Towards a Strategic Plan for Research to Support the Global Program to EIiminate Lymphatic FiIariasis: Summary of Immediate Needs and Opportunities for Research on Lymphatic Filariasis. 2.2 Essential tools – Drugs and Clinical Drug Trials

A series of advances during the past decade transformed LF from a neglected disease of poor countries into a disease now recognized as potentially eradicable. Principal among the reasons for these advances were the identification of ivermectin and albendazole as new, effective anti-filarial agents and the discovery of new virtues for an old anti-filarial drug, DEC (i.e., its single-dose efficacy and macrofilaricidal action). These discoveries were essential for the subsequent creation of the Global Program to Eliminate LF,1 whose very basis is the large-scale use of DEC, ivermectin (Mectizan�; Merck and Co., Inc., Rahway, NJ) and albendazole. Indeed, in many endemic countries literally millions of tablets of these drugs are distributed over a few short days each year (often on a single day), making GPELF the largest chemotherapy program ever undertaken. Currently it is just these three drugs that are available for use in single-dose, annual MDA programs. Albendazole is co-administered with ivermectin in areas of Africa and Yemen where LF and onchocerciasis are co-endemic. For all other LF-endemic regions, albendazole is co-administered with DEC. At the recommended dose levels, none of the drugs is completely macrofilaricidal, although all appear to inflict some lasting damage to adult worms. Both DEC and ivermectin kill mf efficiently; albendazole, on the other hand, has no direct effect on mf, but rather appears to suppress embryogenesis in the adult female worm. An alternative treatment strategy involving the use of DEC as a fortificant in table/cooking salt for a period of 1−2 years is currently used in just one country, but was a mainstay of the earlier, successful LF elimination program in China

On the occurrence of buckler crab Cryptopodia angulata in the coastal waters of India

464-467The trend of marine non-indigenous species in India has been increasing, with more than half of the species probably being introduced by shipping. A live specimen of buckler crab Cryptopodia angulata was found along the west coast of India at 40 m depth. The recent new records at different Indian coastal locations suggest that the crab is widening its distribution. Shipping is thought to be the possible introduction vector (via ballast) for the spread of C. angulata in the coastal waters of India. Further, the favorable environmental conditions prevalent in the Indian coastal waters may facilitate the establishment and subsequent spread of C. angulata. The invasion of this buckler crab may have negative impact on the native species. Although not present in detectable numbers, C. angulata may pose a major threat to the native species, if it establishes. Information on the establishment and distribution of C. angulata from other locations along the Indian coast would be essential to comprehensively and effectively address the threat

Heterogeneous microbial oceanographic environments: Application of GIS technology in deciphering of microenvironment scenarios off the central west coast of India

In the vast oceanic microbial environment of 2468.83km 2, GIS modeling techniques involving sixty query steps, enabled the deciphering of Microenvironments as low as 1.19km 2 to 38.6 km 2 for the summer of 2004 and in case of summer 2005 where 84 query steps were involved to decipher Microenvironments of 10.55km 2 to 25.94km 2. Thirtythree sampling stations were established between Betul to Ankola off the central west coast of India accounting for a spatial coverage of 2468.83km 2. GIS query-modeling investigation was carried out using spatial layers of depth, optical parameters (k-Irradiance attenuation Coefficient, c-Beam attenuation coefficient), sediment size parameters (Sediment Mean Size and Sediment Sorting) and Benthic Foraminifera Suborders (Rotaliina, Textulariina, Miliolina, Lagenina). Foraminifera have been used as a surrogate parameter. However, any microbial parameter could proxy for foraminifers providing for the numerical deciphering of microenvironments. This is suggestive of the assimilation of GIS technology for a better appreciation of microbial oceanography

A rapid dipstick test for serological diagnosis of brugian filariasis: evaluation results

A total of 753 serum samples from six institutions were used to evaluate an immunochromatographic rapid dipstick test (Brugia Rapid) for diagnosis of Brugia malayi infection.The samples comprised of sera from 207 microfilaria positive individuals and 546 individuals from filaria non-endemic areas.The latter consisted of 70 individuals with soil-transmitted helminthic infections, 68 individuals with other helminthic infections, 238 individuals with protozoan infections, 12 individuals with bacterial and viral infections and 158 healthy individuals. The dipstick is lined with goat anti-mouse antibody (control line) and a B. malayi recombinant antigen (test line).First, the dipstick is dipped into a well containing diluted patient sera, thus allowing specific anti-filarial antibody in the serum to react with the recombinant antigen.Then the dipstick is placed into an adjacent well containing reconstituted anti-human IgG4-gold.After 10 minutes, development of two red-purplish lines denotes a positive result and one line indicates a negative reaction. The overall results of the evaluation showed 91% sensitivity, 99% specificity, 97% positive predictive value and 99% negative predictive value. Brugia Rapid is thus a promising diagnostic tool for detection of B. malayi infection,and would be especially useful for the brugian filariasis elimination programme

Bacteriological studies of blood, tissue fluid, lymph and lymph nodes in patients with acute dermatolymphangioadenitis (DLA) in course of ‘filarial’ lymphedema

Filarial lymphedema is complicated by frequent episodes of dermatolymphangioadenitis (DLA). Severe systemic symptoms during attacks of DLA resemble those of septicemia. The question we asked was whether bacterial isolates can be found in the peripheral blood of patients during the episodes of DLA. Out of 100 patients referred to us with ‘filarial’ lymphedema 14 displayed acute and five subacute symptoms of DLA. All were on admission blood microfilariae negative but had a positive test in the past. Blood bacterial isolates were found in nine cases, four acute (21%) and five subacute (26%). In 10 acute cases blood cultures were found negative. Six blood isolates belonged to Bacilli, four to Cocci and one was Sarcina. To identify the sites of origin of bacterial dissemination, swabs taken from the calf skin biopsy wounds and tissue fluid, lymph and lymph node specimens were cultured. Swabs from the calf skin biopsy wound contained isolates in nine (47%) cases. They were Bacilli in nine, Cocci in three, Acinetobacter and Erwinia in two cases. Tissue fluid was collected from 10 patients and contained Bacilli in four (40%) and Staphylococci in three (30%). Lymph was drained in four patients and contained isolates in all samples (100%). They were Staphylococcus epidermis, xylosus and aureus, Acinetobacter, Bacillus subtilis and Sarcina. Three lymph nodes were biopsied and contained Staphylococcus chromogenes, xylosus, Enterococcus and Bacillus cereus. In six cases the same phenotypically defined species of bacteria were found in blood and limb tissues or fluids. In the ‘control’ group of patients with lymphedema without acute or subacute changes all blood cultures were negative. Interestingly, swabs from biopsy wound of these patients contained isolates in 80%, tissue fluid in 68%, lymph in 70% and lymph nodes in 58% of cases. In healthy controls, tissue fluid did not contain bacteria, and lymph isolates were found only in 12% of cases. This study demonstrates that patients with acute episodes of DLA reveal bacteriemia in a high percentage of cases. Diversity of blood and tissue bacterial isolates in these patients points to a breakdown of the skin immune barrier in lymphedema and subsequently indiscriminate bacterial colonization of deep tissues and spread to an blood circulation. © 1999 Elsevier Science B.V. All rights reserved

Exome sequencing identifies titin mutations causing hereditary myopathy with early respiratory failure (HMERF) in families of diverse ethnic origins

Background: Hereditary myopathy with early respiratory failure (HMERF) was described in several North European families and recently linked to a titin gene (TTN) mutation. We independently studied HMERF-like diseases with the purpose to identify the cause, refine diagnostic criteria, and estimate the frequency of this disease among myopathy patients of various ethnic origins. Methods: Whole exome sequencing analysis was carried out in a large U. S. family that included seven members suffering from skeletal muscle weakness and respiratory failure. Subsequent mutation screening was performed in further 45 unrelated probands with similar phenotypes. Studies included muscle strength evaluation, nerve conduction studies and concentric needle EMG, respiratory function test, cardiologic examination, and muscle biopsy. Results: A novel TTN p.Gly30150Asp mutation was identified in the highly conserved A-band of titin that co-segregated with the disease in the U. S. family. Screening of 45 probands initially diagnosed as myofibrillar myopathy (MFM) but excluded based on molecular screening for the known MFM genes led to the identification of a previously reported TTN p.Cys30071Arg mutation in one patient. This same mutation was also identified in a patient with suspected HMERF. The p.Gly30150Asp and p.Cys30071Arg mutations are localized to a side chain of fibronectin type III element A150 of the 10th C-zone super-repeat of titin. Conclusions: Missense mutations in TTN are the cause of HMERF in families of diverse origins. A comparison of phenotypic features of HMERF caused by the three known TTN mutations in various populations allowed to emphasize distinct clinical/pathological features that can serve as the basis for diagnosis. The newly identified p.Gly30150Asp and the p.Cys30071Arg mutation are localized to a side chain of fibronectin type III element A150 of the 10th C-zone super-repeat of titin

Acute tropical pulmonary eosinophilia: characterization of the lower respiratory tract inflammation and its response to therapy

Although acute tropical pulmonary eosinophilia (TPE) is well recognized as a manifestation of filarial infection, the processes that mediate the abnormalities of the lung in TPE are unknown. To evaluate the hypothesis that the derangements of the lower respiratory tract in this disorder are mediated by inflammatory cells in the local milieu we utilized bronchoalveolar lavage to evaluate affected individuals before and after therapy. Inflaminatory cells recovered from the lower respiratory tract of individuals with acute, untreated TPE (a = 8) revealed a striking eosinophilic alveolitis, with marked elevations in both the proportion of eosinophils (TPE 54±5%; normal 2±5%; P < 0.001) and the concentration of eosinophils in the recovered epithelial lining fluid (ELF) (TPE 63±20 X 103/Al; normal 03±0.1 X 103/jl; P < 0.01). Importantly, when individuals (a = 5) with acute TPE were treated with diethylcarbamazine (DEC), there was a marked decrease of the lung eosinophils and concomitant increase in lung function. These observations are consistent with the concept that at least some of the abnormalities found in the lung in acute TPE are mediated by an eosinophil-dominated inflammatory process in the lower respiratory tract

Transcriptomic profile of adverse neurodevelopmental outcomes after neonatal encephalopathy

A rapid and early diagnostic test to identify the encephalopathic babies at risk of adverse outcome may accelerate the development of neuroprotectants. We examined if a whole blood transcriptomic signature measured soon after birth,predicts adverse neurodevelopmental outcomeeighteenmonths after neonatal encephalopathy.We performed next generation sequencing on whole blood ribonucleic acid obtained within sixhours of birth from the first 47encephalopathic babies recruited to the Hypothermia for Encephalopathy in Low and middle-income countries (HELIX)trial. Two infants with blood culture positive sepsis were excluded, and the data from remaining 45 were analysed. A total of 855genes were significantly differentially expressed between the good and adverse outcome groups, of which RGS1and SMC4 werethe most significant. Biological pathway analysis adjusted for gender, trial randomisation allocation (cooling therapy versus usual care) and estimated blood leukocyte proportions revealed over-representation of genes from pathways related to melatoninand polo-like kinase in babieswith adverse outcome. These preliminary data suggest that transcriptomic profiling may be a promising tool for rapid risk stratification in neonatal encephalopathy. It may provide insights into biological mechanismsand identify novel therapeutic targetsfor neuroprotection

Ivermectin, ‘Wonder drug’ from Japan: the human use perspective

Discovered in the late-1970s, the pioneering drug ivermectin, a dihydro derivative of avermectin—originating solely from a single microorganism isolated at the Kitasato Intitute, Tokyo, Japan from Japanese soil—has had an immeasurably beneficial impact in improving the lives and welfare of billions of people throughout the world. Originally introduced as a veterinary drug, it kills a wide range of internal and external parasites in commercial livestock and companion animals. It was quickly discovered to be ideal in combating two of the world’s most devastating and disfiguring diseases which have plagued the world’s poor throughout the tropics for centuries. It is now being used free-of-charge as the sole tool in campaigns to eliminate both diseases globally. It has also been used to successfully overcome several other human diseases and new uses for it are continually being found. This paper looks in depth at the events surrounding ivermectin’s passage from being a huge success in Animal Health into its widespread use in humans, a development which has led many to describe it as a “wonder” drug