Creutzfeldt-Jakob disease and blood transfusion safety.

Transmissible spongiform encephalopathies (TSEs) are untreatable, fatal neurologic diseases affecting mammals. Human disease forms include sporadic, familial and acquired Creutzfeldt-Jakob disease (CJD). While sporadic CJD (sCJD) has been recognized for near on 100 years, variant CJD (vCJD) was first reported in 1996 and is the result of food-borne transmission of the prion of bovine spongiform encephalopathy (BSE, 'mad cow disease'). Currently, 230 vCJD cases have been reported in 12 countries, the majority in the UK (178) and France (27). Animal studies demonstrated highly efficient transmission of natural scrapie and experimental BSE by blood transfusion and fuelled concern that sCJD was potentially transfusion transmissible. No such case has been recorded and case-control evaluations and lookback studies indicate that, if transfusion transmission occurs at all, it is very rare. In contrast, four cases of apparent transfusion transmission of vCJD infectivity have been identified in the UK. Risk minimization strategies in response to the threat of vCJD include leucodepletion, geographically based donor deferrals and deferral of transfusion recipients. A sensitive and specific, high-throughput screening test would provide a potential path to mitigation but despite substantial effort no such test has yet appeared. The initial outbreak of vCJD appears to be over, but concern remains about subsequent waves of disease among those already infected. There is considerable uncertainty about the size of the infected population, and there will be at least a perception of some continuing risk to blood safety. Accordingly, at least some precautionary measures will remain in place and continued surveillance is necessary.

Patient Outcomes and Cerebral Infarction after Ruptured Anterior Communicating Artery Aneurysm Treatment.

BACKGROUND AND PURPOSE: Anterior communicating artery aneurysm rupture and treatment is associated with high rates of dependency, which are more severe after clipping compared with coiling. To determine whether ischemic injury might account for these differences, we characterized cerebral infarction burden, infarction patterns, and patient outcomes after surgical or endovascular treatment of ruptured anterior communicating artery aneurysms. MATERIALS AND METHODS: We performed a retrospective cohort study of consecutive patients with ruptured anterior communicating artery aneurysms. Patient data and neuroimaging studies were reviewed. A propensity score for outcome measures was calculated to account for the nonrandom assignment to treatment. Primary outcome was the frequency of frontal lobe and striatum ischemic injury. Secondary outcomes were patient mortality and clinical outcome at discharge and at 3 months. RESULTS: Coiled patients were older (median, 55 versus 50 years; P = .03), presented with a worse clinical status (60% with Hunt and Hess Score >2 versus 34% in clipped patients; P = .02), had a higher modified Fisher grade (P = .01), and were more likely to present with intraventricular hemorrhage (78% versus 56%; P = .03). Ischemic frontal lobe infarction (OR, 2.9; 95% CI, 1.1-8.4; P = .03) and recurrent artery of Heubner infarction (OR, 20.9; 95% CI, 3.5-403.7; P < .001) were more common in clipped patients. Clipped patients were more likely to be functionally dependent at discharge (OR, 3.2; P = .05) compared with coiled patients. Mortality and clinical outcome at 3 months were similar between coiled and clipped patients. CONCLUSIONS: Frontal lobe and recurrent artery of Heubner infarctions are more common after surgical clipping of ruptured anterior communicating artery aneurysms, and are associated with poorer clinical outcomes at discharge.

PIFA-mediated ethoxyiodination of enamides with potassium iodide.

The regioselective ethoxyiodination of enamides was developed using PIFA in combination with potassium iodide in ethanol. The reaction proceeds regioselectively with excellent yields and diastereoselectivities, providing valuable synthons for further functionalisations. Control experiments were conducted, indicating that the transformation occurs through an ionic manifold involving an in situ generated hypoiodite species.

Human Papillomavirus and Head and Neck Cancer: Psychosocial Impact in Patients and Knowledge of the Link - A Systematic Review.

Head and neck cancer (HNC) currently affects approximately 11 200 people in the UK, with an increasing proportion known to be caused by the human papillomavirus (HPV). We undertook a systematic review of studies measuring the psychosocial impact of HPV-related HNC and also studies measuring knowledge about the link between HPV and HNC among different populations. Searches were conducted on MEDLINE, Embase, PsycINFO, CINAHL Plus and Web of Science, with reference and forward citation searches also carried out on included studies. Studies were selected if they (i) were original peer-reviewed research (qualitative or quantitative), (ii) mentioned HPV and HNC, (iii) measured an aspect of the psychosocial impact of the diagnosis of HPV-related HNC as the dependent variable and/or (iv) measured knowledge of the association between HPV and HNC. In total, 51 papers met the inclusion criteria; 10 measuring psychosocial aspects and 41 measuring knowledge of the link between HPV and HNC. Quality of life in those with HPV-positive HNC was found to be higher, lower or equivalent to those with HPV-negative HNC. Longitudinal studies found quality of life in patients was at its lowest 2-3 months after diagnosis and some studies found quality of life almost returned to baseline levels after 12 months. Knowledge of the link between HPV and HNC was measured among different populations, with the lowest knowledge in the general population and highest in medical and dental professionals. Due to the limited studies carried out with patients measuring the psychosocial impact of a diagnosis of HPV-positive HNC, future work is needed with the partners of HPV-positive HNC patients and health professionals caring for these patients. The limited knowledge of the association between HPV and HNC among the general population also indicates the need for research to explore the information that these populations are receiving.

Myogenic transcription factors regulate pro-metastatic miR-182.

Approximately 30% of patients with soft-tissue sarcoma die from pulmonary metastases. The mechanisms that drive sarcoma metastasis are not well understood. Recently, we identified miR-182 as a driver of sarcoma metastasis in a primary mouse model of soft-tissue sarcoma. We also observed elevated miR-182 in a subset of primary human sarcomas that metastasized to the lungs. Here, we show that myogenic differentiation factors regulate miR-182 levels to contribute to metastasis in mouse models. We find that MyoD directly binds the miR-182 promoter to increase miR-182 expression. Furthermore, mechanistic studies revealed that Pax7 can promote sarcoma metastasis in vivo through MyoD-dependent regulation of pro-metastatic miR-182. Taken together, these results suggest that sarcoma metastasis can be partially controlled through Pax7/MyoD-dependent activation of miR-182 and provide insight into the role that myogenic transcription factors have in sarcoma progression.

Current and future implications of basic and translational research on amyloid-ß peptide production and removal pathways.

Inherited variants in multiple different genes are associated with increased risk for Alzheimer's disease (AD). In many of these genes, the inherited variants alter some aspect of the production or clearance of the neurotoxic amyloid ß-peptide (Aß). Thus missense, splice site or duplication mutants in the presenilin 1 (PS1), presenilin 2 (PS2) or the amyloid precursor protein (APP) genes, which alter the levels or shift the balance of Aß produced, are associated with rare, highly penetrant autosomal dominant forms of Familial Alzheimer's Disease (FAD). Similarly, the more prevalent late-onset forms of AD are associated with both coding and non-coding variants in genes such as SORL1, PICALM and ABCA7 that affect the production and clearance of Aß. This review summarises some of the recent molecular and structural work on the role of these genes and the proteins coded by them in the biology of Aß. We also briefly outline how the emerging knowledge about the pathways involved in Aß generation and clearance can be potentially targeted therapeutically. This article is part of Special Issue entitled "Neuronal Protein".

Chronic Treatment with a Promnesiant GABA-A α5-Selective Inverse Agonist Increases Immediate Early Genes Expression during Memory Processing in Mice and Rectifies Their Expression Levels in a Down Syndrome Mouse Model.

Decrease of GABAergic transmission has been proposed to improve memory functions. Indeed, inverse agonists selective for α5 GABA-A-benzodiazepine receptors (α5IA) have promnesiant activity. Interestingly, we have recently shown that α5IA can rescue cognitive deficits in Ts65Dn mice, a Down syndrome mouse model with altered GABAergic transmission. Here, we studied the impact of chronic treatment with α5IA on gene expression in the hippocampus of Ts65Dn and control euploid mice after being trained in the Morris water maze task. In euploid mice, chronic treatment with α5IA increased IEGs expression, particularly of c-Fos and Arc genes. In Ts65Dn mice, deficits of IEGs activation were completely rescued after treatment with α5IA. In addition, normalization of Sod1 overexpression in Ts65Dn mice after α5IA treatment was observed. IEG expression regulation after α5IA treatment following behavioral stimulation could be a contributing factor for both the general promnesiant activity of α5IA and its rescuing effect in Ts65Dn mice alongside signaling cascades that are critical for memory consolidation and cognition.

Specific targeting of the GABA-A receptor α5 subtype by a selective inverse agonist restores cognitive deficits in Down syndrome mice.

An imbalance between inhibitory and excitatory neurotransmission has been proposed to contribute to altered brain function in individuals with Down syndrome (DS). Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system and accordingly treatment with GABA-A antagonists can efficiently restore cognitive functions of Ts65Dn mice, a genetic model for DS. However, GABA-A antagonists are also convulsant which preclude their use for therapeutic intervention in DS individuals. Here, we have evaluated safer strategies to release GABAergic inhibition using a GABA-A-benzodiazepine receptor inverse agonist selective for the α5-subtype (α5IA). We demonstrate that α5IA restores learning and memory functions of Ts65Dn mice in the novel-object recognition and in the Morris water maze tasks. Furthermore, we show that following behavioural stimulation, α5IA enhances learning-evoked immediate early gene products in specific brain regions involved in cognition. Importantly, acute and chronic treatments with α5IA do not induce any convulsant or anxiogenic effects that are associated with GABA-A antagonists or non-selective inverse agonists of the GABA-A-benzodiazepine receptors. Finally, chronic treatment with α5IA did not induce histological alterations in the brain, liver and kidney of mice. Our results suggest that non-convulsant α5-selective GABA-A inverse agonists could improve learning and memory deficits in DS individuals.

Intraoperative angiography for cranial dural arteriovenous fistula.

BACKGROUND AND PURPOSE: IA is a valuable adjunct during surgery for a variety of neurovascular diseases; however, there are no reported series describing IA for DAVFs. This study was undertaken to evaluate the safety and efficacy of IA for DAVFs. MATERIALS AND METHODS: A retrospective review of DAVF surgical cases during a 20-year period was conducted, and cases with IA were evaluated. Clinical details, surgical and angiographic findings, and postoperative outcomes were reviewed. The incidence of residual fistula on IAs, the utility of the surgical procedure, and the incidence of false-negative findings on IA were also determined. RESULTS: IA was performed in 29 patients (31 DAVFs) for DAVFs. The distribution of the fistulas was the following: transverse-sigmoid (n = 9), tentorial (n = 6), torcular (n = 3), cavernous sinus (n = 4), SSS (n = 4), foramen magnum (n = 3), and temporal-middle fossa (n = 2). Twelve patients had undergone prior embolization, while 6 patients had unsuccessful embolization procedures. Thirty-eight surgeries were performed for DAVF in 29 patients, and IA was performed in 34 surgeries. Forty-four angiographic procedures were performed in the 34 surgeries. Nine patients underwent multiple angiographies. In 11 patients (37.9%), IA revealed residual fistula after the surgeon determined that no lesion remained. This led to further exploration at the same sitting in 10 patients, while in 1 patient, further surgery was performed at a later date. False-negative findings on IA occurred in 3 patients (10.7%). CONCLUSIONS: IA is an important adjunct in surgery for DAVF. In this series, it resulted in further surgical treatment in 37.9% of patients. However, there was a 10% false-negative rate, which justified subsequent postoperative angiography.

The expression and function of Ca(2+)-sensing receptors in rat mesenteric artery; comparative studies using a model of type II diabetes.

BACKGROUND AND PURPOSE: The extracellular calcium-sensing receptor (CaR) in vascular endothelial cells activates endothelial intermediate-conductance, calcium-sensitive K(+) channels (IK(Ca)) indirectly leading to myocyte hyperpolarization. We determined whether CaR expression and function was modified in a rat model of type II diabetes. EXPERIMENTAL APPROACH: Pressure myography, western blotting, sharp microelectrode and K(+)-selective electrode recordings were used to investigate the functional expression of the CaR and IK(Ca) in rat mesenteric arteries. KEY RESULTS: Myocyte hyperpolarization to the CaR activator calindol was inhibited by Calhex 231. U46619-induced vessel contraction elevated the extracellular [K(+)] around the myocytes, and inhibition of this 'K(+) cloud' by iberiotoxin was needed to reveal calindol-induced vasodilatations. These were antagonized by Calhex 231 and significantly smaller in Zucker diabetic fatty rat (ZDF) vessels than in Zucker lean (ZL) controls. Myocyte hyperpolarizations to calindol were also smaller in ZDF than in ZL arteries. In ZDF vessels, endothelial cell CaR protein expression was reduced; IK(Ca) expression was also diminished, but IK(Ca)-generated hyperpolarizations mediated by 1-EBIO were unaffected. CONCLUSIONS AND IMPLICATIONS: The reduced CaR-mediated hyperpolarizing and vasodilator responses in ZDF arteries result from a decrease in CaR expression, rather than from a modification of IK(Ca) channels. Detection of CaR-mediated vasodilatation required the presence of iberiotoxin, suggesting a CaR contribution to vascular diameter, that is, inversely related to the degree of vasoconstriction. Compromise of the CaR pathway would favour the long-term development of a higher basal vascular tone and could contribute to the vascular complications associated with type II diabetes.

Health, development and the Millennium Development Goals.

The Millennium Development Goals (MDG), which emerged from the United Nations Millennium Summit in 2000, are increasingly recognized as the over-arching development framework. As such, the MDG are increasingly guiding the policies of poor countries and aid agencies alike. This article reviews the challenges and opportunities for health presented by the MDG. The opportunities include that three of the eight MDG relate to health--a recognition that health is central to global agenda of reducing poverty, as well as an important measure of human well-being in its own right. A related point is that the MDG help to focus attention on those health conditions that disproportionally affect the poor (communicable disease, child health and maternal health), which should, in turn, help to strengthen the equity focus of health policies in low-income countries. Further, because the MDG are concrete, it is possible to calculate the cost of achieving them, which in turn strengthens the long-standing calls for higher levels of aid for health. The challenges include that, while the MDG focus on specific diseases and conditions, they cannot be achieved without strengthening health systems. Similarly, progress towards the MDG will require health to be prioritized within overall development and economic policies. In practice, this means applying a health 'lens' to processes such as civil-service reform, decentralization and the drawing-up of frameworks of national expenditure. Finally, the MDG cannot be met with the resources available in low-income countries. While the MDG framework has created pressure for donors to commit to higher levels of aid, the challenge remains to turn these commitments into action. Data are presented to show that, at current rates of progress, the health-related MDG will not be achieved. This disappointing trend could be reversed, however, if the various challenges outlined are met.

Salivary gland adenoid cystic carcinoma: a review of chemotherapy and molecular therapies.

Adenoid cystic carcinoma (ACC) accounts for about 1% of all head and neck malignancies. It has a tendency for a prolonged clinical course, with local recurrences and distant metastases sometimes occurring many years after presentation. Standard treatment for salivary gland ACC is surgery and post-operative radiotherapy. The aim of this review was to examine the reported efficacy of various chemotherapy regimens and molecular therapies on recurrent/metastatic salivary gland ACC. One hundred and fourteen publications were reviewed on chemotherapy as well as possible molecular targets of therapy, including KIT, epidermal growth factor receptor (EGFR), human epidermal growth receptor-2 (HER-2), oestrogen and progesterone receptors, proliferating cell nuclear antigen (PCNA), Ki-67 and the p53, bcl-2 and SOX-4 genes. Reported response rates to combination chemotherapy are low and response duration generally short lived. The response to molecular therapies is low also. More research into novel molecular targets is needed.

Effectiveness of human T-lymphotropic virus (HTLV) recipient tracing (lookback) and the current HTLV-I and -II confirmatory algorithm, 1999 to 2004.

BACKGROUND: This study reports on the efficacy of an investigational human T-lymphotropic virus (HTLV)-I and -II lookback program in the context of differing confirmatory testing algorithms. STUDY DESIGN AND METHODS: The results of testing approximately 35 million donations for anti-HTLV-I and -II were evaluated for two recent periods reflecting the use of two different confirmatory algorithms. The number of seroconverting donors was established for the entire period, and the results of lookback on their prior donations were investigated. RESULTS: The dual enzyme immunoassay (EIA) strategy was used throughout both study periods and resulted in a 57 to 76 percent reduction in the number of samples requiring confirmatory testing. From May 2000 to February 2002, a total of 9138 samples were repeatedly reactive by the primary screening test; of the concordant EIA-reactive samples, 461 (12%) were confirmed by Western blot, whereas 3083 (79%) were indeterminate. From March 2002 to December 2004, a total of 21,291 samples were repeatedly reactive; of the concordant EIA-reactive samples, 1099 (22%) were confirmed by the State of California's reference laboratory and only 273 (5%) were equivocal. Overall, 38 or 1 in 921,000 donations were from a seroconverting donor with 32 prior donations within the lookback period. Of those 32, components from only 11 were transfused to recipients who survived; of these, 4 were tested and all were nonreactive for HTLV-I and -II antibodies. CONCLUSION: Use of creative algorithms can increase the efficacy of anti-HTLV-I and -II confirmatory testing and reduce the number of indeterminate results. Currently, lookback for HTLV-I and -II has a very low yield, and its public health benefit is questionable.

Self-reported symptoms associated with West Nile virus infection in RNA-positive blood donors.

BACKGROUND: In 2003, West Nile virus (WNV) nucleic acid amplification testing (NAT) was implemented to detect potentially infected donors. Of more than 5.3 million donations screened prospectively by the American Red Cross during the epidemic periods of 2003 and 2004, 974 were NAT-reactive and 519 confirmed-positive. A subset of both the confirmed-positive and the false-positive groups was assessed for demographic characteristics, symptoms, and symptom reporting relative to date of donation. STUDY DESIGN AND METHODS: All donors with initial WNV NAT-reactive results were invited to participate in a study that included a demographic, symptom, and date-of-symptom questionnaire. WNV confirmed-positive cases were compared to false-positive controls for comparison of frequency of symptom reporting before, on the day of, and after donation. RESULTS: Enrolled cases and controls were similar in all characteristics except cases were more likely to live in rural areas. Symptoms were reported by 61 percent of cases versus 20 percent of controls, with 74 percent of symptoms reported by cases within the 14 days after donation. The frequency of headache and fever reported together in the 7 days before donation was not significantly different between cases and controls; only the individual frequencies of headache, eye pain, and new rash during this time were significantly different. The most commonly reported symptoms, after adjustment for symptom reporting by controls, were headache, new rash, and generalized weakness; these symptoms were reported by 25 percent of cases. CONCLUSIONS: The demographic characteristics of infected donors reflected the rural nature of the 2003 to 2004 WNV epidemics. This study suggests that asking donors about predonation headache and fever had no detectable contribution to blood safety.