Effect of short-term heat acclimation with permissive dehydration on thermoregulation and temperate exercise performance.

We examined the effect of short-term heat acclimation with permissive dehydration (STHADe) on heat acclimation (HA) and cycling performance in a temperate environment. Ten trained male cyclists [mean (SD) maximal oxygen uptake: 63.3(4.0) mL/kg/min; peak power output (PPO): 385(40) W; training: 10 (3) h/week] underwent a STHADe program consisting of 5 days of exercise (maximum 90 min/day) in a hot environment (40 °C, 50% RH) to elicit isothermic heat strain [rectal temperature 38.64(0.27) °C]. Participants abstained from fluids during, and 30 min after, HA sessions. Pre- and post-STHADe HA was evaluated during euhydrated fixed-intensity exercise (60 min) in hot conditions; the effect of STHADe on thermoregulation was also examined under temperate conditions (20 min fixed-intensity exercise; 22 °C, 60% RH). Temperate cycling performance was assessed by a graded exercise test (GXT) and 20-km time trial (TT). STHADe reduced thermal and cardiovascular strain in hot and temperate environments. Lactate threshold [Δ = 16 (17) W] and GXT PPO [Δ = 6 (7) W] were improved following STHADe (P < 0.05), but TT performance was not affected (P > 0.05), although there was a trend for a higher mean power (P = 0.06). In conclusion, STHADE can reduce thermal and cardiovascular strain under hot and temperate conditions and there is some evidence of ergogenic potential for temperate exercise, but longer HA regimens may be necessary for this to meaningfully influence performance.

Rearing goat kids away from their dams 2. Understanding farmers' views on changing management practices.

Improving animal welfare is an important aim of livestock industries and is dependent on human management. Understanding attitudes to change and perceived barriers is therefore a key consideration for welfare scientists. A survey that aimed to investigate farmers' attitudes towards changing goat kid-rearing practices was distributed. Likert scales examined willingness to change and the importance of factors in decision-making alongside open-text responses for further explanation. A total of 242 farmers (United States of America (USA) 72; United Kingdom (UK) 71; Australia 33; Canada 23; New Zealand 20; European Union 14; Other 9) rearing goat kids away from their dams responded. All respondents rated from one (highly unwilling) to seven (highly willing), how willing they would be to supply three enrichment types. Willingness to provide enrichments differed (χ2(2) = 190.114,P < 0.001), with farmers most likely to provide climbing or loose items rather than swinging items. The most common reasons cited for unwillingness to provide enrichment were related to safety (101 responses/76.5%). Those currently abruptly weaning were asked how willing they would be to use gradual weaning methods. Those abruptly weaning from ad libitum milk systems (n = 47) showed no difference in willingness to change to different gradual weaning methods; the median (Interquartile Range (IQR)) for the willingness to change to removing teats was 2 (1-4), reducing milk temperature 3 (1-5) and diluting milk 2 (1-5), with most concerns relating to feasibility. Those abruptly weaning from bottle feeding (n = 18) also showed no difference in willingness to change to gradual weaning methods. Median (IQR) score for willingness to change to reduced number of bottle feeds was 4 (1-7), reducing milk quantity 3 (1-6.25), and diluting milk 1 (1-5), respectively. Health concerns were the most common reason for not being willing to change. All 242 respondents were asked to rate how important different factors are when deciding to implement a new management practice. There was a significant difference in importance between factors (χ2(2) = 34.779, P < 0.001). Median (IQR) importance of the factors was labour/time 5 (4-7), cost 5 (4-7), evidence beneficial to welfare 6 (5-7), evidence beneficial to health 6 (5-7), and evidence beneficial to growth 6 (4-7). To our knowledge, this is the first study to examine goat farmers' attitudes towards changing management practices and could help ensure that future research addresses farmer concerns and therefore has the best opportunity to be implemented on-farm.

Rearing goat kids away from their dams 1. A survey to understand rearing methods.

Despite an estimated global goat population of over one billion, little is known about methods being used to feed milk to artificially reared kids (reared away from their dams) and how kids are weaned from these systems. Quantifying and characterising current methods utilised on farms will enable future targeted research to investigate best practice methods for milk feeding and weaning of artificially rearedkids.A recall-based survey that investigated on-farmkid-rearingpractices (focusing on the milk feeding and weaning stages) was distributed via social media, and regional goat organisations across multiple countries. A total of 242 responses from 16 countries were collected and geographically grouped. Responses that could not be grouped sufficiently were removed (nine responses from eight countries). A total of 233 responses from eight countries (United States of America (USA) 72; United Kingdom (UK) 71; Australia 33; Canada 23; New Zealand 20; European Union (EU) 14), were analysed. Most farms (217; 93%) bred their own kids. The most common milk feeding method was bottle feeding, used on 135 farms (57.9%), followed by ad libitum feeding used by 72 (30.9%). A relationship between number of kids reared and feeding system was identified, χ2(3, N = 233) = 89.605,P < 0.001, with farms rearing > 100 kids more likely to feed milk ad libitum. A total of 170 farms (72.9%) were weaned based on a target age and 85 (36.4%) on a target weight, 53 (22.7%) used both and 45 (19.3%) neither. Target weaning ages and weights varied across countries; the median age was 84 days (interquartile range (IQR) 56-84), and the median weight was 16 kg (IQR 15-18). A difference was found between milk feeding systems for weaning method (Χ2(2, N = 232) = 63.797,P≤0.001), with kids most likely to be abruptly weaned from ad libitum systems (or gradually weaned from bottle feeding). Abrupt weaning was used by 67 farms (28.8%), and gradual weaning was used by 165 (71.1%). Gradual weaning strategies included reducing milk quantity (150 farms; 93% of farms providing detail) and diluting milk (six farms; 4%). A total of 169 (72.5%) supplied enrichment that met the survey's definition; items to climb on/hide in were most common, provided by 157 farms (92.8%). Findings suggest differing practices in smaller-scalebottle-fedversuslarger-scalead libitummilksystems, likely reflecting differing system needs.This highlights a requirement for welfare-focused research in kids reared artificiallyin order to identify and communicatebest practices to ensure on-farm welfare is optimised within each system.

Identification of the major protein adduct formed in rat liver after thioacetamide administration.

The in vivo covalent binding of the hepatocarcinogen thioacetamide to rat liver protein has been examined. Following administration of 3H- or 14C-labeled thioacetamide, the modified amino acids present in the hepatic cytosolic proteins were isolated by enzymatic digestion and ion-exchange chromatography. Approximately 70% of the radioactivity covalently bound to cytosolic protein was recovered in a compound which upon acid hydrolysis yielded lysine and radiolabeled acetate. Additional studies indicated the structure of this adduct was N-epsilon-acetyllysine.

On the use of Bayesian decision theory for issuing natural hazard warnings.

Warnings for natural hazards improve societal resilience and are a good example of decision-making under uncertainty. A warning system is only useful if well defined and thus understood by stakeholders. However, most operational warning systems are heuristic: not formally or transparently defined. Bayesian decision theory provides a framework for issuing warnings under uncertainty but has not been fully exploited. Here, a decision theoretic framework is proposed for hazard warnings. The framework allows any number of warning levels and future states of nature, and a mathematical model for constructing the necessary loss functions for both generic and specific end-users is described. The approach is illustrated using one-day ahead warnings of daily severe precipitation over the UK, and compared to the current decision tool used by the UK Met Office. A probability model is proposed to predict precipitation, given ensemble forecast information, and loss functions are constructed for two generic stakeholders: an end-user and a forecaster. Results show that the Met Office tool issues fewer high-level warnings compared with our system for the generic end-user, suggesting the former may not be suitable for risk averse end-users. In addition, raw ensemble forecasts are shown to be unreliable and result in higher losses from warnings.

An examination of octanol and octanal metabolism to octanoic acid by horse liver alcohol dehydrogenase.

The kinetics of the horse liver alcohol dehydrogenase (alcohol: NAD+ oxidoreductase EC 1.1.1.1) catalyzed metabolism of octanol and octanal to octanoic acid have been examined. On incubation of octanol with horse liver alcohol dehydrogenase in the presence of NAD+, NADH as well as octanal and octanoic acid were seen as the initial products. However, on continued incubation, the octanal concentration progressively decreased to where only negligible quantities were present in the incubation after 10 min. The production of NADH was biphasic. An initial phase was followed in about 2 min with a slower but linear rate of NADH production. The production of octanoic acid was approximately linear throughout the 10 min incubation period. Since octanal is an intermediate in the oxidation of octanol to octanoic acid, the ability of semicarbazide to inhibit the metabolism of octanol to octanoic acid was examined. At a concentration of semicarbazide which was 63 times the concentration of octanol in the incubation media, the rate of formation of octanoic acid was inhibited by only 30%. The results of these experiments suggest that in the oxidation of octanol to octanoic acid a portion of the octanal formed from octanol is not released from the enzyme but, in the presence of NAD+, is oxidized to octanoic acid.

Selective inhibition of Leishmania dihydrofolate reductase and Leishmania growth by 5-benzyl-2,4-diaminopyrimidines.

The classical anti-microbial antifolates trimethoprim, pyrimethamine, and cycloguanil are poor inhibitors of purified dihydrofolate reductase (DHFR) from Leishmania major. They show no selectivity for Leishmania DHFR relative to the human enzyme, and it is not surprising that they are ineffectual as anti-leishmanial agents. Several 5-(substituted-benzyl)-2,4-diaminopyrimidines have been screened as inhibitors for purified L. major and human DHFRs. These compounds inhibit Leishmania DHFR with I50 values ranging from 0.2 to 11 microM, and show about 5 to greater than 100-fold greater selectivity for the parasite DHFR than the human enzyme. These pyrimidine analogs are more potent inhibitors of Leishmania promastigote and amastigote growth than the classical anti-microbial antifolates, and serve as lead compounds for the development of new selective antileishmanial agents.

Oxidative metabolism of carbon disulfide by isolated rat hepatocytes and microsomes.

The oxidative metabolism of carbon disulfide (CS2) was investigated in isolated rat hepatocytes and liver microsomes. In microsomes, CS2 metabolism was increased by phenobarbital pretreatment of the rats and decreased with pretreatment of the rats with cobaltous chloride. In both microsomes and hepatocytes, CS2 metabolism was inhibited by SKF-525A. Carbon dioxide (CO2) was the major volatile metabolite of CS2 in hepatocytes, and carbonyl sulfide (COS) was the major volatile metabolite in microsomal incubations. Addition of cytosol to microsomal incubations shifted the predominant volatile metabolite from COS to CO2 but did not change total volatile metabolite formation. Acetazolamide, a carbonic anhydrase inhibitor, significantly decreased COS metabolism but not CS2 metabolism in isolated hepatocytes or microsomes fortified with dialyzed cytosol. When [18O]H2O was included in incubations of microsomes and CS2, a substantial portion of the resulting COS was [18O] enriched, indicating that the oxygen atom was derived from water. These data are consistent with the hypothesis that CS2 is oxidized predominantly by the cytochrome P-450 containing monooxygenase system, and the product of this reaction is an unstable intermediate which reacts with water to form monothiocarbonate and reactive sulfur species. Monothiocarbonate is the hydrated form of COS. In intact hepatocytes, it is metabolized predominantly to CO2 and hydrogen sulfide. Unmetabolized monothiocarbonate can be dehydrated to COS. The majority of the reactive sulfur species and hydrogen sulfide are oxidized to nonvolatile sulfur compounds, including sulfate, but by different mechanisms.

The activity of alkyl phosphorylcholines and related derivatives against Leishmania donovani.

Several alkyl phosphorylcholines and related derivatives were tested against Leishmania donovani amastigotes in mouse peritoneal macrophages in vitro and ED50 values were determined in the range of 1-12 microM. The three alkyl phosphorylcholines tested against L. donovani in BALB/c mice were active, an ED50 of 12.8 mg/kg/day X 5 was ascertained for one compound, but an alkyl phosphorylethanolamine was inactive.

Mechanisms of the biological effects of PCBs, polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans in experimental animals.

Polychlorinated biphenyls, certain polychlorinated dibenzo-p-dioxins and certain polychlorinated dibenzofurans cause a variety of biological effects in experimental animals. The mechanism of the induction of certain enzymes is perhaps best understood. That is, there is binding of certain chlorinated biphenyls, dibenzo-p-dioxins and dibenzofurans to a receptor, translocation of the compound-receptor complex into the nucleus followed by an increased activity of a number of enzymes in the cell. Although the concentration of this receptor in various tissues of some mouse strains correlates well with the intensity of some of the biological effects observed in the mouse strains exposed to these compounds, this correlation apparently does not extend across various species. The current evidence suggests that the acute toxic effects of TCDD in various species is in some way associated with binding of TCDD to the receptor. However, biological effects of TCDD in addition to those resulting from binding to the receptor may be required to produce acute toxicity and, perhaps, other effects. The acute toxic effects of TCDD are probably caused by the parent compound rather than metabolites; however, this conclusion must be viewed as tentative. Also, it cannot be excluded at this time that biological effects other than acute toxicity may be caused by metabolites of TCDD. Finally, the acute toxic effects of TCDD appear not to be related, at least not directly, to the rate of metabolism of TCDD in experimental animals nor to the half-life of excretion.

The trouble with TEFs.

Comments on Van den Berg, et al. Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. Environ Health Perspect 106:775-792 (1998)

Effectiveness of allopurinol against Leishmania braziliensis panamensis in Aotus trivirgatus.

Orally administered allopurinol at 50 mg/kg for 21 days showed pronounced antileishmanial activity against experimentally induced lesions of Leishmania braziliensis panamensis on the nose of Panamanian Aotus trivirgatus monkeys, with complete healing in 4 of 5, although parasitologic cure was achieved in only 2 of 5. The same total daily dose of drug, given in a divided dose twice daily, resulted in complete healing in all 5, and parasitologic cure in 4 of 5 animals. Standard treatment controls receiving 40 mg/kg of antimony stibogluconate intramuscularly for 15 days showed healing in 4 of 5 monkeys. It is not known if a similar level of effectiveness would result with this dose of allopurinol in humans, since Aotus may have a different pattern of metabolic conversion of the drug to the more active riboside.

Comparative studies of drug susceptibility of five strains of Trypanosoma cruzi in vivo and in vitro.

A comparative study showed that 5 laboratory strains of Trypanosoma cruzi could be divided into a non-responsive group (Sonya clone and Colombiana) and a responsive group (Tulahuén, Y and Peru), based on long-term treatment of mouse infections with nifurtimox and benznidazole. In vitro sensitivity of epimastigotes and blood-stream trypomastigotes in macrophage cultures did not distinguish the strains, nor did the rate of development of nifurtimox resistance by epimastigote cultures. 7 novel anti-T. cruzi compounds also behaved similarly with respect to the 2 groups. A small decrease in sensitivity was observed in vitro by non-responsive strains of T. cruzi after re-isolation from treated mice. It is postulated that there could be an immunological component involved in successful treatment of T. cruzi infection.

A comparison of challenge with Trypanosoma cruzi blood-stream trypomastigotes and metacyclic trypomastigotes from Rhodnius prolixus in mice immunized with killed antigens.

Groups of CD-1 mice were immunized with vaccines prepared from freeze-thawed or ultra-sonicated epimastigotes, blood trypomastigotes, or "plasma antigen", of Trypanosoma cruzi strains Y, M1 and Tulahuen. The mice were challenged by the injection of blood stream trypomastigotes obtained from mice, or of metacyclic trypomastigotes harvested from the rectum of Rhodnius prolixus. Both challenges induced virulent infections in control mice. Blood-stream trypomastigotes killed mice more rapidly than the same number of bug-derived trypomastigotes. Vaccinated mice resisted infection with bug-derived trypomastigotes as well as with blood trypomastigotes, and in some instances better. It is concluded that results obtained with the more convenient, but artificial blood trypomastigote challenge are comparable with the more natural, bug-derived, challenge.

The effect of allopurinol ribonucleoside and formycin B on Trypanosoma cruzi infections in mice.

The anti-Trypanosoma cruzi effect of allopurinol ribonucleoside and formycin B was examined against infections of the sensitive Y and Peru strains in inbred mice, strain DBA/1. Allopurinol ribonucleoside given in the drinking water at doses calculated to be 239, 511 and 929 mg/kg/day for 28 days, prevented the death of the mice but did not eradicate the infection. Formycin B given orally at 100 and 10 mg/kg/day X 5 days, showed a similar effect.

Leishmania infecting man and wild animals in Saudi Arabia. 7. Partial protection of mice against Leishmania major by prior infection with L. arabica.

A survey of inbred mouse strains showed that strain C3H/he was the most comparable to man in respect of its susceptibility to Leishmania major and the subsequent healing of lesions produced by this organism. L. arabica proved to have a lower virulence than L. major and prior inoculation with the former resulted in a decrease of the lesion sizes following subsequent L. major challenge. Moreover, L. major lesions that did develop in mice previously inoculated with L. arabica generally healed faster.

Aminosidine ointments for the treatment of experimental cutaneous leishmaniasis.

A 15% aminosidine sulphate (AS)/10% urea/white soft paraffin (WSP) ointment cured all Leishmania major lesions on Balb/C mice following topical application for 10 d. Some relapses were observed 10 weeks after treatment. AS alone in WSP ointment was also highly effective. The ointment containing urea was non-irritant to mice, whereas ointments containing quaternary ammonium compounds were irritant. The 15% AS/10% urea/WSP ointment was not effective in the treatment of L. mexicana or L. panamensis lesions on Balb/C mice, no cure being observed.

Reversal of drug resistance in Trypanosoma cruzi and Leishmania donovani by verapamil.

Following previous studies of verapamil reversal of chloroquine resistance in malaria and multi-drug resistance in cancer cells, the effect of verapamil was investigated on nifurtimox-resistant Trypanosoma cruzi in vitro and antimony-resistant Leishmania donovani in vitro and in vivo. Verapamil alone was not active against either parasite, but in combination with nifurtimox it reversed the drug resistance of T. cruzi and in combination with sodium stibogluconate reversed the drug resistance of L. donovani.

A comparative study of Entamoeba histolytica (NIH :200, HK9, etc.), "E. histolytica-like" and other morphologically identical amoebae using isoenzyme electrophoresis.

Cultures of old, well documented strains of Entamoeba histolytica (NIH:200, HK9 etc.) have been compared with "E. histolytica-like" strains and, in turn, with E. moshkovskii, E. invadens and E. chattoni. They have been grouped according to their isoenzyme patterns. The "E. histolytica-like" organisms give patterns similar to E. moshkovskii and both of these are different from E. histolytica Groups I to IV. E. invadens and E. chattoni have easily distinguished characteristic isoenzyme bands. "E. polecki" is indistinguishable from E. histolytica.