Field study of early implementation of UV sources and their relative effectiveness for public health and safety.

The emergence of COVID-19 and its corresponding public health burden has prompted industries to rapidly implement traditional and novel control strategies to mitigate the likelihood of SARS-CoV-2 transmission, generating a surge of interest and application of ultraviolet germicidal irradiation (UVGI) sources as disinfection systems. With this increased attention the need to evaluate the efficacy and safety of these types of devices is paramount. A field study of the early implementation of UVGI devices was conducted at the Space Needle located in Seattle, Washington. Six devices were evaluated, including four low-pressure (LP) mercury-vapor lamp devices for air and surface sanitation not designed for human exposure and two krypton chloride (KrCl*) excimer lamp devices to be operated on and around humans. Emission spectra and ultraviolet (UV) irradiance at different locations from the UV devices were measured and germicidal effectiveness against SARS-CoV-2 was estimated. The human safety of KrCl* excimer devices was also evaluated based on measured irradiance and estimated exposure durations. Our results show all LP devices emitted UV radiation primarily at 254 nm as expected. Both KrCl* excimers emitted far UVC irradiation at 222 nm as advertised but also emitted at longer, more hazardous wavelengths (228 to 262 nm). All LP devices emitted strong UVC irradiance, which was estimated to achieve three log reduction of SARS-CoV-2 within 10 sec of exposure at reasonable working distances. KrCl* excimers, however, emitted much lower irradiance than needed for effective disinfection of SARS-CoV-2 (>90% inactivation) within the typical exposure times. UV fluence from KrCl* excimer devices for employees was below the American Conference of Governmental Industrial Hygienists (ACGIH) Threshold Limit Values (TLVs) under the reported device usage and work shifts. However, photosensitive individuals, human susceptibility, or exposure to multiple UV sources throughout a worker's day, were not accounted for in this study. Caution should be used when determining the acceptability of UV exposure to workers in this occupational setting and future work should focus on UVGI sources in public settings.

Quantitative Human Immunodeficiency Virus (HIV)-1 Antibodies Correlate With Plasma HIV-1 RNA and Cell-associated DNA Levels in Children on Antiretroviral Therapy.

BACKGROUND: This study measured serial plasma human immunodeficiency virus (HIV)-1-specific antibody (Ab) levels in children who initiated antiretroviral therapy (ART) prior to 2 years of age, and evaluated their relationship to peripheral blood HIV-1 RNA and DNA levels. METHODS: We studied 46 HIV-1-infected children, stratified by age at ART initiation (<3 mo, early therapy [ET]; >3 mo-2 years, late therapy [LT]) and by virologic response (R) or non-response (NR), before and up to 4 years following ART. We studied 20 HIV-1-uninfected children born to HIV-1-infected mothers (seroreverters [SR]) as controls. Plasma immunoglobulin G (IgG) Ab levels directed against HIV-1 envelope (gp160, gp41), gag (capsid, p24; matrix, p17), reverse transcriptase (p66/51), and integrase (p31) were serially measured using quantitative enzyme-linked immunosorbent assays. HIV-1 Ab rates of decline were estimated over the first 15 months of the study. RESULTS: The HIV-1 Ab rates of decline in the ET-R group were similar to those in the SR group for all Ab specificities, except for p17 (P = .01). Ab decline rates in the LT-R group and the NR group were significantly slower than in the SR group for all tested Ab specificities. After 1 year of age, Ab levels to p31 and p17 were significantly associated with HIV-1 RNA levels (P < .001); Ab levels to gp160 (P < .001) and gp41 (P < .001) were significantly associated with cell-associated HIV-1 DNA levels. CONCLUSIONS: Quantitative HIV-1-specific Ab levels may be useful for screening children on ART for viral suppression or for residual, cell-associated HIV-1 DNA levels. CLINICAL TRIALS REGISTRATION: NCT00000872.

Early Epstein-Barr Virus Genomic Diversity and Convergence toward the B95.8 Genome in Primary Infection.

Over 90% of the world's population is persistently infected with Epstein-Barr virus. While EBV does not cause disease in most individuals, it is the common cause of acute infectious mononucleosis (AIM) and has been associated with several cancers and autoimmune diseases, highlighting a need for a preventive vaccine. At present, very few primary, circulating EBV genomes have been sequenced directly from infected individuals. While low levels of diversity and low viral evolution rates have been predicted for double-stranded DNA (dsDNA) viruses, recent studies have demonstrated appreciable diversity in common dsDNA pathogens (e.g., cytomegalovirus). Here, we report 40 full-length EBV genome sequences obtained from matched oral wash and B cell fractions from a cohort of 10 AIM patients. Both intra- and interpatient diversity were observed across the length of the entire viral genome. Diversity was most pronounced in viral genes required for establishing latent infection and persistence, with appreciable levels of diversity also detected in structural genes, including envelope glycoproteins. Interestingly, intrapatient diversity declined significantly over time (P < 0.01), and this was particularly evident on comparison of viral genomes sequenced from B cell fractions in early primary infection and convalescence (P < 0.001). B cell-associated viral genomes were observed to converge, becoming nearly identical to the B95.8 reference genome over time (Spearman rank-order correlation test; r = -0.5589, P = 0.0264). The reduction in diversity was most marked in the EBV latency genes. In summary, our data suggest independent convergence of diverse viral genome sequences toward a reference-like strain within a relatively short period following primary EBV infection.IMPORTANCE Identification of viral proteins with low variability and high immunogenicity is important for the development of a protective vaccine. Knowledge of genome diversity within circulating viral populations is a key step in this process, as is the expansion of intrahost genomic variation during infection. We report full-length EBV genomes sequenced from the blood and oral wash of 10 individuals early in primary infection and during convalescence. Our data demonstrate considerable diversity within the pool of circulating EBV strains, as well as within individual patients. Overall viral diversity decreased from early to persistent infection, particularly in latently infected B cells, which serve as the viral reservoir. Reduction in B cell-associated viral genome diversity coincided with a convergence toward a reference-like EBV genotype. Greater convergence positively correlated with time after infection, suggesting that the reference-like genome is the result of selection.

High Epstein-Barr Virus Load and Genomic Diversity Are Associated with Generation of gp350-Specific Neutralizing Antibodies following Acute Infectious Mononucleosis.

The Epstein-Barr virus (EBV) gp350 glycoprotein interacts with the cellular receptor to mediate viral entry and is thought to be the major target for neutralizing antibodies. To better understand the role of EBV-specific antibodies in the control of viral replication and the evolution of sequence diversity, we measured EBV gp350-specific antibody responses and sequenced the gp350 gene in samples obtained from individuals experiencing primary EBV infection (acute infectious mononucleosis [AIM]) and again 6 months later (during convalescence [CONV]). EBV gp350-specific IgG was detected in the sera of 17 (71%) of 24 individuals at the time of AIM and all 24 (100%) individuals during CONV; binding antibody titers increased from AIM through CONV, reaching levels equivalent to those in age-matched, chronically infected individuals. Antibody-dependent cell-mediated phagocytosis (ADCP) was rarely detected during AIM (4 of 24 individuals; 17%) but was commonly detected during CONV (19 of 24 individuals; 79%). The majority (83%) of samples taken during AIM neutralized infection of primary B cells; all samples obtained at 6 months postdiagnosis neutralized EBV infection of cultured and primary target cells. Deep sequencing revealed interpatient gp350 sequence variation but conservation of the CR2-binding site. The levels of gp350-specific neutralizing activity directly correlated with higher peripheral blood EBV DNA levels during AIM and a greater evolution of diversity in gp350 nucleotide sequences from AIM to CONV. In summary, we conclude that the viral load and EBV gp350 diversity during early infection are associated with the development of neutralizing antibody responses following AIM. IMPORTANCE: Antibodies against viral surface proteins can blunt the spread of viral infection by coating viral particles, mediating uptake by immune cells, or blocking interaction with host cell receptors, making them a desirable component of a sterilizing vaccine. The EBV surface protein gp350 is a major target for antibodies. We report the detection of EBV gp350-specific antibodies capable of neutralizing EBV infection in vitro The majority of gp350-directed vaccines focus on glycoproteins from lab-adapted strains, which may poorly reflect primary viral envelope diversity. We report some of the first primary gp350 sequences, noting that the gp350 host receptor binding site is remarkably stable across patients and time. However, changes in overall gene diversity were detectable during infection. Patients with higher peripheral blood viral loads in primary infection and greater changes in viral diversity generated more efficient antibodies. Our findings provide insight into the generation of functional antibodies, necessary for vaccine development.

The effect of short-duration sprint interval exercise on plasma postprandial triacylglycerol levels in young men.

It is well established that regular exercise can reduce the risk of cardiovascular disease, although the most time-efficient exercise protocol to confer benefits has yet to be established. The aim of the current study was to determine the effects of short-duration sprint interval exercise on postprandial triacylglycerol. Fifteen healthy male participants completed two 2 day trials. On day 1, participants rested (control) or carried out twenty 6 s sprints, interspersed with 24 s recovery (sprint interval exercise--14 min for total exercise session). On day 2, participants consumed a high-fat meal for breakfast with blood samples collected at baseline, 2 h and 4 h. Gas exchange was also measured at these time points. On day 2 of control and sprint interval exercise trials, there were no differences (P < 0.05) between trials in plasma glucose, triacylglycerol, insulin or respiratory exchange ratio (RER). The area under the curve for plasma triacylglycerol was 7.67 ± 2.37 mmol · l(-1) x 4 h(-1) in the control trial and 7.26 ± 2.49 mmol · l(-1) x 4 h(-1) in the sprint interval exercise trial. Although the sprint exercise protocol employed had no significant effect on postprandial triacylglycerol, there was a clear variability in responses that warrants further investigation.

Some pressures are more equal than others: Effects of isolated pressure on performance.

It is commonly assumed that performance is impaired by pressure and that different types of individual situational factors can produce equivalent pressure. Our aim was to explore the psychophysiological effects of pressure to test this assumption. Eighty-one novices completed a golf putting task under control and eight individual pressure conditions: time, difficulty, video, team, goal, fame, shame, and distraction. Performance was measured by the number of holed putts and ball-hole distance. Psychological, physiological and kinematic measures were collected. Performance was impaired by time and difficulty conditions but improved by team, goal and shame conditions compared to control. Perceived pressure and effort were higher than control in all conditions except distraction. Conscious processing was greater than control in all conditions except distraction and time constraint. Heart rate was faster with time, team, fame and shame. Heart rate variability and muscle activity were largely unaffected. Putter kinematics provided evidence of swing profiles slowing and/or becoming constrained in conditions where conscious processing increased, while the swing became faster in the time-pressure condition where conscious processing was decreased. Taken together, these results reveal heterogenous effects of pressure on performance, with performance impaired, unaffected, and improved by individual pressure situations. Similarly, heterogeneity characterized the effects of pressure on psychological, physiological and kinematic responses associated with task performance. In sum, the evidence challenges the standard tacit assumptions about the pressure-performance relationship in sport.

Effects of task difficulty on performance and event-related bradycardia during preparation for action.

The slowing of heart rate prior to movement onset has been presented as a marker of task-related cognitive processing and linked with performance accuracy. Here we examined this event-related bradycardia and task performance as a function of task difficulty. Forty experienced golfers completed a series of golf putting conditions that manipulated task difficulty by varying target distance, target size, and surface contour. Performance was measured by the number of holed putts and finishing distance from the hole. Physiological activity was recorded throughout. Analyses confirmed that performance varied as a function of task difficulty, worsening with longer distances to target, smaller targets, and sloping paths to target. Task difficulty also impacted the cardiac response, including the rate of heart rate deceleration, change in heart rate, and heart rate at impact. These heart rate metrics were found to correlate with performance strongly, moderately, and weakly, respectively. In conclusion, heart rate deceleration in the moments preceding movement onset was affected by task difficulty. Features of this cardiac deceleration pattern were characteristic of successful performance. Our findings are discussed in terms of the role of cognitive and motor processes during the execution of complex motor skills.

Building a pharmacy technician structure for the future: A lesson from a multihospital academic health system.

PURPOSE: Over the past decade there has been increased attention on the need for highly skilled and trained pharmacy technicians; however, few best practices to assist health-system pharmacies in meeting technician workforce challenges have been identified. These challenges have been further revealed since 2019 through rising inflation, increased cost of living, and competing opportunities for skilled technical workers. This article describes an 18-hospital academic health system's experience implementing an innovative pharmacy technician career structure focused on increasing pharmacy technician engagement as well as improving recruitment and retention. METHODS: Prior to creating a new career structure, the department of pharmacy had one development track for pharmacy technicians, which included only 2 nonsupervisory job titles. Due to recruitment, retention, and employee engagement challenges, the department of pharmacy, in collaboration with the human resources department, developed a new pharmacy technician structure that included 3 pharmacy technician tracks and 4 nonsupervisory levels. Outcomes collected to determine the success of the program included pharmacy technician engagement survey scores, annual voluntary turnover rate, rolling 12-month voluntary turnover rate, monthly vacancy rate, and average years of service at termination. The monthly discharge prescription capture rate was also measured to support efforts to keep the cost of the new structure budget neutral. CONCLUSION: The change in career structure assisted in the improvement of each outcome identified. The close collaboration of the departments of pharmacy and human resources can lead to positive solutions of national problems and have a sustained impact on department operations.

Benefits of introducing universal umbilical cord blood gas and lactate analysis into an obstetric unit.

BACKGROUND: Current evidence suggests that umbilical arterial pH analysis provides the most sensitive reflection of birth asphyxia. However, there's debate whether umbilical cord blood gas analysis (UC-BGA) should be conducted on some or all deliveries. AIM: The aim of this study was to evaluate the impact of introducing universal UC-BGA at delivery on perinatal outcome. METHODS: An observational study of all deliveries > or =20 weeks' gestation at a tertiary obstetric unit between January 2003 and December 2006. Paired UC-BGA was performed on 97% of deliveries (n = 19,646). Univariate and adjusted analysis assessed inter-year UC-BGA differences and the likelihood of metabolic acidosis and nursery admission. RESULTS: There was a progressive improvement in umbilical artery pH, pO(2), pCO(2), base excess and lactate values in univariate and adjusted analyses (P < 0.001). There was a significant reduction in the newborns with an arterial pH <7.10 (OR = 0.71; 95%CI 0.53-0.95) and lactate >6.1 mmol/L (OR = 0.37; 95%CI 0.30-0.46). Utilising population specific 5th and 95th percentiles, there was a reduction in newborns with arterial pH less than 5th percentile (pH 7.12; OR = 0.75; 95%CI 0.59-0.96) and lactate levels greater than 95th percentile (6.7 mmol/L; OR = 0.37; 95%CI 0.29-0.49). There was a reduction in term (OR = 0.65; 95%CI 0.54-0.78), and overall (OR = 0.75; 95%CI 0.64-0.87) nursery admissions. These improved perinatal outcomes were independent of intervention rates. CONCLUSIONS: These data suggest that introduction of universal UC-BGA may result in improved perinatal outcomes, which were observed to be independent of obstetric intervention. We suggest that these improvements might be attributed to provision of biochemical data relating to fetal acid-base status at delivery influencing intrapartum care in subsequent cases.

Enhancing long-term care for older adults: an exploration of interagency collaboration within geriatric education centers.

This article examines how the study of geriatric education provides a collaborative environment in which nonprofits can work together and with government in order to effectively manage the challenges in caring for older adults in the coming decades. The U.S. Department of Health and Human Services Health Resources and Services Administration (HRSA) provides federal funding to implement and maintain Geriatric Education Centers (GECs) in health care facilities across the country. These GECs have recently been directed to focus on strengthening the availability and quality of comprehensive interdisciplinary training for health care professionals that work with older adults. The funding has come at a time when the nation is faced with both a shortage of health care professionals and a dramatic increase in the older adult population in future years. Due to the critical relevance of GEC offerings for health care and the baby boomer generation, this study provides an exploratory evaluation of programs offered by GECs and the degree of both interdisciplinary and interagency collaboration between GECs, community nonprofits, and government partners in the provision of geriatric health care training. Findings suggest the interdisciplinary and interagency partnerships do exist but are vulnerable to conflicts especially between GECs.

Viewpoints of the Occupational Therapist Assistant-Physiotherapist Assistant Role on Inter-Professional Teams: A Mixed-Methods Study.

Purpose: Occupational therapist assistants and physiotherapist assistants work on inter-professional teams in both institutional and community settings to facilitate patients' rehabilitation and recovery. Examination of how the assistant role is viewed by assistants and other inter-professional team members is needed to inform how to support and sustain development of the role and associated practice relationships. Method: In this explanatory sequential-design mixed-methods study, we first surveyed rehabilitation personnel, then held focus groups at a large urban health care organization. Statistical and thematic analysis was conducted to combine the findings from both data sources. Results: A total of 89 therapists and assistants completed surveys; 30 also contributed to four focus groups. Five themes were developed that expressed the perceptions of the assistant role on inter-professional teams: (1) left out of the loop, (2) living in the grey: negotiating and navigating the assistant role, (3) who's the boss? (4) things just don't fall into your lap: pursuing professional development, and (5) (not) just the assistant: the influence of norms and attitudes and external perspectives. Conclusions: The findings describe perceptions and institutional norms of the assistant practice role. They can inform discussions on regulation and accreditation as well as professional and continuing education, and they can promote reflection on team dynamics and supervisory practices.

Objectif : les assistants-ergothérapeutes et les assistants-physiothérapeutes travaillent dans des équipes interprofessionnelles en établissement et en milieu communautaire afin de faciliter la réadaptation et la convalescence des patients. Un examen de la perception du rôle de l'assistant par les assistants et les autres membres de l'équipe interprofessionnelle s'impose pour déterminer comment soutenir et faire évoluer ce rôle et les relations connexes liées à la pratique. Méthodologie : dans le cadre de la présente étude à méthodologie mixte explicative, les chercheurs ont d'abord sondé le personnel de réadaptation, puis tenu des groupes de travail dans une grande organisation de santé urbaine. Ils ont ensuite procédé à une analyse statistique et thématique pour combiner les résultats des deux sources de données. Résultats : au total, 89 thérapeutes et assistants-thérapeutes ont participé au sondage et 30 ont également participé à quatre groupes de travail. Cinq thèmes ont été dégagés, qui expriment la perception du rôle des assistants au sein des équipes interprofessionnelles : 1) laissés à l'écart, 2) vivre en zone grise : négocier et naviguer le rôle d'assistant, 3) qui est le patron?, 4) les choses ne vous tombent pas tout cuit dans le bec : la recherche de perfectionnement professionnel et 5) [pas] seulement l'assistant : l'influence des normes et des attitudes et les points de vue externes. Conclusion : ces observations décrivent les perceptions des normes et les normes réelles quant au rôle de l'assistant en établissement. Elles peuvent éclairer les discussions sur la réglementation et l'agrément, de même que sur le perfectionnement professionnel et la formation continue, et favoriser une réflexion sur les dynamiques de l'équipe et les pratiques de supervision.

The neuronal RhoA GEF, Tech, interacts with the synaptic multi-PDZ-domain-containing protein, MUPP1.

Tech is a RhoA guanine nucleotide exchange factor (GEF) that is highly enriched in hippocampal and cortical neurons. To help define its function, we have conducted studies aimed at identifying partner proteins that bind to its C-terminal PDZ ligand motif. Yeast two hybrid studies using the Tech C-terminal segment as bait identified MUPP1, a protein that contains 13 PDZ domains and has been localized to the post-synaptic compartment, as a candidate partner protein for Tech. Co-transfection of Tech and MUPP1 in human embryonic kidney 293 cells confirmed that these full-length proteins interact in a PDZ-dependent fashion. Furthermore, we confirmed that endogenous Tech co-precipitates with MUPP1, but not PSD-95, from hippocampal and cortical extracts prepared from rat brain. In addition, immunostaining of primary cortical cultures revealed co-localization of MUPP1 and Tech puncta in the vicinity of synapses. In assessing which PDZ domains of MUPP1 mediate binding to Tech, we found that Tech can bind to either PDZ domain 10 or 13 of MUPP1 as mutation of both these domains is needed to disrupt their interaction. Taken together, these findings demonstrate that Tech binds to MUPP1 and suggest that it regulates RhoA signaling pathways in the vicinity of synapses.

Disrupted secretory activation of the mammary gland after antenatal glucocorticoid treatment in sheep.

Antenatal glucocorticoids are administered to women at risk of preterm delivery to prevent neonatal respiratory morbidity. The effects of exogenous glucocorticoids on the development of lactation are unknown. This study investigated the effects of a single dose of antenatal glucocorticoids on secretory activation in sheep before and after parturition. Pregnant ewes (N=36) were randomised to receive either medroxyprogesterone acetate (MPA) at 118 days of pregnancy and betamethasone at 125 days (BETA group), MPA at 118 days and saline at 125 days (MPA group) or saline at 118 and 125 days (SALINE group). The concentration of lactose, progesterone, cortisol and prolactin in maternal plasma was measured during pregnancy. After term parturition, the concentration of lactose in milk and maternal plasma was measured daily for 5 days. Lambs were weighed at birth and at 5 days of age; milk volume was measured on day 5. The concentration of lactose in maternal plasma increased significantly after betamethasone administration, corresponding to a fall in plasma progesterone. No changes in lactose were observed in MPA or SALINE ewes. Transient decreases in cortisol and increases in prolactin were observed in the BETA group, but not in either the MPA or SALINE group. After parturition, BETA ewes experienced reduced milk yield and lamb weight gain, and delayed increases in milk lactose levels compared with MPA and saline controls. This study demonstrated that, in sheep, antenatal glucocorticoid administration disrupted secretory activation, causing precocious mammary secretion before parturition and compromising postpartum milk production and lamb growth.

Microporous polysaccharide hemospheres do not inhibit bone healing compared to bone wax or microfibrillar collagen.

Topical hemostats may reduce bone bleeding but the presence of residual matter may inhibit bone growth. We compared a recently approved hemostat, microporous polysaccharide hemospheres (Arista AH, Medafor Inc, Minneapolis, Minnesota), with conventional hemostatic agents in a rabbit calvarial model. Standard defects were created and microfibrillar collagen (Avitene; C.R. Bard Inc, Murray Hill, New Jersey), bonewax, or microporous polysaccharide hemospheres was applied. Bone growth was evaluated after fluorescent labeling the mineralization front. At 7 weeks bonewax and microfibrillar collagen had reduced bone growth compared to control or microporous polysaccharide hemospheres. Microporous polysaccharide hemospheres and control animals also had reduced rabbit calvarial defects compared to bonewax or microfibrillar collagen.

Mandibular Advancement Device-Emergent Central Sleep Apnea Can Resolve Spontaneously: A Case Report.

ABSTRACT: The development of treatment emergent central sleep apnea (CSA) has been described after almost all obstructive sleep apnea (OSA) therapies. While the course of positive airway pressure (PAP) emergent CSA, is better established; little is known about the natural course of mandibular advancement device (MAD) emergent CSA. Previous reports failed to comment on its natural course or report treatment with advanced ventilator modes such as adaptive servoventilation. We describe spontaneous resolution of MAD emergent CSA in a patient with moderate OSA who refused PAP. We also highlight the need for follow up polysomnography (PSG) after maximal advancement with a MAD and the possible association between MAD emergent CSA and atrial fibrillation. The exact pathophysiology of this phenomenon remains unclear but may relate to high loop gain of the respiratory system resulting in ventilatory overshoot after treatment and atrial fibrillation associated increased susceptibility to periodic ventilation.

Modeling the hospital safety partnership preferences of patients and their families: a discrete choice conjoint experiment.

BACKGROUND: Patients and their families play an important role in efforts to improve health service safety. OBJECTIVE: The objective of this study is to understand the safety partnership preferences of patients and their families. METHOD: We used a discrete choice conjoint experiment to model the safety partnership preferences of 1,084 patients or those such as parents acting on their behalf. Participants made choices between hypothetical safety partnerships composed by experimentally varying 15 four-level partnership design attributes. RESULTS: Participants preferred an approach to safety based on partnerships between patients and staff rather than a model delegating responsibility for safety to hospital staff. They valued the opportunity to participate in point of service safety partnerships, such as identity and medication double checks, that might afford an immediate risk reduction. Latent class analysis yielded two segments. Actively engaged participants (73.3%) comprised outpatients with higher education, who anticipated more benefits to safety partnerships, were more confident in their ability to contribute, and were more intent on participating. They were more likely to prefer a personal engagement strategy, valued scientific evidence, preferred a more active approach to safety education, and advocated disclosure of errors. The passively engaged segment (26.7%) anticipated fewer benefits, were less confident in their ability to contribute, and were less intent on participating. They were more likely to prefer an engagement strategy based on signage. They preferred that staff explain why they thought patients should help make care safer and decide whether errors were disclosed. Inpatients, those with immigrant backgrounds, and those with less education were more likely to be in this segment. CONCLUSION: Health services need to communicate information regarding risks, ask about partnership preferences, create opportunities respecting individual differences, and ensure a positive response when patients raise safety concerns.

Responses of chinchilla inferior colliculus neurons to amplitude-modulated tones with different envelopes.

Responses of single neurons in the inferior colliculus of the chinchilla to amplitude-modulated tones were obtained. In one condition, the modulating waveform was a low-frequency sinusoid (SAM tone). In the other, the modulator was a trapezoid with fixed parameters, used to create trains of brief tone bursts presented at various repetition rates (TRAM tone). Modulation frequency (or repetition rate) was varied over the range from 10 to 200 Hz. Many individual neurons exhibited strong selectivity for modulator type. Neurons with pauser discharge patterns to steady-state tones usually exhibited greater responsiveness to SAM tones than to TRAM. In contrast, neurons that responded transiently to steady-state tones usually exhibited greater responsiveness to TRAM tones than to SAM. Neurons with sustained responses to steady-state tones responded strongly to both types of modulated tones. The selectivity for modulator type suggests that transient neurons may play a different functional role in the representation of envelopes than do other types of neurons.

4-(N,N-dipropylamino)benzaldehyde inhibits the oxidation of all-trans retinal to all-trans retinoic acid by ALDH1A1, but not the differentiation of HL-60 promyelocytic leukemia cells exposed to all-trans retinal.

BACKGROUND: The signal transduction pathways mediated by retinoic acid play a critical role in the regulation of cell growth and differentiation during embryogenesis and hematopoiesis as well as in a variety of tumor cell lines in culture. Following the reports that two members of the superfamily of aldehyde dehydrogenase (ALDH) enzymes, ALDH1A1 and ALDH1A2, were capable of catalyzing the oxidation of all-trans retinal to all-trans retinoic acid with submicromolar Km values, we initiated an investigation of the ability of 4-(N,N-dipropylamino)benzaldehyde (DPAB) to inhibit the oxidation of retinal by purified mouse and human ALDH1A1. RESULTS: Our results show that DPAB potently inhibits retinal oxidation, with IC50 values of 0.11 and 0.13 microM for purified mouse and human ALDH1A1, respectively. Since the HL-60 human myeloid leukemic cell line has been used extensively to study the retinoic acid induced differentiation of HL-60 cells to granulocytes, and ALDH1A1 activity had previously been reported in HL-60 cells, we investigated the ability of DPAB to block differentiation of HL-60 promyelocytic leukemia cells exposed to retinal in culture. In HL-60 cells coincubated with 1 microM retinal and 50 microM DPAB for 144 hours, cell differentiation was inhibited only 30%. Furthermore, the NAD-dependent oxidation of propanal or retinal was less than 0.05 nmoles NADH formed/min-10(7) cells in spectrophotometric assays using HL-60 cell extracts. CONCLUSION: Although ALDH1A1 may be the major catalytic activity for retinal oxidation in some retinoid-dependent mouse and Xenopus embryonic tissues and in adult human and mouse hematopoietic stem cells, another catalytic activity appears to synthesize the retinoic acid ligand necessary to stimulate the differentiation of HL-60 cells to end stage granulocytes.