Clinico-pathological characteristics and outcome of upper urinary tract urothelial carcinoma presenting to a tertiary care urology unit in Sri Lanka

Introduction: Upper urinary tract urothelial cancers account for 5% of urothelial tumours. In the West, the majority affect the pelvicalyceal system, with pyelocalyceal to ureteric ratio of 3:1. This study aims to describe the clinico-pathological features and outcome of upper urinary tract urothelial cancer treated surgically in a tertiary care unit in Sri Lanka. Methods: A retrospective analysis of all patients who underwent nephroureterectomy for upper urinary tract urothelial cancer at the Urology Unit at National Hospital of Sri Lanka between January1997 and December 2016 was carried out. Results: There were 43 patients. Male: female=1.87. Median age was 65 years (range:42-83). Macroscopic haematuria was the commonest presentation (n=29; 67.4%). Median duration of symptoms was 3 months (range 0.5-6). In the majority (n=20;46.5%) the tumour was confined to the ureter. Thirty-three (75.6%) were papillary tumours. Twenty-one had non-muscle invasive tumours (pTa: n=6(14%), pT1: n=15(34.9%) and others had invasive cancers (pT2: n=11(25.6%), pT3: n=7(16.3%) and pT4: n=4(9.3%)). Majority were low grade tumours (n=23;53.5%). Twelve (27.9%) had preceding urothelial bladder cancer. Nineteen (44.2%) were lost to follow up after surgery. Median follow up duration of the rest was 40 months (range:4-224months). Of them, 9(20.9%) developed metachronous bladder tumours. Nine had recurrence free survival of ≥5years and 15 had overall survival of ≥5 years. Of them, 4 patients survived ≥10 years. Older age (p=0.015) and presence of necrosis(p=0.05) were the only clinico-pathological parameters predictive of tumour recurrence. Conclusions: A relatively higher number females and high number of ureteric tumours were noted compared to similar studies from Asia.

Insulin resistance in a cohort of 5-15 year old children in urban Sri Lanka.

BACKGROUND: South Asian populations develop insulin resistance from a young age. Poor intrauterine growth and increased rates of post natal growth predisposes to develop insulin resistance later in life. This study identifies insulin resistance and relation to birth weight among a group of 5-15 year old children of urban Sri Lanka. METHODS: A cross sectional descriptive study, using two-stage probability proportionate cluster sampling technique. After a 12 h overnight fast, blood was drawn for fasting blood glucose and insulin. OGTT was performed with 2 h random blood glucose. Basic anthropometry was assessed and insulin resistance measured by HOMA-IR. RESULTS: Of 309 children (boys 133) 13 (4.2%) were obese and 35 (11.3%) were overweight. Eight had impaired glucose homeostasis but no diabetes mellitus. The mean (SD) fasting insulin was 37.8 (37.9) and 32.5 (40.4) pmol/L in girls and boys respectively. 2 h post glucose insulin in girls and boys were 258 (324) and 152 (168) pmol/L respectively. The mean HOMA-IR was 1.1 (1.1) and 0.94 (1.2) for girls and boys respectively. The 4th quartile value of HOMA-IR for the whole population was 1.2 (95% CI 1.1, 1.3) and in obese children 2.26 (95% CI 2.0, 3.1). Fasting and 2 h insulin and HOMA-IR was not affected by birth weight but showed significant difference when compared across present BMI tertile with significantly high values in the highest tertile. CONCLUSION: Although many children were able to control glucose within normal limits, evidence of early development of insulin resistance was seen. Children born small but became obese, had the highest risk of developing insulin resistance.

Validity of newly-developed BMI and waist cut-off values for Sri Lankan children.

BACKGROUND: Excess body fat leads to obesity-related morbidity and population/ethnicity-specific cut-off values of anthropometric measures are useful for better diagnosis. This study assesses the suitability of newly-developed Sri Lankan anthropometric cut-off values in the diagnosis of obesity in Sri Lankan children. METHODS: A cross-sectional study was conducted at University of Colombo, Sri Lanka involving 5-15 year old children. Height, weight, waist (WC), and hip (HC) circumferences were measured. Total body fat (FM) was measured using whole body BIA. WHR and WHtR were calculated. Validity of anthropometric measures in detecting childhood obesity (Sri Lankan BMI/WC; IOTF, WHO, British and CDC BMI and British WC cut-off values) were evaluated. RESULTS: Nine hundred and twenty children were assessed. FM showed significant associations with BMI (r = 0.92, p < 0.001), WC (r = 0.90, p < 0.001) and HC (r = 0.85, p < 0.001), but poor association with WHR (r = 0.17, p < 0.001). However, WHtR had a high association with FM (r = 0.75, p < 0.001) and %FM (r = 0.78, p < 0.001). Based on %FM cut-offs, 85 (22.8%) girls and 101 (18.5%) boys were obese. All international anthropometric cut-off values under-estimated obesity. Sri Lankan WC and BMI cut-off values over-estimated obesity. International BMI based cut-off values had high specificity (>99%) but a low sensitivity (∼12-33%), while Sri Lankan BMI cut-off values had high sensitivity (>93.1) but low specificity (>79.7). CONCLUSIONS: Internationally available BMI cut-off values are poor in diagnosing obesity in Sri Lankan children. Newly developed Sri Lankan BMI cut-off values for children improved the diagnosis. WC can be used successfully as an alternative diagnostic tool of obesity.

Distribution of obesity-related metabolic markers among 5-15 year old children from an urban area of Sri Lanka.

BACKGROUND: Obesity-associated metabolic consequences are commonly seen among young South Asians. OBJECTIVE: To assess the nutritional status, prevalence of metabolic derangements and to identify the validity of different obesity diagnostic criteria in the detection of metabolic derangements among 5-15 year old school children in the Colombo district of Sri Lanka. MATERIALS AND PROCEDURES: After a 12-hour overnight fast, blood was drawn for glucose, lipid profile and alanine amino transferase (ALT) enzyme. Oral glucose tolerance test (OGTT) was done with blood taken for random blood sugar 2 hours after glucose load. Height, weight, waist circumference (WC) and blood pressure were measured. RESULTS: Nine hundred and twenty children were studied (boys, n = 547). Thirty-two (3.5%) were obese according to IOTF classification. Five (0.5%) and 57 (6.2%) children had systolic and diastolic hypertension. Twelve (1.3%) and three (0.3%) had impaired fasting glucose and 2-hour OGTT, respectively. One hundred and thirty-nine (15.1%) had hypercholesterolemia and 36 (3.9%) hypertriglyceridaemia. Two hundred and fifteen (23.3%) had low HDL. Fifteen (1.6%) had metabolic syndrome according to IDF definition. Two hundred and eighty-three (30.7%) had one metabolic derangement; 95 (10.3%) had two metabolic derangements; and 16 (1.7%) had three or more metabolic derangements. Sri Lankan BMI and WC obesity cut-offs had a higher sensitivity in detecting metabolic abnormalities than international cut-offs. CONCLUSION: Metabolic derangements are prevalent in children who were detected to be non-obese by anthropometric measures, and clinicians should actively look and correct them. New research is needed to study the long-term effects on health.

Evidence that renal arginine transport is impaired in spontaneously hypertensive rats.

Low renal nitric oxide (NO) bioavailability contributes to the development and maintenance of chronic hypertension. We investigated whether impaired l-arginine transport contributes to low renal NO bioavailability in hypertension. Responses of renal medullary perfusion and NO concentration to renal arterial infusions of the l-arginine transport inhibitor l-lysine (10 µmol·kg(-1)·min(-1); 30 min) and subsequent superimposition of l-arginine (100 µmol·kg(-1)·min(-1); 30 min), the NO synthase inhibitor N(G)-nitro-l-arginine (2.4 mg/kg; iv bolus), and the NO donor sodium nitroprusside (0.24 µg·kg(-1)·min(-1)) were examined in Sprague-Dawley rats (SD) and spontaneously hypertensive rats (SHR). Renal medullary perfusion and NO concentration were measured by laser-Doppler flowmetry and polarographically, respectively, 5.5 mm below the kidney surface. Renal medullary NO concentration was less in SHR (53 ± 3 nM) compared with SD rats (108 ± 12 nM; P = 0.004). l-Lysine tended to reduce medullary perfusion (-15 ± 7%; P = 0.07) and reduced medullary NO concentration (-9 ± 3%; P = 0.03) while subsequent superimposition of l-arginine reversed these effects of l-lysine in SD rats. In SHR, l-lysine and subsequent superimposition of l-arginine did not significantly alter medullary perfusion or NO concentration. Collectively, these data suggest that renal l-arginine transport is impaired in SHR. Renal l-[(3)H]arginine transport was less in SHR compared with SD rats (P = 0.01). Accordingly, we conclude that impaired arginine transport contributes to low renal NO bioavailability observed in the SHR kidney.

In vitro neurotoxic and myotoxic effects of the venom from the black whip snake (Demansia papuensis).

1. Black whip snakes belong to the family elapidae and are found throughout the northern coastal region of Australia. The black whip snake (Demansia papuensis) is considered to be potentially dangerous due to its size and phylogenetic distinctiveness. Previous liquid chromatography-mass spectrometry analysis of D. papuensis venom indicated a number of components within the molecular mass ranges compatible with neurotoxins. For the first time, this study examines the in vitro neurotoxic and myotoxic effects of the venom from D. papuensis. 2. Venom (10 microg/mL) caused significant inhibition of twitches elicited by stimulation (0.2 ms, 0.1 Hz, supramaximal V) of motor nerves in the chick biventer cervicis nerve-muscle preparation. This neurotoxic effect, which was postsynaptic in origin, was weak in comparison to that of most other Australian elapids. Prior addition (10 min) of polyvalent (PSAV) or tiger snake (TSAV) antivenom (5 units/mL) prevented venom-induced twitch inhibition. Addition of PSAV (5 units/mL) at t(50) failed to reverse the inhibitory effect but prevented further inhibition of nerve-mediated twitches. 3. The venom (20-50 microg/mL) is also myotoxic as indicated by a slowly developing contracture and inhibition of twitches elicited by direct stimulation (2 ms, 0.1 Hz, supramaximal V, in the presence of tubocurarine 10 micromol/L) of the chick biventer muscle. This activity was confirmed by histological examination of the muscle. 4. Fractionation and characterization of venom components is required to further investigate the reasons for the weak neurotoxic activity of D. papuensis venom.

Presynaptic neuromuscular activity of venom from the brown-headed snake (Glyphodon tristis).

The brown-headed snake (Glyphodon tristis) inhabits the forest regions of Papua New Guinea, Torres Strait Islands, and far northern Queensland, Australia. Although bites by Glyphodon dunmalli have been reported, G. tristis was regarded as innocuous until 1989 when a healthy 20 year old man was bitten (Sutherland, S.K., Tibballs, J., 2001. Australian Animal Toxins, the Creatures, their Toxins and Care of the Poisoned Patient. University Press, Oxford). Treatment of envenomation by this species is empirical with no specific antivenom available. While no published studies on the venom of G. tristis are available, unpublished studies suggest neurotoxicity as being the main symptom of envenomation. In this study, the in vitro effects of G. tristis venom were examined using the chick biventer cervicis nerve muscle (CBCNM) preparation. Venom (10 microg/ml) inhibited indirect (0.2 ms, 0.1 Hz, supramaximal V) twitches of the CBCNM. This inhibition appeared to be presynaptic in origin as evidenced by the lack of effect of venom on responses to exogenous acetylcholine (1 mM), carbachol (20 microM) and KCl (40 mM) in the non-stimulated CBCNM. Prior addition (10 min) of polyvalent snake antivenom (5 U/ml; CSL Ltd) attenuated twitch inhibition. The venom (10-50 microg/ml) also appears to be myotoxic as indicated by a slowly developing contracture and inhibition of direct (2 ms, 0.1 Hz, supramaximal V, in the presence of tubocurarine 10 microM) twitches. Myotoxicity was confirmed by subsequent histological examination of tissues. This myotoxicity was prevented by the prior addition of polyvalent snake antivenom (30 U/ml). The phospholipase A inhibitor 4-BPB (1.8 mM) significantly attenuated the inhibition of indirect and direct twitches of the CBCNM preparation, indicating the involvement of a PLA2 component in the toxic action of the venom.

Cardiovascular, haematological and neurological effects of the venom of the Papua New Guinean small-eyed snake (Micropechis ikaheka) and their neutralisation with CSL polyvalent and black snake antivenoms.

Cardiovascular and haematological effects of venom of the small-eyed Snake (Micropechis ikaheka) were examined in ventilated anaesthetised piglets. Neurotoxic effects were examined in chick biventer cervicis nerve-muscle preparations. Immunoreactivity of venom was tested against the monovalent antivenom components in a CSL Ltd Venom Detection Kit. Neutralisation was tested in vivo and in vitro with CSL Ltd polyvalent snake and Black Snake (Pseudechis australis) antivenoms. Venom in 0.1% bovine serum albumin in saline was infused into piglets in doses 1-2000 microg/kg. Pulmonary hypertension (P= 0.0007) and depression of cardiac output (P= 0.002) were observed up to 3 h after 150-160 microg/kg. The concentration of plasma free-haemoglobin increased more than 50-fold, indicating haemolysis. Neither coagulopathy nor thrombocytopenia occurred. Creatine phosphokinase and serum potassium levels did not increase suggesting absence of acute rhabdomyolysis. The venom caused post-synaptic neurotoxicty. Immunoreactivity of venom with Black Snake antivenom was observed at very high venom concentrations. Cardiovascular effects were absent and haemolysis was less after venom was pre-incubated at 37 degrees C for 30 min with polyvalent antivenom. Neutralisation by Black Snake antivenom was less effective. The neurotoxicity was neutralised by polyvalent or Black Snake antivenoms. Human envenomation may be treated with CSL Ltd polyvalent snake antivenom.