Dysregulated energy metabolism impairs chondrocyte function in osteoarthritis.

OBJECTIVES: Metabolic pathways are a series of chemical reactions by which cells take in nutrient substrates for energy and building blocks needed to maintain critical cellular processes. Details of chondrocyte metabolism and how it rewires during the progression of osteoarthritis (OA) are unknown. This research aims to identify what changes in the energy metabolic state occur in OA cartilage. METHODS: Patient matched OA and non-OA cartilage specimens were harvested from total knee replacement patients. Cartilage was first collected for metabolomics, proteomics, and transcriptomics analyses to study global alterations in OA metabolism. We then determined the metabolic routes by tracking [U-13C] isotope with liquid chromatography-mass spectrometry (LC-MS). We further evaluated cellular bioenergetic profiles by measuring oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) and investigated the effects of low-dose and short-term effects of 2-deoxyglucose (2DG) on chondrocytes. RESULTS: OA chondrocytes showed increased basal ECAR and more lactate production compared to non-OA chondrocytes. [U-13C] glucose labelling revealed that less glucose-derived carbon entered the tricarboxylic acid (TCA) cycle. On the other hand, mitochondrial respiratory rates were markedly decreased in the OA chondrocytes compared to non-OA chondrocytes. These changes were accompanied by decreased cellular ATP production, mitochondrial membrane potential and disrupted mitochondrial morphology. We further demonstrated in vitro that short-term inhibition of glycolysis suppressed matrix degeneration gene expression in chondrocytes and bovine cartilage explants cultured under inflammatory conditions. CONCLUSION: This study represents the first comprehensive comparative analysis of metabolism in OA chondrocytes and lays the groundwork for therapeutic targeting of metabolism in OA.

An infant with 49XXXXY syndrome: a case report.

BACKGROUND: 49XXXXY syndrome is the rarest X chromosome aneuploidy, with approximate incidence of 1:85,000-100,000 male births. Worldwide, around 100 cases have been reported. In this report, we describe one such case seen in Sri Lanka. CASE PRESENTATION: A 10-day-old Sri Lankan neonate born in a tertiary care center was referred to the pediatric endocrinology unit of Lady Ridgeway Hospital due to detection of ambiguous genitalia at birth. He was the first child born to nonconsanguineous healthy parents following an uncomplicated antenatal period. He was born at term via normal vaginal delivery, with a birth weight of 2.385 kg. The baby was active, and there was no documented hypoglycemia or alteration in basic biochemical investigations. On examination, the child had hypertelorism, upslanting palpebral fissures, flat occiput, and mild webbing of the neck. System examination was normal. Genitalia examination revealed bifid scrotum, perineal urethra, 2 cm phallus, and bilateral testis in situ. Hormonal analysis, including dehydroepiandrosterone sulfate, testosterone, and 17-OH progesterone levels, was normal except for an elevated level of follicle-stimulating hormone, indicating gonadal dysgenesis. Ultrasound of the abdomen detected testis located at bilateral inguinal canal, and no Müllerian structures were visible. Echocardiography showed a small patent foramen ovale with otherwise normal heart. Chromosome analysis revealed 49XXXXY syndrome. CONCLUSION: 49XXXXY syndrome should be entertained as a rare possibility for ambiguous genitalia, and karyotyping is an essential investigation for evaluation of such patients.

WHO/INRUD Core drug use indicators and commonly prescribed medicines: a National Survey from Sri Lanka.

BACKGROUND: Identification of internationally comparable indicators of medicines use are important for a country to implement strategies and regulations to improve usage of medicines. Sri Lanka established a new National Medicines Regulatory Authority in 2015 and this survey evaluated the medication use indicators in Sri Lanka, according to the International Network on Rational Use of Drugs (INRUD), prior to its implementation. METHODS: This descriptive-cross-sectional study was conducted in 80 pharmacies, representing all 25 districts of the country. Three pharmacy categories were included; privately owned pharmacies, 'Rajya Osusala' pharmacies operated by the State Pharmaceuticals Corporation (SPC) of Sri Lanka and SPC Franchisee pharmacy outlets. Selection of pharmacies from respective districts were done proportionate to estimated population. Data were collected to identify WHO/INRUD core drug use indicators and the commonly prescribed medicines. RESULTS: Total of 2328 prescriptions were included ('Rajya Osusala 559; SPC Franchise 711; private pharmacies 1058). Altogether 7,255 medicines were prescribed, and the 3 most commonly prescribed medicines were atorvastatin, losartan and metformin. Average number of medicines per encounter was 3.1±1.9 (Median: 3; range 1-12) Highest average number of medicines per encounter was reported in prescriptions received at 'Rajya Osusala' pharmacies (3.6±2.2), significantly higher than in other categories of pharmacies (p<0.001). Percentage of medicines prescribed by generic name was only 35.5%, highest at the 'Rajya Osusala' pharmacies (40.6%), significantly higher than other categories of pharmacies. The overall percentage of medicines prescribed from essential medicine list (EML) was 68.8%, without any significant variation between different categories of pharmacies. The percentage of medicines actually dispensed and accurately labelled were 92.4 and 98.5% respectively. CONCLUSIONS: The average number of medicines per encounter was higher than the WHO recommended value but the usage of antibiotic and injectable drugs were within recommended standards. Generic prescribing, was very much lower. The EML prescribing, labelling and percentage dispensed medicines fared much better although lower than the WHO recommended 100% compliance. This island wide study has provided national wide data before the implementation of key changes in regulation of medicines in Sri Lanka and a repeat survey will be useful to identify impact of the new legislations.

Sustainable energy towards air pollution and climate change mitigation.

This is an evidence from a high-income economy in Southeast Asia and a support for scientific planning of the energy sector in ensuring air pollution and climate change mitigation. A comparative analysis of the energy options for electricity generation in the nation was made considering availability, cost and greenhouse gases emission - CO2, N2O and CH4, using a two-stage method comprising multi-objective optimization and TOPSIS. The renewable (RE) and non-renewable energy (NRE) options available were assessed through the lifecycle approach to determine the lifecycle greenhouse gas emission (LCGHG) and levelized cost of energy (LCOE) per MWh of electricity. Considering historical electricity consumption, annual GDP and population growth from 1965, energy consumption for the year 2035 was forecasted using support vector machine regressor in Weka. Future plans in energy diversification pathways were examined through various scenario multi-objective optimizations with a constraint on resource availability and energy target using genetic algorithm in MATLAB. The outputs were ranked using TOPSIS method. Results showed that greenhouse gases emission could be reduced by 10.3 percent compared to business as usual scenario while the energy mix could attain 10 percent renewable energy in the grid at a relatively lower generation cost.

Effect of Vitamin D therapy on urinary albumin excretion, renal functions, and plasma renin among patients with diabetic nephropathy: A randomized, double-blind clinical trial.

BACKGROUND: Despite different management strategies, progression of proteinuria occurs in a sizable category of patients with diabetic nephropathy (DN). Increase in serum renin levels induced by the renin-angiotensin system (RAS) may contribute to this. Vitamin D therapy is found to have an inhibitory effect on the RAS. We aimed to study the effects of Vitamin D therapy on renal functions of patients with DN. METHODS: This was a double-blind, randomized, placebo-controlled study. Patients with DN (urinary albumin [UA] >30 mg/g of creatinine) whose estimated glomerular filtration rate (eGFR) was more than 30 mL/min were selected and their plasma renin, parathyroid hormone, serum Vitamin D, serum calcium, serum creatinine, fasting blood sugar were done as baseline measurements. Subjects were randomized into two groups and treatment group was given Vitamin D, 50000 IU (0.25 ml) intramuscularly (IM) monthly for 6 months; control group received distilled water IM. Investigations were repeated after 6 months of therapy. RESULTS: Of 155 patients invited, 85 were randomly assigned to two groups. After 6 months, mean reduction of UA to creatinine ratio in the treatment and control group was 51.8 mg/g (95% confidence interval [CI]; 66.1--37.5, P ≤ 0.001); 22.4 mg/g (95% CI; -45.7-0.8, P = 0.06), respectively (between group difference P = 0.001). Significant increase in the eGFR observed in the treatment group while eGFR remained unchanged in the control group (P = 0.03 for the between-group difference). Mean reduction in plasma renin in treatment group and control group was 5.85 pg/mL (95% CI; -6.7--4.6) (P < 0.001) and 0.95 pg/mL (95% CI; -1.4--0.14, P = 0.02), respectively. CONCLUSIONS: Vitamin D 50000 IU given IM monthly for 6 months reduces urine albumin, serum creatinine, and renin levels in patients with DN.

Corticosteroids in management of anaphylaxis; a systematic review of evidence.

SUMMARY: As anaphylaxis is a medical emergency, there are no randomized controlled clinical trials on its emergency management. Therefore, current guidelines are mostly based on data from observational studies, animal and laboratory studies. Although epinephrine is the mainstay of recommended treatment, corticosteroids are also frequently used. This review evaluates the evidence on the use of corticosteroids in emergency management of anaphylaxis from published human and animal or laboratories studies. Thirty original research papers were found with 22 human studies and eight animal or laboratory studies. The average rate of corticosteroid use in emergency treatment was 67.99% (range 48% to 100%). Corticosteroids appear to reduce the length of hospital stay, but did not reduce revisits to the emergency department. There was no consensus on whether corticosteroids reduce biphasic anaphylactic reactions. None of the human studies had sufficient data to compare the response to treatment in different treatment groups (i.e. corticosteroids, epinephrine, antihistamines). Animal studies demonstrated that corticosteroids act through multiple mechanisms. These modulate gene expression, with effects becoming evident 4 to 24 hours after administration. A much quicker response has been detected within 5 to 30 minutes, through blockade of signal activation of glucocorticoid receptors independent of their genomic effects. Therefore, we conclude that there is no compelling evidence to support or oppose the use of corticosteroid in emergency treatment of anaphylaxis. However, based on the available data, it appears to be beneficial and there was no evidence of adverse outcomes related to the use of corticosteroids in emergency treatment of anaphylaxis.

Influence of Southeast Asian Haze episodes on high PM10 concentrations across Brunei Darussalam.

Particulate matter (PM10) is the key indicator of air quality index in Brunei Darussalam and the principal pollutant for haze related episodes in Southeast Asia. This study examined the temporal and spatial distribution of PM10 base on a long-term monitoring data (2009-2014) in order to identify the emission sources and favorable meteorological conditions for high PM10 concentrations across the country. PM10 concentrations measured at the various locations differ significantly but the general temporal characteristics show clear patterns of seasonal variations across the country with the highest concentrations recorded during the southwest monsoon. The high PM10 values defined in the study were not evenly distributed over the years but occurred mostly within the southwest monsoon months of June to September. Further investigations with bivariate polar concentrations plots and k-means clustering demonstrated the significant influence of Southeast Asian regional biomass fires on the high PM10 concentrations recorded across the country. The results of the polar plots and cluster analyses were further confirmed by the evaluations with Hybrid Single-Particle Lagrangian Integrated Trajectory (HYSPLIT) backward air masses trajectories analysis and the Moderate Resolution Imaging Spectroradiometer (MODIS) fire records. Among the meteorological variables considered, temperature, rainfall and relative humidity were the most important meteorological variables that influence the concentration throughout the year. High PM10 values are associated with high temperatures and low amounts of rainfall and relative humidity. In addition, wind speed and direction also play significant role in the recorded high PM10 concentrations and were mainly responsible for its seasonality during the study period.

Current infant feeding practices and impact on growth in babies during the second half of infancy.

BACKGROUND: Sri Lanka has made remarkable improvements in health, social and educational indices. However, child malnutrition exists as a significant health problem. Infant feeding indicators have not reached expected levels and improvements are partly constrained by a lack of data. The present study aimed to determine current infant feeding practices and their impact on growth among 6-12-month-old infants. METHODS: The study comprised a descriptive cross-sectional investigation conducted in randomly selected (n = 7) Public Health Midwife areas in Galle, Sri Lanka. An interviewer-administered questionnaire was used to obtain data on sociodemographics and infant feeding. Mothers (n = 515) attending well-baby clinics were recruited on voluntary and consecutive basis. Infants' body weights and lengths were measured using standard procedures. RESULTS: Exclusive breastfeeding rate for first 6 months was 49.0%. In total, 42.6% infants (219 out of 515) were given rice as first weaning food, followed by salt (58.6%) and sugar (42.3%). Oil had been introduced to 84.9% of infants by the end of 12 months. Most infants (over 71%) were given dairy products, whereas 62.3% were being fed various liquid foods using bottles. The introduction of commercial infant cereals, chocolates, plain tea, ice cream and deep fried snacks was noted. Age-specific body weight and length were not achieved by 30.5% and 29.5% of infants, respectively. Weight for length was not achieved by 25.5% of the infants. Delayed achievements of motor milestones were observed. Mothers' knowledge scores on basic nutrients were low. CONCLUSIONS: Complementary feeding indices of the study group were not satisfactory. Maternal and child healthcare personnel need to identify causative factors for inappropriate feeding with a view to improve the complementary feeding patterns.

Cryptogenic cirrhosis is the leading cause for listing for liver transplantation in Sri Lanka.

Hepatitis B and C are rare in Sri Lanka. Nonalcoholic fatty liver disease is increasing in the country. Eighty-one patients referred for liver transplantation (LT) over a period of 18 months were prospectively evaluated. Ninety-two percent (n = 74) were males. Cryptogenic cirrhosis was the leading indication for LT (58%, n = 47) followed by alcohol in 27% (n = 33). Hepatitis B and C were not seen in our cases. The liver biochemistry and clinical status of cirrhosis were similar in cryptogenic and alcoholic cirrhotics. Fourteen patients died while waiting for transplant, and nine transplants were performed. Cryptogenic cirrhosis is the leading cause for LT in Sri Lanka.

Transanal endoscopic microsurgery: a new technique for completion proctectomy.

AIM: Following subtotal colectomy, the retained rectal stump is a potential source of morbidity. Although restorative ileal pouch-anal anastomosis is the gold standard for ulcerative colitis, up to 14% of patients will opt for a permanent ileostomy and undergo completion proctectomy, traditionally by an abdomino-perineal approach, which itself carries significant morbidity. We describe a new technique of perineal proctectomy using transanal endoscopic microsurgery (TEMS) equipment. To our knowledge, this technique has not previously been described in the literature. METHOD: Twelve patients, mean (SD) age 66 (±13) years, underwent TEMS proctectomy, performed by a single surgeon between January 2007 and October 2011. Excision began with an intersphincteric dissection following which the TEMS (WOLF) proctoscope was inserted and close rectal dissection was performed, entering the peritoneal cavity (if the top of the stump was intraperitoneal). Following perineal extraction of the specimen, the external sphincter and skin were closed with an absorbable suture. RESULTS: Nine patients had inflammatory bowel disease, two had neoplasia and one had intractable radiation proctitis. The mean (SD) rectal stump length was 17.8 (±6.1) cm and the peritoneal cavity was entered in nine patients, with no small-bowel injury. The median postoperative hospital stay was 5.5 days. In four patients there was delayed healing of the perineal wound. There was no perioperative mortality. CONCLUSION: TEMS perineal proctectomy is a novel, but safe, technique that may avoid the need for a traditional abdominoperineal approach in selected patients.

Prolonged pudendal nerve terminal motor latency is associated with decreased resting and squeeze pressures in the intact anal sphincter.

AIM: To determine the contribution of the pudendal nerve to the anal continence mechanism by determining the correlation between pudendal nerve terminal motor latency (PNTML) and resting and squeeze anal canal pressures. METHOD: In all, 1051 patients were investigated with anorectal physiology studies between January 1998 and July 2010. Of these, 213 patients had intact anal sphincters on endoanal ultrasound and had undergone PNTML testing and anal manometry with measurement of resting and squeeze pressures. The relationship between PNTML and mean resting and squeeze pressures was compared in these patients with an intact anal sphincter. Values were compared using a two-sample t test with equal variances. A P value of < 0.05 was considered significant. RESULTS: Of these patients 40.8% had normal PNTML bilaterally, 9.9% had slow PNTML bilaterally and 21.6% had a unilateral slow PNTML. Mean resting pressure was significantly reduced in patients with unilateral slow and bilateral slow PNTML compared with normal. The magnitude of the reduction was 28% and 19% respectively. Mean squeeze pressure was significantly reduced in patients with unilateral slow and bilateral slow PNTML compared with normal. The magnitude of the reduction was 18% and 23% respectively. CONCLUSION: In patients with an intact anal sphincter, either unilaterally or bilaterally prolonged PNTMLs are associated with significantly decreased resting and squeeze pressures. Our results suggest that both internal and external sphincter function is impaired with pudendal nerve injury. The inhibition of internal sphincter function may be due to damage of autonomic, principally sympathetic fibres carried in the pudendal nerve.

Efficacy of 'Thriposha' supplementation in improving the micronutrient status of preschool children.

INTRODUCTION: The islandwide comprehensive supplementary feeding scheme, the 'Thriposha' programme has been in existence in the country for over three decades. However, its effectiveness in improving micronutrient status has not yet been evaluated. OBJECTIVE: We examined the effects of 'Thriposha' on micronutrient status, assessed haematologically and biochemically, in young children. METHODS: Preschool children (aged 3-5 years) from two well-baby clinics were grouped into interventional (n = 137) arm and control (n = 130) arm. Children in the interventional group were fed 'Thriposha' (50 g/day) while the control group of children was fed with 50 g 'Thriposha' made without mineral and vitamin premix, for a period of nine months. Serum calcium, ferritin, folate, freeT4, ceruloplasmin, zinc, vitamin A, vitamin D and haemoglobin (Hb) levels were measured before and one week after completing intervention. RESULTS: The baseline Hb levels of the intervention and control groups were 113.20 (SD10.9) g/l and 112.30 (SD 9.0) g/l respectively. After the intervention, the interventional group showed a significant improvement (repeated measures ANOVA, p = 0.02) in the Hb (mean of 118.10 (7.7) vs. 114.70 (7.0) g/l of the control). The prevalence of anaemia dropped from 37% to 15% in the intervention group (p = 0.03). Serum ferritin and ceruloplasmin levels also improved. CONCLUSION: Regular consumption of conventional 'Thriposha' for 9 months led to improvements in Hb, ferritin and ceruloplasmin levels in the blood.

Dietary macro- and micro-nutrient intake among a cohort of pre-school children from Southern Sri Lanka.

OBJECTIVE: To establish a database on dietary intake among children aged 3-5 years in southern Sri Lanka. METHODS: A retrospective, quantitative method (24-hour dietary recall on 3 consecutive days) in combination with a food composition database was used to assess the nutrient intake among 248 children in Galle. Anthropometry measurements were done to assess their nutritional status. RESULTS: There were no significant correlations between the constituents of the diet with the anthropometric parameters. The overall mean (SD) energy intake of male children 6.23 (1.3) MJ/day was significantly higher (p = 0.05) than female counterparts [5.75 (1.3) MJ/day]. 44.0% (n=45) of males and 55.0% (n=57) of females had an energy intake below the recommended level. None of the females of 3 years of age met the daily energy requirement. CONCLUSIONS: The intake of energy, protein, calcium, beta-carotene, vitamin D and iron was satisfactory in preschool children. Consumption of nutrients except iron and energy was better in males than in females. The dietary macro- and micro- nutrient intake by both sexes exponentially increased with age.

A new technique for suture rectopexy without resection for rectal prolapse.

BACKGROUND: We surmised that if rectopexy was performed without dissection of the lateral rectal stalks in patients with full-thickness rectal prolapse and normal preoperative transit, sigmoid resection may not be required. This study evaluated a new approach to abdominal suture rectopexy for rectal prolapse. METHODS: A total of 81 patients (57 male, 24 female; median age 37 years, range 5-82 years) with rectal prolapse were assessed by clinical examination, anal manometry (maximum resting pressure, MRP, and squeeze pressure, MSP) and radioopaque marker transit studies. Of the 81 patients, 70 with normal preoperative transit underwent suture fixation alone, without resection, performed under spinal anaesthesia, through a 7-cm transverse left lower quadrant incision gaining access to the presacral space via a left pararectal "window", preserving the lateral stalks. RESULTS: Average surgical time was 50 min, mortality was zero, and morbidity was 9% (three patients with wound infection, four with urinary retention). Anal incontinence improved in 43 of 53 patients (81%, p=0.001). MRP and MSP had improved at 3 months after surgery: MRP from a mean of 27.6+/-1.4 mmHg (range 2-30 mmHg) before surgery to 32.5+/-2.21 mmHg (2-60 mmHg) after surgery (p=0.008); MSP from 69.25+/-6.4 mmHg (8-153 mmHg) before surgery to 79+/-4.77 mmHg (35-157 mmHg) after surgery (p=0.001).. Transit was unchanged in 18 of 20 patients (90%) who were evaluated before and after surgery; none was constipated after surgery. At 56 months, prolapse had recurred in five patients (7%). CONCLUSION: Abdominal suture rectopexy with a left pararectal approach without sigmoid resection in those with normal preoperative transit resulted in an improvement in anal incontinence and satisfactory long-term control of prolapse. The operation did not alter transit and did not result in significant constipation.

The efficacy of micronutrient supplementation in reducing the prevalence of anaemia and deficiencies of zinc and iron among adolescents in Sri Lanka.

OBJECTIVE: To determine the effectiveness of combined iron and zinc over the iron or zinc-only supplementation in correcting deficiency and possible interactive effects in a group of adolescent school children. SUBJECTS AND METHODS: Schoolchildren (n=821) of 12-16 years of age were randomized into four groups and supplemented with iron (50 mg/day), zinc (14 mg/day), iron+zinc or placebo capsules 5 days per week for 24 weeks. Anthropometry, and haemoglobin (Hb), serum zinc (SZn) and serum ferritin (SF) concentrations were determined before and after the intervention. RESULTS: There were no significant effects between-groups in their weight, height and Hb concentrations with the intervention when compared with the placebo group. Iron-only and combination-supplemented groups had reached mean SF concentrations of 55.1 microg/l with no difference between them (P=0.99). The zinc-only group had a mean change of 4.3 micromol//l whereas the combine-supplemented group had a mean change of 4.0 micromol/l (P=0.82). The prevalence of anaemia was found to be 70.3% in the iron group at baseline; this was reduced to 14.5% after the supplementation. In the combine-supplemented group anaemia, prevalence was reduced from 64.8 to 19.3%. CONCLUSIONS: Zinc alone or in combination with iron has not shown a significant improvement in growth in adolescence. Severe and moderate forms of anaemia were successfully treated in children who received iron supplementation. Initial high prevalence of low SZn and iron stores was significantly improved with micronutrient supplementation.

Locating an insulinoma by surgical exploration.

The case of a 79-year old man who was suspected to have an insulinoma is presented. Although clinically and biochemically an insulinoma was the most probable diagnosis there was no supportive radiological evidence. Open surgery and exploration revealed a lesion which was confirmed to be an insulinoma. The patient's hypoglycaemia improved immediately following surgery. In the Sri Lankan setting where sophisticated imaging procedures are not freely available, open exploration of the pancreas is a good alternative to locate a suspected insulinoma.