Assessment of low-dose cisplatin as a model of nausea and emesis in beagle dogs, potential for repeated administration

Cisplatin is a highly emetogenic cancer chemotherapy agent, which is often used to induce nausea and emesis in animal models. The cytotoxic properties of cisplatin also cause adverse events that negatively impact on animal welfare preventing repeated administration of cisplatin. In this study, we assessed whether a low (subclinical) dose of cisplatin could be utilized as a model of nausea and emesis in the dog while decreasing the severity of adverse events to allow repeated administration. The emetic, nausea-like behavior and potential biomarker response to both the clinical dose (70 mg/m2) and low dose (15 mg/m2) of cisplatin was assessed. Plasma creatinine concentrations and granulocyte counts were used to assess adverse effects on the kidneys and bone marrow, respectively. Nausea-like behavior and emesis was induced by both doses of cisplatin, but the latency to onset was greater in the low-dose group. No significant change in plasma creatinine was detected for either dose groups. Granulocytes were significantly reduced compared with baseline (P = 0.000) following the clinical, but not the low-dose cisplatin group. Tolerability of repeated administration was assessed with 4 administrations of an 18 mg/m2 dose cisplatin. Plasma creatinine did not change significantly. Cumulative effects on the granulocytes occurred, they were significantly decreased (P = 0.03) from baseline at 3 weeks following cisplatin for the 4th administration only. Our results suggest that subclinical doses (15 and 18 mg/m2) of cisplatin induce nausea-like behavior and emesis but have reduced adverse effects compared with the clinical dose allowing for repeated administration in crossover studies

Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma

Daratumumab, a human CD38 immunoglobulin G1 kappa (IgG1κ) monoclonal antibody, has activity as monotherapy in multiple myeloma (MM). This phase 1/2 study investigated daratumumab plus lenalidomide/dexamethasone in refractory and relapsed/refractory MM. Part 1 (dose escalation) evaluated 4 daratumumab doses plus lenalidomide (25 mg/day orally on days 1-21 of each cycle) and dexamethasone (40 mg/week). Part 2 (dose expansion) evaluated daratumumab at the recommended phase 2 dose (RP2D) plus lenalidomide/dexamethasone. Safety, efficacy, pharmacokinetics, immunogenicity, and accelerated daratumumab infusions were studied. In part 1 (13 patients), no dose-limiting toxicities were observed, and 16 mg/kg was selected as the R2PD. In part 2 (32 patients), median time since diagnosis was 3.2 years, with a median of 2 prior therapies (range, 1-3 prior therapies), including proteasome inhibitors (91%), alkylating agents (91%), autologous stem cell transplantation (78%), thalidomide (44%), and lenalidomide (34%); 22% of patients were refractory to the last line of therapy. Grade 3 to 4 adverse events (≥5%) included neutropenia, thrombocytopenia, and anemia. In part 2, infusion-related reactions (IRRs) occurred in 18 patients (56%); most were grade ≤2 (grade 3, 6.3%). IRRs predominantly occurred during first infusions and were more common during accelerated infusions. In part 2 (median follow-up of 15.6 months), overall response rate was 81%, with 8 stringent complete responses (25%), 3 complete responses (9%), and 9 very good partial responses (28%). Eighteen-month progression-free and overall survival rates were 72% (95% confidence interval, 51.7-85.0) and 90% (95% confidence interval, 73.1-96.8), respectively. Daratumumab plus lenalidomide/dexamethasone resulted in rapid, deep, durable responses. The combination was well tolerated and consistent with the safety profiles observed with lenalidomide/dexamethasone or daratumumab monotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01615029

Work-related upper extremity disorders: one-year follow-up in an occupational diseases registry

To study the course and consequences of work-related upper extremity disorders in the registry of the Netherlands Centre for Occupational Diseases (NCvB). A follow-up study was performed in a sample of consecutive cases of work-related upper extremity disorders notified to the NCvB. Perceived severity was measured with VAS (0-100), quality of life with VAS (0-100) and SF-36, functional impairment with DASH and sickness absence with a questionnaire. Measurements took place directly after notification (T0) and after 3, 6 and 12 months (T1-T3). A linear mixed model was used to compare scores over time. Average age of the 48 consecutive patients (89% response) was 42 years; 48% were men. Perceived severity, functional impairment and sickness absence decreased statistically significant during the follow-up period, and quality of life scores improved. Patients older than 45 years scored worse on perceived severity of the disease, functional impairment and quality of life than did younger patients. The role of registries of occupational diseases for preventive policy can be extended by creating longitudinal data in sample projects. In the sample from our registry, work-related upper extremity disorders had a favourable cours

Unified framework for generalized and transverse-momentum dependent parton distributions within a 3Q light-cone picture of the nucleon

We present a systematic study of generalized transverse-momentum dependent parton distributions (GTMDs). By taking specific limits or projections, these GTMDs yield various transverse-momentum dependent and generalized parton distributions, thus providing a unified framework to simultaneously model different observables. We present such simultaneous modeling by considering a light-cone wave function overlap representation of the GTMDs. We construct the different quark-quark correlation functions from the 3-quark Fock components within both the light-front constituent quark model as well as within the chiral quark-soliton model. We provide a comparison with available data and make predictions for different observables.Comment: version to appear in JHE

Surgical Simulator Design and Development

With the introduction of minimally invasive surgery (MIS), it became necessary to develop training methods to learn skills outside the operating room. Several training simulators have become commercially available, but fundamental research into the requirements for effective and efficient training in MIS is still lacking. Three aspects of developing a training program are investigated here: what should be trained, how it should be trained, and how to assess the results of training. In addition, studies are presented that have investigated the role of force feedback in surgical simulators. Training should be adapted to the level of behavior: skill-based, rule-based, or knowledge-based. These levels can be used to design and structure a training program. Extra motivation for training can be created by assessment. During MIS, force feedback is reduced owing to friction in the laparoscopic instruments and within the trocar. The friction characteristics vary largely among instruments and trocars. When force feedback is incorporated into training, it should include the large variation in force feedback properties as well. Training different levels of behavior requires different training methods. Although force feedback is reduced during MIS, it is needed for tissue manipulation, and therefore force application should be trained as well

The Spin Structure of the Nucleon

We present an overview of recent experimental and theoretical advances in our understanding of the spin structure of protons and neutrons.Comment: 84 pages, 29 figure

The effectiveness of surgical correction of uterine prolapse: cervical amputation with uterosacral ligament plication (modified Manchester) versus vaginal hysterectomy with high uterosacral ligament plication

Item does not contain fulltextINTRODUCTION AND HYPOTHESIS: The objective of this study is to evaluate cervical amputation with uterosacral ligament plication (modified Manchester) and compare it to vaginal hysterectomy with high uterosacral ligament plication procedure with special regard to the middle compartment. METHODS: Consecutive women with pelvic organ prolapse who underwent either vaginal hysterectomy or a modified Manchester procedure were included. Assessments were made preoperatively and at 1-year follow-up, including physical examination with pelvic organ prolapse quantification standardised questionnaires (incontinence impact questionnaire, urogenital distress inventory, and defaecatory distress inventory). RESULTS: Between 2002 and 2007, 156 patients were included. Ninety-eight patients returned for a 1-year follow-up. In the modified Manchester group, we found no middle compartment recurrence versus two (4%) in the vaginal hysterectomy group. Anterior and posterior compartment prolapse recurrences (stage >or=2) were similar (approximately 50%). Considering operating time and blood loss, modified Manchester was more favourable. There was no difference in the pre- and postoperative subjective scores. The overall functional outcome was acceptable. CONCLUSIONS: We found an excellent performance of both procedures regarding middle compartment recurrences

Bone pain and extremely low bone mineral density due to severe vitamin D deficiency in celiac disease

Case report A 29-year-old wheelchair-bound woman was presented to us by the gastroenterologist with suspected osteomalacia. She had lived in the Netherlands all her life and was born of Moroccan parents. Her medical history revealed iron deficiency, growth retardation, and celiac disease, for which she was put on a gluten-free diet. She had progressive bone pain since 2 years, difficulty with walking, and about 15 kg weight loss. She had a short stature, scoliosis, and pronounced kyphosis of the spine and poor condition of her teeth. Laboratory results showed hypocalcemia, an immeasurable serum25-hydroxyvitamin D level, and elevated parathyroid hormone and alkaline phosphatase levels. Spinal radiographs showed unsharp, low contrast vertebrae. Bone mineral density measurement at the lumbar spine and hip showed a T-score of -6.0 and -6.5, respectively. A bone scintigraphy showed multiple hotspots in ribs, sternum, mandible, and long bones. A duodenal biopsy revealed villous atrophy (Marsh 3C) and positive antibodies against endomysium, transglutaminase, and gliadin, compatible with active celiac disease. A bone biopsy showed severe osteomalacia but normal bone volume. She was treated with calcium intravenously and later orally. Furthermore, she was treated with high oral doses of vitamin D and a gluten-free diet. After a few weeks of treatment, her bone pain decreased, and her muscle strength improved. Discussion In this article, the pathophysiology and occurrence of osteomalacia as a complication of celiac disease are discussed. Low bone mineral density can point to osteomalacia as well as osteoporosis. © International Osteoporosis Foundation and National Osteoporosis Foundation 2011

Pre-operative chemotherapy in early stage resectable non-small-cell lung cancer: a randomized feasibility study justifying a multicentre phase III trial

Surgical resection offers the best chance for cure for early stage non-small-cell lung cancer (NSCLC, stage I, II, IIIA), but the 5-year survival rates are only moderate, with systemic relapse being the major cause of death. Pre-operative (neo-adjuvant) chemotherapy has shown promise in small trials restricted to stage IIIA patients. We believe similar trials are now appropriate in all stages of operable lung cancer. A feasibility study was performed in 22 patients with early stage (IB, II, IIIA) resectable NSCLC; randomized to either three cycles of chemotherapy [mitomycin-C 8 mg m−2, vinblastine 6 mg m−2 and cisplatin 50 mg m−2 (MVP)] followed by surgery (n = 11), or to surgery alone. Of 40 eligible patients, 22 agreed to participate (feasibility 55%) and all complied with the full treatment schedule. All symptomatic patients achieved either complete (50%) or partial (50%) relief of tumour-related symptoms with pre-operative chemotherapy. Fifty-five per cent achieved objective tumour response, and a further 27% minor tumour shrinkage; none had progressive disease. Partial pathological response was seen in 50%. No severe (WHO grade III–IV) toxicities occurred. No significant deterioration in quality of life was detected during chemotherapy. Pre-operative MVP chemotherapy is feasible in early stage NSCLC, and this study has now been initiated as a UK-wide Medical Research Council phase III trial. © 1999 Cancer Research Campaig

Institutional Mergers in Ireland

The importance of knowledge as a driver of social and economic growth and prosperity, and the increasingly competitive “global race for knowledge and talent” (Hazelkorn, Higher Educ Manage Policy 21(1):55–76, 2009) have combined to transform the higher education landscape, forcing national governments and higher education institutions (HEIs) to pursue new ways of addressing the challenges of a multi-polar world order. Rising demand for higher education (HE), as part of the broader shift from elite to mass to universal participation, has led to the emergence of new models of provision. At the same time, many governments face restrictions on public resources due to high levels of public and private debt; accordingly, system-level and institutional restructuring has been contemplated as a way to enhance quality, performance and efficiency