Use of diagnostic reports to estimate prevalence and distribution of skeletal lesions in young Thoroughbreds.

Diagnostic reports written to assist stud managers in the sale of young Thoroughbreds have not previously been used as a data source for the study of skeletal lesions. However, analyses of these reports may provide efficient and cost-effective insights into the prevalence and distribution of skeletal lesions within a population. Diagnostic reports written by veterinarians were acquired from Thoroughbred stud managers in Australia and New Zealand. The reports were based on approximately 1300 sets of weanling and yearling radiographs taken between 2002 and 2007. The prevalence and anatomical distribution of skeletal lesions in weanlings (299 horses) and yearlings (1004 horses) were determined from these reports. Overall, 69.9% of weanlings and 64.5% of yearlings were reported as having one or more skeletal lesions. Diagnostic reports in weanlings were a strong indication of what was likely to be seen in subsequent yearling reports. These diagnostic reports are typically used by stud managers in the sales process and the potential drawback is that some categories of skeletal lesions may be under-reported. However, there was substantial agreement between the prevalence and distribution of several skeletal lesions reported in this study and those previously reported from direct evaluation of radiographs for Australian and New Zealand Thoroughbred yearlings. Strong agreement was found for osteophytes, enthesiophytes and other modelling in the hocks, and for lesions in the hind fetlocks and stifles. This indicates that written diagnostic reports are a useful and a reliable source of data for the study of some skeletal lesions in young Thoroughbred horses.

Addition of short-term androgen deprivation therapy to dose-escalated radiation therapy improves failure-free survival for select men with intermediate-risk prostate cancer.

BACKGROUND: Dose-escalated (DE) radiation therapy (RT) and androgen deprivation therapy (ADT) improve prostate cancer outcomes over standard-dose RT. The benefit of adding ADT to DE-RT for men with intermediate-risk prostate cancer (IR-PrCa) is uncertain. PATIENTS AND METHODS: We identified 636 men treated for IR-PrCa with DE-RT (>75Gy). The adult comorbidity evaluation-27 index classifed comorbidity. Kaplan-Meier and log-rank tests compared failure-free survival (FFS) with and without ADT. RESULTS: Forty-five percent received DE-RT and 55% DE-RT with ADT (median 6 months). On Cox proportional hazard regression that adjusted for comorbidity and tumor characteristics, ADT improved FFS (adjusted hazard ratio 0.36; P = 0.004). Recursive partitioning analysis of men without ADT classified Gleason 4 + 3 = 7 or ≥50% positive cores as unfavorable disease. The addition of ADT to DE-RT improved 5-year FFS for men with unfavorable disease (81.6% versus 92.9%; P = 0.009) but did not improve FFS for men with favorable disease (96.3% versus 97.4%; P = 0.874). When stratified by comorbidity, ADT improved FFS for men with unfavorable disease and no or mild comorbidity (P = 0.006) but did not improve FFS for men with unfavorable disease and moderate or severe comorbidity (P = 0.380). CONCLUSION: The addition of ADT to DE-RT improves FFS for men with unfavorable IR-PrCa, especially those with no or minimal comorbidity.

Symmetry of hip dysplasia traits in the German Shepherd Dog in Australia.

Canine hip dysplasia (CHD) is a common and debilitating developmental condition of the canine coxofemoral (hip) joint, exhibiting a multifactorial pattern of inheritance. British Veterinary Association hip traits (BVAHTs) are nine radiographic features of hips used in several countries to ordinally score both the right and left hip of potential breeding candidates to assess their suitability for breeding. The objective of this study was to examine some aspects of the relationship between contralateral scores for each BVAHT in a cohort of 13 124 Australian-registered German Shepherd Dogs. Goodman and Kruskal gamma coefficients of 0.48-0.95 and correlation coefficients of 0.50-0.74 demonstrate that the association between right and left hip scores varies between moderate and strong for BVAHTs. Principal component analysis of scores detected a sizeable left-versus-right effect, a finding supported by symmetry and quasi-symmetry analyses which found that seven of the nine BVAHTs display significant marginal asymmetry. Dogs showing asymmetry for one BVAHT are significantly more likely to display asymmetry at other BVAHTs. When asymmetry is expressed as a binary trait (either symmetrical or asymmetrical), it displays low to moderate heritability. Estimates of genetic correlations between right and left scores are very high for all BVAHTs (>0.945), suggesting right and left scores for each BVAHT are largely determined by the same set of genes. The marginal asymmetries are therefore more likely to be of environmental and non-additive genetic origin. In breeding programmes for CHD, we recommend that scores from both hips be used to estimate breeding values, with a term for side-of-hip included in the model to account for score variation owing to asymmetry.

The repositioning of the anti-fungal agent ciclopirox olamine as a novel therapeutic agent for the treatment of haematologic malignancy.

WHAT IS KNOWN AND OBJECTIVE: 6-Cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone (ciclopirox) and specifically its olamine salt 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone 2-aminoethanol salt (ciclopirox olamine) are anti-fungal agents currently used for the treatment of mild to moderate cutaneous fungal infection. Our objective is to comment on the opportunity to rapidly reposition ciclopirox and its olamine for the treatment of haematologic malignancy by leveraging its prior published toxicology and pharmacology data. COMMENT: Ciclopirox olamine chelates intracellular iron and displays preclinical efficacy in the treatment of haematologic malignancy. Currently, an ongoing study is evaluating topical ciclopirox olamine for the treatment of cervical cancer. Doses of ciclopirox olaine required for a systemic anti-cancer effect appear pharmacologically achievable. However, caution is required as at the highest doses tested in animal toxicology studies, irreversible cardiac degeneration was observed. WHAT IS NEW AND CONCLUSION: The existing pharmacology and toxicology data suggest that systemic ciclopirox olamine could be repositioned as a new investigational anti-cancer agent. The available pharmacology and toxicology data should aid in the design of phase I clinical trials of this agent in patients with refractory haematologic malignancies.

The importance of physiological ecology in conservation biology.

Many of the threats to the persistence of populations of sensitive species have physiological or pathological mechanisms, and those mechanisms are best understood through the inherently integrative discipline of physiological ecology. The desert tortoise was listed under the Endangered Species Act largely due to a newly recognized upper respiratory disease thought to cause mortality in individuals and severe declines in populations. Numerous hypotheses about the threats to the persistence of desert tortoise populations involve acquisition of nutrients, and its connection to stress and disease. The nutritional wisdom hypothesis posits that animals should forage not for particular food items, but instead, for particular nutrients such as calcium and phosphorus used in building bones. The optimal foraging hypothesis suggests that, in circumstances of resource abundance, tortoises should forage as dietary specialists as a means of maximizing intake of resources. The optimal digestion hypothesis suggests that tortoises should process ingesta in ways that regulate assimilation rate. Finally, the cost-of-switching hypothesis suggests that herbivores, like the desert tortoise, should avoid switching food types to avoid negatively affecting the microbe community responsible for fermenting plants into energy and nutrients. Combining hypotheses into a resource acquisition theory leads to novel predictions that are generally supported by data presented here. Testing hypotheses, and synthesizing test results into a theory, provides a robust scientific alternative to the popular use of untested hypotheses and unanalyzed data to assert the needs of species. The scientific approach should focus on hypotheses concerning anthropogenic modifications of the environment that impact physiological processes ultimately important to population phenomena. We show how measurements of such impacts as nutrient starvation, can cause physiological stress, and that the endocrine mechanisms involved with stress can result in disease. Finally, our new syntheses evince a new hypothesis. Free molecules of the stress hormone corticosterone can inhibit immunity, and the abundance of "free corticosterone" in the blood (thought to be the active form of the hormone) is regulated when the corticosterone molecules combine with binding globulins. The sex hormone, testosterone, combines with the same binding globulin. High levels of testosterone, naturally occurring in the breeding season, may be further enhanced in populations at high densities, and the resulting excess testosterone may compete with binding globulins, thereby releasing corticosterone and reducing immunity to disease. This sequence could result in physiological and pathological phenomena leading to population cycles with a period that would be essentially impossible to observe in desert tortoise. Such cycles could obscure population fluctuations of anthropogenic origin.

Susceptibility of the Siberian polecat to subcutaneous and oral Yersinia pestis exposure.

To determine if the Siberian polecat (Mustela eversmannii) represents a suitable model for the study of plague pathogenesis and prevention in the black-footed ferret (Mustela nigripes), polecats were exposed to 10(3), 10(7), or 10(10) Yersinia pestis organisms by subcutaneous injection; an additional group was exposed to Y. pestis via ingestion of a plague-killed mouse. Plague killed 88% of polecats exposed to Y. pestis (71% mortality in the 10(3) group, 100% mortality in the 10(7) and 10(10) groups, and 83% mortality in the mouse-fed group). Within the challenged group, mean day of death post-challenge ranged from 3.6 to 7.6 days; all polecats died on or before day 12 post-challenge. Animals receiving the lowest parenteral dose survived significantly longer than those receiving higher parenteral doses. Within challenged animals, mean survival time was lower in those presenting with significant weight loss by day 3, lethargy, and low fecal output; time to onset of lethargy and other signs was also related to risk of dying and/or plague dose. Six polecats developed serum antibody titers to the Y. pestis F1 protein. Three seropositive polecats survived the initial challenge and a subsequent exposure to a plague-killed mouse, while two seropositive animals later died. This study confirms that the Siberian polecat is susceptible to plague and suggests that this species will offer an appropriate surrogate for black-footed ferrets in future plague studies and related vaccine trials.

A randomized comparison of two doses of human lymphoblastoid interferon-alpha in hairy cell leukemia. Wellcome HCL Study Group.

One hundred thirty-eight patients with hairy cell leukemia were randomized to receive either a dose of 2.0 megaunits (MU)/m2 or a 10-fold lower dose of 0.2 MU/m2 of a highly purified natural alpha-interferon, administered daily for 28 days followed by a three times a week schedule. Ninety-seven of these patients had previously undergone splenectomy, but otherwise none of the patients had received prior therapy for their leukemia. The two doses were comparable in their effect on improving the neutrophil and platelet count, whereas the higher dose had a greater beneficial effect on the hemoglobin level and a greater antileukemic effect on the marrow. Acute toxicity in the form of a flu-like syndrome, neurologic side effects, neutropenia, and the need for platelet transfusions was observed less frequently in the low-dose group, as was the chronic fatigue syndrome. No neutralizing antibody activity was seen in the sera from 61 patients examined. Because of its beneficial effect on the neutrophil and platelet count and a lower degree of toxicity (ie, a superior therapeutic/toxicity ratio), the low dose is recommended as initial therapy in patients with hairy cell leukemia. This therapy may be followed by dose escalation once clinical improvement is observed.

T-cell cloning to detect the mutant 6-thioguanine-resistant lymphocytes present in human peripheral blood.

Rare thioguanine-resistant T lymphocytes, present in vivo in human peripheral blood, were isolated and grown in vitro as thioguanine-resistant cultured T cells. The conditions for their selection in vitro were such that thioguanine resistance had to have arisen in vivo. The mutant cells bore T-cell surface markers, maintained their thioguanine resistance in vitro in the presence or absence of selection, and were deficient in hypoxanthine-guanine phosphoribosyltransferase activity.

Functional properties of lymphocyte subpopulations in hepatitis B virus infection. I. Suppressor cell control of T lymphocyte responsiveness.

Hepatocellular injury in hepatitis B virus infection may be produced by an autoaggressive hepatocytotoxic immune response. To test the hypothesis that acquired suppressor cell defects may participate in such a response, we assessed the functional integrity of 2 suppressor cell populations in patients with type B viral hepatitis. Spontaneous suppression of the 1-way mixed lymphocyte response by radiation-resistant, adherent peripheral blood mononuclear cells decreases during the acute phase of disease, returns towards normal with clinical recovery, but remains depressed in patients with chronic hepatitis. The degree of spontaneous suppressor cell dysfunction correlates inversely with at least 1 biochemical parameter of hepatocellular injury (SGPT). The functional integrity of this suppressor cell fluctuates during chronic hepatitis and may reflect currently undefined biologic variables in this disease. Mitogen-induced suppression on lymphocyte activation by radiation resistant, nonadherent suppressor cells is also depressed in acute and chronic hepatitis, but it does not correlate with biochemical evidence of hepatocellular injury on an individual-patient basis. Documentation of these generalized defects of nonspecific suppressor cell function establishes a basis for the possible existence of specific anomalies of immuno-regulation that may permit the expression of normally suppressed auoaggressive hepatocytotoxic immune mechanisms in viral hepatitis.