Expression patterns of HENMT1 and PIWIL1 in human testis: implications for transposon expression.

This study aimed to define the expression patterns of HENMT1 and PIWI proteins in human testis and investigate their association with transposon expression, infertility sub-type or development of testicular germ cell tumours (TGCTs). Testis biopsies showing normal spermatogenesis were used to identify normal localisation patterns of HENMT1 and PIWIL1 by immunolocalisation and RT-PCR after laser microdissection. 222 testis biopsies representing normal spermatogenesis, hypospermatogenesis, spermatogenic arrests, Sertoli cell-only (SCO) tumours and TGCTs were analysed by RT-qPCR for expression of HENMT1/PIWIL1/PIWIL2/PIWIL3/PIWIL4 and LINE-1 Additionally, HENMT1-overexpressing TCam2 seminoma cell lines were analysed for the same parameters by RT-qPCR. We found that HENMT1 and PIWIL1 are coexpressed in pachytene spermatocytes and spermatids. Expression of HENMT1, PIWIL1 and PIWIL2 was mainly dependent on germ cell content but low levels of expression were also detected in some SCO samples. Levels of HENMT1, PIWIL1 and PIWIL2 expression were low in TGCT. Samples with HENMT1, PIWIL2 and PIWIL4 expression showed significantly (P < 0.05) lower transposon expression compared to samples without expression in the same histological group. HENMT1-overexpressing TCam2 cells showed lower LINE-1 expression than empty vector-transfected control lines. Our findings support that the transposon-regulating function of the piRNA pathway found in the mouse is conserved in adult human testis. HENMT1 and PIWI proteins are expressed in a germ-cell-specific manner and required for transposon control.

Rare presentation of idiopathic duodenoduodenal intussusception.

Enteroenteric intussusception is a condition in which the full-thickness bowel wall becomes telescoped into the lumen of distal bowel. Intussusception in adult occurs infrequently and varies from childhood intussusception, particularly in its presentation, aetiology and treatment. Duodenoduodenal intussusception is rare because the duodenum is fixed in the retroperitoneal position. It usually occurs secondary to tumour, lipoma, Brunner's gland hamartomatous polyp or adenoma. The diagnosis in adults is usually made at laparotomy, where presentation is with intestinal obstruction. In non-emergency presentation, it may be difficult to arrive at an accurate diagnosis as symptoms may be vague, self-limiting intermittent abdominal pain. Clinical examinations and investigations may not be conclusive and another working diagnosis such as irritable bowel syndrome would be made. We describe a case where a patient initially presented with symptoms mimicking pancreatitis but his symptoms persisted over the course of 2 weeks. When a laparotomy was performed, duodenoduodenal intussusception was discovered and confirmed with histopathology. In this case, a discernible leading point could not be identified.

Ordering of mutations in acute myeloid leukemia with partial tandem duplication of MLL (MLL-PTD).

Partial tandem duplication of MLL (MLL-PTD) characterizes acute myeloid leukemia (AML) patients often with a poor prognosis. To understand the order of occurrence of MLL-PTD in relation to other major AML mutations and to identify novel mutations that may be present in this unique AML molecular subtype, exome and targeted sequencing was performed on 85 MLL-PTD AML samples using HiSeq-2000. Genes involved in the cohesin complex (STAG2), a splicing factor (U2AF1) and a poorly studied gene, MGA were recurrently mutated, whereas NPM1, one of the most frequently mutated AML gene, was not mutated in MLL-PTD patients. Interestingly, clonality analysis suggests that IDH2/1, DNMT3A, U2AF1 and TET2 mutations are clonal and occur early, and MLL-PTD likely arises after these initial mutations. Conversely, proliferative mutations (FLT3, RAS), typically appear later, are largely subclonal and tend to be unstable. This study provides important insights for understanding the relative importance of different mutations for defining a targeted therapeutic strategy for MLL-PTD AML patients.

KPT-330 has antitumour activity against non-small cell lung cancer.

BACKGROUND: We investigated the biologic and pharmacologic activities of a chromosome region maintenance 1 (CRM1) inhibitor against human non-small cell lung cancer (NSCLC) cells both in vitro and in vivo. METHODS: The in vitro and in vivo effects of a novel CRM1 inhibitor (KPT-330) for a large number of anticancer parameters were evaluated using a large panel of 11 NSCLC cell lines containing different key driver mutations. Mice bearing human NSCLC xenografts were treated with KPT-330, and tumour growth was assessed. RESULTS: KPT-330 inhibited proliferation and induced cell cycle arrest and apoptosis-related proteins in 11 NSCLC cells lines. Moreover, the combination of KPT-330 with cisplatin synergistically enhanced the cell kill of the NSCLC cells in vitro. Human NSCLC tumours growing in immunodeficient mice were markedly inhibited by KPT-330. Also, KPT-330 was effective even against NSCLC cells with a transforming mutation of either exon 20 of EGFR, TP53, phosphatase and tensin homologue, RAS or PIK3CA, suggesting the drug might be effective against a variety of lung cancers irrespective of their driver mutation. CONCLUSIONS: Our results support clinical testing of KPT-330 as a novel therapeutic strategy for NSCLC.

Review of an 11-year Experience in Retrosigmoid Approach for Treatment of Acoustic Neuromas.

This study reviews surgery on acoustic neuromas by the second author using retrosigmoid approach from January 2000 to June 2010 in the state of Sarawak. There was a total of 32 patients in this study. The commonest presenting symptom was hearing loss (81.3%), followed by headache and tinnitus (each 37.5%), ataxia (34.4%) and facial numbness (21.9%). Twenty-seven patients (84.4%) had large tumor (≥ 3cm) while 5 patients (15.6%) had medium size tumor (1.5-2.9cm). The mean tumor size was 3.6 cm. Facial nerve outcome was good to moderate in 93.7% (House and Brackmann Grade I-IV). The most common complications were CSF leak with 3 patients(9.4%) and facial numbness with 2 patients(6.3%). All either resolved with treatment or improved. There was no mortality. Excision of acoustic neuromas using retrosigmoid approach could achieve acceptable facial nerve outcome with a low incidence of morbidity without mortality.

Single-breath vital capacity high concentration sevoflurane induction in children: with or without nitrous oxide?

BACKGROUND: Single-breath vital capacity inhalation induction with high concentration sevoflurane (SBVC-HC) is a rapid and 'needleless' technique, preferred and well tolerated in the cooperative child. The addition of nitrous oxide may speed up induction by its second gas effects. Previous studies done in children looking at the effect of N(2)O on this technique lacked power and showed conflicting results. This study aims to investigate the effect of N(2)O on induction time for SBVC-HC sevoflurane induction in children. METHODS: Eighty unpremedicated, ASA I and II children, aged 5-15 yr having elective surgical procedures under general anaesthesia, were recruited and randomized to: Group A: 8% sevoflurane in O(2) 6 litre min(-1), and Group B: 8% sevoflurane in N(2)O 4 litre min(-1) and O(2) 2 litre min(-1). The primary outcome was the time to 'loss of eyelash reflex'. The time to return of 'regular respiration' and 'conjugate gaze' were also noted. RESULTS: The difference in the 'time to loss of eyelash reflex' was small but statistically significant. Group B: mean duration 53.6 s, standard deviation (SD) 16.1, compared with Group A: 63.5 s, SD 16.1 (mean difference 9.9, 95% confidence interval 2.5-17.3, P=0.01). Differences in the time to return of 'regular breathing' and 'conjugate gaze' were not statistically significant. Patients receiving N(2)O had less excitatory movements (P=0.007), but incidence of other adverse events was low and did not differ significantly between both groups. More than 94% of children would choose this method of induction again in both groups. CONCLUSIONS: We conclude that for SBVC-HC sevoflurane induction in children, the addition of N(2)O resulted in faster loss of consciousness and reduced excitatory movements.

Clinics in diagnostic imaging (123).

A 60-year-old Indian man presented with lower thoracic pain and bilateral lower limb weakness. Radiographs showed compression fractures of T8 and T9 and destruction of the T7 and T10 endplates. Magnetic resonance imaging confirmed the vertebral changes and showed subligamentous spread, paravertebral masses, and epidural involvement leading to cord compression. Computed tomography-guided biopsy showed granulomatous caseous necrosis and acid-fast bacilli, confirming the diagnosis of tuberculosis spondylitis. The imaging features of infective spondylitis, with emphasis on tuberculous spondylitis, are discussed.

Promoter hypermethylation of FANCF and outcome in advanced ovarian cancer.

The Fanconi gene family has a role in DNA repair and inactivation of FANCF has been proposed as a mechanism of sensitisation to platinum chemotherapy. This study sought to confirm this hypothesis in cell lines and a large series of ovarian cancer samples. Promoter methylation was assessed by methylation-sensitive polymerase chain reaction of FANCF in nine ovarian cancer cell lines and 74 ovarian cancer samples taken from patients entered on a trial of cisplatin-based chemotherapy. This study confirmed methylation-dependent silencing of FANCF in one out of nine ovarian cancer cell lines. Methylation of FANCF was demonstrated in 13.2% of 53 evaluable ovarian tumour samples. Progression-free survival gave an HR of 3.63 (95% CI: 1.54-8.54, P=0.0016) in favour of the unmethylated cases. There was no association with overall survival. This study does not support methylation-dependent silencing of FANCF as a mechanism of sensitisation to platinum-based chemotherapy in ovarian cancer.

Beyond Ortner's syndrome--unusual pulmonary complications of the giant left atrium.

INTRODUCTION: The giant left atrium (GLA) is a complication of severe mitral valve disease and causes morbidity by compressing adjacent intra-thoracic structures. CLINICAL PICTURE: We report 2 cases of unusual pulmonary complications of the GLA. Case 1 developed recurrent collapse of the left lung due to left main bronchus compression. Case 2 was diagnosed with right middle lobe compression and collapse. TREATMENT AND OUTCOME: Case 1 was successfully treated by mitral valve replacement and left atrial reduction surgery. Case 2 was treated conservatively. CONCLUSION: Pulmonary atelectasis may occur in patients with GLA due to bronchopulmonary compression. Surgical management with valve replacement and atrial reduction may be necessary to relieve airway compression.

Surgery for atrial fibrillation.

Atrial fibrillation is the most common sustained cardiac arrhythmia and is associated with significant morbidity and mortality. Surgical treatment is the most effective means of curing atrial fibrillation. The classic Cox maze procedure eliminates atrial fibrillation in more than 90% of patients and has remained the gold standard in surgery for atrial fibrillation. Despite being highly effective, the complexity of the procedure and long operating time associated with the operation has prevented its widespread application by surgeons. Advances in the understanding of the pathogenesis of atrial fibrillation and development of new ablation technologies have fuelled renewed interest in and development of surgical ablation procedures for atrial fibrillation. These new procedures are simpler and easily reproducible and cure atrial fibrillation in approximately 80% of patients. This article reviews the development of surgery for atrial fibrillation and our experience with the radiofrequency Cox maze III procedure.

Osteoporotic hip fractures in Singapore--costs and patient's outcome.

INTRODUCTION: Little data are available on costs and outcome associated with osteoporotic hip fractures in Singapore. MATERIALS AND METHODS: A retrospective study was carried out on 280 consecutive hip fractures in patients older than 60 years admitted over a 3-year period. RESULTS: The mean age of patients was 80 years. Sixty-eight per cent were female and 58% were intertrochanteric fractures. Two hundred and sixty-four patients (95%) were operated upon. The mean total hospitalisation period was 17 days. Seventy-six per cent were staying in their own homes prior to the hip fracture while 22% were admitted from nursing homes. After surgery, 63% of patients returned to their homes while 26% needed nursing home care. The index admission mortality rate was 5.7%. Mortality was 26% at 1 year. Of those alive at 1 year, ambulatory status was: 28% were walking without aids, 39% were walking with aids, 24% were wheelchair bound and 9% were bedridden. Poor ambulatory function at discharge was related to increased mortality at 1 year. The average cost incurred was S$7367. The average government subsidy amounted to 82%. Ninety-one per cent of patients were warded in subsidized beds. Breakdown of cost was as follows: hospital stay, 42.6%; surgery, 36.5%; ward treatment, fee 9%; laboratory and X-ray investigations, 4.4%; implant costs, 3.5%; drugs, 1.6% and rehabilitation, 1.1%. Multivariate analysis showed that the cost is significantly related to days spent awaiting surgery, preoperative sepsis, operative complications and cerebrovascular accidents. Young age, good American Society of Anesthetists (ASA) status and endoprosthesis replacement were factors that allowed for early ambulation and lower costs. CONCLUSION: The mortality rates and functional outcome are not very different from published studies in the West. More of our patients returned to their own homes after hospitalisation. Early surgery, close involvement of the medical social worker and intensive physiotherapy or provision of outpatient therapy facilities may help cut cost of treatment.

Clinical outcome and bowel function following total abdominal colectomy and ileorectal anastomosis in the Oriental population.

UNLABELLED: Total abdominal colectomy with ileorectal anastomosis is a commonly performed surgical procedure. The postoperative outcome of these patients, however, has not been studied in detail in the Asian population. AIM: The purpose of this study was to analyze the functional outcome of patients following total abdominal colectomy and ileorectal anastomosis. METHOD: All patients subjected to a total abdominal colectomy with ileorectal anastomosis during a six-year period from February 1989 to October 1995 were reviewed. RESULTS: Sixty-six patients (male:female, 40:26) with a mean age of 55.2 (range, 20-88) years underwent total abdominal colectomy with ileorectal anastomosis. Median follow-up after surgery was 26 (range, 4-78) months. Indications for surgery were synchronous or metachronous tumors (18), complicated pancolonic diverticular disease (15), obstructed tumors with impending perforation (13), familial adenomatous polyposis (7), slow-transit constipation (6), and others (7). Mean operative time was 137 +/- 48 minutes. Mean postoperative hospitalization was 13.3 +/- 11.9 days. Time to first bowel movement and commencement of solid diet were 4.7 +/- 1.8 and 7.2 +/- 2.4 days, respectively. Four patients had prolonged postoperative ileus. Average stool frequencies per day were 5.5 at one week, 4.3 at one month, 3.9 at six months, 3.2 at one year, and 2.9 at two years postoperatively. Thirty-three patients (50 percent) required antidiarrheal treatment for a transient period, but none required long-term therapy. Ninety-seven percent of all patients rated the functional outcome as good to excellent, and 3 percent said it was fair. There was two perioperative mortalities. Five cases required re-laparotomy, three for anastomotic complications and two for hemoperitoneum. Five patients had recurrent admissions for adhesion colic, which resolved with nonsurgical therapy. Ten patients succumbed on follow-up, six to tumor recurrence, two to unrelated cancers (stomach and bladder), and three to medical conditions. CONCLUSION: The functional outcome of ileorectal anastomosis is generally rated as good to excellent by patients. Acceptable bowel function and control is regained within six months of the operation and levels off at one year after surgery, and no patient requires long-term antidiarrheal medication.

Chronic 17beta-estradiol augments relaxant role of basal nitric oxide in blood vessels from rats with heart failure.

The effects of chronic 17beta-estradiol on endothelium-dependent relaxation to acetylcholine (ACh) and contraction to NG-nitro-L-arginine methyl ester (L-NAME), and endothelium-independent relaxation to sodium nitroprusside (SNP) were examined on blood vessels from rats with chronic heart failure (CHF). Two groups of ovariectomized female (50-60 days) rats were implanted with pellets containing 17beta-estradiol (25 microg/day) or vehicle, and given ligation of the left main coronary artery 1 week later. Another group of ovariectomized rats was implanted with vehicle pellets, and sham-operated. After 7 weeks, thoracic aortic rings, pulmonary artery rings, and portal vein strips were prepared for in vitro studies. Relative to sham-operated rats treated with the vehicle, vessels from vehicle-treated, coronary-ligated rats had similar relaxation to ACh and SNP but reduced response to L-NAME that was significant (P<0.05) for the aorta and portal vein but not pulmonary artery. Treatment of ligated rats with 17beta-estradiol augmented responses to L-NAME in the aorta, pulmonary artery and portal vein to values above those in sham-operated rat. 17beta-Estradiol did not affect relaxation of any vessels to SNP and increased maximum relaxation to ACh only in the portal vein. Hence, 17beta-estradiol enhances the relaxant role of basal nitric oxide in CHF.

Review of liver trauma management in Tasmania: an analysis of risk factors for mortality and morbidity.

A review of liver trauma treated by the major trauma care facilities of Tasmania in the 5 year period between 1989 and 1993 is presented. The aim of this retrospective review was to provide an audit of the management of liver trauma in the island of Tasmania and to analyse the risk factors contributing to mortality and major morbidity. Thirty-seven patients were treated with a median Injury Severity Score (ISS) of 14 (range 9-34). The overall mortality rate of this series was 5.8%. Age, mechanism of injury (blunt or penetrating), delay prior to hospital presentation and modality of treatment (operative or non-operative) were not significant risk factors for mortality and morbidity; however, transfusion requirement of over 10 units of blood (P < 0.005), ISS score of over 20 (P < 0.0005), haemodynamic instability at presentation (P < 0.05) and a Hepatic Injury Score (HIS) grade of 3 or more (P < 0.05) were statistically significant risk factors.