Utilization of Organs From Donors According to Hepatitis C Antibody and Nucleic Acid Testing Status: Time for Change.

Previous studies have grouped all donors positive for hepatitis C virus (HCV) antibody (Ab). Only recently has donor HCV nucleic acid testing (NAT) become routine, and the impact of Ab and NAT status on organ utilization is unknown. Using the United Network for Organ Sharing database, we identified 9290 donors from 2015 to 2016 for whom both HCV Ab and NAT data were available and compared organ utilization by HCV status. Overall, 93.8% of donors were Ab negative and NAT negative (Ab-NAT-), 0.15% were Ab negative and NAT positive, 1.8% were Ab positive and NAT negative (Ab+NAT-), and 4.2% were both Ab and NAT positive (Ab+NAT+). Ab-NAT- donors donated at the highest rate for all organs except livers, of which Ab+NAT- donors donated at a higher rate (81.2% vs 73.2%, p = 0.03). Livers were discarded for reasons related to abnormal biopsies in Ab+NAT+ donors, whereas kidneys from Ab- or NAT-positive donors were discarded for reasons related to HCV status. Using a propensity score-matched model, we estimated that using Ab+NAT- donors at the same rate as Ab-NAT- donors could result in 48 more kidney donors, 37 more heart donors, and 15 more lung donors annually. We urge the use of HCV Ab+NAT- donors for appropriately selected and consenting recipients.

18-electron rule and the 3c/4e hyperbonding saturation limit.

We show that the empirical 18-electron rule of transition metal chemistry corresponds to an intrinsic saturation limit for the 3c/4e hyperbonding interactions that are a ubiquitous feature of D-block aggregation phenomena. Such a "rule" therefore requires no "p-orbital participation," "d(2) sp(3) hybridization," "valence shell expansion," or other p-type intrusions into the Aufbau orbital filling sequence. Instead, 18e stability corresponds to the natural terminus of post-Lewis 3c/4e resonance-type stabilizations that lead to successive ligand additions (and formal increments of electron count) at a transition metal center, all within the normal (s + 5d) confines of D-block valence space.

Daily salivary cortisol patterns in midlife women with hot flashes.

OBJECTIVE: Diurnal salivary cortisol patterns in healthy adults are well established but have not been studied in midlife women with hot flashes. We hypothesized that frequent hot flashes are associated with aberrant cortisol patterns similar to sleep-deficient individuals. DESIGN: Cross-sectional. PARTICIPANTS: A total of 306 women, ages 40-62, randomized to a behavioural intervention for hot flashes. MEASUREMENTS: Baseline comparisons of cortisol geometric means (nmol/l) from four daily time points averaged over two consecutive days plus other calculated cortisol measures were made between groups defined by baseline: (i) mean daily hot flash frequency tertile (≤5·5, N = 103; >5·5-8·8, N = 103; >8·8, N = 100) and (ii) selected characteristics. Repeated-measures linear regression models of log-transformed cortisol evaluated group differences, adjusting for covariates. RESULTS: Women were 67% White and 24% African American, with 7·6 (SD 3·9) hot flashes per day. Salivary cortisol geometric means (nmol/l) among all women were as follows: 75·0 (SD 44·8) total, 8·6 (SD 5·6) wake, 10·0 (SD 7·5) wake +30 min, 3·7 (SD 3·3) early afternoon and 1·6 (SD 1·8) bedtime. Wake + 30-minute values showed an 18% median rise from wake values (interquartile range -24 to 96%), and means varied by hot flash frequency tertile, from lowest to highest: 11·4(SD 7·3), 10·3 (SD 6·5) and 8·6 (SD 7·8), respectively, P = 0·003. Beside the early afternoon value (P = 0·02), cortisol values did not vary by hot flash frequency. CONCLUSION: Taken together, these findings suggest that high frequency of moderate-to-severe hot flashes may be associated with subtle abnormalities in cortisol concentrations - a pattern consistent with chronic sleep disturbance.

Prospective Multicenter Observational Study of Overt Hepatic Encephalopathy.

BACKGROUND: Overt hepatic encephalopathy (OHE) is a frequent complication of decompensated cirrhosis. AIMS: A multicenter prospective observational study was performed to assess the most commonly recorded presenting manifestations of OHE and its associated health-care burden. METHODS: Qualifying patients must have experienced ≥1 OHE episode within 30 days of enrollment (qualifying OHE) and were followed for recurrence (on-study OHE). RESULTS: Two hundred and sixty-five patients were enrolled at 30 sites and followed for up to 9 months (mean 72 days). Seventy-two patients experienced 122 on-study episodes; with 72, 23, and 13 having ≥1, ≥2, or ≥3 on-study episodes with median days to occurrence of the 1st, 2nd, and 3rd episode of 34, 19, and 11, respectively. The most frequently recorded OHE manifestations included confusion (78 %), change in mental status (57 %), disorientation (48 %), lethargy (46 %), and asterixis (45 %). West Haven grade was used inconsistently and recorded for only 28 % of episodes. Most qualifying and on-study episodes occurred on rifaximin (60 and 82 %, respectively) and were associated with hospitalization (68 and 85 %, respectively). Twenty-three patients experienced ≥2 on-study episodes within 2 months of enrollment on average (median 45 days) and accounted for 60 % of on-study episodes. CONCLUSIONS: In this prospective study, OHE's most commonly recorded presenting manifestations included confusion, altered mental status, disorientation, lethargy, and asterixis. As reflected by frequent recurrence and hospitalizations, OHE, particularly the approximately 10 % of "high-resource-utilizing" patients with frequent recurrence, continues to pose a major unmet medical need and health-care burden despite the use of rifaximin.

Differential escape patterns within the dominant HLA-B*57:03-restricted HIV Gag epitope reflect distinct clade-specific functional constraints.

UNLABELLED: HLA-B*57:01 and HLA-B*57:03, the most prevalent HLA-B*57 subtypes in Caucasian and African populations, respectively, are the HLA alleles most protective against HIV disease progression. Understanding the mechanisms underlying this immune control is of critical importance, yet they remain unclear. Unexplained differences are observed in the impact of the dominant cytotoxic T lymphocyte (CTL) response restricted by HLA-B*57:01 and HLA-B*57:03 in chronic infection on the Gag epitope KAFSPEVIPMF (KF11; Gag 162 to 172). We previously showed that the HLA-B*57:03-KF11 response is associated with a >1-log-lower viral setpoint in C clade virus infection and that this response selects escape mutants within the epitope. We first examined the relationship of KF11 responses in B clade virus-infected subjects with HLA-B*57:01 to immune control and observed that a detectable KF11 response was associated with a >1-log-higher viral load (P = 0.02). No evidence of HLA-B*57:01-KF11-associated selection pressure was identified in previous comprehensive analyses of >1,800 B clade virus-infected subjects. We then studied a B clade virus-infected cohort in Barbados, where HLA-B*57:03 is highly prevalent. In contrast to findings for B clade virus-infected subjects expressing HLA-B*57:01, we observed strong selection pressure driven by the HLA-B*57:03-KF11 response for the escape mutation S173T. This mutation reduces recognition of virus-infected cells by HLA-B*57:03-KF11 CTLs and is associated with a >1-log increase in viral load in HLA-B*57:03-positive subjects (P = 0.009). We demonstrate functional constraints imposed by HIV clade relating to the residue at Gag 173 that explain the differential clade-specific escape patterns in HLA-B*57:03 subjects. Further studies are needed to evaluate the role of the KF11 response in HLA-B*57:01-associated HIV disease protection. IMPORTANCE: HLA-B*57 is the HLA class I molecule that affords the greatest protection against disease progression in HIV infection. Understanding the key mechanism(s) underlying immunosuppression of HIV is of importance in guiding therapeutic and vaccine-related approaches to improve the levels of HIV control occurring in nature. Numerous mechanisms have been proposed to explain the HLA associations with differential HIV disease outcome, but no consensus exists. These studies focus on two subtypes of HLA-B*57 prevalent in Caucasian and African populations, HLA-B*57:01 and HLA-B*57:03, respectively. These alleles appear equally protective against HIV disease progression. The CTL epitopes presented are in many cases identical, and the dominant response in chronic infection in each case is to the Gag epitope KF11. However, there the similarity ends. This study sought to better understand the reasons for these differences and what they teach us about which immune responses contribute to immune control of HIV infection.

3c/4e σ-type long-bonding: a novel transitional motif toward the metallic delocalization limit.

We describe a novel "long-bonding" motif that appears in the framework of natural bond orbital (NBO) analysis as a surprising form of 3-center, 4-electron (3c/4e) L···A···L' bonding with "inverted" electronegativity pattern Ξ(A) > Ξ(L), Ξ(L'). Such long-bonding (denoted L(^)L') underlies the predicted (meta)stability of exotic rare gas species with highly electronegative ligands (e.g., HeF2, NeF2) as well as the absolute stability of low-electronegativity metallic triads (e.g., BeLi2, ZnCu2, and related species) that are experimentally unknown but can be anticipated from simple valency and electronegativity trends. We focus particularly on the BeLi2 triad, whose Lewis-type Li(^)Li' long bond is of paradoxical antibonding phase pattern, denoted σ*(LiLi') to suggest its essential 2(-1/2)(s(Li) - s(Li')) orbital composition. We demonstrate how the long-bonded triad serves as a fundamental building-block for numerous 1-, 2-, and 3-d structures that are predicted to exhibit extraordinary calorimetric, vibrational, and electric polarizability properties, commonly associated with the delocalized metallic limit. Both thermodynamic and kinetic results support the NBO inference that σ/σ*-type long-bonding signals the transition to a fundamentally new regime of chemical association, separated by significant activation barriers from the covalent molecular domain and characterized by reversed perturbative precedence of Lewis-type vs resonance-type donor-acceptor contributions. Long-bond resonance therefore appears to be of central importance to a broadened conceptual picture of molecular and metallic interaction phenomena.

Two G protein oncogenes in human endocrine tumors.

Somatic mutations in a subset of growth hormone (GH)-secreting pituitary tumors convert the gene for the alpha polypeptide chain (alpha s) of Gs into a putative oncogene, termed gsp. These mutations, which activate alpha s by inhibiting its guanosine triphosphatase (GTPase) activity, are found in codons for either of two amino acids, each of which is completely conserved in all known G protein alpha chains. The likelihood that similar mutations would activate other G proteins prompted a survey of human tumors for mutations that replace either of these two amino acids in other G protein alpha chain genes. The first gene so far tested, which encodes the alpha chain of Gi2, showed mutations that replaced arginine-179 with either cysteine or histidine in 3 of 11 tumors of the adrenal cortex and 3 of 10 endocrine tumors of the ovary. The mutant alpha i2 gene is a putative oncogene, referred to as gip2. In addition, gsp mutations were found in 18 of 42 GH-secreting pituitary tumors and in an autonomously functioning thyroid adenoma. These findings suggest that human tumors may harbor oncogenic mutations in various G protein alpha chain genes.

Genomic and antigenic characterization of bovine parainfluenza-3 viruses in the United States including modified live virus vaccine (MLV) strains and field strains from cattle.

This study investigated the genetic and antigenic characterization of parainfluenza-3 virus (PI3V) of cattle. Using molecular tests including real time PCR and viral genome sequencing, PI3V strains could be separated into PI3V types, including PI3V A, PI3V B, and PI3V C. Isolates from cattle with bovine respiratory disease clinical signs and commercial vaccines in the U.S. with MLV PI3V were typed using these molecular tests. All the MLV vaccine strains tested were PI3V A. In most cases PI3V field strains from calves receiving MLV vaccines were types heterologous to the vaccine type A. Also antigenic differences were noted as PI3V C strains had lower antibody levels than PI3V A in serums from cattle receiving MLV PI3V A vaccines. This study further demonstrates there is genetic variability of U.S. PI3V strains and also antigenic variability. In addition, isolates from cattle with BRD signs and receiving MLV vaccines may have heterologous types to the vaccines, and molecular tests should be performed to differentiate field from vaccine strains. Potentially the efficacy of current PI3V A vaccines should be evaluated with other types such a PI3V B and PI3V C.

Weight change in the management of youth-onset type 2 diabetes: the TODAY clinical trial experience.

BACKGROUND: The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial documented that metformin plus rosiglitazone, but not metformin plus lifestyle intervention, provided superior durability of glycemic control relative to metformin monotherapy. OBJECTIVES: We examined weight changes among TODAY participants that completed at least 6 months of treatment, evaluated predictors of lifestyle outcome, and examined whether weight changes were related to cardiometabolic outcomes across treatment arms. METHODS: The 595 youth with type 2 diabetes, (85.1% of randomized participants aged 11-17 years) completed assessments of weight-related and cardiometabolic measures at months 0, 6, 12 and 24. Repeated measures models were used to investigate associations over time. RESULTS: Lifestyle intervention did not enhance outcome relative to metformin alone and no predictors of response to lifestyle treatment were identified. However, changes in percent overweight across treatment arms were associated with changes in multiple cardiometabolic risk factors, and decreases of ≥ 7% in overweight were associated with significant benefits over 24 months. CONCLUSIONS: Although adjunctive intensive lifestyle intervention did not improve weight-related outcomes, weight changes in the full TODAY sample were associated with small, but significant improvements in cardiometabolic status, highlighting the importance of optimizing weight management in youth with T2DM.

Detection and characterization of viruses as field and vaccine strains in feedlot cattle with bovine respiratory disease.

This study investigated viruses in bovine respiratory disease (BRD) cases in feedlots, including bovine herpesvirus-1 (BoHV-1), bovine viral diarrhea virus (BVDV), bovine respiratory syncytial virus (BRSV), bovine coronaviruses (BoCV) and parainfluenza-3 virus (PI3V). Nasal swabs were collected from 114 cattle on initial BRD treatment. Processing included modified live virus (MLV) vaccination. Seven BRD necropsy cases were included for 121 total cases. Mean number of days on feed before first sample was 14.9 days. Swabs and tissue homogenates were tested by gel based PCR (G-PCR), quantitative-PCR (qPCR) and quantitative real time reverse transcriptase PCR (qRT-PCR) and viral culture. There were 87/114 (76.3%) swabs positive for at least one virus by at least one test. All necropsy cases were positive for at least one virus. Of 121 cases, positives included 18/121 (14.9%) BoHV-1; 19/121 (15.7%) BVDV; 76/121 (62.8%) BoCV; 11/121 (9.1%) BRSV; and 10/121 (8.3%) PI3V. For nasal swabs, G-PCR (5 viruses) detected 44/114 (38.6%); q-PCR and qRT-PCR (4 viruses) detected 81/114 (71.6%); and virus isolation detected 40/114 (35.1%). Most were positive for only one or two tests, but not all three tests. Necropsy cases had positives: 5/7 G-PCR, 5/7 q-PCR and qRT-PCR, and all were positive by cell culture. In some cases, G-PCR and both real time PCR were negative for BoHV-1, BVDV, and PI3V in samples positive by culture. PCR did not differentiate field from vaccines strains of BoHV-1, BVDV, and PI3V. However based on sequencing and analysis, field and vaccine strains of culture positive BoHV-1, BoCV, BVDV, and PI3V, 11/18 (61.1%) of BoHV-1 isolates, 6/17 (35.3%) BVDV isolates, and 1/10 (10.0%) PI3V identified as vaccine. BRSV was only identified by PCR testing. Interpretation of laboratory tests is appropriate as molecular based tests and virus isolation cannot separate field from vaccine strains. Additional testing using sequencing appears appropriate for identifying vaccine strains.

Subjective and objective sleep indices in women with irritable bowel syndrome.

Patients with irritable bowel syndrome (IBS) commonly report sleep disturbances. This study examined self-report (Pittsburgh Sleep Quality Inventory) sleep quality and polysomnography (PSG) sleep variables in 18 women with mild-to-moderate IBS, 18 with severe IBS and 38 with age- and gender-matched controls. All women were studied on two consecutive nights in a sleep research laboratory where PSG data were collected. Retrospective and daily measures were obtained of self-reported sleep quality, psychological distress and gastrointestinal symptoms across one menstrual cycle. Self-report measures of psychological distress and sleep quality were significantly worse in the IBS-severe (IBS-S) group compared with controls. Rapid eye movement (REM) latency was higher in the two IBS groups on Night 1 than the control group (P = 0.06). Percentage time in REM was highest in the IBS-S on Night 2. All groups demonstrated greater sleep disruption on Night 1 (adaptation) when compared with Night 2. These results highlight the importance of considering the 'first-night effect' in those with IBS and the lack of concordance between self-report and objective indices of sleep in women with IBS.

Liver Transplantation for Urea Cycle Disorders: Analysis of the United Network for Organ Sharing Database.

BACKGROUND: Urea cycle disorders (UCD) are caused by rare inherited defects in the urea cycle enzymes leading to diminished ability to convert ammonia to urea in the liver. The resulting excess of circulating ammonia can lead to central nervous system toxicity and irreversible neurologic damage. Most cases are identified in children. However, UCDs can also be diagnosed in adulthood, and liver transplant is occasionally required. METHODS: We examined the UNOS database to evaluate outcomes in adult and pediatric patients who underwent liver transplant as treatment for a UCD. We identified 265 pediatric and 13 adult patients who underwent liver transplant for a UCD between 1987 and 2010. RESULTS: The majority (68%) of these patients were transplanted before age 5 years. Ornithine transcarbamylase (OTC) deficiency was the most common UCD in both adults and children who underwent transplant. UCD patients who underwent liver transplant were younger, more likely to be male (67%), had lower pediatric end-stage liver disease/model for end-stage liver disease scores, and were more likely to be Caucasian or Asian compared with all other patients transplanted during the same time period. UCD patients did not have an increased utilization of living donor transplantation in this US cohort. Univariate and multivariate risk factor analyses were performed and did not reveal any significant factors that were predictive of post-transplant death or graft loss. CONCLUSIONS: Excellent outcomes were seen in both children and adults with UCDs who underwent transplant with overall 1-, 5-, and 10-year survivals of 93%, 89%, and 87%, respectively.

A reactor for high-throughput high-pressure nuclear magnetic resonance spectroscopy.

The design of a reactor for operando nuclear magnetic resonance (NMR) monitoring of high-pressure gas-liquid reactions is described. The Wisconsin High Pressure NMR Reactor (WiHP-NMRR) design comprises four modules: a sapphire NMR tube with titanium tube holder rated for pressures as high as 1000 psig (68 atm) and temperatures ranging from -90 to 90 °C, a gas circulation system that maintains equilibrium concentrations of dissolved gases during gas-consuming or gas-releasing reactions, a liquid injection apparatus that is capable of adding measured amounts of solutions to the reactor under high pressure conditions, and a rapid wash system that enables the reactor to be cleaned without removal from the NMR instrument. The WiHP-NMRR is compatible with commercial 10 mm NMR probes. Reactions performed in the WiHP-NMRR yield high quality, information-rich, and multinuclear NMR data over the entire reaction time course with rapid experimental turnaround.

Constitutively active stimulatory G-protein alpha s in beta-cells of transgenic mice causes counterregulation of the increased adenosine 3',5'-monophosphate and insulin secretion.

To evaluate the effect of chronically elevated adenylyl cyclase, we targeted the expression of a constitutively active mutant alpha-subunit (alpha s+) of Gs to the insulin-producing pancreatic beta-cells of transgenic mice. As assessed by the polymerase chain reaction, expression of alpha s+ mRNA was restricted to the transgenic pancreas. Histological analysis by light microscopy and immunohistochemistry for insulin, glucagon, and somatostatin appeared normal in transgenic islets. Pancreatic insulin content was quantitatively the same for alpha s+ transgenic and control mice. Comparisons of glucose homeostasis, insulin secretion, and islet cAMP revealed the expected differences between alpha s+ transgenic and control mice; in every case, however, responses to glucose alone were normal, and the differences were observed only when measurements were performed in the presence of isobutylmethylxanthine (IBMX), an inhibitor of cAMP phosphodiesterase. 1) In vivo, ip glucose tolerance was normal in alpha s+ transgenics; when ip glucose was preceded by administration of IBMX, the rise in blood glucose was approximately 33% less in the transgenic than in the control mice. 2) Insulin secretion from the perfused pancreas stimulated sequentially with 11 and 22 mM glucose caused characteristic first and second phase insulin release that did not differ between transgenic and control pancreases. IBMX increased biphasic insulin release from all pancreases, but caused a 2-fold greater than normal release from the transgenics. 3) Similarly, batch-incubated alpha s+ and control islets secreted equivalent amounts of insulin in the presence of glucose (22 mM) alone, whereas the combination of glucose plus IBMX was twice as effective on alpha s+ islets. 4) Islet cAMP levels paralleled insulin secretion; in the presence of IBMX, but not glucose alone, cAMP was increased 2-fold more in alpha s+ vs. control islets. We conclude that expression of constitutively active alpha s mutant in pancreatic beta-cells of transgenic mice is functionally effective, causing the physiological phenotype of increased islet cAMP and insulin secretion. However, these changes are uncovered only in the presence of IBMX; without IBMX, glucose homeostasis and islet function appear normal. This normalization, or counterregulation, of cAMP synthesis presumably is accomplished by a compensatory increase in cAMP degradation, possibly via increased activity of cAMP phosphodiesterase.

Clinical characteristics of acromegalic patients whose pituitary tumors contain mutant Gs protein.

Activating mutations in the gene for the alpha-chain of Gs, the stimulatory regulator of adenylyl cyclase, have been identified in human GH-secreting pituitary tumors. Using the polymerase chain reaction and allele-specific oligonucleotide hybridization, we screened 25 GH-secreting tumors for the presence of the activating mutations. We also reviewed the clinical charts of the patients from whom the tumors were removed. Of 25 tumors, 10 (40%) contained activating mutations. Patients in the mutation-positive group came to surgery with smaller tumors and had lower GH levels. The activating mutations identify a subgroup of GH-secreting pituitary tumors that probably arise from a shared oncogenic mechanism.

Decreased nocturnal levels of prolactin and growth hormone in women with fibromyalgia.

Fibromyalgia (FM) is a complex syndrome, primarily of women, characterized by chronic pain, fatigue, and sleep disturbance. Altered function of the somatotropic axis has been documented in patients with FM, but little is known about nocturnal levels of PRL. As part of a laboratory study of sleep patterns in FM, we measured the serum concentrations of GH and PRL hourly from 2000--0700 h in a sample of 25 women with FM (mean, 46.9 +/- 7.6 yr) and in 21 control women (mean, 42.6 +/- 8.1 yr). The mean (+/-SEM ) serum concentrations (micrograms per L) of GH and of PRL during the early sleep period were higher in control women than in patients with FM [GH, 1.6 +/- 0.4 vs. 0.6 +/- 0.2 (P < 0.05); PRL, 23.2 +/- 2.2 vs. 16.9 +/- 2.0 (P < 0.025)]. The mean serum concentrations of GH and PRL increased more after sleep onset in control women than in patients with FM [GH, 1.3 +/- 0.4 vs. 0.3 +/- 0.2 (P < 0.05); PRL, 16.2 +/- 2.4 vs. 9.7 +/- 1.5 (P < 0.025)]. Sleep efficiency and amounts of sleep or wake stages on the blood draw night were not different between groups. There was a modest inverse relationship between sleep latency and PRL and a direct relationship between sleep efficiency and PRL in FM. There was an inverse relationship between age and GH most evident in control women. Insulin-like growth factor I levels were not different between the groups. These data demonstrate altered functioning of both the somatotropic and lactotropic axes during sleep in FM and support the hypothesis that dysregulated neuroendocrine systems during sleep may play a role in the pathophysiology of FM.

Sleep deprivation in the rat: XV. Ambient temperature choice in paradoxical sleep-deprived rats.

Previous studies of total sleep deprivation (TSD) and paradoxical sleep deprivation (PSD) in the rat by the disk-over-water method have indicated that both produce changes in thermoregulation. In both kinds of deprivation, there was a progressive, large increase in heat production as indicated by measures of energy expenditure (EE). In TSD there was an initial increase in waking body temperature (Tb) followed by a later decrease; in PSD there was only a progressive decrease. The increases in heat production far in excess of heat storage indicated increased heat loss in both groups. Because the increase in Tb in TSD rats was supported by ambient temperature choices (Tch) in a thermal gradient that became progressively higher during deprivation, an increase in waking temperature setpoint (TSET) was indicated. Because the rats resorted to behavioral warming in spite of greatly increased thermogenesis, they must have had some failure to retain body heat. Prior to the present study, changes in TSET, had not been evaluated in PSD rats. Because they had not shown increases in Tb, PSD rats might not have an elevated TSET, which would indicate a functional difference between PS and nonrapid eye movement (NREM) sleep. Also, an evaluation of behavioral thermoregulation in PSD rats would clarify whether their Tb decline resulted from excessive heat loss or from a lowered TSET. To evaluate changes in heat flow and TSET, EE, Tb and Tch were measured in five PSD rats and their yoked control (PSC) rats. PSD rats showed progressive increases in EE and decreases in Tb as in the earlier PSD study; Tch rose progressively. PSC rats showed minimal changes in all three parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Decreased slow-wave and paradoxical sleep in a rat chronic pain model.

Diurnal sleep-wake patterns in the normal and the adjuvant arthritic rat were measured during the first 3 h of both light and dark periods. During the hours of maximal sleep in the normal rat, arthritic rats showed a significant increase in wakefulness (Wake), a shift to non-rapid-eye-movement (NREM) stages with lower amplitudes (LS and HS1), and a large reduction of NREM sleep with the highest-amplitude (HS2) and paradoxical sleep. Arthritic rats also showed marked sleep fragmentation manifested by more episodes of Wake, LS, and HS1 and shorter episodes of HS2 during both the light and the dark periods. Thus, arthritic rats cannot sustain long periods of sleep. In contrast to control rats, arthritic rats lacked a diurnal variation in Wake, total sleep, and electroencephalographic (EEG) delta activity. They also showed a decrease in overall EEG amplitude. In addition, there was a positive correlation between the severity of arthritis and the percentages of NREM sleep with low (LS) and moderate (HS1) amplitude. Thus, the decline in EEG amplitude could indicate a deficit of EEG generating mechanisms or some aspect of disease severity, such as pain.

Sleep deprivation in the rat: XVII. Effect of aspirin on elevated body temperature.

Previous studies of total sleep deprivation (TSD) in the rat have shown an elevation of waking body temperature (Tb) early in the deprivation period. TSD rats defend this rise behaviorally by selecting warm ambient temperatures and autonomically by increasing heat production, thus indicating an elevation of thermoregulatory setpoint. Prostaglandins (PGs) can elevate setpoint and Tb. To investigate whether the TSD-induced rise in setpoint and Tb was mediated by PGs, aspirin, which blocks the synthesis of PGs, was administered 100 mg/kg s.q. to 11 TSD and 13 control (TSC) rats in baseline and deprivation. During baseline, aspirin produced a nonsignificant (0.16 degrees C) rise across all rats in waking Tb. For the sampled time period, waking Tb during deprivation day 3 was significantly elevated in TSD rats (0.64 degrees C, p < 0.01) but not in TSC rats (0.27 degrees C). Aspirin was administered on deprivation day 4. It produced a fall in waking Tb in TSD rats from its deprivation-induced elevation. The difference between the response to aspirin during baseline and during deprivation was significant (-0.25 degrees C, p < 0.05) for TSD rats but not TSC rats (-0.17 degrees C). Time awake after aspirin increased significantly (16.2%, p < 0.05) during baseline and declined nonsignificantly (1.1%) during deprivation. These data imply that at least part of the rise in Tb that is characteristic of TSD is mediated by PGs. To the extent that PGD2 promotes lower Tb and sleep in rats but PGE2 has opposite effects, the results are consistent with a shift from PGD2 predominance in baseline toward PGE2 predominance during TSD.(ABSTRACT TRUNCATED AT 250 WORDS)

Sleep deprivation in the rat: XVIII. Regional brain levels of monoamines and their metabolites.

Several theories have linked sleep with change in monoamine activity. However, the use of sleep deprivation to show that changes in sleep generate changes in monoamines (directly or through feedback) has produced inconsistent results. To explore whether longer sleep deprivation, better documented sleep loss, more complete controls or regional brain analyses would produce clear sleep loss-induced change, eight rats were subjected to total sleep deprivation (TSD) by the disk-over-water method for 11-20 days and were guillotined along with yoked control (TSC) and home-cage control (HCC) rats. Brains were removed and dissected to obtain the caudate, frontal cortex, hippocampus, hypothalamus, midbrain and hindbrain (pons-medulla). Tissue sections were analyzed for concentrations of serotonin (5HT), its metabolite 5-hydroxyindoleacetic acid (5HIAA), dopamine (DA), its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), and either norepinephrine or, in the caudate section, the DA metabolite homovanillic acid. The ratios DOPAC/DA and 5HIAA/5HT, which under some conditions are indicators of turnover, were also calculated. Because sleep deprivation time varied across sets of TSD, TSC and HCC rats and not all eight sets were analyzed simultaneously, a repeated-measures ANOVA was performed within sets with HCC, TSC and TSD considered as successive levels of sleep deprivation treatment. In no case did TSD rats have significantly higher or lower values of amines, metabolites or ratios than both HCC and TSC rats. The most common outlying values were for TSC rats. Thus, these results failed to demonstrate sleep loss-induced regional changes in levels of major brain monoamines or their metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)