Lymphatic filariasis elimination in the Dominican Republic: History,progress, and remaining steps

Lymphatic filariasis (LF) is a mosquito-transmitted parasitic disease that is a leading cause of disability globally. The island of Hispaniola, which the Dominican Republic shares with Haiti, accounts for approximately 90% of LF cases in the Americas region. In 1998, the Dominican Ministry of Public Health created the Program to Eliminate Lymphatic Filariasis (PELF) with the goal of eliminating LF transmission by 2020. Baseline mapping revealed 19 (12% of total) endemic municipalities clustered into three geographic foci (Southwest, La Ciénaga and East), with a total at-risk population of 262,395 people. Beginning in 2002, PELF sequentially implemented mass drug administration (MDA) in these foci using albendazole and diethylcarbamazine (DEC). In total, 1,174,050 treatments were given over three to five annual rounds of house-to-house MDA per focus with a median coverage of 81.7% (range 67.4%–92.2%). By 2018, LF antigen prevalence was less than 2% in all foci, thus meeting criteria to stop MDA and begin post-treatment surveillance (PTS). This success has been achieved against a shifting landscape of limited domestic funding, competing domestic public health priorities, and sporadic external donor support. Remaining steps include the need to scale-up morbidity management and disability prevention services for LF and to continue PTS until LF transmission is interrupted across Hispaniola.     

Determinants of Bed Net Use in Southeast Nigeria following Mass Distribution of LLINs: Implications for Social Behavior Change Interventions

Millions of long-lasting insecticide treated nets (LLINs) have been distributed as part of the global malaria control strategy. LLIN ownership, however, does not necessarily guarantee use. Thus, even in the ideal setting in which universal coverage with LLINs has been achieved, maximal malaria protection will only be achieved if LLINs are used both correctly and consistently. This study investigated the factors associated with net use, independent of net ownership. Data were collected during a household survey conducted in Ebonyi State in southeastern Nigeria in November 2011 following a statewide mass LLIN distribution campaign and, in select locations, a community-based social behavior change (SBC) intervention. Logistic regression analyses, controlling for household bed net ownership, were conducted to examine the association between individual net use and various demographic, environmental, behavioral and social factors. The odds of net use increased among individuals who were exposed to tailored SBC in the context of a home visit (OR = 17.11; 95% CI 4.45–65.79) or who received greater degrees of social support from friends and family (ptrend < 0.001). Factors associated with decreased odds of net use included: increasing education level (ptrend = 0.020), increasing malaria knowledge level (ptrend = 0.022), and reporting any disadvantage of bed nets (OR = 0.39; 95% CI 0.23–0.78). The findings suggest that LLIN use is significantly influenced by social support and exposure to a malaria-related SBC home visit. The malaria community should thus further consider the importance of community outreach, interpersonal communication and social support on adoption of net use behaviors when designing future research and interventions.     

Thiobenzothiazole-modified Hydrocortisones Display Anti-inflammatory Activity with Reduced Impact on Islet β-Cell Function

Glucocorticoids signal through the glucocorticoid receptor (GR) and are administered clinically for a variety of situations, including inflammatory disorders, specific cancers, rheumatoid arthritis, and organ/tissue transplantation. However, glucocorticoid therapy is also associated with additional complications, including steroid-induced diabetes. We hypothesized that modification of the steroid backbone is one strategy to enhance the therapeutic potential of GR activation. Toward this goal, two commercially unavailable, thiobenzothiazole-containing derivatives of hydrocortisone (termed MS4 and MS6) were examined using 832/13 rat insulinoma cells as well as rodent and human islets. We found that MS4 had transrepression properties but lacked transactivation ability, whereas MS6 retained both transactivation and transrepression activities. In addition, MS4 and MS6 both displayed anti-inflammatory activity. Furthermore, MS4 displayed reduced impact on islet β-cell function in both rodent and human islets. Similar to dexamethasone, MS6 promoted adipocyte development in vitro, whereas MS4 did not. Moreover, neither MS4 nor MS6 activated the Pck1 (Pepck) gene in primary rat hepatocytes. We conclude that modification of the functional groups attached to the D-ring of the hydrocortisone steroid molecule produces compounds with altered structure-function GR agonist activity with decreased impact on insulin secretion and reduced adipogenic potential but with preservation of anti-inflammatory activity.     

Early effects of luteinizing hormone on mitochondrial phosphoinositides in ovarian follicles

It is not clear if luteinizing hormone (LH) stimulates breakdown as well as synthesis of phosphoinositides in ovarian tissue. Possibly, LH stimulation results in hydrolysis of ovarian phosphoinositides in discrete subcellular compartments while increasing their synthesis at other sites. To investigate this hypothesis, we determined the effects of LH on phosphoinositide metabolism in whole homogenates and mitochondria of ovarian follicles. Medium (3-7 mm) follicles from porcine ovaries were preincubated for 2 h in phosphate (PO4)-free medium with 32PO4, and incubated without or with LH (1 microgram/ml). Phosphatidylinositol (PI) and related compounds, phosphatidic acid (PA), phosphatidylinositol phosphate (PIP) and phosphatidylinositol bisphosphate (PIP2), accounted for 40% of the radiolabeled phospholipids in whole homogenates and over 60% in mitochondria from preincubated follicles. After 5 min, LH caused a significant decrease in radiolabeling of PIP2 and PIP in mitochondria, but not in whole homogenates. Luteinizing hormone increased radiolabeling of PIP2, PIP, PI and PA within 10 min in whole homogenates, and within 20 to 30 min in mitochondria. This delayed increase in radiolabeling of mitochondrial phosphoinositides after LH treatment was accompanied by decreases in PIP2, PIP and PI radiolabeling in whole homogenates. Follicles also were preincubated for 4 h with [3H]inositol, then for 15 min with 10 mM LiCl (an inhibitor of inositol phosphate hydrolysis). Inositol phosphate accumulation in 30 min was 2.7 times higher in homogenates of LH-treated follicles then in untreated follicles. Also, LH significantly decreased inositol bisphosphate, but did not change inositol trisphosphate accumulation. Accumulation of inositol phosphates in mitochondria was not measurable.(ABSTRACT TRUNCATED AT 250 WORDS)     

Counter-regulatory anti-parasite cytokine responses during concurrent Plasmodium yoelii and intestinal helminth infections in mice

Malaria and helminth infections are two of the most prevalent parasitic diseases globally. While concomitant infection is common, mechanisms contributing to altered disease outcomes during co-infection remain poorly defined. We have previously reported exacerbation of normally non-lethal Plasmodium yoelii malaria in BALB/c mice chronically infected with the intestinal trematode Echinostoma caproni. The goal of the present studies was to determine the effect of helminth infection on IFN-γ and other key cytokines during malaria co-infection in the P. yoelii-E. caproni and P. yoelii-Heligmosomoides polygyrus model systems. Polyclonally stimulated spleen cells from both E. caproni- and H. polygyrus-infected mice produced significantly lower amounts of IFN-γ during P. yoelii co-infection than malaria-only infected mice. Furthermore, the magnitude of IFN-γ suppression was correlated with the relative amounts of IL-4 induced by these helminths (E. caproni = low; H. polygyrus = high), but not IL-10. Concurrent malaria infection also suppressed helminth-associated IL-4 responses, indicating that immunologic counter-regulation occurs during co-infection with malaria and intestinal helminths.     

Calcium-induced modification of the acrosomal matrix in digitonin-permeabilized guinea pig spermatozoa

In this report we describe and partially characterize a preparation of digitonin-permeabilized guinea pig spermatozoa that undergo a rapid and synchronous modification of the acrosomal matrix in response to calcium. Permeabilization of cauda epididymal spermatozoa by digitonin was monitored by using adenylate cyclase activity as an indicator. Spermatozoa (5 x 10(7) cells) treated with 0.005% digitonin for 15 s exhibited maximal adenylate cyclase activity but generally retained their structural morphology, as examined by phase-contrast and transmission electron microscopy. The ratio fo cell number to detergent concentration was the critical factor for determining both the efficiency of permeabilization and the maintenance of structural integrity. When permeabilized spermatozoa were treated with 2 mM CaCl2, the cells underwent a rapid and synchronous modification of the acrosomal matrix (AM). As observed by phase-contrast microscopy, the response to CaCl2 was characterized by events that occurred in the following temporal sequence: disruption of the sperm rouleaux, the loss of refractility by the apical segment of the sperm acrosome, and detachment of the apical segment from the spermatozoa. Transmission electron microscopy indicated that the loss of refractility from the sperm apical segment was coincident with a calcium-induced dispersion of the AM. Analysis of the proteins released during this response, by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, revealed that a specific subset of sperm proteins was released from the spermatozoa, including a major = staining, 45,000 Mr protein apparently generated from a higher molecular weight precursor during the acrosome reaction.