Observation of coherent elastic neutrino-nucleus scattering.

The coherent elastic scattering of neutrinos off nuclei has eluded detection for four decades, even though its predicted cross section is by far the largest of all low-energy neutrino couplings. This mode of interaction offers new opportunities to study neutrino properties and leads to a miniaturization of detector size, with potential technological applications. We observed this process at a 6.7σ confidence level, using a low-background, 14.6-kilogram CsI[Na] scintillator exposed to the neutrino emissions from the Spallation Neutron Source at Oak Ridge National Laboratory. Characteristic signatures in energy and time, predicted by the standard model for this process, were observed in high signal-to-background conditions. Improved constraints on nonstandard neutrino interactions with quarks are derived from this initial data set.

Using the Eco-Map and Ecosystems Perspective to Guide Skilled Nursing Facility Discharge Planning.

Growing numbers of seniors across the United States require skilled nursing facility care after an inpatient hospital stay. Previous studies indicate that roughly 20 percent of all hospitalized Medicare beneficiaries are admitted to a skilled nursing facility following a qualifying hospital stay. Social workers address psychosocial problems, social support, networks, and healthcare needs during transitions in care, particularly discharge planning. Ecosystems perspective and the eco-map as a discharge planning tool is presented. Social workers can use these tools to examine the patient with respect to their transactional relationships with systems. This will further will facilitate provision of wrap-around services upon discharge.

First-in-human phase I study of SOR-C13, a TRPV6 calcium channel inhibitor, in patients with advanced solid tumors.

Introduction This was an open-label, dose escalation (3 + 3 design), Phase I study of SOR-C13 in patients with advanced tumors of epithelial origin. Primary objectives were to assess safety/tolerability and pharmacokinetics. Secondary goals were to assess pharmacodynamics and efficacy of SOR-C13. Methods SOR-C13 was administered IV QD on days 1-3 and 8-10 of a 21-day cycle. Doses were 2.75 and 5.5 mg/kg (20-min infusion) and 1.375, 2.75, 4.13 and 6.2 mg/kg (90-min infusion). Toxicity was assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Dose limiting toxicity (DLT) was assessed within the first treatment cycle. Tumors were evaluated, using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, after two cycles. Results Twenty-three patients were treated. No drug-related serious adverse events occurred. DLTs occurred in six patients: asymptomatic, drug-related, transient Grade 2 hypocalcemia (4 patients), and unrelated Grade 3 anemia and Grade 3 atrial fibrillation, 1 patient each. Calcium and vitamin D supplementation eliminated further Grade 2 hypocalcemia. One Grade 3 treatment emergent adverse event, urticaria, was definitely related to SOR-C13. Four possibly drug-related, Grade 3 events (alanine aminotransferase and aspartate aminotransferase elevation, headache, and hypokalemia) were observed. Of 22 evaluable patients, 54.5% showed stable disease ranging from 2.8 to 12.5 months. The best response was a 27% reduction in a pancreatic tumor with a 55% reduction in CA19-9 levels at 6.2 mg/kg. Conclusion SOR-C13 was safe and tolerated up to 6.2 mg/kg. The Maximal Tolerated Dose (MTD) was not established. Stable disease suggested antitumor activity.

Search for an annual modulation in a p-type Point Contact germanium dark matter detector.

Fifteen months of cumulative CoGeNT data are examined for indications of an annual modulation, a predicted signature of weakly interacting massive particle (WIMP) interactions. Presently available data support the presence of a modulated component of unknown origin, with parameters prima facie compatible with a galactic halo composed of light-mass WIMPs. Unoptimized estimators yield a statistical significance for a modulation of ∼2.8σ, limited by the short exposure.

Results from a search for light-mass dark matter with a p-type point contact germanium detector.

We report on several features in the energy spectrum from an ultralow-noise germanium detector operated deep underground. By implementing a new technique able to reject surface events, a number of cosmogenic peaks can be observed for the first time. We discuss an irreducible excess of bulklike events below 3 keV in ionization energy. These could be caused by unknown backgrounds, but also dark matter interactions consistent with DAMA/LIBRA. It is not yet possible to determine their origin. Improved constraints are placed on a cosmological origin for the DAMA/LIBRA effect.

"Care and feeding": the Asian environmental tobacco smoke consultants programme.

STUDY OBJECTIVE: To review the tobacco industry's Asian environmental tobacco smoke (ETS) consultants programme, focusing on three key nations: China, Hong Kong, and Malaysia. METHODS: Systematic keyword and opportunistic website searches of formerly private internal industry documents. MAIN RESULTS: The release of the 1986 US Surgeon General's report on second hand smoke provoked tobacco companies to prepare for a major threat to their industry. Asian programme activities included conducting national/international symposiums, consultant "road shows" and extensive lobbying and media activities. The industry exploited confounding factors said to be unique to Asian societies such as diet, culture and urban pollution to downplay the health risks of ETS. The industry consultants were said to be "..prepared to do the kinds of things they were recruited to do". CONCLUSIONS: The programme was successful in blurring the science on ETS and keeping the controversy alive both nationally and internationally. For the duration of the project, it also successfully dissuaded national policy makers from instituting comprehensive bans on smoking in public places.

Chasing Ernst L Wynder: 40 years of Philip Morris' efforts to influence a leading scientist.

STUDY OBJECTIVE: To highlight strategies used by the Philip Morris tobacco company to try to manipulate the eminent scientist, Dr Ernst Wynder between 1955 and 1995. METHODS: Systematic keyword and opportunistic searching of www.pmdocs.com for formerly internal tobacco industry documents concerning Philip Morris executives and Wynder. Available materials included reports, budget reviews, and correspondence. MAIN RESULTS: The emergence of smoking as a priority issue on the American public health agenda can be largely attributed to Wynder's research and publicity efforts. Philip Morris viewed Wynder as a prestigious scientist whose commitment to the pursuit of reduced harm cigarettes could lend legitimacy to its desire to position itself as a responsible company intent on addressing consumer concerns. Philip Morris courted Wynder with large equipment loans and grants for more than 30 years, and used its public relations agency to sanitise press releases to remove material unacceptable to the company. Wynder consistently failed to acknowledge industry support while routinely acknowledging other funding from the National Cancer Institute and the American Cancer Society. In retrospect, Wynder realised the insidious effect of tobacco industry research support but failed to acknowledge this may have applied to his own association with the industry. CONCLUSIONS: Industry documents reveal a deliberate attempt by Philip Morris to pursue and manipulate Dr Wynder to legitimise their company positions.

Phase 1 trial of transforming growth factor beta 2 in chronic progressive MS.

Transforming growth factor (TGF)-beta2 is a pleiotropic cytokine associated with remissions in multiple sclerosis (MS) and amelioration of allergic encephalomyelitis. We assessed the safety of TGF-beta2 in an open-label trial of 11 patients with secondary progressive (SP) MS. Five patients had a reversible decline in the glomerular filtration rate. There was no change in expanded disability status scale or MRI lesions during treatment. Systemic TGF-beta2 may be associated with reversible nephrotoxicity, and further investigation of its therapeutic potential in MS should be performed with caution.

ELI-spot of Th-1 cytokine secreting PBMC's in multiple sclerosis: correlation with MRI lesions.

The Th1-like cytokines, interleukin 2 (IL-2), interferon gamma (IFN-gamma), and lymphotoxin alpha (LT-alpha) have been implicated in the immunopathogenesis of multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE), an animal model of immune mediated demyelination. These cytokines have been associated with opening of the blood brain barrier (BBB) in EAE and in vitro, but not in MS. We used an enzyme-linked immunospot (ELI-spot) assay to measure relative numbers of cytokine-secreting peripheral blood mononuclear cells (PBMC) from eight MS patients who were followed with serial monthly contrast-enhanced head magnetic resonance imagings (MRI) and phlebotomy. We found a significant positive correlation between changes in IL-2 secreting cells and MRI lesions over a 6-month time period. There was a weaker association between contrast-enhancing MRI lesions and IFN-gamma or LT-alpha secreting cells. These data are the first to show a significant positive correlation between any cytokine and serial gadolinium (Gd-) MRI disease activity in MS patients. The association between IFN-gamma and LT-alpha secretion and MRI lesions is less clear.

Clinical safety of serial monthly administrations of gadopentetate dimeglumine in patients with multiple sclerosis: implications for natural history and early-phase treatment trials.

Serial contrast magnetic resonance imaging (MRI) has played an increasingly important role in understanding natural-history and early-treatment trials of multiple sclerosis patients. The purpose of this study is to determine whether the serial administration of gadopentetate dimeglumine at the conventional dose has any demonstrable effect on routine hematologic or serum chemistries. This study followed 56 patients with multiple sclerosis in a longitudinal natural-history trial using contrast-enhanced MRI scans over a four-year period between 1988 and 1993. Patients received between 3 and 53 doses of gadopentetate dimeglumine at 0.1 mmol/kg intravenously. A retrospective review of regular blood screening tests over this period identified no significant effect either on routine hematologic studies, as defined by complete blood count (hemoglobin, hematocrit, platelet and white blood cell counts, and mean corpuscular volume); standard serum chemistry studies, including electrolytes (sodium, potassium, chloride) and renal and liver function tests; or serum iron profiles. We conclude, therefore, that serial contrast-enhanced MRIs can be used safely as an outcome measure for Phase I/II evaluations of new therapies for multiple sclerosis.

Density and composition of microorganisms during long-term (418 day) growth of potato using biologically reclaimed nutrients from inedible plant biomass.

A study evaluating alternative methods for long term operation of biomass production systems was recently completed at the Kennedy Space Center (KSC). The 418-day study evaluated repeated batch versus mixed-aged production of potato grown on either standard 1/2-strength Hoagland's nutrient solution or solutions including nutrients recycled from inedible plant material. The long term effects of closure and recycling on microbial dynamics were evaluated by monitoring the microbial communities associated with various habitats within the plant growth system (i.e., plant roots, nutrient solution, biofilms within the hydroponic systems, atmosphere, and atmospheric condensate). Plate count methods were used to enumerate and characterize microorganisms. Microscopic staining methods were used to estunate total cell densities. The primary finding was that the density and composition of microbial communities associated with controlled environmental plant growth systems are stable during long term operation. Continuous production resulted in slightly greater stability. Nutrient recycling, despite the addition of soluble organic material from the waste processing system, did not significantly increase microbial density in any of the habitats.

Effects of the arterial vasodilator minoxidil on cardiovascular structure and sympathetic activity in spontaneously hypertensive rats.

OBJECTIVE AND DESIGN: In spontaneously hypertensive rats (SHR) arterial vasodilators do not cause regression and might cause further progression of cardiac hypertrophy. To assess whether these effects extend to the vasculature, and to examine the possible mechanisms involved, cardiac and mesenteric arterial structure was evaluated with respect to changes in cardiac volume load and cardiac and arterial sympathetic activity during long-term (5- and 10-week) treatment of 16-week-old SHR with the arterial vasodilator minoxidil, alone or in combination with the diuretic hydrochlorothiazide. RESULTS: Despite causing a persistent decrease in blood pressure in SHR, minoxidil further increased left and right ventricular weights and left ventricular internal diameter. In combination with hydrochlorothiazide, minoxidil caused concentric, rather than eccentric, left ventricular hypertrophy. In the mesenteric arterial bed of SHR, minoxidil increased the lumen of the superior mesenteric artery, and prevented further increases in the medial area of the large and small mesenteric arteries. The increase in lumen size of the superior mesenteric artery by minoxidil was abolished when hydrochlorothiazide was added to the treatment. After 10 weeks' treatment with minoxidil, noradrenaline turnover rates were still significantly increased in the left ventricle but were decreased in the mesenteric arteries in the SHR. Minoxidil increased plasma and blood volumes, the increases being largely prevented by concomitant diuretic treatment. CONCLUSIONS: We conclude that there are regional differences in the response of the cardiovascular system to minoxidil in SHR. Some of these differences may be related to differences in regional sympathetic activity, whereas volume load appears to play a modulatory role.

Arterial vasodilation and cardiovascular structural changes in normotensive rats.

In normotensive rats, the arterial vasodilator minoxidil causes right ventricular hypertrophy (RVH) and eccentric left ventricular hypertrophy (LVH). To assess whether this trophic effect of minoxidil extends to the vasculature and to examine possible mechanisms involved, alterations in cardiac and arterial (superior, large and small mesenteric arteries, carotid and basilar arteries) structure were evaluated in relation to changes in indexes of cardiac volume load and cardiac and arterial sympathetic activity during long-term (35 and 70 days) treatment of normotensive rats with minoxidil alone or in combination with the diuretic hydrochlorothiazide (HCTZ). Minoxidil alone increased LV and RV weights, LV internal diameter, and medial area of the superior mesenteric artery but did not affect any of the other arteries evaluated. When combined with HCTZ, long-term minoxidil caused concentric LVH rather than eccentric LVH and no longer increased the medial area of the superior mesenteric artery. Neither treatment had any persistent effect on blood pressure, heart rate, or plasma catecholamines. However, minoxidil significantly increased cardiac and arterial (superior and large mesenteric artery) norepinephrine turnover rates, cardiac filling pressures, and plasma and blood volumes. When combined with HCTZ, short-term (1 wk) minoxidil still increased cardiac filling pressures. However, intravascular volume expansion during chronic treatment was significantly attenuated. These results suggest that chronic cardiac volume load appears to determine the type of cardiac hypertrophy induced by a nonhemodynamic mechanism (possibly cardiac sympathetic activity) activated by minoxidil. Intravascular volume expansion or increased arterial flow appears to be responsible for medial hypertrophy of the superior mesenteric artery, but absence of a trophic response in other arteries suggests that another, local mechanism contributes.

Sodium-induced cardiac hypertrophy. Cardiac sympathetic activity versus volume load.

To investigate the possible contributions of cardiac volume overload and cardiac sympathetic hyperactivity in the effects of sodium on cardiac mass, we evaluated the effects of treatment with saline (1%) and deoxycorticosterone acetate + saline (DOCA/saline) for 10 days and 3 and 6 weeks on ventricular anatomy and intracardiac pressures. Sympathetic activity in the heart and other tissues was assessed at 10 days and 3 weeks by catecholamine turnover rates and tyrosine hydroxylase activity. Both saline and DOCA/saline produced concentric left ventricular (LV) hypertrophy. Right ventricular weight showed only small increases. Saline treatment did not affect LV end-systolic pressure, whereas DOCA/saline caused a moderate increase (to 159 mm Hg). Right atrial pressure was not affected by either treatment, whereas LV end-diastolic pressure increased but only after the development of LV hypertrophy. Both saline and DOCA/saline decreased LV norepinephrine concentration; only DOCA/saline decreased norepinephrine content per LV. However, neither treatment altered the norepinephrine turnover rate constant, the absolute turnover rate, or the tyrosine hydroxylase activity. The results demonstrate that increased saline intake or DOCA/saline produces concentric LV hypertrophy without any increase in blood pressure in the case of saline and with increases in LV filling pressure following rather than preceding the appearance of LV hypertrophy. The lack of an increase in LV norepinephrine turnover and tyrosine hydroxylase activity suggests that the hypertrophy is not mediated through increased cardiac neuronal sympathetic activity.

Contrasting effects of calcium antagonists vs. arterial vasodilators on cardiac anatomy and sympathetic activity in spontaneously hypertensive rats.

In spontaneously hypertensive rats (SHRs) we evaluated the effects of 35 and 70 days of treatment with nisoldipine (2 mg/g of food) vs. minoxidil (120 mg/L of drinking water) on cardiac anatomy [i.e., left ventricular (LV) and right ventricular (RV) weights and LV internal diameter and wall thickness] and cardiac sympathetic activity assessed by the norepinephrine turnover rate. The minoxidil-induced antihypertensive response was associated with a marked increase in cardiac sympathetic activity, potentiation of RV hypertrophy (RVH), and the development of eccentric LV hypertrophy (LVH). Nisoldipine decreased both blood pressure (BP) and cardiac sympathetic activity, but caused only small decreases in LV weight and LV wall thickness and no change in RV weight. With regard to minoxidil, the increase in sympathetic activity may contribute to the minoxidil-induced potentiation of cardiac mass. Nisoldipine, despite decreasing BP as well as cardiac sympathetic activity, unexpectedly resulted in only a small decrease in cardiac mass, suggesting that additional mechanisms may play a role in the effects of calcium antagonists on cardiac mass.

Opposite effects of arterial vasodilators on cardiac vs. arterial hypertrophy and sympathetic activity in spontaneously hypertensive rats.

To investigate whether cardiac and arterial structure and sympathetic activity changes in a similar fashion during chronic arterial vasodilation, we evaluated the morphology and sympathetic activity of the mesenteric arterial bed and the left (LV) and right (RV) ventricles of 16-week-old Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHRs) after 35 and 70 days of treatment with the arterial vasodilator minoxidil. The minoxidil-induced antihypertensive response was associated with an increase in ventricular sympathetic activity, potentiation of RV hypertrophy (RVH), and the development of eccentric LV hypertrophy (LVH). In the mesenteric arterial bed, minoxidil decreased the sympathetic activity, increased the lumen of the superior mesenteric artery, and decreased the medial area of the large and small mesenteric arteries. We conclude that the contrasting effects of minoxidil on cardiac vs. arterial structure may--in part--relate to selective effects on regional sympathetic activity.