Comparison of postreceptor effects of 1-34 human hypercalcemia factor and 1-34 human parathyroid hormone in rat osteosarcoma cells.

A tumor-derived factor believed to cause hypercalcemia by acting on the parathyroid hormone (PTH) receptor was recently purified, cloned, and found to have NH2-terminal sequence homology with PTH. The 1-34 region of this protein was synthesized, evaluated for its postreceptor effects on the ROS 17/2.8 cell line, and its properties were compared to 1-34 PTH. Both 1-34 human humoral hypercalcemia factor (HCF) and 1-34 PTH stimulated adenylate cyclase with an effective concentration (EC)50 of approximately 1 nM. The extent of stimulation by both peptides was equally enhanced by dexamethasone. They both had a pronounced inhibitory effect on growth in the presence of dexamethasone, with an EC50 of approximately 0.1 nM, reduced alkaline phosphatase (AP) activity by approximately 70% in the absence of dexamethasone and by approximately 80% in the presence of dexamethasone with an EC50 of 0.03 nM, and when present at a concentration of 10 nM, reduced AP mRNA levels (estimated by Northern analysis) by approximately 80% in the presence or absence of dexamethasone. Thus, in addition to similar dose-response curves for adenylate cyclase stimulation, both HCF and PTH produced identical postreceptor effects in ROS 17/2.8 cells. These effects of HCF are probably mediated by the interaction of the tumor-derived factor with the PTH receptor.     

Impact of human mobility on the emergence of dengue epidemics in Pakistan

The recent emergence of dengue viruses into new susceptible human populations throughout Asia and the Middle East, driven in part by human travel on both local and global scales, represents a significant global health risk, particularly in areas with changing climatic suitability for the mosquito vector. In Pakistan, dengue has been endemic for decades in the southern port city of Karachi, but large epidemics in the northeast have emerged only since 2011. Pakistan is therefore representative of many countries on the verge of countrywide endemic dengue transmission, where prevention, surveillance, and preparedness are key priorities in previously dengue-free regions. We analyze spatially explicit dengue case data from a large outbreak in Pakistan in 2013 and compare the dynamics of the epidemic to an epidemiological model of dengue virus transmission based on climate and mobility data from ∼40 million mobile phone subscribers. We find that mobile phone-based mobility estimates predict the geographic spread and timing of epidemics in both recently epidemic and emerging locations. We combine transmission suitability maps with estimates of seasonal dengue virus importation to generate fine-scale dynamic risk maps with direct application to dengue containment and epidemic preparedness.Dengue is the most rapidly spreading mosquito-borne disease worldwide (1, 2). Half the global population now lives in at-risk regions for dengue virus transmission, due to the wide distribution of the mosquito vector, Aedes aegypti, which thrives in peri-urban areas and transmits the virus between humans (3). Dengue virus can cause acute febrile illness and carries the risk of severe disease, hospitalization, and shock syndrome, especially in clinical settings with little experience treating dengue patients. There is currently no specific therapeutic protocol for, or vaccine against, infection (1). Current control measures focus on vector control, although these measures are often logistically difficult and have shown varying efficacy in controlling epidemics (4). In the absence of effective prevention and treatment, public health system preparedness remains the single most important tool for minimizing morbidity and mortality as dengue epidemics spread beyond endemic areas (5, 6).The introduction of dengue into new populations is mediated by travel of infected individuals to areas that can support transmission, because mosquito vectors move only short distances during their lifespans (3, 7–12). International travel to endemic countries has resulted in imported cases and outbreaks in Europe and the Americas (2, 8, 10, 13). Local variation in transmission, within a single city for example, is also driven by mobility patterns of individuals on short timescales (7). Forecasting methods are needed to spatially target interventions and epidemic preparedness measures that reflect both the changing temporal risks of importation and environmental suitability that go beyond solely climate-based methods (14).Dengue has long been endemic in most Southeast Asian countries (1), but has more recently emerged in parts of the Middle East and South Asia, including Pakistan (15, 16). In Pakistan, the transmission of dengue viruses was largely confined to the southern city of Karachi until 2011 when a large dengue epidemic with over 20,000 cases occurred in the northeastern city of Lahore (16), causing significant morbidity and mortality. In 2013, a second large epidemic occurred in northeastern Pakistan in Punjab and Khyber-Pakhtunkhwa (KP) provinces, establishing the region as an emerging focus of seasonal dengue epidemics. It has been hypothesized that the recent geographic expansion of A. aegypti mosquito vectors, changing environmental suitability, and human importation of dengue from endemic regions all contributed to the emergence of dengue in northern areas (17). Pakistan is therefore representative of many countries that are on the verge of countrywide endemic dengue transmission and are struggling to contain its emergence into previously dengue-free regions.Measuring changing risks of importation events that spark epidemics has been extremely challenging on the refined temporal and spatial scales necessary to inform local policies (18). Being able to predict when to prepare surveillance systems and health facilities for dengue outbreaks could dramatically reduce the morbidity and mortality associated with epidemics and would allow policy makers to pinpoint regions that are particularly vulnerable to imported cases, for vector control. Mobile phone data offer direct measures of human aggregation and movement and represent a unique source of information on the human determinants of the geographic expansion of emerging epidemic diseases like dengue. Here, we conduct a retrospective epidemiological analysis of large dengue outbreaks in Pakistan in 2013, to examine the predictive ability of an epidemiological model that integrates human mobility from the largest mobile phone dataset analyzed to date with climate information. We show that within-country human mobility predicts emerging epidemics in Pakistan, and epidemiological models incorporating this type of data can predict the spatial extent and timing of outbreaks, providing a new approach to forecasting.     

Pilot Evaluation of the Ability of Men Who Have Sex with Men to Self-Administer Rapid HIV Tests,Prepare Dried Blood Spot Cards,and Interpret Test Results,Atlanta, Georgia, 2013

In the United States, an estimated 67% of new HIV diagnoses are among men who have sex with men (MSM), however 25% of HIV-positive MSM in the 2014 National HIV Behavioral Surveillance Survey were unaware of their infection. HIV self-testing (HIVST) with rapid diagnostic tests (RDTs) may facilitate access to HIV testing. We evaluated the ability of 22 MSM to conduct two HIV RDTs (OraQuick ^® In-Home HIV Test and a home-use prototype of Sure Check ^® HIV 1/2 Assay), interpret sample images of test results, and collect a dried blood spot (DBS) specimen. While some participants did not follow every direction, most participants were able to conduct HIVST and correctly interpret their results. Interpretation of panels of RDT images was especially difficult when the “control” line was missing, and 27% of DBS cards produced were rated as of bad quality. Modifications to the DBS instructions were necessary prior to evaluating the performance of these tests in real-world settings.     

Growth stimulation of rat calvaria osteoblastic cells by acidic fibroblast growth factor

Purified acidic fibroblast growth factor (aFGF) from bovine brain stimulates the proliferation of calvaria-derived osteoblastic cells. Maximum stimulation, relative to corresponding controls, was seen at 0.2% serum (2- to 3-fold), and no stimulation was seen in the absence of serum or under serum replete conditions. The effect was dose-dependent with an ED50 of around 750 pg/ml (47 pM). aFGF (5 ng/ml) sustained the growth of calvaria cells in culture during multiple passages (72 days) at 0.2% serum. In DNA synthesis assays aFGF produced 2- to 4-fold stimulation; insulin-like growth factor I had a slight effect on DNA synthesis on its own, but enhanced the effect of aFGF 2-fold. In cells fully stimulated by epidermal growth factor (5-fold), aFGF had no further effect. Stimulation of DNA synthesis peaked at 5 ng/ml, while higher concentrations were inhibitory. Recombinant aFGF (bovine sequence) also stimulated cell proliferation (1.5-fold), and its potency was augmented by heparin (50 micrograms/ml), about 2-fold. Using simultaneous histochemical staining for alkaline phosphatase activity and [3H]thymidine nuclear uptake we found that aFGF stimulates DNA synthesis to the same extent in alkaline phosphatase-rich (osteoblastic) and alkaline phosphatase-poor (nonosteoblastic) cells. However, after cell division there is a significant decrease in PTH-responsive adenylate cyclase (2- to 3-fold) and in alkaline phosphatase levels (4- to 8-fold). These findings indicate that aFGF is mitogenic to rat calvaria osteoblastic cells, its action requires additional factors, and its growth stimulation is associated with a reduction in phenotypic expression.     

Gene selective mRNA cleavage inhibits the development of Plasmodium falciparum

Unique peptide-morpholino oligomer (PMO) conjugates have been designed to bind and promote the cleavage of specific mRNA as a tool to inhibit gene function and parasite growth. The new conjugates were validated using the P. falciparum gyrase mRNA as a target (PfGyrA). Assays in vitro demonstrated a selective degradation of the PfGyrA mRNA directed by the external guide sequences, which are morpholino oligomers in the conjugates. Fluorescence microscopy revealed that labeled conjugates are delivered into Plasmodium-infected erythrocytes during all intraerythrocytic stages of parasite development. Consistent with the expression of PfGyrA in all stages of parasite development, proliferation assays showed that these conjugates have potent antimalarial activity, blocking early development, maturation, and replication of the parasite. The conjugates were equally effective against drug sensitive and resistant P. falciparum strains. The potency, selectivity, and predicted safety of PMO conjugates make this approach attractive for the development of a unique class of target-specific antimalarials and for large-scale functional analysis of the malarial genome.     

Improving executive function disorders in brain-injured clients

In 1983, Lezak described executive functioning as the ability to engage in independent, purposeful, self-directive and self-serving behaviour [1]. Self initiation, problem-solving and self-monitoring or regulation of behaviour are important components of executive functioning. This paper presents the results of efforts to improve executive functioning in three areas: problem solving, self-initiation and self-regulation.     

Teaching socially appropriate behavior to eliminate hoarding in a brain injured adult

A brain injured male hoarded large quantities of unuseable items at every opportunity. The treatment consisted of two phases. First, he was taught to collect baseball cards. Second, after each meal, the client was provided with an apron and a glove and asked to pick up trash in the area and deposit the trash in an appropriate receptacle. If he hoarded, he was told not to pick up trash without his apron and glove and escorted to a quiet area for about 10 seconds. The procedure was successful in suppressing the behavior within 8 days.     

Renal arteriovenous transit times of technetium-radiolabeled chelates

A noninvasive method was developed for quantitating the distribution of renal arteriovenous transit times of technetium-99m (99mTc) radiopharmaceuticals. Using this method, the characteristic transit times and amplitudes of the first two components of [99mTC] DTPA or MDP transit through the renal vasculature were calculated. The first component amplitude (A1) was evaluated for its ability to discriminate between 20 hypertensive patients with renovascular disease and 21 normotensive subjects. A1 was compared with three other quantitative indices: the ascending slope of the initial renal time-activity curve, the kidney-to-aorta slope ratio (K/A), and renal size. A1 nearly perfectly separated the hypertensive patients from the normotensive subjects; the ability of A1 to discriminate between these two groups is clearly superior to renal size, the initial renal slope, and K/A. We conclude that measurements of the intrarenal distribution of blood flow have distinct advantages over indices of renal blood flow that have been derived from scintillation camera measurements of 99mTc radiopharmaceuticals.