The strategies to reduce iron deficiency in blood donors randomized trial: design, enrolment and early retention.

BACKGROUND AND OBJECTIVES: Repeated blood donation produces iron deficiency. Changes in dietary iron intake do not prevent donation-induced iron deficiency. Prolonging the interdonation interval or using oral iron supplements can mitigate donation-induced iron deficiency. The most effective operational methods for reducing iron deficiency in donors are unknown. MATERIALS AND METHODS: 'Strategies To Reduce Iron Deficiency' (STRIDE) was a two-year, randomized, placebo-controlled study in blood donors. 692 donors were randomized into one of two educational groups or one of three interventional groups. Donors randomized to educational groups either received letters thanking them for donating, or, suggesting iron supplements or delayed donation if they had low ferritin. Donors randomized to interventional groups either received placebo, 19-mg or 38-mg iron pills. RESULTS: Iron deficient erythropoiesis was present in 52·7% of males and 74·6% of females at enrolment. Adverse events within 60 days of enrolment were primarily mild gastrointestinal symptoms (64%). The incidence of de-enrolment within 60 days was more common in the interventional groups than in the educational groups (P = 0·002), but not more common in those receiving iron than placebo (P = 0·68). CONCLUSION: The prevalence of iron deficient erythropoiesis in donors enrolled in the STRIDE study is comparable to previously described cohorts of regular blood donors. De-enrolment within 60 days was higher for donors receiving tablets, although no more common in donors receiving iron than placebo.

Understanding the neuropsychiatric phenotype of fragile X-associated tremor ataxia syndrome: a systematic review.

Fragile X-associated tremor ataxia syndrome (FXTAS) is a recently identified X-linked neurodegenerative disorder affecting a proportion of premutation carriers of the Fragile X Mental Retardation 1 (FMR1) gene. Previous research suggests that cognitive and psychiatric features of FXTAS may include primary impairments in executive function and increased vulnerability to mood and anxiety disorders. A number of these reports, however, are based on overlapping cohorts or have produced inconsistent findings. A systematic review was therefore conducted to further elucidate the neuropsychiatric features characteristic of FXTAS. Fourteen papers met inclusion criteria for the review and were considered to represent nine independent FXTAS cohorts. Findings from the review suggest that the neuropsychiatric phenotype of FXTAS is characterised primarily by poorer performance on measures of executive function, working memory, information processing speed, and fine motor control when compared to matched comparison groups. Two studies were identified in which psychiatric symptoms in FXTAS were compared with controls, and these yielded mixed results. Overall the results of this review support previous reports that the neuropsychiatric profile of FXTAS is consistent with a dysexecutive fronto-subcortical syndrome. However, additional controlled studies are required to progress our understanding of FXTAS and how the neuropsychiatric profile relates to underlying pathological mechanisms.

Risk factors for human immunodeficiency virus infection among Brazilian blood donors: a multicentre case-control study using audio computer-assisted structured interviews.

BACKGROUND: Although risk factors for HIV infection are known, it is important for blood centres to understand local epidemiology and disease transmission patterns. Current risk factors for HIV infection in blood donors in Brazil were assessed. METHODS: A case-control study was conducted at large public blood centres located in four major cities between April 2009 and March 2011. Cases were persons whose donations were confirmed positive by enzyme immunoassays followed by Western blot confirmation. Audio computer-assisted structured interviews (ACASI) were completed by all cases and controls. Multivariable logistic regression was used to estimate adjusted odds ratios (AORs) and associated 95% confidence intervals (CIs). RESULTS: There were 341 cases, including 47 with recently acquired infection, and 791 controls. Disclosed risk factors for both females and males were sex with an HIV-positive person AOR 11.3, 95% CI (4.1, 31.7) and being an IVDU or sexual partner of an IVDU [AOR 4.65 (1.8, 11.7)]. For female blood donors, additional risk factors were having male sex partners who also are MSM [AOR 13.5 (3.1, 59.8)] and having unprotected sex with multiple sexual partners [AOR 5.19 (2.1, 12.9)]. The primary risk factor for male blood donors was MSM activity [AOR 21.6 (8.8, 52.9)]. Behaviours associated with recently acquired HIV were being a MSM or sex partner of MSM [13.82, (4.7, 40.3)] and IVDU [11.47, (3.0, 43.2)]. CONCLUSION: Risk factors in blood donors parallel those in the general population in Brazil. Identified risk factors suggest that donor compliance with selection procedures at the participating blood centres is inadequate.

Low abdominoperineal excision rates are associated with high-workload surgeons and lower tumour height. Is further specialization needed?

AIM: Wide variation, independent of disease extent and case mix, has been observed in the rate of use of abdominoperineal excision (APE) for rectal cancer. Previous analyses have, however, been confounded by failure to adjust for the location of the tumour within the rectum. This population-based study sought to examine whether variations in tumour height explained differences in APE use. METHOD: Information was obtained on all individuals who underwent a major resection for a rectal tumour diagnosed between 1998 and 2005 across the Northern and Yorkshire regions of the UK. Median distances from the dentate line were calculated for all tumours excised by APE and compared with rates of use of APE between specialists and nonspecialist surgeons and across hospital trusts. RESULTS: The completeness of pathological reporting of height of tumour within the rectum was variable. A low rate of APE use was associated with a lower median distance of tumours from the dentate line. Specialist colorectal cancer surgeons performed fewer APEs on patients with a tumour located lower in the rectum than nonspecialist surgeons. CONCLUSION: Variations in the height of tumour did not explain the variation in APE use. Specialist high-volume surgeons undertook fewer APEs and those they performed were closer to the dentate line than low-volume nonspecialist surgeons.

Molecular analysis of cellulose biosynthesis in Arabidopsis.

Cellulose, an abundant, crystalline polysaccharide, is central to plant morphogenesis and to many industries. Chemical and ultrastructural analyses together with map-based cloning indicate that the RSW1 locus of Arabidopsis encodes the catalytic subunit of cellulose synthase. The cloned gene complements the rsw1 mutant whose temperature-sensitive allele is changed in one amino acid. The mutant allele causes a specific reduction in cellulose synthesis, accumulation of noncrystalline beta-1,4-glucan, disassembly of cellulose synthase, and widespread morphological abnormalities. Microfibril crystallization may require proper assembly of the RSW1 gene product into synthase complexes whereas glucan biosynthesis per se does not.

TRPA1 receptor localisation in the human peripheral nervous system and functional studies in cultured human and rat sensory neurons.

TRPA1 is a receptor expressed by sensory neurons, that is activated by low temperature (<17 degrees C) and plant derivatives such as cinnamaldehyde and isoeugenol, to elicit sensations including pain. Using immunohistochemistry, we have, for the first time, localised TRPA1 in human DRG neurons, spinal cord motoneurones and nerve roots, peripheral nerves, intestinal myenteric plexus neurones, and skin basal keratinocytes. TRPA1 co-localised with a subset of hDRG neurons positive for TRPV1, the heat and capsaicin receptor. The number of small/medium TRPA1 positive neurons (< or =50 microm) was increased after hDRG avulsion injury [percentage of cells, median (range): controls 16.5 (7-23); injured 46 (34-55); P<0.005], but the number of large TRPA1 neurons was unchanged [control 19.5 (13-31); injured 21 (11-35)]. Similar TRPA1 changes were observed in cultured hDRG neurons, after exposure to a combination of key neurotrophic factors NGF, GDNF and NT-3 (NTFs) in vitro. We used calcium imaging to examine responses of HEK cells transfected with hTRPA1 cDNA, and of human and rat DRG neurons cultured with or without added NTFs, to cinnamaldehyde (CA) and isoeugenol (IE). Exposure to NTFs in vitro sensitized cultured human sensory neuronal responses to CA; repeated CA exposure produced desensitisation. In rDRG neurons, low (225 microM) CA preincubation enhanced capsaicin responses, while high (450 microM and 2mM) CA caused inhibition which was partially reversed in the presence of 8 bromo cAMP, indicating receptor dephosphorylation. While TRPA1 localisation is more widespread than TRPV1, it represents a promising novel drug target for the treatment of chronic pain and hypersensitivity.

Engineered detoxification confers resistance against a pathogenic bacterium.

We generated transgenic sugarcane plants that express an albicidin detoxifying gene (albD), which was cloned from a bacterium that provides biocontrol against leaf scald disease. Plants with albicidin detoxification capacity equivalent to 1-10 ng of AlbD enzyme per mg of leaf protein did not develop chlorotic disease symptoms in inoculated leaves, whereas all untransformed control plants developed severe symptoms. Transgenic lines with high AlbD activity in young stems were also protected against systemic multiplication of the pathogen, which is the precursor to economic disease. We have shown that genetic modification to express a toxin-resistance gene can confer resistance to both disease symptoms and multiplication of a toxigenic pathogen in its host.

Sciatic nerve injury caused by pre-operative intraneural injection of local anaesthetic during total hip replacement.

We report a case of iatrogenic sciatic nerve injury caused by pre-operative intraneural injection of local anaesthetic at total hip replacement. To our knowledge, this is unreported in the orthopaedic literature. We consider sacral nerve blockade in patients undergoing total hip replacement to be undesirable and present guidelines for the management of peri-operative sciatic nerve injury.

Caution is required in the implementation of 90-day mortality indicators for radiotherapy in a curative setting: A retrospective population-based analysis of over 16,000 episodes.

BACKGROUND: 90-day mortality (90DM) has been proposed as a clinical indicator in radiotherapy delivered in a curative setting. No large scale assessment has been made. Its value in allowing robust comparisons between centres and facilitating service improvement is unknown. METHODS: All radiotherapy treatments delivered in a curative setting over seven years were extracted from the local electronic health record and linked to cancer registry data. 90DM rates were assessed and factors associated with this outcome were investigated using logistic regression. Cause of death was identified retrospectively further characterising the cause of 90DM. RESULTS: Overall 90DM was 1.25%. Levels varied widely with diagnosis (0.20-5.45%). Age (OR 1.066, 1.043-1.073), year of treatment (OR 0.900, 0.841-0.969) and diagnosis were significantly associated with 90DM on multi-variable logistic regression. Cause of death varied with diagnosis; 50.0% post-operative in rectal cancer, 40.4% treatment-related in head and neck cancer, 59.4% disease progression in lung cancer. CONCLUSION: Despite the drive to report centre level comparative outcomes, this study demonstrates that 90DM cannot be adopted routinely asa clinical indicator due to significant population heterogeneity and low event rates. Further national investigation is needed to develop a meaningful robust indicator to deliver appropriate comparisons and drive improvements in care.

Primary sciatic nerve lymphoma: a case report and review of the literature.

A patient with primary B cell non-Hodgkin's lymphoma of the sciatic nerve is described. He presented with neuropathic symptoms in the left leg, initially diagnosed as tarsal tunnel syndrome. Magnetic resonance imaging (MRI) identified the abnormality in the sciatic nerve. A fascicular biopsy of the sciatic nerve showed a diffuse large B cell non-Hodgkin's lymphoma. The patient was treated with chemotherapy and rituximab (anti-CD20 monoclonal antibody). Four months later he was in remission, and remains so 48 months from presentation. Primary lymphoma of single peripheral nerves may be a unique subtype of extranodal lymphoma, which usually follows an aggressive course and has a variable response to current therapeutic strategies. MRI is useful, alongside electrophysiological studies, in patients with atypical peripheral nerve symptoms.

The effect of neurotrophic factors on morphology, TRPV1 expression and capsaicin responses of cultured human DRG sensory neurons.

We have studied the effect of key neurotrophic factors (NTFs) on morphology, levels of the vanilloid receptor-1 (TRPV1) and responses to capsaicin in adult human sensory neurons in vitro. Avulsed dorsal root ganglia (DRG, n = 5) were cultured with or without a combination of nerve growth factor (NGF), glial cell (line)-derived growth factor (GDNF) and neurotrophin3 (NT3) for 5 days. In the absence of NTFs, the diameter of neurons ranged from 20 to 100 microm (mean 42 +/- 4 microm). Adding NTFs caused a significant increase in neuronal sizes, up to 120 microm (mean diameter 62 +/- 5 microm, P < 0.01, t-test), an overall 35% increase of TRPV1-positive neurons (P < 0.003), and notably of large TRPV1-positive neurons > 80 microm (P < 0.05). Responses to capsaicin were significantly enhanced with calcium ratiometry (P < 0.0001). Short duration (1h) exposure of dissociated sensory neurons to NTFs increased numbers of TRPV1-positive neurons, but not of TRPV3, Nav 1.8 and IK1 and the morphological size-distribution remained similar to intact post-mortem DRG neurons. NTFs thus increase size, elevate TRPV1 levels and enhance capsaicin responses in cultured human DRG neurons; these changes may relate to pathophysiology in disease states, and provide an in vitro model to study novel analgesics.

Clinical outcome of nerve injuries associated with supracondylar fractures of the humerus in children: the experience of a specialist referral centre.

Between 1998 and 2002, 37 neuropathies in 32 patients with a displaced supracondylar fracture of the humerus who were referred to a nerve injury unit were identified. There were 19 boys and 13 girls with a mean age of 7.9 years (3.6 to 11.3). A retrospective review of these injuries was performed. The ulnar nerve was injured in 19, the median nerve in ten and the radial nerve in eight cases. Fourteen neuropathies were noted at the initial presentation and 23 were diagnosed after treatment of the fracture. After referral, exploration of the nerve was planned for 13 patients. Surgery was later cancelled in three because of clinical recovery. Six patients underwent neurolysis alone. Excision of neuroma and nerve grafting were performed in four. At follow-up, 26 patients had an excellent, five a good and one a fair outcome.

Posterior subluxation and dislocation of the shoulder in obstetric brachial plexus palsy.

We describe the results of surgical treatment in a prospective study of 183 consecutive cases of subluxation (101) and dislocation (82) of the shoulder secondary to obstetric brachial plexus palsy between 1995 and 2000. Neurological recovery was rated 'good' or 'useful' in all children, whose lesions fell into groups 1, 2 or 3 of the Narakas classification. The mean age at operation was 47 months (3 to 204). The mean follow-up was 40 months (24 to 124). The mean gain in function was 3.6 levels (9.4 to 13) using the Mallet score and 2 (2.1 to 4.1) on the Gilbert score. The mean active global range of shoulder movement was increased by 73 degrees ; the mean range of active lateral rotation by 58 degrees and that of supination of the forearm by 51 degrees . Active medial rotation was decreased by a mean of 10 degrees . There were 20 failures. The functional outcome is related to the severity of the neurological lesion, the duration of the dislocation and onset of deformity.

The effects of operative delay on the relief of neuropathic pain after injury to the brachial plexus: a review of 148 cases.

We investigated the effect of delay before nerve repair on neuropathic pain after injury to the brachial plexus. We studied 148 patients, 85 prospectively and 63 retrospectively. The mean number of avulsed spinal nerves was 3.2 (1 to 5). Pain was measured by a linear visual analogue scale and by the peripheral nerve injury scale. Early repair was more effective than delayed repair in the relief from pain and there was a strong correlation between functional recovery and relief from pain.

Recombinant interleukin-2 and adoptive immunotherapy alternated with dacarbazine therapy in melanoma: a National Biotherapy Study Group trial.

We evaluated adoptive cellular therapy with recombinant interleukin-2 (rIL-2) plus lymphokine-activated killer (LAK) cells alternating with sequential dacarbazine chemotherapy in 27 patients with metastatic melanoma. rIL-2 was given to the patients as a 5-day continuous-infusion priming cycle followed by 1 day of rest, 4 days of leukapheresis for in vitro LAK cell expansion, and then 4 1/2 days of continuous rIL-2 infusion in conjunction with reinfusion of LAK cells during the first 3 days of the continuous infusion. Two weeks later, patients received dacarbazine (1,200 mg/m2) chemotherapy. Two patients achieved complete remission, and five achieved a partial remission for a response rate of 26% (95% confidence interval = 12%-47%). Three patients had mixed responses. The partial and mixed responses were brief, ranging from 1 month to 6 months, whereas the two complete responses have been sustained for 13+ and 24+ months. There were no additive toxic effects except for thrombocytopenia, which delayed treatment in two patients. Alternating adoptive immunotherapy and dacarbazine chemotherapy appear to be reasonably tolerated by patients, but the response rate is not clearly better than that achieved with other rIL-2 regimens or with chemotherapy alone.

Pain phenomena and sensory recovery following brachial plexus avulsion injury and surgical repairs.

Seventy-six patients with severe brachial plexus avulsion injuries were studied using pain questionnaires and quantitative sensory testing. There was significant correlation between pain intensity and the number of roots avulsed prior to surgery (P=0.0004) and surgical repairs were associated with pain relief. Sensory recovery to thermal stimuli was observed, mainly in the C5 dermatome. Allodynia to mechanical and thermal stimuli was observed in the border zone of affected and unaffected dermatomes in 18% of patients assessed early (<6 months) and 37% patients at later stages. Pain and sensations referred to the original source of afferents occurred at a later stage (>6 months) in 12% of patients and were related to nerve regeneration. By contrast, "wrong-way" referred sensations (e.g. down the affected arm while shaving or drinking cold fluids) were reported by 44% of patients and often occurred early, suggesting CNS plasticity. Understanding sensory mechanisms will help develop new treatments for severe brachial plexus injuries.

Phase I study and pharmacokinetics of weekly high-dose 13-cis-retinoic acid.

In an attempt to increase the peak plasma levels of 13-cis-retinoic acid (13-cis-RA) and its efficacy in vivo, a Phase I study and pharmacokinetics of weekly high-dose, oral 13-cis-RA was conducted in 23 cancer patients who were refractory to conventional treatments. At 200 mg/sq m, the mean peak plasma level of 13-cis-RA was 1.5 +/- 0.1 (SE) micrograms/ml; at 400 mg/sq m, the mean peak plasma level increased to 3.8 +/- 0.7 micrograms/ml. Further increases of the 13-cis-RA dose up to 1800 mg/sq m did not lead to proportional increases in either the mean peak plasma levels or area under the curve, indicating a saturable absorption phenomenon. The terminal half-life was highly variable (range, 2.8 to 101.3 h) and was not related to the dose given. A secondary peak plasma concentration was seen in five patients, suggesting enterohepatic circulation. The toxicities such as headache, cheilitis, dry skin, and dry eyes were frequent on the weekly schedule but were not dose-limiting. One patient had an elevation of the triglycerides of 2 to 5 times the upper limit of normal; five patients had an elevation of 1.1 to 2 times normal. No objective responses were observed to treatment with 13-cis-RA. Of 20 patients receiving an adequate trial of the drug, 18 showed progression of their cancer, and two had stable disease.

Light-stimulated synthesis of chloroplast DNA.

Light-stimulated chloroplast DNA synthesis was studied during chloroplast development in the absence of cell division and nuclear DNA synthesis. Incorporation of 32Pi was stimulated 10-15 fold, however, the ratio of chloroplast DNA to nuclear DNA remained constant. Isotope dilution experiments suggested that stimulated labeling of chloroplast DNA represented more efficient utilization of exogenously supplied Pi rather than stimulated turnover of chloroplast DNA. The low level of DNA synthesis and chloroplast development were resistant to nalidixic acid which inhibits semiconservative replication of chloroplast DNA.

Randomized phase III comparison of three doxorubicin-based chemotherapy regimens in advanced non-small cell lung cancer: a Southeastern Cancer Study Group trial.

From 1978 to 1981, 537 patients with advanced non-small cell lung cancer were randomly assigned to three regimens containing cyclophosphamide and doxorubicin alone or in combination with methotrexate or cisplatin. Eligible patients had measurable disease and had no prior exposure to chemotherapy. Of the patients entered on the study, 505 were evaluable for toxicity and 488 were evaluable for response. The overall response rate (complete and partial responses) was only 9%. Response rates did not vary significantly with respect to treatment regimen, histologic subtypes, extent of disease, or performance status. There was no survival advantage for any regimen. The major toxicities were myelosuppression and nausea-vomiting. These doxorubicin-based chemotherapy regimens produced disappointing results in patients with advanced non-small cell lung cancer. A search for more active antitumor agents in lung cancer is necessary.

Effect of CD34(+) cell dose on resource utilization in patients after high-dose chemotherapy with peripheral-blood stem-cell support.

PURPOSE: The mean time to neutrophil and platelet recovery for patients receiving high-dose chemotherapy (HDC) supported with peripheral-blood stem cells (PBSCs) is related to the dose of CD34(+) cells infused. The effect of cell dose on resource utilization after transplantation has not been previously reported. MATERIALS AND METHODS: We assessed CD34(+) cell dose and resource utilization for 1,317 patients undergoing transplantation with PBSCs from April 1991 to June 1997. PBSCs were collected after mobilization with chemotherapy and recombinant human granulocyte colony-stimulating factor (rhG-CSF). Daily measurement of the CD34(+) content of the PBSC collection was performed by a central laboratory using a single CD34(+) analysis technique. Resource utilization included engraftment parameters, length of stay, and transfusion requirements for 100 days posttransplantation. Analysis included descriptive statistics and multiple regression. RESULTS: Mean patient age was 47 years, and 86% of patients were female. Median cell dose was 3.6 x 10(6)/kg and 13.2 x 10(6)/kg for patients receiving less than 5.0 x 10(6) CD34(+) cells/kg and 5.0 x 10(6) or more CD34(+) cells/kg, respectively. Patients receiving less than 5. 0 x 10(6) CD34(+) cells/kg were more likely to have metastatic breast cancer or non-Hodgkin's lymphoma and required more platelet and RBC transfusions, 3.3 more hospital days, and increased antibiotic and antifungal use. In univariate analysis, the cost of care was $41,516 (+/-$20,876 SD) and $32,382 (+/-$16,353 SD) for patients with less than 5.0 x 10(6) CD34(+) cells/kg and 5.0 x 10(6) or more CD34(+) cells/kg, respectively. In multivariate analysis, patients with less than 5.0 x 10(6) CD34(+) cells/kg had an increase in costs of $5,062 (+/- $1,262 SE). CONCLUSION: Infusion of more than 5.0 x 10(6) CD34(+) cells/kg was associated with a reduction in resource utilization. Achieving a target of 5.0 x 10(6) CD34(+) cells/kg should have important clinical and economic benefits for patients.