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1.  Controlled Trial of Transfusions for Silent Cerebral Infarcts in Sickle Cell Anemia 
The New England journal of medicine  2014;371(8):699-710.
BACKGROUND
Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood-transfusion therapy than among those who received standard care.
METHODS
In this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct.
RESULTS
A total of 196 children (mean age, 10 years) were randomly assigned to the observation or transfusion group and were followed for a median of 3 years. In the transfusion group, 6 of 99 children (6%) had an end-point event (1 had a stroke, and 5 had new or enlarged silent cerebral infarcts). In the observation group, 14 of 97 children (14%) had an end-point event (7 had strokes, and 7 had new or enlarged silent cerebral infarcts). The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events, respectively, per 100 years at risk, corresponding to an incidence rate ratio of 0.41 (95% confidence interval, 0.12 to 0.99; P = 0.04).
CONCLUSIONS
Regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia. (Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial ClinicalTrials.gov number, NCT00072761, and Current Controlled Trials number, ISRCTN52713285.)
doi:10.1056/NEJMoa1401731
PMCID: PMC4195437  PMID: 25140956
2.  Does it Matter What You Call It? A Randomized Trial of Language Used to Describe Palliative Care Services 
Purpose
Integration of palliative care into oncology practice remains suboptimal. Misperceptions about the meaning of palliative care may negatively impact utilization. We assessed whether the term and/or the description of palliative care services affected patient views.
Methods
2×2 between-subject randomized factorial telephone survey of 169 patients with advanced cancer. Patients were randomized into 1 of 4 groups that differed by name (supportive care vs. palliative care) and description (patient-centered vs. traditional). Main outcomes (0–10 Likert scale) were patient understanding, impressions, perceived need, and intended use of services.
Results
When compared to palliative care, the term supportive care was associated with better understanding (7.7 vs. 6.8; p=0.021), more favorable impressions (8.4 vs. 7.3; p=0.002), and higher future perceived need (8.6 vs. 7.7; p=0.017). There was no difference in outcomes between traditional and patient-centered descriptions. In adjusted linear regression models, the term supportive care remained associated with more favorable impressions (p=0.003) and higher future perceived need (p=0.022) when compared to palliative care.
Conclusions
Patients with advanced cancer view the name supportive care more favorably than palliative care. Future efforts to integrate principles of palliative medicine into oncology may require changing impressions of palliative care or substituting the term supportive care.
doi:10.1007/s00520-013-1919-z
PMCID: PMC3823760  PMID: 23942596
Palliative Care; Supportive Care; Advanced Cancer; Communication; Oncology
3.  Hepcidin levels in diabetes mellitus and polycystic ovary syndrome 
Diabetic Medicine  2013;30(12):1495-1499.
Aim
Increased body iron is associated with insulin resistance. Hepcidin is the key hormone that negatively regulates iron homeostasis. We hypothesized that individuals with insulin resistance have inadequate hepcidin levels for their iron load.
Methods
Serum concentrations of the active form of hepcidin (hepcidin-25) and hepcidin:ferritin ratio were evaluated in participants with Type 2 diabetes (n = 33, control subjects matched for age, gender and BMI,n = 33) and participants with polycystic ovary syndrome (n = 27, control subjects matched for age and BMI,n = 16). To investigate whether any changes observed were associated with insulin resistance rather than insulin deficiency or hyperglycaemia per se, the same measurements were made in participants with Type 1 diabetes (n = 28, control subjects matched for age, gender and BMI,n = 30). Finally, the relationship between homeostasis model assessment of insulin resistance and serum hepcidin:ferritin ratio was explored in overweight or obese participants without diabetes (n = 16).
Results
Participants with Type 2 diabetes had significantly lower hepcidin and hepcidin:ferritin ratio than control subjects (P < 0.05 and P < 0.01, respectively). Participants with polycystic ovary syndrome had a significantly lower hepcidin:ferritin ratio than control subjects (P < 0.05). There was no significant difference in hepcidin or hepcidin:ferritin ratio between participants with Type 1 diabetes and control subjects (P = 0.88 and P = 0.94). Serum hepcidin:ferritin ratio inversely correlated with homeostasis model assessment of insulin resistance (r = –0.59, P < 0.05).
Conclusion
Insulin resistance, but not insulin deficiency or hyperglycaemia per se, is associated with inadequate hepcidin levels. Reduced hepcidin concentrations may cause increased body iron stores in insulin-resistant states.
doi:10.1111/dme.12262
PMCID: PMC4232927  PMID: 23796160
4.  Non-myeloablative allogeneic hematopoietic transplantation for patients with hematologic malignancies: 9-year single-centre experience 
Current Oncology  2014;21(3):e434-e440.
Matched related and unrelated allogeneic nonmyeloablative hematopoietic transplantation (nmt) is increasingly being used in patients with hematologic malignancies. Conditioning regimens and indications for nmt vary considerably from centre to centre. Our institution uses intravenous fludarabine and cyclophosphamide, plus graft-versus-host disease (gvhd) prophylaxis with tacrolimus and mycophenolate mofetil. We retrospectively analyzed 89 consecutive patients who underwent nmt (65 related, 24 unrelated) at our institution from October 2002 to September 2011. The most frequent indications for nmt were acute myelocytic leukemia (high-risk in first complete or subsequent remission: n = 20, 22.5%) and relapsed follicular lymphoma (n = 18, 20.2%). The cumulative incidence of acute gvhd (grades 2–4) was 28.1% (n = 25), and rates were similar for related (n = 18, 28%) and unrelated (n = 7, 29%) nmt. At a median follow-up of 22.6 months, the cumulative incidence of chronic gvhd (limited and extensive) was 68% (n = 61): 68.5% (n = 44) for related and 71% (n = 17) for unrelated nmt. The 100-day transplant-related mortality rate was 2.2%: 1.5% for related and 4.2% for unrelated nmt. Of the 89 patients, 30 (33.7%) have relapsed: 41.5% after related and 12.5% after unrelated nmt. Relapse rates were similar in patients with myeloid and lymphoid malignancies (36.4% vs. 33.3%). The 3-year overall and progression-free survival rates were 50.0% and 43.4% respectively, with multivariate analysis showing that neither rate was affected by age, disease group, status at transplantation, or related compared with unrelated nmt. Our findings indicate that, despite its limitations, including the incidence of chronic gvhd, nmt is an important treatment modality for a selected subgroup of patients with hematologic malignancies.
doi:10.3747/co.21.1846
PMCID: PMC4059807  PMID: 24940103
Non-myeloablative stem-cell transplantation; conditioning regimens; graft-versus-host disease
5.  Phase I and II enzyme polymorphisms as risk factors for Barrett’s esophagus and esophageal adenocarcinoma: a systematic review and meta-analysis 
SUMMARY
Although several studies have examined the association between phase I/II enzyme polymorphisms and esophageal adenocarcinoma (EAC) and/or Barrett’s esophagus (BE), their overall findings remain unclear. We performed a systematic review and meta-analysis to determine whether phase I/II polymorphisms are independent risk factors for either BE or EAC. We employed keyword searches in multiple databases to identify studies published before October 1, 2007. Single-nucleotide polymorphisms (SNPs) examined in ≥3 studies were meta-analyzed to obtain a pooled estimate of effect. Meta-analysis suggested the minor allele for GSTP1 Val105 conveys modest excess risk (odds ratio [OR]BE = 1.50, 95% confidence interval [CI] 1.16–1.95; OREAC = 1.20, 95% CI 0.94–1.54). No excess risk was observed with GSTM1 null (ORBE = 0.77, 95% CI: 0.56–1.08; OREAC = 1.08, 95% CI: 0.79–1.48), GSTT1 null (ORBE = 1.35, 95% CI: 0.91–2.01; OREAC = 0.84, 95% CI: 0.48–1.49), or CYP1A Val462 (OREAC = 0.89, 95% CI: 0.40–1.97). Insufficient data existed to meta-analyze remaining SNPs. Our review identified GSTP1Ile105Val as a possible risk factor for BE and EAC in Caucasian males. No excess risk was observed for other phase I/II polymorphisms with sufficient data to meta-analyze. Additional studies are needed to determine if GSTP1 conveys excess risk in females or non-Caucasians and to evaluate other phase I/II polymorphisms.
doi:10.1111/j.1442-2050.2009.00947.x
PMCID: PMC4018839  PMID: 19222528
Barrett’s esophagus; epidemiology; esophageal adenocarcinoma; genetic association; GST; single-nucleotide polymorphism (SNP)
6.  Loss of OPA1 disturbs cellular calcium homeostasis and sensitizes for excitotoxicity 
Cell Death and Differentiation  2012;20(2):353-365.
Optic atrophy 1 (OPA1) mutations cause dominant optic atrophy (DOA) with retinal ganglion cell (RGC) and optic nerve degeneration. The mechanism for the selective degeneration of RGCs in DOA remains elusive. To address the mechanism, we reduced OPA1 protein expression in cell lines and RGCs by RNA interference. OPA1 loss results in mitochondrial fragmentation, deficiency in oxidative phosphorylation, decreased ATP levels, decreased mitochondrial Ca2+ retention capacity, reduced mtDNA copy numbers, and sensitization to apoptotic insults. We demonstrate profound cristae depletion and loss of crista junctions in OPA1 knockdown cells, whereas the remaining crista junctions preserve their normal size. OPA1-depleted cells exhibit decreased agonist-evoked mitochondrial Ca2+ transients and corresponding reduction of NAD+ to NADH, but the impairment in NADH oxidation leads to an overall more reduced mitochondrial NADH pool. Although in our model OPA1 loss in RGCs has no apparent impact on mitochondrial morphology, it decreases buffering of cytosolic Ca2+ and sensitizes RGCs to excitotoxic injury. Exposure to glutamate triggers delayed calcium deregulation (DCD), often in a reversible manner, indicating partial resistance of RGCs to this injury. However, when OPA1 is depleted, DCD becomes irreversible. Thus, our data show that whereas OPA1 is required for mitochondrial fusion, maintenance of crista morphology and oxidative phosphorylation, loss of OPA1 also results in defective Ca2+ homeostasis.
doi:10.1038/cdd.2012.128
PMCID: PMC3554330  PMID: 23138851
calcium; mitochondria; OPA1
7.  Sleep duration and incidence of colorectal cancer in postmenopausal women 
British Journal of Cancer  2013;108(1):213-221.
Background:
Sleep duration is dependent on circadian rhythm that controls a variety of key cellular functions. Circadian disruption has been implicated in colorectal tumorigenesis in experimental studies. We prospectively examined the association between sleep duration and risk of colorectal cancer (CRC).
Methods:
In the Women's Health Initiative Observational Study, 75 828 postmenopausal women reported habitual sleep duration at baseline 1993–1998. We used Cox proportional hazards regression model to estimate the hazard ratio (HR) of CRC and its associated 95% confidence interval (CI).
Results:
We ascertained 851 incident cases of CRC through 2010, with an average 11.3 years of follow-up. Compared with 7 h of sleep, the HRs were 1.36 (95% CI 1.06–1.74) and 1.47 (95% CI 1.10–1.96) for short (⩽5 h) and long (⩾9 h) sleep duration, respectively, after adjusting for age, ethnicity, fatigue, hormone replacement therapy (HRT), physical activity, and waist to hip ratio. The association was modified by the use of HRT (P-interaction=0.03).
Conclusion:
Both extreme short and long sleep durations were associated with a moderate increase in the risk of CRC in postmenopausal women. Sleep duration may be a novel, independent, and potentially modifiable risk factor for CRC.
doi:10.1038/bjc.2012.561
PMCID: PMC3553538  PMID: 23287986
sleep; colorectal neoplasms; risk factors; women; prospective studies
9.  Upper airway collapsibility, dilator muscle activation and resistance in sleep apnoea 
The European respiratory journal  2007;30(2):10.1183/09031936.00063406.
The calibre of the upper airway is thought to be dependant upon its passive anatomy/collapsibility and the activation of pharyngeal dilator muscles. During awake periods, the more collapsible upper airway in obstructive sleep apnoea (OSA) increases the dilator muscle activity through a negative-pressure reflex.
A direct correlation between the critical closing pressure (Pcrit), as a measure of anatomy/collapsability and electromyogram (EMG) activity of genioglossus EMG (GG-EMG) and tensor palatini EMG (TP-EMG), was hypothesised. The relationship between these indices and pharyngeal resistance (Rphar) was also examined.
The study involved eight males with a mean age of 48 (interquartile range 46–52) yrs with OSA, and an apnoea/hypopnoea index of 75 (65–101)·hr−1 on two nights breathing normally and on nasal continuous positive airway pressure (nCPAP). The Pcrit was measured during nonrapid eye movement sleep on nCPAP using brief, incremental reductions in mask pressure. GG-EMG and TP-EMG were measured breath-by-breath, awake, during sleep onset and on nCPAP. Rphar was measured using airway pressures and flow.
Wakeful GG-EMG, early sleep TP-EMG and the sleep decrement in TP-EMG were directly related to Pcrit. Muscle activation was negatively correlated with Rphar for TP-EMG awake and GGEMG early in sleep.
In conclusion these results confirm that dilator muscle activation is directly related to airway narrowing and reduces resistance across patients with obstructive sleep apnoea.
doi:10.1183/09031936.00063406
PMCID: PMC3817291  PMID: 17459896
Airway mechanics; airways resistance; muscle function; obstructive sleep apnoea; pharynx
10.  Evaluation of the Safety and Immunogenicity of a Candidate Tuberculosis Vaccine, MVA85A, Delivered by Aerosol to the Lungs of Macaques 
Tuberculosis (TB) is a reemerging disease. The only available vaccine, Mycobacterium bovis BCG, is delivered intradermally and confers highly variable efficacy against pulmonary disease. There is an urgent need for improved vaccination strategies. Murine studies suggest that immunizations delivered directly to the respiratory mucosa might be a more effective route of vaccination. This study compared the immunogenicity of a leading candidate tuberculosis (TB) vaccine, modified vaccinia virus Ankara expressing antigen 85A (MVA85A), in rhesus macaques, delivered either as an aerosol or as an intradermal boost immunization 12 weeks after an intradermal BCG prime vaccine. Aerosol vaccination was well tolerated. MVA85A delivered by aerosol or by intradermal injection induced antigen-specific immune responses in the periphery and the lung, with a trend toward the highest response when the compartment and route of delivery were matched. The ability of poxvirus-vectored vaccines delivered by the systemic route to induce responses in the mucosal immune compartment in macaques is in contrast to the independent compartmentalization of mucosal and systemic immune systems described in mice. Unlike intradermal vaccination, aerosol vaccination did not induce a detectable serum anti-vector antibody response. The delivery of vaccines to the lungs might provide an immunization strategy that limits the induction of systemic anti-vector immunity, which would be extremely useful in the development of improved vaccine strategies. This is the first study to show a recombinant MVA-vectored vaccine to be highly immunogenic when delivered by the aerosol route to nonhuman primates. These results provide important safety and proof-of-concept data for further evaluation of this route of immunization for use in human clinical trials.
doi:10.1128/CVI.00690-12
PMCID: PMC3647747  PMID: 23446219
11.  Rapidly progressive multifocal phyllodes tumour of the breast: A case report and review of the literature☆ 
INTRODUCTION
Malignant transformation of a phyllodes tumour is a rare form of breast cancer, accounting for just 0.5% of all breast cancer cases.1
PRESENTATION OF CASE
We report a case of a 49 year old female with rapidly progressive, multifocal disease. She initially presented with two giant fibroadenomas which were excised. She represented eight months post surgery with two new lesions in the same breast, one suspicious, one suggestive of fibroadenoma. Biopsy was borderline. Surgery was therefore scheduled for wide local excision. At localisation two weeks later, at least eight lesions were seen on ultrasound scan. Three were removed as histology was at this point unknown to conserve the breast. Histology revealed intermediate grade DCIS, benign Phyllodes and borderline/malignant phyllodes. She was scheduled for mastectomy and immediate Strattice reconstruction. An MRI was performed pre-operatively to ascertain extent of disease. Two weeks post localisation, 13 lesions were identified. The right breast was entirely unaffected. Surgery interval was three weeks and final histology revealed 18 lesions, ranging from fibroadenoma through to borderline/malignant phyllodes with an incidental papilloma.
DISCUSSION
This is the first report of such rapid progression of disease, with 16 new lesions, of varied histology, developing in just an eight week period.
CONCLUSION
This case highlights the difficulty of forming a clear diagnostic and therapeutic pathway in this highly variable disease. Arguments for over and under treating these patients remain but those with any borderline/malignant potential have to be removed as recurrence is both common and aggressive, with a clear surgical margin the only proven protective factor.
doi:10.1016/j.ijscr.2013.04.042
PMCID: PMC3785922  PMID: 24013041
Breast; Phyllodes; Cancer; Surgery; Multifocal
12.  Contrasting effects of diclofenac and ibuprofen on active imatinib uptake into leukaemic cells 
British Journal of Cancer  2012;106(11):1772-1778.
Background:
The human organic cation transporter-1 (OCT-1) is the primary active protein for imatinib uptake into target BCR-ABL-positive cells. Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used by chronic myeloid leukaemia (CML) patients on imatinib to manage musculoskeletal complaints.
Methods:
Here we investigated the impact of NSAIDs on functional activity of the OCT-1 (OCT-1 activity; OA) in CML cells.
Results:
Although ten of twelve NSAIDs tested had no significant impact on OA (P>0.05), we observed increased OA (27% increase in K562; 22% increase in KU812 cells, P<0.05) and reduced IC50imatinib when treated with diclofenac. Co-incubation with imatinib and diclofenac resulted in a significantly lower viable cell number compared with imatinib alone. In contrast, ibuprofen led to a significant decrease in OA, an increase in IC50imatinib and thus reduced the cytotoxicity of imatinib. In primary CML samples, diclofenac significantly increased OA, particularly in patients with low OA (<4 ng per 200 000 cells), and significantly decreased IC50imatinib. Ibuprofen induced significant decreases in OA in CML samples and healthy donors.
Conclusion:
On the basis of the expected impact of these two drugs on OA, ibuprofen should be avoided in combination with imatinib. Further studies are warranted regarding the potential benefit of diclofenac to improve OA in a clinical setting.
doi:10.1038/bjc.2012.173
PMCID: PMC3364120  PMID: 22531634
CML; OCT-1; drug–drug interaction; NSAIDs; imatinib
13.  MEMRI study - feedback of MEMS dosing history improves adherence to long-term HAART: adherence is associated with incidence of ‘blips’ in viral load 
In routine clinical care we investigated the effect on adherence to HAART of feedback to each patient of graphical plots highlighting recent errors in their dosing history, as compiled electronically using MEMS®. Patients established on HAART were randomised to receive either active feedback of recent dosing errors (Group A) at clinic visits, or to serve as controls (no feedback) (Group B). After 12 months the control group were un-blinded and given feedback for a further 6 months. Questionnaires were completed in the waiting room for adherence (GEEMA), Necessity/Concerns, Intrusiveness, Self-efficacy and Conscientiousness (baseline only). Those declining/excluded from using MEMS were invited to complete baseline questionnaires (Group C). Adherence was estimated from MEMS data as the average proportion of days with at least the prescribed number of doses taken between successive appointments. Drug Holidays (DH) were defined as 3 or more consecutive days without dosing. Of a cohort of 727 ~270 were approached. 180 were randomised. 147 had evaluable MEMS data (68 Group B: 79 Group A). 85 were in Group C (questionnaires only). Baseline characteristics were similar between Group A and B. Group C had a less common past history of AIDS. There was no significant difference in baseline conscientiousness between Groups A and B. Missed doses were much more likely at weekends than weekdays (OR=1.25; [1.15–1.35]). Those taking <95% of prescribed doses during the first interval between visits were defined as poor adherers, which included 69 patients (49%). Their average baseline adherence was 78%. In Group A, average adherence increased (p=0.001) to 90% after the first feedback session, while in Group B average adherence remained stable (p=0.405). In Group B, after un-blinding and start of feedback, adherence increased to 93%. Patients in Group B were significantly less likely to bring back their MEMS for reading at each appointment (p=0.031). The incidence of viral load ‘blips’ (>50 copies/ml) was significantly increased by DH (p=0.007), frequency of DH (p=0.016), length of DH (p=0.005), and missed doses during the 4 weeks before attendance (p=0.001). Feedback of electronically compiled dosing history data improves adherence to HAART treatment and appears to be an effective intervention for reducing the incidence of viral load ‘blips’. Further results including analysis of the questionnaires will be presented.
doi:10.7448/IAS.15.6.18062
PMCID: PMC3512467
14.  Weight Loss Goals among African American Women with Type 2 Diabetes in a Behavioral Weight Control Program 
Obesity (Silver Spring, Md.)  2011;19(11):2283-2285.
African American women with type 2 diabetes experience limited weight loss in behavioral weight control programs. Some research suggests overly ambitious weight loss expectations may negatively affect weight losses achieved but it is unknown whether they affect weight loss among African American women. The current study examined personal weight loss goals and expected satisfaction with a reasonable weight loss among African American women with type 2 diabetes starting a behavioral obesity treatment. We also explored associations among these factors and weight loss treatment outcomes. Self-identified African American women (N= 84) in a 24-session group program were assessed at baseline and 6-month follow up. At baseline, women indicated weight loss goals of 14.1 ± 6.6 kg (14% of initial weight). They also reported relatively high expected satisfaction with a reasonable weight loss (7–10%). On average, participants lost 3.0 ± 3.9 kg (3% of initial weight) and attended 73 ± 21% of group sessions. Neither weight loss goals nor expected satisfaction with a reasonable weight loss was correlated with either actual weight loss outcome or attendance. Having higher personal weight loss goals was associated with lower expectations of satisfaction with a reasonable weight loss. This suggests African American women with type 2 diabetes enter treatment hoping to lose far more weight than they are likely to achieve. It is important to understand the psychosocial sequelae of failing to reach these goals on subsequent weight maintenance and future weight loss attempts within this population.
doi:10.1038/oby.2010.350
PMCID: PMC3123677  PMID: 21273996
weight loss goals; weight loss; African American women; obesity; type 2 diabetes
15.  Gastric ulcers and swollen kidneys: a rare diagnosis complicating Crohn's disease 
BMJ Case Reports  2010;2010:bcr0320102809.
We present a case of a 48-year-old woman with Crohn's colitis admitted with abdominal pain and fever. She had been started on azathioprine 6 months before presentation and had received three doses of infliximab.
Abdominal CT scan revealed a liver abscess. Azathioprine was stopped and antibiotics started. She was subsequently discharged with follow-up imaging planned.
She presented 3 weeks later with haematemesis. Gastroscopy revealed multiple gastric ulcers. A repeat CT scan showed bilateral renal masses and a renal biopsy was arranged. Gastric and renal biopsies were consistent with B cell lymphoma. Chemotherapy was started and resulted in improvement in CT scan findings as well as ulcer healing.
doi:10.1136/bcr.03.2010.2809
PMCID: PMC3029454  PMID: 22778189
16.  Fenretinide-dependent upregulation of death receptors through ASK1 and p38α enhances death receptor ligand-induced cell death in Ewing's sarcoma family of tumours 
British Journal of Cancer  2010;103(9):1380-1390.
Background:
Sustained p38MAPK phosphorylation upregulates p75 neurotrophin (p75NTR) and induces apoptosis in Ewing's sarcoma family of tumours (ESFT). As fenretinide induces ESFT death through sustained p38MAPK phosphorylation, we hypothesised that this may be effected through upregulation of death receptors (DRs) and that treatment of fenretinide plus DR ligands may enhance apoptosis.
Methods:
DR expression was determined by flow cytometry. Trypan blue exclusion assays, caspase-8 flow cytometry and immunoblotting for Bid were used to measure cell death.
Results:
Fenretinide upregulated cell surface expression of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors, FAS and p75NTR, in an ASK1- and p38α-dependent manner. Cotreatment with fenretinide and DR ligands resulted in synergistic death compared with either agent alone; caspase-8 and Bid were cleaved in a time-dependent manner. Fenretinide did not increase DR expression in non-malignant cells. Furthermore, fenretinide, TRAIL or a combination of both agents was non-cytotoxic to non-malignant cells. Etoposide and actinomycin D increased expression of all DRs examined, whereas vincristine increased FAS alone. Only actinomycin D and TRAIL, and etoposide with TRAIL or FasL, enhanced death compared with either agent alone.
Conclusion:
The synergistic death observed with fenretinide and DR ligands suggests that this combination may be an attractive strategy for the treatment of ESFT.
doi:10.1038/sj.bjc.6605896
PMCID: PMC2990598  PMID: 20877355
ASK1; death receptors; Ewing's sarcoma family of tumours; fenretinide; p38MAPK; TRAIL
17.  Do-not-resuscitate orders and predictive models after intracerebral hemorrhage(e–Pub ahead of print) 
Neurology  2010;75(7):626-633.
Objective:
To quantify the accuracy of commonly used intracerebral hemorrhage (ICH) predictive models in ICH patients with and without early do-not-resuscitate orders (DNR).
Methods:
Spontaneous ICH cases (n = 487) from the Brain Attack Surveillance in Corpus Christi study (2000–2003) and the University of California, San Francisco (June 2001–May 2004) were included. Three models (the ICH Score, the Cincinnati model, and the ICH grading scale [ICH-GS]) were compared to observed 30-day mortality with a χ2 goodness-of-fit test first overall and then stratified by early DNR orders.
Results:
Median age was 71 years, 49% were female, median Glasgow Coma Scale score was 12, median ICH volume was 13 cm3, and 35% had early DNR orders. Overall observed 30-day mortality was 42.7% (95% confidence interval [CI] 38.3–47.1), with the average model-predicted 30-day mortality for the ICH Score, Cincinnati model, and ICH-GS at 39.9% (p = 0.005), 40.4% (p = 0.007), and 53.9% (p < 0.001). However, for patients with early DNR orders, the observed 30-day mortality was 83.5% (95% CI 78.0–89.1), with the models predicting mortality of 64.8% (p < 0.001), 57.2% (p < 0.001), and 77.8% (p = 0.02). For patients without early DNR orders, the observed 30-day mortality was 20.8% (95% CI 16.5–25.7), with the models predicting mortality of 26.6% (p = 0.05), 31.4% (p < 0.001), and 41.1% (p < 0.001).
Conclusions:
ICH prognostic model performance is substantially impacted when stratifying by early DNR status, possibly giving a false sense of model accuracy when DNR status is not considered. Clinicians should be cautious when applying these predictive models to individual patients.
GLOSSARY
= Brain Attack Surveillance in Corpus Christi;
= confidence interval;
= do not resuscitate;
= Glasgow Coma Scale;
= intracerebral hemorrhage;
= intracerebral hemorrhage grading scale;
= receiver operating characteristic;
= San Francisco General Hospital;
= University of California San Francisco.
doi:10.1212/WNL.0b013e3181ed9cc9
PMCID: PMC2931769  PMID: 20610832
18.  Trauma history and risk of irritable bowel syndrome in women veterans 
Background
Over 1.8 million women in the U.S. are veterans of the armed services. They are at increased risk of occupational traumas, including military sexual trauma. We evaluated the association between major traumas and irritable bowel syndrome among women veterans accessing VA healthcare.
Methods
We administered questionnaires to assess trauma history as well as IBS, PTSD and depression symptoms to 337 women veterans seen for primary care at VA Women’s Clinic between 2006 and 2007. Logistic regression was used to evaluate the association between individual traumas and IBS risk after adjustment for age, ethnicity, PTSD and depression.
Results
IBS prevalence was 33.5%. The most frequently reported trauma was sexual assault (38.9%). Seventeen of eighteen traumas were associated with increased IBS risk after adjusting for age, ethnicity, PTSD and depression, with six statistically significant (range of adjusted odds ratios (OR) between 1.85 [95% CI, 1.08–3.16] and 2.6 [95% CI, 1.28–3.67]). Depression and PTSD were significantly more common in IBS cases than controls, but neither substantially explained the association between trauma and increased IBS risk.
Conclusions
Women veterans report high frequency of physical and sexual traumas. Lifetime history of a broad range of traumas is independently associated with an elevated IBS risk.
doi:10.1111/j.1365-2036.2010.04387.x
PMCID: PMC2906642  PMID: 20528828
Irritable bowel syndrome; veterans; women; PTSD; trauma; Department of Veterans Affairs; depression
19.  The independent effect of pain in one versus two knees on the presence of low physical function: The MOST Study 
Arthritis care & research  2010;62(7):938-943.
While knee pain severity is thought to greatly impact function, the additional contribution of pain in one versus two knees is not known. We examined the relation between unilateral versus bilateral pain with low physical functioning at baseline and at 30 months while accounting for knee pain severity.
The Multicenter Osteoarthritis Study (MOST) is a cohort study of people who have or are at high risk for knee OA. We defined low physical function as WOMAC PF scores ≥28/68, consistent with poor functional outcome. Incidence and improvement from low physical function were defined as scores that declined below and improved above this threshold at 30 months. We examined the association between pain in one or two knees with low physical function with risk ratios adjusting for known confounders.
Of the 2069 subjects (Age 63 ± 8 yrs, BMI 31 ± 6 kg/m2, female 63%), the prevalence of low physical functioning was 50% lower among persons with unilateral pain compared with those with bilateral pain [adj PR 0.5 (95% CI 0.4-0.7)]. Of those without low physical functioning at baseline, the risk of incidence at 30 months was 30% less for unilateral pain compared with bilateral pain [adj RR 0.7 (95% CI 0.5-1.0)]. Of those with low physical functioning at baseline, the risk of improvement was 1.7 times more likely for unilateral pain compared with bilateral pain [adj RR 1.7 (95%CI 1.3-2.2)].
The presence of pain in one versus two knees provides important information regarding present and future physical functioning.
doi:10.1002/acr.20166
PMCID: PMC2902715  PMID: 20191572
20.  Multiple new Phytophthora species from ITS Clade 6 associated with natural ecosystems in Australia: evolutionary and ecological implications 
During surveys of dying vegetation in natural ecosystems and associated waterways in Australia many new taxa have been identified from Phytophthora ITS Clade 6. For representative isolates, the region spanning the internal transcribed spacer region of the ribosomal DNA, the nuclear gene encoding heat shock protein 90 and the mitochondrial cox1 gene were PCR amplified and sequenced. Based on phylogenetic analysis and morphological and physiological comparison, four species and one informally designated taxon have been described; Phytophthora gibbosa, P. gregata, P. litoralis, P. thermophila and P. taxon paludosa. Phytophthora gibbosa, P. gregata and P. taxon paludosa form a new cluster and share a common ancestor; they are homothallic and generally associated with dying vegetation in swampy or water-logged areas. Phytophthora thermophila and P. litoralis are sister species to each other and more distantly to P. gonapodyides. Both new species are common in waterways and cause scattered mortality within native vegetation. They are self-sterile and appear well adapted for survival in an aquatic environment and inundated soils, filling the niche occupied by P. gonapodyides and P. taxon salixsoil in the northern hemisphere. Currently the origin of these new taxa, their pathogenicity and their role in natural ecosystems are unknown. Following the precautionary principle, they should be regarded as a potential threat to native ecosystems and managed to minimise their further spread.
doi:10.3767/003158511X557577
PMCID: PMC3160797  PMID: 22025801
aquatic habitat; breeding systems; evolution; phylogeny; radiation; sterility; survival
21.  Oesophagogastric fistula: a post-operative complication 
BMJ Case Reports  2009;2009:bcr2006105551.
doi:10.1136/bcr.2006.105551
PMCID: PMC3105878  PMID: 21687198
22.  Vulvovaginal candidiasis 
Sexually Transmitted Infections  2006;82(Suppl 4):iv28-iv30.
doi:10.1136/sti.2006.023168
PMCID: PMC2563903  PMID: 17151050
vulvovaginal candidiasis
23.  Montelukast in the treatment of HIV associated immune reconstitution disease 
Sexually Transmitted Infections  2006;82(6):513-514.
The pathogenesis of immune reconstitution disease (IRD) is not well understood and it can be difficult to manage. Leukotrienes exert proinflammatory effects, have an important role in the innate immune response, and are relatively deficient in HIV infection. Montelukast is a leukotriene receptor antagonist (LTRA) currently licensed for the treatment of asthma. We report a series of three patients with severe HIV associated IRD (cases 1 and 2 associated with starting HAART and unresponsive to steroids), who obtained clinically dramatic responses to treatment with montelukast. The first case is of IRD to secondary syphilis and the second and third to tuberculosis. Cases 1 and 3 both relapsed after a temporary break from montelukast and resolved on restarting. Montelukast should be considered in HIV associated IRD as an alternative to steroids and where these are not effective. Leukotriene overactivity may be implicated in IRD.
doi:10.1136/sti.2005.017863
PMCID: PMC2563887  PMID: 17151039
HIV; immune reconstitution disease; tuberculosis; syphilis; leukotriene receptor antagonists
24.  Catastrophic lower gastrointestinal complications following spinal surgery 
Gut  2006;55(9):1262.
doi:10.1136/gut.2005.084707
PMCID: PMC1860048  PMID: 16905696
non‐steroidal anti‐inflammatory drugs; colonic perforation; colonic ulceration; colonic haemorrhage
25.  Trazodone increases arousal threshold in obstructive sleep apnoea 
A low arousal threshold is believed to predispose to breathing instability during sleep. The present authors hypothesised that trazodone, a nonmyorelaxant sleep-promoting agent, would increase the effort-related arousal threshold in obstructive sleep apnoea (OSA) patients.
In total, nine OSA patients, mean±SD age 49±9 yrs, apnoea/hypopnoea index 52±32 events·h-1, were studied on 2 nights, one with trazodone at 100 mg and one with a placebo, in a double blind randomised fashion. While receiving continuous positive airway pressure (CPAP), repeated arousals were induced: 1) by increasing inspired CO2 and 2) by stepwise decreases in CPAP level. Respiratory effort was measured with an oesophageal balloon. End-tidal CO2 tension (PET,CO2) was monitored with a nasal catheter.
During trazodone nights, compared with placebo nights, the arousals occurred at a higher PET,CO2 level (mean±SD 7.30±0.57 versus 6.62±0.64 kPa (54.9±4.3 versus 49.8±4.8 mmHg), respectively). When arousals were triggered by increasing inspired CO2 level, the maximal oesophageal pressure swing was greater (19.4±4.0 versus 13.1±4.9 cmH2O) and the oesophageal pressure nadir before the arousals was lower (-5.1±4.7 versus -0.38±4.2 cmH2O) with trazodone. When arousals were induced by stepwise CPAP drops, the maximal oesophageal pressure swings before the arousals did not differ.
Trazodone at 100 mg increased the effort-related arousal threshold in response to hypercapnia in obstructive sleep apnoea patients and allowed them to tolerate higher CO2 levels.
doi:10.1183/09031936.00067607
PMCID: PMC2732198  PMID: 18256066
Arousal threshold; carbon dioxide; oesophageal pressure; sleep-disordered breathing; trazodone

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