 841 patients with endometrial cancer, who underwent the initial surgery at the Keio University Hospital. Clinicopathologic factors related to para-aortic lymph node metastasis significant on a univariate analysis were analyzed in a multivariate fashion using a logistic model. According to the multivariate analysis, the clinicopathologic factor most strongly related to the existence of para-aortic lymph node metastasis was positive pelvic lymph node metastasis (P < 0.01). Among the 155 patients who underwent pelvic and para-aortic lymph node dissection, the difference of 5-year overall survival by the presence of retroperitoneal lymph node metastasis was examined by Kaplan-Meier method. The prognosis was poor even if para-aortic lymph node dissection was performed in cases of positive para-aortic lymph node metastasis. In conclusion, when deciding whether to perform para-aortic lymph node dissection in patients with endometrial cancer, it is necessary to consider the pelvic lymph nodal status. If there is no pelvic lymph node metastasis, it could not be necessary to perform para-aortic lymph node dissection.

Overexpression of p16 INK4a as an indicator for human papillomavirus oncogenic activity in cervical squamous neoplasia.

Overexpression of p16(INK4a) has been observed when retinoblastoma protein is inactivated by high-risk human papillomavirus (HPV) oncoprotein E7. We investigated overexpression of p16(INK4a) and HPV infection in cervical squamous neoplasia to evaluate the oncogenic potential among various HPV subtypes. The high-risk HPV was detected by PCR in 69.8% (37/53), 97.5% (39/40), 91.7% (44/48), and 100% (16/16) of cervical intraepithelial neoplasia (CIN)1, CIN2, CIN3, and squamous cell carcinoma (SCC), respectively. The p16(INK4a) overexpression was investigated immunohistochemically using a p16(INK4a)-specific monoclonal antibody (clone E6H4). In high-risk HPV positive cases, 32.4% (12/37) of CIN1, 82.1% (32/39) of CIN2, 93.2% (41/44) of CIN3, and all (16/16) SCC showed p16(INK4a) overexpression. The incidence of p16(INK4a) overexpression was significantly different between CIN1 and CIN2, suggesting that the disorder of cell cycle regulation by HPV frequently occurred from CIN2. As for CIN1 cases, p16(INK4a) overexpression was observed more frequently in HPV16 and HPV52 than in HPV51 and HPV35. Using p16(INK4a) as a bio marker of HPV oncogenic activity, we demonstrate that the level of pRb dysfunction by high-risk HPV varied from subtypes and was getting more frequent from CIN2.

Sensitivity to cisplatin determined by the histoculture drug response assay and clinical response of endometrial cancer.

This study investigated the value of the in vitro histoculture drug response assay (HDRA) for predicting the efficacy of chemotherapy in patients with endometrial cancer. Specimens were obtained from 115 patients with endometrial cancer treated at Keio University Hospital between 1994 and 2002. Tumor fragments were cultured on collagen sponge gel with cisplatin for 7 days, and cell viability was assessed. The cutoff value of the 50% inhibitory concentration of cisplatin was set at 23 microg/mL. Sensitivity of stage III or IV disease to chemotherapy was investigated, and differences of 5-year progression-free survival between patients with sensitive and resistant tumors were evaluated by the Kaplan-Meier method. Tumors were evaluable in 93.0% of patients (107/115). Among 38 patients in stages III or IV, 23 received chemotherapy containing cisplatin. Seven sensitive tumors did not recur, while recurrence/progression occurred within 6 months in 8/16 patients with tumors showing low sensitivity. Among stages III and IV patients, there was a significant difference of 5-year progression-free survival (P < 0.05) between those with tumors showing high or low sensitivity. Accordingly, the HDRA may predict the efficacy of chemotherapy for endometrial cancer.

8-1A, a human monoclonal antibody that reacts with intact human chorionic gonadotropin.

The incidence of choriocarcinoma has decreased over time and therapeutic results have improved about 90% complete remission in patients without extensive metastasis. However, some choriocarcinomas metastasize to other organs and show resistance to chemotherapy, having a poor prognosis despite multidisciplinary treatment. Better methods of early diagnosis for recurrence or micrometastasis, and treatment against cases with intractable gestational trophoblastic neoplasia (GTN) are needed to improve the prognosis. Human chorionic gonadotropin (hCG) is a glycoprotein hormone composed of two dissimilar subunits and a tumor marker to make a diagnosis and monitor therapeutic effect in GTN. Even when hCG levels in the serum become too low to measure with the hCG beta-CTP system which is the most sensitive assay, there are estimated to be approximately 10,000 trophoblastic cells in the body. Residual trophoblast cells may cause symptoms such as bleeding or undergo malignant transformation to choriocarcinoma. Since most monoclonal antibodies developed so far are murine, administration creates human anti-mouse antibodies, resulting in clinical failure. More recent mouse/human chimeric antibodies or humanized antibodies still possess substantial immunogenicity that makes repeated administration difficult. In the present study, KM mice that can produce completely human monoclonal antibodies were used to prepare hCG-specific human monoclonal antibody. This yielded 8-1A, a human monoclonal antibody capable of reacting with intact hCG. In the future, new diagnostic techniques and treatments for chorionic diseases may be developed using this kind of human monoclonal antibody.

Semen quality of 324 fertile Japanese men.

BACKGROUND: A number of studies have indicated regional differences in semen quality. To examine the current status in Japan, we undertook a cross-sectional study on the semen quality of fertile Japanese men for comparison with recent European results. METHODS: Semen parameters of 324 fertile men from the Kawasaki/Yokohama area were investigated. The semen parameters were compared with those published for fertile men from four European cities, Copenhagen, Paris, Edinburgh and Turku. RESULTS: When adjusting for confounders such as ejaculation abstinence period and age, the lowest sperm concentrations were detected in men from Kawasaki/Yokohama followed by men from Copenhagen, Paris, Edinburgh and Turku, but only the differences between men from Kawasaki/Yokohama and men from Edinburgh and Turku were significant (P=0.0008 and P<0.0001, respectively). Total sperm count, percentage of motile sperm and percentage of normal sperm observed in Kawasaki/Yokohama were significantly lower than those from all European centres except for motile sperm in men from Paris. CONCLUSIONS: Japanese fertile men had a semen quality at the level of Danish men, who have been reported to have the lowest among investigated men in Europe. The low level of semen quality of the fertile Japanese men may be due to lifestyle or other environmental factors; however, ethnic differences caused by different genetic variation or combinations cannot be ruled out by this study.

Phase II trial of docetaxel in advanced or metastatic endometrial cancer: a Japanese Cooperative Study.

The purpose of this study was to determine whether docetaxel has antitumour activity in patients with advanced or recurrent endometrial carcinoma. Chemotherapy-naïve or previously treated patients (one regimen) with histopathologically documented endometrial carcinoma and Eastern Cooperative Oncology Group performance status