Kidney Cadmium Concentrations in an Urban Sri Lankan Population: an Autopsy Study.

Contamination and bioaccumulation of toxic heavy metals in our geo-environment is a growing public health concern. Human biomonitoring is an essential step in assessing the population risk of chronic exposure to environmental contaminants. Whole kidneys collected from a cohort of 92 deceased individuals undergoing forensic autopsies in Colombo, Sri Lanka, were analysed for cadmium (Cd) bioaccumulation using ICP-MS. Mean age of the population was 55.4 ± 15.4 years. Mean and median renal Cd concentrations of the total population were 4.38 and 2.60 µg g-1 w/w, respectively, which were below estimated toxic ranges. Males accumulated higher levels of Cd than females (p = 0.377). Cd concentrations were higher in the < 60 age group than the > 60 age group (p = 0.92), while the highest levels were reported in 51-60 age group. However, no significant correlation was found between renal Cd concentration and age (Æ®b = - 0.005, p = 0.94). Individuals who smoked, chewed betel or consumed alcohol were found to have elevated renal Cd concentrations in comparison to those who did not use these substances. This is the largest autopsy study on renal Cd bioaccumulation in Sri Lanka, and the findings do not indicate a high exposure risk to environmental Cd contamination at present.

Swarna Makshika Bhasma preparation using an alternative heating method to traditional Varaha Puta.

BACKGROUND: Metals, minerals and gemstones are used to prepare drugs in combination with various herbal materials in ayurvedic treatments. During the process of preparation, metals, minerals or gemstones are converted into special form known as bhasma by series of pharmaceutical processes; shodhana, bhavana and marana. Puta is the amount of heat required to produce specific bhasma in a cycle of treatment in the process of marana. Traditionally, heat is produced by burning cow dung cakes and the amount of heat to be provided is described in terms of cow dung cakes (fuel) burnt. OBJECTIVE: The present study was aimed to obtain the temperature profile of the traditional Varaha Puta and to establish a complementary temperature profile in a muffle furnace. MATERIALS AND METHODS: The temperature profile of Varaha puta was determined using dried cow dung cakes (which were prepared using cow dung and paddy husk) with an average calorific value of 15.44 MJ/kg as the fuel. Then temperature profile of traditional Varaha Puta was mapped with an electric muffle furnace and Swarna Makshika (Chalcopyrite) bhasma was prepared using both traditional method and in electric muffle furnace. RESULTS: Bhasma prepared using both Varaha Puta and muffle furnace have shown similar properties according to classical tests of Ayurveda and laboratory techniques. CONCLUSION: The results show the possibility of using a muffle furnace to prepare Swarna Makshika bhasma instead of using traditional Varaha Puta.

Forensic age estimation in anti-piracy trials in Seychelles: Experiences and challenges faced.

Forensic age estimation (FAE) was conducted using a multifactorial method on thirteen Somali detainees claiming juvenile status during the anti-piracy trials of the Seychelles Supreme Court in 2014/2015. A multidisciplinary team, comprising of four of the authors covering specialties in forensic medicine, forensic odontology and radiology, conducted the FAE using a five-stage protocol. Each detainee was interviewed with an interpreter and examined for disorders affecting dental/skeletal development and for assessment of genital development through Tanner staging. Dental maturity was assessed clinically and radiologically. Eruption stage was assessed using Olze et al. and mandibular third-molar maturity was assessed using Demirjian's classification. Skeletal maturity was assessed from hand-wrist X-rays according to Greulich & Pyle and from CT-clavicle according to Kellinghaus et al. and Schultz et al. Interpretation of findings was done using reference population data from similar ethnic and social backgrounds wherever possible. Final age-ranges were calculated by combining dental and clavicle maturity stages using the regression formula developed by Bassed et al. followed by a 10% correction factor. The team later testified on their findings under cross-examination. The protocol adopted by the authors increased the scientific validity of the findings and was useful in addressing cross-examination queries on exclusion of developmental disorders, ethnic/socioeconomic variability and maintaining chain of custody. Unforeseen jurisdictional and practical limitations were experienced but did not affect the outcome. Combining dental and clavicle developmental data provided the court with a much clearer picture on the likelihood of the detainees' juvenile status which emphasizes the importance of conducting more population studies using combinations of different developmental sites. The authors note that available reference data is mostly from affluent populations whereas FAE is mostly required in individuals from less-developed regions. Regional networks that collate and share population-specific data need to be established to overcome these limitations.

Modelling strategies to break transmission of lymphatic filariasis--aggregation, adherence and vector competence greatly alter elimination.

BACKGROUND: With ambitious targets to eliminate lymphatic filariasis over the coming years, there is a need to identify optimal strategies to achieve them in areas with different baseline prevalence and stages of control. Modelling can assist in identifying what data should be collected and what strategies are best for which scenarios. METHODS: We develop a new individual-based, stochastic mathematical model of the transmission of lymphatic filariasis. We validate the model by fitting to a first time point and predicting future timepoints from surveillance data in Kenya and Sri Lanka, which have different vectors and different stages of the control programme. We then simulate different treatment scenarios in low, medium and high transmission settings, comparing once yearly mass drug administration (MDA) with more frequent MDA and higher coverage. We investigate the potential impact that vector control, systematic non-compliance and different levels of aggregation have on the dynamics of transmission and control. RESULTS: In all settings, increasing coverage from 65 to 80 % has a similar impact on control to treating twice a year at 65 % coverage, for fewer drug treatments being distributed. Vector control has a large impact, even at moderate levels. The extent of aggregation of parasite loads amongst a small portion of the population, which has been estimated to be highly variable in different settings, can undermine the success of a programme, particularly if high risk sub-communities are not accessing interventions. CONCLUSION: Even moderate levels of vector control have a large impact both on the reduction in prevalence and the maintenance of gains made during MDA, even when parasite loads are highly aggregated, and use of vector control is at moderate levels. For the same prevalence, differences in aggregation and adherence can result in very different dynamics. The novel analysis of a small amount of surveillance data and resulting simulations highlight the need for more individual level data to be analysed to effectively tailor programmes in the drive for elimination.

Primary immune deficiency among patients with recurrent infections.

OBJECTIVES: Primary immune deficiency is relatively rare. Patients present with recurrent or persistent infections or infections with opportunistic pathogens. We investigated patients who presented during the years 2005-7 with recurrent or persistent infections or infections with opportunistic organisms, for underlying immune deficiency. DESIGN: Descriptive study. SETTING: Department of Immunology, Medical Research Institute, Colombo. STUDY POPULATION: 257 patients referred to the Department of Immunology, Medical Research Institute, Colombo, with a history of recurrent infections, for evaluation of possible immune deficiency. MEASUREMENTS: Appropriate evaluation of immunological competence of the humoral and cell mediated immune systems. RESULTS: There were 8 patients with agammaglobulinaemia (X linked agammaglobulinaemia and autosomal recessive agammaglobulinaemia), 2 patients each with ataxia telangiectasia, IgA deficiency and hyper-IgE syndrome, 3 patients with common variable immune deficiency (CVID), and 1 patient each with Griscelli syndrome, hyper-IgM syndrome and X linked severe combined immune deficiency (SCID). CONCLUSIONS: Primary immune deficiency must be included in the evaluation of patients with recurrent infections, and timely intervention can prevent morbidity and mortality.

Effects of mitral regurgitation on the reflex diuresis to pulmonary lymphatic obstruction in rabbits.

Increasing the extravascular fluid of the airways acutely by obstructing pulmonary lymph drainage causes a reflex diuresis mediated by neuronal nitric oxide synthase in the renal medulla. The authors examined this reflex in rabbits with a chronic increase in extravascular fluid of the airways resulting from surgically induced mitral regurgitation. Intact rabbits served as controls. Renal neuronal (nNOS) and endothelial (eNOS) nitric oxide synthase expressions were also examined. The reflex was absent in rabbits with mitral regurgitation. There were significant increases in medullary and cortical nNOS mRNA compared to controls. The observed changes in mRNA levels correlated with nNOS protein levels. eNOS mRNA was unaffected.

Large-cell calcifying sertoli cell tumour of the testis detected at screening of a family with Carney syndrome.

We report the detection of a large-cell calcifying Sertoli cell tumour (LCCSCT) in a 34-year-old male during screening of a family with Carney syndrome. The patient had ignored the testicular swelling for 7 years. He also had a cardiac myxoma. The LCCSCT in this patient had prognostically unfavourable features such as large size (>6 cm) and a high mitotic rate. There is only one previous report of a malignant LCCSCT in a patient with Carney syndrome.

Role of nitric oxide in the reflex diuresis in rabbits during pulmonary lymphatic obstruction.

The role of nitric oxide in the reflex diuresis in response to pulmonary lymphatic drainage was examined in anaesthetized, artificially ventilated New Zealand White rabbits. Pulmonary lymphatic drainage was obstructed by raising the pressure in a pouch created from the right external jugular vein. Pulmonary lymphatic obstruction resulted in a significant increase in urine flow from an initial control value of 8.9 +/- 0.5 ml (10 min)(-1) to 12.1 +/- 0.6 ml (10 min)(-1) during lymphatic obstruction (mean +/-s.e.m.; n= 17, P < 0.001). This increase in urine flow was accompanied by a significant increase in the excretion of sodium. Additionally, renal blood flow remained unchanged during the increase in urine flow caused by lymphatic obstruction. Intravenous infusion of L-NAME, a non-selective inhibitor of nitric oxide synthase (NOS), abolished the reflex diuresis. Furthermore, intraperitoneal administration of the relatively selective neuronal NOS blocker, 7-nitroindazole also abolished the response. It was observed that infusion of a more soluble neuronal NOS blocker, 7-nitroindazole sodium salt (7-NINA), into the renal medulla also abolished the reflex diuresis. These findings suggest that the increase in urine flow in rabbits caused by pulmonary lymphatic obstruction is dependent upon the integrity of neuronal NOS activity within the renal medulla.

Tetrasomy 15q25.3 --> qter resulting from an analphoid supernumerary marker chromosome in a patient with multiple anomalies and bilateral Wilms tumors.

We describe a girl who had been followed since birth for apparent Shprintzen-Goldberg syndrome (SGS), with macrosomia, long fingers and toes, and craniosynostosis, and presented at 4 years of age with bilateral Wilms tumors (also called nephroblastoma). Cytogenetic analysis of her peripheral blood revealed a de novo supernumerary marker chromosome. This stable marker chromosome is present in 19 of 20 lymphocytes analyzed, as well as in all 40 tumor cells (20 from each tumor) studied. Classical and molecular cytogenetic studies indicate that the marker is derived from an inverted duplication of chromosome 15q25.3 --> qter and contains a neocentromere. The presence of this marker chromosome in our patient results in tetrasomy 15q25.3 --> qter. The relationship between her genotype and phenotype are discussed in light of genes, including IGF1R and FES, mapped to the aneusomic segment.

Responses of C fiber afferents of the rabbit airways and lungs to changes in extra-vascular fluid volume.

Effects of changes in extra-vascular fluid volume produced by pulmonary lymphatic obstruction and plasmapheresis on the activities of bronchial and pulmonary C fiber receptors and rapidly adapting receptors (RARs) were investigated in New Zealand White rabbits. In intact rabbits, pulmonary lymphatic obstruction either alone or in combination with plasmapheresis did not stimulate pulmonary C fiber receptors. Only the combined stimulus activated the bronchial C fiber receptors. Bronchial C fiber receptors were also stimulated by graded increases in left atrial pressure (+5 and +10 mmHg). In contrast, RARs were activated by lymphatic obstruction either alone or in combination with plasmapheresis. These procedures increase the extra-vascular fluid volume in the carina and bronchi but not in the lungs (alveoli). In rabbits with chronic pulmonary venous congestion secondary to mitral valve damage, bronchial C fiber receptors were not stimulated by these increments in left atrial pressure which were insufficient to increase the extra vascular fluid content of the airways. However, both pulmonary and bronchial C fiber receptors were stimulated when the left atrial pressure was raised to 25 mmHg in these animals to cause pulmonary edema.

Primary endodermal sinus (yolk sac) tumour of the liver.

Primary endodermal sinus tumour of the liver is an extremely rare neoplasm. A 37-year-old man presented with a mass in the left lobe of the liver and a raised serum alpha-fetoprotein concentration. A left hepatic lobectomy was performed. Histological examination revealed an endodermal sinus tumour of the liver. There was no evidence of an extrahepatic primary source.

Volume overload left ventricular hypertrophy: effects on coronary microvascular reactivity in rabbits.

The mechanisms controlling the coronary vascular responses of vessels perfusing the left ventricular (LV) myocardium that is hypertrophied from chronic volume overload are unclear. We hypothesised that endothelial function is compromised, and receptor-mediated contraction is exacerbated, in coronary resistance vessels from rabbits with LV hypertrophy compared to controls. The mitral valve of 10 rabbits was damaged surgically to cause mitral regurgitation and chronic volume overload, resulting in LV hypertrophy (LV hypertrophy rabbits). Echocardiographic assessment at 12 weeks verified that mitral regurgitation was present in LV hypertrophy but not sham-operated, weight- and age-matched animals (control rabbits; n = 17). Percentage increases from weeks 0 to 12 in LV cross-sectional area (47 +/- 7 % vs. 2 +/- 8 %), LV volume (47 +/- 14 % vs. 7 +/- 10 %) and LV mass (27 +/- 4 % vs. 3 +/- 6 %), were greater (all P < 0.05) in LV hypertrophy vs. control rabbits, respectively. At 12 weeks, coronary resistance vessel (approximately 130 microm, internal diameter) reactivity was evaluated using wire myography. Endothelium-dependent (i.e. acetylcholine, 10(-8)-10(-5) M) and -independent (i.e. sodium nitroprusside, 10(-9)-10(-4) M) relaxation, and receptor-mediated vasocontraction (i.e. endothelin-1, 10(-11)-10(-7) M) were similar between groups. However, tension development in response to nitric oxide synthase inhibition (10(-6) M N (G)-monomethyl-L-arginine) was greater (P < 0.05) in LV hypertrophy compared to control rabbits. These results indicate that while coronary resistance vessel function is similar between groups, our estimate of basal nitric oxide production is greater in vessels from LV hypertrophy than control rabbits.

Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in Drosophila.

We tested the hypothesis that amyloid precursor protein (APP) and its relatives function as vesicular receptor proteins for kinesin-I. Deletion of the Drosophila APP-like gene (Appl) or overexpression of human APP695 or APPL constructs caused axonal transport phenotypes similar to kinesin and dynein mutants. Genetic reduction of kinesin-I expression enhanced while genetic reduction of dynein expression suppressed these phenotypes. Deletion of the C terminus of APP695 or APPL, including the kinesin binding region, disrupted axonal transport of APP695 and APPL and abolished the organelle accumulation phenotype. Neuronal apoptosis was induced only by overexpression of constructs containing both the C-terminal and Abeta regions of APP695. We discuss the possibility that axonal transport disruption may play a role in the neurodegenerative pathology of Alzheimer's disease.

Cell-mediated immune responses (CMIR) in human rhinosporidiosis.

Cell mediated immune responses (CMIR) to Rhinosporidium seeberi in human patients with rhinosporidiosis have been studied. With immuno-histochemistry, the cell infiltration patterns in rhinosporidial tissues from 7 patients were similar. The mixed cell infiltrate consisted of many plasma cells, fewer CD68+ macrophages, a population of CD3+ T lymphocytes, and CD56/57+ NK lymphocytes which were positive for CD3 as well. CD4+ T helper cells were scarce. CD8+ suppressor/cytotoxic-cytolytic cells were numerous. Most of the CD8+ cells were TIA1+ and therefore of the cytotoxic subtype. CD8+ T cells were not sub-typed according to their cytokine profile; 1L2, IFN-gamma (Tcl); IL4, ILS (Tc2). In lympho-proliferative response (LPR) assays in vitro, lymphocytes from rhinosporidial patients showed stimulatory responses to Con A but lymphocytes from some patients showed significantly diminished responses to rhinosporidial extracts as compared with unstimulated cells or cells stimulated by Con A, indicating suppressor immune responses in rhinosporidiosis. The overall stimulatory responses with Con A suggested that the rhinosporidial lymphocytes were not non-specifically anergic although comparisons of depressed LPR of rhinosporidial lymphocytes from individual patients, to rhinosporidial antigen with those to Con A, did not reveal a clear indication as to whether the depression was antigen specific or non-specific. The intensity of depression of the LPR in rhinosporidial patients bore no relation to the site, duration, or the number of lesions or whether the disease was localized or disseminated. Rhinosporidial extracts showed stimulatory activity on normal control lymphocytes, perhaps indicating mitogenic activity. These results indicate that CMIR develops in human rhinosporidiosis, while suppressed responses are also induced.

The pattern of hypogammaglobulinaemia in Sri Lankan children.

OBJECTIVE: To evaluate the prevalence of hypogammaglobulinaemia in Sri Lankan children who present with recurrent or severe bacterial infections. DESIGN: A descriptive study. SETTING: Medical Research Institute (MRI), Colombo. SUBJECTS: 100 children between the ages of four months to twelve years referred to the Department of Immunology, MRI, for evaluation of immune status during four years from 1993 to 1997. MEASUREMENTS: Immunoglobulin G, A and M levels were measured using radial immunodiffusion technique. RESULTS: 22 out of 100 children had an underlying antibody deficiency, of whom IgA deficiency was the commonest (18 patients). Two patients had low IgG and A and elevated IgM levels, and they were diagnosed as having X linked-hyper-IgM syndrome. One patient had deficient IgA and IgM, and all three immunoglobulins were deficient in another. CONCLUSIONS: Results indicate that IgA deficiency is the commonest immunodeficiency in Sri Lanka, which is comparable with studies done in the West. This study also shows the need to improve the standard of care in patients with immunodeficiency.

Direct evidence for interphase chromosome movement during the mid-blastula transition in Drosophila.

In Drosophila, several genetic phenomena are most easily explained by a model in which homologous chromosomes pair, at least transiently, and use regulatory information present on only one homolog to pattern expression from both homologs [1] [2] [3]. To accomplish pairing of sites on different chromosomes, there must be a mechanism by which communication between homologs is facilitated. However, except in the case of meiotic prophase, directed, rapid chromosomal movement has not yet been observed. Some studies suggest that chromosomes are relatively immobile during interphase [4] [5], while others suggest that chromatin can reposition during interphase [6] [7] [8] and may be free to undergo substantial Brownian motion [9]. Using high-resolution, three-dimensional imaging techniques, we determined directly the structure and nuclear location of eleven different loci, both active and inactive, in embryos at cycle 14, the mid-blastula transition. We show that during a single interphase, portions of chromosomes moved in a cell-cycle-specific, directed fashion, independently and over long distances. All eleven regions showed movement, although the genes closer to the centromere moved faster (0.7 microm/minute) and over long distances (5-10 microm), whereas those nearer the telomere expanded in the same place and became oriented along the nuclear axis. Gene motion was independent of replication, transcription and changes in nuclear shape. Because individual genes on the same chromosome move independently, the movement is unlikely to be mediated by centromeres, Brownian motion or random drift and must be caused by an active mechanism.

Seroconversion rate following measles vaccination.

OBJECTIVE: To assess the seroconversion rate following measles vaccination in Sri Lankan children. DESIGN: A descriptive study. SETTING: Immunisation clinic, Lady Ridgeway Hospital, Colombo (LRHC). SUBJECTS: 134 infants who attended the LRHC for measles vaccination. MEASUREMENTS: Pre- and post-vaccination blood samples were collected and serum was tested for the presence of anti-measles 1gG antibodies using the ELISA technique. RESULTS: Of the 134 infants only 102 were brought for the post-vaccination sample. Of these 102 samples, 101 were negative for anti-measles antibodies before vaccination. Of the 101 sero-negative samples 94 became sero-positive 6 to 8 weeks after vaccination. These results indicate that the seroconversion rate is 93.06%, which is similar to the results of studies done in other countries. CONCLUSION: Most infants are susceptible to measles infection by the age of 9 months, and it is appropriate to vaccinate infants at this age, as is the practice at present. However, further studies are needed to assess the duration of protection with a single dose of measles vaccine.

Rapidly adapting receptors in a rabbit model of mitral regurgitation.

1. Unlike in normal rabbits, pulmonary rapidly adapting receptors (RARs) in rabbits with chronic mitral regurgitation (MR) do not respond to small changes in extravascular fluid (EVF) volume in major airways. The present study examined the effect of shrinking the EVF volume in rabbits with chronic MR by infusing hypertonic albumin, to see whether this response of RARs is restored. The effect of raising the left atrial pressure (LAP) acutely above 25 mmHg (to cause pulmonary oedema) on RARs was also investigated. 2. Mean RAR activities in rabbits with MR (n = 6) at initial control, LAP +5 mmHg, LAP +10 mmHg and final control periods were 20.9 +/- 9. 5, 18.8 +/- 11.3, 27.0 +/- 11.2 and 17.2 +/- 9.8 action potentials min-1, respectively (P > 0.05, ANOVA). After infusion of 35 % bovine serum albumin i.v. these values were 9.4 +/- 3.2, 30.6 +/- 14.6, 48. 9 +/- 10.1 and 18.4 +/- 7.3 action potentials min-1, respectively (P < 0.01, ANOVA). In rabbits with chronic MR (n = 7) raising the LAP above 25 mmHg stimulated RARs. 3. EVF content of the airways and lungs was measured in rabbits with MR and in control rabbits, at baseline and after elevation of the LAP by 10 or 25 mmHg for 20 min. In control rabbits the EVF contents in the lower trachea, carina and bronchi at baseline and at LAP +10 mmHg were 52.1 +/- 1.2 and 57.8 +/- 1.7 %, respectively (P < 0.05, Student's t test). In rabbits with MR these values were 58.3 +/- 1.5 and 56.9 +/- 1.9 %, respectively. When the LAP was elevated by 25 mmHg the EVF content increased to 62.4 +/- 1.1 % (P < 0.05, t test compared with baseline and LAP +10 mmHg). 4. We concluded that in rabbits with chronic MR, RARs are unable to respond to acute, small elevations of LAP because there is no concomitant increase in EVF content in the vicinity of these receptors. Furthermore, these receptors can be activated in these animals by elevating the LAP above 25 mmHg or can be made sensitive to acute small elevations of LAP by shrinking the chronically expanded EVF compartment.