Intravenous thrombolysis for multi-ethnic Asians with acute ischaemia stroke in Malaysian public primary stroke centres versus acute stroke ready hospitals: Comparison of real-world clinical outcomes.

INTRODUCTION: Intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator is beneficial in acute ischaemic stroke (AIS). We aim to compare the realworld clinical outcomes and service efficiency of IVT in Malaysian primary stroke centres (PSCs) versus acute stroke ready hospitals (ASRHs). MATERIALS AND METHODS: We conducted a multi-centre cohort study involving 5 PSCs and 7 ASRHs in Malaysia. Through review of medical records of AIS patients who received IVT from 01 January 2014 to 30 June 2021, real-world data was extracted for analysis. Univariate and multivariate regression models were employed to evaluate the role of PSCs versus ASRHs in post-IVT outcomes and complications. Statistical significance was set at p<0.05. RESULTS: A total of 313 multi-ethnic Asians, namely 231 from PSCs and 82 from ASRHs, were included. Both groups were comparable in baseline demographic, clinical, and stroke characteristics. The efficiency of IVT delivery (door-toneedle time), functional outcomes (mRS at 3 months post- IVT), and rates of adverse events (intracranial haemorrhages and mortality) following IVT were comparable between the 2 groups. Notably, 46.8% and 48.8% of patients in PSCs and ASRHs group respectively (p=0.752) achieved favourable functional outcome (mRS≤1 at 3 months post-IVT). Regression analyses demonstrated that post-IVT functional outcomes and adverse events were independent of the role of PSCs or ASRHs. CONCLUSION: Our study provides real-world evidence which suggests that IVT can be equally safe, effective, and efficiently delivered in ASRHs. This may encourage the establishment of more ASRHs to extend the benefits of IVT to a greater proportion of stroke populations and enhance the regional stroke care.

Clinical outcomes of acute stroke thrombolysis in neurologist and non-neurologist centres - A comparative study in Malaysia.

BACKGROUND: Thrombolytic therapy with intravenous alteplase is a well-established treatment for acute ischaemic stroke (AIS). However, in Malaysia, treatment prescription is often limited by the availability of neurologists. The objective was to compare the outcomes of acute stroke thrombolysis therapy prescribed by neurologists in the Seberang Jaya Hospital (SJH) and non-neurologists in the Taiping Hospital (TH). METHODS: In this cross-sectional study, all AIS patients who received thrombolytic therapy in SJH and TH between January 2012 and September 2019 were included. Clinical data was extracted from admission records. The outcomes assessed were the percentage of patients who achieved excellent functional outcome at 3 months (modified Rankin scale of 0 to 1), rates of symptomatic intracranial haemorrhage (SICH), and mortality. RESULTS: A total of 63 AIS patients who received thrombolytic therapy were included, of which 37 patients (58.7%) were treated in SJH. The median NIHSS on admission was 12 in SJH and 11.5 in TH. In all 21.6% of patients from SJH and 30.7% of patients from TH achieved favourable functional outcome at 3 months (p=0.412). There were no significant differences between the two centres in terms of the rates of SICH (10.8% in SJH and 3.8% in TH, p=0.314) and 3-month mortality (24.3% versus 12.5%, p=0.203). CONCLUSION: The 3-month functional outcomes and complication rates of stroke thrombolysis in hospitals with or without neurologists are not significantly different. Thus non-neurologist hospitals may be able to provide thrombolysis service to AIS patients safely and effectively.

Dedifferentiated endometrioid adenocarcinoma of the uterus: A case series and review of literature.

Introduction Dedifferentiated endometrioid adenocarcinoma (DEAC) was first described in 2007. However, it has only been recognised as a distinct subtype of endometrioid adenocarcinoma in the last 1-2 years. DEAC is a more aggressive histological subtype and carries a poorer prognosis. Patients with DEAC tend to present with advanced disease compared the other endometrioid adenocarcinomas. Methodology The study is a retrospective review of patients with DEAC diagnosed in two institutions in Singapore between January 2012 and October 2017. Results 7 patients were diagnosed with DEAC. The mean age was 56.4 years. All patients presented with either abnormal uterine bleeding or post menopausal bleeding. Out of the 7 patients, one was diagnosed with Stage 2 disease, 5 were diagnosed with Stage 3 disease and 1 was diagnosed with Stage 4 disease. One patient had neoadjuvant chemotherapy, followed by surgery, and completion chemotherapy post surgery. The other 6 patients (87.5%) underwent primary debulking surgery. Out of these 6 patients, 5 patients had adjuvant chemotherapy post surgery and one patient had both adjuvant chemotherapy and radiotherapy. Lymphovascular invasion was found in 71.4% of the cases. Conclusion DEAC is a more aggressive histological subtype of endometrioid adenocarcinomas. Better awareness of this condition can lead to proper diagnosis and treatment.

Mitochondrial uncoupling reveals a novel therapeutic opportunity for p53-defective cancers.

There are considerable challenges in directly targeting the mutant p53 protein, given the large heterogeneity of p53 mutations in the clinic. An alternative approach is to exploit the altered fitness of cells imposed by loss-of-wild-type p53. Here we identify niclosamide through a HTS screen for compounds selectively killing p53-deficient cells. Niclosamide impairs the growth of p53-deficient cells and of p53 mutant patient-derived ovarian xenografts. Metabolome profiling reveals that niclosamide induces mitochondrial uncoupling, which renders mutant p53 cells susceptible to mitochondrial-dependent apoptosis through preferential accumulation of arachidonic acid (AA), and represents a first-in-class inhibitor of p53 mutant tumors. Wild-type p53 evades the cytotoxicity by promoting the transcriptional induction of two key lipid oxygenation genes, ALOX5 and ALOX12B, which catalyzes the dioxygenation and breakdown of AA. Therefore, we propose a new paradigm for targeting cancers defective in the p53 pathway, by exploiting their vulnerability to niclosamide-induced mitochondrial uncoupling.

Development of a 10 kHz high harmonic source up to 140 eV photon energy for ultrafast time-, angle-, and phase-resolved photoelectron emission spectroscopy on solid targets.

We present a newly developed high harmonic beamline for time-, angle-, and carrier-envelope phase-resolved extreme ultraviolet photoemission spectroscopy on solid targets for the investigation of ultrafast band structure dynamics in the low-fs to sub-fs time regime. The source operates at a repetition rate of 10 kHz and is driven by 5 fs few-cycle near-infrared laser pulses generating high harmonic radiation with photon energies up to 120 eV at a feasible flux. The experimental end station consists of a complementary combination of photoelectron detectors which are able to spectroscopically address electron dynamics both in real and in k-space. The versatility of the source is completed by a phase-meter which allows for tracking the carrier-envelope phase for each pulse and which is synchronized to the photoelectron detectors, thus enabling phase sensitive measurements on the one hand and the selection of single attosecond pulses for ultimate time resolution in pump-probe experiments on the other hand. We demonstrate the applicability of the source by an angle- and carrier-envelope phase-resolved photoemission measurement on a tungsten (110) surface with 95 eV extreme ultraviolet radiation.

Case report of granular cell tumor of the vulva and review of current literature.

► We present four cases of benign granular cell tumours of the vulva managed between 1998 and 2001. ► We discuss the clinical and histopathological features of this condition. ► Treatment of this condition is primarily surgical.

Florid polypoid endometriosis of the cervix with left ureteric obstruction: a mimic of cervical malignancy.

Polypoid endometriosis, in contrast to typical (non-polypoid) endometriosis, presents as masses that project from a serosal or mucosal surface or from the lining of an endometriotic cyst. Generally large, these masses can simulate a malignant tumor on imaging and at surgery. We report a case of florid polypoid endometriosis arising from the cervix with extension into the left parametrium and involving the left ureter, mimicking a locally advanced cervical malignancy on ultrasound and magnetic resonance imaging.

A hybrid mobile-based patient location tracking system for personal healthcare applications.

In the next generation of Infocommunications, mobile Internet-enabled devices and third generation mobile communication networks have become reality, location based services (LBS) are expected to be a major area of growth. Providing information, content and services through positioning technologies forms the platform for new services for users and developers, as well as creating new revenue channels for service providers. These crucial advances in location based services have opened up new opportunities in real time patient tracking for personal healthcare applications. In this paper, a hybrid mobile-based location technique using the global positioning system (GPS) and cellular mobile network infrastructure is employed to provide the location tracking capability. This function will be integrated into the patient location tracking system (PLTS) to assist caregivers or family members in locating patients such as elderly or dependents when required, especially in emergencies. The capability of this PLTS is demonstrated through a series of location detection tests conducted over different operating conditions. Although the model is at its initial stage of development, it has shown relatively good accuracy for position tracking and potential of using integrated wireless technology to enhance the existing personal healthcare communication system through location based services.

Adjuvant sequential chemotherapy and radiotherapy in uterine papillary serous carcinoma.

PURPOSE: To evaluate the efficacy and toxicity of adjuvant combination of sequential chemotherapy followed by radiotherapy in uterine papillary serous carcinoma (UPSC). METHODS AND MATERIALS: From April 1994 to June 2003, 26 patients (median age 61.7 years, range 46.9-78.4) with UPSC were treated with a platinum-based chemoradiation protocol after definitive surgery. 9 patients were assigned as stage I (35%), 4 were stage II (15%), 11 were stage III (42%), and 2 were stage IV (8%) according to the FIGO staging for gynecological cancers. All patients underwent total hysterectomy, salpingo-oophorectomy, pelvic +/- perioartic lymph nodes dissection/sampling, omentectomy, and peritoneal washing. The adjuvant chemoradiation protocol consists of 4 cycles of platinum-based chemotherapy followed by pelvic irradiation and vaginal vault brachytherapy. In selected stage I patients with no or minimal myometrial invasion, only vault brachytherapy was given after adjuvant chemotherapy. RESULTS: After a median follow-up of 28 months (range 9-113 months), 14 (54%) patients were alive and free of disease. 12 out of these 14 patients were FIGO stage I/II. 9 patients (35%) had died (8 from distant metastases). The Kaplan-Meier 2-year and 5-year survival estimates were 69.5% and 57%, respectively. Only 4 (15%) patients had pelvic recurrence. None of the patients developed local vault recurrence. The treatment was well tolerated, only 1 patient developed congestive cardiac failure from the chemotherapy and 6 patients had grade 2 peripheral neuropathy on follow-up. CONCLUSION: In our series of UPSC patients treated with adjuvant chemotherapy followed by radiotherapy, local control can be achieved in a majority of patients. Distant failure remains the major cause of mortality. Further investigations into finding a more effective systemic therapy are required if improvement in outcome for this form of uterine cancer is to be achieved.

Phagocytosis of degenerating myelin in transected feline optic nerve: an immunohistochemical study.

The phagocytic activity of neuroglial cells in adult feline degenerating optic nerve was investigated by immunocytochemistry at both light and electron microscopy levels. Degeneration was initiated by unilateral eye enucleation and the segment distal to the transection showing true Wallerian degeneration was examined. Following enucleation, twelve adult domestic cats were examined over a period of seven to 215 days. All cases showed slow clearance of myelin debris and absence of proliferating monocytes throughout the post-enucleation period. All phagocytic cells present were neuroglial cells, and many of these cells expressed oligodendroglial antigens. These findings demonstrate the persistence of an active population of oligodendrocytes that might play an additional functional role during Wallerian degeneration of feline optic nerve.

A rare case of metastatic ovarian carcinoma originating from primary intrahepatic cholangiocarcinoma. Case report.

BACKGROUND: A rare case of metastatic ovarian carcinoma arising from intrahepatic cholangiocarcinoma is reported and the literature reviewed. CASE: A 49-year-old woman presented with ascites and a left pelvic mass. Optimal debulking surgery was carried out including a segmental resection of segment 5/6 of the liver. Histopathology confirmed an intrahepatic cholangiocarcinoma metastatic to the ovaries and omentum. CONCLUSION: Distinguishing a metastatic tumor from a primary ovarian tumoris critical for appropriate management. A high index of suspicion intraoperatively and subsequent expert pathological review are essential in making the correct diagnosis.

Malignant ovarian germ cell tumors: the KK Hospital experience.

Ovarian germ cell malignancies pose a therapeutic challenge especially amongst young patients. This is a retrospective review of 49 patients treated for such malignancies at KK Women's and Children's Hospital over a 13-year period. The relative proportion of such tumors was 6.2%. Age at presentation ranged from 14 to 51 years (mean 25.4 years). Forty-nine percent of tumors were immature teratomas and 81.6% had stage I disease. All patients had surgery initially and 67.3% required postoperative adjuvant chemotherapy. The patients were followed-up for one to 145 months (mean 51.6 months). All the 87.8% of patients on follow-up are alive and disease-free. There was one recurrence. Five patients had eight successful pregnancies, with no congenital anomalies. Mean duration when menstruation was resumed and regular was 2.5 and 3.5 months, respectively. With combination chemotherapy and conservative surgery, the outlook for patients is excellent, with emphasis on preservation of ovarian function and fertility.

Identification of molecular markers for the early detection of human squamous cell carcinoma of the uterine cervix.

To identify novel cellular genes that could potentially act as predictive molecular markers for human cervical cancer, we employed RT--PCR differential display, reverse Northern and Northern blot analysis to compare the gene expression profiles between squamous cell carcinoma biopsies and adjacent histo-pathological normal epithelium tissues. Twenty-eight cDNA clones were isolated that were demonstrated to be consistently over-expressed in squamous cell cervical cancer biopsies of FIGO stages 1B to 3B. Most importantly, it was observed that, in addition to their over-expression in cancer lesions, some of these genes are upregulated in the presumably histo-pathological normal adjacent tissues. Of particular interest is clone G30CC that has been identified to be the gene that encodes S12 ribosomal protein. When employed for RNA--RNA in situ hybridization experiments, expression of G30CC could be detected in the immature basal epithelial cells of histo-pathological normal tissues collected from cervical cancer patients of early FIGO stages. In comparison, the expression of G30CC was not detected in cervical tissues collected from patients admitted for surgery of non-malignant conditions. These results allow the distinct possibility of employing the ribosomal protein S12 gene as an early molecular diagnostic identifier for the screening of human cervical cancer and a potential target employed for cancer gene therapy trials.

Identification and characterization of genes involved in the carcinogenesis of human squamous cell cervical carcinoma.

We utilized RT-PCR differential display and cDNA microarrays to identify cellular genes involved in the multi-step carcinogenesis of squamous cell cervical carcinoma. Thirty-eight cervical cancer patients in various stages of the disease and 5 non-cervical cancer patients were studied. Twenty-five cDNA clones were identified and these were subsequently demonstrated to be consistently over-expressed in squamous cell cervical carcinoma biopsies of various FIGO stages. To further evaluate the possible role that these genes may play in the progression of disease, we performed Northern blot analysis and RNA-RNA in situ hybridization studies using cervical cancer biopsies of various FIGO stages. Of particular interest are the 2 clones G32C4B and G30CC that have been identified to be the NADH dehydrogenase 4 gene and the gene that encodes ribosomal protein S12 respectively when compared to sequences available in the GenBank database. Increased expression of these 2 genes were detected in the matched normal tissues collected together with the late FIGO stages of cervical cancer biopsies. In comparison, upregulation of these 2 genes was not detected in cervical squamous epithelium collected from patients admitted for surgery for non-malignant conditions, suggesting that expression of these 2 genes may have altered in the adjacent histopathologically "normal" cervical squamous epithelial tissue from cervical cancer patients. The ribosomal protein S12 and the NADH dehydrogenase 4 genes may therefore be potentially useful as early pre-transformation diagnostic markers for human cervical cancer.

Implantation of a nerve ending into a vein.

Neuromas can be painful and physically and psychologically disabling. Among the many methods of treatment available, translocation away from noxious stimuli, such as implantation in muscle or bone, has been used. Veins are easily available and accessible to nerves. The outcome of a nerve ending implanted into a vein and the effects of the implanted nerve on the vein have not been studied. This study evaluated neuroma prevention with a new technique that involves implanting a nerve ending into a vein. The medial branches of the right femoral nerve of 20 rats were transected at midthigh level. The distal segments were excised. The proximal segments were implanted into the femoral vein. The epineurium was sutured to the tunica adventitia using interrupted 10-0 Ethilon sutures. The left side served as controls where the proximal nerve stumps were left lying in their beds. The animals were sacrificed 12 weeks after the operation. Histologic analysis of 12 controls showed neuromas. Twelve implanted nerves showed neuromas that were smaller than those of the controls. The difference was statistically significant. The regenerated nerve fibers were found within the adventitia and muscular wall of the vein. There was no extension of nerve tissue into the vessel lumen and no thrombosis of the vein. Electron microscopic study on the other eight rats showed abnormal large myelinated fibers in the controls and in the implanted nerves. The fibers in the implanted group were degenerated.

Morphology and DNA content analysis in the evaluation of first trimester placentas for partial hydatidiform mole (PHM).

Partial hydatidiform moles (PHM) have defined villous abnormalities and are usually triploid. Their diagnosis often can be made by morphology alone, without confirmation of ploidy, but considerable interobserver variability exists. Other genetic abnormalities such as trisomy can result in placentas with abnormal villous morphology (AVM) similar to that seen in PHMs, leading to diagnostic confusion. Twenty-three cases originally diagnosed as either PHM or AVM were independently reviewed by 3 pathologists. The consensus diagnosis was PHM in 14 cases and AVM in 9. Cases with AVM showed insufficient features for an unequivocal diagnosis of PHM. DNA content was determined on paraffin-embedded tissue by fluorescence in situ hybridization (fsSH) using a chromosome 1 centromeric probe and by image cytometry (IC). Thirteen of 14 cases (93%) classified as PHM were triploid by both FISH and IC. Seven cases of AVM were diploid by FISH and IC, and 1 was triploid by FISH and IC. One of the 9 cases of AVM was determined to be trisomy 18 by karyotyping. This good correlation of consensus diagnosis with ploidy data was much greater than that obtained based on original diagnoses. Comparative genomic hybridization performed on 6 cases of AVM showed gain of chromosome 21 in 1 case and loss of X in another. PHMs displayed at least 3 of the following histologic features: 2 discrete populations of villi, circumferential mild trophoblastic hyperplasia, trophoblastic inclusions, prominent scalloping of villi, cistern formation. Nontriploid AVMs displayed at most 2 of the diagnostic features of PHM. Placentas with genetic abnormalities other than triploidy can display morphologic changes suggestive of PHM and can be misinterpreted as such by routine light microscopy. Stringent application of morphologic criteria improves the correlation of the diagnosis of PHM with triploidy.

End-to-side anastomosis of transected nerves to prevent neuroma formation.

Neuroma can be painful and physically and psychologically disabling. Among the many methods of treatment available, one of the more successful is centrocentral nerve union with an autologous graft. However, it cannot be used in small nerves that lack two fascicles. This study evaluated neuroma prevention in an end-to-side anastomosis, a new technique applicable to all nerves. The lateral branch of the right sciatic nerve in 20 rats was transected at the midthigh level. The proximal segment was looped back to the main nerve and an end-to-side epineural anastomosis was performed. The lateral branch of the left sciatic nerve was transected to serve as a control, and the proximal nerve stump was closed by interrupted epineural sutures. The animals were sacrificed 12 weeks after the operation. Histologic analysis of specimens from the 12 controls showed neuroma formation. Specimens from 12 side-to-end anastomoses contained regenerated nerve tissues and formed smaller masses compared with that of the controls. The regenerated tissues at the anastomoses were orientated more orderly than were tissues from the controls in 75% of cases. The differences were statistically significant. Electron microscopic study on specimens from the remaining eight controls showed the presence of abundant large abnormal myelinated fibers (10-15 microns) with thick irregular myelin sheaths scattered among smaller myelinated fibers (2-10 microns) that had thin myelin sheaths. In the remaining eight end-to-side anastomoses, large abnormal myelinated fibers were absent. The myelinated fibers were 2 to 10 microns in diameters and had a normal appearance with thin myelin sheaths. End-to-side anastomosis formed a smaller mass of regenerated nerve tissues. Ultrastructurally they were formed better and orientated more orderly resembling normal nerve.

Prognostic factors in endometrial carcinoma.

Endometrial carcinoma is the third most common carcinoma of the female genital tract in Singapore. Although most endometrial carcinomas are detected while still at low stage, there is still a significant mortality from the disease. It is desirable that patients at high risk of relapse are identified early for consideration for additional treatment. Some information required for management can be obtained from clinical history, gross examination of the uterus and routine microscopy. These are age, stage of disease, histologic type of carcinoma (serous carcinoma and clear cell carcinomas are poor prognostic types), grade and lympho-vascular space involvement. Of less certain significance are tumour size, location and status of peritoneal cytology. Other factors currently being investigated are oestrogen and progesterone receptor status, p53 status, flow cytometric analysis for ploidy and S-phase fraction, and oncogenes such as HER-2/neu (c erbB-2). Although some of these show independent prognostic significance on multivariate analysis, it is still uncertain if the information adds significantly to the information available from routine evaluation.

Mechanism of pellet coat rupture and its effect on drug release.

In the formation of a coated controlled release preparation with functional coat layers, hydroxypropyl-methylcellulose was used to form a diffusion layer which swelled immediately upon wetting. Eudragit RS30D was used to form the outer retention layer. The rupture of pellet coat occurred when the Eudragit RS30D was unable to withstand the expansion in volume due to the influx of water and swelling of the hydroxypropylmethylcellulose diffusion layer. The sucrose core was able to contribute an osmotic effect. The hydrostatic pressure built up within the pellet can cause the pellet coat to rupture. Sodium chloride deposited in the diffusion coat was able to delay the bursting of the pellet coat. This was due to the competition for the imbibed water between sodium chloride and hydroxypropylmethylcellulose. The rupture of the pellet coat did not result in a total failure of the controlled drug delivery mechanism. Similar drug release rates were obtained irrespective whether there was a puncture in the pellet coat or not. Pressure built-up in the region away from the puncture pushed the core material towards the point of puncture and sealed the puncture point. In addition, the swelling of polymer around the point of rupture ensured continuity in the drug diffusion barrier.

Uterine leiomyosarcoma--a Singapore experience.

Uterine leiomyosarcoma is an aggressive tumour. In our retrospective series of 27 patients, there were 25 with nonmyxoid high-grade leiomyosarcoma of the uterus. The stage distribution was Stage 1, 16; Stage 3, 5 and Stage 4, 4. In the patients with Stage 1 disease, 3 of the 8 patients who received adjuvant chemotherapy subsequently developed recurrent disease. In contrast, 6 of the 8 patients who did not receive adjuvant chemotherapy subsequently developed recurrent disease; 2 of the patients in the latter group also received adjuvant radiotherapy. Six of the 9 women with recurrences were distant 'failures' alone, 2 were both distant and pelvic 'failures' and 1 was pelvic 'failure' alone. All the patients with advanced-stage disease eventually succumbed to the disease despite the therapies given. This study is small and retrospective but it suggests that there might be a role for adjuvant chemotherapy in the management of the early stage of this disease.