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1.  Prevalence of Abnormal Glucose Tolerance and Risk Factors in Urban and Rural Malaysia 
Diabetes Care  2011;34(6):1362-1364.
To determine the prevalence of prediabetes and diabetes among rural and urban Malaysians.
This cross-sectional survey was conducted among 3,879 Malaysian adults (1,335 men and 2,544 women). All subjects underwent the 75-g oral glucose tolerance test (OGTT).
The overall prevalence of prediabetes was 22.1% (30.2% in men and 69.8% in women). Isolated impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) were found in 3.4 and 16.1% of the study population, respectively, whereas 2.6% of the subjects had both IFG and IGT. Based on an OGTT, the prevalence of newly diagnosed type 2 diabetes was 12.6% (31.0% in men and 69.0% in women). The prediabetic subjects also had an increased prevalence of cardiovascular disease risk factors.
The large proportion of undiagnosed cases of prediabetes and diabetes reflects the lack of public awareness of the disease.
PMCID: PMC3114358  PMID: 21498788
2.  Effects of xanthan, guar, carrageenan and locust bean gum addition on physical, chemical and sensory properties of meatballs 
This study evaluated the effects of xanthan gum, guar gum, carrageenan and locust bean gum on physical, chemical and sensory properties of meatballs. Meatball samples were produced with three different formulations including of 0.5, 1, and 1.5% each gum addition and gum added samples were compared with the control meatballs. Physical and chemical analyses were carried out on raw and cooked samples separately. Moisture contents of raw samples decreased by addition of gums. There were significant decreases (p < 0.05) in moisture and fat contents of raw and cooked meatball samples formulated with gum when compared with control. Ash contents and texture values increased with gum addition to meatballs. Meatball redness decreased with more gum addition in raw and cooked meatball samples, which means that addition of gums resulted in a lighter-coloured product. According to sensory analysis results, locust bean gum added (1%) samples were much preferred by the panelists.
PMCID: PMC4008741  PMID: 24803701
Meatball; Xanthan; Guar; Carrageenan; Locust bean; Quality characteristics
3.  Enlarged Vestibular Aqueduct in Congenital Non-Syndromic Sensorineural Hearing Loss in Egypt 
To estimate the frequency of isolated enlarged vestibular aqueduct (EVA) in patients with non-syndromic sensorineural hearing loss (SNHL) in an Egyptian population sample and to correlate its size with the degree of hearing loss. The study group comprised 16 patients (32 ears) suffering from non-syndromic SNHL since childhood. After a complete basic audiological evaluation, all patients were submitted to non contrast CT scan of the petrous bone in both axial & coronal planes. Vestibular aqueduct (VA) was measured at two points (midpoint & operculum) on right & left sides. The study group was divided according to VA size into three groups: group A, B and C. Group A included 6 ears (4 patients) with EVA, group B included 11 ears (7 patients) with borderline EVA and group C included 15 ears (9 patients) with normal VA size. There were no statistically significant differences between the three groups as regards laterality, degree of hearing loss and audiometric configuration. There was no correlation between VA midpoint & operculum and different variables (age and average pure tone thresholds). However, a significant correlation between VA midpoint & operculum was found. EVA was diagnosed in 6 out of 32 ears (18.75%) in the study sample. EVA size was not related to the degree of hearing loss or configuration. Despite the insignificant findings, moderate and high frequency sloping SNHL were considered the most common findings seen in patients with EVA.
PMCID: PMC3918291  PMID: 24533365
Enlarged vestibular aqueduct syndrome (EVAS); Non-syndromic sensorineural hearing loss (SNHL) in children; Vestibular aqueduct midpoint (Mp) and operculum (Op)
4.  Effect of Anti-Adhesive Barrier Use on Laryngotracheal Movement After Total Thyroidectomy: An Electrophysiological Study 
Impairment of laryngotracheal movement is a possible complication after total thyroidectomy. Here, we aimed to investigate the frequency and extent of impairment of laryngotracheal movement after total thyroidectomy and the effect of anti-adhesive barrier hyaluronic acid-carboxymethylcellulose membrane positioning between strap muscles and laryngotracheal complex on deglutition. The study design is prospective clinical study. Istanbul Training and Research Hospital, Laboratory of Electrophysiology, Istanbul Training and Research Hospital. The patients who underwent total thyroidectomy were selected and dichotomized according to use of seprafilm. Each group consisted of 8 female patients. All patients were assessed clinically and electrophysiologically in the pre/postop period. Electrophysiological investigations included cricopharyngeal muscle (CPM) electromyography (EMG), submental EMG, single bolus analysis [foreburst, reburst, swallowing (pause) patterns], laryngotracheal movement analysis and results were compared between two groups. CPM EMG was normal in both groups. Duration of submental muscle activity during dry and 15 cc water swallowing was similar between two groups (P = 0.751). Pause duration was shorter in group with seprafilm (P < 0.01). Dysphagia limit was 15 cc in both groups. The fore/rebound bursts duration, the time of laryngeal elevation, closure and suspension were similar (P = 0.954). We concluded that use of seprafilm between larynx and strap muscles during total thyroidectomy does not have any adverse effects on swallowing. Anti-adhesive barrier can be used safely during thyroid surgery.
PMCID: PMC3918315  PMID: 24533362
Swallowing; Anti-adhesive barrier; Laryngotracheal movement; Thyroidectomy
5.  Effect of frozen storage on the characteristics of a developed and commercial fish sausages 
The effect of frozen storage on the physiochemical, chemical and microbial characteristics of two types of fish sausages was studied. Fish sausages developed (DFS) with a spice-sugar formulation and commercial fish sausages (CFS) were stored at −20 °C for 3 months. Fresh DFS contained 12.22% lipids and had a 3.53 cfu/g total bacteria count (TBC) whereas, CFS contained 5.5% lipids and had a 4.81 cfu/g TBC. During storage, TBC decreased significantly (p < 0.05) in DFS whereas it did not change (p > 0.05) in CFS. A peroxide value (PV) was not detectable until week four and eight of storage in CFS and DFS, respectively. The salt-soluble proteins (SSP) level was stable in DFS but in CFS it declined significantly (p < 0.05). Colour values did not change significantly (p > 0.05) in both sausage types. This study showed that the effect of storage at −20 °C on fish sausages characteristics varied between formulations and depended on the ingredients of fish sausages.
PMCID: PMC3791238  PMID: 24426029
Color; Fish; Frozen storage; Rancidity; Sausages
6.  Towards a consensus on diagnostic criteria, measurement and trial design of the premenstrual disorders: the ISPMD Montreal consensus 
Premenstrual disorders (PMD) are characterised by a cluster of somatic and psychological symptoms of varying severity that occur during the luteal phase of the menstrual cycle and resolve during menses (Freeman and Sondheimer, Prim Care Companion J Clin Psychiatry 5:30–39, 2003; Halbreich, Gynecol Endocrinol 19:320–334, 2004). Although PMD have been widely recognised for many decades, their precise cause is still unknown and there are no definitive, universally accepted diagnostic criteria. To consider this issue, an international multidisciplinary group of experts met at a face-to-face consensus meeting to review current definitions and diagnostic criteria for PMD. This was followed by extensive correspondence. The consensus group formally became established as the International Society for Premenstrual Disorders (ISPMD). The inaugural meeting of the ISPMD was held in Montreal in September 2008. The primary aim was to provide a unified approach for the diagnostic criteria of PMD, their quantification and guidelines on clinical trial design. This report summarises their recommendations. It is hoped that the criteria proposed here will inform discussions of the next edition of the World Health Organisation's International Classification of Diseases (ICD-11), and the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-V) criteria that are currently under consideration. It is also hoped that the proposed definitions and guidelines could be used by all clinicians and investigators to provide a consistent approach to the diagnosis and treatment of PMD and to aid scientific and clinical research in this field.
PMCID: PMC4134928  PMID: 21225438
PMS; PMDD; Premenstrual disorder; Diagnostic criteria; Quantification; Trial design; International consensus
7.  Effect of polydextrose on physicochemical properties of threadfin bream (Nemipterus spp) surimi during frozen storage 
Physicochemical properties of threadfin bream surimi with different levels of polydextrose (3%, 6%, 9% and 12%), raw surimi, raw surimi with addition sodium tripolyphosphate and commercial surimi (sucrose) during 6 months of frozen storage were investigated. The analyses included the measurement of Ca2+-ATPase, sulfhydryl contents, protein solubility, sodium dodecyl sulfate polyacrylamide gel electrophoresis, differential scanning calorimetry and scanning electron microscopy. The Ca2+-ATPase, sulfhydryl content and protein solubility levels added with 3%, 6%, 9% and 12% polydextrose can be maintained until the 6 months of storage by 47.33%, 41.60% and 51.41%, respectively. Differential scanning calorimetry showed decreases in thermal stabilization of myosin with regard to transition termperature. Analysis by scanning electron microscopy demonstrated that the number of pores formed was increased after storage. This study suggested that surimi stored with the polydextrose as a cryoprotectant was able to maintain physicochemical of surimi better compared to raw surimi with no additives or raw surimi with sodium tripolyphosphate.
PMCID: PMC3671047  PMID: 24425976
Cryoprotectant; Myofibrillar protein; Physicochemical properties; Polydextrose; Surimi
8.  Reaction of Tris(2-chloroethyl)phosphate with Reduced Sulfur Species 
Chemosphere  2011;83(7):941-947.
Tris(2-chloroethyl)phosphates (TCEP) is a widely used flame retardant in the U.S. It has recently been identified as one of the most frequently detected contaminants in U.S. streams. This contaminant is of toxicological concern in sensitive coastal ecosystems such as estuaries and salt marshes. It is likely that reactions with reduced sulfur species such as polysulfides (Sn2−), bisulfide (HS−), and thiophenolate (PhS−) present in anoxic subregions of coastal water bodies could have a significant impact on rates of removal of such a contaminant. The kinetics of reaction of reduced sulfur species with tris(2-chloroethyl)phosphate have been determined in well-defined aqueous solutions under anoxic conditions. Reactions were monitored at varying concentrations of reduced sulfur species to obtain the second-order rate constants from the observed pseudo-first order rate constants. The determined second-order rate constant for the reaction of TCEP with polysulfide at 25°C is 5.0 (± 1.4) × 10−4 M−1 s−1, with thiophenolate at 50 °C is 34 (± 2) × 10−4 M−1 s−1 and with bisulfide at 50 °C is 0.9 × 10−4 M−1 s−1, respectively. In addition, the degradation products of hydrolysis and the reactions with polysulfides, thiophenolate, and bisulfide with TCEP were studied with GC-FID and LC-MS-MS and were quantified.
PMCID: PMC4112502  PMID: 21419471
tris(2-chloroethyl)phosphate; bis(2-chloroethyl)phosphate; flame retardants; reduced sulfur species; bisulfide; polysulfide
9.  Intractable neonatal jaundice due to hereditary spherocytosis and Gilbert’s syndrome 
BMJ Case Reports  2011;2011:bcr0520114293.
In this article the authors present a case of pathological neonatal jaundice resistant to phototherapy in a baby with a family history of Gilbert’s syndrome and hereditary spherocytosis. Her presentation was ultimately explained with a diagnosis of both conditions, and required treatment with phenobarbitone. The authors discuss the mechanism by which Gilbert’s syndrome results in hyperbilirubinaemia and its similarities with Crigler–Najjar syndrome. The presentation of hereditary spherocystosis in the neonatal period is also explored, as is the mechanism of exaggerated hyperbilirubinaemia when the two conditions co-exist.
PMCID: PMC3149415  PMID: 22689841
10.  Pre-osteoblastic MC3T3-E1 cells promote breast cancer growth in bone in a murine xenograft model 
Chinese journal of cancer  2011;30(3):189-196.
The bones are the most common sites of breast cancer metastasis. Upon arrival within the bone microenvironment, breast cancer cells coordinate the activities of stromal cells, resulting in an increase in osteoclast activity and bone matrix degradation. In late stages of bone metastasis, breast cancer cells induce apoptosis in osteoblasts, which further exacerbates bone loss. However, in early stages, breast cancer cells induce osteoblasts to secrete inflammatory cytokines purported to drive tumor progression. To more thoroughly evaluate the role of osteoblasts in early stages of breast cancer metastasis to the bones, we used green fluorescent protein-labeled human breast cancer cell lines MDA-MB-231 and MDA-MB-435, which both induce osteolysis after intra-femoral injection in athymic mice, and the murine pre-osteoblastic cell line MC3T3-E1 to modulate osteoblast populations at the sites of breast cancer metastasis. Breast cancer cells were injected directly into the femur with or without equal numbers of MC3T3-E1 cells. Tumors grew significantly larger when co-injected with breast cancer cells and MC3T3-E1 cells than injected with breast cancer cells alone. Osteolysis was induced in both groups, indicating that MC3T3-E1 cells did not block the ability of breast cancer cells to cause bone destruction. MC3T3-E1 cells promoted tumor growth out of the bone into the extraosseous stroma. These data suggest that breast cancer cells and osteoblasts communicate during early stages of bone metastasis and promote tumor growth.
PMCID: PMC3661213  PMID: 21352696
MC3T3-E1; osteoblast; breast cancer; bone; metastasis
11.  Laboratory evolution of Geobacter sulfurreducens for enhanced growth on lactate via a single-base-pair substitution in a transcriptional regulator 
The ISME Journal  2011;6(5):975-983.
The addition of organic compounds to groundwater in order to promote bioremediation may represent a new selective pressure on subsurface microorganisms. The ability of Geobacter sulfurreducens, which serves as a model for the Geobacter species that are important in various types of anaerobic groundwater bioremediation, to adapt for rapid metabolism of lactate, a common bioremediation amendment, was evaluated. Serial transfer of five parallel cultures in a medium with lactate as the sole electron donor yielded five strains that could metabolize lactate faster than the wild-type strain. Genome sequencing revealed that all five strains had non-synonymous single-nucleotide polymorphisms in the same gene, GSU0514, a putative transcriptional regulator. Introducing the single-base-pair mutation from one of the five strains into the wild-type strain conferred rapid growth on lactate. This strain and the five adaptively evolved strains had four to eight-fold higher transcript abundance than wild-type cells for genes for the two subunits of succinyl-CoA synthase, an enzyme required for growth on lactate. DNA-binding assays demonstrated that the protein encoded by GSU0514 bound to the putative promoter of the succinyl-CoA synthase operon. The binding sequence was not apparent elsewhere in the genome. These results demonstrate that a single-base-pair mutation in a transcriptional regulator can have a significant impact on the capacity for substrate utilization and suggest that adaptive evolution should be considered as a potential response of microorganisms to environmental change(s) imposed during bioremediation.
PMCID: PMC3329115  PMID: 22113376
evolution; genome sequencing; geobacter; subsurface
12.  Long-term results of total knee arthroplasty following high tibial osteotomy according to Wagner 
International Orthopaedics  2011;36(4):761-764.
There is relatively little information available about the long-term results of total knee arthroplasty (TKA) following high tibial osteotomy. The aim of our study was to share our experiences and long-term results of TKA after a previous closing wedge high tibial osteotomy according to Wagner.
In a retrospective study we identified 48 consecutive patients who had undergone TKA after a previous closing wedge high tibial osteotomy according to Wagner with a follow-up of over ten years. The average duration of follow-up after the TKA was 13.3 years (min 10.0, max 15.5). X-rays were taken in two planes before TKA, one week after TKA and at the latest follow-up. Tibio-femoral alignment was measured on weightbearing long-leg anteroposterior radiographs. Radiolucent lines at the latest follow-up were documented. Functional evaluations were performed preoperatively and postoperatively (at the time of latest follow-up).
The mean Knee Society function score increased from 63.1 points preoperatively to 90.0 points postoperatively. The mean overall Knee Society score increased from 93.2 points preoperatively to 160.8 points postoperatively. The mean average femoro-tibial angle was corrected from varus 0.8° (varus 14°–valgus 8.0°) preoperatively to valgus 7.6° (valgus 2–9°) at the last follow-up.
The closing wedge high tibial osteotomy according to Wagner does not compromise subsequent total knee replacement and leads to good clinical and radiological results.
PMCID: PMC3311789  PMID: 21983941
13.  An Evaluation of Preoperative Computed Tomography on Patients with Chronic Otitis Media 
This study aimed to compare the veracity of computed tomography findings on patients undergoing surgery for chronic otitis media (COM) with the surgical findings, and to determine to what extent the preoperative computerized tomography (CT) findings are useful to the surgeon. A series of 56 patients with COM undergoing preoperative CT scanning followed by surgical exploration of the middle ear and mastoid. Operative notes were recorded and data collected on the nature of soft tissue masses, the status of the ossicles, presence or absence of facial canal dehiscence and semicircular canal (SCC) dehiscence and the presence or absence of dural plate erosion, and sigmoid sinus thrombosis. Fifty-six patients were recruited in the study, 30 males and 26 females. The age range was from 16 to 67 years with a mean of 26.51 ± 1.4 years. The preoperative CT scan imaging in cases of cholesteatoma, ossicular chain erosion and SCC dehiscence have good correlation with the intraoperative findings. The specificity of preoperative CT scan in detecting facial canal dehiscence, dural plate erosion and sigmoid sinus thrombosis in patient of COM were weak. Preoperative computed tomography evaluation is fairly useful especially in cases of cholesteatoma. According to the results of this study, CT is of value particularly in the definition of cholesteatoma, and in determining ossicular chain erosion and semicircular canal fistula.
PMCID: PMC3244578  PMID: 23449285
Chronic otitis media; Mastoidectomy; Computed tomography
Shortages of health care workers (HCWs) represents a serious challenge to ensuring effective HIV care in resource-limited settings (RLS). Stress, motivation, and job satisfaction have been linked with HCW retention and are important in addressing HCW shortages. In this cross-sectional study HCW stress, motivation, and perceived ability to meet patient needs were assessed in PEPFAR-supported urban HIV care and treatment clinics (CTCs) in Tanzania.
A self-administered questionnaire measuring motivation, stress, and perceived ability to meet patient needs was given to HCWs at 16 CTCs. Scales measuring HCW satisfaction, motivation, and stress were developed using principle components analysis. Hierarchical linear models were used to explore the association of HCW and site characteristics with reported satisfaction, stress, motivation, and ability to meet patient needs.
Seventy-three percent (279) of HCWs completed the questionnaire. Most (73%) HCWs reported minimal/no work-related stress, with 48% reporting good/excellent motivation, but 41% also reporting feeling emotionally drained. Almost all (98%) reported feeling able to help their patients, with 68% reporting work as rewarding. Most reported receipt of training and supervision, with good availability of resources. In the multivariate model, direct clinical providers reported lower motivation than management (p<0.05) and HCWs at medium-sized sites reported higher motivation than HCWs at larger sites (p<0.05). HCWs at small and medium sites were more likely to feel able to help patients than those from larger sites (p<0.05 and p<0.001 respectively).
Despite significant patient loads, HCWs in these PEPFAR-supported CTCs reported high levels of motivation, job satisfaction, ability to meet patient needs, low levels of stress but significant emotional toll. Understanding the relationship between support systems such as strong supervision and training and these outcomes is critical in designing interventions to improve motivation, reduce stress and increase retention of HCWs.
PMCID: PMC3580277  PMID: 22066277
HIV; motivation; stress; health care workers; resource limited settings
15.  Hereditary multiple intestinal atresia (HMIA) with severe combined immunodeficiency (SCID): a case report of two siblings and review of the literature on MIA, HMIA and HMIA with immunodeficiency over the last 50 years 
BMJ Case Reports  2011;2011:bcr0520103031.
Hereditary multiple intestinal atresia (HMIA), a presumed autosomal recessive disorder, is an unusual and rare form of recurrent intestinal atresia which can be associated with severe combined immunodeficiency (SCID). The combination of HMIA and SCID is invariably lethal. The authors describe this fatal association in two siblings. The parents are consanguineous and have three other normal healthy children. Both index cases had abnormal antenatal ultrasounds and were symptomatic after birth. The final diagnosis of HMIA with SCID was confirmed in both siblings. They were never able to receive enteral feeds, remained totally dependent on parenteral nutrition, had repeated episodes of sepsis and died after a very difficult neonatal intensive care course. In this article we have reviewed the clinical course and outcome of both cases. The existing literature on multiple intestinal atresia, HMIA and HMIA with immunodeficiency is also reviewed.
PMCID: PMC3062839  PMID: 22715199
16.  Conservatively treated perforation of the neovagina in a male to female transsexual patient 
BMJ Case Reports  2011;2011:bcr0820103241.
An unknown number of patients have had male to female gender transformation. Various surgical techniques have been employed to construct the neovagina. The more traditional techniques include inverted penile grafts and vascular pedicle grafts, but also the small bowel and sigmoid colon have been used. In this case, the authors present a patient who previously had a gender transformation from male to female with use of bowel for the neovagina. The patient presented with severe abdominal pain, fever and leukocytosis. A CT scan revealed retroperitoneal free air, and an x-ray examination with contrast through the neovagina showed leakage from the neovaginal top. The patient was treated conservatively with antibiotics and discharged after 7 days.
PMCID: PMC3062371  PMID: 22714607
17.  Urinary Symptoms in Breast Cancer: A Systematic Review 
Cancer  2011;118(3):582-593.
A large body of research has documented the prevalence and severity of menopausal symptoms, especially vasomotor symptoms, in breast cancer survivors and their impact on quality of life. Urinary symptoms as part of the constellation of menopausal symptoms, however, have received relatively little attention. Thus, less is known about the prevalence and severity of urinary symptoms in breast cancer survivors.
We conducted a systematic review of studies published between 1990 and 2010 to describe the prevalence and severity of urinary symptoms in breast cancer survivors.
We identified 16 eligible studies involving more than 2,500 women. Studies varied with respect to purpose, design, and nature of samples included; the majority used the same definition and assessment approach for urinary symptoms. Prevalence rates for symptoms ranged from 12% of women reporting burning or pain on micturition to 58% reporting difficulty with bladder control. Although in many studies the largest percentage of women rated symptoms as mild, as many as 23% reported severe symptoms.
Mild to moderate urinary symptoms are common in breast cancer survivors and some women report severe symptoms. Symptoms appear to adversely affect women’s quality of life. There is a need for additional research assessing the natural history of urinary symptoms using consensus definitions and validated measures in diverse populations. Nevertheless, this review suggests that clinicians should screen for urinary symptoms in breast cancer survivors and offer treatment recommendations or make referrals as appropriate.
PMCID: PMC3193898  PMID: 21751193
breast cancer; menopause; urogenital system; survivorship
18.  Use of Insulin Sensitizers for the Treatment of Major Depressive Disorder: A Pilot Study of Pioglitazone for Major Depression Accompanied by Abdominal Obesity 
Journal of Affective Disorders  2011;136(3):1164-1173.
This study was conducted to examine the safety and efficacy of pioglitazone, a thiazolidinedione insulin sensitizer, in adult outpatients with major depressive disorder.
In a 12-week, open-label, flexible-dose study, 23 patients with major depressive disorder received pioglitazone monotherapy or adjunctive therapy initiated at 15mg daily. Subjects were required to meet criteria for abdominal obesity (waist circumference >35 in. in women and >40 in. in men) or metabolic syndrome. The primary efficacy measure was the change from baseline to Week 12 on the Inventory of Depressive Symptomatology (IDS) total score. Partial responders (≥25% decrease in IDS total score) were eligible to participate in an optional extension phase for an additional three months.
Pioglitazone decreased depression symptom severity from a total IDS score of 40.3 ± 1.8 to 19.2 ± 1.8 at week 12 (p<.001). Among partial responders (≥ 25% decrease in IDS total score), an improvement in depressive symptoms was maintained during an additional 3-month extension phase (total duration = 24 weeks) according to IDS total scores (p<.001). Patients experienced a reduction in insulin resistance from baseline to Week 12 according to the log homeostasis model assessment (−0.8 ± 0.75; p<.001) and a significant reduction in inflammation as measured by log highly- sensitive C-reactive protein (−0.87 ± 0.72; p<.001). During the current episode, the majority of participants (74%, n=17), had already failed at least one antidepressant trial. The most common side effects were headache and dizziness; no patient discontinued due to side effects.
These data are limited by a small sample size and an open-label study design with no placebo control.
Although preliminary, pioglitazone appears to reduce depression severity and improve several markers of cardiometabolic risk, including insulin resistance and inflammation. Larger, placebo-controlled studies are indicated.
PMCID: PMC3225727  PMID: 21782251
Clinical Cancer Research  2011;18(3):748-757.
Compared to the numerous broad screens for oncogene mutations in adult cancers, very few have been performed in pediatric solid tumors. To identify novel mutations and potential therapeutic targets in pediatric cancers, we performed a high-throughput Sequenom-based analysis in large sets of several major pediatric solid cancers, including neuroblastoma (NB), Ewing sarcoma (ES), rhabdomyosarcoma (RMS), and desmoplastic small round cell tumor (DSRCT).
Experimental Design
We designed a highly multiplexed Sequenom-based assay to interrogate 275 recurrent mutations across 29 genes. Genomic DNA was extracted from 192 NB, 75 ES, 89 RMS, and 24 DSRCT samples. All mutations were verified by Sanger sequencing.
Mutations were identified in 13% of NB samples, 4% of ES samples, 21.1% of RMS samples, and no DSRCT samples. ALK mutations were present in 10.4% of NB samples. The remainder of NB mutations involved the BRAF, RAS, and MAP2K1 genes and were absent in samples harboring ALK mutations. Mutations were more common in embryonal RMS (ERMS) samples (28.3%) than alveolar RMS (ARMS) (3.5%). In addition to previously identified RAS and FGFR4 mutations, we report for the first time PIK3CA and CTNNB1 (Beta-Catenin) mutations in 4.9% and 3.3% of ERMS, respectively.
In ERMS, ES, and NB, we identified novel occurrences of several oncogene mutations recognized as drivers in other cancers. Overall, NB and ERMS contain significant subsets of cases with non-overlapping mutated genes in growth signaling pathways. Tumor profiling can identify a subset of pediatric solid tumor patients as candidates for kinase inhibitors or RAS-targeted therapies.
PMCID: PMC3271129  PMID: 22142829
mutation; rhabdomyosarcoma; neuroblastoma; Ewing sarcoma; desmoplastic small round cell tumor
20.  Manipulating Cofactor Binding Thermodynamics in an Artificial Oxygen Transport Protein 
Biochemistry  2011;50(47):10254-10261.
We report the mutational analysis of an artificial oxygen transport protein, HP-7, which operates via a mechanism akin to human neuroglobin and cytoglobin. This protein destabilizes one of two heme-ligating histidine residues by coupling histidine side chain ligation with the burial of three charged glutamate residues on the same helix. Replacement of these glutamate residues with alanine, which is uncharged, increases the affinity of the distal histidine ligand by a factor of thirteen. Paradoxically, it also decreases heme binding affinity by a factor of five in the reduced state and sixty in the oxidized state. Application of a three-state binding model, in which an initial pentacoordinate binding event is followed by a protein conformational change to hexacoordinate, provides insight into the mechanism of this seemingly counterintuitive result: the initial pentacoordinate encounter complex is significantly destabilized by the loss of the glutamate side chains, and the increased affinity for the distal histidine only partially compensates. These results point to the importance of considering each oxidation and conformational state in the design of functional artificial proteins.
PMCID: PMC3561710  PMID: 22004125
21.  Subsets of ATP-Sensitive Potassium Channel (KATP) inhibitors increase gap junctional intercellular communication in metastatic cancer cell lines independent of SUR expression 
FEBS letters  2011;586(1):27-31.
Gap junctional intercellular communication (GJIC) regulates cellular homeostasis by propagating signaling molecules, exchanging cellular metabolites, and coupling electrical signals. In cancer, cells exhibit altered rates of GJIC which may play a role in neoplastic progression. KATP channels help maintain membrane polarity; and, linkages between KATP channel activity and rates of GJIC have been established. The mechanistic relationship has not been fully elucidated. We report the effects of treatment with multiple KATP antagonist compounds on GJIC in metastatic cell lines demonstrating an increase in communication rates following treatment with compounds possessing specificities towards the SUR2 subunit of KATP. These effects remained consistent using cell lines with different expression levels of SUR1 and SUR2, suggesting possible off target effects on GJIC by these compounds.
PMCID: PMC3249498  PMID: 22119728
Sulfonylurea; KATP; gap junction; glibenclamide
22.  Acute renal failure following lung transplantation: risk factors, mortality, and long-term consequences 
Acute renal failure (ARF) frequently complicates lung transplantation. This study determined the prevalence, predictive factors, and consequences of ARF on long-term renal function and survival.
One hundred and seventy-four lung transplantation recipients were divided into two groups based on the presence or absence of ARF defined as a 50% decrease in creatinine clearance from baseline (group I: 67 patients with ARF; group II: 107 patients without ARF). Multivariate analysis compared pre-operative, operative, and post-operative risk factors to assess predictive factors. Renal function over time was assessed by two-way repeated measures analysis of variance (ANOVA).
ARF developed in 67 (39%) of patients. Multivariate analysis identified aprotinin (OR 2.20 (1.11; 4.36), p = 0.02) and double lung transplantation (OR 2.61 (1.32; 5.15), p = 0.006) as risk factors for post-operative renal failure. At 5 years following transplant, creatinine clearance was similar between the two groups (group I CrCl: 73 ml s−1; group II CrCl: 53 ml s−1; p = 0.54). Survival at 5 years was the same in the two groups. Multivariate analysis associated age at the time of transplantation (HR 1.030 (1.004; 1.057), p = 0.02) and intensive care unit (ICU) length of stay (HR 1.029 (1.008; 1.051), p = 0.007) with decreased survival.
The use of aprotinin and double lung transplantation are associated with ARF following lung transplantation. Age at the time of transplantation and a longer intensive care stay predict decreased survival. ARF after lung transplantation is not predictive of late renal dysfunction or decreased long-term survival.
PMCID: PMC3241081  PMID: 21665487
Lung transplantation; Acute renal failure; Aprotinin
24.  Serum anti-Müllerian hormone and antral follicle count as predictive markers of OHSS in ART cycles 
To evaluate predictive role of day–3 serum anti-Müllerian hormone (AMH) levels and antral follicle count (AFC) in ovarian hyperstimulation syndrome (OHSS) in patients undergoing IVF/ICSI cycles.
Materials and methods
Forty-one women with moderate/severe OHSS and 41 age matched women without OHSS were compared to evaluate the predictive value of certain risk factors for OHSS. AFC, and E2, FSH, LH, AMH, inhibin-B levels measured on day 3 of the menstrual cycle before controlled ovarian hyperstimulation.
Mean FSH was significantly lower (p < 0.0001); and mean LH, AFC and AMH were significantly higher in women with OHSS compared to women without OHSS (p = 0.049, p < 0.0001 and p < 0.0001, respectively). There was no significant difference in inhibin B (p = 0.112) and estradiol (p = 0.706) between the groups. The ROC area under curve (AUC) for AMH presented the largest AUC among the listed risk factors. AMH (AUC = 0.87) and AFC (AUC = 0.74) had moderate accuracy for predicting OHSS while Inhibin B (AUC = 0.58) and LH (AUC = 0.61) had low accuracy. The cut-off value for AMH 3.3 ng/mL provided the highest sensitivity (90%) and specificity (71%) for predicting OHSS. It’s positive (PPV) and negative predictive values (NPV) were 61% and 94%, respectively. The cut-off value for AFC was 8 with 78% sensitivity, 65% specificity, 52% PPV and 86% NPV.
Measurement of basal serum AMH and AFC can be used to determine the women with high risk for OHSS.
PMCID: PMC3241835  PMID: 21882017
Antimullerian hormone; Ovarian hyperstimulation syndrome; Antral follicle count
25.  Attention-deficit hyperactive disorder presenting with school truancy in an adolescent: a case report 
Mental Health in Family Medicine  2011;8(4):249-254.
Attention-deficit hyperactive disorder (ADHD) is a psychiatric illness commonly diagnosed during the early years of childhood. In many adolescents with undiagnosed ADHD, presentation may not be entirely similar to that in younger children. These adolescents pose significant challenges to parents and teachers coping with their disability. Often adolescents with behavioural problems are brought to medical attention as a last resort. This case describes an adolescent who presented to a primary care clinic with school truancy. He was initially treated for depression with oppositional defiant disorder and sibling rivalry. Only following a careful detailed history and further investigations was the diagnosis of ADHD made. He showed a positive improvement with the use of methylphenidate for his ADHD and escitalopram for his depression. The success of his management was further supported by the use of behavioural therapy and parenting interventions. There is a need to increase public awareness of ADHD, especially among parents and teachers so that early intervention can be instituted in these children.
PMCID: PMC3487600  PMID: 23205066
attention-deficit hyperactive disorder; primary care; school truancy

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