Enantiomer separation of 2-halomandelic acids via diastereomeric salt formation with chiral N-substituted 2-amino-2-phenylethanols.

Chiral N-substituted secondary 1,2-aminoalcohols have been developed for the enantioseparation of ortho-halomandelic acids (o-X-MAs) via diastereomeric salt formation. Two structural isomers, N-methyl-2-amino-1,2-diphenylethanol and N-benzyl-2-amino-2-phenylethanol, showed high separation abilities for o-X-MAs (X = Cl, Br, I). The chiral recognition mechanism was elucidated by crystallographic analysis of the less-soluble salts. The substituents on the nitrogen atom of the resolving agents and the inclusion of the crystallization solvent stabilized the salt and enhanced their separation ability.

Identification of treatment responders based on multiple longitudinal outcomes with applications to multiple sclerosis patients.

Identification of treatment responders is a challenge in comparative studies where treatment efficacy is measured by multiple longitudinally collected continuous and count outcomes. Existing procedures often identify responders on the basis of only a single outcome. We propose a novel multiple longitudinal outcome mixture model that assumes that, conditionally on a cluster label, each longitudinal outcome is from a generalized linear mixed effect model. We utilize a Monte Carlo expectation-maximization algorithm to obtain the maximum likelihood estimates of our high-dimensional model and classify patients according to their estimated posterior probability of being a responder. We demonstrate the flexibility of our novel procedure on two multiple sclerosis clinical trial datasets with distinct data structures. Our simulation study shows that incorporating multiple outcomes improves the responder identification performance; this can occur even if some of the outcomes are ineffective. Our general procedure facilitates the identification of responders who are comprehensively defined by multiple outcomes from various distributions. Copyright © 2017 John Wiley & Sons, Ltd.

A flexible mixed-effect negative binomial regression model for detecting unusual increases in MRI lesion counts in individual multiple sclerosis patients.

We develop a new modeling approach to enhance a recently proposed method to detect increases of contrast-enhancing lesions (CELs) on repeated magnetic resonance imaging, which have been used as an indicator for potential adverse events in multiple sclerosis clinical trials. The method signals patients with unusual increases in CEL activity by estimating the probability of observing CEL counts as large as those observed on a patient's recent scans conditional on the patient's CEL counts on previous scans. This conditional probability index (CPI), computed based on a mixed-effect negative binomial regression model, can vary substantially depending on the choice of distribution for the patient-specific random effects. Therefore, we relax this parametric assumption to model the random effects with an infinite mixture of beta distributions, using the Dirichlet process, which effectively allows any form of distribution. To our knowledge, no previous literature considers a mixed-effect regression for longitudinal count variables where the random effect is modeled with a Dirichlet process mixture. As our inference is in the Bayesian framework, we adopt a meta-analytic approach to develop an informative prior based on previous clinical trials. This is particularly helpful at the early stages of trials when less data are available. Our enhanced method is illustrated with CEL data from 10 previous multiple sclerosis clinical trials. Our simulation study shows that our procedure estimates the CPI more accurately than parametric alternatives when the patient-specific random effect distribution is misspecified and that an informative prior improves the accuracy of the CPI estimates.

Personalized activity index, a new safety monitoring tool for multiple sclerosis clinical trials.

BACKGROUND: An abnormal increase of contrast-enhancing lesion (CEL) counts on frequent MRIs is interpreted as a signal of potential worsening in multiple sclerosis (MS) clinical trials. We demonstrate the utility of the MR personalized activity index (MR-pax) to identify such increases. METHODS: We analyzed a previous Phase II study in relapsing patients (n = 167) with MRIs at screening, baseline and months 1-6. We performed five consecutive reviews at 90-day intervals. At each review, we evaluate the MR-pax for each patient and also identify those who meet the rule-of-five (an ad-hoc guideline currently in use). To evaluate its clinical relevance, we assess the relation between having a small MR-pax (≤0.05; indicating an unexpected CEL increase) and relapse status in the 12 weeks post-review. RESULTS: Of the 399 patient reviews, 35 cases met the rule-of-five; 35 had an MR-pax ≤ 0.05; 18 met both criteria. The proportions experiencing clinical relapse are 63% among those meeting the rule-of-five, 61% among those with MR-pax ≤0.05, and 83% for those meeting both criteria, more than double the rate of those meeting neither criterion (40%). CONCLUSION: A guideline combining this new personalized index and the existing threshold-based criterion is able to better identify patients with a higher risk of experiencing relapses.

Evaluation of the efficacy of afoxolaner against Haemaphysalis longicornis on dogs.

A controlled study to assess the acaricidal efficacy of afoxolaner in dogs after a single oral administration was conducted against Haemaphysalis longicornis ticks. The study was characterized by a negative controlled randomized block design and included sixteen beagle dogs of both sexes. Starting two days before treatment, each dog was infested weekly with 50 ticks over 4 weeks. The number of live ticks was determined 48 h after treatment and then 48 h after each infestation. The mean dose of afoxolaner received by dogs was 3.0mg/kg (range: 2.5-3.1mg/kg). Afoxolaner rapidly eliminated pre-existing tick infestations (100% ticks killed within 48 h of treatment) and controlled weekly re-infestations (91.9% prophylactic efficacy at Day 30).

Extranodal lymphoma with peripheral nervous system involvement in a dog.

An 8-year-old neutered female Cavalier King Charles spaniel was evaluated for progressing right forelimb lameness. Magnetic resonance imaging revealed that the right-side radial nerves and the caudal brachial plexus were swollen. The histological and molecular biological diagnosis by partial biopsy of the C8 spinal nerve was T-cell lymphoma. Coadministration of lomustine and irradiation was started. However, this therapy was ineffective. At necropsy, neoplastic tissues were seen extending into the subarachnoid space of the spinal cord, liver, pancreas and kidneys as gross findings. A large mass was also identified occupying the caudal thorax. Histologic findings included infiltration in these organs and the mass by neoplastic lymphocytes. To date, involvement of peripheral nerves (neurolymphomatosis) is rarely reported in veterinary species.

Testicular yolk sac tumor of myxomatous, reticular, and polyvesicular vitelline type in a newborn calf.

Yolk sac tumors (YSTs) are rare neoplasms of germ cell origin. In humans, the tumors primarily occur in the testes or ovaries, but occasionally develop at other sites. The neoplastic cells of YSTs form many histological patterns resembling embryonal structures, and the World Health Organization classification lists 11 such patterns: reticular, macrocystic, endodermal sinus, papillary, solid, glandular-alveolar, myxomatous, sarcomatoid, polyvesicular vitelline, hepatoid, and parietal. Among domestic animals, only 2 cases of YST, which were of testicular and abdominal cavity origin, have been reported in calves. In both cases, neoplastic cells had epithelial properties and disseminated metastases in the abdomen. In the present study, the enlarged testis of a newborn calf, which was subsequently diagnosed as YST and exhibited myxomatous, reticular, and polyvesicular vitelline histological patterns, is described. There was no metastasis in this case, and histological and immunohistochemical features varied from previous cases of YST.

Efficacy and safety of firocoxib for the treatment of pain associated with soft tissue surgery in dogs under field conditions in Japan.

Use of firocoxib in dogs for postoperative pain control has not been published in any of the journals in Japan. A field study was conducted to evaluate the efficacy and safety of firocoxib in dogs in controlling pain associated with soft tissue surgery in Japan. The study followed a negative control, double-blind, multicenter clinical efficacy study using a randomized block design. A total of 131 client-owned dogs presented to the clinical practices for soft tissue surgery were enrolled. Sixty-nine dogs were allocated to the firocoxib-treated group and received 5 mg/kg of firocoxib orally on Day 0 before the surgery and once daily through Day 2, while 62 dogs were allocated to the non-treated group handled in a similar manner only without the firocoxib administration. Pain assessment took place on Day 0 before the surgery through Day 2. The primary efficacy variable was a success/failure variable based on whether the dog needed rescue medication (based on pain assessment after the surgery or Investigator's judgment) and a significant difference between firocoxib-treated group (16.4%) and non-treated group (50.0%) (P=0.0031) was observed. There was no adverse event during the study that was considered to be related to the administration of firocoxib. This study indicated the clinical efficacy and safety profile of firocoxib administered to control pain associated with soft tissue surgery under field condition.

Prognosis of canine patients with nasal tumors according to modified clinical stages based on computed tomography: a retrospective study.

To evaluate the efficacy of clinical staging based on computed tomography (CT) imaging over the World Health Organization (WHO) staging system based on radiography for nasal tumors in dogs, a retrospective study was conducted. This study used 112 dogs that had nasal tumors; they had undergone radiography and CT and had been histologically confirmed as having nasal tumors. Among 112 dogs, 85 (75.9%) were diagnosed as adenocarcinoma. Then they were analyzed for survival time according to each staging system. More than 70% of the patients with adenocarcinoma were classified as having WHO stage III. The patients classified under WHO stage II tended to survive longer than those classified under WHO stage III. Dogs classified under WHO stage III were further grouped into CT stages III and IV, and CT stage III patients had a significantly longer survival time than CT stage IV patients. In addition, patients treated with a combination of surgery and radiation had a significantly longer survival time than the patients who did not receive any treatment in CT stage III. On the other hand, different treatment modalities did not show a significant difference in the survival time of CT stage IV dogs. The results suggest that WHO stage III dogs may have various levels of tumor progression, indicating that the CT staging system may be more accurate than the WHO staging system.

Influence of amino acid numbers between two ligand cysteines of zinc finger proteins on affinity and specificity of DNA binding.

The C(2)H(2)-type zinc finger motif has the consensus sequence X(2)-Cys-X(2,4)-Cys-X(12)-His-X(3-5)-His and two or four amino acid residues between two ligand cysteines are well conserved. To evaluate this conservation, we prepared six mutant peptides derived from the three-zinc-finger domain of Sp1 whose C-terminal finger has two amino acid residues between the two invariant cysteines. Their circular dichroism spectra suggest that these mutants have an ordered secondary structure comparable with that of the wild type. The insertion mutants (X=3-5) bind to DNA with the somewhat lower affinity than the wild type (X=2). On the other hand, the DNA binding affinity of the deletion mutants (X=0 and 1) is significantly reduced. In particular, the extent of the reduction in two mutants with Cys-Cys and Cys-Pro-Cys is remarkable. The methylation interference analyses demonstrate that this decreased DNA binding affinity is due to lowering of the extent of the base contacts by the central and C-terminal fingers. This information reveals not only a clue to evolution of the zinc finger but also the possibility of the existence of the zinc finger with altered number of amino acid residues between the two ligand cysteines.