Association of rumination time and health status with milk yield and composition in early-lactation dairy cows.

The objective of this study was to determine the associations of rumination time (RT) and health status with milk yield and milk composition. This study used 339 dairy cows from 4 commercial dairy farms in Ontario, Canada (first lactation, n = 107; second lactation, n = 112; ≥third lactation, n = 120). Rumination time was monitored (24 h/d) using an automated system from 1 to 28 d in milk (DIM). Cows were milked 3×/d on each farm, and 2 farms recorded milk weights at each milking to determine daily milk yield (n = 170). Cows were also monitored for milk composition (fat and protein content) 1×/wk. Last, subclinical ketosis (SCK) was diagnosed 1×/wk; cows with at least one blood sample with ß-hydroxybutyrate ≥1.2 mmol/L postcalving were diagnosed with SCK. Cases of retained placenta, metritis, milk fever, or mastitis during the study period were also recorded. Cows were categorized into 1 of 4 groups: healthy cows that had no SCK or any other health issue (HLT; n = 139); cows that were treated for at least one health issue other than SCK (HLT+; n = 50); SCK cows with no other health problems during transition (HYK; n = 97); or cows that had SCK and one or more other health problems (HYK+; n = 53). All data were summarized by week across cows, and the associations between rumination time and milk yield (n = 170) and milk composition (n = 339) were modeled. Across all lactations, and including all health categories, milk yield increased by week, whereas fat and protein content both decreased by week. A positive association was found between summarized RT and milk yield in first-lactation (+0.006 ± 0.003 kg/min of RT) and second-lactation (+0.015 ± 0.004 kg/min of RT) cows from 4 to 28 DIM, as well as in ≥third-lactation cows; however, the relationship between RT and milk yield differed across weeks in those cows. A negative association between RT and milk fat content was found in ≥third-lactation cows (-0.002 ± 0.00059 percentage points/min of RT). From 4 to 28 DIM, ≥third-lactation HYK and HYK+ cows produced less protein (0.11 ± 0.051 and 0.13 ± 0.056 percentage points, respectively) than HLT cows. Over the 4-wk observation period, first-lactation HYK+ cows tended to deposit 0.11 ± 0.056 percentage points less protein in their milk compared with HLT cows. Second-lactation HYK+ cows produced less milk than HLT cows each week during early lactation. In summary, RT was positively associated with milk yield in early-lactation dairy cows, across all lactations, and negatively associated with milk fat content in ≥third-lactation cows. Further, the results showed that early-lactation cows that experience SCK, particularly with one or more other health problems, might have decreased milk yield and milk protein content.

Association of rumination time with subclinical ketosis in transition dairy cows.

The objective of this study was to characterize the relationship between rumination and subclinical ketosis (SCK) in transition dairy cows. A study was conducted on 4 commercial dairy farms in eastern Ontario, Canada. A total of 339 Holstein dairy cows (107 primiparous and 232 multiparous) were monitored for rumination activity and SCK from 14 d before calving until 28 d after calving. Rumination was recorded daily using an automated monitoring system. A blood sample was taken from the coccygeal vein of each cow for measurement of ß-hydroxybutyrate (BHB) once weekly throughout the 6-wk observation period. Cows with BHB ≥1.2mmol/L in any of the 4 postpartum samples were considered to have SCK. Cases of retained placenta, metritis, milk fever, or mastitis during the study period were also recorded. Cows were categorized into 1 of 4 groups: healthy cows (HLT) that had no SCK or any other recorded health problem (n=139); cows treated for at least one health issue other than SCK (HLT+; n=50); cows with SCK (hyperketonemia; HYK) with no other health problems during transition (n=97); or cows (HYK+) that had SCK and one or more other health problems (n=53). Daily rumination time was summarized by week and comparisons were made between HLT and HYK and HYK+. From 2 wk before calving (wk -2) to 4 wk after calving (wk +4), there was no difference in rumination time (409±9.8min/d) among HLT, HYK, and HYK+ cows in their first lactation. Multiparous cows in HLT spent an average of 459±11.3min/d ruminating from wk -2 to wk +4. Multiparous HYK cows ruminated 25±12.8min/d less than HLT cows, whereas HYK+ cows ruminated 44±15.6min/d less than HLT cows. The largest differences in rumination time between HLT and HYK+ cows were seen during wk -1, +1, and +2, when HYK+ cows ruminated 48±17.2, 73±16.0, and 65±19.4min/d less than HLT cows, respectively. In multiparous cows, increased odds of HYK were associated with greater milk yield in the previous lactation, greater loss of body condition over the transition period, greater stall stocking density in wk -1, and reduced rumination time in wk -1. Increased odds of HYK+ were associated with higher parity, longer dry period, greater stall stocking density in wk -1, and reduced rumination time in wk +1. These results suggest that rumination monitoring across the transition period might contribute to identification of SCK and other health problems in multiparous cows.

Short communication: Association of lying behavior and subclinical ketosis in transition dairy cows.

The objective of this study was to characterize the association of lying behavior and subclinical ketosis (SCK) in transition dairy cows. A total of 339 dairy cows (107 primiparous and 232 multiparous) on 4 commercial dairy farms were monitored for lying behavior and SCK from 14d before calving until 28 d after calving. Lying time, frequency of lying bouts, and average lying bout length were measured using automated data loggers 24h/d. Cows were tested for SCK 1×/wk by taking a blood sample and analyzing for ß-hydroxybutyrate; cows with ß-hydroxybutyrate ≥1.2mmol/L postpartum were considered to have SCK. Cases of retained placenta, metritis, milk fever, or mastitis during the study period were recorded and cows were categorized into 1 of 4 groups: healthy (HLT) cows had no SCK or any other health problem (n=139); cows treated for at least 1 health issue other than SCK (n=50); SCK (HYK) cows with no other health problems during transition (n=97); or subclinically ketotic plus (HYK+) cows that had SCK and 1 or more other health problems (n=53). Daily lying time was summarized by week and comparisons were made between HLT, HYK, and HYK+, respectively. We found no difference among health categories in lying time, bout frequency, or bout length fromwk -2 towk +4 relative to calving for first-lactation cows. Differences in lying time for multiparous cows were seen inwk +1, when HYK+ cows spent 92±24.0 min/d more time lying down than HLT cows, and duringwk +3 and +4 when HYK cows spent 44±16.7 and 41±18.9 min/d, respectively, more time lying down than HLT cows. Increased odds of HYK+ were found to be associated with higher parity, longer dry period, and greater stall stocking density inwk -1 and longer lying time duringwk +1. When comparing HYK to HLT cows, the same variables were associated with odds of SCK; however, lying time was not retained in the final model. These results suggest that monitoring lying time may contribute to identifying multiparous cows experiencing SCK with another health problem after calving, but may not be useful in the early detection of SCK.

Inter-observer agreement for diagnostic classification of esophageal motility disorders defined in high-resolution manometry.

High-resolution esophageal manometry (HRM) is a recent development used in the evaluation of esophageal function. Our aim was to assess the inter-observer agreement for diagnosis of esophageal motility disorders using this technology. Practitioners registered on the HRM Working Group website were invited to review and classify (i) 147 individual water swallows and (ii) 40 diagnostic studies comprising 10 swallows using a drop-down menu that followed the Chicago Classification system. Data were presented using a standardized format with pressure contours without a summary of HRM metrics. The sequence of swallows was fixed for each user but randomized between users to avoid sequence bias. Participants were blinded to other entries. (i) Individual swallows were assessed by 18 practitioners (13 institutions). Consensus agreement (≤ 2/18 dissenters) was present for most cases of normal peristalsis and achalasia but not for cases of peristaltic dysmotility. (ii) Diagnostic studies were assessed by 36 practitioners (28 institutions). Overall inter-observer agreement was 'moderate' (kappa 0.51) being 'substantial' (kappa > 0.7) for achalasia type I/II and no lower than 'fair-moderate' (kappa >0.34) for any diagnosis. Overall agreement was somewhat higher among those that had performed >400 studies (n = 9; kappa 0.55) and 'substantial' among experts involved in development of the Chicago Classification system (n = 4; kappa 0.66). This prospective, randomized, and blinded study reports an acceptable level of inter-observer agreement for HRM diagnoses across the full spectrum of esophageal motility disorders for a large group of clinicians working in a range of medical institutions. Suboptimal agreement for diagnosis of peristaltic motility disorders highlights contribution of objective HRM metrics.

Acceptability of anal cancer screening tests for women living with HIV in the EVVA study.

Background: Anal cancer is potentially preventable through screening. For screening to be implemented, the screening procedures must be acceptable to the affected population. The objective of the present study was to measure the acceptability of currently available anal cancer screening tests in a population of women living with hiv who had experienced the tests. Methods: The evva study ("Evaluation of Human Immunodeficiency Virus, Human Papillomavirus, and Anal Intraepithelial Neoplasia in Women") is a prospective cohort study of adult women living with hiv in Montreal, Quebec. Participants were screened with cervical or anal hpv testing and cervical or anal cytology every 6 months for 2 years. High-resolution anoscopy (hra) and digital anal rectal examination (dare) were also performed systematically, with biopsies, at baseline and at 2 years. An acceptability questionnaire was administered at the final visit or at study withdrawal. Results: Of 124 women who completed the acceptability questionnaire, most considered screening "an absolute necessity" in routine care for all women living with hiv [77%; 95% confidence interval (ci): 69% to 84%]. Yearly anal cytology or anal hpv testing was considered very acceptable by 81% (95% ci: 73% to 88%); hra every 2 years was considered very acceptable by 84% (95% ci: 77% to 90%); and yearly dare was considered very acceptable by 87% (95% ci: 79% to 92%). Acceptability increased to more than 95% with a longer proposed time interval. Pain was the main reason for lower acceptability. Conclusions: Most participating women considered anal cancer screening necessary and very acceptable. Longer screening intervals and adequate pain management could further increase the acceptability of repeated screening.

A comparison of the pharmacological properties of guinea-pig and human recombinant 5-HT4 receptors.

BACKGROUND AND PURPOSE: 5-HT(4) receptor agonists are used therapeutically to treat disorders of reduced gastrointestinal motility. Since such compounds are evaluated in guinea-pigs, we cloned, expressed and pharmacologically characterized the guinea-pig 5-HT(4) and human 5-HT(4(b)) splice variant, which share 95% homology. The functional properties of guinea-pig 5-HT(4(b)) receptors were compared with native receptors in guinea-pig colon. EXPERIMENTAL APPROACH: Membrane radioligand binding and whole cell cAMP accumulation assays were used to determine the affinities, potencies and intrinsic activities (IA). Contraction of the guinea-pig distal colon longitudinal muscle myenteric plexus preparation (LMMP) was monitored to evaluate functional activity. KEY RESULTS: pK(i) values for guinea-pig and human recombinant receptors, and guinea-pig striatum 5-HT(4) receptors, were in agreement, as were the potency and IA values for guinea-pig and human 5-HT(4) receptors expressed at a similar density ( approximately 0.2 pmol mg(-1) protein). Tegaserod was a potent (pEC(50)=8.4 and 8.7, respectively), full agonist at both guinea-pig and human 5-HT(4) receptors. In contrast, in the LMMP preparation, tegaserod was a potent, partial agonist (pEC(50)=8.2; IA=66%). CONCLUSIONS AND IMPLICATIONS: Close agreement between the pharmacological properties of guinea-pig and human 5-HT(4) receptors support the use of guinea-pig model systems for the identification of 5-HT(4) receptor therapeutics. However, the mechanisms underlying the different agonist properties of tegaserod in recombinant and isolated tissue preparations, and the extent to which these impact the clinical efficacy of tegaserod as a prokinetic agent, remain to be determined.

Reversion analysis of mutations induced by 5-bromodeoxyuridine mutagenesis in mammalian cells.

Two protocols have been developed, both of which utilize the thymidine analog 5-bromodeoxyuridine (BrdUrd) to induce mutations in mammalian cells in culture (E. R. Kaufman and R. L. Davidson, Proc. Natl. Acad. Sci. USA 75:4982-4986, 1978; E. R. Kaufman, Mol. Cell. Biol. 4:2449-2454, 1984). The first protocol, termed incorporational (INC) mutagenesis, utilizes high concentrations of BrdUrd in the culture medium to generate a high intracellular ratio of BrdUTP/dCTP. The second protocol, termed replicational (REP) mutagenesis, entails the incorporation of BrdUrd into DNA under nonmutagenic conditions, the removal of all BrdUrd from the culture medium, and the subsequent replication of the bromouracil-containing DNA in the presence of high intracellular levels of dTTP and dGTP. Genetic studies using reversion analysis at the hypoxanthine-guanine phosphoribosyltransferase locus were used to determine whether the mechanisms of these two BrdUrd mutagenesis protocols had enough specificity to be distinguishable by their ability to revert various mutants. The results of these studies indicated that (i) mutants induced by INC mutagenesis were induced to revert only by REP mutagenesis and not by INC mutagenesis, (ii) mutants induced by REP mutagenesis were more efficiently reverted by INC mutagenesis than by REP mutagenesis, and (iii) both spontaneous mutants and mutants induced by the chemical mutagen ethyl methanesulfonate showed a high degree of specificity when tested for reversion by the BrdUrd mutagenesis protocols.

Replication of DNA containing 5-bromouracil can be mutagenic in Syrian hamster cells.

A new protocol for inducing mutations in mammalian cells in culture by exposure to the thymidine analog 5-bromodeoxyuridine (BrdUrd) was established. This protocol, called "DNA-dependent" mutagenesis, involved the incorporation of BrdUrd into DNA under nonmutagenic conditions and the subsequent replication of the 5-bromouracil (BrUra)-containing DNA under mutagenic conditions but with no BrdUrd present in the culture medium. The mutagenic conditions were induced by allowing BrUra-containing DNA to replicate in the presence of high concentrations of thymidine. This generated high intracellular levels of dTTP and dGTP, causing nucleotide pool imbalance. The mutagenesis induced by this protocol was found to correlate with the level of BrUra substituted for thymine in DNA.

The in vitro pharmacology of the peripherally restricted opioid receptor antagonists, alvimopan, ADL 08-0011 and methylnaltrexone.

This study characterized the pharmacology of the peripherally restricted opioid receptor antagonists, alvimopan, its metabolite, ADL 08-0011, and methylnaltrexone. The activities of the compounds were investigated with respect to human or guinea pig opioid receptor binding and function in recombinant cell lines and mechanical responsiveness of the guinea pig ileum. Alvimopan and ADL 08-0011 had higher binding affinity than methylnaltrexone at human mu opioid receptors (pK (i) values of 9.6, 9.6, and 8.0, respectively). The compounds had different selectivities for the mu receptor over human delta and guinea pig kappa opioid receptors. ADL 08-0011 had the highest mu receptor selectivity. With respect to their mu opioid receptor functional activity ([(35)S]GTPgammaS incorporation), methylnaltrexone had a positive intrinsic activity, consistent with partial agonism, unlike alvimopan and ADL 08-0011, which had negative intrinsic activities. Alvimopan, ADL 08-0011, and methylnaltrexone antagonized inhibitory responses mediated by the mu opioid agonist, endomorphin-1 (pA (2) values of 9.6, 9.4, and 7.6, respectively) and by U69593, a kappa opioid agonist (pA (2) values of 8.4, 7.2, and 6.7, respectively). In morphine-naive guinea pig ileum, methylnaltrexone reduced, while alvimopan and ADL 08-0011 increased, the amplitude of electrically evoked contractions and spontaneous mechanical activity. In tissue from morphine-dependent animals, alvimopan and ADL 08-0011 increased spontaneous activity to a greater degree than methylnaltrexone. The data suggested that alvimopan-induced contractions resulted predominantly from an interaction with kappa opioid receptors. It is concluded that alvimopan, ADL 08-0011, and methylnaltrexone differ in their in vitro pharmacological properties, particularly with respect to opioid receptor subtype selectivity and intrinsic activity. The clinical significance of the data from this study remains to be determined.

Resistance to 5-fluorouracil associated with increased cytidine triphosphate levels in V79 Chinese hamster cells.

Clones stably resistant to the toxic effects of 5-fluorouracil have been isolated from V79.5 Chinese hamster fibroblast cells by a single-step selection procedure. The 5-fluorouracil-resistant lines were found to (a) have an auxotrophic requirement when grown in dialyzed fetal calf serum that was satisfied by the addition of either thymidine, deoxyuridine, or deoxycytidine to the medium, (b) be cross-resistant to the toxic effects of 1-beta-D-arabinofuranosylcytosine and to high concentrations of thymidine, (c) have increased intracellular levels of cytidine 5'-triphosphate (CTP) and deoxycytidine 5'-triphosphate and decreased levels of uridine 5'-triphosphate, (d) also be resistant to 5-fluorouridine but not to 5-fluorodeoxyuridine, and (e) incorporate less 5-fluorouracil into RNA than do the wild-type cells. The primary lesion in these mutant appears to be an altered CTP synthetase activity which is no longer sensitive to negative regulation by CTP. The resulting increased CTP levels appear to be responsible for the various phenotypic characteristics of these mutants, including the resistance to 5-fluorouracil.

Effect of bivalent interaction upon apparent antibody affinity: experimental confirmation of theory using fluorescence photobleaching and implications for antibody binding assays.

The affinity of a monoclonal antibody for its tumor-associated antigen is one of several parameters governing in vivo monoclonal antibody distribution. However, there is a lack of apparent correlation between the affinity of a bivalent monoclonal antibody measured using equilibrium binding experiments and its in vivo delivery. Furthermore, differences in the reported affinity for identical antibody/antigen pairs are quite common in the literature. In this paper, both of these discrepancies are addressed in terms of variation in avidity due to bivalent interaction. The enhancement of avidity afforded by bivalent attachment is addressed theoretically by extending the model of Crothers and Metzger (Immunochemistry, 9: 341-357, 1972). Theoretical assessment of Lineweaver-Burk, Scatchard, Steward-Petty, Langmuir, fluorescence recovery after photobleaching, and Sips models demonstrates quantitatively that the measured affinity using equilibrium binding experiments may vary over four orders of magnitude with similar variation in experimental cellular antigen density. Further, the measured affinity is a function of the experimental protocol. Predictions of avidity enhancement were confirmed experimentally using fluorescence recovery after photobleaching. These experiments measured the equilibrium binding constant and concentration of binding sites for an immunoglobulin G monoclonal antibody and its F(ab) fragment directed against the rabbit VX2 carcinoma cell line. Bivalent binding data agree quantitatively with those predicted by the bivalent model with no adjustable parameters. It is concluded that bivalent equilibrium binding constants are useful only in antibody screening, where experimental conditions are identical for all series. They must be used with caution in predicting in vivo antibody distribution, and it is recommended that the intrinsic, monovalent affinity be measured in tandem with any bivalent antibody study as a standard reference.

Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer.

PURPOSE: Most breast cancer survivors experience hot flashes; many use complementary or alternative remedies for these symptoms. We undertook a randomized clinical trial of black cohosh, a widely used herbal remedy for menopausal symptoms, among breast cancer patients. PATIENTS AND METHODS: Patients diagnosed with breast cancer who had completed their primary treatment were randomly assigned to black cohosh or placebo, stratified on tamoxifen use. At enrollment, patients completed a questionnaire about demographic factors and menopausal symptoms. Before starting to take the pills and at 30 and 60 days, they completed a 4-day hot flash diary. At the final visit, they completed another menopausal symptom questionnaire. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were measured in a subset of patients at the first and final visits. RESULTS: Of 85 patients (59 on tamoxifen, 26 not on tamoxifen) enrolled in the study, 42 were assigned to treatment and 43 were assigned to placebo; 69 completed all three hot flash diaries. Both treatment and placebo groups reported declines in number and intensity of hot flashes; the differences between the groups were not statistically significant. Both groups also reported improvements in menopausal symptoms that were, for the most part, not significantly different. Changes in blood levels of FSH and LH also did not differ in the two groups. CONCLUSION: Black cohosh was not significantly more efficacious than placebo against most menopausal symptoms, including number and intensity of hot flashes. Our study illustrates the feasibility and value of standard clinical trial methodology in assessing the efficacy and safety of herbal agents.

A comparison of T-wave alternans, signal averaged electrocardiography and programmed ventricular stimulation for arrhythmia risk stratification.

OBJECTIVES: The goal of this study was to compare T-wave alternans (TWA), signal-averaged electrocardiography (SAECG) and programmed ventricular stimulation (EPS) for arrhythmia risk stratification in patients undergoing electrophysiology study. BACKGROUND: Accurate identification of patients at increased risk for sustained ventricular arrhythmias is critical to prevent sudden cardiac death. T-wave alternans is a heart rate dependent measure of repolarization that correlates with arrhythmia vulnerability in animal and human studies. Signal-averaged electrocardiography and EPS are more established tests used for risk stratification. METHODS: This was a prospective, multicenter trial of 313 patients in sinus rhythm who were undergoing electrophysiologic study. T-wave alternans, assessed with bicycle ergometry, and SAECG were measured before EPS. The primary end point was sudden cardiac death, sustained ventricular tachycardia, ventricular fibrillation or appropriate implantable defibrillator (ICD) therapy, and the secondary end point was any of these arrhythmias or all-cause mortality. RESULTS: Kaplan-Meier survival analysis of the primary end point showed that TWA predicted events with a relative risk of 10.9, EPS had a relative risk of 7.1 and SAECG had a relative risk of 4.5. The relative risks for the secondary end point were 13.9, 4.7 and 3.3, respectively (p < 0.05). Multivariate analysis of 11 clinical parameters identified only TWA and EPS as independent predictors of events. In the prespecified subgroup with known or suspected ventricular arrhythmias, TWA predicted primary end points with a relative risk of 6.1 and secondary end points with a relative risk of 8.0. CONCLUSIONS: T-wave alternans is a strong independent predictor of spontaneous ventricular arrhythmias or death. It performed as well as programmed stimulation and better than SAECG in risk stratifying patients for life-threatening arrhythmias.

Reduction of paclitaxel-induced peripheral neuropathy with glutamine.

PURPOSE: Dose-limiting toxicity of many newer chemotherapeutic agents is peripheral neuropathy. Prior attempts to reduce this side effect have been unsuccessful. We report on the possible successful reduction of peripheral neuropathy with glutamine administration after high-dose paclitaxel. EXPERIMENTAL DESIGN: Patients entered a high-dose chemotherapy protocol in which the first high-dose cycle was paclitaxel at 825 mg/m(2) given over 24 h. The first cohort of patients did not receive glutamine, and the second cohort of patients received glutamine at 10 g orally three times a day for 4 days starting 24 h after completion of paclitaxel. Neurological assessment was performed at baseline, and at least 2 weeks after paclitaxel, and consisted of a complete neurological exam and nerve conduction studies. RESULTS: There were paired pre- and post-paclitaxel evaluations on 33 patients who did not receive glutamine and 12 patients who did. The median interval between pre- and post-exams was 32 days. For patients who received glutamine, there was a statistically significant reduction in the severity of peripheral neuropathy as measured by development of moderate to severe dysesthesias and numbness in the fingers and toes (P < 0.05). The degree and incidence of motor weakness was reduced (56 versus 25%; P = 0.04) as well as deterioration in gait (85 versus 45%; P = 0.016) and interference with activities of daily living (85 versus 27%; P = 0.001). Moderate to severe paresthesias in the fingers and toes were also reduced (55 versus 42% and 64 versus 50%, respectively), although this value was not statistically significant. All of these toxicities were reversible over time. CONCLUSIONS: Glutamine may reduce the severity of peripheral neuropathy associated with high-dose paclitaxel; however, results from randomized, placebo-controlled clinical trials will be needed to fully assess its impact, if any. Trials are currently ongoing to assess its efficacy for standard-dose paclitaxel in breast cancer and other tumors for which peripheral neuropathy is the dose-limiting toxicity.

Phase I trial of sequential high-dose chemotherapy with escalating dose paclitaxel, melphalan, and cyclophosphamide, thiotepa, and carboplatin with peripheral blood progenitor support in women with responding metastatic breast cancer.

A single high-dose cycle of chemotherapy with stem cell support can produce disease-free survival of 15-20% for at least 3 years in women with responding stage IV breast cancer. North American Autologous Bone Marrow Transplant Registry data suggest that a complete response (CR) is the single most important prognostic factor associated with prolonged disease-free survival. Therefore, if sequential high-dose chemotherapy can increase the CR rate, then perhaps an increased proportion of patients will remain disease free. Women with at least a partial response (PR) to induction chemotherapy received three separate high-dose cycles of chemotherapy with peripheral blood progenitor support and granulocyte colony-stimulating factor. The first intensification was a dose escalation of paclitaxel (400-825 mg/ m2), the second intensification was melphalan (180 mg/m2), and the third intensification consisted of 6000 mg/m2 cyclophosphamide (1500 mg/m2/day), 500 mg/m2 thiotepa (125 mg/m2/day), and 800 mg/m2 carboplatin (200 mg/m2/day; CTCb). Thirty-six women were enrolled and 31 completed all three cycles. After the paclitaxel infusion most patients developed reversible predominantly sensory neuropathy. Of the 19 patients with measurable disease, 6 converted to CR, 7 converted to a PR* (the complete resolution of all soft tissue or visceral disease with sclerosis of prior lytic bone lesions), and 2 had a further PR for an overall response rate of 79%. Two patients had no further response and disease in two patients progressed, and thus they were taken off the study before CTCb. Seventy-eight percent are progression-free at a median follow-up of 14 months (range, 3-24+). Three sequential cycles of high-dose chemotherapy are feasible and were administered in this study with no mortality. Single agent paclitaxel at doses up to 825 mg/m2 were well tolerated with moderate reversible toxicity.

Receptor depletion in diabetes mellitus: correction with therapy.

This report describes two patients with diabetes mellitus, presenting with insulin resistance and depression of erythrocyte insulin receptor binding to less than one-third of normal. Scatchard analysis of the data was consistent with a depletion in insulin receptors in these poorly controlled diabetic patients. Therapy with tolbutamide and reduced insulin administration resulted in restoration of erythrocyte receptor binding, clinical resolution of the insulin resistance, and amelioration of hyperglycemia. These data suggest a role for transient depletion and/or dysfunction of cellular receptors of insulin activity in the evolution of insulin resistance in diabetes.

Coiled-coil domain containing 68 (CCDC68) demonstrates a tumor-suppressive role in pancreatic ductal adenocarcinoma.

Using integrative genomics and functional screening, we identified coiled-coil domain containing 68 (CCDC68) as a novel putative tumor suppressor gene (TSG) in pancreatic ductal adenocarcinoma (PDAC). CCDC68 allelic losses were documented in 48% of primary PDAC patient tumors, 50% of PDAC cell lines and 30% of primary patient derived xenografts. We also discovered a single nucleotide polymorphism (SNP) variant (SNP rs1344011) that leads to exon skipping and generation of an unstable protein isoform CCDC68Δ(69-114) in 31% of PDAC patients. Overexpression of full length CCDC68 (CCDC68(wt)) in PANC-1 and Hs.766T PDAC cell lines lacking CDCC68 expression decreased proliferation and tumorigenicity in scid mice. In contrast, the downregulation of endogenous CCDC68 in MIAPaca-2 cells increased tumor growth rate. These effects were not observed with the deletion-containing isoform, CCDC68Δ(69-114).

The right to treatment suit as an agent of change.

Right to treatment suits can serve as agents of change in the standards and function of psychiatric institutions. The author evaluated five state psychiatric institutions as an expert witness in right to treatment suits. He found that changes for the better were made in most of these institutions as a result of the suit, whether it was settled or unsettled. Although he enumerates the problems caused by such suits, he concludes that they can be a positive force for improving mental health care.

The violation of psychiatric standards of care in prisons.

The author evaluated psychiatric care in three U.S. prison systems. Major problems included limitations imposed by prison architecture, inadequate staff, medication prescription and distribution by unlicensed, untrained personnel, and a punitive rather than therapeutic attitude. Following the standards of care recommended by American Correctional Association would correct most of these problems. Psychiatrists should guard against prescribing unnecessary medications, particularly minor tranquilizers and sedatives, and should be concerned with prison conditions conductive to mental illness, particularly overcrowding, abuses of solitary confinement, and inadequate programs for inmates who are mentally disturbed but not overtly psychotic. The author recommends minimum staffing standards and suggests considering the transfer of mentally ill inmates to appropriate psychiatric hospitals outside the prison system.

The current status of psychiatric education in alcoholism and drug abuse.

The authors conducted a survey of psychiatric education in alcoholism and drug abuse in the United States. Ninety-seven percent of 106 undergraduate training programs and 91% of 169 residency programs offered curriculum units in this field. Most of these programs also provided supervised clinical care. Areas of reported faculty dissatisfaction included problems with attitude and interest of psychiatric faculty and with the amount of curriculum time allotted. The authors conclude that although the amount of curriculum time devoted to training in alcoholism and drug abuse is growing, further investment in developing faculty and fellowships is warranted to increase the quality of teaching commitment.