Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability.

De novo mutations in specific mTOR pathway genes cause brain overgrowth in the context of intellectual disability (ID). By analyzing 101 mMTOR-related genes in a large ID patient cohort and two independent population cohorts, we show that these genes modulate brain growth in health and disease. We report the mTOR activator gene RHEB as an ID gene that is associated with megalencephaly when mutated. Functional testing of mutant RHEB in vertebrate animal models indicates pathway hyperactivation with a concomitant increase in cell and head size, aberrant neuronal migration, and induction of seizures, concordant with the human phenotype. This study reveals that tight control of brain volume is exerted through a large community of mTOR-related genes. Human brain volume can be altered, by either rare disruptive events causing hyperactivation of the pathway, or through the collective effects of common alleles.

Timing of antenatal steroids exposure and its effects on neonates.

OBJECTIVE: Antenatal corticosteroid (ACS) has long been regarded as the standard of care for women at risk of preterm labour. There are, however, varying practices and regimes in ACS administration. It is unclear if "a window of efficacy" truly exists and if the benefits of ACS would diminish after 7 days from the first dose. The objective of this study is to determine if the time interval between antenatal corticosteroids and delivery influences the neonatal outcomes in preterm deliveries from 23+5 to 36+6 weeks' gestation. METHODS: This is a retrospective analysis of 302 women and 352 infants who delivered from 23+5 to 36+6 weeks' gestation in KK Women's and Children's Hospital from 1st November 2014 to 31st January 2015. The timings of the first two doses of corticosteroids and the delivery were retrieved. Neonatal outcomes were compared between those delivering within 7 days and those delivering beyond 7 days of first dose of ACS. RESULTS: 61.2% of preterm infants received at least one dose of antenatal corticosteroids, of which 23.6% received it within the window of efficacy. Overall incidence of respiratory distress asyndrome in our study is 17.6%. Significantly, neonates with ACS exposure beyond 7 days were seven times more likely to have RDS as compared to those exposed to ACS within the window of efficacy (RR 0.535, 95% CI 0.166-1.72), after adjusting for potential confounders. CONCLUSION: The results of this study support the current practice among obstetricians to aim to administer ACS within 7 days of delivery.

A single-center experience of cytomegalovirus infections in Asian pediatric patients undergoing allogeneic hematopoietic stem cell transplant for leukemia in Singapore.

INTRODUCTION: Cytomegalovirus (CMV) infection remains a significant cause of morbidity and mortality in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) despite improved surveillance and the current preemptive approach. Few data on its prevalence in the Asian pediatric population exist. METHODS: We retrospectively reviewed the prevalence of CMV infections in 33 patients with 37 transplants who received HSCT for leukemia from 1998 to 2008, and who were managed preemptively for infections. RESULTS: In the 37 transplants, 16 patients (43%) had CMV DNAemia. Of the patients who were CMV seropositive before transplant and received stem cells from seropositive donors (R+/D+), 69% had DNAemia; of those who received stem cells from seronegative donors (R+/D-), 36% had CMV DNAemia. Of the patients who were CMV naïve before transplant and received stem cells from seropositive donors (R-/D+), 25% had CMV DNAemia. In CMV-seronegative donor-recipient transplants (R-/D-), 20% of patients had CMV DNAemia. The median time to the first episode of CMV DNAemia was 21 (range: 10-107) days after the transplants, and the median duration of CMV DNAemia was 22 (range: 2-315) days. CMV DNAemia recurred in 44% (7 of 16) of these patients. Only 1 patient developed CMV disease (retinitis). No deaths were related to CMV infections. CONCLUSIONS: CMV infection manifesting as DNAemia is a common complication in pediatric patients undergoing allogeneic HSCT for leukemia. Pre-transplant serostatus predicts reactivation risks; invasive CMV disease is rare using the preemptive approach in our patient population.

Mn(2+) and Mg(2+) synergistically enhanced lactic acid production by Lactobacillus rhamnosus FTDC 8313 via affecting different stages of the hexose monophosphate pathway.

AIMS: The study aimed to evaluate the effects of Mn(2+) and Mg(2+) on lactic acid production using response surface methodology and to further study their effects on interactions between the enzymes and substrates along the hexose monophosphate pathway using a molecular modelling approach. METHODS AND RESULTS: A rotatable central composite design matrix for lactic acid production was generated with two independent factors namely, manganese sulfate and magnesium sulfate. The second-order regression model indicated that the quadratic model was significant (P < 0·05), suggesting that the model accurately represented the data in the experimental region. Three-dimensional response surface showed that lactic acid production was high along the region where the ratio of MnSO4 to MgSO4 was almost 1 : 1, justifying the need for both Mg(2+) and Mn(2+) to be present simultaneously in stimulating the production of lactic acid. Molecular docking simulation was performed on a total of 13 essential enzymes involved in the hexose monophosphate pathway for the production of lactic acid with four different conditions namely in the presence of Mg(2+) , Mn(2+) , both Mg(2+) and Mn(2+) and in the absence of metal ions. Results showed that the presence of both Mg(2+) and Mn(2+) within the binding site improved the binding affinity for substrates in five enzymes namely, glucose-6-phosphate dehydrogenase, phosphogluconate dehydrogenase, glyceraldehyde-3-phosphate dehydrogenase, phosphopyruvate hydratase and pyruvate kinase. CONCLUSIONS: Using response surface methodology and molecular modelling approach, we illustrated that Mg(2+) and Mn(2+) synergistically enhanced lactic acid production by Lactobacillus rhamnosus FTDC 8313 via affecting different stages of the hexose monophosphate pathway. SIGNIFICANCE AND IMPACTS OF THE STUDY: Mg(2+) and Mn(2+) synergistically improved lactic acid production of Lact. rhamnosus via improved binding affinity of the enzyme-substrate along the hexose monophosphate pathway, instead of purely affecting growth as previously understood.

Hematopoietic SCT activity in Asia: a report from the Asia-Pacific Blood and Marrow Transplantation Group.

The hematopoietic SCT (HSCT) activity in nine Asian countries/regions was surveyed to overview the current situation. Data of 58 113 HSCTs (allogeneic: 63% vs autologous: 37%) performed between 1986 and 2006 by 432 transplant teams were collected. The number of HSCTs has been increasing in the past two decades in most countries/regions. The increase in allogeneic HSCTs is greater than in autologous HSCTs. The proportion of unrelated donors among allogeneic HSCTs in 2006 varied widely from <1% (Iran and Vietnam) to 62% (Japan). The use of each stem cell source, that is, BM, PBSC, cord blood and others (including co-infusion of BM and PBSC), also varied widely (36, 58, 0.1 and 6% in HSCT from related donors, respectively, and 53, 11, 35 and 1% in HSCT from unrelated donors, respectively). HSCTs have been continuously increasing for all indications except for chronic myelogenous leukemia and solid tumors. Hemoglobinopathy is a common indication among non-malignant diseases in many Asian countries/regions except for China, Japan and Korea. This survey clearly shows the recent progress of HSCTs in Asia and also some differences in donor and stem cell selection and disease application among countries/regions.

Severe Kikuchi's disease responsive to immune modulation.

Kikuchi's disease, although an uncommon entity, has been increasingly reported since it was first discovered in 1972. The most common manifestation of Kikuchi's disease, cervical lymphadenopathy, has no clinically distinguishable features. Therefore, a diagnosis of Kikuchi's disease has largely been based on clinical suspicion and histopathological confirmation. We present a 15-year-old Chinese girl with severe Kikuchi's disease, whose relapsing course was only responsive to highdose steroid and intravenous immunoglobulin therapy.

Encapsulated living choroid plexus cells: potential long-term treatments for central nervous system disease and trauma.

In neurodegenerative disease and in acute brain injury, there is often local up-regulation of neurotrophin production close to the site of the lesion. Treatment by direct injection of neurotrophins and growth factors close to these lesion sites has repeatedly been demonstrated to improve recovery. It has therefore been proposed that transplanting viable neurotrophin-producing cells close to the trauma lesion, or site of degenerative disease, might provide a novel means for continuous delivery of these molecules directly to the site of injury or to a degenerative region. The aim of this paper is to summarize recent published information and present new experimental data that indicate that long-lasting therapeutic implants of choroid plexus (CP) neuroepithelium may be used to treat brain disease. CP produces and secretes numerous biologically active neurotrophic factors (NT). New gene microarray and proteomics data presented here indicate that many other anti-oxidant, anti-toxin and neuronal support proteins are also produced and secreted by CP cells. In the healthy brain, these circulate in the cerebrospinal fluid through the brain and spinal cord, maintaining neuronal networks and associated cells. Recent publications describe how transplanted CP cells and tissue, either free or in an immunoprotected encapsulated form, can effectively deliver therapeutic molecules when placed near the lesion or site of degenerative disease in animal models. Using simple techniques, CP neuroepithelial cell clusters in suspension culture were very durable, remaining viable for 6 months or more in vitro. The cell culture conditions had little effect on the wide range and activity of genes expressed and proteins secreted. Recently, completed experiments show that implanting CP within alginate-poly-ornithine capsules effectively protected these xenogeneic cells from the host immune system and allowed their survival for 6 months or more in the brains of rats, causing no adverse effects. Previously reported evidence demonstrated that CP cells support the survival and differentiation of neuronal cells in vitro and effectively treat acute brain injury and disease in rodents and non-human primates in vivo. The accumulated preclinical data together with the long-term survival of implanted encapsulated cells in vivo provide a sound base for the investigation of these treatments for chronic inherited and established neurodegenerative conditions.

Streptococcal cellulitis following preparation of fresh raw seafood.

We describe three zoonotic streptococcal soft tissue infections resulting from fresh seafood contact. One was a localized thumb infection with Streptococcus iniae in an immunocompetent healthy young male resulting from a puncture wound from a crab pincer. The other two were cases of ascending upper limb cellulitis associated with bacteraemia in mastectomy patients. One of these infections was caused by S. iniae while the other was caused by Streptococcus dysgalactiae subsp. dysgalactiae, a species that has not been previously described as a cause of zoonotic infection. Hence when cleaning raw seafood, protective equipment should be used to minimize the risk of percutaneous injuries.

The ability of ultrasound to detect gynaecological neoplasms and their ultrasound morphological features.

To determine first, the accuracy of a gynaecological ultrasound service in the detection of four clinically significant pathologies, namely, uterine body malignancy, ovarian malignancy, ovarian dermoid cysts and other benign ovarian pathologies and second, to review the ultrasound imaging appearances of ovarian masses with histopathological correlation. Retrospective data collection from consecutive weekly multidisciplinary team meetings over a 12-month period. All patients had undergone ultrasound examination before surgery. Data included patient demographics, menopausal status, indications for ultrasound, type of practitioner carrying out the scan, operative findings and final histopathological diagnosis. Ultrasound imaging appearances were correlated to histology. Of the 47 cases of uterine malignancy, 45 had endometrial carcinoma. All had either a thickened or poorly seen or not seen endometrium. Twenty-four per cent of these women were premenopausal. Forty-seven of the 48 cases of ovarian malignancy had abnormal ultrasound findings. In six of these, the findings were of a purely cystic lesion. There were 62 cases of benign ovarian pathology (excluding dermoid cyst), all of which had an abnormal ultrasound; 16 of these had possible ultrasound features of malignancy. All 30 cases of ovarian dermoid cyst had an abnormal ultrasound with a specific diagnosis being made in 27. This study shows that ultrasound is accurate in the detection of both endometrial and ovarian disease. The endometrium that is not seen or is poorly seen is an indication for endometrial biopsy in women with postmenopausal bleeding. There is considerable overlap in the ultrasound appearances of benign and malignant ovarian lesions. Ultrasound is a good method for the accurate and specific diagnosis of an ovarian dermoid cyst.

Bilateral pleural effusions following central venous cannulation.

We describe a patient who developed bilateral pleural effusions as a delayed complication following central venous catheter insertion. Respiratory distress should not only raise the clinical suspicion of a pneumothorax but also of erosion and perforation of the central vein. The mechanism, diagnosis, management and prevention of this complication are discussed.

MRI of the diabetic foot: differentiation of infection from neuropathic change.

The aim of this review is to illustrate the magnetic resonance imaging features that can help differentiate osteomyelitis from neuropathic osteoarthropathy in the foot.

The Transplantation Society--new key opinion leaders of tomorrow 2006.

One of the new initiatives taken by the immediate past president of The Transplantation Society, KJ Wood, is to introduce a new series of meetings named 'New Key Opinion Leaders of Tomorrow'. The Transplantation Society invites the leading young investigators in the field of transplantation to participate in this meeting together with the present leaders of the field. The key objective of this meeting is to identify the potential key opinion leaders of tomorrow. Each presentation during the meeting was jointly given by the senior and junior investigators. The meeting in Buenos Aires covered six main topics on clinical, translational and basic transplantation. These included: innate immunity and inflammation; transplant infectious diseases; tumour and transplantation; medical and ethical aspects of transplantation; dendritic cells (stimulating and manipulating the immune response to a transplant); and ABO incompatible donor recipient pairs. This report focuses on the emerging biological therapeutics and their ramifications on clinical transplantation.

Cerclage-wiring-assisted fixation of difficult hand fractures.

Difficult hand fractures with multiple butterfly fragments, multiple cortical splits or intraarticular extension continue to pose a challenge for optimal stable fixation that allows early postoperative mobilisation. In this study, we describe the use of cerclage-wire-assisted fixation of 17 difficult hand fractures in 16 patients. The cerclage wires helped to maintain the reduction, so providing sufficient initial stability for placement of a plate and screws. Stable fixation of the fracture was then accomplished without losing the reduction. One to three cerclages of stainless-steel wires were used for the preliminary fixation. Stable fixation was then accomplished by a bridging or neutralising plate technique. Postoperatively, the fixation was sufficiently stable to allow immediate mobilisation. With an average follow up of 44.5 months, all 17 fractures united without loss of reduction. At final follow-up, the average total active range of motion was 247 degrees (range 220-260 degrees ).

Diffusion weighted magnetic resonance imaging for acute stroke: practical and popular.

AIM: To evaluate the feasibility and impact of diffusion weighted magnetic resonance imaging (DW MRI) as the first line neuroimaging of stroke at a district general hospital. METHODS: Prospective audit of all in-patients admitted with clinically suspected acute stroke and referred for imaging over a consecutive 17 week period. The data collected included scan type, time from cerebral event to imaging request, and time from formal radiological request to neuroimaging. Clinicians' (general physicians, neurologists, and radiologists) perceptions were assessed by a questionnaire. RESULTS: 148 patients had neuroimaging for clinically suspected stroke during this period. Eighty one per cent of patients (120 of 148) had DW MRI as first line. Ninety two per cent of these patients had DW MRI within 24 hours of the formal radiological request. Twenty eight patients did not undergo DW MRI because lack of MRI safety, clinical state, unavailability because of maintenance service or lack of trained staff. Clinicians found the introduction of the DW MRI based service a significant improvement on computed tomography, especially for equivocal cases. CONCLUSION: DW based MRI service is both feasible and sustainable in the setting of a district general hospital and most clinicians feel that this is a significant improvement to stroke services.

Central venous catheters: the role of radiology.

The insertion and management of long-term venous catheters have long been the province of anaesthetists, intensive care physicians and surgeons. Radiologists are taking an increasing role in the insertion of central venous catheters (CVCs) because of their familiarity with the imaging equipment and their ability to manipulate catheters and guide-wires. The radiological management of the complications of CVCs has also expanded as a result. This article reviews the role of radiology in central venous access, covering the detection and management of their complications.

Intraperitoneal alginate-encapsulated neonatal porcine islets in a placebo-controlled study with 16 diabetic cynomolgus primates.

BACKGROUND: A nonhuman primate model of diabetes is valuable for assessing porcine pancreatic islet transplants that might have clinical benefits in humans. METHODS: Neonatal porcine islets, microencapsulated in alginate-polyornithine-alginate, were injected intraperitoneally (10,000 IEQs/kg islets) into eight adult male cynomolgus monkeys rendered diabetic with streptozotocin. Eight diabetic controls were given an equivalent dose of empty placebo capsules. All subjects received a repeat transplant 3 months after the first. RESULTS: The transplant was well tolerated and no adverse or hypoglycemic events occurred. There were two deaths from nontransplant treatment or diabetic complications unrelated to the transplants. After transplantation, the average insulin dose was reduced in the islet-treated group and increased in the control group. At 12 weeks after the first transplant there was a mean 36% (95% CI: 6% to 65%, P = .02) drop in daily insulin dose compared with the control group. After 24 weeks the difference increased to a mean of 43% (95% CI: 12% to 75%, P = .01) without significant differences in blood glucose values between the two groups. Individual responses after islet transplant varied and one monkey was weaned off insulin by 36 weeks. At terminal autopsy, organs appeared normal and there was no visible peritoneal reaction. No animal had polymerase chain reaction (PCR)-amplified signals of porcine endogenous retrovirus or exogenous virus infections in blood or tissues. CONCLUSION: Repeated intraperitoneal transplantation of microencapsulated neonatal porcine islets is a safe procedure in diabetic primates. It was shown to result in a significant reduction in insulin dose requirement in the majority of animals studied, whereas insulin requirement increased in controls.

Radiological appearances in the pelvis following rectal cancer surgery.

Radiology has a significant role in the evaluation of surgery for rectal cancer. With recent developments in surgical techniques, the number of neorectal reservoir configurations has increased. It is important to recognize the normal and abnormal appearances, both early and late, following pelvic surgery. The aim of this pictorial review is to demonstrate the imaging techniques that are used in both the investigation and the follow-up of patients who have undergone uncomplicated or complicated rectal resection.

Incidental heterotopic pregnancy demonstrated on magnetic resonance imaging.

We report a case of an assisted pregnancy in an asymptomatic woman who was found to have an extrauterine mass on ultrasound and MRI. This complex mass had equivocal imaging features and was found to be a ruptured ovarian ectopic pregnancy at surgery. This case illustrates that vigilance is required regarding the possibility of coexisting ectopic and intrauterine pregnancy following assisted conception, even in entirely asymptomatic cases.