In sub-Saharan Africa, malaria infection in pregnancy contributes to low birth weight through intrauterine growth retardation (IUGR) and preterm delivery (PTD). It was hypothesized that ...malaria-associated PTD and IUGR have differing etiologies due to timing of infection. In a prospective cohort of primigravid women enrolled at the antenatal clinic of Mangochi District Hospital in Malawi, the associations were investigated between antenatal or delivery parasitemias and IUGR or PTD. Among 178 singleton deliveries, 35% of infants were preterm or had IUGR. Cord blood parasitemia (odds ratio OR = 3.34; 95% confidence interval CI, 1.3–8.8, placental parasitemia (OR = 2.43; 95% CI, 1.2–5.1), and postdelivery maternal peripheral parasitemia (OR = 2.78; 95% CI, 1.3–6.1) were associated with PTD. Parasitemia and/or clinically diagnosed malaria in the antenatal period was associated with IUGR (OR = 5.13; 95% CI, 1.4–19.4). Delivery parasitemias had borderline associations with IUGR. The risk patterns observed suggest that the timing and severity of infection influences the occurrence of IUGR or PTD.
Hevin, also known as SC1, MAST 9, SPARC-like 1, RAGS1 and ECM2, is a member of the SPARC-related family of matricellular proteins. Mouse hevin is 53% identical to mouse SPARC, and both proteins share ...a follistatin-like module and an extracellular Ca2+-binding (E-C) domain. SPARC functions as a modulator of cell-matrix interactions, a regulator of growth factor activity, a de-adhesive protein, and a cell cycle inhibitor. Although the functions of mouse hevin are unknown, its human orthologue has been shown to be de-adhesive for endothelial cells. We now report the production of recombinant mouse hevin in insect cells through the use of a baculoviral expression system and its purification by anion-exchange, size-exclusion chromatography, and isoelectric focusing. Furthermore, we have produced rat anti-hevin monoclonal antibodies (MAbs) that have been characterized by indirect and capture ELISAs, immunoblotting, immunoprecipitation, and immunohistochemistry (IHC). Recombinant hevin, present as a soluble factor or bound to tissue-culture plastic, inhibited the spreading of bovine aortic endothelial cells in vitro. IHC analysis of hevin in normal human and mouse tissues revealed a limited expression pattern in many tissues, with particularly dominant staining in dermis, ducts, vasculature, muscle, and brain. In lung and pancreatic tumor xenografts, we found distinct reactivity with MAbs that were selective for stromal cells, tumor cells, and/or endothelial cells. Although similar to SPARC in its anti-adhesive activities, hevin nevertheless exhibits a distinctive histological distribution that, in certain invasive tumors, is associated with desmoplasia.
We explore the impact of a host genetic factor on heterosexual HIV epidemics by using a deterministic mathematical model. A protective allele unequally distributed across populations is exemplified ...in our models by the 32-bp deletion in the host-cell chemokine receptor CCR5, CCR5Δ32. Individuals homozygous for CCR5Δ32 are protected against HIV infection whereas those heterozygous for CCR5Δ32 have lower pre-AIDS viral loads and delayed progression to AIDS. CCR5Δ32 may limit HIV spread by decreasing the probability of both risk of infection and infectiousness. In this work, we characterize epidemic HIV within three dynamic subpopulations: CCR5/CCR5 (homozygous, wild type), CCR5/CCR5Δ32 (heterozygous), and CCR5Δ32/CCR5Δ32 (homozygous, mutant). Our results indicate that prevalence of HIV/AIDS is greater in populations lacking the CCR5Δ32 alleles (homozygous wild types only) as compared with populations that include people heterozygous or homozygous for CCR5Δ32. Also, we show that HIV can provide selective pressure for CCR5Δ32, increasing the frequency of this allele.
Hypereosinophilic syndromes (HES) are a heterogeneous group of disorders characterized by peripheral eosinophilia and eosinophil-related end organ damage. Whereas most patients respond to steroid ...therapy, high doses are often necessary and serious side effects are common. Dexpramipexole (KNS-760704) is an orally bioavailable synthetic amino-benzothiazole that was in development for the treatment of amyotrophic lateral sclerosis (ALS). Despite failure to meet the primary efficacy endpoint in a phase 3 trial in ALS patients, dexpramipexole showed an excellent safety profile and was found to significantly decrease absolute eosinophil counts (AEC) in >70% of the study participants. Consequently, a proof-of-concept study was designed to evaluate the safety and efficacy of dexpramipexole as a steroid-sparing agent in 10 HES subjects.
Subjects with HES on steroid monotherapy were eligible for the study if they required ≥10 mg prednisone or equivalent for control of symptoms and eosinophilia. Subjects with AEC <1000/uL and no active symptoms entered a lead-in period, consisting of a standardized steroid taper with weekly assessment of AEC and symptoms to establish a "minimally effective corticosteroid dose (MECD)". Those with AEC ≥1000/uL entered directly into the treatment phase. Once the MECD was established, treatment with dexpramipexole (150 mg twice daily) was initiated. After 12 weeks of treatment, a standardized corticosteroid taper was attempted to determine the "MECD on dexpramipexole". Clinical assessments, including bone marrow and tissue biopsies of affected organs (when possible), were performed prior to and after 12 weeks of dexpramipexole. The primary efficacy endpoint was defined as a ≥50 % change in prednisone dose to maintain AEC at or below baseline levels and control clinical symptoms.
Study enrollment is complete. Median age at enrollment was 51 years (22-72) with 40% women. Baseline clinical manifestations included eosinophilic gastrointestinal disease (60%), pulmonary involvement (50%), skin, muscle, sinus, and cardiac disease. Median baseline AEC was 670/uL (280-2540) and median MECD at baseline was 18.75 mg of prednisone (10-25). To date, the MECD on dexpramipexole has been determined for 7 subjects, and 3 subjects continue on study and have not completed the steroid taper on dexpramipexole. Two of the 7 evaluable subjects met the primary end point. Both subjects reached a MECD of 0 mg of prednisone and had complete symptom resolution with AEC of 0/uL within 3 months of initiating treatment with dexpramipexole. They remain in clinical remission on dexpramipexole monotherapy for 7 and 12 months, respectively. One additional subject who did not meet the primary endpoint at 3 months, was able to maintain a stable dose of 12.5 mg of prednisone with clinical improvement. She has remained on dexpramipexole and has demonstrated a delayed response with AEC 100/uL on 8.75 mg prednisone (50% of her baseline MECD) at 6 months. The remaining 4 evaluable subjects failed to respond and were taken off study. No deaths or drug related adverse events were observed, although 2 subjects reported transient palpitations and insomnia that resolved without drug discontinuation.
Bone marrow biopsies performed at 12 weeks revealed markedly decreased AEC and basophils in responders as compared to baseline samples, and residual eosinophils appeared left-shifted. Other cell lineages were unchanged. Gastrointestinal biopsies in 1 responder demonstrated complete resolution of tissue eosinophilia after 5 months on dexpramipexole. Flow cytometry demonstrated no difference in CD34+ or CD34+IL-5R+ cell numbers after 12 weeks of treatment, but a decrease in eosinophil expression of Siglec 8, an inhibitory receptor expressed only on mature eosinophils. These changes were not observed in the non-responders. CD34+ cell cultures using normal cord blood samples also suggest a delay in maturation of the eosinophil lineage in the presence of dexpramipexole.
Given the frequency of steroid-induced morbidity in patients with HES, alternate therapeutic options are critical. In this pilot study, dexpramipexole showed remarkable efficacy as a steroid-sparing agent without apparent toxicity in a subset of subjects with steroid-responsive HES. Although the mechanism of action is unknown, preliminary data suggest that dexpramipexole may affect eosinophil maturation in the bone marrow.
Bozik:Knopp Biosciences: Employment. Brown:Leidos Biomedical Research Inc.: Employment. Demarco:Knopp Biosciences: Employment. Komarov:Knopp Biosciences: Employment. Magee:Leidos Biomedical Research Inc.: Employment. Prussin:Knopp Biosciences: Employment. Signore:Knopp Biosciences: Employment. Sullivan:Knopp Biosciences: Employment. Wetzler:Leidos Biomedical Research Inc.: Employment. Dunbar:Novartis: Research Funding. Dworetzky:Knopp Biosciences: Employment.
Background Nephrology fellows need expertise navigating challenging conversations with patients throughout the course of advanced kidney disease. However, evidence shows that nephrologists receive ...inadequate training in this area. This study assessed the effectiveness of an educational quality improvement intervention designed to enhance fellows’ communication with patients who have advanced kidney disease. Study Design Quality improvement project. Setting & Participants Full-day annual workshops (2013-2014) using didactics, discussion, and practice with simulated patients. Content focused on delivering bad news, acknowledging emotion, discussing care goals in dialysis decision making when prognosis is uncertain, and addressing dialysis therapy withdrawal and end of life. Participants were first-year nephrology fellows from 2 Harvard-affiliated training programs (N = 26). Quality Improvement Plan Study assessed the effectiveness of an intervention designed to enhance fellows’ communication skills. Outcomes Primary outcomes were changes in self-reported patient communication skills, attitudes, and behaviors related to discussing disease progression, prognostic uncertainty, dialysis therapy withdrawal, treatments not indicated, and end of life; responding to emotion; eliciting patient goals and values; and incorporating patient goals into recommendations. Measurements Surveys measured prior training, pre- and postcourse perceived changes in skills and values, and reported longer term (3-month) changes in communication behaviors, using both closed- and open-ended items. Results Response rates were 100% (pre- and postsurveys) and 68% (follow-up). Participants reported improvement in all domains, with an overall mean increase of 1.1 (summed average scores: precourse, 2.8; postcourse, 3.9 1-5 scale; 5 = “extremely well prepared”; P < 0.001), with improvement sustained at 3 months. Participants reported meaningful changes integrating into practice specific skills taught, such as “Ask-Tell-Ask” and using open-ended questions. Limitations Self-reported data may overestimate actual changes; small sample size and the programs’ affiliation with a single medical school may limit generalizability. Conclusions A day-long course addressing nephrology fellows’ communication competencies across the full course of patients’ illness experience can enhance fellows’ self-reported skills and practices.
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