BACKGROUND: Diabetes mellitus (DM) increases the risk of TB disease and poor treatment outcomes such as delayed sputum culture conversion due to inadequate drug exposure. Therapeutic drug monitoring ...(TDM) has improved these outcomes in some settings.METHODS: To compare
treatment outcomes in programs with routine TDM vs. programs that did not use TDM, we conducted a retrospective study among people with DM and TB at health departments in four US states.RESULTS: A total of 170 patients were enrolled (73 patients in the non-TDM group and 97 patients
in the TDM group). Days to sputum culture conversion and total treatment duration were significantly shorter in the TDM group vs. the non-TDM group. In adjusted analyses, patients who underwent TDM were significantly more likely to achieve sputum culture conversion at 2 months (P =
0.007).CONCLUSION: TDM hastened microbiological cure from TB among people with DM and a high risk for poor treatment outcomes in the programmatic setting.
TRPS-1 is a new GATA transcription factor that is differentially expressed in breast cancer (BC) where it been found recently to regulate epithelial-to-mesenchymal transition (EMT).
We carried out a ...quantitative immunohistochemistry (qIHC) analysis of TRPS-1 expression in 341 primary-stage I–III BC samples in relation to patient clinical characteristics as well as its prognostic value, especially in an estrogen receptor-positive (ER+) subgroup.
Higher TRPS-1 expression was significantly associated with a number of clinical and pathological characteristics as well as with improved overall survival (OS) and disease-free survival (DFS). Among stage I/II ER+ BC patients who received endocrine therapy alone, those with high TRPS-1 expression had significantly longer OS and DFS. There was also a strong association between TRPS-1 levels and the EMT marker E-cadherin in the ER+ invasive ductal carcinoma cases. Analysis of gene expression data on a panel of BC lines found that TRPS-1 expression was low or absent in BC lines having enriched mesenchymal features.
Our data indicated that TRPS-1 is an independent prognostic marker in early-stage BC and a new EMT marker that can distinguish patients with ER+ BC who will respond longer to adjuvant endocrine therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Preclinical studies have demonstrated that the adenovirus type 5 E1A gene is associated with antitumor activities by transcriptional repression of HER-2/neu and induction of apoptosis. Indeed, E1A ...gene therapy is known to induce regression of HER-2/neu-overexpressing breast and ovarian cancers in nude mice. Therefore, we evaluated the feasibility of intracavitary injection of E1A gene complexed with DC-Chol cationic liposome (DCC-E1A) in patients with both HER-2/neu-overexpressing and low HER-2/neu-expressing breast and ovarian cancers in a phase I clinical trial.
An E1A gene complexed with DCC-E1A cationic liposome was injected once a week into the thoracic or peritoneal cavity of 18 patients with advanced cancer of the breast (n = 6) or ovary (n = 12).
E1A gene expression in tumor cells was detected by immunohistochemical staining and reverse transcriptase-polymerase chain reaction. This E1A gene expression was accompanied by HER-2/neu downregulation, increased apoptosis, and reduced proliferation. The most common treatment-related toxicities were fever, nausea, vomiting, and/or discomfort at the injection sites.
These results argue for the feasibility of intracavitary DCC-E1A administration, provide a clear proof of preclinical concept, and warrant phase II trials to determine the antitumor activity of the E1A gene.
Characterizing Europa’s subsurface ocean is essential for assessing Europa’s habitability. The suite of instruments on the Europa Clipper spacecraft will, among others, magnetically sound Europa’s ...interior by measuring the ocean’s induced magnetic field. This magnetic field is generated in response to the Jovian time-varying magnetic environment in which Europa is immersed. However, the dynamic magnetized plasma flow of the Jovian magnetosphere creates electrical currents that give rise to magnetic perturbations near Europa. These perturbations complicate the interpretation of the induction signal, and hence the characterization and inferences on potential habitability. Thus, characterization of the ocean by magnetic sounding requires an accurate characterization of the plasma as it flows across Europa.
We present the Plasma Instrument for Magnetic Sounding (PIMS), the instrument for the Europa Clipper mission that will measure the plasma contribution to the magnetic field perturbations sensed by the Europa Clipper Magnetometer. PIMS is composed of four Faraday Cup plasma spectrometers that use voltage-biased gridded apertures to dissect the space plasmas that they encounter. The instrument uses sensitive preamplifiers and processing electronics to measure the current that results when charged particles strike the instrument’s metal collector plates, thus enabling a measure of the plasma characteristics near Europa to produce a more accurate magnetic sounding of Europa’s subsurface ocean. PIMS consists of two sensors: one placed near the top of the Europa Clipper spacecraft and one near the bottom. Each sensor contains two Faraday Cups with a 90° full-width field-of-view. The sensors were specifically designed to withstand the Europa environment, measure both ions and electrons, and have two separate voltage ranges intended to analyze the magnetospheric and ionospheric environments, respectively. In this paper, we describe the scientific motivation for this experiment, the design considerations for the PIMS instrument, the details of the ground calibration, and other details pertinent to understanding the scientific data retrieved by PIMS.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Among nonhospitalized patients with Covid-19–related symptoms that began less than a week previously, a 3-day course of remdesivir resulted in an 87% lower risk of hospitalization or death than ...placebo. Adverse effects in the remdesivir group were similar to those in the placebo group.
CONTEXT Preterm infants have a high prevalence of long-term cognitive and behavioral
disturbances. However, it is not known whether the stresses associated with
premature birth disrupt regionally ...specific brain maturation or whether abnormalities
in brain structure contribute to cognitive deficits. OBJECTIVE To determine whether regional brain volumes differ between term and
preterm children and to examine the association of regional brain volumes
in prematurely born children with long-term cognitive outcomes. DESIGN AND SETTING Case-control study conducted in 1998 and 1999 at 2 US university medical
schools. PARTICIPANTS A consecutive sample of 25 eight-year-old preterm children recruited
from a longitudinal follow-up study of preterm infants and 39 term control
children who were recruited from the community and who were comparable with
the preterm children in age, sex, maternal education, and minority status. MAIN OUTCOME MEASURES Volumes of cortical subdivisions, ventricular system, cerebellum, basal
ganglia, corpus callosum, amygdala, and hippocampus, derived from structural
magnetic resonance imaging scans and compared between preterm and term children;
correlations of regional brain volumes with cognitive measures (at age 8 years)
and perinatal variables among preterm children. RESULTS Regional cortical volumes were significantly smaller in the preterm
children, most prominently in sensorimotor regions (difference: left, 14.6%;
right, 14.3% P<.001 for both) but also in premotor
(left, 11.2%; right, 12.6% P<.001 for both),
midtemporal (left, 7.4% P = .01; right, 10.2% P<.001), parieto-occipital (left, 7.9% P = .01; right, 7.4% P = .005), and subgenual
(left, 8.9% P = .03; right, 11.7% P = .01) cortices. Preterm children's brain volumes were significantly
larger (by 105.7%-271.6%) in the occipital and temporal horns of the ventricles
(P<.001 for all) and smaller in the cerebellum (6.7%; P = .02), basal ganglia (11.4%-13.8%; P≤.005),
amygdala (left, 20.2% P = .001; right, 30.0% P<.001), hippocampus (left, 16.0% P = .001; right, 12.0% P = .007), and corpus
callosum (13.1%-35.2%; P≤.01 for all). Volumes
of sensorimotor and midtemporal cortices were associated positively with full-scale,
verbal, and performance IQ scores (P<.01 for all). CONCLUSIONS Our data indicate that preterm birth is associated with regionally specific,
long-term reductions in brain volume and that morphological abnormalities
are, in turn, associated with poorer cognitive outcome.
Background: Resource utilisation and direct costs associated with glaucoma progression in Europe are unknown. As population progressively ages, the economic impact of the disease will increase. ...Methods: From a total of 1655 consecutive cases, the records of 194 patients were selected and stratified by disease severity. Record selection was based on diagnoses of primary open angle glaucoma, glaucoma suspect, ocular hypertension, or normal tension glaucoma; 5 years minimum follow up were required. Glaucoma severity was assessed using a six stage glaucoma staging system based on static threshold visual field parameters. Resource utilisation data were abstracted from the charts and unit costs were applied to estimate direct costs to the payer. Resource utilisation and estimated direct cost of treatment, per person year, were calculated. Results: A statistically significant increasing linear trend (p = 0.018) in direct cost as disease severity worsened was demonstrated. The direct cost of treatment increased by an estimated €86 for each incremental step ranging from €455 per person year for stage 0 to €969 per person year for stage 4 disease. Medication costs ranged from 42% to 56% of total direct cost for all stages of disease. Conclusions: These results demonstrate for the first time in Europe that resource utilisation and direct medical costs of glaucoma management increase with worsening disease severity. Based on these findings, managing glaucoma and effectively delaying disease progression would be expected to significantly reduce the economic burden of this disease. These data are relevant to general practitioners and healthcare administrators who have a direct influence on the distribution of resources.
Tellurium compounds have shown several biological properties and recently the leishmanicidal effect of one organotellurane was demonstrated. These findings led us to test the effect of the ...organotellurium compound RF07 on Leishmania (Leishmania) chagasi, the agent of visceral leishmaniasis in Latin America. In vitro assays were performed in L. (L.) chagasi-infected bone marrow derived macrophages treated with different concentrations of RF07. In in vivo experiments Golden hamsters were infected with L. (L.) chagasi and injected intraperitoneally with RF07 whereas control animals received either Glucantime or PBS. The effect of RF07 on cathepsin B activity of L. (L.) chagasi amastigotes was assayed spectrofluorometrically using fluorogenic substrates. The main findings were: 1) RF07 showed significant leishmanicidal activity against intracellular parasites at submicromolar concentrations (IC50 of 529.7±26.5 nM), and the drug displayed 10-fold less toxicity to macrophages (CC50 of 5,426±272.8 nM); 2) kinetics assays showed an increasing leishmanicidal action of RF07 at longer periods of treatment; 3) one month after intraperitoneal injection of RF07 L. (L.) chagasi-infected hamsters showed a reduction of 99.6% of parasite burden when compared to controls that received PBS; 4) RF07 inhibited the cathepsin B activity of L. (L.) chagasi amastigotes. The present results demonstrated that the tellurium compound RF07 is able to destroy L. (L.) chagasi in vitro and in vivo at concentrations that are non toxic to the host. We believe these findings support further study of the potential of RF07 as a possible alternative for the chemotherapy of visceral leishmaniasis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Nerve injury results in increases in spinal glutamate, which opens the NMDA ionophore channel, causing an influx of calcium. A glycine-binding site must be occupied for the channel to open. GV196771 ...is a selective antagonist of the glycine-binding site of the NMDA ionophore.
To determine the efficacy of GV196771 in subjects with chronic neuropathic pain in a proof-of-concept study.
With informed consent, 63 subjects (31 placebo, 32 GV196771) with neuropathic pain (diabetic neuropathy, postherpetic neuralgia, complex regional pain syndrome, or peripheral nerve injury), a visual analogue score averaging > or =30 mm during the screening period, and a well-defined primary area of mechanical allodynia were recruited for the study. A multicenter, randomized, double-blind, placebo-controlled, parallel-group study design was utilized. Subjects came to the research center for a total of five visits over a 21-day period, which consisted of a 14-day treatment period followed by a 7-day washout period. Spontaneous and evoked pain scores, mechanical sensory testing, quantitative sensory testing, Short Form McGill Pain Questionnaire, patient global satisfaction, and safety assessments were made during the study.
There was no significant effect of GV196771 on spontaneous or evoked pain, quantitative sensory testing, or patient global satisfaction. There was a significant effect of GV196771 on the area of dynamic and static allodynia on days 7 and 14. The overall incidence of adverse events during treatment was similar for GV196771 (56%) and placebo (71%). The incidence of drug-related adverse events during treatment was higher for placebo (42%) than GV196771 (28%).
Although the glycine antagonists show anti-hyperalgesic action in animal models of neuropathic pain, GV196771 does not appear to be an effective treatment in subjects with chronic neuropathic pain. This may be due to insufficient penetration of GV196771 to central sites of action, differences between the human and animal glycine receptors, or differences between neuropathic pain in animal models and humans.
Ketamine hydrochloride is a well known general anesthetic and short acting analgesic in use for almost 3 decades. The role of the NMDA receptor in the processing of nociceptive input has led ...naturally to renewed clinical interest in N-methyl-D-aspartate (NMDA) receptor antagonists such as ketamine. This paper reviews the use and efficacy of low-dose ketamine in the management of acute postoperative pain. The literature was obtained from a computer search of the MEDLINE database from 1966 through December 1998. Studies were included for review if they were randomized, prospective, controlled, double-blind and reported pain scores. We evaluate the clinical literature and discuss the efficacy of low-dose ketamine in the management of acute postoperative pain when administered alone or in conjunction with other agents via the oral, intramuscular, subcutaneous, intravenous and intraspinal routes. Low-dose ketamine is defined as a bolus dose of less than 2 mg/g when given intramuscularly or less than 1 mg/kg when administered via the intravenous or epidural route. For continuous i.v. administration low-dose ketamine is defined as a rate of < or =20 microg/kg per min. We conclude that ketamine may provide clinicians with a tool to improve postoperative pain management and to reduce opioid related adverse effects. The evidence suggests that low-dose ketamine may play an important role in postoperative pain management when used as an adjunct to local anesthetics, opioids, or other analgesic agents. Further research is required in the following areas: (a) dose-finding studies for ketamine as an adjunct to opioids and local anesthetics (b) efficacy and optimal route of administration (c) the role of S(+)-ketamine; (d) the influence of ketamine on long-term outcome such as chronic pain (e) long-term physical and chemical stability of mixtures containing ketamine (f) spinal toxicity of ketamine and (g) effects of low-dose ketamine on cognitive and memory functioning after surgery.
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IJS, IMTLJ, KILJ, SBCE, SBJE, UPUK
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