Two single nucleotide polymorphisms in <Emphasis Type="Italic">PRDM9</Emphasis> (<Emphasis Type="Italic">MEISETZ</Emphasis>) gene may be a genetic risk factor for Japanese patients with azoospermia by meiotic arrest

Purpose

To investigate whether defects in human PRDM9, CDK2 and PSMC3IP are associated with azoospermia Mutational analysis was performed in Japanese patients with azoospermia caused by meiotic arrest.

Methods

Mutational screening of the coding regions of human PRDM9, CDK2 and PSMC3IP was done by direct sequencing using genomic DNA from 18 Japanese patients. Statistical analysis of the detected coding single nucleotide polymorphisms (cSNPs) in patients and normal control men was then carried out.

Results

One cSNP was detected in CDK2 and PSMC3IP. There were no significant differences in genotype distribution and allele frequencies between the patient and control groups in these two genes. However, three novel cSNPs were detected in the PRDM9. The genotype and allele frequencies of heterozygotes in SNP2 and SNP3 of PRDM9 were significantly higher in the patient group than in the control group.

Conclusion

We found a possible association between PRDM9 and azoospermia by meiotic arrest.

     

Absolute lymphocyte count and C-reactive protein-albumin ratio can predict prognosis and adverse events in patients with recurrent esophageal cancer treated with nivolumab therapy

Predicting the prognosis and adverse events (AEs) of nivolumab therapy for recurrent esophageal cancer is very important. The present study investigated whether a simple blood biochemical examination could be used to predict prognosis and AEs following nivolumab treatment for relapse of esophageal cancer. A total of 41 patients who received nivolumab treatment for recurrent esophageal cancer after esophagectomy were analyzed. The absolute lymphocyte count (ALC), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR) and C-reactive protein-albumin ratio (CAR) were assessed at the time of nivolumab induction as indices that can be calculated by blood biochemical examinations alone. Median values were 1,015 for ALC, 3.401 for NLR, 242.6 for PLR, 0.458 for MLR and 0.119 for CAR, and patients were divided into two groups according to values. A high ALC, low NLR, low PLR, low MLR and low CAR were associated with a better response to nivolumab. In addition, patients with the aforementioned indices, with the exception of low PLR, or better response were more likely to develop AEs in univariate analysis. In multivariate analysis, a high ALC [odds ratio (OR): 4.857, P=0.043] and low CAR (OR: 9.099, P=0.004) were identified as independent risk factors for AEs. Survival analysis revealed that overall survival and progression-free survival (PFS) rates after nivolumab treatment differed significantly between the high and low groups of ALC, NLR, PLR, MLR and CAR. The multivariate analysis identified a low ALC [hazard ratio (HR): 3.710, P=0.003] and high CAR (HR: 2.953, P=0.007) as independent poor prognostic factors of PFS. In conclusion, ALC and CAR have potential as biomarkers for outcomes of recurrent esophageal cancer following nivolumab treatment.     

Disease-associated CIAS1 mutations induce monocyte death, revealing low-level mosaicism in mutation-negative cryopyrin-associated periodic syndrome patients

Cryopyrin-associated periodic syndrome (CAPS) is a spectrum of systemic autoinflammatory disorders in which the majority of patients have mutations in the cold-induced autoinflammatory syndrome (CIAS)1 gene. Despite having indistinguishable clinical features, some patients lack CIAS1 mutations by conventional nucleotide sequencing. We recently reported a CAPS patient with mosaicism of mutant CIAS1, and raised the possibility that CIAS1 mutations were overlooked in "mutation-negative" patients, due to a low frequency of mosaicism. To determine whether there were latent mutant cells in "mutation-negative" patients, we sought to identify mutation-associated biologic phenotypes of patients' monocytes. We found that lipopolysaccharide selectively induced necrosis-like cell death in monocytes bearing CIAS1 mutations. Monocyte death correlated with CIAS1 up-regulation, was dependent on cathepsin B, and was independent of caspase-1. Cell death was intrinsic to CIAS1-mutated monocytes, was not mediated by the inflammatory milieu, and was independent of disease severity or anti-IL-1 therapy. By collecting dying monocytes after lipopolysaccharide treatment, we succeeded in enriching CIAS1-mutant monocytes and identifying low-level CIAS1-mosaicism in 3 of 4 "mutation-negative" CAPS patients. Our findings reveal a novel effect of CIAS1 mutations in promoting necrosis-like cell death, and demonstrate that CIAS1 mosaicism plays an important role in mutation-negative CAPS patients.     

Successful treatment of tracheomalacia associated with esophageal atresia without a tracheoesophageal fistula by aortopexy: Report of a case

Tracheomalacia (TM) is well known as a complication associated with esophageal atresia (EA) and tracheoesophageal fistula (TEF); however, the occurrence of TM requiring surgical treatment in a patient having EA without a tracheoesophageal fistula has never been reported. We describe herein a rare case of TM associated with EA without TEF. Respiratory distress was caused by compression of the trachea by a severely dilated upper esophageal pouch with weakness of the tracheal wall. Aortopexy was performed, and an excellent postoperative result was achieved.     

Relation between vertical orientation and stability of acetabular component in the dysplastic hip simulated by nonlinear three-dimensional finite element method

In acetabular dysplasia, more vertical orientation of the acetabular component is often used to minimize the superolateral bone grafting. This study was designed to determine the effects of vertical orientation of the cup on the stability and polyethylene wear of the acetabular component in uncemented total hip arthroplasty (THA). Three-dimensional finite element models of the hemipelvis with dysplastic acetabulum were developed. Metal-backed hemispherical cups were placed in the true acetabulum with abduction angles of 35, 45, 55, and 65 degrees. It was found that more vertical orientation of the cup was associated with larger relative motion of the metal shell between the acetabulum and metal shell. Furthermore, tilting and torsional shear stresses in the model of the cup abduction angle of 65 degrees were found to be 1.7 times larger than that in the model with 35 degrees at the bone-metal shell interface. More vertically oriented cups caused larger contact stresses at the articulating surfaces of the polyethylene liners. The results suggest that the abduction angle of the acetabular component significantly influences cup loosening and polyethylene wear in THA.     

A case of transitional cell carcinoma of the renal pelvis with adenocarcinoma producing CEA and CA19-9

We report a case of invasive renal pelvic tumor with high serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen (CA 19-9). An 86-year-old man presented with macrohematuria. Retrograde pyelography demonstrated a filling defect in right upper calyx, suspected of renal pelvic tumor. The levels of serum CEA and CA 19-9 were elevated to 28.0 ng/ml and 122 U/ml, respectively. No abnormalities were found in the gastrointestinal tract. Right nephroureterectomy was performed, and histopathological diagnosis was transitional cell carcinoma, grade 2>grade 3, accompanied with adenocarcinoma immuno-stained for CEA and CA19-9. A part of the tumor showed a tubular growth pattern. Both serum levels of CEA and CA 19-9 immediately decreased to the normal range after the operation, but increased again with lung and hepatic metastases.     

Clinicopathological features of peripheral small-sized (2 cm or less in diameter) non-small cell lung cancer

Ninety-three patients with completely resected peripheral non-small cell lung cancer, clinically diagnosed 2 cm or less in diameter, were retrospectively reviewed. Their preoperative computed tomography (CT) and positron emission tomography (PET) findings, carcinoembryonic antigen (CEA) values, clinico-pathological features and postoperative outcomes were analysed. Ground-glass opacity (GGO) ratio( soft tissue density area of the tumor/maximum area of the tumor in diameter) was measured. The overall survival rate at 3 years was 93.3% and the relapse-free survival rate at 3 years was 89.4% with a median follow-up period of 38.5 months. Patients with GGO ratio 0.25 or less had no lymph node (LN) involvement nor lymph vascular invasion. Only 2 of them (8%) had vascular invasion. Fisher's exact probability test revealed CEA ≥ 5 ng/ ml as risk factor for LN involvement( p=0.0400). Multiple logistic regression analysis showed that solid adenocarcinoma and squamous cell carcinoma recurred more frequently than adenocarcinoma with GGO (p=0.0619, odds ratio 4.969, 95%CI 0.9242~37.67).     

Efficacy of rhBMP-2 during distraction osteogenesis

Background Osteoinductive ability of bone morphogenetic protein-2 (BMP-2) has been studied in recent reports. In this study, we evaluated the efficacy of BMP-2 during distraction osteogenesis. Methods A group of 24 Japanese white rabbits were divided into four groups randomly and underwent lengthening of the right femur. Distraction was performed for 2 weeks (1.0 mm/day). Group A began distraction following a 7-day waiting period after surgery. For all other groups (B–D), distraction was started immediately after surgery. Groups A and B did not undergo any surgical intervention at the osteotomy site, as a control. The delivery system for rhBMP-2 used a polymer-coated gelatin sponge (PGS). Buffer/PGS was implanted into the osteotomy site in group C, and group D received rhBMP-2/PGS. Callus was evaluated radiographically at 1, 2, 4, and 6 weeks after the surgery, and all rabbits were killed at 6 weeks. One rabbit from each group was examined histologically; the remaining five rabbits underwent biomechanical testing. Results A significant increase in callus formation was evident in group D compared with that in other groups. In group D, regenerative changes were evident during the earlier phase. Formation of bone cortex and bone marrow cavity was almost complete in group D, and the cortex was thicker than that in the other groups. Torsional strength values (10⁻² Nm) of each group were as follows: A, 118.7 ± 52.4; B, 160.0 ± 40.7; C, 106.8 ± 8.1; D, 266.1 ± 93.1. Stiffness values (10⁻³ Nm/degree) were as follows: A, 390.2 ± 137.2; B, 391.8 ± 158.4; C, 183.1 ± 78.5; D, 624.4 ± 214.2. Group D exhibited the highest values for both torsional strength and stiffness. Conclusions Acceleration of the regenerative changes during the early phase occurred in the BMP-2-treated group. The efficacy of BMP-2 in distraction osteogenesis was recognized radiographically, histologically, and by biomechanical testing (torsional strength and stiffness).     

Rotational acetabular osteotomy for osteonecrosis with collapse of the femoral head in young patients

BACKGROUND: While rotational acetabular osteotomy has been reported to be successful for the treatment of osteoarthritis of the dysplastic hip, little is known about its efficacy in the treatment of osteonecrosis of the femoral head. METHODS: We retrospectively reviewed the results for a consecutive series of twenty-one patients (twenty-five hips) who had undergone rotational acetabular osteotomy between 1995 and 2001 for the treatment of extensive osteonecrosis of the femoral head associated with collapse. All but two of the patients had a history of steroid therapy as part of a treatment regimen for various diseases. At the time of surgery, the mean age of the five men and sixteen women was 29.0 years. The mean duration of follow-up was forty-nine months. No patient was lost to follow-up. The lesions were classified according to the staging system described by Steinberg et al., and the extent of necrosis was measured with use of the criteria described by Kerboul et al. Clinical evaluation was performed with use of the scoring system of Merle d'Aubigne and Postel. Radiographic evaluation was performed with use of yearly serial anteroposterior and lateral plain radiographs. RESULTS: The mean Merle d'Aubigne and Postel score improved from 11.3 points preoperatively to 14.9 points at the time of the final follow-up (p < 0.001). The mean pain score improved from 3.0 to 5.6 points (p < 0.001). However, the mean mobility score was 5.3 points preoperatively but only 4.9 points postoperatively (p = 0.1). All of the osteotomy sites showed radiographic evidence of osseous union at the time of the latest follow-up. Collapse of the femoral head progressed in seven hips, but in six of these hips the change in the extent of collapse was <2 mm. CONCLUSIONS: In the present study of young patients with extensive osteonecrosis and collapse of the femoral head, rotational acetabular osteotomy was associated with symptomatic relief and absence of substantial collapse of the femoral head at the time of early to intermediate-term follow-up.