Randomized comparison of single dose of recombinant human IL-12 versus placebo for restoration of hematopoiesis and improved survival in rhesus monkeys exposed to lethal radiation

BACKGROUND: The hematopoietic syndrome of the acute radiation syndrome (HSARS) is a life-threatening condition in humans exposed to total body irradiation (TBI); no drugs are approved for treating this condition. Recombinant human interleukin-12 (rHuIL-12) is being developed for HSARS mitigation under the FDA Animal Rule, where efficacy is proven in an appropriate animal model and safety is demonstrated in humans. METHODS: In this blinded study, rhesus monkeys (9 animals/sex/dose group) were randomized to receive a single subcutaneous injection of placebo (group 1) or rHuIL-12 at doses of 50, 100, 250, or 500 ng/kg (groups 2–5, respectively), without antibiotics, fluids or blood transfusions, 24–25 hours after TBI (700 cGy). RESULTS: Survival rates at Day 60 were 11%, 33%, 39%, 39%, and 50% for groups 1–5, respectively (log rank p < 0.05 for each dose vs. control). rHuIL-12 also significantly reduced the incidences of severe neutropenia, severe thrombocytopenia, and sepsis (positive hemoculture). Additionally, bone marrow regeneration following TBI was significantly greater in monkeys treated with rHuIL-12 than in controls. CONCLUSIONS: Data from this study demonstrate that a single injection of rHuIL-12 delivered one day after TBI can significantly increase survival and reduce radiation-induced hematopoietic toxicity and infections. These data significantly advance development of rHuIL-12 toward approval under the Animal Rule as an effective stand-alone medical countermeasure against the lethal effects of radiation exposure

Vascular Regeneration by Local Growth Factor Release Is Self-Limited by Microvascular Clearance

Background— The challenge of angiogenesis science is that stable sustained vascular regeneration in humans has not been realized despite promising preclinical findings. We hypothesized that angiogenic therapies powerfully self-regulate by dynamically altering tissue characteristics. Induced neocapillaries increase drug clearance and limit tissue retention and subsequent angiogenesis even in the face of sustained delivery. Methods and Results— We quantified how capillary flow clears fibroblast growth factor after local epicardial delivery. Fibroblast growth factor spatial loading was significantly reduced with intact coronary perfusion. Penetration and retention decreased with transendothelial permeability, a trend diametrically opposite to intravascular delivery, in which factor delivery depends on vascular leak, but consistent with a continuum model of drug transport in perfused tissues. Model predictions of fibroblast growth factor sensitivity to manipulations of its diffusivity and transendothelial permeability were validated by conjugation to sucrose octasulfate. Induction of neocapillaries adds pharmacokinetic complexity. Sustained local fibroblast growth factor delivery in vivo produced a burst of neovascularization in ischemic myocardium but was followed by drug washout and a 5-fold decrease in fibroblast growth factor penetration depth. Conclusions— The very efficacy of proangiogenic compounds enhances their clearance and abrogates their pharmacological benefit. This self-limiting property of angiogenesis may explain the failures of promising proangiogenic therapies.National Institutes of Health (U.S.) (Grant R01 GM 49039

Examining responsiveness of India’s trade flows to exchange rate movements

Determinants of trade flows have always attracted researchers. In this paper, we model monthly trade flows in India over January 2000 – December 2007 in a bid to gauge their responsiveness to exchange rate movements. Capital account and overall BOP surplus have led the Indian Rupee (INR) to appreciate and forex reserves to accumulate. In so far as the RBI intervenes to stem this forex accretion by the net purchase of USD, it puts further pressure on the INR to appreciate. It therefore becomes important to study the response of the current account to these changes in the exchange rate. We employ standard empirical estimations of India’s export supply and import demand functions using data from the Reserve Bank of India. We also assess the short-term dynamics of these trade flows through error correction models. Finally, we estimate vector auto regression models to gauge the extent of contemporaneous interaction between trade flows and the explanatory variables in the system

Sound radiation from a plate immersed in water near the free surface

The results on the acoustic response of a heavy fluid-loaded baffled plate excited by a harmonic point force are presented. The displacements of the fluid-loaded plate are decomposed on the basis of the in-vacuo plate modes and the radiated acousic waves are determined solving the Helmholtz equation in a fluid. The Green's function for the acoustic waveguide domain formed by the baffled plate and the free surface is modelled by the source-image method. Predictions for the radiated sound power from the plate and pressure spectra are calculated for varying depths of the free surface and compared against results from an unbounded domain to infer the effect of the free surface on the acoustic response of the plate. The proposed analytical model is verified by comparison with finite element simulations

Occupational Animal Contact in Southern and Central Vietnam

Despite the global zoonotic disease burden, the underlying exposures that drive zoonotic disease emergence are not understood. Here, we aimed to assess exposures to potential sources of zoonotic disease and investigate the demographics, attitudes, and behavior of individuals with sustained occupational animal contact in Vietnam. We recruited 581 animal workers (animal-raising farmers, slaughterers, animal health workers, and rat traders) and their families in southern and central Vietnam into a cohort. Cohort members were followed for 3 years and interviewed annually regarding (1) demography and attitudes regarding zoonotic disease, (2) medical history, (3) specific exposures to potential zoonotic infection sources, and (4) socioeconomic status. Interview information over the 3 years was combined and analyzed as cross-sectional data. Of the 297 cohort members interviewed, the majority (79.8%; 237/297) reported raising livestock; almost all (99.6%; 236/237) reported being routinely exposed to domestic animals, and more than a quarter (28.7%; 68/237) were exposed to exotic animals. Overall, 70% (208/297) reported slaughtering exotic animals; almost all (99.5%; 207/208) reported consuming such animals. The consumption of raw blood and meat was common (24.6%; 73/297 and 37%; 110/297, respectively). Over half (58.6%; 174/297) reported recent occupational animal-induced injuries that caused bleeding; the use of personal protective equipment (PPE) was limited. Our work demonstrates that individuals working with animals in Vietnam are exposed to a wide range of species, and there are limited procedures for reducing potential zoonotic disease exposures. We advocate better education, improved animal security, and enforced legislation of PPE for those with occupational animal exposure in Vietnam.Peer reviewe

Management of Patients with Refractory Cardiogenic Shock and Cardiointestinal Syndrome with Impella 5.5 as Bridge to Decision: Case Series

Patients with advanced heart failure require multi-system management as a majority succumb to end-organ dysfunction, including gastrointestinal sequelae. Temporizing measures, such as early mechanical circulatory support, can assist in the recovery of patients with acute cardiogenic shock. The temporary support can improve patient characteristics to enable future definitive heart failure therapies such as durable left ventricular assist devices and orthotopic heart transplantation. We present two cases of cardiogenic shock that were successfully bridged with an Impella 5.5 (Abiomed). The management enabled the patients to recover from reversible cardiointestinal syndrome and undergo successful definitive therapies

An Investigation of Compensation and Adaptation to Auditory Perturbations in Individuals With Acquired Apraxia of Speech

Two auditory perturbation experiments were used to investigate the integrity of neural circuits responsible for speech sensorimotor adaptation in acquired apraxia of speech (AOS). This has implications for understanding the nature of AOS as well as normal speech motor control. Two experiments were conducted. In Experiment 1, compensatory responses to unpredictable fundamental frequency (F0) perturbations during vocalization were investigated in healthy older adults and adults with acquired AOS plus aphasia. F0 perturbation involved upward and downward 100-cent shifts versus no shift, in equal proportion, during 2 s vocalizations of the vowel /a/. In Experiment 2, adaptive responses to sustained first formant (F1) perturbations during speech were investigated in healthy older adults, adults with AOS and adults with aphasia only (APH). The F1 protocol involved production of the vowel /ε/ in four consonant-vowel words of Australian English (pear, bear, care, dare), and one control word with a different vowel (paw). An unperturbed Baseline phase was followed by a gradual Ramp to a 30% upward F1 shift stimulating a compensatory response, a Hold phase where the perturbation was repeatedly presented with alternating blocks of masking trials to probe adaptation, and an End phase with masking trials only to measure persistence of any adaptation. AOS participants showed normal compensation to unexpected F0 perturbations, indicating that auditory feedback control of low-level, non-segmental parameters is intact. Furthermore, individuals with AOS displayed an adaptive response to sustained F1 perturbations, but age-matched controls and APH participants did not. These findings suggest that older healthy adults may have less plastic motor programs that resist modification based on sensory feedback, whereas individuals with AOS have less well-established and more malleable motor programs due to damage from stroke