Knowledge, attitude and factors influencing public willingness towards organ donation among hospital patients and relatives in Negeri Sembilan, Malaysia.

BACKGROUND: Malaysia continues to have a very low cadaveric organ donation rate of 0.48 per million population. The aim of this paper is to assess the attitude, beliefs and knowledge of patients and relatives at three different hospitals in Negeri Sembilan towards organ donation to increase the acceptability of organ transplant. METHODS: A cross-sectional descriptive study with convenient sampling was carried out Hospital Tuanku Ja'afar, Hospital Port Dickson and Hospital Tuanku Ampuan Najihah in Negeri Sembilan, Malaysia. The participants answered a questionnaire regarding the source of their information about organ donation, their knowledge about brain death and willingness to donate. The association between variables was tested using chi-squared test or Fischer's exact test as appropriate. RESULTS: A total of 385 individuals completed the survey of whom 134 (35%) were willing to donate their organs upon death and 25(19%) were registered donors. Higher educational level (41%), age 30 and below (42%) and people who attended organ donation awareness campaigns (60%) were more willing to donate their organs. Correct understanding of brain death was associated with willingness to be an organ donor. The commonest reason cited for unwillingness to donate was opposition from family members. CONCLUSION: Marital status, religion, source of knowledge and occupation are significant factors in willingness to donate organs among Malaysians. Lower age and higher educational level were positive factors towards organ donation. Direct personal contact through awareness campaigns, family and friends has a potential for greater positive impact on organ donation.

Emergency general surgery in a public hospital in Malaysia.

INTRODUCTION: Patients undergoing emergency general surgery (EGS) are at risk for death and complications. Information on the burden of EGS is critical for developing strategies to improve the outcomes. METHODS: In this retrospective cohort study, medical records of all general surgical operations in a public hospital were reviewed for the period 1st January 2017 to 31st December 2017. Data on patient demographics, operative workload, case mix, time of surgery and outcomes were analysed. RESULTS: Of the 2960 general surgical operations that were performed in 2017, 1720 (58.1%) of the procedures were performed as emergencies. The mean age for the patients undergoing emergency general surgical procedures was 37.9 years (Standard Deviation, ±21.0), with male preponderance (57.5%). Appendicitis was the most frequent diagnosis for the emergency procedures (43%) followed by infections of the skin and soft tissues (31.6%). Disorders of the colon and rectum ranked as the third most common condition, accounting for 6.7% of the emergency procedures. Majority of emergency surgery (59.3%) took place after office hours and on weekends. Post-operative deaths and admissions to critical care facilities increased during EGS when compared to elective surgery, p<0.01. CONCLUSIONS: EGS constitutes a major part of the workload of general surgeons and it is associated significant risk for death and post-operative complications. The burden of EGS must be recognised and patient care systems must evolve to make surgery safe and efficient.

Comparison of features and outcomes of perforated peptic ulcer between Malaysians and foreigners.

BACKGROUND: Perforated peptic ulcers (PPU) present as serious surgical emergencies that carry high mortality and morbidity. Foreigners with PPU are also managed in our hospital setting. Their inclusion significantly alters the trend and pattern of PPU seen in Malaysia. AIM: To compare per-operative and post-operative features and outcomes of perforated peptic ulcers between Malaysians and foreigners. MATERIAL AND METHODS: This was an analytical crosssectional study. All patients who underwent repair of perforated peptic ulcer disease during a 6-year period were included. 50 consecutive patients' records with perforated peptic ulcer were analysed. Data were collected from operation theatre database and hospital medical records. Chi square and t test were performed using SPSS statistical software. RESULTS: Total of 50 patients, of which 30 were Malaysians and 20 were foreigners. The mean age of Malaysian patients was 58.3 ± 15.2 years whereas the mean age for foreign patients was 30.3 ± 6.7 years, with foreign patients being significantly younger than local patients. Foreigners had significantly smaller ulcers with only 5% of them having ulcers more than 1cm while 36.7% of Malaysian patients had ulcers more than 1cm. Post-operative complications are significantly higher in Malaysian patients (p<0.05) with 40% of Malaysian patients and 10% of foreign patients developing post-operative complications. CONCLUSION: Foreign patients are younger with significantly smaller perforated ulcers and better post-operative outcomes.

First metatarsophalangeal joint arthrodesis - Do joint configuration and preparation technique matter?

BACKGROUND: The purpose of this study was to investigate the influence of joint configuration and preparation on first metatarsophalangeal (MTPJ) union rates. METHODS: We performed a retrospective analysis of first MTPJ arthrodeses undertaken in our institution. Clinical notes, radiographs and postal questionnaires were used to determine outcome. RESULTS: Two hundred first MTPJ arthrodeses (172 patients) were included in the analysis (34 male: 138 female; mean age 62 yr). The overall union rate was 93.5%. Union was achieved in 109/118 MTPJs (92.4%) prepared in the flat-on-flat configuration and in 78/82 (95%) prepared in the ball-and-socket configuration (p=0.438). Higher union rates favoured low-velocity joint preparation [using rongeur only 21/21 (100%), rongeur and burr 26/27 (96.3%) and conical reamer 31/34 (91.2%)] but this did not reach statistical significance (p=0.317). There was a 95% satisfaction rate with surgery but male patients were less satisfied (p=0.031). CONCLUSION: Union rates were not influenced by joint configuration or preparation techniques.

Impact of a new conceptualized anti-reflux Trumpet stent on the quality of life of patients with advanced carcinoma of the cardio-oesophageal junction.

Objectives: To evaluate a newly developed, self-expandable anti-reflux Trumpet (ART) stent customized for cardio oesophageal junctional (COJ) cancer on the feasibility of deployment, stent migration, quality of life, and symptom relief. Design: Prospective case series, Proof of concept pilot study. Setting: Tertiary Health Care Center, Hospital Tuanku Jaafar, Seremban, Malaysia. Department of Surgery. Participants: A total of 17 patients diagnosed with advanced COJ tumour and who had never undergone any surgical, endoscopic, or chemoradiotherapy and indicated for stenting were recruited. Interventions: The study period was over nine months, and follow-up was one-month post-stenting. Main outcome measures: Endpoint measures were feasibility of deployment of the new design, symptoms relief, early stent migration, early complication, GERD Q score, and (QOL)assessment. Results: The ART stent was inserted successfully in all cases (17/17, 100%). There were two stent migrations due to the flexibility of the stent at the neck. There were no early or post-stenting one-month complications associated with the procedure. A good flow of contrast was seen in all the stents deployed. GERD Q score was low in all patients pre and post-stenting. Post-stenting there was a relief of dysphagia, weight gain, and a 60% improvement in QOL score. Conclusions: ART stent is feasible and technically successful in COJ tumours. It provides good symptom relief, improves the QOL, and has minimal early complications. Funding: None declared.

A phase I pharmacokinetic and pharmacodynamic study of AT7519, a cyclin-dependent kinase inhibitor in patients with refractory solid tumors.

BACKGROUND: AT7519 is an inhibitor of multiple cyclin-dependent kinases (CDKs). Based on potent antitumor activity in preclinical models, a first-in-human clinical trial in refractory solid tumors investigated its safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD). PATIENTS AND METHODS: AT7519 was administered in a '3 + 3' dose- escalation scheme on 5 consecutive days every 3 weeks to patients with advanced, refractory solid tumors. Samples to monitor AT7519 PK and PD were obtained. RESULTS: Twenty-eight patients were treated at seven dose levels (1.8-40 mg/m(2)/day). At 40 mg/m(2)/day, one patient developed hypotension and ST segment elevation. At 34 mg/m(2)/day, dose-limiting toxic effects (DLTs) were QTc prolongation with one death (grade 5), fatigue (grade 4) and mucositis (grade 3). Electrocardiogram review suggested a dose-dependent increase in QTc and recruitment was discontinued without establishing a maximum tolerated dose. Four patients exhibited stable disease for >6 months and one had a prolonged partial response. PK profile revealed modest interpatient variation with linear exposure at increasing doses. Inhibition of markers of CDK activity was observed across the dose range and manifested in antiproliferative activity at a dose of 28 mg/m(2). CONCLUSION: AT7519 elicited clinical and PD activity resulting from CDK inhibition at doses below the appearance of DLT of QTc prolongation.

Marbelization of the gallbladder, a variant of acute gangrenous cholecystitis.

Cholelithiasis can present from a milder form of biliary colic to a more severe and complicated one like empyema gallbladder and a lesser-known variant of gangrenous gallbladder called marbleization of the gallbladder. The clinical signs and symptoms are similar to acute cholecystitis. Diabetes mellitus could have a role in the process of marbleization. Diagnosing marbleization of the gall bladder is not easy preoperatively. Computerized tomography is a better diagnostic modality when compared to laboratory investigations. Urgent cholecystectomy is the only option, and there is no role of conservative treatment. We report a case of a 36-year-old man with newly diagnosed Diabetes Mellitus diagnosed initially as acute cholecystitis and managed conservatively. He did not respond to treatment and hence underwent cholecystectomy and intraoperatively was found to have marbleization of the gall bladder.

A case of rectal cancers in teenager: A conundrum of genetics and clinical medicine.

INTRODUCTION: Signet cell carcinoma (SRCC)of the rectum is a rare subtype of the rectum cancer which accounts for only 0.8% of colorectal cancer in adolescents and young adults (AYAs) which spread aggressively to other organs and peritoneum. CASE PRESENTATION: We present a case of 15-year-old boy from rural area, presented with chronic diarrhea and per rectal bleeding for 3 months. The diagnosis was determined by colonoscope which revealed a fungating mass identified at 10cm from anal verge. Histological examination confirmed diagnosis of signet ring cell adenocarcinoma. CT scan of the abdomen showed thickening involving the recto-sigmoid colon and rectal mass, without evidence of distant metastatic disease. The patient's carcinoembryonic antigen level was within the normal range. He underwent a colostomy and was subjected to neoadjuvant CCRT and surgery. DISCUSSION: This CASE highlights the importance and challenges in achieving early diagnosis and surgical intervention of signet-ring cell carcinoma in adolescents, as most cases are detected at an advanced stage coupled with the scarcity of information on these rarer subtypes which leads to a poor prognosis. CONCLUSION: In managing Signet cell carcinoma of the colorectal, physician have to know that it has a poor prognosis in patients of any age. However, in young teenagers delayed diagnosis and treatment option are narrowed to palliative management. Genetic profiling of family members and similar environment population may be a key to early detection.

Biological function of PDGF-induced PI-3 kinase activity: its role in alpha PDGF receptor-mediated mitogenic signaling.

The tyrosine phosphorylation sites in the human alpha PDGF receptor (alpha PDGFR) required for association with PI-3 kinase have been identified as tyrosines 731 and 742. Mutation of either tyrosine substantially reduced PDGF-induced PI-3 kinase activity but did not impair the receptor-mediated mitogenic response. We sought to determine whether PDGF-induced PI-3 kinase activity could be further ablated so as to exclude a low threshold requirement for PDGFR signal transduction. Thus, we mutated both tyrosine 731 and 742 and expressed the double mutant (Y731F/Y742F) in 32D hematopoietic cells. In such transfectants, PDGF induced no detectable receptor-associated or anti-P-Tyr recoverable PI-3 kinase activity. Under the same conditions, neither mobility shift of raf-1 nor tyrosine phosphorylation of either PLC gamma or MAP kinase was impaired. 32D transfectants expressing the double mutant showed wild-type alpha PDGFR levels of mitogenic and chemotactic responses to PDGF. To examine the effect of the double mutation in cells that normally respond to PDGF, we generated chimeras in which the cytoplasmic domains of wild-type alpha PDGFR, Y731F, and Y731F/Y742F were linked to the extracellular domain of colony-stimulating factor-1 (CSF-1) receptor (fms). After introduction of the chimeric receptors into mouse NIH/3T3 fibroblasts, the ability of CSF-1 to stimulate growth of these transfectants was examined. Our data show that all these chimeric receptors exhibited similar abilities to mediate CSF-1-stimulated cell growth. These findings lead us to conclude that PDGF-induced PI-3 kinase activity is not required for PDGF-stimulated mitogenic pathway in both NIH/3T3 fibroblasts and 32D hematopoietic cells.

A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors.

KIT or alpha-platelet-derived growth factor receptor (alpha-PDGFR) activating mutations are the pathogenic mechanisms that characterize gastrointestinal stromal tumors (GIST). Despite excellent responses to imatinib mesylate (IM), patients are relapsing. We developed an IM-resistant GIST cell line (GIST-R) from the IM-sensitive GIST882 cell line (GIST-S) by growing these cells in IM. Gene expression profiling (GEP) of GIST-S, GIST-R cells and two IM resistant GIST patients demonstrated that KIT is downregulated implying a major role in IM resistance. Instead, GIST-R cells have acquired IM resistance by overexpressing the oncogenic receptor tyrosine kinase - AXL - in a 'kinase switch'. Further, the two IM resistant GIST patients express AXL and not c-Kit, seen by immunohistochemistry (IHC). Real time reverse transcriptase-polymerase chain reaction and Western blotting of the GIST-S and GIST-R cells confirmed the switch from Kit to AXL. In GIST-R, AXL is tyrosine phosphorylated and its ligand growth-arrest-specific gene 6 is overexpressed implying autocrine activation. The kinase switch is associated with a morphological change from spindle to epithelioid. Molecular modeling of the kinase domain of mutant c-Kit (V654A) and AXL showed no binding to IM but efficient binding to MP470, a novel c-Kit/AXL kinase inhibitor. MP470 synergizes with docetaxel (taxotere) and is cytotoxic to GIST cells.

Laparoscopic appendicectomy: the ideal procedure for laparoscopic skill training for surgical registrars.

OBJECTIVE: Appendicectomy is a very common surgical procedure performed by registrars. It is mainly carried out by surgical registrars as an open procedure in many government hospitals. We aimed to evaluate laparoscopic appendicectomy as a laparoscopic training skill in a clinical setting for our registrars. METHODS: A retrospective analysis of all attempted laparoscopic appendicectomies over 12 months by experienced surgeons and registrars was done. Factors evaluated were operating time, conversion rate, postoperative hospital stay, morbidity and mortality. RESULTS: There was no statistically significant difference in operating time for surgeons and registrars (mean, 53 minutes vs. 60 minutes), conversion rate (10% vs. 11%). Mean hospital stay for patients operated on by surgeons was 3.1 days and 3.2 days for registrars. Morbidity was equal with both surgeons and registrars. CONCLUSION: We conclude that laparoscopic appendicectomy is a safe laparoscopic training tool for registrars with basic laparoscopic knowledge who have had a proper apprenticeship, and can be done in a clinical setting.

Gastric outlet obstruction secondary to a pedunculated hyperplastic polyp with early malignant changes.

Hyperplastic polyps are the most common polypoidal lesions of the stomach showing a varied presentation. They may be asymptomatic; however, occasionally they can cause anaemia and gastric outlet obstruction. Malignant transformation is a serious complication associated with such polyps. We present the case of an elderly woman who complained of epigastric pain and intermittent vomiting. Oesophagogastroduodenoscopy (OGDS) showed a large pedunculated polyp along the lesser curvature of the stomach, 4 cm from the gastro-oesophageal junction, extending into the first part of the duodenum that caused gastric outlet obstruction. Computed tomography reported a soft-tissue mass arising from the incisura and extending through the pylorus into the duodenum (D1 and proximal D2). An endoscopic polypectomy was performed, and histopathological examination reported evidence of early gastric carcinoma. She underwent regular endoscopic follow-up with biopsies performed over 2 years, and the last follow-up showed mild-to-moderate dysplasia at the previous excision site. She underwent a planned laparoscopic wedge resection, and histopathological examination confirmed the presence of a hyperplastic polyp showing low-grade dysplasia.

Phase I single dose, two-period and two-sequence cross-over trial to evaluate the relative bioavailability of two oral pimasertib formulations in advanced cancer patients.

PURPOSE: A phase I two-period two sequence cross-over study compared the bioavailability of two pimasertib (MSC1936369B/AS703026) formulations (capsule versus tablet) in advanced cancer patients. METHODS: Patients with advanced solid tumors were randomized to one of two treatment sequences utilizing pimasertib tablet (test; 3 × 20 mg, PO QD) and capsule (standard; 2 × 30 mg, PO QD). The trial comprised a screening and baseline period, two time periods or parts A and B, and a trial extension phase. RESULTS: N = 38 patients were randomized to two treatment sequences S1 and S2. PK parameters t 1/2, CL/f, and V z/f were within the same range for the two formulations. Tablet had bioavailability comparable to capsule based on the analysis of AUC0-t, however, tablet administration resulted in an increase of ~25% in C max versus capsule. Common predicted adverse events of pimasertib included ocular events, diarrhea and creatine phosphokinase elevation. Disease control rate was ~29% with 1 partial response and 4 of 10 patients with stable disease >4 months. CONCLUSIONS: Pimasertib tablet was overall well tolerated, had a similar safety and efficacy profile to standard capsule formulation and had bioavailability comparable to capsule.

Corticosteroid injection for Morton's neuroma with or without ultrasound guidance: a randomised controlled trial.

AIMS: The objective of this double-blind randomised controlled trial was to assess whether ultrasound guidance improved the efficacy of corticosteroid injections for Morton's neuroma (MN). PATIENTS AND METHODS: In all, 50 feet (40 patients) were recruited for this study but five feet were excluded due to the patients declining further participation. The mean age of the remaining 36 patients (45 feet) was 57.8 years (standard deviation (sd) 12.9) with a female preponderance (33F:12M). All patients were followed-up for 12 months. Treatment was randomised to an ultrasound guided (Group A) or non-ultrasound guided (Group B) injection of 40 mg triamcinolone acetonide and 2 ml 1% lignocaine, following ultrasound confirmation of the diagnosis. RESULTS: The mean visual analogue score for pain improved significantly in both groups (Group A - from 64 mm, sd 25 mm to 29 mm, sd 27; Group B - from 69 mm, sd 23 mm to 37 mm, sd 25) with no statistical difference between them at all time-points. The failure rate within 12 months of treatment was 11/23 (48%) and 12/22 (55%) in Groups A and B, respectively (p = 0.458). The improvement in Manchester Oxford Foot Questionnaire Index and patient satisfaction favoured Group A in the short-term (three months) that almost reached statistical significance (p = 0.059 and 0.066 respectively). However, this difference was not observed beyond three months. CONCLUSION: This study has shown that ultrasound guidance did not demonstrably improve the efficacy of corticosteroid injections in patients with MN. TAKE HOME MESSAGE: In the presence of a clear diagnosis of MN, a trained clinician who understands the forefoot anatomy may perform an injection without ultrasound guidance with good and safe results.

Functional interactions between isolated SH2 domains and insulin/Ras signaling pathways of Xenopus oocytes: opposite effects of the carboxy- and amino-terminal SH2 domains of p85 PI 3-kinase.

Purified amino-terminal Src homology 2 (SH2) domains of GAP, PLCgamma1 and the p85alpha subunit of PI 3-kinase, as well as the carboxy-terminal SH2 domain of the latter protein and the unique SH2 domain of Grb2, were injected into full grown, stage VI Xenopus laevis oocytes. None of the injected domains showed any effect when injected alone, nor did they affect the rate of GVBD induced by progesterone, an adenylate cyclase-dependent process. On the other hand, the unique Grb2 SH2 domain and all N-terminal SH2 domains injected inhibited to various degrees the rate of insulin-induced GVBD, a tyrosine kinase dependent pathway. Interestingly, and in contrast to the behavior shown by the N-terminal domain of the same molecule, the C-terminal SH2 domain of p85 did not inhibit, but slightly accelerated the rate of GVBD induced by insulin. Furthermore, whereas the Grb SH2 domain and all N-terminal SH2 domains tested failed to co-operate with normal Ras protein to induce GVBD, the C-terminal SH2 domain of p85alpha exhibited significant synergy when coinjected with normal Ras protein, indicating that the C- and N-terminal SH2 domains of p85alpha exert opposite (positive and negative, respectively) regulatory roles in the control of oocyte insulin/Ras signaling pathways. Our results demonstrate that the purified, isolated SH2 domains retain structural and functional specificity and that Xenopus oocytes constitute an useful biological system to analyse their functional role in tyrosine kinase signaling pathways.

Identification of a Frizzled-like cysteine rich domain in the extracellular region of developmental receptor tyrosine kinases.

In Drosophila, members of the Frizzled family of tissue-polarity genes encode proteins that appear to function as cell-surface receptors for Wnts. The Frizzled genes belong to the seven transmembrane class of receptors (7TMR) and have on their extracellular region a cysteine-rich domain that has been implicated as the Wnt binding domain. This region has a characteristic spacing of ten cysteines, which has also been identified in FrzB (a secreted antagonist of Wnt signaling) and Smoothened (another 7TMR, which is involved in suppression of the hedgehog pathway). We have identified, using BLAST, sequence similarity between the cysteine-rich domain of Frizzled and several receptor tyrosine kinases, which have roles in development. These include the muscle-specific receptor tyrosine kinase (MuSK), the neuronal specific kinase (NSK2), and ROR1 and ROR2. At present, the ligands for these developmental tyrosine kinases are unknown. Our results suggest that Wnt-like ligands may bind to these developmental tyrosine kinases.

Identification of a Frizzled-like cysteine rich domain in the extracellular region of developmental receptor tyrosine kinases.

In Drosophila, members of the Frizzled family of tissue-polarity genes encode proteins that appear to function as cell-surface receptors for Wnts. The Frizzled genes belong to the seven transmembrane class of receptors (7TMR) and have on their extracellular region a cysteine-rich domain that has been implicated as the Wnt binding domain. This region has a characteristic spacing of ten cysteines, which has also been identified in FrzB (a secreted antagonist of Wnt signaling) and Smoothened (another 7TMR, which is involved in the hedgehog signalling pathway). We have identified, using BLAST, sequence similarity between the cysteine-rich domain of Frizzled and several receptor tyrosine kinases, which have roles in development. These include the muscle-specific receptor tyrosine kinase (MuSK), the neuronal specific kinase (NSK2), and ROR1 and ROR2. At present, the ligands for these developmental tyrosine kinases are unknown. Our results suggest that Wnt-like ligands may bind to these developmental tyrosine kinases

The extracellular regions of PSMA and the transferrin receptor contain an aminopeptidase domain: implications for drug design.

The Aeromonas proteolytica aminopeptidase (AMP), Pseudomonas sp. (RS-16) carboxypeptidase G2 (CPG2), and Streptomyces griseus aminopeptidase (SGAP) are zinc dependent proteolytic enzymes with cocatalytic zinc ion centers and a conserved aminopeptidase fold. A BLAST search with the sequence of the solved AMP structure indicated that a similar domain could be found in prostate-specific membrane antigen (PSMA) and the transferrin receptor (TfR). When the PSMA or TfR sequence was input into the THREADER program, the top structural matches were SGAP and AMP confirming that these are structurally conserved domains. Optimal sequence alignment of PSMA and TfR using the known three-dimensional structures of AMP, CPG2, and SGAP shows that the critical amino acids involved in forming the catalytic pocket are conserved in PSMA but absent in the TfR. The specificity pocket in AMP is formed from four aromatic side chains and the equivalent region in CPG2/PSMA has a changed sequence pattern. Since CPG2 and PSMA are folate hydrolases, the changed specificity pocket leaves space to accommodate the large pteroate moiety of folic acid. In contrast, no enzyme function has been ascribed to the TfR.

Prediction of domain organisation and secondary structure of thyroid peroxidase, a human autoantigen involved in destructive thyroiditis.

Organ specific autoimmune diseases are relatively common immunological disorders in man which include thyroid autoimmune disease, insulin-dependent diabetes mellitus and myasthenia gravis. The target autoantigens in some of these diseases have recently been characterised. In thyroid autoimmune disease this includes the key enzyme, thyroid peroxidase (TPO), which is involved in the generation of thyroid hormone. Structural knowledge about autoantigens such as thyroid peroxidase will allow a greater understanding of the interaction between autoantigens and the aberrant immune response, and facilitate the development of strategies for antigen-specific therapeutic manipulation. We report here a prediction of the secondary structure of thyroid peroxidase, together with the results of circular dichroic spectroscopy of a homologous purified enzyme. A combination of 3 secondary structure prediction programs has been used, following multiple sequence alignment, and TPO has been found to consist mainly of alpha-helical conformation, with little beta-sheet present. This structure prediction, together with knowledge of the exon-intron boundaries allows a model for the domain organisation of the TPO molecule to be proposed.