Tetanus prophylaxis in horses: guidelines for New Zealand and Australia based on a critical appraisal of the evidence.

Horses are exquisitely sensitive to tetanus neurotoxin and are exposed to the risk of infection with Clostridium tetani throughout life. The vaccine against tetanus is highly effective at preventing disease, whereas tetanus in unvaccinated populations is associated with high mortality rates. Current guidelines in New Zealand and Australia for the available vaccine contain contradictions and limitations surrounding the optimal tetanus immunisation protocols for both adult horses and foals. This review critically evaluates the scientific literature on tetanus prophylaxis in horses within the context of equine practice and available products in New Zealand and Australia. The review was conducted by a panel of industry and specialist veterinarians to obtain agreement on nine equine tetanus prophylaxis guidelines for practising veterinarians. The primary protocol for tetanus toxoid (TT) immunisation consists of a three-dose series IM for all horses ≥ 6 months of age, and a four-dose series IM is proposed if commencing vaccination in foals between 3 and 6 months of age. Tetanus prophylaxis in foals < 3 months of age relies on passive immunity strategies. Following the completion of the primary protocol, a TT booster dose IM should be administered within 5 years, and every 5 years thereafter. When followed, these protocols should provide adequate protection against tetanus in horses. Additional tetanus prophylaxis guidelines are provided for veterinarians attending a horse experiencing a known "risk event" (e.g. wound, hoof abscess, surgery, umbilical infection). When a correctly vaccinated horse experiences a risk event, pre-existing immunity provides protection against tetanus. When an unvaccinated horse or one with unknown vaccination status, or a foal born to an unvaccinated dam, experiences a risk event, TT IM and tetanus antitoxin (TAT) 1,500 IU SC should be administered simultaneously at separate sites, and the TT primary immunisation protocol should subsequently be completed for the horse's respective age. In previously immunised pregnant broodmares, a TT booster dose administered 4-8 weeks prior to parturition optimises the transfer of passive immunity against tetanus to the newborn foal via colostrum; provided that post-natal IgG concentration in serum is > 800 mg/dL (8 g/L), such foals should be passively protected against tetanus up to 6 months of age. Survivors of clinical tetanus must still receive the primary protocol for vaccination against tetanus. In summary, all horses in New Zealand and Australia should be vaccinated against tetanus with protection maintained throughout life via TT booster doses, facilitated by accurate medical record keeping and client education.

A metabolite sensor subunit of the Atg1/ULK complex regulates selective autophagy.

Cells convert complex metabolic information into stress-adapted autophagy responses. Canonically, multilayered protein kinase networks converge on the conserved Atg1/ULK kinase complex (AKC) to induce non-selective and selective forms of autophagy in response to metabolic changes. Here we show that, upon phosphate starvation, the metabolite sensor Pho81 interacts with the adaptor subunit Atg11 at the AKC via an Atg11/FIP200 interaction motif to modulate pexophagy by virtue of its conserved phospho-metabolite sensing SPX domain. Notably, core AKC components Atg13 and Atg17 are dispensable for phosphate starvation-induced autophagy revealing significant compositional and functional plasticity of the AKC. Our data indicate that, instead of functioning as a selective autophagy receptor, Pho81 compensates for partially inactive Atg13 by promoting Atg11 phosphorylation by Atg1 critical for pexophagy during phosphate starvation. Our work shows Atg11/FIP200 adaptor subunits bind not only selective autophagy receptors but also modulator subunits that convey metabolic information directly to the AKC for autophagy regulation.

A national Health and Work Strategy: a search for evidence.

BACKGROUND: The Health and Safety Executive's new Health and Work Strategy is based on an up-to-date assessment of workplace health priorities. Rather than replicating traditional prioritization approaches, a broader assessment of health and work priorities was carried out using a range of stakeholders. AIMS: To develop a set of health priorities for further research and intervention activity. METHODS: Four exercises were carried out, including internal prioritization, two external web-hosted questionnaire studies of younger workers and occupational health professionals, focus groups and tele-depth interviews with workplace health and safety professionals. RESULTS: The highest rated internal priorities (weighted priority scores) were identified as mesothelioma (70), lung cancer (69.25), chronic obstructive pulmonary disease (COPD; 69), musculoskeletal disorders (MSDs; 66.25), hearing loss (65.75), stress (65.5), asthma (64.5) and hand-arm vibration syndrome (61.5). Using the three highest ranked criteria developed by occupational health professionals ((i) the preventability of the condition, (ii) the impact of the condition and (iii) the number of workers affected), mesothelioma, lung cancer, COPD, MSDs, hearing loss, stress and asthma were identified as the top seven priorities. Generic issues identified included ageing and work, obesity, newer technologies, and ethnicity and cultures of workforces. Apprentices identified stress, depression, anxiety, musculoskeletal and respiratory disorders, fatigue and workload as important workplace health considerations. CONCLUSIONS: This process identified a number of expected and new areas of health research interest. We believe the findings reflect the real world requirements of work as assessed by occupational health and safety practitioners and workers.

Correction to: Prediction of unfavorable outcomes in cryptococcal meningitis: results of the multicenter infectious Diseases International Research Initiative (ID-IRI) cryptococcal meningitis study.

In the original version of this article, Mustafa Sunbul was not included in the list of authors for this article. The name has been added accordingly.

Prediction of unfavorable outcomes in cryptococcal meningitis: results of the multicenter Infectious Diseases International Research Initiative (ID-IRI) cryptococcal meningitis study.

Cryptococcal meningitis (CM) is mostly seen in immunocompromised patients, particularly human immunodeficiency virus (HIV)-positive patients, but CM may also occur in apparently immunocompetent individuals. Outcome analyses have been performed in such patients but, due to the high prevalence of HIV infection worldwide, CM patients today may be admitted to hospitals with unknown HIV status, particularly in underdeveloped countries. The objective of this multicenter study was to analyze all types of CM cases in an aggregate cohort to disclose unfavorable outcomes. We retrospectively reviewed the hospitalized CM patients from 2000 to 2015 in 26 medical centers from 11 countries. Demographics, clinical, microbiological, radiological, therapeutic data, and outcomes were included. Death, neurological sequelae, or relapse were unfavorable outcomes. Seventy (43.8%) out of 160 study cases were identified as unfavorable and 104 (65%) were HIV infected. On multivariate analysis, the higher Glasgow Coma Scale (GCS) scores (p = 0.021), cerebrospinal fluid (CSF) leukocyte counts > 20 (p = 0.038), and higher CSF glucose levels (p = 0.048) were associated with favorable outcomes. On the other hand, malignancy (p = 0.026) was associated with poor outcomes. Although all CM patients require prompt and rational fungal management, those with significant risks for poor outcomes need to be closely monitored.

The use of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry for rapid bacterial identification in patients with smear-positive bacterial meningitis.

OBJECTIVES: To assess the potential of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) in rapid identification of bacteria from smear-positive cerebrospinal fluid (CSF) in a cohort of patients with meningitis. METHODS: Single-centre observational study, including adults and children with community-acquired or postneurosurgical bacterial meningitis. Meningitis was defined using established criteria. Samples of CSF that had a positive CSF Gram stain were directly examined by MALDI-TOF-MS. Identification was considered accurate when identical to the CSF culture or PCR results (species and genus level). Laboratory workers performing the MALDI-TOF-MS and interpreting its results were blinded to the direct smear results, except for the fact that it was positive. MALDI-TOF-MS results were not conveyed to clinicians. RESULTS: MALDI-TOF-MS was tested on 44 CSF samples; ten samples were obtained from patients with community-acquired meningitis, and 34 samples were from patients with postneurosurgical meningitis. The assay identified bacteria correctly in 17/21 of the samples with Gram-negative rods observed on the direct smear, all obtained from patients who had undergone neurosurgery, (sensitivity 81%, 95% CI 64.2%-97.7%). In the postneurosurgical group, Gram-positive cocci were identified correctly in only 1/11 (9.1%) of the samples, and Candida species were not identified in two samples. Among patients with community-acquired meningitis, the assay did not identify Streptococcus pneumoniae in eight of eight samples, Neisseria meningitidis in one sample (1/1), and Streptococcus agalactiae in one sample (1/1). CONCLUSIONS: We found MALDI-TOF-MS to be useful in the rapid identification of Gram-negative rods directly from smear-positive CSF samples, but not of Gram-positive bacteria.

The 9-d CIDR-PG protocol II: Characterization of endocrine parameters, ovarian dynamics, and pregnancy rates to fixed-time AI following use of long-term CIDR-based estrus synchronization among mature beef cows.

An experiment was designed to evaluate endocrine parameters, ovarian dynamics, and pregnancy rates to fixed-time artificial insemination (FTAI) following the 9-d CIDR-PG protocol in comparison to the 14-d CIDR-PG protocol. While both are long-term protocols using CIDR treatment for presynchronization, the 9-d CIDR-PG protocol differs from the 14-d CIDR-PG protocol in that prostaglandin F2α (PG) is administered at CIDR insertion and removal to facilitate a decreased length of progestin treatment and potentially enhance response to the presynchronization treatment. Estrus was synchronized for 393 mature beef cows across five locations. Treatments were represented in each location, and cows within each location were randomly assigned to one of the two protocols based on age, days postpartum (DPP), and body condition score (BCS). Cows assigned to the 14-d CIDR-PG treatment received a CIDR insert (1.38 g progesterone) on Day 0 with removal of CIDR on Day 14, and 25 mg PG 16 d after CIDR removal on Day 30. Cows assigned the 9-d CIDR-PG treatment received 25 mg PG and a CIDR insert (1.38 g progesterone) on Day 5; 25 mg PG and removal of CIDR on Day 14; and 25 mg PG 16 d after CIDR removal on Day 30. In both treatments, cows received FTAI on Day 33, 72 h after PG. All cows were administered 100 µg gonadotropin-releasing hormone (GnRH) concurrent with insemination. For a subset of animals in each treatment, ovarian ultrasound was performed and blood samples were collected for determination of serum estradiol concentrations at CIDR removal, PG administration, and FTAI. Protocols were compared on the basis of estrous response and pregnancy rate resulting from FTAI. Serum estradiol concentrations, follicle size, and estrous response did not differ based on treatment. However, cows assigned to the 9-d CIDR-PG protocol tended to achieve greater FTAI pregnancy rates than cows assigned to the 14-d CIDR-PG protocol (62% versus 52%; P = 0.07). Across treatments, greater pregnancy rates tended (P = 0.10) to be achieved by cows that expressed estrus prior to FTAI (69% for 9-d CIDR-PG, 58% for 14-d CIDR-PG) than by cows that failed to express estrus (55% for 9-d CIDR-PG, 47% for 14-d CIDR-PG). In summary, the 9-d CIDR-PG protocol is an effective protocol for synchronization of estrus among mature beef cows, and pregnancy rates to FTAI tended to be improved through use of the 9-d CIDR-PG compared to the 14-d CIDR-PG protocol.

Split-time artificial insemination in beef cattle: III. Comparing fixed-time artificial insemination to split-time artificial insemination with delayed administration of GnRH in postpartum cows.

This experiment was designed to compare pregnancy rates in postpartum beef cows following split-time (STAI) or fixed-time (FTAI) artificial insemination. Estrus was synchronized for 671 cows at seven locations following administration of the 7-d CO-Synch + CIDR protocol (100 µg GnRH + CIDR insert [1.38 g progesterone] on d 0; 25 mg prostaglandin F2α [PG] at CIDR removal on d 7). Cows were assigned to treatments that were balanced across locations based on age, body condition score, and days postpartum at the time treatments were initiated. All cows in treatment 1 (n = 333; FTAI) were inseminated at 66 h after PG and GnRH was administered concurrent with insemination regardless of estrus expression. For cows in treatment 2 (n = 338; STAI), inseminations were performed at 66 or 90 h after PG, and estrous status was recorded at these times. Cows in the STAI treatment that exhibited estrus by 66 h were inseminated at that time and did not receive GnRH, whereas AI was delayed 24 h until 90 h after PG for cows that failed to exhibit estrus by 66 h. Gonadotropin-releasing hormone (100 µg) was administered concurrent with AI at 90 h only to cows failing to exhibit estrus. Estrus expression that occurred during the 24 h delay period among cows assigned to the STAI treatment increased the total proportion of cows that expressed estrus prior to insemination (1 = 60%; 2 = 86%; P < 0.001). Pregnancy rates for cows inseminated at 66 h that exhibited estrus did not differ between treatments (1 = 58%; 2 = 58%; P = 0.93); however, pregnancy rates among non-estrous cows at 66 h were improved (1 = 35%; 2 = 51%; P = 0.01) among cows assigned to the STAI treatment when insemination was postponed by 24 h. Consequently, total AI pregnancy rate tended to be higher for cows that received STAI (1 = 49%; 2 = 56%; P = 0.06). In summary, following administration of the 7-d CO-Synch + CIDR protocol, total estrous response increased and pregnancy rates resulting from AI tended to be higher among cows assigned to STAI versus FTAI treatments.

Evaluation of the 14-d CIDR-PG and 9-d CIDR-PG protocols for synchronization of estrus in Bos indicus-influenced and Bos taurus beef heifers.

Two long-term, CIDR-based estrus synchronization protocols were evaluated among Bos indicus-influenced and Bos taurus beef heifers. Treatments were evaluated on the basis of estrous response and pregnancy rate resulting from fixed-time artificial insemination (FTAI), and these outcomes were analyzed retrospectively relative to reproductive tract score (RTS; Scale 1-5) at treatment initiation. Estrus was synchronized for 1139 heifers in three locations, and heifers were assigned to one of two treatments within each location based on RTS. Heifers assigned to the 14-d CIDR-PG protocol received a controlled internal drug release (CIDR) insert (1.38 g progesterone) on Day 0, CIDR removal on Day 14, administration of prostaglandin F2α (PG; 25 mg im) on Day 30, and administration of gonadotropin-releasing hormone (GnRH; 100 µg im) concurrent with FTAI on Day 33, 66 h after PG. Heifers assigned to the 9-d CIDR-PG protocol received administration of PG concurrent with CIDR insertion on Day 5, administration of PG concurrent with CIDR removal on Day 14, administration of PG on Day 30, and administration of GnRH concurrent with FTAI on Day 33, 66 h after PG. Estrus detection aids were applied at CIDR removal on Day 14 and at PG on Day 30 to evaluate estrous response rate. Mean RTS differed (P < 0.0001) based on biological type due to higher rates of estrous cyclicity (RTS 4 and 5) among Bos taurus heifers (72%; 416/574) than among Bos indicus-influenced heifers (27%; 150/565). The proportion of heifers expressing estrus following CIDR removal was greater (P = 0.01) among heifers assigned to the 14-d CIDR-PG treatment (88%; 492/559) compared to the 9-d CIDR-PG treatment (83%; 480/580). Estrous response following CIDR removal was also higher (P < 0.0001) among Bos taurus (95%; 547/574) compared to Bos indicus-influenced (75%; 425/565) heifers. Rate of estrous response prior to FTAI did not differ significantly based on treatment but was higher (P < 0.0001) among Bos taurus heifers (60%; 344/574) than among Bos indicus-influenced heifers (45%; 253/565). However, the effect of biological type on estrous response was not significant when RTS was included in the model, as RTS significantly (P < 0.0001) affected the rate of estrous response both at CIDR removal and prior to FTAI. Across treatments and biological types, heifers that expressed estrus prior to AI achieved higher (P < 0.0001) AI pregnancy rates than heifers failing to express estrus. Pregnancy rates to FTAI did not differ significantly based on treatment in either biological type. Higher rates of estrous cyclicity among Bos taurus heifers resulted in higher FTAI pregnancy rates among Bos taurus (51%; 290/574) compared to Bos indicus-influenced heifers (39%; 218/565). However, pregnancy rates of respective RTS did not differ based on biological type. In summary, long-term CIDR-based protocols provide a simple, effective method of estrus synchronization in Bos indicus-influenced and Bos taurus beef heifers. Moreover, these results highlight the importance of management practices that result in high rates of estrous cyclicity prior to protocol initiation, particularly among later maturing breeds and biological types.

Split-time artificial insemination in beef cattle: II. Comparing pregnancy rates among nonestrous heifers based on administration of GnRH at AI.

This experiment was designed to evaluate split-time artificial insemination (AI) in beef heifers following administration of the 14-day controlled internal drug release (CIDR)-prostaglandin F2α (PG) protocol and to compare pregnancy rates among nonestrous heifers based on administration of GnRH at AI. Estrus was synchronized for 1138 heifers across six locations. Heifers received a CIDR insert (1.38 g progesterone) on Day 0 with removal on Day 14. Estrus detection aids (Estrotect) were applied at PG (25 mg), 16 days after CIDR removal on Day 30. Heifers were assigned to balanced treatments based on reproductive tract score and weight, and treatments were represented within each location. Split-time AI was performed at 66 and 90 hours after PG, and estrus was recorded at these times. Heifers in both treatments that exhibited estrus by 66 hours were inseminated and did not receive GnRH, whereas AI was delayed 24 hours until 90 hours after PG for heifers that failed to exhibit estrus by 66 hours. For heifers in treatment 1 that were inseminated at 90 hours, GnRH (100 µg) was administered concurrent with AI at 90 hours. Heifers in treatment 2 that were inseminated at 90 hours did not receive GnRH. Estrous response did not differ between treatments at 66 hours after PG (treatment 1 = 70%; treatment 2 = 71%; P = 0.58) or during the 24-hour delay period (treatment 1 = 59%; treatment 2 = 52%; P = 0.21). There was no effect of treatment on pregnancy rates resulting from AI for heifers inseminated at 66 hours (treatment 1 = 58%; treatment 2 = 62%; P = 0.86) or 90 hours (treatment 1 = 44%; treatment 2 = 39%; P = 0.47) after PG; and there was no difference between treatments when considering total AI pregnancy rate (treatment 1 = 54%; treatment 2 = 56%; P = 0.60). Ovulation was confirmed via ultrasonography for a subset of heifers that failed to exhibit estrus prior to 90 hours after PG. For heifers that failed to exhibit estrus by 90 hours, success of ovulation did not differ between treatments (treatment 1 = 52%; treatment 2 = 50%; P = 0.64) nor did AI pregnancy rate (treatment 1 = 24%; treatment 2 = 15%; P = 0.97). In summary, when split-time AI was used in conjunction with the 14-day CIDR-PG protocol in heifers, comparable pregnancy rates were achieved without administering GnRH.

Comparing strategies to synchronize estrus before fixed-time artificial insemination in primiparous 2-year-old beef cows.

Two experiments evaluated controlled internal drug release (CIDR)-based protocols to synchronize estrus in primiparous 2-year-old beef cows. In each experiment, treatments were balanced according to body condition score and days postpartum. Experiment 1 compared the 14-day CIDR-PG (14-d) and 7-day CO-Synch + CIDR (7-d) protocols on the basis of estrous response, pregnancy rates after fixed-time artificial insemination (FTAI), and final pregnancy rate. Cows assigned to 14-d (n = 355) received a CIDR insert on Day 0 with removal on Day 14. Cows assigned to 7-d (n = 349) received gonadotropin releasing hormone (GnRH) and a CIDR insert on Day 23. On Day 30, CIDRs were removed from 7-d cows, and PGF2α was administered to all cows in each treatment. On Day 33, GnRH was administered concurrent with FTAI at 66 and 72 hours after PGF2α for 7-d and 14-d treated cows, respectively. Estrous response before FTAI was higher for 7-d compared with 14-d cows (74% vs. 43%, respectively; P < 0.0001); however, pregnancy rates resulting from FTAI were similar (14-d 63%; 7-d 64%; P = 0.52). Ovarian follicular dynamics and serum estradiol-17ß concentrations were evaluated among a subset of cows assigned to each protocol. Dominant follicle diameter was smaller at PGF2α (P = 0.04) and FTAI (P = 0.002) among 14-d cows compared with 7-d cows; however, estradiol-17ß at PGF2α (P = 0.06) and FTAI (P = 0.001) was greater for 14-d versus 7-d treated cows. Experiment 2 compared estrous response and pregnancy rates in 2-year-old beef cows after FTAI- or split-time artificial insemination (STAI) following synchronization of estrus with the 14-day protocol. Cows assigned to FTAI (n = 266) were inseminated at a fixed time concurrent with GnRH at 72 hours after PGF2α regardless of estrus expression, whereas cows assigned to STAI (n = 257) were inseminated based on estrus expression as determined by activation of an estrus detection aid. Cows assigned to STAI that exhibited estrus by 72 hours were inseminated; however, AI was delayed until 24 hours after GnRH (96 hours after PGF2α) for nonestrous cows. Total estrous response was increased for STAI- versus FTAI-treated cows (STAI 64%; FTAI 42%; P < 0.0001); pregnancy rates resulting from AI were similar (STAI 55%; FTAI 56%; P = 0.60). In summary, the 14-day CIDR-PG and 7-day CO-Synch + CIDR protocols can be used effectively to synchronize estrus before FTAI in primiparous 2-year-old beef cows. Although expression of estrus was increased using STAI in conjunction with the 14-day protocol, this approach did not increase pregnancy rates compared with FTAI.

Split-time artificial insemination in beef cattle: I-Using estrous response to determine the optimal time(s) at which to administer GnRH in beef heifers and postpartum cows.

Two experiments evaluated timing of GnRH administration in beef heifers and cows on the basis of estrous status during split-time artificial insemination (AI) after controlled internal drug release (CIDR) based protocols. In experiment 1, estrus was synchronized for 816 pubertal and prepubertal or peripubertal heifers using the 14-day CIDR-PGF2α (PG) protocol, and in experiment 2, estrus was synchronized for 622 lactating cows using the 7-day CO-Synch + CIDR protocol. For both experiments, estrus detection aids (Estrotect) were applied at PG, with estrus recorded at 66 and 90 hours after PG. Treatments were balanced across locations for heifers using reproductive tract score and weight; whereas for cows, treatments were assigned and balanced to treatment according to age, body condition score, and days postpartum. Timing of AI for heifers and cows was on the basis of estrus expression 66 hours after PG. Females in each treatment that exhibited estrus before 66 hours were inseminated at 66 hours, whereas AI was delayed 24 hours until 90 hours after PG for females failing to exhibit estrus before 66 hours. Females in treatment one received GnRH 66 hours after PG irrespective of estrus expression; however, in treatment 2, GnRH was administered coincident with delayed AI only to females not detected in estrus at 66 hours after PG. Among heifers, there was no effect of treatment on overall estrous response (P = 0.49) or AI pregnancy rate (P = 0.54). Pregnancy rate for heifers inseminated at 66 hours was not influenced by GnRH (P = 0.65), and there were no differences between treatments in estrous response during the 24 hours delay period (P = 0.22). Cows in treatment 2 had a greater (P = 0.04) estrous response during the 24-hour delay period resulting in a greater overall estrous response (P = 0.04), but this did not affect AI pregnancy rate at 90 hours (P = 0.51) or total AI pregnancy rate (P = 0.89). Pregnancy rate resulting from AI for cows inseminated at 66 hours was not influenced by GnRH (P = 0.50). In summary, when split-time AI was used with the 14-day CIDR-PG protocol in heifers or the 7-day CO-Synch + CIDR protocol in cows, administration of GnRH at AI to females that exhibited estrus before 66 hours after PG was not necessary. Furthermore, among heifers for which AI was delayed on the basis of failure to exhibit estrus before 66 hours after PG, timing of GnRH (66 vs. 90 hours after PG) was more flexible. Delayed administration of GnRH to 90 hours after PG coincident with AI for cows that failed to exhibit estrus before 66 hours improved overall estrous response; however, in this study, a corresponding increase in pregnancy rate resulting from AI was not observed.

Risk factors associated with death or neurological deterioration among patients with Gram-negative postneurosurgical meningitis.

In a retrospective cohort of 115 patients with Gram-negative postneurosurgical meningitis, factors associated with 30-day mortality or neurological deterioration on multivariate analysis included days from admission to meningitis (OR 1.05 per day, 95% CI 1.02-1.09), decreased level of consciousness (OR 2.69, 95% CI 0.99-7.31), blood glucose level >180 mg/dL (OR 3.70, 95% CI 1.27-10.77), higher creatinine level (OR 4.07 per 1 mg/dL, 95% CI 1.50-11.08), and cerebrospinal fluid glucose <50 mg/dL (OR 5.02, 95% CI 1.71-14.77) at diagnosis. A predictive score triaged patients into three groups with low (4/44, 9.1%), intermediate (16/38, 42.1%) and high (22/33, 66.7%) unfavourable outcome rates. Validation on a different group of 36 patients with Gram-negative postneurosurgical meningitis was acceptable.

Extrapolating the acute behavioral effects of toluene from 1- to 24-h exposures in rats: roles of dose metric and metabolic and behavioral tolerance.

Recent research on the acute effects of volatile organic compounds suggests that extrapolation from short (∼1 h) to long durations (up to 4 h) may be improved by using estimates of brain toluene concentration (Br[Tol]) instead of cumulative inhaled dose (C × t) as a metric of dose. This study compared predictions of these two dose metrics on the acute behavioral effects of inhaled toluene in rats during exposures up to 24 h in duration. We first evaluated estimates of Br[Tol] with a physiologically based toxicokinetic (PBTK) model for rats intermittently performing an operant task while inhaling toluene for up to 24 h. Exposure longer than 6 h induced P450-mediated metabolism of toluene. Adjusting the corresponding parameters of the PBTK model improved agreement between estimated and observed values of Br[Tol] in the 24-h exposure scenario. Rats were trained to perform a visual signal detection task and were then tested while inhaling toluene (0, 1125, and 1450 ppm for 24 h and 1660 ppm for 21 h). Tests occurred at times yielding equivalent C × t products but different estimates of Br[Tol], and also at 1 and 6 h afterexposure. Effects of toluene were better predicted by Br[Tol] than by C × t. However, even using Br[Tol] as the dose metric (after accounting for metabolic induction), acute dose-effect functions during 24-h exposures were shifted to the right relative to 1-h exposures, indicating that a dynamic behavioral tolerance also developed during prolonged exposure to toluene.

Chasing our tails: psychological, institutional and societal paradoxes in natural resource management, sustainability, and climate change in Australia.

Natural Resource Management (NRM) and Ecologically Sustainable Development (ESD) have been guiding frameworks in Australia for a number of decades. Recently, NRM and ESD have become central to climate change mitigation. In this paper, we explore the psychological paradoxes that function within climate change settings, with particular attention devoted to the way that research and development reinforces these paradoxes by advocating for participatory forms of inquiry. Paradox emerges in NRM at psychological, institutional, and organisational levels. Paradoxes are also features of different forms of democracy such as neoliberal and participatory democracy. Although NRM, ESD and climate change are often conceptualised as distinct issue domains, these policy areas are fundamentally interconnected in both theory and in practice. This interconnection between these policy and research settings, reflections on paradox, and the experience of incorporating community psychology into the paradoxical settings of NRM and climate change are captured in this paper.

Development of a nonintegrating Rev-dependent lentiviral vector carrying diphtheria toxin A chain and human TRAF6 to target HIV reservoirs.

Persistence of human immunodeficiency virus (HIV) despite highly active antiretroviral therapy (HAART) is a lasting challenge to virus eradication. To develop a strategy complementary to HAART, we constructed a series of Rev-dependent lentiviral vectors carrying diphtheria toxin A chain (DT-A) and its attenuated mutants, as well as human tumor necrosis factor receptor-associated factor 6 (TRAF6). Expression of these suicide genes following delivery through viral particles is dependent on Rev, which exists only in infected cells. Among these toxins, DT-A has been known to trigger cell death with as little as a single molecule, whereas two of the attenuated mutants in this study, DT-A(176) and DT-A(Delta N), were well tolerated by cells at low levels. TRAF6 induced apoptosis only with persistent overexpression. Thus, these suicide genes, which induce cell death at different expression levels, offer a balance between efficacy and safety. To minimize possible mutagenesis introduced by retroviral integration in nontarget cells, we further developed a nonintegrating Rev-dependent (NIRD) lentiviral vector to deliver these genes. In addition, we constructed a DT-A-resistant human cell line by introducing a human elongation factor 2 mutant into HEK293T cells. This allowed us to manufacture the first high-titer NIRD lentiviral particles carrying DT-A to target HIV-positive cells.

Swallowing outcomes following laryngectomy and pharyngolaryngectomy.

OBJECTIVES: To determine the incidence of dysphagia (defined as the inability to manage a diet of normal consistencies) at hospital discharge and beyond 1 year postsurgery and examine the impact of persistent dysphagia on levels of disability, handicap, and well-being in patients. DESIGN: Retrospective review and patient contact. SETTING: Adult acute care tertiary hospital. PATIENTS: The study group, consecutively sampled from January 1993 to December 1997, comprised 55 patients who underwent total laryngectomy and 37 patients who underwent pharyngolaryngectomy with free jejunal reconstruction. Follow-up with 36 of 55 laryngectomy and 14 of 37 pharyngolaryngectomy patients was conducted 1 to 6 years postsurgery. MAIN OUTCOME MEASURES: Number of days until the resumption of oral intake; swallowing complications prior to and following discharge; types of diets managed at discharge and follow-up; and ratings of disability, handicap, and distress levels related to swallowing. RESULTS: Fifty four (98%) of the laryngectomy and 37 (100%) of the pharyngolaryngectomy patients experienced dysphagia at discharge. By approximately 3 years postsurgery, 21 (58%) of the laryngectomy and 7 (50%) of the pharyngolaryngectomy patients managed a normal diet. Pharyngolaryngectomy patients experienced increased duration of nasogastric feeding, time to resume oral intake, and incidence of early complications affecting swallowing. Patients experiencing long-term dysphagia identified significantly increased levels of disability, handicap, and distress. Patients without dysphagia also experienced slight levels of handicap and distress resulting from taste changes and increased durations required to complete meals of normal consistency. CONCLUSIONS: The true incidence of patients experiencing a compromise in swallowing following surgery has been underestimated. The significant impact of impaired swallowing on a patient's level of perceived disability, handicap, and distress highlights the importance of providing optimal management of this negative consequence of surgery to maximize the patient's quality of life.