Progressive multifocal leukoencephalopathy in a patient post allo-HCT successfully treated with JC virus specific donor lymphocytes.

BACKGROUND: Progressive multifocal leukoencephalopathy is a demyelinating CNS disorder. Reactivation of John Cunningham virus leads to oligodendrocyte infection with lysis and consequent axonal loss due to demyelination. Patients usually present with confusion and seizures. Late diagnosis and lack of adequate therapy options persistently result in permanent impairment of brain functions. Due to profound T cell depletion, impairment of T-cell function and potent immunosuppressive factors, allogeneic hematopoietic cell transplantation recipients are at high risk for JCV reactivation. To date, PML is almost universally fatal when occurring after allo-HCT. METHODS: To optimize therapy specificity, we enriched JCV specific T-cells out of the donor T-cell repertoire from the HLA-identical, anti-JCV-antibody positive family stem cell donor by unstimulated peripheral apheresis [1]. For this, we selected T cells responsive to five JCV peptide libraries via the Cytokine Capture System technology. It enables the enrichment of JCV specific T cells via identification of stimulus-induced interferon gamma secretion. RESULTS: Despite low frequencies of responsive T cells, we succeeded in generating a product containing 20 000 JCV reactive T cells ready for patient infusion. The adoptive cell transfer was performed without complication. Consequently, the clinical course stabilized and the patient slowly went into remission of PML with JCV negative CSF and containment of PML lesion expansion. CONCLUSION: We report for the first time feasibility of generating T cells with possible anti-JCV activity from a seropositive family donor, a variation of virus specific T-cell therapies suitable for the post allo transplant setting. We also present the unusual case for successful treatment of PML after allo-HCT via virus specific T-cell therapy.

The Influence of Donor and Recipient Gender Incompatibility on Corneal Transplant Rejection and Failure.

In vascularized organ transplants, gender mismatches have higher rates of immunological rejection. We investigated the influence of gender incompatibility, including H-Y incompatibility, on corneal transplant graft rejection and failure. Patients were included who had undergone a first corneal transplant for keratoconus (KC), Fuchs endothelial dystrophy (FED), pseudophakic bullous keratopathy (PBK), infection and other indications. A Cox regression model was fitted for each indication to determine factors affecting graft failure and rejection at 5 years. The impact of gender, including H-Y, matching was analyzed after accounting for other factors, including known risk factors. Of 18 171 patients, 4314 had undergone a transplant for FED, 4783 for KC, 3669 for PBK, 1903 for infection and 3502 for other disorders. H-Y mismatched (male [M]→female [F]) corneas were at greater risk of graft failure or rejection. For FED, F→F were 40% less likely to fail (p < 0.0001) and 30% less likely to reject (p = 0.01); M→M were 20% less likely to fail (p = 0.04) and 30% less likely to reject (p = 0.01). For KC, M→M matched corneas were 30% less likely to fail (p = 0.05) and 20% less likely to reject (p = 0.01) compared with H-Y mismatches. H-Y antigen mismatched (M→F) patients were at greater risk of rejection or graft failure.

The epidemiology and outcomes of women with postpartum haemorrhage requiring massive transfusion with eight or more units of red cells: a national cross-sectional study.

OBJECTIVE: To ascertain the incidence of massive transfusion (MT) in obstetrics in the UK, and describe its management and clinical outcomes. DESIGN: A population-based cross-sectional study conducted through the UK Obstetric Surveillance System (UKOSS). SETTINGS: All UK hospitals with consultant-led maternity units. POPULATION: Any pregnant woman at ≥20 weeks of gestation receiving ≥8 units of red blood cells within 24 hours of giving birth, from July 2012 to June 2013. METHODS: Prospective case identification through the monthly mailing of UKOSS. RESULTS: We identified 181 women who had undergone MT, making the estimated incidence of MT associated with postpartum haemorrhage (PPH) 23 per 100 000 maternities (95% confidence interval 19-26) per year. The median estimated blood loss was 6 l (interquartile range 4.5-8.0 l). The majority of women presented outside working hours (63%), 40% had had previous caesarean sections and 3% had normal vaginal births without risk factors. The main cause for MT was uterine atony (40%) and the main mode of birth was caesarean section (69%). Of the 181 women, 15 received >20 units of red blood cells. In total, 45% of women underwent hysterectomy, and among all causes of PPH, placenta accreta had the highest hysterectomy rate. Two women died, 82% were admitted to intensive care/high-dependency units, and 28% developed major morbidities. CONCLUSION: Massive transfusion due to PPH is associated with high rates of morbidity and hysterectomy. Clinical and research efforts should focus on approaches to recognise and optimise timely resuscitation and management of these severe cases. TWEETABLE ABSTRACT: Massive transfusion due to postpartum haemorrhage is associated with high rates of morbidity and hysterectomy.

Peatland-fire interactions: A review of wildland fire feedbacks and interactions in Canadian boreal peatlands.

Boreal peatlands store a disproportionately large quantity of soil carbon (C) and play a critical role within the global C-climate system; however, with climatic warming, these C stores are at risk. Increased wildfire frequency and severity are expected to increase C loss from boreal peatlands, contributing to a shift from C sink to source. Here, we provide a comprehensive review of pre- and post-fire hydrological and ecological interactions that affect the likelihood of peatland burning, address the connections between peatland fires and the C-climate cycle, and provide a conceptual model of peatland processes as they relate to wildland fire, hydro-climate, and ecosystem change. Despite negative ecohydrological feedback mechanisms that may compensate for increased C loss initially, the cumulative effects of climatic warming, anthropogenic peatland fragmentation, and subsequent peatland drying will increase C loss to the atmosphere, driving a positive C feedback cycle. However, the extent to which negative and positive feedbacks will compensate for one another and the timelines for each remains unclear. We suggest that a multi-disciplinary approach of combining process knowledge with remotely sensed data and ecohydrological and wildland fire models is essential for better understanding the role of boreal peatlands and wildland fire in the global climate system.

Shrub changes with proximity to anthropogenic disturbance in boreal wetlands determined using bi-temporal airborne lidar in the Oil Sands Region, Alberta Canada.

In this study, we used bi-temporal airborne lidar data to compare changes in vegetation height proximal to anthropogenic disturbances in the Oil Sands Region of Alberta, Canada. We hypothesize that relatively low-impact disturbances such as seismic lines will increase the fragmentation of wetlands, resulting in shrub growth. Bi-temporal lidar data collected circa 2008 and 2018 were used to identify correspondence between the density of anthropogenic disturbances, wetland shape complexity and changes in vegetation height within >1800 wetlands near Fort McKay, Alberta, Canada. We found that up to 50% of wetlands were disturbed by anthropogenic disturbance in some parts of the region, with the highest proportional disturbance occurring within fens. Areas of dense anthropogenic disturbance in bogs resulted in increased growth and expansion of shrubs, while we found the opposite to occur in fens and swamps during the 10-year period. Up to 30% of bogs had increased shrubification, while shrub changes in fens and swamps varied depending on density of disturbance and did not necessarily correspond with shrub growth. As wetland shapes became increasingly elongated, the prevalence of shrubs declined between the two time periods, which may be associated with hydrological drivers (e.g. elongated may indicate surface and ground-water discharge influences). The results of this study indicate that linear disturbances such as seismic lines, considered to have relatively minimal impacts on ecosystems, can impact proximal wetland shape, fragmentation and vegetation community changes, especially in bogs.

Net energy analysis of alcohol production from sugarcane.

Energy requirements were calculated for the agricultural and the industrial phase of ethyl alcohol production from sugarcane grown in Louisiana. Agricultural energy requirements comprised 54 percent of all energy inputs, with machinery, fuel, and nitrogen fertilizer representing most of the energy subsidies. Overall net energy benefits (output:input) for alcohol production ranged from 1.8:1 to 0.9:1 depending on whether crop residues or fossil fuels were used for industrial processes.

A retrospective audit exploring the use of relaxation as an intervention in oncology and palliative care.

The benefits of relaxation in cancer care have been well documented within the literature, with the majority of research being undertaken by nursing professionals. However, evidence of the effectiveness of relaxation interventions by occupational therapists is lacking. Occupational therapists are in an ideal situation to provide information and practical relaxation sessions. Although in numerical terms, the outcome of relaxation interventions is small, functional outcome related to quality of life and independence in activities of daily living is immeasurable. This article reports the findings of a retrospective audit exploring relaxation-specific referrals to occupational therapy, and identifies effectiveness of a variety of different techniques currently employed within this specific programme. Patients with a primary diagnosis of breast cancer were the most frequently seen, and this prevalence is reflected in current national statistics. Similarly, those between 50 and 59 years of age comprised the largest group. Guided visualization was the most commonly used technique, although there appeared to be very little change in perceived tension between all the techniques. Further study of the impact relaxation has on occupational performance would be worthwhile.

Successful resolution of dermatophyte mycetoma following terbinafine treatment in two cats.

Microsporum canis sensitive to itraconazole and terbinafine was isolated from two cats presented with generalized dermatophytosis and dermatophyte mycetoma. Itraconazole therapy was withdrawn through lack of efficacy in one cat (a Persian) and unacceptable adverse effects in the other (a Maine Coon). Both cats achieved clinical and mycological cure after 12-14 weeks therapy with 26-31 mg kg(-1) terbinafine every 24 h per os (PO). Clinical signs in the Maine Coon resolved completely after 7 weeks treatment. Four weeks of therapy with additional weekly washes with a 2% chlorhexidine/2% miconazole shampoo following clipping produced a 98% reduction in the Persian cat's mycetoma, which was then surgically excised. Recurrent generalized dermatophytosis in the Persian cat has been managed with pulse therapy with 26 mg kg(-1) terbinafine every 24 h PO for 1 week in every month. No underlying conditions predisposing to dermatophytosis were found in either cat despite extensive investigation. Terbinafine administration was associated with mild to moderate lethargy in the Persian cat, but no other adverse effects or changes in blood parameters were seen. To the best of the authors' knowledge this is the first report of a dermatophyte mycetoma in a Maine Coon and of successful resolution of this condition in cats following terbinafine therapy.

Concentration of oestradiol, progesterone, luteinizing hormone and follicle-stimulating hormone in the jugular venous plasma of ewes during the oestrous cycle.

Changes in the concentrations of ovarian steroids and pituitary gonadotrophins were measured by radioimmunoassay in the jugular plasma of six Clun Forest ewes throughout the oestrous cycle. The concentration of oestradiol began to rise 12-14 h before the onset of oestrus from values of 11-2 +/- 0-36 (S.E.M.) pg/ml during the luteal phase to 21-1 +/- 2-01 pg/ml at -8 to 0 h (oestrus). There was no distinct increase during the luteal phase. Circulating progesterone varied in a cyclic manner with the highest values at the mid-luteal phase (3-70 +/- 0-28 ng/ml; n = 28). In five out of six ewes the concentration was still quite high (1-86 +/- 0-43 ng/ml) at 35 h before the onset of oestrus. The concentration declined rapidly thereafter, reaching minimum values about 12 h before oestrus coincident with the increase in oestradiol concentration. Plasma LH increased from very low values of 2-59 +/- 0-09 ng/ml during the luteal phase to 75-3 +/- 7-4 ng/ml about 9 h after the onset of oestrus. Two peaks of plasma FSH concentration were detected after the onset of oestrus. The first peak (171-0 +/- 35-5 ng/ml) coincided with the LH peak and the second (133-0 +/- 10-7 ng/ml) occurred about 24 h later at a time when LH values were low. The mean FSH concentration at other times during the cycle was 61-9 +/- 2-8 ng/ml.

Smoking, drinking, and other life style factors and cognitive function in men in the Caerphilly cohort.

STUDY OBJECTIVES: To examine the cognitive function in a large, ongoing cohort study of older men, and to identify associations with social and lifestyle factors. DESIGN: A cross sectional study of cognitive function was conducted within the Caerphilly Prospective Study of Heart Disease and stroke. SETTING: The Caerphilly Study was originally set up in 1979-83 when the men were 45-59 years of age. Extensive data are available on a wide range of lifestyle and other factors of possible relevance to cognitive decline. Associations between some of these and cognitive function are reported. PARTICIPANTS: A representative sample of 1870 men aged 55-69 years. MAIN RESULTS: Age, social class, medication, and mood were found to be powerful determinants of performance. Self report data on the involvement of the men in leisure pursuits were examined by factor analysis. This indicated that the more intellectual leisure pursuits are the most strongly linked with performance. A measure of social contact showed a weak positive association with the test scores. Current cigarette smokers gave lower test cognitive function scores than either men who had never smoked, or ex-smokers. There was however no evidence of any gradient in function with the total lifetime consumption of tobacco. The disparity between these two data sets suggests that there had been prior selection of men who had originally started to smoke, but more particularly selection of those who later quit smoking. There was no significant association between alcohol consumption and cognitive function, though ex-drinkers had markedly lower test scores than either current drinkers or men who had never drunk alcohol. This seemed probably to be a consequence of an high prevalence of illness among the ex-drinkers. CONCLUSIONS: Age and social class show strong associations with cognitive function. Leisure persuits and social contact are also both positively associated. Neither tobacco smoking nor the drinking of alcohol seem to be associated with cognitive function, though there is evidence suggestive of self selection of both men who had never smoked and ex-smokers.

Warm-up exercises: can learning be fun?

This article explores the principles and practice of warm-up exercises or icebreakers during interpersonal skills training for Project 2000 student nurses. Warm-up exercises--an example of an experiential learning activity--may be useful but they must always have an educational purpose and allow participants to opt out. The author suggests that in reality educational principles are not always the basis for such exercises and that the very nature of these exercises may make students feel opting out is not always possible.

Toward the development of generally applicable models of the microbial loop in aquatic ecosystems.

Simulation modeling has been an integral, albeit ad hoc, component of the field of aquatic microbial ecology for the past two decades. One of the most critical steps in simulation modeling is the initial formulation of a clear set of questions and goals. It is doubtful that a single generic model could be constructed to address adequately all questions of interest concerning the microbial loop because of the tremendous range in time scales that define these questions. Progress in the field of aquatic microbial ecology will benefit from an integrated research program including experimental and modeling approaches. A submodel of bacterial utilization of various qualities of organic matter that we have under construction is presented. This submodel will be a component of a larger model to evaluate the effects of quality and quantity of organic matter and inorganic nutrient inputs on estuarine food web structure and efficiency. The overall model will be general enough in its structure that it should be applicable to a wide range of questions concerning the microbial loop, with time scales ranging from hours to days.

Inactivation of two hyperactive LH-RH analogues by rat hypothalamic peptidases.

Hyperactive analogues of luteinizing hormone-releasing hormone (LH-RH) are beleived to derive their properties from either increased binding affinity to anterior pituitary receptor sites or through decreased susceptibility to enzymic degradation. To investigate the latter suggestion and to examine the possible sites of hypothalamic peptidases inactivating LH-RH, D-Ser(TBU)6-EA10-LH-RH and D-Leu6-EA10-LH-RH, which are known to have considerably greater activity than LH-RH, were incubated with a hypothalamic supernatant fraction containing active peptidases degrading LH-RH, and their gonadotrophin-releasing ability after incubation with the enzymes was tested in normal, adult male rats; LH-RH was also tested in the same way. From a comparison of the relative losses of biological activity, both the LH-RH analogues treated proved to be more resistant to the hypothalamic peptidases than LH-RH itself; the D-Leu6-EA10-LH-RH retained its gonadotrophin-releasing activity longer than the D-Ser(TUB)6-EA10-LH-RH. These findings indicate that increased activity of the analogues may, in part be due to increased resistance to enzymic inactivation and suggest initial sites of cleavage at the Gly-leu and Pro-Gly NH2 bonds in the LH-RH decapeptide by the hypothalamic enzymes. Studies on the action of peptidases on LH-RH and its analogues may yield useful information in the design of peptidase with increased biological activity.

Purification of "inhibin" from human ovarian follicular fluid.

Following the earlier demonstration of inhibin-like activity in human ovarian follicular fluid a method for its purification to apparent homogeneity is described. The fluid was converted to acetone powder and subjected sequentially to ammonium sulphate fractionation, gel chromatography on Sephadex G-200, continuous gradient ion-exchange chromatography on DEAE-cellulose, first with a pH gradient from 8.0 to 4.0 and then with a NaCl gradient to 1 M at pH 5.2. The active fraction from this step was subjected to gel filtration on Sephadex G-100 and finally passed through an Amicon Centriflo membrane CF-25 (cut off point: 25,000 m.w.). The ultrafiltrate was homogeneous by SDS-polyacrylamide gel electrophoresis, had a molecular weight of the order of 23 000 and was capable of suppressing serum gonadotrophin levels in the castrated male rats in as low a dose as 25 microgram/rat.