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Competing Interests: The authors declare that they have no conflict of interest.

Introduction and Hypothesis: The aim of this study was to assess the incidence and risk factors for premalignant and malignant pathology in patients receiving vaginal hysterectomy (VH) and pelvic floor repair (PFR) for pelvic organ prolapse (POP)., Methods: We performed a retrospective cohort study of pathological results after VH and PFR of 569 women at our institution from January 2011 through December 2020. Age, body mass index (BMI), POP-Q stage, and preoperative ultrasound results were evaluated as risk factors for occult malignancy., Results: Six of the 569 patients (1.1%) had unanticipated premalignant uterine pathology and 2 (0.4%) had unanticipated malignant uterine pathology (endometrial cancer). There was no significant difference in the incidence of premalignant or malignant uterine pathology according to age, BMI, and POP-Q stage. However, if endometrial pathology is confirmed on preoperative ultrasonography, the probability of confirming malignant pathology increases (OR 4.63; 95% CI 1.84-51.4; p=0.016)., Conclusion: The incidence of occult malignancy during VH for POP was significantly lower than that found in hysterectomy owing to benign disease. In the case of POP patients, for whom uterine-conserving surgery is not absolutely contraindicated, it can be performed. However, if endometrial pathology is confirmed by preoperative ultrasonography, uterine-conserving surgery is not recommended., (© 2023. The International Urogynecological Association.)

Objectives: This study aims to examine the clinical outcomes of women who underwent a midurethral sling surgery for stress urinary incontinence and compare postoperative urinary symptoms among different body mass index (BMI) groups., Methods: A retrospective cohort study on results after midurethral sling surgery according to BMI was conducted at the institution of the current study from January 2010 to December 2019. The study population was classified into three groups according to patients' BMI (in kg/m²) during surgery: normal weight (BMI < 23.0 kg/m²), overweight (BMI, 23.0-24.9 kg/m²), and obese (BMI ≥ 25.0 kg/m²). The primary outcome was the recurrence of urinary symptoms after surgery. The secondary outcomes were operation time, estimated blood loss, length of hospital stay, and postoperative complications., Results: This study included 376 patients (normal weight, 148; overweight, 74; and obese women, 154) who underwent midurethral sling surgery. No significant difference was noted in urinary symptom recurrence after midurethral sling surgery. Of the patients, 6.8% (n = 10), 9.5% (n = 7), and 7.8% (n = 12) were normal weight, overweight, and obese women, respectively ( P = 0.775). Moreover, operation time ( P = 0.589), blood loss ( P = 0.138), and complication rate ( P = 0.865) showed no significant difference., Conclusions: Midurethral sling surgery is effective regardless of BMI. Even when midurethral sling surgery was performed as a concomitant surgery, no significant difference in urinary symptom recurrence, operation time, intraoperative blood loss, and complication rate was noted among different BMI groups., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2021 by The Korean Society of Menopause.)

Background: Childhood intracranial germ cell tumor (GCT) survivors are prone to radiotherapy-related neurotoxicity, which can lead to neurocognitive dysfunctions. Diffusion kurtosis imaging (DKI) is a diffusion MRI technique that is sensitive to brain microstructural changes. This study aimed to investigate the association between DKI metrics versus cognitive and functional outcomes of childhood intracranial GCT survivors., Methods: DKI was performed on childhood intracranial GCT survivors (n = 20) who had received cranial radiotherapy, and age and gender-matched healthy control subjects (n = 14). Neurocognitive assessment was performed using the Hong Kong Wechsler Intelligence Scales, and functional assessment was performed using the Lansky/Karnofsky performance scales (KPS). Survivors and healthy controls were compared using mixed effects model. Multiple regression analyses were performed to determine the effects of microstructural brain changes of the whole brain as well as the association between IQ and Karnofsky scores and the thereof., Results: The mean Intelligence Quotient (IQ) of GCT survivors was 91.7 (95% CI 84.5 - 98.8), which was below the age-specific normative expected mean IQ ( P = 0.013). The mean KPS score of GCT survivors was 85.5, which was significantly lower than that of controls ( P < 0.001). Cognitive impairments were significantly associated with the presence of microstructural changes in white and grey matter, whereas functional impairments were mostly associated with microstructural changes in white matter. There were significant correlations between IQ versus the mean diffusivity (MD) and mean kurtosis (MK) of specific white matter regions. The IQ scores were negatively correlated with the MD of extensive grey matter regions., Conclusion: Our study identified vulnerable brain regions whose microstructural changes in white and grey matter were significantly associated with impaired cognitive and physical functioning in survivors of pediatric intracranial GCT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tso, Hui, Lee, Liu, Ip, Vardhanabhuti, Cheng, Fong, Chang, Ho, Yip, Ku, Cheuk, Luk, Shing, Leung, Khong and Chan.)

Introduction: The anterior vaginal wall is the segment most commonly affected by prolapse. Traditionally, anterior vaginal wall prolapse is repaired via anterior colporrhaphy, which is known to have a high recurrence rate. Several factors might affect the outcome of anterior colporrhaphy, and the use of absorbable sutures might also be associated with the high recurrence rate because the sutures might not be able to retain adequate strength until the plicated pubocervical fascia remodels and regains maximum tensile strength. Nonetheless, no comparative data exist about the relative efficacy and safety of anterior colporrhaphy using non-absorbable versus absorbable sutures. The objective of this study is to compare the surgical outcomes of anterior colporrhaphy using non-absorbable sutures with those of anterior colporrhaphy using absorbable sutures., Methods and Analysis: This is a randomised, multicentre, superiority trial. Anterior colporrhaphy will be performed in a traditional manner with midline plication of the fibromuscular layer using either non-absorbable or absorbable sutures. The primary outcome is composite surgical success 1 year after surgery defined as the absence of all of the following: (1) anterior vaginal descent beyond the hymen, (2) the presence of vaginal bulge symptoms and (3) retreatment for recurrent anterior vaginal wall prolapse with either surgery or pessary. The secondary outcomes include the individual components of the composite primary end point, anatomical outcomes, condition-specific quality of life and adverse events related to anterior colporrhaphy. The planned number of participants is 192., Ethics and Dissemination: This study was approved by the Institutional Review Board of Seoul National University Hospital (H-1810-037-977). The results of the study will be published in peer-reviewed journals, and the findings will be presented at scientific meetings., Trial Registration Number: NCT03736811., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Because of high-risk behaviours, sedentary lifestyle and side effects of medications, psychiatric patients are at risk of viral hepatitis, alcohol-related liver disease and non-alcoholic fatty liver disease. We aimed to study the incidence of hepatocellular carcinoma (HCC) and cirrhotic complications in psychiatric patients., Methods: We identified consecutive adult patients in all public hospitals and clinics in Hong Kong with psychiatric diagnoses between year 2003 and 2007 using the Clinical Data Analysis and Reporting System, which represents in-patient and out-patient data of approximately 80% of the 7.4-million local population. The patients were followed for liver-related events (HCC and cirrhotic complications) and deaths until December 2017. Age- and sex-standardized incidence ratio (SIR) of HCC in psychiatric patients to the general population was estimated by Poisson model., Results: We included 105,763 psychiatric patients without prior liver-related events in the final analysis. During a median (interquartile range) follow-up of 12.4 (11.0-13.7) years, 1461 (1.4%) patients developed liver-related events; 472 (0.4%) patients developed HCC. Compared with the general population, psychiatric patients had increased incidence of HCC (SIR 1.42, 95% confidence interval [CI] 1.28-1.57, P < 0.001). The SIR was highest in patients with drug-induced (SIR 3.18, 95% CI 2.41-4.11, P < 0.001) and alcohol-induced mental disorders (SIR 2.98, 95% CI 2.30-3.81, P < 0.001), but was also increased in patients with psychotic disorders (SIR 1.39, 95% CI 1.16-1.65, P < 0.001) and mood disorders (SIR 1.16, 95% CI 1.00-1.34, P = 0.047). Liver disease was the fifth most common cause of death in this population, accounting for 595 of 10,614 (5.6%) deaths. Importantly, 569 (38.9%) patients were not known to have liver diseases at the time of liver-related events. The median age at HCC diagnosis (61 [range 26-83] years) was older and the median overall survival (8.0 [95% CI 5.0-10.9] months) after HCC diagnosis was shorter in this cohort of psychiatric patients than other reports from Hong Kong., Conclusions: HCC, cirrhotic complications, and liver-related deaths are common in psychiatric patients, but liver diseases are often undiagnosed. More efforts are needed to identify liver diseases in the psychiatric population so that treatments and screening for HCC and varices can be provided to patients in need.

Introduction and Hypothesis: Trans-obturator tape (TOT) and tension-free vaginal tape (TVT) comprise minimally invasive surgical management for stress urinary incontinence (SUI). The aim of this retrospective cohort study was to investigate outcomes of TOT and TVT among different age groups of women., Methods: Medical records of patients who underwent TOT and TVT from January 2010 to December 2015 were reviewed. Patients were stratified into three groups according to age. All patients were interviewed routinely before and after surgery. The primary outcome was cure rate after surgery. Secondary outcomes included hospital stay, operative time, blood loss in surgery, and complication rate. A total of 616 patients diagnosed with SUI and 262 patients who had not undergone any concurrent surgery were eligible for study inclusion., Results: A total of 616 patients diagnosed with SUI and 262 patients who had not undergone any concurrent surgery were eligible for study inclusion. There were 81 patients in group 1 (≤ 50 years), 97 patients in group 2 (51-59 years), and 84 patients in group 3 (≥ 60 years). After surgery, there were no significant differences in cure rates among the three groups (96.3% vs. 94.8% vs. 97.6%, P = 0.623). There were also no significant differences in operation time, blood loss, hospital stay, and complication rate among the three groups. When analyzing the TOT group (217 patients) and TVT group (45 patients) separately, primary and secondary outcomes did not differ significantly according to age group., Conclusions: As surgical management for SUI, midurethral sling procedures, both TOT and TVT, were found to be safe and effective among different age groups.

Purpose: Descent of the uterus is a major etiology of uterine prolapse. However, true cervical elongation can cause uterine prolapse without uterine descent. The aim of study was to investigate the clinical outcomes of Manchester operation in patients with uterine prolapse caused by "true cervical elongation," compared with vaginal hysterectomy (VH)., Materials and Methods: Medical records of patients who underwent Manchester operation or VH from 2006 to 2015 were reviewed. True cervical elongation was defined on the basis of C point of the Pelvic Organ Prolapse Quantification (POP-Q) system ≥0 and D point ≤-4, as well as estimated cervical length of ≥5 cm. The primary outcome was recurrence of pelvic organ prolapse (POP) evaluated by POP-Q system. The outcomes of two groups were compared after propensity score matching, for age, parity, and preoperative POP-Q stage., Results: During the study period, 23 patients underwent Manchester operation and 374 patients underwent VH. The recurrence rate of POP ( p =0.317) and complication rate were not statistically significant different between the two study groups. Manchester operation exhibited shorter operation time than VH ( p =0.033). In subgroup analysis (POP-Q stage III), body mass index [odds ratio (OR)=1.74; 95% confidence interval (CI), 1.08-2.81] and not having concurrent anterior colporrhaphy (OR for concurrent anterior colporrhaphy, 0.06; 95% CI, 0.01-0.75) were identified as significant risk factors for recurrence of POP., Conclusion: The Manchester operation technique seems to be an effective and safe alternative procedure for the treatment of uterine prolapse caused by true cervical elongation, compared with VH., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2019.)

Background: Intracranial germ cell tumors (GCT) are more common in Asia than in the West, accounting for about 15% of brain tumors in Asian children. The survival rate for intracranial GCT is excellent, but there are concerns about the effects of radiotherapy on neuropsychological function and quality of life of patients., Methods: Intracranial germ cell tumors (GCT) are more common in Asia than in the West, accounting for about 15% of brain tumors in Asian children. The survival rate for intracranial GCT is excellent, but there are concerns about the effects of radiotherapy on neuropsychological function and quality of life of patients. Intracranial GCT survivors in Hong Kong aged ≥ 6 years who received cranial irradiation in the past 15 years were recruited. Neurocognitive function and performance status were assessed by the Hong Kong Wechsler Intelligence scale and Karnofsky/Lansky performance scales (KPS), respectively. Quality of life was assessed using the Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales. A chart review was performed for tumor characteristics and complications related to the tumor and its treatment., Results: Twenty-five intracranial GCT survivors were recruited. Longer length of time since treatment was associated with lower IQ scores. Larger tumor size was associated with lower KPS scores. Hemiparesis, poor manual dexterity, and complications with multi-organ involvement were associated with significantly lower KPS scores. Higher irradiation dosage was associated with lower PedsQL physical scores., Conclusions: The majority of GCT survivors had average intellectual functioning, satisfactory performance status and relatively good quality of life, except in the physical aspect. Comprehensive evaluation and long-term follow-up of GCT survivors are essential to provide timely support and improve long-term outcomes.

Objectives: To examine the clinical outcome of obesity in women who underwent the transobturator tape procedure for stress urinary incontinence and to compare postoperative urinary symptoms after transobturator tape surgery between normal-weight women and overweight and obese women., Methods: We performed a retrospective cohort study of the risk of postoperative urinary symptoms, including recurrence after transobturator tape surgery, in normal-weight women compared with overweight and obese women at our institution from January 2009 through October 2011. We compared the body mass index (BMI) among the four groups. The primary outcome was the occurrence of postoperative urinary symptoms., Results: Three hundred ten patients who underwent transobturator tape surgery were reviewed. At the 1-year follow-up, 281 women were analyzed: 89 (34%) normal-weight women, 78 (25%) overweight women, 101 (37%) obese 1 women, and 13 (3%) obese 2 women. There was a significant difference in the occurrence of postoperative urinary symptoms. They occurred in 3.4% (n=3) of normal-weight women, 5.1% (n=4) of overweight women, and 12.9% (n=13) of obese 1 women ( P =0.038). The most common postoperative urinary symptom was frequent urination (n=14). There was a significant difference in leakage; it occurred in 1.1% (n=1) of normal-weight women, 3.9% (n=3) of overweight women, and 7.9% (n=8) of obese 1 women ( P =0.139). Postoperative urinary symptoms were almost four times more likely to occur in obese 1 women than in normal-weight women., Conclusion: Transobturator tape surgery seems effective regardless of BMI, but obese women had a higher occurrence of postoperative urinary symptoms than did normal-weight women., Competing Interests: Conflict of interest: No potential conflict of interest relevant to this article was reported.

Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through genetic mapping of disease loci and whole-exome sequencing in four unrelated multiplex families presenting with severe AMC, we identified biallelic loss-of-function mutations in LGI4 (leucine-rich glioma-inactivated 4). LGI4 is a ligand secreted by Schwann cells that regulates peripheral nerve myelination via its cognate receptor ADAM22 expressed by neurons. Immunolabeling experiments and transmission electron microscopy of the sciatic nerve from one of the affected individuals revealed a lack of myelin. Functional tests using affected individual-derived iPSCs showed that these germline mutations caused aberrant splicing of the endogenous LGI4 transcript and in a cell-based assay impaired the secretion of truncated LGI4 protein. This is consistent with previous studies reporting arthrogryposis in Lgi4-deficient mice due to peripheral hypomyelination. This study adds to the recent reports implicating defective axoglial function as a key cause of AMC., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD.

Pelvic organ prolapse is a common condition, occurring in up to 11% of women in the United States. Often, pelvic organ prolapse recurs after surgery; when it recurs after hysterectomy, it frequently presents as vaginal apical prolapse. There are many different surgical treatments for vaginal apical prolapse; among them, abdominal sacral colpopexy is considered the gold standard. However, recent data reveal that other surgical procedures also result in good outcome. This review discusses the various surgical treatments for vaginal apical prolapse including their risks and benefits.

The ent-kaurene is a dedicated precursor pool and is responsible for synthesizing natural sweeteners such as steviol glycosides. In this study, to produce ent-kaurene in Escherichia coli, we modularly constructed and expressed two ent-kaurene genes encoding ent-copalyl diphosphate synthase (CPPS) and ent-kaurene synthase (KS) from Stevia rebaudiana known as a typical plant producing steviol glycoside. The CPPS and KS from S. rebaudiana were functionally expressed in a heterologous host E. coli. Furthermore, in order to enhance ent-kaurene production in E. coli, six geranylgeranyl diphosphate synthases (GGPPS) from various microorganisms and eight strains of E. coli as host were compared by measuring ent-kaurene production. The highest ent-kaurene production of approximately 41.1mg/L was demonstrated in E. coli strain MG1655 co-expressing synthetic CPPS-KS module and GGPPS from Rhodobacter sphaeroides. The ent-kaurene production was further increased up to 179.6 mg/L by overexpression of the three key enzymes for isoprenoid precursor, 1-deoxyxylulose-5-phosphate synthase (DXS), farnesyl diphosphate synthase (IspA) and isopentenyl diphosphate isomerase (IDI) from E. coli. Finally, the highest titer of ent-kaurene (578 mg/L) with a specific yield of ent-kaurene of 143.5mg/g dry cell weight was obtained by culturing E. coli strain MG1655 co-expressing the ent-kaurene module, DXS, IDI and IspA in 1L bioreactor containing 20 g/L glycerol., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: The Bishop score and length of the uterine cervix are good predictors of successful labor induction. However, little is known about the association between the funneling of the uterine cervix and successful labor induction. The study aimed to evaluate cervical funneling as a predictor of successful labor induction., Methods: This study was designed as a prospective observational study. Subjects who delivered a baby by labor induction were enrolled in the study from July 2011 to August 2013. Cervical funneling and length were examined with transvaginal ultrasonography. The Bishop score was rated by digital pelvic examination., Results: A total of 163 primigravida women were recruited for the study. Of these, 137 participants (84.0%) delivered vaginally by labor induction. Cervical funneling was observed in 93 women (57.1%). Successful labor induction was significantly higher in patients with cervical funneling than those without it (91.4% vs. 74.3%, P<0.01), and was significantly associated with cervical funneling, as well as the Bishop score and cervical length. In a multivariate analysis, cervical funneling was an independent predictor for successful vaginal delivery by labor induction ( odd ratio, 2.70; 95% confidence interval, 1.02 to 7.10; P=0.04). However, the Bishop score and cervical length had no association with successful vaginal delivery., Conclusion: This study showed that cervical funneling could be a predictive marker for vaginal delivery during labor induction.

Background: Dementia caregiving is often associated with increase in depressive symptoms and strained relationships. This study tested whether telephone-delivered psychoeducation combined with an enhanced behavioral activation (BA) module had a better effect on the well-being of Alzheimer's caregivers than psychoeducation alone. The focus is on enhancing the competent use of coping skills via BA. The program is delivered by telephone to increase accessibility and sustainability for caregivers. Senior citizens are trained as paraprofessionals to deliver the BA module to increase the potential for sustainability of the program., Methods and Subjects: The study compared two telephone interventions using a 4-month longitudinal randomized controlled trial. For the first 4 weeks, all participants received the same psychoeducation program via telephone. Then for the following 4 months, eight biweekly telephone follow-up calls were carried out. For these eight follow-up calls, participants were randomized into either one of the two following groups with different conditions. For the psychoeducation with BA (PsyED-BA) group, participants received eight biweekly sessions of BA practice focused on pleasant event scheduling and improving communications. For the psychoeducation only (PsyED only) group, participants received eight biweekly sessions of general discussion of psychoeducation and related information. A total of 62 family caregivers of persons living with dementia were recruited and 59 (29 in the PsyED-BA group and 30 in the PsyED only group) completed the whole study., Results: As compared to the group with psychoeducation and discussion, the group with enhanced BA had decreased levels of depressive symptoms. The study had a low attrition rate., Conclusion: Results suggested that competence-based training could be effectively administered through the telephone with the help of senior citizens trained and engaged as paraprofessionals. Results contribute to the present literature by offering some framework for developing effective, accessible, sustainable, and less costly interventions.

1,4-Butanediol (1,4-BDO) is currently produced from succinate via six enzymatic reactions in an engineered Escherichia coli strain. Butyraldehyde dehydrogenase (Bld) and butanol dehydrogenase of Clostridium saccharoperbutylacetonicum were selected based on their activities of catalyzing the final two reactions in the 1,4-BDO pathway. To fit Bld into the non-natural 1,4-BDO pathway, we engineered it through random mutagenesis. Five Bld mutants were then isolated using a colorimetric Schiff's reagent-based method. Subsequent site-directed mutagenesis of Bld generated the two best Bld mutants, L273I and L273T, which produced 1,4-BDO titers fourfold greater than those of wild-type Bld. The enhanced 1,4-BDO titers obtained using L273I and L273T clearly correlated with their enhanced activities, which were caused by amino acid mutations at position 273 of Bld. The highest titer of 1,4-BDO (660 ± 40 mg/L) was obtained in a knock-out E. coli strain [ΔldhA ΔpflB ΔadhE ΔlpdA::K. lpd(E354K) Δmdh ΔarcA gltA(R164L)] coexpressing Bld273T+Bdh., (© 2014 Wiley Periodicals, Inc.)

An adaptive response is a biological response where the exposure of cells or animals to a low priming exposure induces mechanisms that protect the cells or animals against the detrimental effects of a subsequent larger challenging exposure. In realistic environmental situations, living organisms can be exposed to a mixture of stressors, and the resultant effects due to such exposures are referred to as multiple stressor effects. In the present work we demonstrated, via quantification of apoptosis in the embryos, that embryos of the zebrafish (Danio rerio) subjected to a priming exposure provided by one environmental stressor (cadmium in micromolar concentrations) could undergo an adaptive response against a subsequent challenging exposure provided by another environmental stressor (alpha particles). We concluded that zebrafish embryos treated with 1 to 10 μM Cd at 5 h postfertilisation (hpf) for both 1 and 5 h could undergo an adaptive response against subsequent ~4.4 mGy alpha-particle irradiation at 10 hpf, which could be interpreted as an antagonistic multiple stressor effect between Cd and ionising radiation. The zebrafish has become a popular vertebrate model for studying the in vivo response to ionising radiation. As such, our results suggested that multiple stressor effects should be carefully considered for human radiation risk assessment since the risk may be perturbed by another environmental stressor such as a heavy metal.

We described a patient of refractory cytomegalovirus (CMV) limbic encephalitis who received matched unrelated bone marrow transplantation. Pyrosequencing study on serial cerebrospinal fluid samples revealed the emergence of resistant strains associated with exposure of antiviral agents. Combinations of antiviral agents had a role in partial suppression of CMV viral load but the clearance of virus mainly relied on the recovery of host's immunity and resulted in intact survival of host. Donor's CMV-seronegative status may contribute to the delay in controlling this serious infection. Prompt identification of drug-resistant mutant helps in selection of antiviral agents.

Osteoarthritis (OA) is the most common rheumatic pathology. One of the major objectives of OA research is the development of early diagnostic strategies such as those using proteomic technology. Synovial fluid (SF) in OA patients is a potential source of biomarkers for OA. The efficient and reliable preparation of SF proteomes is a critical step towards biomarker discovery. In this study, we have optimized a pretreatment method for two-dimensional gel electrophoresis (2DE) separation of the SF proteome, by enriching low-abundance proteins and simultaneously removing hyaluronic acid, albumin, and IgG. SF samples pretreated using this optimized method were then evaluated by 1DE and 2DE separation followed by immunodetection of cartilage oligomeric matrix protein (COMP), a known OA biomarker, and by the identification of 3 proteins (apolipoprotein, haptoglobin precursor, and fibrinogen D fragment) that are related to joint diseases.

Objective: Pneumococcal conjugate vaccine (PCV) is an effective way to prevent invasive pneumococcal diseases in high risk populations. The efficacy of this vaccine in paediatric oncology patients remains unknown., Design and Setting: The authors evaluated the antibody response to seven pneumococcal serotypes in paediatric oncology patients given two doses of heptavalent PCV (PCV-7)., Results: Forty-four patients (20 males; 24 females) with median age 9.5 years were studied. After two doses of PCV-7, 86-100% of patients had protective antibody titres against the seven vaccine serotypes. Increases in geometric mean antibody concentrations ranged from 3.8-fold for serotype 19F to 85.8-fold for serotype 14. There was no documented invasive pneumococcal disease in our cohort during the study period., Conclusion: PCV can elicit protective antipneumococcal antibody responses in paediatric oncology patients.

Background: Childhood cancer survivors were at risk of development of second malignant neoplasms. The aim of this study is to evaluate the incidence, risk factors and outcome of second malignant neoplasms in childhood cancer survivors in a tertiary paediatric oncology centre in Hong Kong, China., Methods: We performed a retrospective review of patients with childhood cancer treated in Children's Cancer Centre in Prince of Wales Hospital, Hong Kong, China between May 1984 and June 2009. Case records of patients who developed second malignant neoplasms were reviewed., Results: Totally 1374 new cases aged less than 21-year old were treated in our centre in this 25-year study period. Twelve cases developed second malignant neoplasms with 10-year and 20-year cumulative incidence of 1.3% (95% confidence interval 0.3% - 2.3%) and 2.9% (95% confidence interval 1.1% - 4.7%) respectively. Another 4 cases were referred to us from other centres for the management of second malignant neoplasms. In this cohort of 16 children with second malignant neoplasms, the most frequent second malignant neoplasms were acute leukemia or myelodysplastic syndrome (n = 6) and central nervous system tumor (n = 4). Median interval between diagnosis of primary and second malignant neoplasms was 7.4 years (range 2.1 - 13.3 years). Eight patients developed second solid tumor within the previous irradiated field. Radiotherapy significantly increased the risk of development of second solid tumor in patients with acute lymphoblastic leukemia (P = 0.027). Seven out of 16 patients who developed second malignant neoplasms had a family history of cancer among the first or second-degree relatives. Nine patients died of progression of second malignant neoplasms, mainly resulted from second central nervous system tumor and osteosarcoma., Conclusions: Cumulative incidence of second cancer in our centre was comparable to western countries. Radiotherapy was associated with second solid tumour among patients with acute lymphoblastic leukemia. Patients who developed second brain tumor and osteosarcoma had a poor outcome.

With the use of intensive chemotherapy and hematopoietic stem cell transplantation (HSCT), the prognosis of childhood acute myeloid leukemia (AML) improved over the last 2 decades. Survival data of Chinese pediatric patients were seldom reported. The authors adopted modified UK Medical Research Council (MRC) AML protocols for treatment of childhood AML since 1994. From 1994 to 2008, the outcomes of Chinese AML patients were studied. Sixty-eight patients were studied. The median age at diagnosis was 9.9 years. Twenty-five patients (36.8%) had favorable cytogenetic karyotypes, including t(15;17), t(8;21) and inv(16). Complete remission (CR) rate was 91.2%. The relapse rate was 29.4%. For non-M3 patients, the 5-year overall survival (pOS) was 64% ± 7% and event-free survival (pEFS) was 53% ± 7%. For those non-good-risk patients who achieved CR, there were no significant differences in outcomes between patients who received HSCT in CR1 and those received chemotherapy alone (5-year pOS 80% ± 13% and 69% ± 9%, P = .52), 5-year pEFS 69% ± 15% and 55% ± 10%, P = .40). The pOS of the 20 relapsed patients was 29% ± 11%. Sixteen patients with t(8;21) and inv(16) had similar outcome with those without favorable cytogenetics (pOS 66% ± 12% versus 65% ± 7%, P = .39; pEFS 60% ± 11% versus 54% ± 8%, P = .45). Patients who achieved CR after 2 or more courses of chemotherapy and presenting white blood cell count (WBC) ≥ 100 × 10(9)/L had poorer outcome (pOS 40% versus 80%P < .01; 43% versus 70%, P = .02, respectively). Intensified chemotherapy improved outcome of Chinese AML children. CR after first course of chemotherapy and WBC at diagnosis were important prognostic factors.

We evaluate the recovery of CMI to various herpes viruses by measuring in vitro LPR to specific recall antigens. CMI was evaluated by the in vitro LPR of PBMC to specific purified HSV-1, VZV, CMV, EBV, HHV-6, -7, -8, antigens. Results were expressed as SI. SI > or = 3 was regarded as positive LPR. Serial measurements were taken prospectively from pretransplant till 12-month post-transplant. Thirty-six patients (M = 19; F = 17) with median age 10.5 yr old were recruited. Most transplants were from MSD with PBSC as the stem cell source. Altogether 50% of subjects started to show positive LPR to HSV-1, CMV, and VZV antigens at two-month post-transplant, major upsurges were noted until 6-month post-transplant. Subjects showed positive LPR to EBV, HHV-6, HHV-7, and HHV-8 antigens were all along <50% throughout the study period. The antibody status of donor and recipient for HSV-1, CMV, and VZV were associated with the timing of recovery of CMI. Choice of donor and stem cell source were important determinants of eventual LPR to various herpes viruses at 3-month post-transplant. At 12-month post-transplant, there was no statistical difference in any parameters in affecting LPR to different herpes viruses.

The role of ganciclovir as HHV-6 prophylaxis in unrelated HSCT setting remains controversial. We performed an eight-yr retrospective review of patients received unrelated HSCT from January 2000 to September 2008. From January 2002, ganciclovir prophylaxis 5 mg/kg twice daily for seven days for all unrelated HSCT before transplant was adopted. The prevalence of HHV-6 encephalitis was studied before and after the change in policy. Fifty-four unrelated HSCT were performed from January 2000 to September 2008. Four cases (7.4%) of HHV-6 encephalitis were diagnosed. All of them were due to variant B infection. Two cases out of 16 cases (12.5%) were diagnosed before adoption of the policy; two cases out of 38 cases (5.3%) were diagnosed afterward. All of them were unrelated UCB transplant recipients. They were all seropositive to HHV-6 before transplant. Two cases complicated with significant residual neurological deficit and refractory seizure. The other two cases died of other transplant-related mortalities. We conclude that HHV-6 encephalitis is still a rare complication of unrelated HSCT and may be more common in unrelated UCB transplant. Routine use of ganciclovir as HHV-6 prophylaxis in all unrelated HSCT recipients may not be justified but may have a role in unrelated UCB transplant., (Copyright (c) 2009 John Wiley & Sons A/S.)

The recovery of antibodies to various vaccine-preventable infectious diseases, humoral and cellular immunity in pediatric oncology patients were evaluated by a prospective longitudinal study for 18 months. Lymphocyte subset (CD3+, CD4+, CD8+, CD16/56+, CD19+), CD4/CD8 ratio, immunoglobulin levels, antibodies to diphtheria, pertussis, tetanus, hepatitis B, measles, mumps, and rubella were measured serially at 6 months till 18 months after stopping all chemotherapy (including maintenance chemotherapy). Twenty-eight children (hematological malignancies, n = 14; solid tumors, n = 14) were studied. The median age was 7.0 +/- 3.8 years old (range 2.6-16.2 years old). Although there was significant increase in CD3+, CD4+, CD8+, CD19+ cells, IgG, IgA, and IgM levels (P < .05), CD4+ and CD8+ counts were still below the age-specific normal range at the end of study period. At 18 months after stopping chemotherapy, 11%, 15%, 60%, 30%, 49%, and 30% of subjects remained seronegative against diphtheria, tetanus, hepatitis B, measles, mumps, and rubella. This will evolve to a significant health care problem if no further intervention is implemented, as the survival rate of pediatric oncology patients improves significantly with the improvement in various cancer treatment protocols. Near complete immune recovery was demonstrated in the subjects. Significant proportion of subjects remained susceptible to vaccine-preventable infectious diseases up to 18 months after stopping all chemotherapy.

Primary sclerosing cholangitis is a rare cause of cholestasis caused by progressive inflammation and fibrosis of both intrahepatic and extrahepatic bile ducts leading to multifocal ductal strictures. Herein, we report a case of primary sclerosing cholangitis and inflammatory bowel disease. The concomitant diagnosis of these two diseases is not typical. The management includes the treatment of inflammatory bowel disease and potential complications of primary sclerosing cholangitis, including dominant strictures of bile duct, portal hypertension, gallbladder diseases, cholangiocarcinoma, and colonoscopic surveillance.

EBV-associated post-transplant lymphoproliferative disorder (PTLD) is a well-recognized complication following solid organ transplantation and hematopoietic stem cell transplantation (HSCT) using bone marrow or peripheral blood as stem cell sources, but rarely reported in umbilical cord blood transplantation (UCBT). We report two cases in unrelated UCBT setting and added the following new information to the literature: (i) EBV-related PTLD can be presented late in recipients of unrelated UCBT; (ii) in contrast to reported literatures that PTLD is a serious complication with unfavorable outcome, especially in monomorphic form, our cases showed that the clinical course may be relatively benign if treatment is initiated promptly., ((c) 2009 Wiley-Liss, Inc.)

Background: The role of post-chemotherapy booster vaccination in pediatric oncology children remains to be established. In this randomized controlled study, we studied the effect of immune responses to diphtheria-tetanus-pertussis (DTP) booster vaccination in children 6 months after completing chemotherapy., Methods: Children 1-18 years old with chemotherapy completed for 6 months (baseline) were eligible. Subjects were randomized into vaccine and control group. In the former, three doses of DTP vaccine (Aventis Pasteur Inc., Lyon, France) were administered. IgG antibody titers against diphtheria, tetanus, pertussis, hepatitis B, measles, mumps, and rubella antibodies were measured serially in vaccine and control groups. Subsets of circulating lymphocytes (CD3(+), CD4(+), CD8(+), CD19(+), and CD16/56(+)) were quantified by flow cytometry using fluorescence-labeled monoclonal antibodies., Results: Fifty-six children (28 vaccinees; 28 controls) were enrolled. Protective antibody levels against diphtheria, tetanus, pertussis were found at baseline in 83.6%, 96.5%, 96.1% of them respectively. After three doses of DTP, all vaccinees demonstrated a sustain rise in antibody levels and the antibody titers were significantly higher than control group. 35.8% of subjects were susceptible to measles mumps and rubella infection and 69% showed anti-HBs antibody titer less than protective level up to 18 months after stopping chemotherapy., Conclusions: Post-chemotherapy booster vaccinations produced a strong and sustained effect in humoral immunity against vaccine-preventable infectious diseases., ((c) 2008 Wiley-Liss, Inc.)

This study investigated the effect of Phellodendri Cortex extract on hyperglycemia and diabetic nephropathy in streptozotocin-induced diabetic rats. Male Sprague-Dawley rats were divided into normal control (NC), diabetic control (DC), and diabetic treatment with Phellodendri Cortex extract (DP). Over a 4-week experimental period, Phellodendri Cortex extract was administered orally at 379 mg/kg BW/day. The final fasting serum glucose level, urine total protein level, and relative left kidney weight in the DP group were significantly lower than the DC group. Renal XO and SOD activities in the DP group were significantly lower than the DC group and renal CAT activity in the DP group was significantly higher than the DC group. Tubular epithelial change was reduced in the DP group compared to the DC group. These results indicated that Phellodendri Cortex can reduce glucose level and prevent or retard the development of diabetic nephropathy in streptozotocin-induced diabetic rats.

Purpose: To compare retinal thickness and retinal height of the original scanned optical coherence tomography (OCT) images with those of the same images after automated retinal thickness analysis., Design: Cross-sectional study., Participants: Thirty normal eyes, 20 eyes with neovascular age-related macular degeneration (AMD), 20 with central serous chorioretinopathy (CSC), 20 with macular holes, and 20 with non-AMD related macular edema from 110 subjects were selected randomly from an OCT database. One of the 6 macular scans in each eye was chosen randomly for analysis., Methods: Two sets of OCT images--original images and analyzed images (after retinal thickness [single eye] analysis)--in each eye were exported for retinal thickness or retinal height measurement. Comparisons of retinal thickness or retinal height at selected locations were performed., Main Outcome Measures: Retinal thickness (defined as the distance between the anterior boundary of the retinal nerve fiber layer [RNFL] and posterior boundary of the photoreceptor layer) and retinal height (defined as the distance between the anterior boundary of the RNFL and baseline level of the anterior boundary of the retinal pigment epithelium [RPE]). Retinal height was measured when there was detachment of neurosensory retina or RPE., Results: No significant difference in retinal thickness was observed between the original and the analyzed OCT images in normal eyes and in eyes with macular holes or non-AMD related macular edema. However, OCT-analyzed images demonstrated retinal thickness or retinal height measurements in eyes with CSC or neovascular AMD significantly lower than the corresponding measurements in the original images (all with Ps< or =0.001, Wilcoxon signed rank test). In the groups of neovascular AMD and CSC, Bland-Altman plots revealed mean differences of 124 mum (95% limits of agreement between -65.5 and 313.6) and 84.4 mum (95% limits of agreement between -178.0 and 346.8), respectively, between the original and analyzed retinal measurements., Conclusions: Retinal thickness and retinal height could be underestimated in patients with CSC or neovascular AMD after retinal thickness analysis in Stratus OCT when either automatic measurements or manual caliper-assisted measurements are performed on the analyzed images. We recommend exporting the original scanned OCT images for retinal thickness and retinal height measurement in patients with CSC or neovascular AMD.

Objective: To investigate the correlation of male infertility with abnormality of chromosomal quantity and construction and with the deletion of DAZ gene copy in the AZFc region of Y chromosome., Methods: Included in the study were 247 azoospermic and 206 severe oligozoospermic patients, as well as 210 fertile men as controls. Multi-PCR and PCR-RFLP were used to analyze the deletion of DAZ gene copies in the AZFc region of Y chromosome. Chromosomal quantity and construction were detected by G-band in the 453 patients., Results: In the azoospermic and severe oligozoospermic patients, the incidences of chromosomal abnormality were 12.6% and 8.3%; the rates of complete DAZ deletion were 7.7% and 11.2%, and the rates of DAZ1/DAZ2 deletion were 7.3% and 4.9% respectively, but no deletion was detected in the controls., Conclusion: There is a high frequency of chromosomal abnormality and DAZ gene copy deletion in patients with azoospermia and oligospermia, which suggests that chromosomal abnormality and partial and complete deletion of DAZ gene copy might be important genetic causes of Chinese male infertility.

Objective: To investigate the possible association between ZNF230 gene and azoospermia., Methods: Screening for mutation of all 6 exons of ZNF230 gene was performed by denaturing high performance liquid chromatography(DHPLC) in 99 patients with azoospermia and in 115 healthy men as controls., Results: An A-->G transition at nucleotide 316 in exon 6 was identified. There were significant differences in the distribution profiles of both allele and genotype frequencies between patient group and control group (P < 0.01 and P < 0.05, respectively). In addition,there was a statistically significant difference in the serum follicle stimulating hormone (FSH) level between the patients with GG/GA genotype and those with AA genotype (P < 0.05)., Conclusion: ZNF230 gene may be associated with azoospermia, and the A316G mutation may be correlated with the serum FSH level.

Purpose: To describe the technology of optical coherence tomography (OCT) in imaging the anterior chamber angles and its impact on understanding the pathophysiology of angle-closure glaucoma (ACG)., Design: Observational case series., Participants: Three subjects with, respectively, impending angle-closure attack, plateau iris syndrome, and phacomorphic glaucoma were recruited., Methods: The anterior chamber angle in each patient was imaged with a commercially available OCT unit. The angle configurations were assessed and compared before and after laser peripheral iridotomy (LPI) and argon laser peripheral iridoplasty (ALPI)., Main Outcome Measures: Visualization of the changes in the anterior chamber angle configurations and normalization of the intraocular pressure (IOP)., Results: A patient with impending angle-closure attack precipitated by a topical mydriatic agent was treated with LPI. Optical coherence tomography imaging of the anterior chamber angles was performed before and after the laser procedure. Conversion of anterior iris bowing and angle crowding to iris straightening and angle opening after LPI was demonstrated. Intraocular pressure became normalized with the change in angle configuration. The second patient presented with symptoms of intermittent angle-closure attacks and was initially diagnosed with primary ACG. Despite successful LPI, the angles remained occludable, and the IOP continued to be elevated. Optical coherence tomography was used to review the anterior chamber angle configuration and demonstrated a typical pattern compatible with the diagnosis of plateau iris syndrome. Subsequent ALPI converted the plateau configuration to open angle, with normalization of IOP and disappearance of symptoms. The third patient presented with an acute angle-closure attack and was diagnosed with phacomorphic glaucoma. Argon laser peripheral iridoplasty was performed successfully to open the angle, as evident by the OCT images, and the IOP was brought under control, together with relief of symptoms., Conclusions: The commercially available OCT unit can be practically employed for anterior chamber angle imaging. The different patterns of angle configurations are correlated with the underlying pathophysiology in different forms of ACG.

Objective: To evaluate macular nerve fiber layer (NFL) thickness in glaucomatous damage by optical coherence tomography (OCT) and to compare its discriminating power for glaucoma and glaucoma suspects with that of total macular thickness and peripapillary NFL thickness., Design: Cross-sectional, case-control, comparative study., Participants: A total of 133 eyes from 133 subjects including 46 normal eyes, 48 glaucoma-suspect eyes, and 39 glaucoma eyes were enrolled., Methods: Macular NFL thickness, total macular thickness, and peripapillary NFL thickness were measured by Stratus OCT in each diagnostic group., Main Outcome Measures: The patterns and measurements of macular NFL, total macular, and peripapillary NFL thickness in total mean, 4 quadrants, and 12 clock hours. The discriminating power of each parameter for detection of glaucoma suspects and glaucoma was evaluated by areas under the receiver operating characteristic curve (AROC). Correspondence with visual field function was studied by linear regression analysis., Results: The macular NFL profile exhibited a double-hump pattern with peaks over superonasal and inferonasal sectors. A significant difference in macular NFL thickness between normal and glaucoma-suspect groups was found at the 6-o'clock position, whereas a difference was found in all except the temporal clock hours between normal and glaucoma subjects. No significant difference in AROCs for detection of glaucoma suspects or glaucoma was found when macular NFL thickness and total macular thickness measurements were compared. However, mean macular NFL thickness demonstrated a stronger correlation with visual function than mean macular thickness (r = 0.39/R2 = 0.15 vs. r = 0.23/R2 = 0.05, P =0.042). Among all the findings, inferior peripapillary NFL thickness had the best performance in discriminating glaucoma (AROC, 0.91) and glaucoma suspects (AROC, 0.67). It also had the strongest correlation with visual function (r = 0.60/R2 = 0.36, P<0.001)., Conclusions: Macular NFL thickness was significantly reduced in glaucoma. It had a similar discriminating power for glaucoma detection but a stronger correlation with visual function than total macular thickness. Peripapillary NFL thickness, however, outperformed both total macular and macular NFL thickness in terms of glaucoma detection and visual function correlation. Peripapillary NFL thickness, as a total measurement of both macular and peripheral NFL, is still the best surrogate marker in glaucoma assessment.

This report describes a Phase II, multicenter, contraceptive efficacy clinical trial using monthly injections of testosterone undecanoate (TU) alone at a dose of 500 mg in healthy Chinese men. Three hundred eight healthy men were recruited in six centers distributed throughout China. Volunteers underwent a control period with no treatment, then a 12-month treatment period including a 6-month suppression phase followed by a 6-month efficacy phase and a 12-month recovery period. During the suppression phase, an initial loading dose of 1000 mg TU, followed by 500 TU at monthly intervals were given until azoospermia or severe oligozoospermia was achieved, up to a maximum of six injections. During the efficacy phase, 500 mg TU were administered at monthly intervals for 6 months. Nine of 308 men did not achieve azoospermia or severe oligozoospermia (<3 x 10(6)/ml) within the 6-month suppression phase. This gave a methodological failure rate of 2.9/100 couple years (95% confidence interval of 1.0-4.8/100 couple years). Two hundred ninety-six men entered the efficacy phase. The continuation rate during the efficacy phase was 95/100 couple years. There were no pregnancies caused by men who achieved azoospermia or severe oligozoospermia. Reappearance of sperm occurred in six men during the efficacy phase, and one pregnancy was attributed to sperm rebound. This gave a secondary failure rate of 2.3/100 couple years (95% confidence interval of 0.5-4.2/100 couple years). Thus, the total failure rate was 5.2%, and total efficacy was 94.8%. Spermatogenesis in all subjects returned to the normal reference range within the recovery period. The mean serum testosterone concentration increased 131%, and the mean serum LH and FSH concentrations decreased 72% and 70%, respectively, after TU injections during the treatment period. The mean level of serum high density lipoprotein cholesterol decreased (14%), and the mean hematocrit increased 6% compared with baseline. No serious adverse events and no significant changes in serum chemistry occurred during the study. The results showed that monthly TU injection at a dose of 500 mg after an initial loading dose of 1000 mg can effectively, safely, and reversibly suppress spermatogenesis in healthy Chinese men without serious adverse effects.