Sleep deprivation, sleep fragmentation, and social jet lag increase temperature preference in Drosophila.

Despite the fact that sleep deprivation substantially affects the way animals regulate their body temperature, the specific mechanisms behind this phenomenon are not well understood. In both mammals and flies, neural circuits regulating sleep and thermoregulation overlap, suggesting an interdependence that may be relevant for sleep function. To investigate this relationship further, we exposed flies to 12 h of sleep deprivation, or 48 h of sleep fragmentation and evaluated temperature preference in a thermal gradient. Flies exposed to 12 h of sleep deprivation chose warmer temperatures after sleep deprivation. Importantly, sleep fragmentation, which prevents flies from entering deeper stages of sleep, but does not activate sleep homeostatic mechanisms nor induce impairments in short-term memory also resulted in flies choosing warmer temperatures. To identify the underlying neuronal circuits, we used RNAi to knock down the receptor for Pigment dispersing factor, a peptide that influences circadian rhythms, temperature preference and sleep. Expressing UAS-PdfrRNAi in subsets of clock neurons prevented sleep fragmentation from increasing temperature preference. Finally, we evaluated temperature preference after flies had undergone a social jet lag protocol which is known to disrupt clock neurons. In this protocol, flies experience a 3 h light phase delay on Friday followed by a 3 h light advance on Sunday evening. Flies exposed to social jet lag exhibited an increase in temperature preference which persisted for several days. Our findings identify specific clock neurons that are modulated by sleep disruption to increase temperature preference. Moreover, our data indicate that temperature preference may be a more sensitive indicator of sleep disruption than learning and memory.

p5RHH nanoparticle-mediated delivery of AXL siRNA inhibits metastasis of ovarian and uterine cancer cells in mouse xenografts.

Ovarian and uterine serous cancers are extremely lethal diseases that often present at an advanced stage. The late-stage diagnosis of these patients results in the metastasis of their cancers throughout the peritoneal cavity leading to death. Improving survival for these patients will require identifying therapeutic targets, strategies to target them, and means to deliver therapies to the tumors. One therapeutic target is the protein AXL, which has been shown to be involved in metastasis in both ovarian and uterine cancer. An effective way to target AXL is to silence its expression with small interfering RNA (siRNA). We investigate the ability of the novel siRNA delivery platform, p5RHH, to deliver anti-AXL siRNA (siAXL) to tumor cells both in vitro and in vivo as well as examine the phenotypic effects of this siRNA interference. First, we present in vitro assays showing p5RHH-siAXL treatment reduces invasion and migration ability of ovarian and uterine cancer cells. Second, we show p5RHH nanoparticles target to tumor cells in vivo. Finally, we demonstrate p5RHH-siAXL treatment reduces metastasis in a uterine cancer mouse xenograft model, without causing an obvious toxicity. Collectively, these findings suggest that this novel therapy shows promise in the treatment of ovarian and uterine cancer patients.

SQ1274, a novel microtubule inhibitor, inhibits ovarian and uterine cancer cell growth.

OBJECTIVE: Paclitaxel, a microtubule inhibitor, is subject to tumor resistance while treating high-grade serous ovarian and uterine cancer. This study aims to directly compare the effects of SQ1274, a novel microtubule inhibitor that binds to the colchicine-binding site on tubulin, and paclitaxel in high-grade serous ovarian and uterine cancer cell lines both in vitro and in vivo. METHODS: We assessed the sensitivity of ovarian (OVCAR8) and uterine (ARK1) cancer cell lines to SQ1274 and paclitaxel using XTT assays. We used western blot and quantitative real-time PCR to analyze changes in AXL RNA and protein expression by SQ1274 and paclitaxel. Differences in cell-cycle arrest and apoptosis were investigated using flow cytometry. Finally, we treated ovarian and uterine xenograft models with vehicle, paclitaxel, or SQ1274. RESULTS: First, we demonstrate that SQ1274 has a much lower IC50 than paclitaxel in both ARK1 (1.26 nM vs. 15.34 nM, respectively) and OVCAR8 (1.34 nM vs. 10.29 nM, respectively) cancer cell lines. Second, we show SQ1274 decreases both RNA and protein expression of AXL. Third, we show that SQ1274 causes increased cell-cycle arrest and apoptosis compared to paclitaxel. Finally, we report that SQ1274 more effectively inhibits tumor growth in vivo compared to paclitaxel. CONCLUSIONS: SQ1274 presents as a viable alternative to paclitaxel for treating ovarian and uterine cancer. This study supports the development of SQ1274 as a chemotherapeutic to treat ovarian and uterine cancer.

Implementation and Analysis of a Lean Six Sigma Program in Microsurgery to Improve Operative Throughput in Perforator Flap Breast Reconstruction.

PURPOSE: Perforator flaps have become a preferred method of breast reconstruction but can consume considerable resources. We examined the impact of a Six Sigma program on microsurgical breast reconstruction at an academic medical center. METHODS: Using methods developed by Motorola and General Electric, we applied critical pathway planning, workflow analysis, lean manufacturing, continuous quality improvement, and defect reduction to microsurgical breast reconstruction. Primary goals were to decrease preoperative-to-cut time and total operative time, through reduced variability and improved efficiency. Secondary goals were to reduce length of stay, complications, and reoperation. The project was divided into 3 phases: (1) Pre-Six Sigma (24 months), (2) Six Sigma (10 months), (3) and Post-Six Sigma (24 months). These periods (baseline, intervention, control) were compared by Student t test and χ analysis. RESULTS: Over a 5-year period, 112 patients underwent 168 perforator flaps for breast reconstructions, by experienced microsurgeons. Total operative time decreased from 714 to 607 minutes (P < 0.01), across the study period, with the greatest drop occurring in unilateral cases, from 672 to 498 minutes (P < 0.01). Length of stay decreased from 6.3 to 5.2 days (P = 0.01). Overall complication rates (35.9% vs 30%, not significant) and take-back rates (20.5% vs 23.9%, not significant) remained similar over the 5-year period. Physician revenue/minute increased from US $6.28 to US $7.59, whereas hospital revenue/minute increased from US $21.84 to US $25.11. CONCLUSIONS: A Six Sigma program in microsurgical breast reconstruction was associated with better operational and financial outcomes. These incremental gains were maintained over the course of the study, suggesting that these benefits were due, in part, to process improvements. However, continued reductions in total operative time and length of stay, well after the intervention period, support the possibility that "learning curve" phenomenon may have contributed to the improvement in these outcomes.

Inpatient Children and Adolescent Mental Health Services (CAMHS): outcomes of young people with and without intellectual disability.

BACKGROUND: Little is known about the effectiveness of inpatient care for young people with co-morbid mental illness and intellectual disability (ID). This study aims to compare the demographics and outcome of young people with mental illness with or without ID admitted to psychiatric hospital. A secondary aim is to look into the outcome of those with ID admitted to general mental health young people's units. METHOD: Data were collected on the outcome of young people's admissions to specialist ID and general adolescent mental health units as part of a larger quality improvement project run by the College Centre for Quality Improvement. Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA) scores were completed by local clinical staff at admission and discharge on 38 young people with and 113 people without ID from 14 units. RESULTS: Young people with mental disorders significantly improved clinically over the admission whether or not they had ID. There were no differences between the groups in age or use of the Mental Health Act but people admitted with ID were more likely to be male and had longer lengths of stay. Admission to a general adolescent unit was associated with clinical improvement for people with ID. CONCLUSIONS: This study needs replication because of the small sample and incomplete data but it suggests that young people with ID and mental disorders significantly improve clinically when admitted to hospital as do their non-disabled peers.

To heal and restore broken bodies: a retrospective, descriptive study of the role and impact of pastoral care in the treatment of patients with burn injury.

INTRODUCTION: Despite advances in resuscitation, resurfacing, and reconstruction, recovery in burn patients often depends upon emotional, psychosocial, and spiritual healing. We characterized the spiritual needs of burn patients to help identify resources necessary to optimize recovery. METHODS: We performed a retrospective review of all patients admitted to a regional, accredited burn center, in 2011. We accessed multiple clinical, financial, and administrative databases, collected demographic data, including religious affiliation, and recorded the number and type of pastoral care visits. Outcome measures included length of stay (LOS), physician and facility charges, and mortality. We compared patients who had a pastoral care visit with those who did not, as well as patients with a religious affiliation with those who had no or an unknown affiliation. RESULTS: During the study period, our burn center admitted 1338 patients, 314 of whom were visited by chaplains, for a total of 1077 encounters (3.43 visits per patient seen). Most frequent interventions were prayer, social support, and spiritual counseling. Compared to patients who had no visit, patients who saw a chaplain had a larger total body surface area burn, longer LOS, higher charges, and higher mortality (10.2% vs. 0.78%, P < 0.001). Patients who had a religious affiliation had slightly lower mortality than patients with unknown or no religious affiliation (0.87% vs. 3.19%), but this did not reach statistical significance. CONCLUSIONS: In burn patients, utilization of pastoral care appears to be linked to size of burn, financial charges, and length of stay, with religious affiliation serving as a possible marker for improved survival. Plastic surgeons and burn providers should consider and address the spiritual needs of burn patients, as a component of recovery.

Magnetic resonance imaging of anal cancer.

AIM: The purpose of this study was to evaluate the magnetic resonance imaging (MRI) appearances of primary and recurrent anal carcinoma, and to demonstrate the commonest patterns of local and distant disease spread. METHODS: A retrospective review was performed of 27 cases of biopsy-proven anal carcinoma, where MRI was used for primary staging (9 patients) or suspected recurrence (18 patients). Two oncological radiologists reviewed the MR images, following a standardized approach. The size, extent and signal characteristics of the anal tumour were documented. Metastatic disease spread to lymph nodes, viscera and bone was recorded. In all, 7 patients with recurrent disease underwent surgery and subsequent histological correlation was performed. RESULTS: Primary and recurrent tumours were of high signal intensity relative to skeletal muscle on T2-weighted images (T2WI), and of low to intermediate signal intensity on T1-weighted images (T1WI). Lymph node metastases were of similar signal intensity to the anal cancer. Recurrent tumours were more locally advanced than primary tumours and extended into adjacent organs and the pelvic skeleton. Recurrent lymph node disease involved perirectal, presacral and internal iliac nodes more commonly than did primary lymph node disease. CONCLUSION: MRI can be useful in the primary staging of bulky tumours or of those with a long craniocaudal extent. MR has a role in the preoperative evaluation and surgical planning of cases of recurrent disease following radiotherapy.

Self management for chronic disease. An introduction.

BACKGROUND: Improving the quality of health care for those with chronic diseases, largely consequent to an increasingly ageing population, is the emerging challenge for health care. One approach to enhancing management of chronic disease is the expansion of patient self management. OBJECTIVE: This article discusses the importance of self care as a means of improving health outcomes for patients with chronic disease. DISCUSSION: The optimum management of persons with chronic disease is facilitated by an effective primary health care system. The Enhanced Primary Care (EPC) package initiated by the Federal Government and designed to assist people with chronic illnesses and complex care needs, recognises the importance of appropriate self management interventions. 'Sharing health care' is part of the EPC package that encompasses self management initiatives and is central to the program as an acknowledgment that the patient is responsible for managing some aspect of their illness.

Blood pressure changes during barium enema.

AIMS: To document blood pressure changes during barium enema examination and to determine at what point in the examination changes are likely to occur. METHODS AND RESULTS: Blood pressure measurements were taken at seven points during the course of barium enema examination in 107 consecutive patients. We found that patients over the age of 60 years had statistically significant decreases in blood pressure when they were stood up during the course of the examination. Many of these patients were asymptomatic. Patients who had symptoms (15/107, 14%) when standing up had a degree of hypotension. The duration of barium enema examination is longer in those patients who experience symptoms. CONCLUSION: During a barium enema examination hypotension occurs at the point of standing up more frequently in patients over 60 years and in those who suffer symptoms at this time. Patients who fall into one of these groups should be considered at risk of fainting at this point in the examination. A modified technique to avoid standing should be considered in at-risk patients. Roach, S. C.et al. (2001). Clinical Radiology56, 393-396.

In vitro study and in vivo application of a reusable double-channel sphincterotome.

BACKGROUND AND STUDY AIMS: Therapeutic endoscopic retrograde cholangiopancreatography (ERCP) has been deemed to be a "cost-prohibitive" procedure, based upon the cumulative costs of one-time-use accessories and current reimbursement plans. One-time-use sphincterotomes comprise a significant component of that cost and, accordingly, we evaluated the disability and clinical usefulness of a recently introduced reusable double-channel sphincterotome. MATERIALS AND METHODS: We studied a reusable 6-Fr sphincterotome at baseline and following contamination with 10(6) Bacillus stearothermophilus. Reprocessing included a unique 30-minute ultrasonic cleaning step in lieu of manual cleaning, followed by steam sterilization. Parameters evaluated included sphincterotome function, electrical integrity, and our ability to sterilize the devices for three in vitro trials. In vivo studies included patient demographics and outcomes, procedural findings, and success rates, and the mean number of times the sphincterotome was used, functional grading at time of use, and reasons for sphincterotome malfunction. RESULTS: Ten out of ten sphincterotomes maintained form, function, and electrical integrity in vitro, and all cultures were negative after sterilization. In the initial in vivo study, ten sphincterotomes were used in 50 patients (mean, 5 uses) with a 94% success rate. Reasons for sphincterotome failure included leak or breakage of the accessory port in 70%, wire fracture in 10%, incorrect wire bow in 10%, and clogged injection port in 10%. Following reconfiguration of the insertion-port polymer, an additional ten sphincterotomes were used in 110 patients (mean, 11 uses). Mechanical failure occurred primarily at the wire-insertion port, resulting in progressive friction with reuse. There were neither electrical nor infectious complications associated with reuse. CONCLUSIONS: A reusable double-channel sphincterotome is available which can theoretically be reprocessed and sterilized without the manual cleaning step of the reprocessing process. Contingent upon both provider and patient, multiple reuse can be anticipated, and contingent upon purchase price and reprocessing costs, the potential for procedural cost savings is significant.

Reusable biopsy forceps: a prospective evaluation of cleaning, function, adequacy of tissue specimen, and durability.

BACKGROUND: Recent studies have indicated that reusable biopsy forceps remain contaminated after reprocessing and can only be used a mean of 12 to 25 times without malfunction. Because this contradicts traditional endoscopic practice, our study investigated the ability to sterilize a type of commercially available biopsy forceps and prospectively evaluated their function in vivo until malfunction and/or breakage. METHODS: Thirty reusable biopsy forceps were studied, 15 of which were contaminated for 5 trials each with 10(6) Bacillus stearothermophilus, and 15 of which were prospectively evaluated clinically over an 18-month period (9/98-3/00). Contaminated forceps were reprocessed by using a standard protocol and placed in a sterile bag containing soy broth. The latter was passed through a 0.2 micron filter and was subsequently cultured. In vivo data included biopsy site, size, adequacy, problems obtaining a biopsy specimen, and reasons for ultimate forceps failure. RESULTS: After contamination, all biopsy forceps yielded a heavy growth of B stearothermophilus. No forceps, including 5 that were piecemeal dismantled with a wire cutter, had residual bacteria after reprocessing. In the in vivo study, 1507 biopsy sessions were undertaken in 1339 procedures. Forceps were categorized as new or like-new in 1259 of 1339 (94%) procedures, some loss of function but usable in 72 of 1339 (5.4%), and inadequate function or broken at use in 8 of 1339 (0.6%). Histologically, 1501 specimen sets were adequate (99.6%) and mean specimen size was 2.7 +/- 0.1 mm. Mechanical problems were noted in only 38 of 1507 (3%) sessions to include such things as sticky forceps, and the mean number of uses to malfunction or breakage was 91 +/- 15 (SEM) (range 19-132). CONCLUSIONS: This reusable biopsy forceps can be sterilized and used a mean of 91 times with adequate tissue sampling. Mechanical problems were minor to time of breakage. Contingent on acquisition and reprocessing costs as well as the number of procedures performed, this reusable forceps has the potential for significant cost savings.

Biomechanical evaluation of thumb opposition transfer insertion sites.

The optimal location for insertion of the transferred tendon in opposition transfer is controversial. The purpose of this study was to examine 4 commonly used insertion sites into the thumb and determine which maximizes thumb opposition. The flexor digitorum superficialis of the ring finger was used as a donor tendon and was attached in random order to the abductor pollicis brevis (APB) tendon, the APB and extensor pollicis longus, the flexor pollicis brevis (FPB) and dorsal radial extensor hood, and the ulnar extensor hood at the base of the proximal phalanx. As normal opposition was simulated, the minimum distance between the thumb and little finger and the pinch force were measured. The FPB and radial dorsal extensor hood site resulted in the statistically highest pinch force. The FPB and radial dorsal extensor hood and the APB sites had statistically smaller minimum distances between the thumb and little finger than the ulnar extensor hood site. A subjective evaluation of the 3-dimensional thumb path of motion revealed that the FPB and radial dorsal extensor hood site and the APB insertion site allowed the closest approximation of normal thumb opposition. This biomechanical study supports the use of the FPB and radial dorsal extensor hood insertion site or APB insertion site for opposition transfers.

Self-esteem differences as a function of race and weight preoccupation: findings and implications.

The relationship of weight and diet preoccupation and self-esteem among black and white college females is examined.

In vitro evaluation of integrity and sterilization of single-use argon beam plasma coagulation probes.

OBJECTIVE: Argon plasma coagulation probes (APC) are currently marketed in the United States as single-use items, and may constitute a significant per-procedure expense. It is unknown whether these probes can be sterilized after endoscopic use and if electrical integrity can be maintained after reprocessing. METHODS: Ten probes (2.3 mm diameter, 220 cm length) manufactured by ERBE Inc., (Marietta, GA) were studied using the ERBE APC 300 at 60 watts. Baseline coagulation depth was measured by coagulating a piece of beefsteak for 60 s. Probes were contaminated with 10(6) Bacillus subtilis spores, cultured, and manually cleaned. Culturing involved introducing 10 cc sterile water through the probes; water was filtered, plated onto blood agar, and incubated for 48 h. After ethylene oxide (ETO), the probes were cultured to determine sterilization. Finally, the per-procedure cost of each probe was assessed. RESULTS: Ten of 10 probes completed 10 testing sessions. One probe split at the proximal end but remained functionally intact. Electrical integrity remained intact for all 10 sessions. All probes grew too numerous to count colonies of B. subtilis after inoculation and no B. subtilis was detected after ETO sterilization. Assuming 10 uses clinically, a total per-procedure equipment cost would approximate $24.00, whereas per-procedure probe cost would equal $42.66 if only five uses were obtained in vivo. CONCLUSIONS: The combination of manual cleaning and ETO sterilization consistently sterilized APC probes. Ninety percent of the probes showed no sign of physical deterioration and 100% maintained their electrical activity after 10 uses. APC probes can potentially be safely and effectively reused up to 10 times, and a significant procedural savings is possible with reuse.

Stroke prevention trial in sickle cell anemia.

Stroke occurs in 7-8% of children with Sickle Cell Disease (Hb SS) and is a major cause of morbidity. Rates of recurrence have been reduced from 46-90% to less than 10% through chronic blood transfusions. Prevention of first stroke, however, would be preferable because even one stroke can cause irreversible brain injury. Transcranial Doppler (TCD) ultrasound can detect arterial blood flow rates associated with subsequent stroke risk. By combining TCD screening and a potentially effective treatment, first stroke may be prevented. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) is the first stroke prevention trial in Hb SS and the first randomized, controlled use of transfusion in Hb SS. This multi-center trial is designed to test whether reducing sickle hemoglobin to 30% or less with periodic blood transfusions will reduce first-time stroke by at least 70% compared to standard care. Primary endpoints will be clinically evident symptoms of cerebral infarction with consistent findings on Magnetic Resonance Imaging and Angiography (MRI/MRA) or symptomatic intracranial hemorrhage. Secondary endpoints will be asymptomatic brain lesions detected by MRI in brain areas not involved in primary endpoints. The design calls for a 6-month start-up interval, 18 months of TCD screening and randomization, and observation for stroke from entry through month 54. Key features of the trial are standardized TCD and MRI/MRA protocols interpreted blindly, and blinded adjudication of endpoints. The sample size (60 per treatment group) is based on prospective data relating TCD velocity to risk of stroke. A time-averaged mean velocity of > or = 200 cm/sec is associated with a 46% risk of cerebral infarction over 39 months. The sample size is sufficient to detect 70% reduction in the primary endpoint at 90% power. This trial will determine if transfusion is effective in the primary prevention of stroke. Secondary aims may further the understanding of the effects of transfusion on the brain and guide future research into cerebrovascular disease in Hb SS.

Prediction of therapy-related acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) after autologous bone marrow transplant (ABMT) for lymphoma.

Therapy-related acute myelogenous leukemia and myelodysplastic syndrome (t-AML/MDS) are being reported with increasing frequency as a complication of ABMT for Hodgkin's disease and non-Hodgkin's lymphoma. At present there is no method available to predict who is at risk or is destined to develop this nearly universally fatal disorder. We therefore investigated whether clonal growth of cells is predictive of the development of t-AML/MDS. In a patient who developed secondary AML/MDS 18 months after ABMT, X-linked clonality analysis at the human androgen receptor locus was performed on serial banked samples, and documented transition from polyclonal to clonal hematopoiesis. Clonal cells could be identified 6 months after transplant (1 year prior to the diagnosis of t-AML/MDS), at a time when there was no morphologic or clinical evidence of disease. Clonality analysis can be predictive of the development of t-AML/MDS after ABMT and may offer important insights into associated risk factors and strategies to minimize the risk of t-AML/MDS.

Inhibition of pancreatic cancer growth by the dietary isoprenoids farnesol and geraniol.

Fruits and vegetables have protective effects against many human cancers, including pancreatic cancer. Isoprenoids are one class of phytochemicals which have antitumor activity, but little is known about their effects on cancer of the pancreas. We tested the hypothesis that isoprenoids would inhibit the growth of pancreatic tumor cells. Significant (60-90%) inhibition of the anchorage-independent growth of human MIA PaCa2 pancreatic tumor cells was attained with 25 microM farnesol, 25 microM geranylgeraniol, 100 microM perillyl amine, 100 microM geraniol, or 300 microM perillyl alcohol. We then tested the relative in vivo antitumor activities of dietary farnesol, geraniol, and perillyl alcohol against transplanted PC-1 hamster pancreatic adenocarcinomas. Syrian Golden hamsters fed geraniol or farnesol at 20 g/kg diet exhibited complete inhibition of PC-1 pancreatic tumor growth. Both farnesol and geraniol were more potent than perillyl alcohol, which inhibited tumor growth by 50% at 40 g/kg diet. Neither body weights nor plasma cholesterol levels of animals consuming isoprenoid diets were significantly different from those of pair-fed controls. Thus, farnesol, geraniol, and perillyl alcohol suppress pancreatic tumor growth without significantly affecting blood cholesterol levels. These dietary isoprenoids warrant further investigation for pancreatic cancer prevention and treatment.

A syndrome of lymphoblastic lymphoma, eosinophilia, and myeloid hyperplasia/malignancy associated with t(8;13)(p11;q11): description of a distinctive clinicopathologic entity.

We report two patients with a distinctive biphenotypic hematologic disorder characterized by lymphoblastic lymphoma (LBL), eosinophilia, and myeloid malignancy and/or hyperplasia associated with a t(8;13)(p11;q11) chromosomal translocation in both bone marrow and lymph node specimens. Both patients presented with lymphadenopathy pathologically classified as LBL with a T-cell immunophenotype, myeloid hyperplasia of the bone marrow, and peripheral blood eosinophilia. The first patient achieved clinical complete remission after receiving several regimens of chemotherapy and remains disease-free 16 months after undergoing allogeneic bone marrow transplantation. The second patient developed progressive lymphadenopathy despite several courses of chemotherapy directed against non-Hodgkin's lymphoma. Eight months after his initial presentation, he developed acute myelogenous leukemia that was refractory to therapy. Comparison of these patients with four similar cases recently reported in the literature suggests that this constellation of findings constitutes a distinctive clinicopathologic syndrome. Molecular analysis of the t(8;13) translocation breakpoint may identify genes located in this region and provide insight into the pathogenesis of this interesting biphenotypic hematologic malignancy.