Radioimmunotherapy of human head and neck squamous cell carcinoma xenografts with 131I-labelled monoclonal antibody E48 IgG.

Monoclonal antibody (MAb) E48 reacts with a 22 kD antigen exclusively expressed in squamous and transitional epithelia and their neoplastic counterparts. Radiolabelled with 99mTc, MAb E48 is capable of targeting metastatic and recurrent disease in patients with head and neck cancer. In this study, the capacity of 131I-labelled MAb E48 to eradicate xenografts of human squamous cell carcinoma of the head and neck (HNSCC) in nude mice was examined. Experimental groups received a single i.v. bolus injection of 400 microCi MAb E48 IgG (number of mice (n = 6, number of tumours (t) = 9) or 800 microCi MAb E48 IgG (n) = 5,t = 7), whereas control groups received either diluent (n = 3,t = 5), unlabelled MAb E48 IgG (n = 4,t = 5) or 800 microCi 131I-labelled isotype-matched control MAb (n = 6,t = 9). A 4.1-fold increase in the median tumour volume doubling time and regression of two out of ten tumours (20%) was observed in mice treated with 400 microCi. In mice treated with 800 microCi. In mice treated with 800 microCi, two out of seven tumours (29%) showed complete remission without regrowth during follow-up (greater than 3 months). Median tumour volume doubling time in the remaining five tumours was increased 7.8-fold. No antitumour effects were observed in mice injected with diluent, unlabelled MAb E48 or 131I-labelled control MAb. In the same xenograft model, chemotherapy with doxorubicin, 5-fluorouracil, cisplatin, bleomycin, methotrexate or 2',2'-difluorodeoxycytidine yielded a less profound effect on tumour volume doubling time. Increases in tumour volume doubling time with these chemotherapeutic agents were 4, 2.2, 2.1, 1.7, 0, and 2.6 respectively. Moreover, no cures were observed with any of these chemotherapeutic agents. From the tissue distribution of 800 microCi MAb E48, the absorbed cumulative radiation doses of tumour and various organs were calculated using the trapezoid integration method for the area under the curve. To tumour xenografts, 12,170 cGy was delivered, blood received 2,984 cGy, whereas in every other tissue the accumulated dose was less than 6% of the dose delivered to tumour. These data, describing the first radiolabelled MAb with therapeutic efficacy against HNSCC, suggest radioimmunotherapy with MAb E48 to be a potential therapeutic modality for the treatment of head and neck cancer

Time-Efficient Black Blood RCA Wall Imaging at 3T Using Improved Motion Sensitized Driven Equilibrium (iMSDE): Feasibility and Reproducibility

The aim of this study was to explore the feasibility and reproducibility of a time-efficient coronary vessel wall measurement approach using an improved motion-sensitized driven equilibrium (iMSDE) pulse sequence.In this study, the iMSDE pulse sequence was first optimized and then applied on a group of healthy volunteers (N = 10) to evaluate its feasibility of vessel wall visualization. The same technique was also applied on a separate group of volunteers (N = 19) for a reproducibility study by scanning the same subject in two separate sessions. The iMSDE sequence was found to provide good coronary vessel wall delineation. It was also found to provide reproducible coronary vessel wall diameter and thickness measurements in both proximal and middle segments of the right coronary artery.The feasibility and reproducibility of iMSDE based coronary vessel wall imaging were demonstrated for the first time, paving the way for further testing in a clinical environment for fast and accurate coronary artery disease detection

Congenital disorder of glycosylation caused by starting site-specific variant in syntaxin-5

Mutations in genes critical for proper intra-Golgi transport can cause human syndromes due to defects in glycosylation of proteins. Here, the authors identify a human variant of Syntaxin-5 that causes fatal multisystem disease and mislocalization of glycosyltransferases due to altered Golgi transport

Multicenter, double-blind, randomized, intraindividual crossover comparison of gadobenate dimeglumine and gadopentetate dimeglumine for MR angiography of peripheral arteries

Purpose: To prospectively compare the image quality and diagnostic performance achieved with doses of gadobenate dimeglumine and gadopentetate dimeglumine of 0.1 mmol per kilogram of body weight in patients undergoing contrast material-enhanced magnetic resonance (MR) angiography of the pelvis, thigh, and lower-leg (excluding foot) for suspected or known peripheral arterial occlusive disease. Materials and Methods: Institutional review board approval was granted from each center and informed written consent was obtained from all patients. Between November 2006 and January 2008, 96 patients (62 men, 34 women;mean age, 63.7 years \ub1 10.4 [standard deviation];range, 39-86 years) underwent two identical examinations at 1.5 T by using three-dimensional spoiled gradient-echo sequences and randomized 0.1-mmol/kg doses of each agent. Images were evaluated on-site for technical adequacy and quality of vessel visualization and offsite by three independent blinded readers for anatomic delineation and detection/exclusion of pathologic features. Comparative diagnostic performance was determined in 31 patients who underwent digital subtraction angiography. Data were analyzed by using the Wilcoxon signed-rank, McNemar, and Wald tests. Interreader agreement was determined by using generalized \u3ba statistics. Differences in quantitative contrast enhancement were assessed and a safety evaluation was performed. Results: Ninety-two patients received both agents. Significantly better performance ( P > .0001; all evaluations) with gadobenate dimeglumine was noted on-site for technical adequacy and vessel visualization quality and offsite for anatomic delineation and detection/exclusion of pathologic features. Contrast enhancement(P 64 .0001) and detection of clinically relevant disease(P 64 .0028) were significantly improved with gadobenate dimeglumine. Interreader agreement for stenosis detection and grading was good to excellent (\u3ba = 0.749 and 0.805, respectively). Mild adverse events were reported for four (six events) and five (eight events) patients after gadobenate dimeglumine and gadopentetate dimeglumine, respectively. Conclusion: Higher-quality vessel visualization, greater contrast enhancement, fewer technical failures, and improved diagnostic performance are obtained with gadobenate dimeglumine, relative to gadopentetate dimeglumine, when compared intraindividually at 0.1-mmol/kg doses in patients undergoing contrast-enhanced MR angiography for suspected peripheral arterial occlusive disease

Antipsychotics, Metabolic Adverse Effects, and Cognitive Function in Schizophrenia

Cognitive impairment is a core symptom domain of schizophrenia. The effect of antipsychotics, the cornerstone of treatment in schizophrenia, on this domain is not fully clear. There is some evidence suggesting that antipsychotics may partially improve cognitive function, and that this improvement may vary depending on the specific cognitive domain. However, this research is confounded by various factors, such as age, duration/stage of illness, medication adherence, and extrapyramidal side effects that complicate the relationship between antipsychotics and cognitive improvement. Furthermore, antipsychotics—particularly the second generation, or “atypical” antipsychotics—can induce serious metabolic side effects, such as obesity, dyslipidemia and type 2 diabetes, illnesses which themselves have been linked to impairments in cognition. Thus, the inter-relationships between cognition and metabolic side effects are complex, and this review aims to examine them in the context of schizophrenia and antipsychotic treatment. The review also speculates on potential mechanisms underlying cognitive functioning and metabolic risk in schizophrenia. We conclude that the available literature examining the inter-section of antipsychotics, cognition, and metabolic effects in schizophrenia is sparse, but suggests a relationship between metabolic comorbidity and worse cognitive function in patients with schizophrenia. Further research is required to determine if there is a causal connection between the well-recognized metabolic adverse effects of antipsychotics and cognitive deficits over the course of the illness of schizophrenia, as well as, to determine underlying mechanisms. In addition, findings from this review highlight the importance of monitoring metabolic disturbances in parallel with cognition, as well as, the importance of interventions to minimize metabolic abnormalities for both physical and cognitive health

Human resource management interventions to improve health workers' performance in low and middle income countries: a realist review

Contains fulltext : 80429.pdf (publisher's version ) (Open Access)BACKGROUND: Improving health workers' performance is vital for achieving the Millennium Development Goals. In the literature on human resource management (HRM) interventions to improve health workers' performance in Low and Middle Income Countries (LMIC), hardly any attention has been paid to the question how HRM interventions might bring about outcomes and in which contexts. Such information is, however, critical to assess the transferability of results. Our aim was to explore if realist review of published primary research provides better insight into the functioning of HRM interventions in LMIC. METHODOLOGY: A realist review not only asks whether an intervention has shown to be effective, but also through which mechanisms an intervention produces outcomes and which contextual factors appear to be of critical influence. Forty-eight published studies were reviewed. Results : The results show that HRM interventions can improve health workers' performance, but that different contexts produce different outcomes. Critical implementation aspects were involvement of local authorities, communities and management; adaptation to the local situation; and active involvement of local staff to identify and implement solutions to problems. Mechanisms that triggered change were increased knowledge and skills, feeling obliged to change and health workers' motivation. Mechanisms to contribute to motivation were health workers' awareness of local problems and staff empowerment, gaining acceptance of new information and creating a sense of belonging and respect. In addition, staff was motivated by visible improvements in quality of care and salary supplements. Only a limited variety of HRM interventions have been evaluated in the health sector in LMIC. Assumptions underlying HRM interventions are usually not made explicit, hampering our understanding of how HRM interventions work. CONCLUSION: Application of a realist perspective allows identifying which HRM interventions might improve performance, under which circumstances, and for which groups of health workers. To be better able to contribute to an understanding of how HRM interventions could improve health workers' performance, a combination of qualitative and quantitative research methods would be needed and the use of common indicators for evaluation and a common reporting format would be required

Quantification in cardiac MRI: advances in image acquisition and processing

Cardiac magnetic resonance (CMR) imaging enables accurate and reproducible quantification of measurements of global and regional ventricular function, blood flow, perfusion at rest and stress as well as myocardial injury. Recent advances in MR hardware and software have resulted in significant improvements in image quality and a reduction in imaging time. Methods for automated and robust assessment of the parameters of cardiac function, blood flow and morphology are being developed. This article reviews the recent advances in image acquisition and quantitative image analysis in CMR

Full-length human placental sFlt-1-e15a isoform induces distinct maternal phenotypes of preeclampsia in mice

<div><p>Objective</p><p>Most anti-angiogenic preeclampsia models in rodents utilized the overexpression of a truncated soluble fms-like tyrosine kinase-1 (sFlt-1) not expressed in any species. Other limitations of mouse preeclampsia models included stressful blood pressure measurements and the lack of postpartum monitoring. We aimed to 1) develop a mouse model of preeclampsia by administering the most abundant human placental sFlt-1 isoform (hsFlt-1-e15a) in preeclampsia; 2) determine blood pressures in non-stressed conditions; and 3) develop a survival surgery that enables the collection of fetuses and placentas and postpartum (PP) monitoring.</p><p>Methods</p><p>Pregnancy status of CD-1 mice was evaluated with high-frequency ultrasound on gestational days (GD) 6 and 7. Telemetry catheters were implanted in the carotid artery on GD7, and their positions were verified by ultrasound on GD13. Mice were injected through tail-vein with adenoviruses expressing hsFlt-1-e15a (n = 11) or green fluorescent protein (GFP; n = 9) on GD8/GD11. Placentas and pups were delivered by cesarean section on GD18 allowing PP monitoring. Urine samples were collected with cystocentesis on GD6/GD7, GD13, GD18, and PPD8, and albumin/creatinine ratios were determined. GFP and hsFlt-1-e15a expression profiles were determined by qRT-PCR. Aortic ring assays were performed to assess the effect of hsFlt-1-e15a on endothelia.</p><p>Results</p><p>Ultrasound predicted pregnancy on GD7 in 97% of cases. Cesarean section survival rate was 100%. Mean arterial blood pressure was higher in hsFlt-1-e15a-treated than in GFP-treated mice (∆MAP = 13.2 mmHg, p = 0.00107; GD18). Focal glomerular changes were found in hsFlt-1-e15a -treated mice, which had higher urine albumin/creatinine ratios than controls (109.3±51.7μg/mg vs. 19.3±5.6μg/mg, p = 4.4x10^-2; GD18). Aortic ring assays showed a 46% lesser microvessel outgrowth in hsFlt-1-e15a-treated than in GFP-treated mice (p = 1.2x10^-2). Placental and fetal weights did not differ between the groups. One mouse with liver disease developed early-onset preeclampsia-like symptoms with intrauterine growth restriction (IUGR).</p><p>Conclusions</p><p>A mouse model of late-onset preeclampsia was developed with the overexpression of hsFlt-1-e15a, verifying the <i>in vivo</i> pathologic effects of this primate-specific, predominant placental sFlt-1 isoform. HsFlt-1-e15a induced early-onset preeclampsia-like symptoms associated with IUGR in a mouse with a liver disease. Our findings support that hsFlt-1-e15a is central to the terminal pathway of preeclampsia, and it can induce the full spectrum of symptoms in this obstetrical syndrome.</p></div