Tissue classification in a canine model of Duchenne Muscular Dystrophy using quantitative MRI parameters.

Duchenne Muscular Dystrophy (DMD) is a genetic disorder caused by dystrophin protein deficiency. Muscle biopsy is the gold standard to determine the disease severity and progression. MRI has shown potential for monitoring disease progression or assessing the treatment effectiveness. In this study, multiple quantitative MRI parameters were used to classify the tissue components in a canine model of DMD disease using histoimmunochemistry analysis as a "ground truth". Results show that multiple MRI parameters may be used to reliably classify the muscular tissue and generate a high-resolution tissue type maps, which can be used as potential non-invasive imaging biomarkers for the DMD.

Combining parallel factor analysis and machine learning for the classification of dissolved organic matter according to source using fluorescence signatures.

Parallel factor (PARAFAC) analysis of dissolved organic matter (DOM) fluorescence has facilitated a surge of investigation into its biogeochemical cycling. However, rigorous, PARAFAC-based methods for holistically distinguishing DOM sources are lacking. This study classified 1029 PARAFAC-analyzed excitation-emission matrices (EEMs) measured using DOM isolated from 24 different leaf leachates, rivers, and organic matter standards using four machine learning methods (MLM). EEMs were also divided into subsets to assess the impact of experimental treatments (i.e. whole EEMs, size fractionation, mixtures, quenching) and dataset properties (i.e. different numbers of EEMs from each leachate/river) on classification. A split-half validated, 10-component PARAFAC model was extended to 12 components to remove consistent peaks evident in model residuals. The 12-component model performed better than the 10-component model, correctly classifying up to 80 additional EEMs, when the dataset included size-fractionated DOM or several different sources (i.e. many leaf species and rivers); however, the 10-component model performed better for whole-sample EEMs when comparing leaf leachates to rivers. The MLM correctly classified whole EEMs of riverine DOM by source with up to 87.0% accuracy, leachates with up to 92.5% accuracy, and distinguished leachates from rivers with 97.2% accuracy. A difference of up to 17.3% in classification accuracy was observed depending on the MLM method used with the following order: multilayer perceptron = support vector machine > k-nearest neighbours â‰« decision tree; however, performances differed widely depending on the data subset. Classification accuracy for whole and size-fractionated rivers compared to whole and size-fractionated leachates using N-way partial least-squares discriminant analysis (NPLS-DA; 97.7%) was similar to that achieved using MLM. Combining MLM with PARAFAC is an effective method for classifying DOM based on its fluorescence signature because PARAFAC can isolate meaningful fluorescent species and unlike PLSDA, MLM constructs a single model which simultaneously classifies EEMs as belonging to one of several categories. A complete accounting of carbon flows through ecosystems should include the processes and sources that contribute to the disparate fluorescence signatures of riverine and leached DOM.

Localized MRI and histological image correlation in a canine model of duchenne muscular dystrophy.

Duchenne Muscular Dystrophy (DMD) is a fatal X-linked disorder. Therapeutic assessments currently require muscle biopsy to ascertain information about the status of disease progression. MRI shows potential to be used in place of muscle biopsy for therapeutic assessments. In this work, localized histological data and various MRI parameters were correlated in a canine model of DMD. The results indicate several MRI parameters may be useful as biomarkers of disease progression.

Impact of compound alpha treatment in vivo on egg production by the liver fluke, Fasciola hepatica.

Sheep infected with the triclabendazole-susceptible Cullompton isolate of Fasciola hepatica were treated with compound alpha at a dosage of 15 mg/kg at 12 weeks post-infection. Adult flukes were recovered from the bile ducts at 24h, 48 h and 72 h post-treatment (pt). They were processed for whole mount analysis, histology and transmission electron microscopy of the female reproductive system: specifically, the uterus, Mehlis' gland, ovary and vitellaria. As judged by the appearance of the uterus, normal egg production ceased within 24h of treatment; this phenomenon preceded significant changes to the other reproductive organs. Over the 3-day pt period, there was a progressive decline in the number of oogonia in the ovary, together with an increase in the number of eosinophilic and apoptotic oocytes and vacuolation and shrinkage of the ovarian tubules. There was a shift in the cell population within the vitelline follicles at 48 h pt, with relatively greater numbers of mature vitelline cells and fewer immature cells. The follicles were vacuolated and the shell globule clusters in the mature cells were disorganised. Greater disruption was seen at 72 h pt, with a reduction in the size of the follicles and rupture of cells, releasing their content into the lumen of the follicles. These histological observations were confirmed and extended at the TEM level. Thus, examination of electron micrographs showed that disruption of the shell globule clusters was evident at 48 h pt, which coincided with the start of the breakdown of the mature cells and of the nurse cell network. These degenerative changes were more conspicuous at 72 h pt. In the Mehlis' gland, shrinkage and vacuolation of the cells and their cytoplasmic extensions became progressively greater from 48 h to 72 h pt, and secretory activity declined. The changes in the reproductive organs and inhibition of egg production are put in context of the overall time-course of drug action.

Early onset of changes to the reproductive system of Fasciola hepatica following in vivo treatment with triclabendazole.

Lambs infected with the Cullompton triclabendazole (TCBZ)-susceptible isolate of Fasciola hepatica were treated with TCBZ at a dosage of 10mg/kg at 16 weeks post-infection. Adult flukes were recovered from the liver at 3h, 24h, 48 h and 60 h post-treatment (pt). They were processed for histological analysis of the uterus, Mehlis' gland, vitellaria, ovary and testis. At 3h pt, the flukes were essentially similar to the controls and were producing normal eggs. Egg production had ceased by 24h pt. At this time period, the cells of the Mehlis' gland showed some evidence of vacuolation, but otherwise were relatively normal. A shift in the population of vitelline cells towards mature cells was observed at 24h pt, and this trend continued at later time-periods. It was accompanied by a breakdown of the cells and the presence of apoptotic bodies. Marked changes to the ovary were first noted at 48 h pt, as evidenced by vacuolation and the presence of apoptotic bodies. Some disruption to the testis was seen at 24h pt, with a reduction in the population of spermatogenic cells, the appearance of apoptotic bodies and some peripheral vacuolation of the tubules. These abnormalities increased in severity with longer time periods pt. The results bring forward the time-line of cessation of egg production by 24h, demonstrating that this process is affected very rapidly pt.

Quantitative Sensory Testing to assess the sensory characteristics of cancer-induced bone pain after radiotherapy and potential clinical biomarkers of response.

BACKGROUND/AIMS: Radiotherapy (XRT) is the gold standard treatment for cancer-induced bone pain (CIBP), but only 50% of patients achieve adequate pain relief within 6 weeks. No predictors of analgesic response to XRT are known. The aim of this preliminary study was to explore the effect of XRT on sensory changes in CIBP with a view to predicting response. METHODS: After ethics committee approval, patients with CIBP were assessed prior to and 4-6 weeks after palliative XRT. This included completion of the Brief Pain Inventory (BPI) and bedside Quantitative Sensory Testing (QST) measuring evoked sensations to quantified stimuli on the skin over the area of CIBP and a control site. RESULTS: Twenty-three patients were assessed pre and post XRT. Thirteen (57%) had an analgesic response (defined as ≥30% reduction in total BPI). Those patients who had normalisation of abnormal warm sensation ("warm responders", n = 6) were different in that they had higher baseline functional BPI pain scores (median score (IQR) in warm responders = 43 (31.75-58) compared to 31 (12-39.5) in the remaining patients, p = 0.039), larger reductions in pain scores (median difference of 33.5 in total BPI, p = 0.027) and increased likelihood of resolution of sensitivity to pinprick. CONCLUSIONS: This is the first clinical study to demonstrate alterations in sensory responses in CIBP. Alterations in specific sensory characteristics seem to be associated with an increased likelihood of successful analgesia from palliative XRT. This supports the use of QST in further biomarker studies to predict response to therapy and aid clinical decision making.

A model of habitability within the Milky Way galaxy.

We present a model of the galactic habitable zone (GHZ), described in terms of the spatial and temporal dimensions of the Galaxy that may favor the development of complex life. The Milky Way galaxy was modeled using a computational approach by populating stars and their planetary systems on an individual basis by employing Monte Carlo methods. We began with well-established properties of the disk of the Milky Way, such as the stellar number density distribution, the initial mass function, the star formation history, and the metallicity gradient as a function of radial position and time. We varied some of these properties and created four models to test the sensitivity of our assumptions. To assess habitability on the galactic scale, we modeled supernova rates, planet formation, and the time required for complex life to evolve. Our study has improved on other literature on the GHZ by populating stars on an individual basis and modeling Type II supernova (SNII) and Type Ia supernova (SNIa) sterilizations by selecting their progenitors from within this preexisting stellar population. Furthermore, we considered habitability on tidally locked and non-tidally locked planets separately and studied habitability as a function of height above and below the galactic midplane. In the model that most accurately reproduces the properties of the Galaxy, the results indicate that an individual SNIa is ∼5.6× more lethal than an individual SNII on average. In addition, we predict that ∼1.2% of all stars host a planet that may have been capable of supporting complex life at some point in the history of the Galaxy. Of those stars with a habitable planet, ∼75% of planets are predicted to be in a tidally locked configuration with their host star. The majority of these planets that may support complex life are found toward the inner Galaxy, distributed within, and significantly above and below, the galactic midplane.

Fasciola hepatica: comparative effects of host resistance and parasite intra-specific interactions on size and reproductive histology in flukes from rats infected with isolates differing in triclabendazole sensitivity.

The efficacies of putative fasciolicides and vaccines against Fasciola hepatica are frequently monitored in clinical and field trials by determination of fluke egg output in host faeces and by worm counts in the host liver at autopsy. Less often used are parameters based on fluke size and histology, yet these can provide important indications of specific effects on the development of particular germ-line or somatic tissues, especially in relation to the timing and profligacy of egg production. In this study, F. hepatica metacercariae of two distinct isolates, the triclabendazole (TCBZ)-sensitive Cullompton isolate and the TCBZ-resistant Oberon isolate, were administered to rats as single-isolate or mixed-isolate infections. At autopsy 16 weeks later individual adult flukes were counted, measured and the reproductive organs were examined histologically. The degree of development of the testis tubules in each fluke was represented by a numerical score, based on the proportion of the histological section profiles occupied by testis tissue. The level of anti-F. hepatica antibody in the serum of each rat was determined by ELISA. It was found that Cullompton flukes were significantly larger than Oberon flukes, and that significantly more Cullompton metacercariae developed to adults than Oberon metacercariae. The Cullompton flukes showed histological evidence of aspermy and spermatogenic arrest, which was reflected in quantitatively reduced testicular development, as compared with the Oberon isolate. In Cullompton flukes, parthenogenetic egg development is implied. The size of Cullompton and Oberon flukes was significantly related to the number of adult flukes recovered, to the number of metacercariae administered, and to the percentage success of infection. The testis development score in both isolates was significantly related to the number of adult flukes recovered but not to the number of metacercariae administered, or to the percentage success of infection. Fluke size was positively related to testis score for both isolates, and a significant negative relationship was found between percentage success of infection and metacercarial dose. The results are interpreted in terms of differing interactions between various numbers of young flukes and host immunity during invasion of and migration in the hepatic parenchyma, and of fluke intra-specific (possibly pheromonal) stimulatory effects in the final stages of development, within the host bile ducts. No significant relationships were found between host antibody levels and fluke size or testis score. False positive serological reactions were found in some rats that had been infected, but found to harbour no flukes at autopsy. Clearly the act of eliminating the flukes involved generation of an immune response.

Reproductive disruption in Fasciola hepatica associated with incomplete efficacy of a new experimental formulation of triclabendazole.

The objective of the present study was to analyse the reproductive viability (using histopathologic studies) of Fasciola hepatica from cattle artificially infected and treated subcutaneously with a new experimental formulation of triclabendazole (8mg/kg b.w.). The results of the efficacy controlled test, which only takes into account the presence of live adult flukes, indicated that, whilst in the control group (n=7) 533 live specimens were recovered, in the test groups (doses of 8 and 12mg/kg b.w.) only 195 and 47 adults were recovered, respectively. These numbers indicate efficacies of 69% and 95.6%, respectively. It was observed in that dose of 8mg/kg b.w. some specimens remained viable, but they were infertile, which severely compromises the biological cycle of the trematode. In the testis tubules of flukes treated with the low dose of TCBZ (8mg/kg), very few cells were present and the vitelline follicles were markedly reduced in size and each follicle contained very few cells. This would have direct implications for the pathogenesis of the parasitosis since the remaining parasites would produce little clinical-productive manifestations, would stimulate the immune response and would find it difficult to establish future re-infestations/re-infections. Consequently, these observations will also prompt a review of certain methodological and interpretative aspects related to efficacy tests, where the only discriminative factor is the reduction of the adult parasite load. On one hand, histopathological studies could be complementary to the efficacy controlled test for TCBZ or other BZD formulations.

Does land-based exercise reduce pain and disability associated with hip osteoarthritis? A meta-analysis of randomized controlled trials.

OBJECTIVE: To determine if clinical guidelines recommending therapeutic exercise for people with hip osteoarthritis (OA) are supported by rigorous scientific evidence. METHODS: A meta-analysis of randomized controlled trials (RCTs) recruiting people with hip OA and comparing some form of land-based exercise program (as opposed to exercises conducted in the water) with a non-exercise group in terms of hip pain and/or self-reported physical function. RESULTS: Thirty-two RCTs were identified, but only five met the inclusion criteria. Only one of the five included RCTs restricted recruitment to people with hip OA, the other four RCTs also recruiting participants with knee OA. The five included studies provided data on 204 and 187 hip OA participants for pain and physical function, respectively. Combining the results of the five included RCTs using a fixed-effects model demonstrated a small treatment effect for pain (standardized mean difference (SMD) -0.38; 95% confidence interval (CI) -0.67 to -0.09). No significant benefit in terms of improved self-reported physical function was detected (SMD -0.02; 95% CI -0.31 to 0.28). CONCLUSION: Currently there is only silver level evidence (one small RCT) supporting the benefit of land-based therapeutic exercise for people with symptomatic hip OA in terms of reduced pain and improved physical function. The limited number and small sample size of the included RCTs restricts the confidence that can be attributed to these results.

Fasciola hepatica: histological changes in the reproductive structures of triclabendazole (TCBZ)-sensitive and TCBZ-resistant flukes after treatment in vivo with TCBZ and the related benzimidazole derivative, Compound Alpha.

Twenty-four shed-reared lambs were each infected orally with 250 metacercariae of Fasciola hepatica, using either the triclabendazole (TCBZ)-sensitive Cullompton isolate or the TCBZ-resistant Sligo isolate. Twelve weeks after infection the lambs were treated with TCBZ (10mg/kg) or with the experimental fasciolicide, Compound Alpha (Cpd alpha), a benzimidazole derivative of TCBZ (15mg/kg). The lambs were euthanised 48, 72 and 96h after TCBZ treatment, or 24, 48 and 72h after Cpd alpha treatment, and flukes were collected from the liver and/or gall bladder of each animal. Untreated animals harbouring 12-week infections were euthanized 24h after administration of anthelmintic to the treatment groups, and the untreated flukes provided control material. A semi-quantitative assessment of the degree of histological change induced by the two drugs after different times of exposure was achieved by scoring the intensity of three well-defined lesions that developed in the testes and uteri of a representative sample of flukes from each lamb. In general, it was found that in those tissues where active meiosis and/or mitosis occurred (testis, ovary, and vitelline follicles), there was progressive loss of cell content due to apparent failure of cell division to keep pace with expulsion of the mature or effete products. Further, actively dividing cell types tended to become individualised, rounded and condensed, characteristic of apoptotic cell death. Protein synthetic activity was apparently inhibited in the Mehlis' secretory cells. In the uterus, where successful formation of shelled eggs represents the culmination of a complex sequence of cytokinetic, cytological and synthetic activity involving the vitelline follicles, the ovary and the Mehlis' gland, histological evidence indicating failure of ovigenesis was evident from 24h post-treatment onwards. The development of these lesions may be related to the known anti-tubulin activity of the benzimidazole class of anthelmintics, to the induction of apoptosis in cells where mitosis or meiosis has aborted due to failure of spindle formation, and to drug-induced inhibition of protein synthesis. The semi-quantitative findings indicated that Cpd alpha is slightly less efficacious than TCBZ itself in causing histological damage to the reproductive structures of TCBZ-sensitive flukes, and that, like TCBZ, it caused no histological damage in flukes of the TCBZ-resistant isolate. This study illustrates the potential utility of histological techniques for conveniently screening representative samples of flukes in field trials designed to validate instances of drug resistance or to test the efficacy of new products against known drug-resistant and drug-susceptible fluke isolates. It also provides reference criteria for drug-induced histopathological changes in fluke reproductive structures which may aid interpretation of TEM findings.

Safety and efficacy of daptomycin in the treatment of osteomyelitis: results from the CORE Registry.

Antibiotic safety is a major determinant in osteomyelitis therapy. Limited data is available describing the long-term safety and efficacy of daptomycin. the safety population was drawn from CORE 2005 and 2006, a retrospective, observational, multicenter study. Clinically evaluable patients received >3 days of daptomycin appropriately adjusted for renal function. three hundred twenty-seven patients were evaluated for safety; 188 (57%) >or=6 mg/kg, 139 (43%) <6 mg/kg. Thirty-one (10%) patients experienced adverse events possibly related to daptomycin and the incidence was similar regardless of dose. No difference was observed in the rate of creatine phosphokinase elevations by dose. A trend toward higher improved rates was noted in patients receiving a final dose of >or=6mg/kg (96% vs. 90%, P=0.08). Daptomycin appeared well-tolerated at doses of 6 mg per kg or greater which were associated with greater clinical improvement. These results require verification via a prospective clinical trial.

Fasciola hepatica: Histology of the testis in egg-producing adults of several laboratory-maintained isolates of flukes grown to maturity in cattle and sheep and in flukes from naturally infected hosts.

A total of 8 calves approximately 6 months old and 22 lambs of similar age were infected with metacercariae of Fasciola hepatica of various laboratory-maintained isolates including: Cullompton (sensitive to triclabendazole) and Sligo, Oberon and Leon (reported as resistant to triclabendazole). Ten to 16 weeks after infection, flukes were harvested from these experimental animals and the histology of the testis tissue was examined in a representative sample of flukes from each population. Adult wild-type flukes were also collected from 5 chronically infected cattle and 7 chronically infected sheep identified at post-mortem inspection. The testis tissue of these flukes was compared with that of the various laboratory-maintained isolates. Whilst the testes of the wild-type, Oberon and Leon flukes displayed all the usual cell types associated with spermatogenesis in Fasciola hepatica (spermatogonia, spermatocytes, spermatids and mature sperm), the Cullompton flukes from both cattle and sheep showed arrested spermatogenesis, with no stages later than primary spermatocytes represented in the testis profiles. The presence of numerous eosinophilic apoptotic bodies and nuclear fragments suggested that meiotic division was anomalous and incomplete. In contrast to the wild-type flukes, no mature spermatozoa were present in the testes or amongst the shelled eggs in the uterus. A high proportion of the eggs collected from these flukes hatched to release normal-appearing miracidia after an appropriate incubation period, as indeed was the case with all isolates examined and the wild-type flukes. It is concluded that the eggs of Cullompton flukes are capable of development without fertilization, i.e. are parthenogenetic. The implications of this for rapid evolution of resistant clones following an anthelmintic selection event are discussed. Amongst the Sligo flukes examined, two subtypes were recognised, namely, those flukes with all stages of spermatogenesis and mature spermatozoa present in the testes (type 1), and those flukes with all stages of spermatogenesis up to spermatids present, but no maturing spermatozoa in the testes (type 2). Each sheep infected with the Sligo isolate had both type 1 (approximately 60%) and type 2 (approximately 40%) flukes present in the population. Spermatozoa were found amongst the eggs in the uterus in 64% of flukes and this did not necessarily reflect the occurrence of spermatozoa in the testis profiles of particular flukes, suggesting that cross-fertilization had occurred. The apparent disruption of meiosis in the spermatocytes of the Cullompton flukes is consistent with reports that Cullompton flukes are triploid (3n=30), whereas the Sligo and wild-type flukes are diploid (2n=20). In the Sligo flukes the populations are apparently genetically heterogenous, with a proportion of the flukes unable to produce fully formed spermatozoa perhaps because of a failure in spermiogenesis involving elongation of the nucleus during morphogenesis.

Exercise for osteoarthritis of the hip or knee.

BACKGROUND: Biomechanical factors, such as reduced muscle strength and joint mal-alignment, have an important role in the initiation and progression of osteoarthritis (OA) of the hip or knee. Currently, there is no known cure for OA, however, disease-related factors, such as impaired muscle function and reduced fitness, are potentially amenable to therapeutic exercise. OBJECTIVES: To determine whether land-based therapeutic exercise is beneficial for people with OA of the hip or knee in terms of reduced joint pain, improved physical function and/or the patient's global assessment of therapeutic effectiveness. SEARCH STRATEGY: Five databases (the Cochrane Controlled Trials Register, the Cochrane Musculoskeletal Group Trials Register, MEDLINE, CINAHL, PEDro) were searched up until November 2002. SELECTION CRITERIA: All randomized controlled trials comparing some form of land-based therapeutic exercise (as opposed to exercises conducted in the water) with a non-exercise group. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed methodological quality. All analyses were conducted on continuous outcomes. MAIN RESULTS: Only 2 studies totaling about 100 participants, could potentially provide data on people with OA of the hip. However, for OA of the knee, 17 included studies provided data on 2562 participants. For pain, combining the results revealed a beneficial treatment effect (standardised mean difference) of.39 (95% confidence interval (CI).30 -.47) while for self-reported physical function a beneficial treatment effect of.31 (95% CI.23 -.39). Group format programs appeared to be as effective as treatments provided on a one-to-one basis. The results were sensitive to various aspects of study design methodology. REVIEWER'S CONCLUSIONS: Land-based therapeutic exercise was shown to reduce pain and improve physical function for people with OA of the knee. There were insufficient data to provide useful guidelines on optimal exercise type or dosage. Supervised exercise classes appeared to be as beneficial as treatments provided on a one-to-one basis.

Effect of interleukin 6 on the hepatic metabolism of itraconazole and its metabolite hydroxyitraconazole using primary human hepatocytes.

A potential cytokine-drug interaction between interleukin 6 (IL-6) and itraconazole (ITZ) was studied using human hepatocytes in primary culture. Cultures from 5 adult males (mean age 42 +/- 15 years) who had not received any medicines known to interact with CYP3A4 were studied. Cultures were exposed to ITZ 500 ng/ml, and the effects of 120 microg/ml cimetidine, 50 ng/ml human IL-6, or IL-6 plus IL-6 receptor antagonist were analyzed for 2, 4, 8, and 12 h. Intracellular ITZ and hydroxyitraconazole concentrations were measured using HPLC and normalized to total cellular protein. Mean intracellular concentrations between groups were compared using one-way Anova (f test; p < 0.10) and corresponding Bonferroni versus control test for multiple comparisons (p < 0.02). Mean intracellular ITZ concentrations between the groups were similar at all time points. Human hepatocytes in primary culture can metabolize ITZ. However, IL-6 did not inhibit hydroxyitraconazole formation, but it may inhibit its subsequent metabolism.

NudC associates with Lis1 and the dynein motor at the leading pole of neurons.

NUDC is a highly conserved protein important for nuclear migration and viability in Aspergillus nidulans. Mammalian NudC interacts with Lis1, a neuronal migration protein important during neocorticogenesis, suggesting a conserved mechanism of nuclear movement in A. nidulans and neuronal migration in the developing mammalian brain (S. M. Morris et al., 1998). To further investigate this possibility, we show for the first time that NudC, Lis1, and cytoplasmic dynein intermediate chain (CDIC) colocalize at the microtubule organizing center (MTOC) around the nucleus in a polarized manner facing the leading pole of cerebellar granule cells with a migratory morphology. In neurons with stationary morphology, NudC is distributed throughout the soma and colocalizes with CDIC and tubulin in neurites as well as at the MTOC. At the subcellular level, NudC, CDIC, and p150 dynactin colocalize to the interphase microtubule array and the MTOC in fibroblasts. The observed colocalization is confirmed biochemically by coimmunoprecipitation of NudC with CDIC and cytoplasmic dynein heavy chain (CDHC) from mouse brain extracts. Consistent with its expression in individual neurons, a high level of NudC is detected in regions of the embryonic neocortex undergoing extensive neurogenesis as well as neuronal migration. These data suggest a biochemical and functional interaction of NudC with Lis1 and the dynein motor complex during neuronal migration in vivo.

Gaining acceptance into veterinary school: a review of medical and veterinary admissions policies.

Veterinary and medical school admissions policies and committees form the gateway for individuals to become doctors. Thus the process of admissions becomes pivotal in directing the future of these professions. This article is a review of the literature pertaining to veterinary and medical admissions.

Subjective criteria as the sole method of selecting veterinary candidates at a US veterinary medical school.

For the past four years, Colorado State University College of Veterinary Medicine and Biomedical Sciences' veterinary Admissions Committee has used a completely subjective process to select veterinary students. The basic premise of the subjective admissions process is to evaluate applicants holistically, with equal emphasis on cognitive and non-cognitive attributes. The system allows the Committee the flexibility to weigh factors deemed by the school and profession to be important without the necessity of creating complex mathematical models to fit the confines of a point system. The subjective system, endorsed by the school's faculty and legal counsel, is summarized in this article.

Doublecortin interacts with mu subunits of clathrin adaptor complexes in the developing nervous system.

Doublecortin is a microtubule-associated protein required for normal corticogenesis in the developing brain. We carried out a yeast two-hybrid screen to identify interacting proteins. One of the isolated clones encodes the mu1 subunit of the adaptor complex AP-1 involved in clathrin-dependent protein sorting. We found that Doublecortin also interacts in yeast with mu2 from the AP-2 complex. Mutagenesis and pull-down experiments showed that these interactions were mediated through a tyrosine-based sorting signal (YLPL) in the C-terminal part of Doublecortin. The functional relevance of these interactions was suggested by the coimmunoprecipitation of Doublecortin with AP-1 and AP-2 from mouse brain extracts. This interaction was further supported by RNA in situ hybridization and immunofluorescence studies. Taken together these data indicate that a certain proportion of Doublecortin interacts with AP-1 and/or AP-2 in vivo and are consistent with a potential involvement of Doublecortin in protein sorting or vesicular trafficking.