Fungus isolated from dermatomycoses: a 9-month prospective study at Hospital Melaka.

INTRODUCTION: Dermatomycoses are common superficial cutaneous fungal infections which affect the skin, nails and human hairs. It affects 20 to 25% of the world population. The causative fungus varies geographically across the globe. Study on dermatomycoses is crucial to identify the aetiological fungus involved locally. The study aimed to determine the causative fungus of superficial fungal infections of the skin, nail and hair in patients presented to Hospital Melaka. METHODS: This was a prospective study conducted from 15th January 2022 till 15th October 2022 at Dermatology Clinic, Hospital Melaka. Subjects with clinical dermatomycoses were included in this study. The samples were collected from skin, nails and hairs clinically affected by tinea corporis/cruris/pedis, onychomycosis and tinea capitis respectively. A potassium hydroxide (KOH) study was performed on the sample in which the fungal hyphae/yeast positive subjects were sent for fungal culture and fungal PCR test. RESULT: A total of 222 clinical samples from skin, nails and hairs with a clinical suspicion of dermatomycoses yielded fungal hyphae/yeast in KOH. Majority of the samples were collected from skin (138, 62.2%), followed by nails (65, 29.3%) and hairs (19, 8.6%). Male to female ratio was 1.18: 1. The age ranged from 2 to 87 with the median of 55.5-yearsold. Out of 222 samples, 150 (67.6%) were fungal culture positive. From fungal culture positive samples, 87 samples were from tinea corporis, 50 samples were from onychomycoses and 13 samples were from tinea capitis. Trichophyton rubrum (39, 44.8%) was the commonest dermatophyte isolated in tinea corporis/cruris/pedis. Nondermatophyte moulds (NDM, 35, 70%) were the main fungi isolated in onychomycosis. Microsporum canis (7/53.8%) was the principal causative fungus among patients with tinea capitis. Among 150 fungal culture positive samples, 76 were fungal PCR positive. Only 38 samples consistently isolated same fungal species in both fungal culture and PCR test. CONCLUSION: Majority of tinea corporis and tinea capitis fungal culture isolated dermatophytes, especially Trichophyton rubrum and Microsporum canis, respectively. Non-dermatophyte moulds were mainly isolated in onychomycosis.

Retrospective study of pelvic and para-aortic lymph nodes positivity in stage 1A to 2A cervical cancer patients.

BACKGROUND: The significance of pelvic and para-aortic lymph nodes (retroperitoneal lymph nodes) metastasis in the five-year survival of early stage cervical cancer (CC) patients is well established. The previous International Federation of Gynaecology and Obstetrics (FIGO) 2009 staging of CC was clinical and excluded advanced radiological assessment in assigning a stage. However, with the current FIGO 2018 staging, advanced radiological assessment and pathological findings were allowed to assign a stage which would alter the subsequent management. This pilot study aims to obtain local data on the correlation between radiological retroperitoneal lymph node positivity and histological lymph node positivity in early stage CC (stage 1A2 to 2A1) and seeks to correlate independent prognostic factors for recurrence to histological lymph node positivity. MATERIALS AND METHODS: In this retrospective cross-sectional analysis, clinical data, including clinical staging, Computed Tomography (CT) scan findings and histopathological results were collected and analysed in the Department of Obstetrics and Gynaecology, Hospital Ampang, Ministry of Health Malaysia. RESULTS: A total of 31 patients had surgery for CC from 1st August 2018 till 31st August 2020. Radical hysterectomy was done on 23 of them as primary treatment for early stage cervical cancer. Both pelvic and para-aortic lymph node dissection was done in 6 patients while 17 patients had only pelvic lymph node dissection. All patients had thoracoabdomino- pelvic CT scans done preoperatively. Among the 82.6% patients with no enlarged pelvic lymph nodes on CT scan, all were confirmed by histology to be negative of malignancy. In the remainder 17.4% of patients with enlarged pelvic nodes on CT scan, three quarters had histology positive pelvic nodes for malignancy (p=0.002). Among patients with no enlarged para-aortic lymph nodes on CT scan, 83.3% had histologically negative para-aortic nodes. Among patients with clinical tumour diameter 2- 3.9 cm, 14.3% had positive pelvic nodes while a quarter of patients with clinical tumour diameter ≥ 4cm had histological positive pelvic nodes. None of the patients with tumour diameter < 2cm had positive pelvic nodes (p=0.993). Positive pelvic lymph nodes involvement was present in 37.5% of those with positive lymphovascular space invasion (LVSI). All patients with negative LVSI had no histological positive pelvic nodes (p=0.103). Among patients with tumour invasion involving the inner third of the stroma, 16.7% had histological positive pelvic nodes while 18.2% with outer third stromal invasion had positive nodes (p=0.977). None of the patients had histologically positive para-aortic lymph nodes with negative pelvic lymph nodes. Among patients with clinical stage 1B2, 20% would have been upstaged to stage 3C based on radiological imaging and final histology confirmation. CONCLUSION: This study shows that in early stage CC, there is a statistically significant correlation between CT scan findings of enlarged pelvic lymph nodes and histological positive pelvic lymph nodes.

Acute renal failure in the same hospital ten years apart.

A three month prospective study was carried out in 1994 (8/3/94 - 7/6/94) and late 2004/early 2005 (24/11/2004 - 15/2/2005) among patients with acute renal failure (ARF) (serum creatinine > 0.200 mmol/1). Incidence of ARF had increased from 0.48% (78/16,418) to 1.1% (211/18,697) of admissions between 1994 and 2004. Two thirds of patients were male. Mean age was 57.7 +/- 20.1 years in 1994 and 55.6 +/- 17.8 years in 2004. No difference was noted in causative factors, rate of oliguric ARF (about 10%) and mean peak urea and creatinine. The cause was pre-renal failure in 43.6% in 1994 and 53.5% in 2004. The second commonest cause was sepsis with 41% in 1994 and 37.9% in 2004. One in six patients needed dialysis and peritoneal dialysis was the main dialysis modality (69.2% and 74.3%). Mortality was 56.4% in 1994 and 44.5% in 2004. A quarter of deaths occurred within two days of admission due to severe underlying illness. Mortality among non-oliguric patients decreased from 52.9% in 1994 to 37.0% in 2004 (p = 0.04); for patients from intensive care units it was 78.3% in 1994 and 68.5% in 2004.

Synthesis, in vitro pharmacologic characterization, and preclinical evaluation of N-[2-(1'-piperidinyl)ethyl]-3-[125I]iodo-4-methoxybenzamide (P[125I]MBA) for imaging breast cancer.

The goal of this study was to investigate the potential use of a radioiodinated benzamide, N-[2-(1'-piperidinyl)ethyl]-3-iodo[125I]-4-methoxybenzamide (P[125I]MBA), a sigma receptor binding radioligand for imaging breast cancer. The chemical and radiochemical syntheses of PIMBA are described. The pharmacological evaluation of PIMBA was carried out for sigma-1 and sigma-2 receptor sites. The in vivo pharmacokinetics of the radioiodinated benzamide were determined in rats and comparison of P[125I]MBA with Tc-99m sestamibi were made in a rat mammary tumor model. Sigma-1 affinity (Ki) for PIMBA in guinea pig brain membranes using [3H](+)pentazocine was found to be 11.82 +/- 0.68 nM, whereas sigma-2 affinity in rat liver using [3H]DTG (1,3-o-di-tolylguanidine) was 206 +/- 11 nM. Sites in guinea pig brain membranes labeled by P[125I]MBA showed high affinity for haloperidol, (+)-pentazocine, BD1008, and PIMBA (Ki = 4.87 +/- 1.49, 8.81 +/- 1.97, 0.057 +/- 0.005, 46.9 +/- 1.8 nM, respectively). Competition binding studies were carried out in human ductal breast carcinoma cells (T47D). A dose-dependent inhibition of specific binding was observed with several sigma ligands. Ki values for the inhibition of P[125I]MBA binding in T47D cells for haloperidol, N-[2-(1'-piperidinyl)]ethyl]4-iodobenzamide (IPAB), N-(N-benzylpiperidin-4-yl)-4-iodobenzamide (4-IBP), and PIMBA were found to be 1.30 +/- 0.07, 13 +/- 1.5, 5.19 +/- 2.3, 1.06 +/- 0.5 nM, respectively. The in vitro binding data in guinea pig brain membranes and breast cancer cells confirmed binding to sigma sites. The saturation binding of P[125I]MBA in T47D cells as studied by Scatchard analysis showed saturable binding, with a Kd = 94 +/- 7 nM and a Bmax = 2035 +/- 305 fmol/mg of proteins. Biodistribution studies in Sprague-Dawley rats showed a rapid clearance of P[125I]MBA from the normal organs. The potential of PIMBA in imaging breast cancer was evaluated in Lewis rats bearing syngeneic RMT breast cancers, a cancer that closely mimics human breast cancer histology. At 1 h postinjection, tumor uptake for P[125I]MBA and Tc-99m sestamibi were found to be 0.35 +/- 0.01 and 0.32 +/- 0.01% injected dose/organ (%ID/g), respectively. The %ID/g for liver, kidneys, and heart were 2, 11, and 20 times lower, respectively, for P[125I]MBA as compared with Tc-sestamibi. Slightly higher uptake of P[125I]MBA in tumors (than Tc-sestamibi) and a low nontarget organ uptake warrants further studies of this and other sigma receptor ligands for their use as breast cancer imaging agents.

Substituted halogenated arylsulfonamides: a new class of sigma receptor binding tumor imaging agents.

The discovery of a series of novel halogenated arylsulfonamides (HAS) as new sigma receptor binding tumor imaging agents is described. Several substituted halogenated sulfonamides have been prepared and characterized. Target compounds were examined for their affinity for sigma1 and sigma2 receptor subtypes using guinea pig brain membranes and rat liver membranes, respectively. A number of substituted halogenated sulfonamides displayed subnanomolar affinities for sigma1 sites and low nanomolar affinities for sigma2 subtype receptors. A limited structure-activity relationship study of this chemical series is discussed. The radioiodination (I-125) of one congener member (4-[125I]iodo-N-[2-(1'-piperidinyl)ethyl]benzenesulfonamide, 4-[125I]IPBS) was accomplished in high yields. The in vitro competition binding studies of 4-[125I]IPBS in guinea pig brain membranes with sigma receptor binding ligands confirmed its sigma pharmacology. The rank order of potency was BD1008 (N-[2-(3, 4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine) > 4-IPBS > haloperidol > (+)-pentazocine > DTG (1, 3-di-o-tolylguanidine) > (-)-pentazocine. The inhibition constants (IC50) were 0.70, 1.46, 6.28, 10.4, 87.2, and 152 nM, respectively, and are consistent with labeling of sigma1 receptors. The tumor imaging potential of 4-[125I]IPBS was studied in C57 black mice bearing B16 melanoma xenograft. A high tumor uptake of 4-[125I]IPBS was observed (7.40% ID/g) at 1 h postinjection. The wash out of activity from the tumor was slow at 6 h postinjection (7.22% ID/g). The tumor also had the highest amount of radioactivity (1.54% ID/g) at 24 h postinjection. These results demonstrate that radiohalogenated benzenesulfonamides could be a potentially useful class of compounds in nuclear oncologic scintigraphy.

99mTc-labeled sigma-receptor-binding complex: synthesis, characterization, and specific binding to human ductal breast carcinoma (T47D) cells.

sigma-Receptors have recently been shown to be expressed in a variety of human tumor cells. In an attempt to prepare 99mTc chelates that would bind to sigma-receptors and be useful for imaging sigma-receptor-positive tumors, we have synthesized and characterized a bisaminothiol (BAT) chelate appended with a sigma-receptor pharmacophore. The synthesis of target ligand VII was accomplished in three steps starting from bicyclic imidazolidino[1,2-d]dithiazapine. The labeling of the BAT ligand with 99mTc was carried out in high yields (> 80%) using stannous tartarate as a reducing agent, resulting in the target sigma-receptor-binding chelate [99mTc]BAT-EN6, III. Similarly, 99gTc chelate with ligand VII was prepared from ammonium pertechnetate by reduction with stannous tartarate. 99nTc-radiolabeled chelate was purified by reversed phase HPLC, and cell binding with human breast ductal carcinoma (T47D) was performed. A high degree of specific binding (90-97%) was obtained when sigma-receptor ligands such as halogenated phenylethylenediamines were used to determine nonspecific binding. A modest affinity dose-dependent inhibition of binding was found with BD1008, I, and 4-IPEMP, II (IC50 = 47 +/- 2 and 59 +/- 5 nM, respectively), known sigma-ligands. No specific binding was found with [99mTc]BAT, VIII [without appended sigma-pharmacophore (N-alkyl-substituted ethylenediamine)], showing that biological activity resulted from the pendent pharmacophore. 99gTc complex was found to be a potent inhibitor (Ki = 42.7 +/- 8.5 nM) of [3H]DTG binding in guinea pig brain membranes. Scatchard analysis of [99mTc]BAT-EN6 (spiked with [99gTc]BAT-EN6) binding in T47D breast cancer cells showed a saturable binding, with a Kd of 43.5 +/- 14.7 nM and a Bmax of 3121 +/- 130 fmol/(mg of protein). A biodistribution study of [99mTc]BAT-EN6 chelates in Sprague Dawley rats showed hepatic clearance, as expected. A blocking study at 4 h postinjection using 2 mumol of BD1008 with [99mTc]BAT-EN6 showed a significant decrease of radiopharmaceutical in liver (15.32 vs 22.31% ID/organ) and kidney (1.01 vs 2.21% ID/ organ), organs known to possess high concentrations of sigma-receptors. These results imply that [99mTc]BAT-EN6 binds with high affinity to sigma-receptors expressed in human breast tumor cells, and it may be useful for imaging breast cancer.

Synthesis of a 2,3-dideoxy-2,3-difluorofuranose with the D-lyxo configuration. An intramolecular rearrangement of methyl 5-O-benzoyl-2,3-dideoxy-2,3-difluoro-D-lyxofuranoside observed during the attempted synthesis of 1-(2,3-dideoxy-2,3-difluoro-beta-D-lyxofuranosyl)thymine.

A new sugar, methyl 5-O-benzoyl-2,3-dideoxy-2,3-difluoro-D-lyxofuranoside (8), which features fluorine substituents on adjacent carbon positions above the plane of the tetrahydrofuran ring, was synthesized from 1,2: 5,6-di-O-isopropylidine-alpha-D-allofuranose in seven steps and 22% overall yield. During the synthesis, introduction of the second fluorine atom required conditions more forceful than those normally used with diethylaminosulfur trifluoride (DAST). An attempt to use 8 in the synthesis of the all-cis nucleoside, 1-(2,3-dideoxy-2,3-difluoro-beta-D-lyxofuranosyl)thymine, failed to give the desired product, providing instead 1-(3-deoxy-3-fluoro-2-O-methyl-beta-D-xylofuranosyl)thymine (11), the structure of which was confirmed by an independent synthesis. Formation of the rearranged product occurred with the concurrent loss of fluorine and retention of the methoxy group which was transposed from the anomeric to the 2'-position. The present work highlights the reactive nature of this novel dideoxydifluoro sugar precursor.

Synthesis and biological activity of novel carbocyclic nucleosides.

The syntheses of several novel carbocyclic nucleosides which incorporate the cyclopentene moiety of neplanocin A will be presented. These include modified pyrimidine derivatives of the very potent antitumor agent cyclopentenyl cytosine and carbocyclic analogues of the ketohexose nucleosides psicofuranine and psicofuranosyl cytosine.