The emergence and spread of drug resistant malaria represents a considerable challenge to controlling malaria. To date, malaria control has relied heavily on a comparatively small number of chemically related drugs, belonging to either the quinoline or the antifolate groups. Only recently have the artemisinin derivatives been used but mostly in south east Asia. Experience has shown that resistance eventually curtails the life-span of antimalarial drugs. Controlling resistance is key to ensuring that the investment put into developing new antimalarial drugs is not wasted. Current efforts focus on research into new compounds with novel mechanisms of action, and on measures to prevent or delay resistance when drugs are introduced. Drug discovery and development are long, risky and costly ventures. Antimalarial drug development has traditionally been slow but now various private and public institutions are at work to discover and develop new compounds. Today, the antimalarial development pipeline is looking reasonably healthy. Most development relies on the quinoline, antifolate and artemisinin compounds. There is a pressing need to have effective, easy to use, affordable drugs that will last a long time. Drug combinations that have independent modes of action are seen as a way of enhancing efficacy while ensuring mutual protection against resistance. Most research work has focused on the use of artesunate combined with currently used standard drugs, namely, mefloquine, amodiaquine, sulfadoxine/pyrimethamine, and chloroquine. There is clear evidence that combinations improve efficacy without increasing toxicity. However, the absolute cure rates that are achieved by combinations vary widely and depend on the level of resistance of the standard drug. From these studies, further work is underway to produce fixed dose combinations that will be packaged in blister packs. This review will summarise current antimalarial drug developments and outline recent clinical research that aims to bring artemisinin based combinations to those that need them most.

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The interaction between the malaria parasite and the human host involves a number of interactions that result in the parasite evading the human immune system. Since the stages of the malaria lifecycle are complex, this allows the use of various immune evasion strategies by the malaria parasite and has major implications in the development of a vaccine for malaria endemic areas. The present review highlights key host:parasite interactions. Plasmodia puts selection pressure on human gene frequencies, and studies into host genetic factors such as the Duffy blood group and sickle cell anaemia offer insight into the host- parasite relationship. In addition, parasite interactions with the different effector arms of the immune system can result in altered peptide ligand (APL) antagonism which alters the immune response from a pro- to an anti-inflammatory T cell response. Recent insights into the interaction between professional antigen presenting cells, dendritic cells (DCs), and malaria parasites is discussed in detail.

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Plasmodium falciparum is the most common cause of severe and life-threatening malaria. Falciparum malaria causes over one million deaths every year. In Africa, a vast majority of these deaths occur in children under five years of age. The presentation of severe malaria varies with age and geographical distribution. The mortality rate is higher in adults than in children but African children develop neuro-cognitive sequelae following severe malaria more frequently. The management of severe malaria includes prompt administration of appropriate parenteral anti-malarial agents and early recognition and treatment of the complications. In children, the complications include metabolic acidosis (often caused by hypovolaemia), hypoglycaemia, hyperlacticacidaemia, severe anaemia, seizures and raised intracranial pressure. In adults, renal failure and pulmonary oedema are more common causes of death. In contrast, concomitant bacterial infections occur more frequently in children and are associated with mortality in children. Admission to critical or intensive care units may help reduce the mortality, and the frequency and severity of sequelae related to severe malaria.

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In most countries where malaria is endemic, P. falciparum malaria is on the rise. This is primarily due to the spread of drug-resistant strains. Drug resistance is mediated by spontaneous changes in the parasite genome that allow resistant parasites to escape the action of the drugs. The spread of drug resistance increases the transmission of malaria parasites. The consequences for the populations at risk are profound both in terms of consequences for health and economy. In order to halt the progression of drug resistance, we need to change the way antimalarials are used. As in tuberculosis and HIV/AIDS, we must use a combination of drugs for the treatment of malaria. Taking into account the pharmacokinetic and pharmacodynamic properties of the various anti-malarial agents, artemisinin-based combination therapy (ACT) seems to be the best option. This strategy should be used in conjunction with early diagnosis and appropriate vector control measures to achieve reduction in the emergence and spread of drug resistance.

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Digital imaging has made major inroads into the routine practice of anatomical pathology and replaces photographic prints and Kodachromes for reporting and conference purposes. More advanced systems coupled to computers allow greater versatility and speed of turnaround as well as lower costs of incorporating macroscopic and microscopic pictures into pathology reports and publications. Digital images allow transmission to remote sites via the Internet for consultation, quality assurance and educational purposes, and can be stored on and disseminated by CD-ROM. Total slide digitisation is now a reality and will replace glass slides to a large extent. Three-dimensional images of gross specimens can be assembled and posted on websites for interactive educational programmes. There are also applications in research, allowing more objective and automated quantitation of a variety of morphological and immunohistological parameters. Early reports indicate that medical vision systems are a reality and can provide for automated computer-generated histopathological diagnosis and quality assurance.

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Thoracic duct injury is a rare but serious complication following chest surgeries and major neck dissections. Clinically, it can present as cervical chylous fistula, chylothorax or chylopericardium. Without treatment, the mortality is up to 50% and thus, early aggressive therapy is indicated. Traditional conservative management includes low-fat diet, parenteral nutrition, careful monitoring of fluid and electrolytes, and drainage of the neck wound or chylothorax. Patients with failed conservative management require definitive treatment in the form of ligation of the thoracic duct, which has traditionally been done by thoracotomy. The advent of Video-Assisted-Thoracoscopic-Surgery (VATS) over the last decade has changed the approach towards the management of numerous chest diseases. Thoracoscopic ligation of the thoracic duct has also been reported. We report herein a case of postoperative cervical chylous fistula managed successfully by VATS thoracic duct ligation and present a systematic analysis of the English literature to highlight the current trends in the management of thoracic duct injury.

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Background: Adverse health effects of exposure to environmental tobacco smoke (ETS) among non-smokers have been studied occasionally in developing countries. Aims: To study the effects of exposure to ETS on outcome in pregnancy Settings and Design: A cross-sectional study at a secondary level teaching hospital Material and Methods: Consecutive 576 non-smoking women delivering a singleton live baby were studied. A pre-designed structured questionnaire was used to record the details of exposure to ETS at home. The maternal and foetal variables were compared among those who were exposed to ETS vis-à-vis not exposed. Unpaired Student t-test was used for the comparison of continuous variables and Fisher's Exact test was used for categorical variables. Multiple logistic regression analysis was performed after including all variables found to have significant differences on univariate analysis. Results: Of the 576 women studied 141 (24%) were exposed to ETS. In the mothers exposed to ETS, there was a significantly higher incidence of pre-term birth (24.1% vs. 16.1%; P = 0.027) and small-for-gestation babies (31.9% vs.17.2%; p< 0.001) as compared to unexposed mothers. The mean birth weight of the babies born to the mothers exposed to ETS was 138 g less than that of babies in the unexposed group (2632 ±577 g vs. 2770 ±562 g respectively, p = 0.014). The multiple logistic regression analyses showed that ETS exposure during pregnancy was significantly associated with a higher risk of small-for-gestation babies (OR 2.10; 95% CI: 1.27- 3.48). Conclusion: Exposure to ETS during pregnancy is associated with higher risk of having a small-for-gestation baby.

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Background: Hypothyroidism is a common, potentially treatable endocrine disorder. Since hypothyroidism is not always associated with the signs and symptoms typically attributed to it, the diagnosis is often missed. Conversely, patients with typical signs and symptoms may not have the disease when laboratory tests are performed. Aims: We aimed to determine the accuracy of physical examination in the diagnosis of hypothyroidism. Setting and design: Prospective, hospital-based, cross-sectional diagnostic study. Material and Methods: Consecutive outpatients from the medicine department were screened and an independent comparison of physical signs (coarse skin, puffy face, slow movements, bradycardia, pretibial oedema and ankle reflex) against thyroid hormone assay (TSH and FT4) was performed. Statistical analysis: Diagnostic accuracy was measured as sensitivity, specificity, positive likelihood ratios, negative likelihood ratios and positive and negative predictive values. Results: Of the 1450 patients screened, 130 patients (102 women and 28 men) underwent both clinical examination and thyroid function tests. Twenty-three patients (18%) were diagnosed to have hypothyroidism by thyroid hormone assays. No single sign could easily discriminate a euthyroid from a hypothyroid patient (range of positive likelihood ratio (LR+) 1.0 to 3.88; range of negative likelihood ratio (LR-): 0.42 to 1.0). No physical sign generated a likelihood ratio large enough to increase the post-test probability significantly. The combination of signs that had the highest likelihood ratios (coarse skin, bradycardia and delayed ankle reflex) was associated with modest accuracy (LR+ 3.75; LR- 0.48). Conclusion: Clinicians cannot rely exclusively on physical examination to confirm or rule out hypothyroidism. Patients with suspected hypothyroidism require a diagnostic workup that includes thyroid hormone assays.

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Background: Aspergillus is a common cause of invasive mycosis, especially in immunocompromised or immunosuppressed individuals. Aims: To study the incidence of invasive pulmonary aspergillosis and evaluate the predisposing factors and clinico-pathological manifestations. Settings and Design: Retrospective analysis of autopsy material from a tertiary care hospital. Material and Methods: All autopsies performed over a 12-year period were reviewed and cases with invasive aspergillosis were analysed with respect to their clinical presentation, predisposing factors, gross and histological features, complications and causes of death. Results: Among a total of 20475 autopsies performed in 12 years, 39 patients (0.19 %) had invasive pulmonary aspergillosis. There were 28 males and 11 females. Their ages ranged from five months to 67 years. Dyspnoea, fever, cough with mucopurulent expectoration, chest pain and haemoptysis were commonly encountered symptoms. Forty-one per cent of the patients had no respiratory symptoms. Fungal aetiology was not entertained clinically in any of the patients. The major underlying conditions were prolonged antibiotic therapy, steroid therapy, and renal transplantation, often associated with underlying lung diseases. Pneumonia, abscesses, vascular thrombosis and infarction were common findings at autopsy. Antecedent tuberculosis, mucormycosis, Pneumocystis carinii pneumonia and Cytomegalovirus infection were also present. In most cases, death was related to extensive pulmonary involvement or fungal dissemination. Conclusion: A diagnosis of invasive pulmonary aspergillosis should always be borne in mind whenever one is dealing with recalcitrant lung infections even with subtle immunosuppression. Radiological investigations and serologic markers can be utilised for confirmation and prompt therapy.

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Gallstone ileus is an unusual cause of colonic obstruction. The formation of a fistula between the gall bladder and the bowel wall may allow a gallstone to enter the intestinal tract. Plain abdominal films, abdominal ultrasound and abdominal computed tomography aid in the diagnosis. Although surgery is the treatment of choice in cases of colonic gallstone ileus, colonoscopic removal of the impacted stone should be attempted. We describe the case of an 85-year-old man who presented with symptoms and signs of large bowel obstruction. Diagnostic evaluation revealed a large gallstone impacted in the sigmoid colon, which is a rather unusual impaction site. Despite our efforts we could not extract the stone endoscopically, mainly due to its large size. Yet, despite its large size, the stone was spontaneously evacuated a few hours later.

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Three cases of rheumatoid arthritis (RA), presenting with refractory anaemia, thrombocytopenia and peripheral lymphocytosis respectively, were observed. In all the cases haematological manifestations were unrelated to disease activity or drug toxicity. These patients were detected to have pure red cell aplasia (PRCA) (normocytic normochromic anaemia, reticulocytopenia and absence of erythroid precursors in the bone marrow), immune thrombocytopenia (IT) (absence of splenomegaly and presence of increased megakaryocytes in the bone marrow) and multiple myeloma (MM) (lytic lesions on skull, paraproteinaemia and bone marrow plasmacytosis) respectively. PRCA and IT responded to glucocorticoids. Association with these three haematological alterations has rarely been reported. Our report highlights the need to regularly monitor blood counts in patients with RA.

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Background: Vomiting is usually a late and an infrequent symptom of colonic obstructions. Contrary to this general rule, it occurs early and more frequently in some cases of sigmoid volvulus. Aim: To study the clinical significance of vomiting in patients with sigmoid volvulus. Setting: Teaching hospital in Western Orissa, India Study Design: Prospective observational study Material and Methods: Prospectively enrolled subjects with sigmoid volvulus diagnosed on the basis of clinical, radiological and laparotomy evidence were included in the study carried out in a tertiary care centre in India. Detailed history was obtained from them, especially to elicit information about the occurrence of various symptoms. Information regarding type of vomiting was also obtained. Efforts were made to exclude other causes of vomiting. Statistical tests such as Chi-Square test, Fisher's exact test or Student's t test were used. Results: Ninety-three consecutive subjects with sigmoid volvulus were enrolled. Five patients with possible other aetiologies for vomiting and seven patients with compound sigmoid volvulus were eliminated from further analysis. Two patterns of vomiting were noted in 81 evaluable patients with sigmoid volvulus. In 33 patients (Group A), vomiting preceded or coincided with the onset of other abdominal symptoms (Type 1 vomiting). In 48 patients (Group B) vomiting occurred after the onset of other abdominal symptoms (Type 2 vomiting). The period between the onset of these symptoms and that of vomiting varied from a few hours to several days. Group A patients sought medical help much earlier than those of Group B. Incidences of circulatory shock (24% vs. 8%), haemorrhagic ascites (21% vs. 6%) and colonic gangrene (64% vs. 35%) were significantly higher in Group A than in Group B. The mortality rate (15% vs. 4%) was higher in Group A as well. About 25% (n = 7) of Group A patients in contrast to 4% (n=2) of Group B required hospitalization exceeding 3 weeks. Vomitus was predominantly non-bilious (21 out of 33 patients) in Group A (64%) and bilious (10 out of 11 patients) in Group B (91%). Conclusion: Type 1 vomiting appears to be an indicator of more severe presentation and is associated with an increased morbidity and mortality. This study suggests that the pattern of vomiting could be a simple and useful predictor of prognosis in sigmoid volvulus.

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Background: Antifolate antimalarials like sulfadoxine-pyrimethamine are used as second-line treatment for Plasmodium falciparum malaria patients who fail to respond to chloroquine. The efficacy of the sulfa-pyrimethamine combination in the treatment is also compromised by the development of resistance in the parasite. Resistance to these drugs has been shown to encode with point mutations in dihydrofolate reductase and dihydropteroate synthetase genes. Settings: An experimental study. Maerial and methods: Forty clinical isolates collected from different geographical locations in India were used to assess the relationships between resistance to sulfadoxine-pyrimethamine (SP) and mutations in P. falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS). In vitro drug susceptibility and mutation-specific polymerase chain reaction (PCR) assays were also done. Results: It was observed that a number of isolates possessed mutant genotypes and showed low sensitivity to SP in vitro. Of the 40 clinical isolates studied, 87.5% had DHFR and 15% had DHPS gene mutations. As observed from PCR results, 55( (22/40) presented double mutation of DHFR Arg-59 and Asn-108 and 32.5 % (13/40) had single mutant type allele of Asn-108. Of the 40 isolates, 10 % (4/40) presented doubly mutated forms of DHPS Phe-436 and Thr-613 and single mutant type allele Gly-581 was detected in 5 % (2/40) isolates. Parasites carrying double or single mutant forms of DHFR/DHPS showed elevated minimum inhibitory concentration (MIC) values of both pyrimethamine (760–6754 nM; r=0.69) and sulfadoxine (108 – 540 µM; r=0.87) when compared to sensitive and resistant strains. Conclusion: Though there was a correlation between molecular techniques and in vitro drug sensitivity profiles, the relevance of these findings to the clinical efficacy of SP combination drugs needs to be established by controlled clinical trials.

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