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Purpose: To characterize the primary ethical issue and contextual features of ethics consultation for patients aged 18-26 years based on setting (adult vs. pediatric)., Methods: A retrospective review of 965 ethics consultation notes to identify patients aged 18-26 years cared for in the pediatric or adult setting between January 1, 2016-December 31, 2020. We collected demographic information and used conceptual content analysis to identify the primary ethical issue and contextual features for each consult and analyzed these using descriptive statistics., Results: We identified 46 consults (30 adult and 16 pediatric) for 40 unique patients (28 adult and 12 pediatric). The median age was 19 years in the pediatric setting and 24 in the adult setting. Fifty-three percent were female, 95% non-Hispanic, 68% White, and 76% were inpatient. The primary ethical issue in the adult setting was Refusal of Recommended Treatment (20%), while the dominant contextual issue was Communication Disputes/Conflicts Between the Staff and Patient (23%). The primary ethical issue for the pediatric setting was Goals of Care (31%) and the dominant contextual feature was concerns for Quality of Life (31%)., Discussion: The primary ethical issues and related contextual features this population experiences differ based on setting. Improved understanding of adolescent and young adult development, especially related to values formation, decision-making, and communication skills training may ameliorate some of these challenges. Referral patterns for this age group overall and particularly for patients on the ends of the spectrum and inpatients raise concerns for ethics consultation use. Further education about ethics services is recommended., (Copyright © 2024 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Thrombotic microangiopathy (TMA) represents a heterogeneous group of disorders characterized by microvascular thrombosis and end-organ damage. Pregnancy-associated thrombotic microangiopathy (p-TMA) has emerged as a distinct clinical entity with unique diagnostic challenges. Identifying the specific form of p-TMA is critical for appropriate and timely management. This review offers a comprehensive overview of the various forms of thrombotic microangiopathies associated with pregnancy, highlighting our current understanding of their pathophysiology and the evolving landscape of diagnosis and treatment for each., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Background & Aims: The predictive validity of the GLIM criteria for survival, length of hospital stay (LOHS) and post-operative complications among people with cancer have not been systematically reviewed. This systematic review aims to determine whether GLIM malnutrition is predictive of these outcomes, and whether the predictive validity is affected by how phenotypic and etiologic criteria are assessed., Methods: Cohort studies published after 2018 were systematically reviewed according to PRISMA guidelines from Embase, Medline Complete and CINAHL Complete. Risk of bias and methodologic quality were assessed using the Journal of the Academy of Nutrition and Dietetics' Quality Criteria Checklist tool for Primary research., Results: In total, 21 studies were included, including 28,726 participants. All studies investigated survival, where 18 reported GLIM malnutrition is associated with decreased survival. LOHS was investigated in six studies, with all finding an association between GLIM malnutrition and longer LOHS. Post-operative complications were assessed in seven studies, of which five reported GLIM malnutrition was predictive of increased post-operative complications. Methods to assess the GLIM phenotypic and etiologic criteria varied, with consistent predictive ability for survival regardless of method of assessing reduced muscle mass. However, predictive ability was more variable across different measures of inflammation and reduced intake., Conclusion: GLIM malnutrition was consistently predictive of worse clinical outcomes. Different measures of reduced muscle mass did not affect the predictive ability of GLIM for survival. However, variation in assessment of the etiologic criteria resulted in varying predictive ability of the GLIM diagnosis for survival., Competing Interests: Conflicts of interest Dr. Kiss reports grants from Medical Nutrition Industry, grants from Medical Research Future Fund, grants from AuSPEN, grants from Amgen OA-ANZBMS, grants from Victorian Cancer Agency, outside the submitted work., (Copyright © 2023 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Microplastics (MPs) were characterized in surficial marine sediment (n = 36) and mussel (n = 29) samples collected along the British Columbia (BC) coast, Canada, using visual identification and Fourier Transform Infrared Spectrometry. MPs counts averaged 32.6 ± 5.3 particles per kg in sediment and 0.38 ± 0.04 particles per individual mussel (0.24 ± 0.04 /g of tissue). Victoria Harbour and the North Coast (Prince Rupert area) were MP hotspots, likely resulting from a combination of local sources and oceanographic conditions. Microfibers <1000 μm dominated the pattern in both matrices (61.1 % in sediment; 65.4 % mussels) highlighting the suspected role of textiles in the widespread distribution of MPs in the marine environment. Overall, polyester was dominant in sediment and mussels (54.1 % and 63.5 %, respectively), followed by polyethylene (16.2 % and 11.5 %, respectively). This is the first report of MPs in sediment and mussels along the coast of BC using standardized methods., Competing Interests: Declaration of competing interest No competing interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

A 74-year-old male with a prior left total knee arthroplasty presented with deformity, loosening, pain, and stiffness associated with multiple raised, erythematous, cutaneous nodules about the anterior knee. Workup was concerning for infection, but the skin nodules were atypical. The patient was sent for biopsy which revealed cutaneous diffuse large B-cell lymphoma. The revision surgery was delayed, and the patient underwent chemotherapy/radiation with complete resolution of his lymphoma. He then underwent a successful aseptic revision total knee arthroplasty. Proper identification and treatment of rare cutaneous skin lesions about a prior surgical site can limit morbidity and result in more desirable outcomes., (© 2022 The Authors.)

Background: Total hip arthroplasty (THA) for developmental hip dysplasia (DDH) often requires a subtrochanteric shortening derotational osteotomy (SDO) to limit leg lengthening, mitigate risk of peripheral nerve palsy, and reduce excessive femoral anteversion. Few studies exist detailing long-term clinical outcomes and survivorship. The aim of this study is to analyze the long-term outcomes and survivorship of an SDO-THA cohort., Methods: We retrospectively reviewed all patients who underwent cementless THA with femoral osteotomy due to Crowe I-IV DDH between 1991 and 2001. Primary outcome measures included revision surgery for any reason and functional outcome measures using modified Harris Hip scores. Secondary outcome measures included mode of implant failure and radiographic assessment for osteotomy union, polyethylene wear, osteolysis, and implant loosening., Results: Our review resulted in 24 SDO-THA cases in 20 patients with a mean follow-up of 19 years (range, 8-27 years). Overall survivorship was 67%. All 8 failures were treated with acetabular revision at a mean time to revision of 11 years (range, 1-25 years). Of the failures, there were 5 cases due to polyethylene wear (62.5%), 2 cases due to acetabular loosening (25%), and 1 case due to recurrent instability (12.5%). The mean postoperative modified Harris Hip score was 76 (range, 52-91) with long-term improvement of 43 points maintained ( P < .001)., Conclusions: THA with SDO can produce durable long-term outcomes for the patient with DDH. It is important to consider some common reasons for revision, namely polyethylene wear and osteolysis, acetabular loosening, and recurrent acetabular dislocations., (© 2022 The Authors.)

Purpose: HIV disparities continue to persist in the southern United States and among some populations. Early HIV diagnosis, prompt linkage to care, and viral suppression among persons with HIV in the South, in particular the Deep South, are critical to reduce disparities and achieve national prevention goals., Methods: Estimated annual percent changes were calculated to assess trends during 2015-2019 in percentage distributions for stage of disease at the time of diagnosis, linkage to HIV medical care, and viral suppression., Results: Among 95,488 persons with HIV diagnosed in the South (Deep South: 81,848; Other South:13,640), the overall percentage that received a diagnosis classified as stage 0 increased 9.0%, stages 1-2 increased 1.8%, linkage to HIV care increased 2.9%, and viral suppression increased 5.9%. Changes in care outcomes among American Indian/Alaska Native persons and persons with infection attributed to injection drug use were minimal., Conclusions: To reach the goals of Ending the HIV Epidemic (EHE) and other federal initiatives, efforts need to focus on prevention and care among persons residing in the South. Addressing factors such as stigma and discrimination and elimination of barriers to HIV testing, care, and treatment are needed to effectively address these disparities in HIV-related care outcomes., (Published by Elsevier Inc.)

A causal relationship between immune dysregulation and schizophrenia has been supported by genome-wide association studies and epidemiological evidence. It remains unclear to what extent the brain immune environment is implicated in this hypothesis. We investigated the immunophenotype of microglia and the presence of perivascular macrophages and T lymphocytes in post-mortem brain tissue. Dorsal prefrontal cortex of 40 controls (22F:18M) and 37 (10F:27M) schizophrenia cases, of whom 16 had active psychotic symptoms at the time of death, was immunostained for seven markers of microglia (CD16, CD32a, CD64, CD68, HLA-DR, Iba1 and P2RY12), two markers for perivascular macrophages (CD163 and CD206) and T-lymphocytes (CD3). Automated quantification was blinded to the case designation and performed separately on the grey and white matter. 3D reconstruction of Iba1-positive microglia was performed in selected cases. An increased cortical expression of microglial Fcγ receptors (CD64 F = 7.92, p = 0.007; CD64/HLA-DR ratio F = 5.02, p = 0.029) highlights the importance of communication between the central and peripheral immune systems in schizophrenia. Patients in whom psychotic symptoms were present at death demonstrated an age-dependent increase of Iba1 and increased CD64/HLA-DR ratios relative to patients without psychotic symptoms. Microglia in schizophrenia demonstrated a primed/reactive morphology. A potential role for T-lymphocytes was observed, but we did not confirm the presence of recruited macrophages in the brains of schizophrenia patients. Taking in account the limitations of a post-mortem study, our findings support the hypothesis of an alteration of the brain immune environment in schizophrenia, with symptomatic state- and age-dependent effects., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Over the last two decades treatment options have drastically improved for patients with pulmonary arterial hypertension (PAH). In the recent times, there is renewed interest in dry powder inhaler (DPI) based inhaled therapies in the treatment of PAH. PAH patients are well known to have respiratory and other muscle weakness either related to the disease itself or due to the underlying diseases like connective tissue disease (CTD). CTD PAH patients are at particular disadvantage as there is a concern if they have enough strength to press the buttons on the inhaler device, needed to pierce the drug capsule inside the device. Additionally, CTD PAH patients develop hand deformities making it difficult to use devices. To our knowledge, this is the first study to systematically examine the pinch force strength needed to pierce the capsule in DPI devices in patients with PAH. We enrolled 35 patients and our results showed that all PAH patients were able to generate enough pinch strength needed to pierce the capsule regardless of the etiology of PAH., Competing Interests: Declaration of competing interest S. Sahay serves as a speaker and consultant for Actelion, United Therapeutics, and Bayer. He is also an Advisor to Liquidia Technologies and Altavant Sciences. R. Holy has nothing to disclose. S. Lyons, M. Maurer and J. Weers are employees of the sponsor Respira Therapeutics, Inc. E. Parsley is a consultant of the sponsor Respira Therapeutics, Inc. Acknowledgements: This study was sponsored by Respira Therapeutics, Inc., Albuquerque, NM, USA; IRB approval: yes. Patient consents: All patients provided informed consent., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Competing Interests: Declaration of Competing Interest None to declare.

Background: The increasing use of pregabalin and the presence of pregabalin in poisoning deaths, particularly with opioids, highlight it as a potential drug of abuse. In this study we examined factors associated with pregabalin-positive poisoning deaths (PPPD) between 2013 and 2016 in Ireland., Methods: Data were extracted from the National Drug-Related Deaths Index (NDRDI). Analysis included univariate and multivariate logistic regression to estimate unadjusted and adjusted odds ratios (OR) and 95 % confidence intervals (CI) for factors associated with PPPD (primary outcome) by logistic regression models for the total sample and stratified by gender., Results: Pregabalin was present on 240 (16 %) toxicology reports of 1489 poisoning deaths; significantly rising from 15 (4.5 %) in 2013 to 94 (26 %) in 2016. Women (AOR 2.69, 95 % CI: 1.95-3.70), opioid misuse (AOR 1.74, 95 % CI: 1.17-2.59), in receipt of treatment for problem drug use (AOR 1.95, 95 % CI: 1.33-2.86) and year of death (2016 vs 2013) (AOR 7.95, 95 % CI: 4.58-13.79) were associated with increased odds of PPPD. Alcohol dependence was associated with reduced odds of PPPD (AOR 0.59, 95 % CI: 0.41-0.85). For men, opioid misuse, in receipt of treatment for problem drug use, and year of death were associated with increased odds of PPPD, while alcohol dependence was associated with reduced odds of PPPD. For women, in receipt of treatment for problem drug use and year of death were associated with increased odds of PPPD., Conclusions: Enhanced training to prescribers and treatment providers on the potential risks associated with pregabalin, particularly among people who use drugs, is required., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Infection of total knee arthroplasty is a complex problem often resulting in multiple surgeries for the patient. We examined the early to midterm results of a retained cemented "low-friction" metal-on-polyethylene articulating antibiotic spacer in total knee arthroplasty., Methods: We retrospectively reviewed patients with a total knee cemented articulating antibiotic spacer performed for joint sepsis. Patients were allowed full weight bearing and normal activities after eradication of the infection at 6 weeks postop. Two months later, patients were given the option of conversion to a revision implant vs retention of the spacer. We examined infection cure rate, mechanical failure, Knee Society Scores, range of motion, and patient factors associated with spacer retention., Results: Fifty-five knees were studied with average follow-up of 1.8 years (0.2-8.4). Among patients choosing spacer retention (40%), the average follow-up time of the spacer was 3.3 years (0.6-8.4). Five patients (9.1%) required a repeat spacer for recurrent infection., Conclusions: Usage of articulating cement antibiotic spacers with a metal-on-polyethylene bearing couple provides excellent infection eradication, while also resulting in good functional outcomes. Early evidence suggests that use of the implant can be extended beyond typical timeframes and, in certain patient populations, may be suitable for a single-stage procedure.

In this article, we suggest that motivation serves to anticipate the energy of the body and meet those needs before they arise, called allostasis. We describe motivation as the output of energy computations that include estimates about future energy/metabolic needs and the value of effort required for potential behaviors (i.e., whether the cost of effort is worthwhile). We bring neuroscience evidence to bear to support this hypothesis. We outline a system of brain networks that have been shown to be important for motivation, and focus in on one hub in this network, the anterior mid-cingulate cortex (aMCC), and discuss its importance for establishing motivation in the service of allostasis. We present evidence that the aMCC, positioned at the intersection of multiple brain networks, is wired to integrate signals relating to allostasis with its sensory consequences, termed interoception, as well as with cognitive control processes, sensory and motor functions. This integration guides the nervous system towards the optimal effort required to achieve a desired goal. Across a variety of task domains, we discuss the role of aMCC in motivation, including a) processing of the value of prior and expected rewards, b) assessment of energetic costs in the brain and the body, c) selectively learning and encoding prediction errors (unexpected changes) that are relevant for allostasis, d) computations for monitoring of internal states of the body and e) modulating the internal state of the body to prepare for action. Finally, we discuss the link between individual differences in aMCC processing and variation in two extreme ends of the range of motivational states, tenacity and apathy.

Objective: To better understand decision role preferences in women diagnosed with breast cancer at a young age for return of results of genome sequencing in research and clinical settings., Methods: Participants were surveyed about communication and decision-making preferences related to genome sequencing results and factors that may affect these preferences. The primary outcome was decision role preference (Control Preference Scale) for selecting what results to receive within medical care or within a research study., Results: For results returned as part of medical care, most patients preferred a collaborative (N = 481, 45%) or active (N = 488, 45%) role with only 107 (10%) choosing a passive role. When making the decision as part of a research study, most patients preferred an active role (N = 617, 57%), 350 (33%) choosing a collaborative role, and110 (10%) choosing a passive role., Conclusion: Most women in this study preferred to share in decision making. Participants had somewhat different role preferences for clinical and research contexts, with greater preference for active roles in the research context., Practice Implications: We advocate for practice guidelines that incorporate discussion of decision role as an integral part of patient centered care and shared decision-making and recognize that more work is needed to inform guidelines., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This paper tests whether higher exposure to coastal blue space is associated with lower risk of depression using data from The Irish Longitudinal Study on Ageing (TILDA), a nationally representative longitudinal study of people aged fifty and over in Ireland. We contribute to the literature on blue space and health by (i) using scores from the Center for Epidemiologic Studies Depression Scale (CES-D) to measure depression outcomes (ii) using new measures of coastal blue space visibility (iii) studying the association in an older population (iv) using data from Ireland. Our results indicate that exposure to coastal blue space is associated with beneficial mental health outcomes: TILDA respondents with the highest share of sea view visibility have lower depression (CES-D) scores, while distance from coastline is not statistically significant when views and proximity are both included in the model. This finding supports the idea that the primary channel through which coastal blue space operates to reduce depression scores is visual rather than related to physical proximity., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Patient falls during an acute hospitalization cause injury, reduced mobility, and increased costs. The laminated paper Fall TIPS Toolkit (Fall TIPS) provides clinical decision support at the bedside by linking each patient's fall risk assessment with evidence-based interventions. Strategies were needed to integrate this evidence into clinical practice., Methods: The Institute for Healthcare Improvement's Framework for Spread is the conceptual model for pilot implementation of Fall TIPS at Brigham and Women's Hospital (BWH; Boston) and Montefiore Medical Center (MMC; Bronx, New York). The key to translating the evidence into practice was engaging stakeholders by leveraging existing shared governance structures, identifying unit champions, holding training sessions for all staff, and implementing auditing to assess and provide feedback on protocol adherence and patient outcomes., Results: BWH unit compliance with using Fall TIPS averaged 82%, the mean fall rate decreased from 3.28 to 2.80 falls per 1,000 patient-days from January through June 2015 versus 2016, and the mean fall with injury rate for these periods decreased from 1.00 to 0.54 per 1,000 patient-days. At MMC, compliance averaged 91%, but the mean fall rate increased marginally from 3.04 to 3.10, while the mean fall with injury rate decreased from 0.47 to 0.31 per 1,000 patient-days. Patient knowledge survey results show improvement in knowledge of the risks for falls and the ways to prevent falls., Conclusion: Engaging hospital and clinical leadership is critical in translating evidence-based care into clinical practice. Barriers to adoption of the protocol have been addressed and detailed to provide guidance for spread to other institutions., (Copyright © 2017 The Joint Commission. Published by Elsevier Inc. All rights reserved.)

Background: Supervised consumption ensures patients take methadone as prescribed and prevents diversion, however, the influence of supervised consumption on retention is unclear. We examined association between supervised consumption and retention across multiple treatment episodes., Methods: Cohort study of persons experiencing ≥1 MMT episodes in primary care (2004-2010), excluding ongoing episodes at the start of follow-up. Length of treatment episodes based on methadone prescriptions, retention classified as no interruption in prescribed methadone lasting >7 days. When a patient did not receive a new prescription within seven days after the end of coverage of a prescription, they were considered to have ceased treatment. We evaluated the relationship between supervised consumption and time to discontinuation of treatment using proportional hazards gamma frailty models to account for recurrent MMT episodes. Age, gender, median daily methadone dose, and comorbidities included as potential confounders., Results: 6393 patients experienced 19,715 treatment episodes over the six-year follow-up period. A J-shaped relationship was observed; having between 20 and 60% of methadone scripts supervised (compared to <20%) associated with reduced time to discontinuation (20-39% HR=0.88, 95% CI 0.81-0.95; 40-59%: HR=0.87, 95% CI 0.81-0.94). Beyond a threshold of 60%, retention reduced (60-79% of scripts: HR=1.28, 95% CI 1.20-1.36;>80% of scripts: HR=3.59, 95% CI 3.38-3.81). Median daily dose between 60 and 120mg/per day, and multiple treatment episodes also associated with longer time to discontinuation of treatment., Conclusion: A J-shaped relationship was observed between supervised consumption and retention in treatment. Additionally, patients experiencing multiple treatment episodes tend to stay in treatment for progressively longer periods of time., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: The aim of this study was to investigate deaths among individuals with epilepsy recorded on the National Drug-Related Deaths Index (NDRDI)., Method: A descriptive analysis of individuals with a known history of epilepsy in the NDRDI from 2004 to 2013 was undertaken., Results: Between 2004 and 2013, 225 (2%) of the recorded cases had a documented history of epilepsy, 82 (36%) of whom had epilepsy recorded as the cause of death. Of these 82 deaths, the majority were male (60-73%) and half (median age) were aged 47 years or younger. A post mortem toxicology report was available for 65 (79%) of these deaths, of which over two thirds (44-68%) did not have any antiepileptic drugs present on toxicology. Over two thirds of these deaths, (31-70%) were among people known to be alcohol dependent., Conclusion: The high percentage of individuals with a diagnosis of alcohol dependency that died as a result of epilepsy and who have no antiepileptic drugs in their system at the time of their death, highlights the need for preventative measures for this at-risk group., (Copyright © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Ketamine is growing in popularity for procedural sedation in the paediatric population, yet safety concerns remain. We performed a retrospective review of practice and outcomes of paediatric ketamine sedation using the World SIVA International Sedation Task Force reporting tool., Methods: A retrospective inspection of the dedicated emergency department electronic sedation database and subsequent note and sedation chart review was performed for all paediatric sedations throughout a 7 yr period from September 2006. All adverse events were stratified., Results: During the study period, procedural sedation was provided for a total of 243 children, of whom 215 were sedated with ketamine, most commonly for wound management (n=131). The median patient age was 4 yr (14 months to 15 yr), and 63.7% were male. Of the total, 76.7% were discharged home either directly (n=101) or after brief observation (n=64). One patient required subsequent general anaesthesia after a failed sedation with paradoxical agitation. Of the total, 9.8% of patients had an adverse event, the most severe risk stratification being 'minor risk'. All interventions were 'minimal risk'. There were no 'sentinel risk' outcomes., Conclusions: These data support the ongoing use of ketamine for paediatric procedural sedation in the emergency department by emergency physicians. Relatively high resource requirements mean that ensuring adequate numbers of procedures may prove challenging., (© The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Paediatric burn follow-up optimally follows a balance between complication detection and avoiding unnecessary hospital visits. In a long-term review, we assessed complication patterns in children with burns requiring surgery. Using the Welsh Burns Centre database, a retrospective note review of paediatric burns over 3 years from 1995 was performed, identifying all children undergoing surgery for their burns. 94 patients were identified with a median follow-up since injury of 13.6 years. Mean age was 5.27 (SD=4.9) years. TBSA ranged from <1 to 70%. 94% underwent split-skin grafting. 18% (n=17) developed contractures and 33% (n=31) developed hypertrophic scarring. Those developing contractures were younger, and suffered significantly greater TBSA burns (p<0.05) than those developing hypertrophic scarring or those without complications. All contractures developed within 1-13 months, and hypertrophic scarring within 1-17 months. All patients sustaining axillary burns developed contractures, whilst 75% of contractures developed around the upper limb. In conclusion, younger patients with larger TBSA burns in the upper limb were at higher risk for contractures and hypertrophic scarring, which all presented within 18 months. Therefore any patients that are complication-free 18 months after-injury can be safely discharged, allowing streamlining of follow-up for the benefit of patients, parents and hospital resources., (Copyright © 2012 Elsevier Ltd and ISBI. All rights reserved.)

Objective: The purpose of this investigation was to determine whether cognitive awareness of carbohydrate beverage consumption affects exercise-induced lymphocyte apoptosis, independent of actual carbohydrate intake., Introduction: Carbohydrate supplementation during aerobic exercise generally protects against the immunosuppressive effects of exercise. It is not currently known whether carbohydrate consumption or simply the knowledge of carbohydrate consumption also has that effect., Methods: Endurance trained male and female (N = 10) athletes were randomly assigned to one of two groups based on either a correct or incorrect cognitive awareness of carbohydrate intake. In the incorrect group, the subjects were informed that they were receiving the carbohydrate beverage but actually received the placebo beverage. Participants completed a 60-min ride on a cycle ergometer at 80% VO₂peak under carbohydrate and placebo supplemented conditions. Venous blood samples were collected at rest and immediately after exercise and were used to determine the plasma glucose concentration, lymphocyte count, and extent of lymphocyte apoptosis. Cognitive awareness, either correct or incorrect, did not have an effect on any of the measured variables., Results: Carbohydrate supplementation during exercise did not have an effect on lymphocyte count or apoptotic index. Independent of drink type, exercise resulted in significant lymphocytosis and lymphocyte apoptosis (apoptotic index at rest = 6.3 ± 3% and apoptotic index following exercise = 11.6 ± 3%, P < 0.01)., Conclusion: Neither carbohydrate nor placebo supplementation altered the typical lymphocyte apoptotic response following exercise. While carbohydrate supplementation generally has an immune-boosting effect during exercise, it appears that this influence does not extend to the mechanisms that govern exercise-induced lymphocyte cell death.

Enteropathy associated T-cell lymphoma (EATL) is a rare type of peripheral T-cell lymphoma. At present, there are no standardized diagnostic or treatment protocols for EATL. We describe EATL in a population-based setting and evaluate a new treatment with aggressive chemotherapy and autologous stem cell transplantation (ASCT). From 1979 onward the Scotland and Newcastle Lymphoma Group prospectively collected data on all patients newly diagnosed with lymphoma in the Northern Region of England and Scotland. Between 1994 and 1998, records of all patients diagnosed with EATL were reviewed, and 54 patients had features of EATL. Overall incidence was 0.14/100 000 per year. Treatment was systemic chemotherapy (mostly anthracycline-based chemotherapy) with or without surgery in 35 patients and surgery alone in 19 patients. Median progression-free survival (PFS) was 3.4 months and overall survival (OS) was 7.1 months. The novel regimen IVE/MTX (ifosfamide, etoposide, epirubicin/methotrexate)-ASCT [corrected] was piloted from 1998 for patients eligible for intensive treatment, and 26 patients were included. Five-years PFS and OS were 52% and 60%, respectively, and were significantly improved compared with the historical group treated with anthracycline-based chemotherapy (P = .01 and P = .003, respectively). EATL is a rare lymphoma with an unfavorable prognosis when treated with conventional therapies. The IVE/MTX-ASCT regimen is feasible with acceptable toxicity and significantly improved outcome.

Background: In May 2005, the revised International Health Regulations, known as IHR (2005), were adopted in response to the evolving nature of communicable diseases (CD) and the rapid increase in global trade and travel. CD surveillance is an integral part of a country's core requirements under the regulations., Methods: The implications of these requirements were assessed as part of a review of the national CD surveillance system of Tunisia using a qualitative methodology of strengths, weaknesses, opportunities and threats (SWOT)., Results: Tunisia is some way towards meeting the requirements of IHR (2005) while some specific areas that need to be addressed are highlighted for improvement: standardization of surveillance documents, strengthening the role of the laboratory in surveillance, increased human resources and training., Conclusions: Tunisia's experience can offer some lessons to other countries in this process. While meeting the capacity obligations of IHR (2005) requires investment and commitment, this investment will enable countries to better protect themselves against public health emergencies arising within their borders and threatening from elsewhere in the world.

Abnormal regulation of apoptosis is an important pathogenic mechanism in many diseases including cancer. Techniques to assess apoptosis in living organisms are limited and, in the case of solid organs, restricted to histological examination of biopsy samples. We investigated the use of (124)I-annexin V, which binds to phosphatidylserine (PS) on the surface of apoptotic cells, as a potential positron emission tomography (PET) radioligand for the noninvasive measurement of apoptosis in vivo. Annexin V and a similar-sized protein, ovalbumin, were directly labelled with (124)I. We report the validation of (124)I-annexin V in vitro and in an animal model of liver apoptosis that has not previously been used to test iodinated annexin V. Also, for the first time, we report metabolite analysis of (124)I-annexin V and the correlation of (124)I-annexin V uptake with apoptotic density (AD). Sixfold more (124)I-annexin V was associated with Jurkat cells after apoptosis induction, indicating that PS binding by annexin V was preserved after iodination. (124)I-ovalbumin did not demonstrate increased uptake in apoptotic cells. In normal BDF-1 mice, the radioligand was rapidly cleared, but some in vivo dehalogenation resulted in the accumulation of activity in the thyroid and stomach content. PET images demonstrated uptake of (124)I-annexin V but not (124)I-ovalbumin in apoptotic liver lesions. In vivo (124)I-annexin V uptake, derived from PET images, correlated with histologically derived AD (r=.86, P<.01). These results demonstrate that (124)I-annexin V is localised to anti-Fas-induced apoptosis, in contrast to (124)I-ovalbumin, which did not show preferential uptake in the apoptotic liver.

A noninvasive method of measuring programmed cell death in the tumors of cancer patients using positron-emission tomography (PET) would provide valuable information regarding their response to therapeutic intervention. Our strategy is to radiolabel annexin V, a protein that binds to phosphatidylserine moieties that are translocated to the external leaflet of plasma membranes during apoptosis. We developed a phosphatidylserine-ELISA capable of distinguishing wild type from point mutant annexin V that is known to have a lower phosphatidylserine binding affinity. A maltose-binding protein/annexin V chimera was synthesized and purified with high yield using amylose resin. We showed that it bound to phosphatidylserine in the ELISA as well as to that exposed on apoptotic Jurkat cells; therefore, it was used in the development of a method for radiolabeling annexin V using iodine radionuclides. MBP-annexin V retained its phosphatidylserine binding properties on direct iodination, but at high levels of oxidizing agents (iodogen and chloramine T), its specificity for phosphatidylserine was compromised. (124)I-MBP-annexin V was successfully used to image Fas-mediated hepatic cell death in BDF-1 mice using PET. In conclusion, we have shown that MBP-annexin V and the phosphatidylserine ELISA are useful tools for the development of methods for radiolabeling annexin V for PET imaging.

Objective: The purpose of this study was to analyze the effects of maternal exercise on fetal heart rate changes to determine prognostic factors for an abnormal trace in labor., Study Design: Two hundred fifty-eight primiparous women who were 33 to 38 weeks of gestation with varying levels of activity were recruited. A symptom-limited incremental exercise test was preformed. Cardiotocography was carried out before and after exercise. Data were analyzed with specialized computer software., Results: A strenuous level of exercise was achieved. The most common fetal heart rate response seen was tachycardia. The incidence did not vary with the level of fitness, maternal body mass index, or fetal weight. Male fetuses were more prone to fetal distress. A significantly higher proportion of distressed babies were born to older women (P <.0001). The percentage of abnormal traces was equal in the vaginal and caesarean delivery groups., Conclusion: The results showed no correlation among the incidence of fetal distress, the mode of delivery, and the fetal heart rate changes after exercise.

The CCAAT/enhancer-binding protein (C/EBP) family consists of transcription factors essential for hematopoiesis. The defining feature of the C/EBPs is a highly conserved carboxy-terminal bZIP domain that is necessary and sufficient for dimerization and DNA binding, whereas their amino-terminal domains are unique. This study reports a novel c/ebp gene (c/ebp1) from zebrafish that encodes a protein homologous to mammalian C/EBPs within the bZIP domain, but with an amino terminus lacking homology to any C/EBP or to any known sequence. In zebrafish embryos, c/ebp1 expression was initially observed in cells within the yolk sac circulation valley at approximately the 16-to 18-somite stage, and at 24 hours postfertilization (hpf), also in circulating cells. Most c/ebp1(+) cells also expressed a known early macrophage marker, leukocyte-specific plastin (l-plastin). Expression of both markers was lost in cloche, a mutant affecting hematopoiesis at the level of the hemangioblast. Expression of both markers was retained in m683 and spadetail, mutants affecting erythropoiesis, but not myelopoiesis. Further, c/ebp1 expression was lost in a mutant with defective myelopoiesis, but intact erythropoiesis. These data suggest that c/ebp1 is expressed exclusively in myeloid cells. In electrophoretic mobility shift assays, c/ebp1 was able to bind a C/EBP consensus DNA site. Further, a chimeric protein containing the amino-terminal domain of c/ebp1 fused to the DNA-binding domain of GAL4 induced a GAL4 reporter 4000-fold in NIH3T3 cells. These results suggest that c/ebp1 is a novel member of the C/EBP family that may function as a potent transcriptional activator in myeloid cells.

To assess alternative methods for introducing expressing transgenes into the germ line of zebrafish, transgenic fish that express a nuclear-targeted, enhanced, green fluorescent protein (eGFP) gene were produced using both pseudotyped retroviral vector infection and DNA microinjection of embryos. Germ-line transgenic founders were identified and the embryonic progeny of these founders were evaluated for the extent and pattern of eGFP expression. To compare the two modes of transgenesis, both vectors used the Xenopus translational elongation factor 1-alpha enhancer/promoter regulatory cassette. Several transgenic founder fish which transferred eGFP expression to their progeny were identified. The gene expression patterns are described and compared for the two modes of gene transfer. Transient expression of eGFP was detected 1 day after introducing the transgenes via either DNA microinjection or retroviral vector infection. In both cases of gene transfer, transgenic females produced eGFP-positive progeny even before the zygotic genome was turned on. Therefore, GFP was being provided by the oocyte before fertilization. A transgenic female revealed eGFP expression in her ovarian follicles. The qualitative patterns of gene expression in the transgenic progeny embryos after zygotic induction of gene expression were similar and independent of the mode of transgenesis. The appearance of newly synthesized GFP is detectable within 5-7 h after fertilization. The variability of the extent of eGFP expression from transgenic founder to transgenic founder was wider for the DNA-injection transgenics than for the retroviral vector-produced transgenics. The ability to provide expressing germ-line transgenic progeny via retroviral vector infection provides both an alternative mode of transgenesis for zebrafish work and a possible means of easily assessing the insertional mutagenesis frequency of retroviral vector infection of zebrafish embryos. However, because of the transfer of GFP from oocyte to embryo, the stability of GFP may create problems of analysis in embryos which develop as quickly as those of zebrafish., (Copyright 1999 Academic Press.)

Unlabelled: BACKGROUND and aims. To compare the metabolic effects induced by the anticancer drugs, 6-mercaptopurine (6-MP), 6-thioguanine (6-TG) and 6-methylmercaptopurine riboside (MMPR), which may inhibit the de novo biosynthesis of purine nucleotides or be mis-incorporated into DNA or RNA., Methods: Leukaemia cells were grown in culture, exposed to a thiopurine and cell extracts were analyzed for NTPs, dNTPs, drug metabolites and P-Rib-PP., Results: In leukaemia cells, 6-MP was converted to MPR-MP, thio-XMP, thio-GMP, thio-GDP and thio-GTP. Metabolites of 6-TG included thio-XMP, thio-GMP, thio-GDP and thio-GTP, while MMPR-MP was the only major metabolite of MMPR, MMPR (25 microM, 4 h) induced a 16-fold increase in P-Rib-PP and 6-MP (25 microM, 4 h) induced a delayed 5.2-fold increase. MPR-MP, thio-GMP and MMPR-MP are inhibitors of amido phosphoribosyltransferase from leukaemia cells with Ki values of 114 +/- 7.10 microM, 6.20 +/- 2.10 microM and 3.09 +/- 0.30 microM, respectively., Conclusion: The nucleoside-5'-monophosphate derivatives of the 3 thiopurines inhibit amido phosphoribosyltransferase in growing leukaemia cells but there is also an initial inhibition of the further conversion of IMP in the pathway. In growing cells, MMPR acts solely as an inhibitor of de novo purine biosynthesis while 6-TG and to a lesser extent, 6-MP, are converted to significant concentrations of di- and tri-phosphate derivatives which may have other mechanisms of cytotoxicity.

Interferons-alpha and -beta (IFN-alpha and -beta) are cytokines that are widely known to induce potent anti-viral activity. However, it has become increasingly apparent that IFN-alpha and -beta exert a variety of other biological effects, including anti-tumour and immunomodulatory activities and are increasingly used clinically to treat a range of malignancies, myelodysplasias and autoimmune diseases, e.g., IFN-beta for multiple sclerosis. The most widely used bioassays for the IFNs are based on their anti-viral activity, but these do not predict the biological activity of the IFNs in anti-tumour and immunomodulatory therapies. Thus, we have developed anti-cytokine-based bioassays that may be more reflective of such activity and which have several advantages over existing anti-viral bioassays. The anti-cytokine bioassay is based on the ability of IFN-alpha, -beta and -omega to inhibit granulocyte-macrophage-colony-stimulating factor (GM-CSF) induced proliferation of the erythroleukaemic cell line TF-1. This assay can take only 24 h, is sensitive to 200 fg (0.04 IU) IFN-alpha or -beta and 100 fg (0.02 IU) IFN-omega and is able to detect down to these levels in serum or plasma samples. The usefulness of anti-cytokine bioassays for IFN-alpha, -beta and -omega is not restricted to the GM-CSF/TF-1 cell format and other alternatives are available, such as erythropoietin (EPO)/TF-1 cells and EPO/UT-7-EPO cells. These assays can be made specific for each of the IFNs by including neutralising antibodies in the bioassay.

Cytosine arabinoside (Ara-C) is used to treat leukemias, with complete remission induced by combination chemotherapy in approximately 70% of cases of acute myelogenous leukemia (AML). Ara-CTP acts as a competitive inhibitor of DNA polymerase and may also be incorporated into DNA. Accumulation of deoxyribonucleoside triphosphates (dNTPs) induced by Ara-C may indicate disruption of DNA synthesis in susceptible leukemia cells. A procedure has been developed for the quantification of Ara-CTP and dNTPs from small samples of leukaemia cells from patients (4 x 10(7) cells) activated with concanavalin A (10 micrograms/ml, 48 hr) and grown in the presence of [32P]orthophosphate (1.1 microM, 9 x 10(6) Ci/mol, 16 hr). The susceptibilities to Ara-C of the human leukemia cell lines CCRF-CEM (IC50 = 6.30 nM), CCRF-HSB-2 (IC50 = 10.4 nM) and MOLT-4 (IC50 = 10.0 nM) may be correlated with their abilities to accumulate high concentrations of Ara-CTP (> 1000 amol/cell) with increases of between 1.3- and 3.4-fold in dATP, dGTP and dTTP for the four cell lines, while dCTP decreased between 0.23- and 0.78-fold. By contrast, an Ara-C-resistant derivative of HL-60 cells (IC50 = 400 nM) accumulated only low concentrations of Ara-CTP (71 amol/cell) without significant changes in dNTPs. High concentrations of Ara-CTP in leukemia cells induce accumulations of dATP, dGTP and dTTP due to inhibition of DNA synthesis, and depletion of dCTP. This imbalance in the pools of the four dNTPs could lead to genetic miscoding and cell death.

Type IIA von Willebrand disease (vWD) is an autosomal dominant bleeding disorder characterized by a qualitative defect in von Willebrand factor (vWF). A number of missense mutations responsible for type IIA vWD have recently been identified. This report examines the type IIA vWD mutations Leu777-->Pro and Ile865-->Thr by expression of recombinant vWF containing mutant and wild-type (WT) sequences. Recombinant vWF containing the L777P mutation (vWFL777P) showed markedly impaired secretion compared with that for wild-type vWF (vWFWT) after DNA transfection into mammalian cells. Multimer analysis of secreted vWFL777P showed predominantly low molecular weight forms. In contrast, recombinant vWF containing the I865T mutation (vWFI865T) was processed in a pattern similar to vWFWT, with secretion of the full spectrum of vWF multimers. Thus, L777P and I865T are subclassified as type IIA group I and group II mutations, respectively. Analysis of platelet vWF from a patient heterozygous for the L777P mutation shows reduced large vWF multimers in a pattern similar to plasma, consistent with the intracellular transport defect predicted for a group I mutation. An increase in the proportion of high molecular weight multimers observed in type IIA vWD patient plasma, after renal transplantation from a normal donor, suggests that the kidney endothelium may be a major source of plasma vWF.

An HIV1 antibody screening assay, the "ImmunoComb" HIV1 kit which uses a dip-stick methodology, was evaluated using a panel of selected sera. The ImmunoComb detected 144 of 147 (98%) Western-blot-confirmed positive sera. However, when the ImmunoComb was compared with a recombinant EIA capable of detecting early seroconversion, only 144 of 156 (92.3%) recombinant EIA or Western-blot-positive sera were ImmunoComb-positive. Thus, while the kit is suitable for serological surveys and prevalence studies, especially in areas where skilled laboratory staff and sophisticated equipment are unavailable, the low sensitivity precludes its use in blood banks and transfusion services.

The significance of indeterminate Western blotting results was assessed by determining their distribution in attenders of sexually transmitted diseases (STD) and family planning (FP) clinics. As expected, it was found that the former had a highly significantly greater prevalence of HIV infection. Indeterminate results were not found more frequently in STD attenders refuting any association with sexual promiscuity. They were, however, found significantly more frequently amongst black compared to white subjects, but no difference was found between males and females. Indeterminate results appear to be a feature of black African sera and what the significance is, still remains to be elucidated.

A number of antagonists of nucleotide metabolism with anti-cancer activity affect the de novo purine pathway. To determine the biochemical mechanisms of cytotoxicity of these drugs, assay procedures have been developed for measurement of the levels of intermediates proximal to IMP in the pathway for de novo purine biosynthesis in mouse L1210 leukemia cells. Purine precursors have been synthesized in vitro from [14C]glycine using enzymes from chicken liver. These 14C-labeled intermediates have been used as marker compounds to define retention times for metabolites of leukemia cells separated by HPLC and the chromatographic mobilities of these intermediates after two-dimensional thin-layer chromatography. These new chromatographic procedures have been used in combination to determine the steady-state concentrations for purine precursors in mouse L1210 leukemia cells in the exponential phase of growth: N-formylglycineamide ribotide (16 microM); N-formylglycineamidine ribotide (4.7 microM); 5-aminoimidazole ribotide (4.0 microM); 4-carboxy-5-aminoimidazole ribotide (0.46 microM); N-succino-5-aminoimidazole-4-carboxamide ribotide (11 microM); 5-aminoimidazole-4-carboxamide ribotide (16 microM); 5-formamidoimidazole-4-carboxamide ribotide (2.7 microM); and IMP (57 microM). The metabolic effects of tiazofurin (25 microM) upon mouse L1210 leukemia cells growing in culture define a "metabolic crossover point" at the reaction catalyzed by IMP dehydrogenase (EC 1.1.1.205) which confirms previous reports of inhibition of this enzyme.

The non-depolarizing muscle relaxant AH8165 has been compared at two doses (0.5 and 1.0 mg/kg) with pancuronium (0.1 mg/kg) during induction of anaesthesia for patients having major cardiac surgery. After barbiturate-opiate premedication and thiopentone induction, administration of pancuronium was followed by no significant alteration in heart rate or arterial pressure. Both doses of AH8165 werr followed by significant tachycardia, and the higher dose by arterial hypotension. The lower dose of AH8165 was unsatisfactory for tracheal intubation, but the AH8165 1 mg/kg gave intubating conditions similar to those with pancuronium 0.1 mg/kg.

Paraquat, bipyridilium herbicide know to cause pulmonary fibrosis, was injected IP into rats. The rate of synthesis of collagen by lung minces from these and control rats was evaluated by measuring the rate of synthesis of hydroxyproline, a specific marker for collagen in lung. Synthesis was measured by incubating lung minces with radioactive proline for various amounts of time, after which proline specific activity and labeled hydroxyproline were determined. The size of the proline pool within the lung minces was significantly elevated in minces from rats that had been injected with paraquat, thus causing the specific activity of the [3H]proline precursor to be lower in these lungs than in those from control animals. Lung minces from rats administered paraquat made more collagen than did those from uninjected controls. The actual increase in rate of collagen synthesis correlated well with other independent estimates of paraquat-induced damage to the lungs.

The water-soluble benzodiazepine, midazolam, was compared with diazepam for postoperative sedation in patients following cardiopulmonary bypass. Midazolam in repeated doses produced a stable plasma concentration within 4 h, showed no tendency to cumulation and was cleared rapidly following discontinuation. Similar doses of diazepam given with the same frequency produced plasma concentrations which were still increasing at the time of discontinuation and which were still greater than their baseline values 24 h later.

Thirty patients with ischaemic heart disease scheduled for coronary artery bypass grafting were randomly allocated to three equal groups. Following morphine, hyoscine and pentobarbitone premedication, anaesthesia was induced with diazepam 0.3 mg kg-1. Five minutes later neuromuscular blockade was induced with pancuronium 0.1 mg kg-1, vecuronium 0.1 mg-1 or atracurium 0.5 mg kg-1, followed after 6 min by fentanyl 25 micrograms kg-1. Pancuronium and atracurium caused significant increases in heart rate, while vecuronium induced little change. Systemic vascular resistance decreased significantly from 1515 dyn s cm-5 to 1200 dyn s cm-5 following atracurium. Cardiac index was increased transiently in the atracurium group, but a more sustained increase was observed following pancuronium. Nine patients in the atracurium group showed skin flushing and one developed skin weals.