Search for Dark-Matter-Nucleon Interactions via Migdal Effect with DarkSide-50.

Dark matter elastic scattering off nuclei can result in the excitation and ionization of the recoiling atom through the so-called Migdal effect. The energy deposition from the ionization electron adds to the energy deposited by the recoiling nuclear system and allows for the detection of interactions of sub-GeV/c^{2} mass dark matter. We present new constraints for sub-GeV/c^{2} dark matter using the dual-phase liquid argon time projection chamber of the DarkSide-50 experiment with an exposure of (12 306±184) kg d. The analysis is based on the ionization signal alone and significantly enhances the sensitivity of DarkSide-50, enabling sensitivity to dark matter with masses down to 40 MeV/c^{2}. Furthermore, it sets the most stringent upper limit on the spin independent dark matter nucleon cross section for masses below 3.6 GeV/c^{2}.

Search for Dark Matter Particle Interactions with Electron Final States with DarkSide-50.

We present a search for dark matter particles with sub-GeV/c^{2} masses whose interactions have final state electrons using the DarkSide-50 experiment's (12 306±184) kg d low-radioactivity liquid argon exposure. By analyzing the ionization signals, we exclude new parameter space for the dark matter-electron cross section σ[over ¯]_{e}, the axioelectric coupling constant g_{Ae}, and the dark photon kinetic mixing parameter κ. We also set the first dark matter direct-detection constraints on the mixing angle |U_{e4}|^{2} for keV/c^{2} sterile neutrinos.

Experiences of Stigma and Support Reported by Participants in a Network Intervention to Reduce HIV Transmission in Athens, Greece; Odessa, Ukraine; and Chicago, Illinois.

A growing body of evidence suggests that network-based interventions to reduce HIV transmission and/or improve HIV-related health outcomes have an important place in public health efforts to move towards 90-90-90 goals. However, the social processes involved in network-based recruitment may pose a risk to participants of increasing HIV-related stigma if network recruitment causes HIV status to be assumed, inferred, or disclosed. On the other hand, the social processes involved in network-based recruitment to HIV testing may also encourage HIV-related social support. Yet despite the relevance of these processes to both network-based interventions and to other more common interventions (e.g., partner services), there is a dearth of literature that directly examines them among participants of such interventions. Furthermore, both HIV-related stigma and social support may influence participants' willingness and ability to recruit their network members to the study. This paper examines (1) the extent to which stigma and support were experienced by participants in the Transmission Reduction Intervention Project (TRIP), a risk network-tracing intervention aimed at locating recently HIV-infected and/or undiagnosed HIV-infected people and linking them to care in Athens, Greece; Odessa, Ukraine; and Chicago, Illinois; and (2) whether stigma and support predicted participant engagement in the intervention. Overall, experiences of stigma were infrequent and experiences of support frequent, with significant variation between study sites. Experiences and perceptions of HIV-related stigma did not change significantly between baseline and six-month follow-up for the full TRIP sample, and significantly decreased during the course of the study at the Chicago site. Experiences of HIV-related support significantly increased among recently-HIV-infected participants at all sites, and among all participants at the Odessa site. Both stigma and support were found to predict participants' recruitment of network members to the study at the Athens site, and to predict participants' interviewer-rated enthusiasm for naming and recruiting their network members at both the Athens and Odessa sites. These findings suggest that network-based interventions like TRIP which aim to reduce HIV transmission likely do not increase stigma-related risks to participants, and may even encourage increased social support among network members. However, the present study is limited by its associational design and by some variation in implementation by study site. Future research should directly assess contextual differences to improve understanding of the implications of site-level variation in stigma and support for the implementation of network-based interventions, given the finding that these constructs predict participants' recruitment of network members and engagement in the intervention, and thereby could limit network-based interventions' abilities to reach those most in need of HIV testing and care.

Food Footprint as a Measure of Sustainability for Grazing Dairy Farms.

Livestock productions require significant resources allocation in the form of land, water, energy, air, and capital. Meanwhile, owing to increase in the global demand for livestock products, it is wise to consider sustainable livestock practices. In the past few decades, footprints have emerged as indicators for sustainability assessment. In this study, we are introducing a new footprint measure to assess sustainability of a grazing dairy farm while considering carbon, water, energy, and economic impacts of milk production. To achieve this goal, a representative farm was developed based on grazing dairy practices surveys in the State of Michigan, USA. This information was incorporated into the Integrated Farm System Model (IFSM) to estimate the farm carbon, water, energy, and economic impacts and associated footprints for ten different regions in Michigan. A multi-criterion decision-making method called VIKOR was used to determine the overall impacts of the representative farms. This new measure is called the food footprint. Using this new indicator, the most sustainable milk production level (8618 kg/cow/year) was identified that is 19.4% higher than the average milk production (7215 kg/cow/year) in the area of interest. In addition, the most sustainable pasture composition was identified as 90% tall fescue with 10% white clover. The methodology introduced here can be adopted in other regions to improve sustainability by reducing water, energy, and environmental impacts of grazing dairy farms, while maximizing the farm profit and productions.

Antimicrobial Stewardship in the Microbiology Laboratory: Impact of Selective Susceptibility Reporting on Ciprofloxacin Utilization and Susceptibility of Gram-Negative Isolates to Ciprofloxacin in a Hospital Setting.

The objective of this study was to determine the impact of selective susceptibility reporting on ciprofloxacin utilization and Gram-negative susceptibility to ciprofloxacin in a hospital setting. Historically at our institution, the microbiology laboratory practice was to report ciprofloxacin susceptibility for all Enterobacteriaceae regardless of susceptibility to other agents. A selective reporting policy was implemented which involved the suppression of ciprofloxacin susceptibility to Enterobacteriaceae when there was lack of resistance to the antibiotics on the Gram-negative panel. Ciprofloxacin utilization (measured in defined daily doses [DDD] per 1,000 patient days) was collected before and after the intervention and compared to moxifloxacin, trimethoprim-sulfamethoxazole, nitrofurantoin, and amoxicillin-clavulanate. Monthly susceptibility of Pseudomonas aeruginosa and Escherichia coli to ciprofloxacin was tabulated. An interrupted time series analysis using segmented regression was performed. The mean monthly ciprofloxacin utilization decreased from 87 (95% CI, 83.7 to 91.2) to 39 (95% CI, 35.0 to 44.0) DDD per 1,000 patient days before and after the implementation of selective reporting, respectively. There was an immediate and sustained reduction in ciprofloxacin usage at 1, 3, 6, 12, and 24 months postintervention (P < 0.001). A compensatory increase in amoxicillin-clavulanate use was noted starting at 6 months postintervention and persisted for the study period (P < 0.027). Susceptibility of E. coli, but not that of P. aeruginosa, to ciprofloxacin was higher than predicted starting 12 months after the intervention (P < 0.05). In conclusion, selective reporting of ciprofloxacin susceptibly may be a useful intervention to reduce targeted antimicrobial utilization and improve Gram-negative susceptibility to ciprofloxacin. This approach should be considered as part of a broader multimodal antimicrobial stewardship program.

Efficacy of motivational interviewing and cognitive behavioral therapy for anxiety and depression symptoms following traumatic brain injury.

BACKGROUND: Anxiety and depression are common following traumatic brain injury (TBI), often co-occurring. This study evaluated the efficacy of a 9-week cognitive behavioral therapy (CBT) program in reducing anxiety and depression and whether a three-session motivational interviewing (MI) preparatory intervention increased treatment response. METHOD: A randomized parallel three-group design was employed. Following diagnosis of anxiety and/or depression using the Structured Clinical Interview for DSM-IV, 75 participants with mild-severe TBI (mean age 42.2 years, mean post-traumatic amnesia 22 days) were randomly assigned to an Adapted CBT group: (1) MI + CBT (n = 26), or (2) non-directive counseling (NDC) + CBT (n = 26); or a (3) waitlist control (WC, n = 23) group. Groups did not differ in baseline demographics, injury severity, anxiety or depression. MI and CBT interventions were guided by manuals adapted for individuals with TBI. Three CBT booster sessions were provided at week 21 to intervention groups. RESULTS: Using intention-to-treat analyses, random-effects regressions controlling for baseline scores revealed that Adapted CBT groups (MI + CBT and NDC + CBT) showed significantly greater reduction in anxiety on the Hospital Anxiety and Depression Scale [95% confidence interval (CI) -2.07 to -0.06] and depression on the Depression Anxiety and Stress Scale (95% CI -5.61 to -0.12) (primary outcomes), and greater gains in psychosocial functioning on Sydney Psychosocial Reintegration Scale (95% CI 0.04-3.69) (secondary outcome) over 30 weeks post-baseline relative to WC. The group receiving MI + CBT did not show greater gains than the group receiving NDC + CBT. CONCLUSIONS: Findings suggest that modified CBT with booster sessions over extended periods may alleviate anxiety and depression following TBI.

Vancomycin-Variable Enterococcal Bacteremia.

Vancomycin-variable enterococcus (VVE) is an emerging pathogen. VVE isolates initially appear phenotypically susceptible to vancomycin but possesses the vanA gene and can develop in vitro and in vivo resistance to vancomycin. We report a case of VVE bacteremia and describe how VVE poses diagnostic and therapeutic dilemmas.

Epidemiology of healthcare-associated Pseudomonas aeruginosa in intensive care units: are sink drains to blame?

BACKGROUND: Pseudomonas aeruginosa (PA) is a common cause of healthcare-associated infection (PA-HAI) in the intensive care unit (ICU). AIM: To describe the epidemiology of PA-HAI in ICUs in Ontario, Canada, and to identify episodes of sink-to-patient PA transmission. METHODS: This was a prospective cohort study of patients in six ICUs from 2018 to 2019, with retrieval of PA clinical isolates, and PA-screening of antimicrobial-resistant organism surveillance rectal swabs, and of sink drain, air, and faucet samples. All PA isolates underwent whole-genome sequencing. PA-HAI was defined using US National Healthcare Safety Network criteria. ICU-acquired PA was defined as PA isolated from specimens obtained ≥48 h after ICU admission in those with prior negative rectal swabs. Sink-to-patient PA transmission was defined as ICU-acquired PA with close genomic relationship to isolate(s) previously recovered from sinks in a room/bedspace occupied 3-14 days prior to collection date of the relevant patient specimen. FINDINGS: Over ten months, 72 PA-HAIs occurred among 60/4263 admissions. The rate of PA-HAI was 2.40 per 1000 patient-ICU-days; higher in patients who were PA-colonized on admission. PA-HAI was associated with longer stay (median: 26 vs 3 days uninfected; P < 0.001) and contributed to death in 22/60 cases (36.7%). Fifty-eight admissions with ICU-acquired PA were identified, contributing 35/72 (48.6%) PA-HAIs. Four patients with five PA-HAIs (6.9%) had closely related isolates previously recovered from their room/bedspace sinks. CONCLUSION: Nearly half of PA causing HAI appeared to be acquired in ICUs, and 7% of PA-HAIs were associated with sink-to-patient transmission. Sinks may be an under-recognized reservoir for HAIs.

A real-world assessment of procalcitonin combined with antimicrobial stewardship in a community ICU.

PURPOSE: We evaluated the feasibility and impact of PCT-guided antibiotic duration combined with an established antibiotic stewardship program (ASP) in a community hospital intensive care unit (ICU). METHODS: We implemented daily PCT levels for ICU patients receiving antibiotics. Our protocol recommended stopping antibiotic therapy if PCT met an absolute or relative stopping threshold. We evaluated the adherence to stopping criteria within 48 h, antibiotic use [days of therapy (DOT) per 1000 patient-days (PD)], length of stay and ICU-mortality. We performed interrupted time series analysis to compare 24 months before and 12 months after implementation. RESULTS: A total of 297 antibiotic courses were monitored with PCT in 217 patients. Protocol adherence was 34% (absolute threshold: 39%, relative threshold: 12%). Antibiotic use pre-PCT was 935 DOTs/1000 PDs and post-PCT was 817 DOTs/1000 PDs (RRadj 0.73, 95% CI: 0.62 to 0.86). No statistically significant changes in clinical outcomes were noted. CONCLUSION: In the context of an established ASP in a community hospital ICU, PCT monitoring was feasible and associated with an adjusted overall decrease of 27% in antibiotic use with no adverse impact on clinical outcomes. Incorporating PCT testing to guide antibiotic duration can be successful if integrated into workflow and paired with ASP guidance.

Qualitative urinary organic acid analysis: methodological approaches and performance.

A programme for proficiency testing of biochemical genetics laboratories undertaking urinary qualitative organic acid analysis and its results for 50 samples examined for factors contributing to poor performance are described. Urine samples from patients in whom inherited metabolic disorders have been confirmed as well as control urines were circulated to participants and the results from 94 laboratories were evaluated. Laboratories showed variability both in terms of their individual performance and on a disease-specific basis. In general, conditions including methylmalonic aciduria, propionic aciduria, isovaleric aciduria, mevalonic aciduria, Canavan disease and 3-methylcrotonyl-CoA carboxylase were readily identified. Detection was poorer for other diseases such as glutaric aciduria type II, glyceric aciduria and, in one sample, 3-methylcrotonyl-CoA carboxylase deficiency. To identify the factors that allow some laboratories to perform well on a consistent basis while others perform badly, we devised a questionnaire and compared the responses with the results for performance in the scheme. A trend towards better performance could be demonstrated for those laboratories that regularly use internal quality control (QC) samples in their sample preparation (p = 0.079) and those that participate in further external quality assurance (EQA) schemes (p = 0,040). Clinicians who depend upon these diagnostic services to identify patients with these defects and the laboratories that provide them should be aware of the potential for missed diagnoses and the factors that may lead to improved performance.

Ethnicity of children with homozygous c.985A>G medium-chain acyl-CoA dehydrogenase deficiency: findings from screening approximately 1.1 million newborn infants.

OBJECTIVES: It has been suggested that homozygous c.985A>G medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a disease of White ethnic origin but little is known regarding its ethnic distribution. We estimated ethnic-specific homozygous c.985A>G MCADD birth prevalence from a large-scale UK newborn screening study. METHODS: Homozygous c.985A>G MCADD cases were ascertained in six English newborn screening centres between 1 March 2004 and 28 February 2007 by screening approximately 1.1 million newborns using tandem mass spectrometry analysis of underivatised blood spot samples to quantitate octanoylcarnitine (C8). Follow-up biochemistry and mutation analyses for cases (mean triplicate C8 value >/=0.5 micromol/L) were reviewed to confirm diagnosis. Ethnicity was ascertained from clinician report and denominators from 2001 UK Census estimates of ethnic group of children less than one year. RESULTS: Sixty-four infants were c.985A>G MCADD homozygotes (overall prevalence 5.8 per 100,000 live births; 95% CI 4.4-7.2). Sixty (93%) were White, two (3%) were mixed/other and two were of unknown ethnic origin. No Asian or Black homozygotes were identified. Proportions of White, mixed/other, Asian and Black births in screening regions were estimated, yielding homozygous c.985A>G MCADD birth prevalence of 6.9 per 100,000 (95% CI 5.2-8.8) in White, and 95% CI estimates of 0-2.7 per 100,000 in Asian and 0-5.8 in Black populations. The c.985A>G carrier frequency in the White group was estimated at one in 65 (95% CI 1/74, 1/61) under Hardy-Weinberg conditions. CONCLUSION: c.985A>G homozygous MCADD is not found in Black and Asian ethnic groups that have been screened at birth in England. This is consistent with the earlier published observations suggesting that MCADD due to the c.985A>G mutation is a disease of White ethnic origin.

Physical, chemical, and immunochemical studies of apolipoprotein A-I from pigeon plasma high density lipoproteins.

Pigeon plasma high density lipoproteins (HDL) were isolated by ultracentrifugation between the densities of 1.063 and 1.21 g/ml. Gel filtration of delipidated HDL in 5 M guanidine-HCl on Sephadex G-150 yielded a major fraction which eluted at the same position as human apolipoprotein A-I isolated from HDL. In SDS-gel electrophoresis, the isolated apolipoprotein co-migrated with human apolipoprotein A-I with a molecular weight of approx. 28 000. The amino acid composition was similar to the apolipoprotein A-I isolated from human and hen plasma. The isolated apolipoprotein from pigeon plasma had therefore been designated as apolipoprotein A-I. As judged by circular dichroism (CD), the apolipoprotein A-I displayed a maximum mean residue ellipticity of approx. -3 000 at 222 nm while at concentrations greater than 0.2 mg/ml. Calculations of alpha-helicial content gave values of 85%. Lowering the concentration of apolipoprotein A-I was found to concomitantly decrease the ellipticity (absolute value) suggesting that there was some conformational change when the apolipoprotein A-I concentration varied. The isolated pigeon apolipoprotein A-I was found bound to the phospholipid (dimyristoyl phosphatidylcholine) and there was no significant conformational change upon lipid binding as judged by CD. Under the same experimental conditions, human apolipoprotein A-I exhibited a drastic conformational change by increasing its helicity in the presence of phospholipid. The helical content of human apolipoprotein A-I was increased from 48 to 85%. This finding suggests that the apolipoprotein may not necessarily increase its helical content during lipid binding. Moreover, immunochemical studies showed that rabbit antiserum prepared against pigeon apolipoprotein A-I could partially react with human apolipoprotein A-I determined by quantitative radioimmunoassay.

Granulocyte colony-stimulating factor stimulates recovery of granulocytes in patients receiving dose-intensive chemotherapy without bone marrow transplantation.

Bone marrow colony-stimulating factors (CSF) ameliorate hematologic toxicity of standard chemotherapy regimens and may allow relatively safe use of intensive and more efficacious doses of anticancer drugs. Twenty-four patients with cancers for which no standard regimens were likely to be effective received repeated courses of a combination of cisplatin (150 mg/m2), etoposide (1,500 mg/m2), and cyclophosphamide (5,000 mg/m2) at doses for which bone marrow transplantation is usually used. A total of 10 patients received escalating doses of recombinant human granulocyte CSF (rhG-CSF); 11 patients receiving identical chemotherapy and supportive therapy without rhG-CSF served as controls for the first cycle of therapy. Five of these patients and 3 additional patients also served as their own controls, receiving rhG-CSF for all cycles after the first. No patient received bone marrow transplantation. rhG-CSF shortened the median duration of severe granulocytopenia (less than or equal to 100/mm3) in a dose-related fashion (P less than .03; Kruskal-Wallis test). Patients not receiving rhG-CSF had a median of 8.5 days of granulocytopenia. Those receiving 40 micrograms/kg of rhG-CSF for approximately 20 days from the third day after chemotherapy had a median of 7.0 days (P less than .23) and those receiving 60 micrograms/kg had a median of 5.5 days (P less than .007) of granulocytopenia. An rhG-CSF dose of 20 micrograms/kg had no effect. Recovery to a granulocyte count of at least 500/mm3 took a median of 12 days in the control group and 8 days (P less than .03) in patients receiving rhG-CSF at a dose of 60 mg/kg. The duration of antibiotic therapy (a median, 9.0 days v 5.0 days) was shortened with the two higher and effective doses of rhG-CSF compared with control patients. The duration of hospitalization (median of 20 days v 19 days) was not shortened. These findings that rhG-CSF decreases the risk of granulocytopenia associated with this particular dose-intensive chemotherapy regimen therapy administered without bone marrow transplantation.

Concentrations of faecal coliforms, Escherichia coli, enterococci and Campylobacter spp. in equine faeces.

AIMS: To determine the concentration of Campylobacter spp. as well as faecal indicator bacteria; faecal coliforms, Escherichia coli and enterococci in the faeces of healthy adult horses in a sample of properties in the Canterbury region of New Zealand. METHODS: The faeces of healthy adult horses (n=59), including ponies, pleasure horses and Thoroughbreds, were collected from eight properties around Christchurch, New Zealand. The faeces were analysed for concentrations of Campylobacter spp and faecal indicator bacteria; faecal coliforms, Escherichia coli and enterococci. The presence of other animals on the properties sampled as well as the age, feed and health of the horses at the time of sampling was recorded. RESULTS: Enterococci and faecal coliforms were isolated from all samples, and E. coli was isolated from 58/59 samples. Mean concentrations of faecal coliforms and E. coli did not differ between properties, but there was a significant difference in mean concentration of enterococci between properties. Campylobacter spp. were detected in two faecal samples with one isolate being determined by PCR analysis to be a thermotolerant Campylobacter species, the other C. jejuni. CONCLUSIONS: This is the first known report quantifying the concentration of Campylobacter spp. present in healthy adult horses in New Zealand. The presence of equine faecal material in water could elevate concentrations of faecal bacteria and therefore needs to be considered as a source of water contamination. The access of horses to waterways and coastal environments may also need to be restricted to prevent transmission of faecal indicator bacteria and potentially zoonotic agents.

Q fever outbreak among travelers to Germany associated with live cell therapy - United States and Canada, 2014: a co-publication.

WHAT IS ALREADY KNOWN ON THIS TOPIC?: Q fever is a zoonotic disease caused by Coxiella burnetii and is usually transmitted through inhalation of air contaminated with animal excreta. The disease is considered to be underdiagnosed because symptoms are nonspecific and can vary from patient to patient, making diagnosis difficult. WHAT IS ADDED BY THIS REPORT?: During September-October 2014, the New York State Department of Health identified Q fever in five patients with exposure to a treatment known as live cell therapy, an alternative medicine practice involving injections of fetal sheep cells, which is a type of xenotransplantation. Investigation revealed that a group of U.S. residents traveled to Germany twice a year to receive this treatment. WHAT ARE THE IMPLICATIONS FOR PUBLIC HEALTH PRACTICE?: Clinicians should consider zoonotic diseases, such as Q fever, in patients whose history includes receipt of a treatment known as live cell therapy. International travel for xenotransplantation procedures can facilitate transmission of zoonotic disease.

Production of heparin-binding epidermal growth factor-like growth factor (HB-EGF) at sites of thermal injury in pediatric patients.

Fluids that accumulate at wound sites may be an important reservoir of growth factors that promote the normal wound healing response. The presence of heparin-binding growth factors was studied in burn wound fluid (BWF) from 45 pediatric patients who had sustained partial thickness burns. One of the growth factors present was similar to platelet-derived growth factor (PDGF) based on its heparin affinity, inhibition of bioactivity by a PDGF antiserum, and detection in a PDGF-AB enzyme-linked immunosorbent assay. A second growth factor was identified as heparin-binding epidermal growth factor-like growth factor (HB-EGF) based on its heparin affinity, competition with 125I-labeled epidermal growth factor (EGF) for EGF receptor binding, and recognition in biological assays and Western blots by two HB-EGF antisera. Amino acid sequence analysis of one form of this second growth factor verified its identity as an N-terminally truncated form of HB-EGF. Immunohistochemical analysis of partial thickness burns demonstrated the presence of HB-EGF in the advancing epithelial margin, islands of regenerating epithelium within the burn wound, and in the duct and proximal tubules of eccrine sweat glands. HB-EGF in the surface epithelium of burn wounds was uniformally distributed, whereas it was restricted to the basal epithelium in nonburned skin. These data support a role for PDGF and HB-EGF in burn wound healing and suggest that the response to injury includes deposition of HB-EGF and PDGF into blister fluid and a redistribution of HB-EGF in the surface epithelium near the wound site.

Changes in tissue concentrations of thyrotropin, free thyrotropin beta, and alpha-subunits after thyroxine administration: comparison of mouse hypothyroid pituitary and thyrotropic tumors.

We have previously demonstrated divergent changes in pituitary free TSH beta and alpha-subunit concentrations in hypothyroid mice during prolongation of experimental hypothyroidism and after T4 administration. This report compares the simultaneous responses of pituitary and thyrotropic tumor TSH, TSH beta, and alpha-subunit to 12 days of T4 administration in four groups of hypothyroid LAF1 mice bearing thyrotropic tumors. Half of each group received daily injections of T4 (10 micrograms/100 g BW, ip) for 12 days; the other half of each group received saline. Plasma concentrations of TSH, free TSH beta, and free alpha-subunit were suppressed by T4 administration to 0.1-1.5%, 2.0-3.9%, and 4.1-25% of control concentrations, respectively. Pituitary TSH and free TSH beta concentrations fell significantly with treatment to 24-43% and 10-28% of control concentrations, respectively. In contrast, pituitary alpha-subunit concentrations did not fall (they were 106-203% of control values), and a rise in the pituitary alpha-subunit concentration was statistically significant in one group (P less than 0.02). Thyrotropic tumor TSH and free TSH beta concentrations fell significantly with treatment to 9-31% and 8-35% of control concentrations, respectively. Tumor alpha-subunit concentrations did not fall (they were 87-195% of control values), and a 2-fold rise was statistically significant in one group (P less than 0.05). Both pituitary and tumor alpha-subunit to TSH beta molar ratios increased significantly with T4 administration in all groups. We conclude that (1) pituitary and thyrotropic tumor TSH beta concentrations fall after 12 days of T4 administration while alpha-subunit concentrations are unchanged or actually rise; (2) this divergent response is qualitatively similar in hypothyroid mouse pituitary and thyrotropic tumors; and (3) these data suggest differences between the regulation of intracellular TSH beta and alpha-subunit.

Mouse pituitary tumor line secreting only the alpha-subunit of the glycoprotein hormones: development from a thyrotropic tumor.

This report describes the conversion of a murine pituitary thyrotropic tumor (MGH 101) to a pure alpha-subunit-secreting tumor (MGH 101A) during a 6-yr period of serial transplantation. MGH 101 was a thyrotropic tumor originating from a hypothyroid mouse pituitary, growing only in hypothyroid hosts, and secreting large quantities of intact TSH and free alpha-subunit. Between the fourth and ninth transplantation generations, tumor TSH secretion declined progressively by at least 500-fold, to undetectable levels. In contrast, tumor secretion of free alpha-subunit decreased only 10-fold, and has since remained stable for nine transplantation generations. During the conversion to pure alpha-subunit secretion, MGH 101A exhibited growth in euthyroid as well as hypothyroid hosts, and increased its growth rate 2 to 3-fold. In contrast, the conventional thyrotropic tumor TtT 97 has maintained its secretion of both intact TSH and free alpha-subunit, its dependence on a hypothyroid environment, and its slower growth rate for nine generations. Gel chromatography of the media from tumor cell cultures confirmed that MGH 101A secreted only the free alpha-subunit, whereas TtT 97 secreted immunoactive TSH, TSH beta, and free alpha-subunit which eluted as separate peaks. We conclude that a dependent thyrotropic tumor has spontaneously developed into a pure alpha-subunit-secreting tumor which is independent of host thyroid function for its growth and alpha-subunit production.

Response programming in patients with schizophrenia: a kinematic analysis.

Schizophrenia may involve disturbed subcortical mechanisms or anomalous functional asymmetries. We therefore examined any anomalies of functional asymmetry in a kinematic analysis of a cued sequential movement task previously found to be sensitive to basal ganglia dysfunction. Twenty patients with schizophrenia and 20 matched controls used preferred or non-preferred hand to connect a series of targets on a WACOM SD420 graphics tablet, in response to the pattern of illumination of light emitting diodes (LEDs). Movements were to be initiated with or without an external cue as to target location. Patients with schizophrenia exhibited relatively normal functional asymmetries, but had programming deficits, taking longer to initiate (i.e. self generate) movements in the absence of an external cue. The movements of patients with schizophrenia were more variable and less efficient, resembling those seen in Huntington's disease. Results supported a hypothesis of disturbance at some level in fronto-subcortical circuitry in schizophrenia.

Localization of the multifunctional protein CAD in astrocytes of rodent brain.

The CAD multidomain protein, which includes active sites of carbamyl phosphate synthetase II (CPS II, glutamine-dependent), aspartate transcarbamylase, and dihydroorotase, was immunostained in normal rat brains, the gliotic brains of myelin-deficient mutant rats, and brains from normal weanling hamsters. In each of these tissues CAD was observed in cells resembling astrocytes. In hamster brain, CAD immunofluorescence was also found in cells closely related to astrocytes, i.e., the Bergmann glia in cerebellum and the tanycytes surrounding the third ventricle. The astrocytic identity of the CAD-positive cells in rat brain was confirmed by double immunofluorescence staining with antibodies against glial fibrillary acidic protein (GFAP). The two enzymes carbonic anhydrase and glutamine synthetase occur in the cytoplasm of normal astrocytes in gray matter and of reactive astrocytes during gliosis. Products of each enzyme, i.e., bicarbonate and glutamine, are required for the CPS II reaction, which is the first step in the biosynthesis of pyrimidines. Therefore, the present results suggest roles for carbonic anhydrase and glutamine synthetase, as well as CAD, in pyrimidine biosynthesis in brain and a role for the astrocytes in the de novo synthesis of pyrimidines.