Healthcare use attributable to COVID-19: a propensity-matched national electronic health records cohort study of 249,390 people in Wales, UK.

BACKGROUND: To determine the extent and nature of changes associated with COVID-19 infection in terms of healthcare utilisation, this study observed healthcare contact 1 to 4 and 5 to 24 weeks following a COVID-19 diagnosis compared to propensity-matched controls. METHODS: Two hundred forty nine thousand three hundred ninety Welsh individuals with a positive reverse transcription-polymerase chain reaction (RT-PCR) test were identified from data from national PCR test results. After elimination criteria, 98,600 positive individuals were matched to test negative and never tested controls using propensity matching. Cohorts were split on test location. Tests could be taken in either the hospital or community. Controls were those who had tested negative in their respective environments. Survival analysis was utilised for first clinical outcomes which are grouped into primary and secondary. Primary outcomes include post-viral-illness and fatigue as an indication of long-COVID. Secondary outcomes include clinical terminology concepts for embolism, respiratory conditions, mental health conditions, fit notes, or hospital attendance. Increased instantaneous risk for positive individuals was quantified using hazard ratios (HR) from Cox regression, while absolute risk (AR) and relative risk were quantified using life table analysis. RESULTS: Analysis was conducted using all individuals and stratified by test location. Cases are compared to controls from the same test location. Fatigue (HR: 1.77, 95% CI: 1.34-2.25, p = < 0.001) and embolism (HR: 1.50, 95% CI: 1.15-1.97, p = 0.003) were more likely to occur in all positive individuals in the first 4 weeks; however, anxiety and depression (HR: 0.83, 95% CI: 0.73-0.95, p = 0.007) were less likely. Positive individuals continued to be more at risk of fatigue (HR: 1.47, 95% CI: 1.24-1.75, p = < 0.001) and embolism (HR: 1.51, 95% CI: 1.13-2.02, p = 0.005) after 4 weeks. All positive individuals are also at greater risk of post-viral illness (HR: 4.57, 95% CI: 1.77-11.80, p = 0.002). Despite statistical association between testing positive and several conditions, life table analysis shows that only a small minority of the study population were affected. CONCLUSIONS: Community COVID-19 disease is associated with increased risks of post-viral-illness, fatigue, embolism, and respiratory conditions. Despite elevated risks, the absolute healthcare burden is low. Subsequently, either very small proportions of people experience adverse outcomes following COVID-19 or they are not presenting to healthcare.

Disease control in chronic rhinosinusitis: a qualitative study of patient perspectives.

BACKGROUND: The definition of disease control in chronic rhinosinusitis (CRS) is an active area of study. However, investigations have not engaged CRS patients in how they think about disease control. This study seeks to understand the patient perspective on CRS disease control. METHODS: Qualitative phenomenological study using constant comparative methodology was applied. The research team conducted 10, one-on-one interviews with CRS patients ranging from 22 to 55 minutes in length. The content of the interview protocol was determined through iterative discussion amongst all authors. Two authors served as coders to identify recurrent themes. Themes were analyzed for meaning and conclusions were summarized. RESULTS: Three recurring themes determined from patients were that (1) use of the terminology control adequately represents this phenomenon, (2) components of control could be classified into four main themes relating to CRS symptomatology, exacerbation of comorbid disease, quality of life and acute exacerbations of CRS, and (3) when patients deem their CRS is uncontrolled they are more willing to escalate their treatment to include escalating their daily maintenance regimen, seeking otolaryngology referral, taking rescue medication or undergoing endoscopic sinus surgery. CONCLUSIONS: CRS patients consider their daily symptoms, the severity and frequency of CRS exacerbations, impact on quality of life as well as exacerbation of comorbid disease when thinking about their disease control. Disease control is a goal of treatment for patients and uncontrolled disease motivates patients to seek further treatment. Physicians should explore all components of CRS control when considering disease status and need for further treatment.

Weighing as part of your care: a feasibility study exploring the re-introduction of weight measurements during pregnancy as part of routine antenatal care.

BACKGROUND: The UK does not currently have guidelines on gestational weight gain owing to gaps in the evidence base. Reintroducing routine weighing of women throughout pregnancy would begin to provide the evidence needed to fill this gap. The aim of this research was to re-introduce measurement of weight at each routine antenatal appointment in a small scale study, in order to determine the feasibility and acceptability of implementing the practice on a larger scale. METHODS: A feasibility study, incorporating quantitative and qualitative components, was conducted in one antenatal hospital clinic and with one community midwifery team. Thirty-eight pregnant women were recruited at their 20 week anomaly scan appointment and weighed at their appointments throughout the rest of their pregnancy; five participated in a telephone interview at approximately 37 weeks gestation. Data were collected on: numbers consenting to be weighed, reasons for declining to be weighed and number of weight measurements recorded. Qualitative interviews were used to explore acceptability of the practice to pregnant women. RESULTS: Overall, 79.2% (38 out of 48) of those approached consented to being weighed throughout pregnancy; of the 10 who declined, three cited not wanting to be weighed. In the interviews, women discussed routine weighing as a positive experience, described several benefits of weighing and indicated they would like more information about weight during pregnancy. No major barriers to the integration of a weight measurement into routine antenatal appointments were encountered. Completion of the weight record sheets that were inserted into women's handheld notes varied between staff: of the 26 sheets recovered from handheld notes, only 3 (11.5%) had no weights recorded, 17 (65.4%) had between one and three weights recorded and six (23.1%) had more than 4 weights recorded. CONCLUSIONS: In this feasibility study, routine weighing was acceptable to pregnant women. No barriers that would inhibit re-introduction of weighing women throughout pregnancy into standard antenatal care were encountered. Implementation of routine weighing during pregnancy on a larger scale should be considered as it may have benefits for women in the short and long-term, particularly with regard to informing appropriate gestational weight gain guidelines in the UK.

Kidney preservation at subzero temperatures using a novel storage solution and insect ice-binding proteins.

BACKGROUND: Contemporary kidney preservation methods involve storing at 4 degree C up to 24 h prior to transplantation. By decreasing the storage temperature to below 0 degree C, we hypothesized that the safe storage time could be significantly lengthened. OBJECTIVE: The efficacy of a proprietary CryoStasis (CrS) storage solution for the subzero preservation of kidneys was tested, with or without addition of a hyperactive insect antifreeze protein (TmAFP). MATERIALS AND METHODS: Rat kidneys were stored in either University of Wisconsin (UW) solution (4 degree C, 24 h), CrS (-2 degree C, 48 h), or CrS with 61.5 µM TmAFP (-4.4 degree C, 72 h). Following storage, viability was assessed with MTT reduction assays and live vs. dead cell (FDA/PI) staining. Markers of ischemic damage were analyzed using fluormetric substrates for caspase-3 and calpain activity. RESULTS: Kidneys stored in CrS for 48 h and CrS with TmAFP for 72 h displayed similar levels of enzymatic activity compared to 24 h UW controls. CONCLUSION: This methodology shows promise to prolong the safe storage time of kidneys and offers the potential of increased organ availability for renal transplants.

Cryopreservation Of Nili-Ravi Buffalo Bull Sperm in Cryodiluent Supplemented with Lolium perenne Protein Preparations.

BACKGROUND: Semen from the Nili-Ravi buffalo bull, Bubalus bubalis, shows poor survival after freeze storage compared to bovine (Bos taurus and Bos indicus) semen. Freeze-susceptibility distinctions in these two genera have been attributed to differences in sperm membranes. MATERIALS AND METHODS: We measured the impact of protein preparations derived from a frost-resistant perennial grass, Lolium perenne, with ice recrystallization inhibition activity on the low temperature storage of B. bubalis semen. RESULTS: When the L. perenne preparations (0.1, 1, 10 µg/mL) were added to buffalo semen [2 ejaculates per bull (N=3) per replicate (r=3)] in Tris-citrate extender (50×106sperm mL-1), there was no impact on semen quality, as measured by sperm motility and plasma membrane integrity, after storage at 4 degree C (P>0.05). However, when semen supplemented with the grass proteins (0.1 and 1 µg mL-1) was evaluated after freezing and storage in liquid nitrogen for 24 h, post-thaw sperm progressive motility and plasma membrane integrity was higher (P<0.05) than in control samples. Post-thaw sperm viability and sperm acrosome integrity was similar (P > 0.05) to controls. CONCLUSION: The improvement in cryopreserved buffalo sperm progressive motility and plasma membrane integrity suggests that the use of these easily-made preparations may improve fertility after cryopreservation and offers the prospect of improved conception rates after artificial insemination with cryopreservation.

Exploring the use of positive psychology interventions in brain injury survivors with challenging behaviour.

OBJECTIVE: To investigate the feasibility and effectiveness of conducting two positive psychology interventions to improve mood and self-concept with survivors of traumatic brain injury (TBI), within a neuro-rehabilitation hospital. METHOD AND PROCEDURES: Ten patients with brain injury were randomly allocated to an intervention and control group. The efficacy of the first intervention, 'three positive things in life' was measured via Seligman's Authentic Happiness Index (AHI), at base-line, directly following the intervention and at the end of the 12-week group programme. The second intervention, the 'Value in Action (VIA) signature strengths intervention' was measured by the Head Injury Semantic Differential Scale (HISDS) at baseline and at the end of the group. RESULTS: Compared to baseline and control group scores, the AHI index showed an increase in the intervention group's happiness following the intervention and at the end of the 12-week programme, albeit the latter increase was non-significant. The HISDS showed non-significant improvement in self-concept and reduction in polarization of the self in the present, future and past in the second intervention. Anecdotal evidence revealed a clear improved mood following the interventions. CONCLUSION: This study shows promising results for the effectiveness of Positive Psychology interventions and methods to improve feasibility when applying this treatment within a hospital setting.

Biofilm, ice recrystallization inhibition and freeze-thaw protection in an epiphyte community.

Microbial communities found on the surface of overwintering plants may be exposed to low temperatures as well as multiple freeze-thaw events. To explore the adaptive mechanisms of these epiphytes, with the objective of identifying products for freeze-protection, enrichment libraries were made from frost-exposed leaves. Of 15 identified bacteria from 60 individual clones, approximately half had ice-association activities, with the great majority showing high freeze-thaw resistance. Isolates with ice nucleation activity and ice recrystallization inhibition activity were recovered. Of the latter, two (Erwinia billingiae J10, and Sphingobacterium kitahiroshimense Y2) showed culture and electron microscopic evidence of motility and/or biofilm production. Mass spectrometric characterization of the E. billingiae extracellular polymeric substance (EPS) identified the major proteins as 35 kDa outer membrane protein A and F, supporting its biofilm character. The addition of the EPS preparation increased the freeze-thaw survival of the more susceptible bacteria 1000-10000 times, and protection was at least partially dependent on the protein component.

Raising awareness of pre-conception care in community pharmacies: a feasibility study.

BACKGROUND: There is growing evidence to support the introduction of pre-conception interventions to optimise the health of mothers and their future children. At present, there is poor awareness regarding the importance of pre-conception care (PCC) amongst healthcare professionals and couples planning a pregnancy. Community pharmacies are ideally placed to reach a range of prospective couples planning a pregnancy and could effectively provide information about PCC. METHODS: This study assessed feasibility of an intervention to raise awareness of PCC in community pharmacies in Northern Ireland over 3 months. INCLUSION CRITERIA: women of childbearing age (16-45 years) engaging with services at participating pharmacies. Study resources: campaign posters, information cards, crib sheets for pharmacy staff. A mixed methods approach was employed, including, brief information provision for women, record of staff interactions with customers, customer feedback cards and qualitative interviews with pharmacy staff. Descriptive statistics assessed distribution of study resources and staff interviews were analysed using a thematic analysis framework. RESULTS: There were eight participating pharmacies, three of which consented to post-study interviews. Three pharmacies chose not to deliver the planned intervention. Distribution of campaign cards (n = 456) varied (0-86%). Analysis of customer feedback cards (n = 9) demonstrated that the majority of respondents were happy to receive information on pre-conception health. Of the women who responded to this question (n = 8), all were 'extremely likely' or 'likely' to act on the information provided. Four main themes emerged from analysis of staff interviews: (1) training and experience in providing health advice, (2) intervention resources, (3) understanding the aims of the intervention, (4) perceived value of the intervention. Barriers to intervention delivery included non-engagement from pharmacies and need for additional training of staff. CONCLUSIONS: An intervention to raise awareness of PCC within a community pharmacy setting was feasible and acceptable to both women and staff in participating pharmacies. This study indicates that a number of factors must be considered to enhance implementation and effectiveness of PCC interventions in this setting. In particular, better understanding of non-engagement, provision of adequate training and support for staff, and exploring incentives for pharmacies to prioritise PCC.

The bugs that came in from the cold: molecular adaptations to low temperatures in insects.

The widespread distribution of insects over many ecological niches is a testimony to their evolutionary success. The colonization of environments at high latitudes or altitudes required the evolution of biochemical strategies that reduced the impact of cold or freezing stress. This review focuses on our current interests in some of the genes and proteins involved in low temperature survival in insects. Although the most widespread form of protection is the synthesis of low molecular weight polyol cryoprotectants, proteins with intrinsic protective properties, such as the thermal hysteresis or antifreeze proteins are also important. These have been cloned and characterized in certain moths and beetles. Molecular techniques allowing the isolation of genes differentially regulated by low temperatures have revealed that heat shock proteins, cold stress proteins, membrane protectants, as well as ice nucleators and other less well characterized proteins likely also play a role in cold hardiness.

Treating osteoporosis in Canada: what clinical efficacy data should be considered by policy decision makers?

UNLABELLED: SAUMMARY: Using a Markov state-transition model, we estimated fractures averted with risedronate using two different types of clinical efficacy data. Summary data, as opposed to individual patient data (IPD), underestimated the number of fractures averted when applied in a specified high risk population. The choice of clinical efficacy data is an important consideration in health economic models evaluating osteoporosis therapies. INTRODUCTION: This paper contrasts fracture reduction estimates for risedronate utilizing efficacy data from two approaches to meta-analysis: summary data versus individual patient data. We also examined differences in fracture reduction explained by varied cohort selection, especially the inclusion of low- versus high-risk populations. METHODS: Using a Markov state-transition model, we compared fractures averted over 3 years in a hypothetical cohort by inputting fracture risk reduction estimates (risedronate versus placebo) from two data sources (summary data versus IPD). The cohort consisted of 100,000 Canadian women, age > or =65 years with osteoporosis (WHO criteria T-score < or = -2.5) and prevalent morphometric vertebral fracture. RESULTS: Non-vertebral fractures averted with risedronate were: 3,571 and 6,584 per 100,000 women for summary data and IPD, respectively. For vertebral fractures, the numbers were 8,552 and 10,127. When IPD versus summary data was used, an additional 3,013 more non-vertebral fractures and 1,575 vertebral fractures were averted. DISCUSSION: Relative risk estimates from IPD analyses were the best choice for modelling fracture outcomes when applied in a specified high-risk population. In addition to superior statistical methodology, they utilized RCT cohorts that are more representative of higher risk patients requiring treatment (osteoporotic women > or =65 years with a prevalent vertebral fracture).

Postnatal sex reversal of the ovaries in mice lacking estrogen receptors alpha and beta.

Mice lacking estrogen receptors alpha and beta were generated to clarify the roles of each receptor in the physiology of estrogen target tissues. Both sexes of alphabeta estrogen receptor knockout (alphabetaERKO) mutants exhibit normal reproductive tract development but are infertile. Ovaries of adult alphabetaERKO females exhibit follicle transdifferentiation to structures resembling seminiferous tubules of the testis, including Sertoli-like cells and expression of Müllerian inhibiting substance, sulfated glycoprotein-2, and Sox9. Therefore, loss of both receptors leads to an ovarian phenotype that is distinct from that of the individual ERKO mutants, which indicates that both receptors are required for the maintenance of germ and somatic cells in the postnatal ovary.

Ammonia toxicity and its prevention in inherited defects of the urea cycle.

The urea cycle is the final pathway for removal of surplus nitrogen from the body, and the major route in humans for detoxification of ammonia. The full complement of enzymes is expressed only in liver. Inherited deficiencies of urea cycle enzymes lead to hyperammonaemia, which causes brain damage. Severe defects present with hyperammonaemic crises in neonates. Equally devastating episodes may occur in previously asymptomatic adults with mild defects, most often X-linked ornithine transcarbamylase (OTC) deficiency. Several mechanisms probably contribute to pathogenesis. Treatment aims to reduce plasma ammonia quickly, reduce production of waste nitrogen, dispose of waste nitrogen using alternative pathways to the urea cycle and replace arginine. These therapies have increased survival and probably improve the neurological outcome. Arginine, sodium benzoate, sodium phenylbutyrate and, less often, sodium phenylacetate are used. Long-term correction is achieved by liver transplantation. Gene therapy for OTC deficiency is effective in animals, and work is ongoing to improve persistence and safety.

Flounder antifreeze protein synthesis under heat shock control in transgenic Drosophila melanogaster.

The gene coding for the most abundant antifreeze protein (AFP) in the winter flounder was placed downstream of the Drosophila melanogaster hsp70 promoter and introduced into the D. melanogaster germ line by P-element-mediated transformation. In each of six transgenic strains tested, heat shock treatment induced the expression of two major AFP gene transcripts and one minor one. All three transcripts were spliced despite the lack of an obvious D. melanogaster internal intron-splicing sequence. The variation in transcript length was caused by selection of different polyadenylation sites. Western blots showed the presence of immunoreactive AFP in hemolymph from heat-shocked transformants. The immunoreactive material had a molecular weight of 6,200, which is consistent with the loss of the signal sequence from the primary translation product and the retention of the pro sequence. Thus, all the signals for flounder pre-mRNA and preprotein processing were recognized in D. melanogaster.

The antifreeze potential of the spruce budworm thermal hysteresis protein.

Antifreeze proteins (AFP) inhibit ice growth by surface adsorption that results in a depression of the freezing point below the melting point. The maximum level of this thermal hysteresis shown by the four structurally unrelated fish AFP is approximately 1.5 degrees C. In contrast, hemolymph and crude extracts from insects can have 5 degrees to 10 degrees C of thermal hysteresis. Based on the isolation, cloning, and expression of a thermal hysteresis protein (THP) from spruce budworm (Choristoneura fumiferana), the vastly greater activity is attributable to a 9 kDa protein. This novel, threonine- and cysteine-rich THP has striking effects on ice crystal morphology, both before and during freezing. It is also 10 to 30 times more active than any known fish AFP, offering the prospect of superior antifreeze properties in cryoprotective applications.

Comparison of limb kinematics between collected and lengthened (medium/extended) trot in two groups of dressage horses on two different surfaces.

BACKGROUND: Dressage horses are often asked to work in lengthened paces during training and competition, but to date there is limited information about the biomechanics of dressage-specific paces. Preliminary work has shown increased fetlock extension in extended compared with collected paces, but further investigation of the kinematic differences between collected, medium and extended trot in dressage horses is warranted. OBJECTIVES: Investigation of the effect of collected vs. medium/extended trot on limb kinematics of dressage horses. STUDY DESIGN: Prospective kinematic evaluation. METHODS: Twenty clinically sound horses in active dressage training were used. Group 1: Ten young horses (≤6 years) were assessed at collected and medium trot and Group 2: Ten mature horses (≥9 years) were assessed at collected and extended trot. All horses were evaluated on two different surfaces. High speed motion capture (240 Hz) was used to determine kinematic variables. Fore- and hindlimb angles were measured at mid-stance. Descriptive statistics and mixed effect multilevel regression analyses were performed. RESULTS: Speed and stride length were reduced and stride duration increased at collected compared with medium/extended trot. Lengthened trot (medium/extended trot) was associated with increased fetlock extension in both the fore- and hindlimbs in both groups of horses. Changes were greater in mature horses compared with young horses. Shoulder and carpus angles were associated with forelimb fetlock angle. Hock angle was not significantly influenced by pace. Surface had no effect on fetlock or hock angles. MAIN LIMITATIONS: Only 2D motion analysis was carried out. Results may have differed in horses with more extreme gait characteristics. CONCLUSIONS: Medium/extended trot increases extension of the fore- and hindlimb fetlock joints compared with collected trot in both young and mature dressage horses, respectively.

Prevalence of Gastroesophageal Reflux in Cats During Anesthesia and Effect of Omeprazole on Gastric pH.

BACKGROUND: Gastroesophageal reflux (GER) is poorly characterized in anesthetized cats, but can cause aspiration pneumonia, esophagitis, and esophageal stricture formation. OBJECTIVE: To determine whether pre-anesthetic orally administered omeprazole increases gastric and esophageal pH and increases serum gastrin concentrations in anesthetized cats, and to determine the prevalence of GER using combined multichannel impedance and pH monitoring. ANIMALS: Twenty-seven healthy cats undergoing elective dental procedures. METHODS: Prospective, double-masked, placebo-controlled, randomized clinical trial. Cats were randomized to receive 2 PO doses of omeprazole (1.45-2.20 mg/kg) or an empty gelatin capsule placebo 18-24 hours and 4 hours before anesthetic induction. Blood for measurement of serum gastrin concentration was collected during anesthetic induction. An esophageal pH/impedance catheter was utilized to continuously measure esophageal pH and detect GER throughout anesthesia. RESULTS: Mean gastric pH in the cats that received omeprazole was 7.2 ± 0.4 (range, 6.6-7.8) and was significantly higher than the pH in cats that received the placebo 2.8 ± 1.0 (range, 1.3-4.1; P < .001). Omeprazole administration was not associated with a significant increase in serum gastrin concentration (P = .616). Nine of 27 cats (33.3%) had ≥1 episode of GER during anesthesia. CONCLUSIONS AND CLINICAL RELEVANCE: Pre-anesthetic administration of 2 PO doses of omeprazole at a dosage of 1.45-2.20 mg/kg in cats was associated with a significant increase in gastric and esophageal pH within 24 hours, but was not associated with a significant increase in serum gastrin concentration. Prevalence of reflux events in cats during anesthesia was similar to that of dogs during anesthesia.

A DNA-binding protein, tfp1, involved in juvenile hormone-regulated gene expression in Locusta migratoria.

A partially palindromic 15-nt. sequence upstream from a juvenile hormone-regulated gene (jhp21) was previously identified in the African migratory locust, Locusta migratoria. This sequence was proposed as a juvenile hormone (JH) response element (JHRE), and a protein that bound to it, as a transcription factor (TF). A yeast strain was constructed containing four tandem copies of the JHRE and after transfection with a cDNA library made to fat bodies from vitellogenic females, yeast one-hybrid experiments yielded sequences for four putative binding proteins. One of these sequences, corresponding to a transcript that was present in fat body irrespective of JH stimulation, encodes a 35kDa protein. This was designated tfp1 and appears to have a leucine zipper motif and a lipid-binding motif. Recombinant tfp1 bound to JHRE in electrophoretic mobility shift experiments and addition of tfp1 antibody in the binding reaction resulted in the disappearance or shift of TF. We suggest that JH induces the association of pre-existing proteins, including tfp1, to form an active complex, which binds to the JHRE upstream from jhp21 and regulates its transcription.

Molecular dosimetry of DNA adduct formation and cell toxicity in rat nasal mucosa following exposure to the tobacco specific nitrosamine 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone and their relationship to induction of neoplasia.

The molecular dosimetry of O6-methylguanine (O6MG) formation in DNA and cytotoxicity in respiratory and olfactory mucosa was determined during administration of 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to male Fischer 344 rats. The dose response for O6MG formation differed considerably between respiratory and olfactory mucosa. The dose response was nonlinear in respiratory mucosa where the slope of the curve was very large for doses of NNK ranging from 0.3 to 3.0 mg/kg but much smaller in the dose range of 10 to 100 mg/kg. In contract, the dose response in the olfactory mucosa did not demonstrate such a large change in slope over the same dose range. The concentration of O6MG formed to dose of NNK ratio, an index of efficiency of alkylation, increased dramatically only in the respiratory mucosa as the dose of NNK was decreased from 100 to 0.3 mg/kg. The concentration of O6MG was four times greater in respiratory than olfactory mucosa after treatment of rats with 1 mg/kg NNK. Alkylation in the two regions of the nose became similar as the dose of NNK was increased. In rats treated for up to 12 days with NNK (10 mg/kg/day), the concentration of O6MG was 60 to 90% greater in respiratory than olfactory mucosa throughout treatment. Regional differences in the amount of O6MG formed may stem from the presence of a low Km pathway for biotransformation of NNK in the cells of the respiratory mucosa. This conclusion is supported by autoradiographic studies. Four h after treatment with 1 mg/kg [3H]NNK, silver grains were more heavily concentrated in respiratory than olfactory epithelium. Histopathological examination of the nasal passages revealed dose related, cell specific differences in toxicity following treatment of rats with 10, 30, or 100 mg/kg NNK for 12 days. No toxicity was observed in the nose when 1 mg/kg NNK was administered. Bowman's glands underlying the olfactory mucosa and Steno's glands were the most sensitive sites for toxicity, exhibiting necrosis after as little as 2 days of treatment with 10 mg/kg NNK. Damage to these glands progressed in a dose- and time-dependent manner. Respiratory epithelium exhibited only mild toxicity while basal cell metaplasia was evident in olfactory epithelium. Rats treated with NNK for 20 weeks (50 mg/kg, three times a week) had a 45% incidence of carcinomas in the olfactory region. These neoplasms appeared to arise from Bowman's glands. In contrast, there was only a 5% incidence of malignant neoplasia and a 29% incidence of benign neoplasia in the respiratory region.(ABSTRACT TRUNCATED AT 400 WORDS)

Molecular dosimetry of ethylene oxide: formation and persistence of N-(2-hydroxyethyl)valine in hemoglobin following repeated exposures of rats and mice.

The formation of N-(2-hydroxyethyl)valine (HEVal) in hemoglobin was investigated in male F344 rats (10/group) and B6C3F1 mice (20/group) exposed to 0, 3, 10, 33, 100, or 300 (rats only) ppm ethylene oxide (ETO) by inhalation for 6 h/day for 4 weeks (5 days/week) or exposed to 100 (mice) or 300 ppm (rats) ETO for 1 or 3 days, or 1, 2, or 4 weeks (5 days/week). The persistence of HEVal was studied in animals killed up to 10 days after cessation of the 4-week time-course studies. HEVal was determined by a modified Edman degradation and quantitation of the resulting pentafluorophenylthiohydantoin derivative, using gas chromatography-mass spectrometry. The resulting experimental data were compared to simulations derived with a model for the formation and removal of hemoglobin adducts (T.R. Fennell, S.C.J. Sumner, and V.E. Walker, Cancer Epidemiol., Biomarkers & Prev., 1: 213-219, 1992). Repeated exposures of rats and mice for 4 weeks to 300 and 100 ppm ETO, respectively, led to an accumulation of HEVal that was 14 (rats) and 15 (mice) times greater than that found after 1 day of exposure [28 +/- 2 (SE) and 9.4 +/- 0.4 (SE) pmol HEVal/mg globin in rats and mice, respectively]. After cessation of exposures, HEVal was lost faster than predicted by the normal erythrocyte life span alone. An initial phase of rapid decline in HEVal concentrations was consistent with the removal of older, more heavily alkylated populations of RBCs, accompanied by a burst of erythropoiesis. The dose-response curves for HEVal were linear between 3 and 33 ppm ETO, with 3.5 +/- 0.2 and 3.4 +/- 0.3 pmol adduct/mg globin formed in rats and mice, respectively, after 4 weeks of exposure to 3 ppm ETO. Above 33 ppm ETO, the slope of the dose-response curves increased. Comparison of the dose response for HEVal in rats exposed to ETO for 4 weeks to the dose-response for N tau-(2-hydroxyethyl)histidine in rats exposed to the same concentrations of ETO for 2 years (S. Osterman-Golkar et al., Teratog. Carcinog. Mutagen., 3: 395-405, 1983) suggested that exposures to ETO can reduce the life span of erythrocytes in a concentration- and time-dependent manner. Correlation of the experimental data and simulations for the formation and removal of HEVal demonstrated that perturbations in erythropoiesis and RBC life span complicate the estimation of exposures to ETO when estimates are based upon hemoglobin adduct measurements in heavily exposed individuals.(ABSTRACT TRUNCATED AT 400 WORDS)