Genotypic Analysis of the V3 Region of HIV from Virologic Nonresponders to Maraviroc-Containing Regimens Reveals Distinct Patterns of Failure

Changes in HIV tropism from R5 to non-R5 or development of drug resistance is often associated with virologic failure in patients treated with maraviroc, a CCR5 antagonist. We sought to examine changes in HIV envelope sequences and inferred tropism in patients who did not respond to maraviroc-based regimens. We selected 181 patients who experienced early virologic failure on maraviroc-containing therapy in the MOTIVATE trials. All patients had R5 HIV by the original Trofile assay before entry. We used population-based sequencing methods and the geno2pheno algorithm to examine changes in tropism and V3 sequences at the time of failure. Using deep sequencing, we assessed whether V3 sequences observed at failure emerged from preexisting subpopulations. From population genotyping data at failure, 90 patients had R5 results, and 91 had non-R5 results. Of the latter group, the geno2pheno false-positive rate (FPR) value fell from a median of 20 at screening to 1.1 at failure. By deep sequencing, the median percentage of non-R5 variants in these patients rose from 1.4% to 99.5% after a median of 4 weeks on maraviroc. In 70% of cases, deep sequencing could detect a pretreatment CXCR4-using subpopulation, which emerged at failure. Overall, there were two distinct patterns of failure of maraviroc. Patients failing with R5 generally had few V3 substitutions and low non-R5 prevalence by deep sequencing. Patients with non-R5 HIV who were failing developed very-high-prevalence non-R5 HIV (median, 99%) and had very low geno2pheno values.     

Extreme sensory modulation behaviors in toddlers with autism spectrum disorders.

This study examined the incidence of extreme sensory modulation behaviors in toddlers with autism spectrum disorders (ASD) and investigated the consistency of sensory information across measures. Parent report of sensory behaviors in 101 toddlers with ASD was compared with 100 toddlers who were typically developing matched on chronological age and 99 additional infants or toddlers matched on mental age. Measures included the Infant/Toddler Sensory Profile, Infant-Toddler Social Emotional Assessment, Autism Diagnostic Interview-Revised, and Autism Diagnostic Observation Schedule-Generic. Toddlers with ASD were most distinct from typically developing groups in their high frequency of underresponsiveness and avoiding behaviors and their low frequency of seeking. Within the toddlers with ASD, there were significant associations across sensory parent report measures, but parent report was not correlated with clinical observation. Findings point to the early onset of an extreme sensory profile in ASD. Occupational therapists need to assess multiple domains of sensory behaviors to accurately identify the needs of toddlers with ASD.     

Ketamine for intravenous regional anesthesia

We studied ketamine intravenous regional anesthesia of the upper extremity in volunteers using concentrations of 0.5%, 0.3%, and 0.2%. Ketamine 0.5 and 0.3% produced adequate intravenous regional anesthesia. Anesthesia was inadequate when a 0.2% concentration was used. However, although the 0.3% concentration provides complete sympathetic, sensory, and motor blockade when injected into the isolated extremity, unpleasant psychotomimetic effects after the release of the tourniquet limit the usefulness of this use of ketamine. Ketamine cannot be recommended for intravenous regional anesthesia unless these unpleasant side effects are abolished or controlled by means of pharmacologic adjuvants.     

Mammographic Density in Women on Postmenopausal Hormone Replacement Therapy

Background . Fine-needle aspiration (FNA) biopsy has been used increasingly in the diagnosis and biologic characterization of breast carcinomas in patients who receive preoperative chemotherapy. Because proliferative activity of breast carcinoma has been shown to be of prognostic significance, the authors compared immunocytochemical Ki-67 growth fraction and flow cytometric S-phase fraction (SPF), both evaluated on FNA samples. Methods . The proliferative activity of 134 FNA samples from primary breast carcinoma patients was studied using both immunocytochemistry with the monoclonal antibody Ki-67 and SPF determined by DNA flow cytometry. Results . Ki-67 and SPF were evaluable in 114 and 107 cases, respectively, and both were evaluable in 95 cases. Of the 134 FNA samples studied, 37% were diploid and 63% were aneuploid. The distribution of both Ki-67 and SPF was different in diploid and aneuploid tumors. The median Ki-67 value as well as the median SPF were significantly higher in aneuploid versus diploid tumors (p < 0.001). Median Ki-67 and SPF values were used to discriminate between low versus high proliferating tumors. The overall concordance between Ki-67 and SPF was 75% (p < 0.001). A good correlation was found between Ki-67 and SPF (correlation coefficient = 0.72; p < 0.001). Conclusions . The results of the current study suggest the Ki-67 growth fraction and SPF determined by FNA may be used as measurements of the proliferative activity of breast carcinoma. The authors recommend these determinations be used as preoperative procedures in patients with a cytologic diagnosis of breast carcinoma who are candidates for neoadjuvant chemotherapy and/or endocrine therapy.