Radiotherapy plus nimotuzumab or placebo in the treatment of high grade glioma patients: results from a randomized, double blind trial

Background The prognosis of patients bearing high grade glioma remains dismal. Epidermal Growth Factor Receptor (EGFR) is well validated as a primary contributor of glioma initiation and progression. Nimotuzumab is a humanized monoclonal antibody that recognizes the EGFR extracellular domain and reaches Central Nervous System tumors, in nonclinical and clinical setting. While it has similar activity when compared to other anti-EGFR antibodies, it does not induce skin toxicity or hypomagnesemia. Methods A randomized, double blind, multicentric clinical trial was conducted in high grade glioma patients (41 anaplastic astrocytoma and 29 glioblastoma multiforme) that received radiotherapy plus nimotuzumab or placebo. Treatment and placebo groups were well-balanced for the most important prognostic variables. Patients received 6 weekly doses of 200 mg nimotuzumab or placebo together with irradiation as induction therapy. Maintenance treatment was given for 1 year with subsequent doses administered every 3 weeks. The objectives of this study were to assess the comparative overall survival, progression free survival, response rate, immunogenicity and safety. Results The median cumulative dose was 3200 mg of nimotuzumab given over a median number of 16 doses. The combination of nimotuzumab and RT was well-tolerated. The most prevalent related adverse reactions included nausea, fever, tremors, anorexia and hepatic test alteration. No anti-idiotypic response was detected, confirming the antibody low immunogenicity. The mean and median survival time for subjects treated with nimotuzumab was 31.06 and 17.76 vs. 21.07 and 12.63 months for the control group. Conclusions In this randomized trial, nimotuzumab showed an excellent safety profile and significant survival benefit in combination with irradiation.

Pre-Cruise Plan: Cruise 64-S-3 - Albacore Survey

(PDF contains 4 pages.)

Resveratrol Metabolites Modify Adipokine Expression and Secretion in 3T3-L1 Pre-Adipocytes and Mature Adipocytes

Objective: Due to the low bioavailability of resveratrol, determining whether its metabolites exert any beneficial effect is an interesting issue. Methods: 3T3-L1 maturing pre-adipocytes were treated during differentiation with 25 mu M of resveratrol or with its metabolites and 3T3-L1 mature adipocytes were treated for 24 hours with 10 mM resveratrol or its metabolites. The gene expression of adiponectin, leptin, visfatin and apelin was assessed by Real Time RT-PCR and their concentration in the incubation medium was quantified by ELISA. Results: Resveratrol reduced mRNA levels of leptin and increased those of adiponectin. It induced the same changes in leptin secretion. Trans-resveratrol-3-O-glucuronide and trans-resveratrol-4'-O-glucuronide increased apelin and visfatin mRNA levels. Trans-resveratrol-3-O-sulfate reduced leptin mRNA levels and increased those of apelin and visfatin. Conclusions: The present study shows for the first time that resveratrol metabolites have a regulatory effect on adipokine expression and secretion. Since resveratrol has been reported to reduce body-fat accumulation and to improve insulin sensitivity, and considering that these effects are mediated in part by changes in the analyzed adipokines, it may be proposed that resveratrol metabolites play a part in these beneficial effects of resveratrol.

The Expanded mtDNA Phylogeny of the Franco-Cantabrian Region Upholds the Pre-Neolithic Genetic Substrate of Basques

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Somatisation in primary care: experiences of primary care physicians involved in a training program and in a randomised controlled trial

Background: A new intervention aimed at managing patients with medically unexplained symptoms (MUS) based on a specific set of communication techniques was developed, and tested in a cluster randomised clinical trial. Due to the modest results obtained and in order to improve our intervention we need to know the GPs' attitudes towards patients with MUS, their experience, expectations and the utility of the communication techniques we proposed and the feasibility of implementing them. Physicians who took part in 2 different training programs and in a randomised controlled trial (RCT) for patients with MUS were questioned to ascertain the reasons for the doctors' participation in the trial and the attitudes, experiences and expectations of GPs about the intervention. Methods: A qualitative study based on four focus groups with GPs who took part in a RCT. A content analysis was carried out. Results: Following the RCT patients are perceived as true suffering persons, and the relationship with them has improved in GPs of both groups. GPs mostly valued the fact that it is highly structured, that it made possible a more comfortable relationship and that it could be applied to a broad spectrum of patients with psychosocial problems. Nevertheless, all participants consider that change in patients is necessary; GPs in the intervention group remarked that that is extremely difficult to achieve. Conclusion: GPs positively evaluate the communication techniques and the interventions that help in understanding patient suffering, and express the enormous difficulties in handling change in patients. These findings provide information on the direction in which efforts for improving intervention should be directed.

Randomised, crossover clinical trial, in healthy volunteers, to compare the systemic availability of two topical intranasal budesonide formulations

Background: Budesonide has a long history as intranasal drug, with many marketed products. Efforts should be made to demonstrate the therapeutic equivalence and safety comparability between them. Given that systemic availability significantly varies from formulations, the clinical comparability of diverse products comes to be of clinical interest and a regulatory requirement. The aim of the present study was to compare the systemic availability, pharmacodynamic effect, and safety of two intranasal budesonide formulations for the treatment of rhinitis. Methods: Eighteen healthy volunteers participated in this randomised, controlled, crossover, clinical trial. On two separated days, subjects received a single dose of 512 mu g budesonide (4 puffs per nostril) from each of the assayed devices (Budesonida nasal 64 (R), Aldo-Union, Spain and Rhinocort 64 (R), AstraZeneca, Spain). Budesonide availability was determined by the measurement of budesonide plasma concentration. The pharmacodynamic effect on the hypothalamic-adrenal axis was evaluated as both plasma and urine cortisol levels. Adverse events were tabulated and described. Budesonide availability between formulations was compared by the calculation of 90% CI intervals of the ratios of the main pharmacokinetic parameters describing budesonide bioavailability. Plasma cortisol concentration-time curves were compared by means of a GLM for Repeated Measures. Urine cortisol excretion between formulations was compared through the Wilcoxon's test. Results: All the enroled volunteers successfully completed the study. Pharmacokinetic parameters were comparable in terms of AUC(t) (2.6 +/- 1.5 vs 2.2 +/- 0.7), AUCi (2.9 +/- 1.5 vs 2.4 +/- 0.7), t(max) (0.4 +/- 0.1 vs 0.4 +/- 0.2), C(max)/AUC(i) (0.3 +/- 0.1 vs 0.3 +/- 0.0), and MRT (5.0 +/- 1.4 vs 4.5 +/- 0.6), but not in the case of C(max) (0.9 +/- 0.3 vs 0.7 +/- 0.2) and t(1/2) (3.7 +/- 1.8 vs 2.9 +/- 0.4). The pharmacodynamic effects, measured as the effect over plasma and urine cortisol, were also comparables between both formulations. No severe adverse events were reported and tolerance was comparable between formulations. Conclusion: The systemic availability of intranasal budesonide was comparable for both formulations in terms of most pharmacokinetic parameters. The pharmacodynamic effect on hypothalamic-pituitary-adrenal axis was also similar. Side effects were scarce and equivalent between the two products. This methodology to compare different budesonide-containing devices is reliable and easy to perform, and should be recommended for similar products intented to be marketed or already on the market.

Pre-packaged fresh fish - Searching for quality descriptive criteria

32 Proben verpackten Frischfischs in Selbstbedienungspackungen, 16 Seelachs- und 16 Rotbarschproben aus deutschen Supermärkten wurden mit physikalischen, chemischen, mikrobiellen und sensorischen Methoden untersucht. Ziel der Untersuchung war dieWertung von Untersuchungsmethoden zur Qualitätsbestimmung. Es zeigte sich, daß neben der sensorischen Beurteilung die Bestimmung des TVB-N geeignet ist, die Qualität dieser Produkte zu beurteilen.

The nutritional status of pre-school children, Kainji Lake communities, Nigeria: a baseline survey

This survey was carried out to provide the Kainji Lake Fisheries Promotion Project (KLFPP), whose overall goal is the improvement of the standard of living of fishing communities around Kainji Lake, Nigeria, and an increase in the availability of fish to consumers, with nutritional status baseline data for long-term monitoring and evaluation of the overall project goal. In a cross-sectional survey, baseline anthropometric data was collected from 768 children, aged 3-60 months in 389 fisherfolk households around the southern sector of Kainji Lake, Nigeria. In addition, data was collected on the nutritional status and fertility of the mothers, vaccination coverage of children and child survival indicators. For control purposes, 576 children and 292 mothers from non-fishing households around Kainji Lake were likewise covered by the survey. A standardised questionnaire was used to collect relevant information, while anthropometric measurements were made using appropriate equipment. Data compilation and analysis was carried out with DATAEASE registered and EPI-INFO registered software, using NCHS reference data for the analysis of anthropometric measurements. The prevalence of stunted children in fishing households was high at 40%, while the prevalence of wasted and underweight children was likewise high at 10% and 29% respectively. Children from non-fishing households had a marginally lower prevalence of stunting, wasting and underweight with 37%, 7% and 25 % respectively, although these differences were not statistically significant. Considering the fact that the survey was carried out during a period of relative food abundance, the prevalence of wasting and underweight children is likely to be much higher during periods of food shortage. The prevalence of stunting, wasting and underweight was relatively high for children aged 3 to 23 months, suggesting an increased risk of malnutrition during this period, most likely associated with inadequate weaning practices. The prevalence of malnourishment amongst women of child-bearing age was relatively high, irrespective of occupation of the household, with an average of 11% undernourished and 6% wasted. Vaccination coverage was very low while infant and child mortality were extremely high with about 1 in 5 children dying before their fifth birthday. Based on the ethical obligation to maximise the potential benefits of the survey, recommendations for activities to improve community nutrition and health were made for communication to relevant authorities. (PDF contains 52 pages)

The nutritional status of pre-school children, Kainji Lake communities, Nigeria: a follow-up survey

This survey was carried out to provide the Kainji Lake Fisheries Promotion Project (KLFPP), whose overall goal is the improvement of the standard of living of fishing communities around Kainji Lake, Nigeria, managing the fisheries on a sustainable basis, with follow-up data for long-term monitoring and evaluation of the overall project goal. A similar survey, conducted in 1996, provided the baseline against which data from the current survey was evaluated. In a cross-sectional survey, anthropometric data was collected from 576 children aged 3-60 months in 282 fisherfolk households around the southern sector of Kainji Lake, Nigeria. In addition, data was collected on the nutritional status and fertility of the mothers, vaccination coverage of children and child survival indicators. For control purposes, 374 children and 181 mothers from non-fishing households around Kainji Lake were likewise covered by the survey. A standardised questionnaire was used to collect relevant data, while anthropometric measurements were made using appropriate equipment. Data compilation and analysis was carried out with a specially designed Microsoft Access application, using NCHS reference data for the analysis of anthropometric measurements. Statistical significance testing was done using EPI-INFO" software. The results of the follow-up survey indicate a slight increase in the percentage of stunted pre-school children in fishing households around Kainji Lake, from 40% in 1996 to 41% in 1999. This increase is however not statistically significant (p= 0.704). Over the same period, the percentage of stunted children in non-fishing households increased from 37% to 39% (p= 0.540), which is also not statistically significant. Likewise, there were no statistically significant differences between the 1996 and 1999 results for the prevalence of either wasted or underweight children in fishing households. The same applies to children from non-fishing households. In addition, vaccination coverage remains very low while infant and child mortality rates continue to be extremely high with about 1 in 5 children dying before their fifth birthday. There has been no perceptible and lasting improvement in the standard of living of fishing households over the course of the second project phase as indicated by the persistently high prevalence of stunting. The situation is the same for the control group, indicating that for the region as a whole, a number of factors beyond the immediate influence of the project continue to negatively impact on the standard of living. The results also show that the project activities have not had any negative long-term effect on the nutritional status of the beneficiaries. (PDF contains 44 pages)

A genetic and biochemical analysis of pre-mRNA splicing in Saccharomyces cerevisiae

Pre-mRNA splicing requires interaction of cis- acting intron sequences with trans -acting factors: proteins and small nuclear ribonucleoproteins (snRNPs). The assembly of these factors into a large complex, the spliceosome, is essential for the subsequent two step splicing reaction. First, the 5' splice site is cleaved and free exon 1 and a lariat intermediate (intron- exon2) form. In the second reaction the 3' splice site is cleaved the exons ligated and lariat intron released. A combination of genetic and biochemical techniques have been used here to study pre-mRNA splicing in yeast.

Yeast introns have three highly conserved elements. We made point mutations within these elements and found that most of them affect splicing efficiency in vivo and in vitro, usually by inhibiting spliceosome assembly.

To study trans -acting splicing factors we generated and screened a bank of temperature- sensitive (ts) mutants. Eleven new complementation groups (prp17 to prp27) were isolated. The four phenotypic classes obtained affect different steps in splicing and accumulate either: 1) pre-mRNA, 2) lariat intermediate, 3) excised intron or 4) both pre-mRNA and intron. The latter three classes represent novel phenotypes. The excised intron observed in one mutant: prp26 is stabilized due to protection in a snRNP containing particle. Extracts from another mutant: prpl8 are heat labile and accumulate lariat intermediate and exon 1. This is especially interesting as it allows analysis of the second splicing reaction. In vitro complementation of inactivated prp18 extracts does not require intact snRNPs. These studies have also shown the mutation to be in a previously unknown splicing protein. A specific requirement for A TP is also observed for the second step of splicing. The PRP 18 gene has been cloned and its polyadenylated transcript identified.

A retrofitting framework for pre-Northridge steel moment-frame buildings

In the 1994 M_w 6.7 Northridge and 1995 M_w 6.9 Kobe earthquakes, steel moment-frame buildings were exposed to an unexpected flaw. The commonly utilized welded unreinforced flange, bolted web connections were observed to experience brittle fractures in a number of buildings, even at low levels of seismic demand. A majority of these buildings have not been retrofitted and may be susceptible to structural collapse in a major earthquake.

This dissertation presents a case study of retrofitting a 20-story pre-Northridge steel moment-frame building. Twelve retrofit schemes are developed that present some range in degree of intervention. Three retrofitting techniques are considered: upgrading the brittle beam-to-column moment resisting connections, and implementing either conventional or buckling-restrained brace elements within the existing moment-frame bays. The retrofit schemes include some that are designed to the basic safety objective of ASCE-41 Seismic Rehabilitation of Existing Buildings.

Detailed finite element models of the base line building and the retrofit schemes are constructed. The models include considerations of brittle beam-to-column moment resisting connection fractures, column splice fractures, column baseplate fractures, accidental contributions from ``simple'' non-moment resisting beam-to-column connections to the lateral force-resisting system, and composite actions of beams with the overlying floor system. In addition, foundation interaction is included through nonlinear translational springs underneath basement columns.

To investigate the effectiveness of the retrofit schemes, the building models are analyzed under ground motions from three large magnitude simulated earthquakes that cause intense shaking in the greater Los Angeles metropolitan area, and under recorded ground motions from actual earthquakes. It is found that retrofit schemes that convert the existing moment-frames into braced-frames by implementing either conventional or buckling-restrained braces are effective in limiting structural damage and mitigating structural collapse. In the three simulated earthquakes, a 20% chance of simulated collapse is realized at PGV of around 0.6 m/s for the base line model, but at PGV of around 1.8 m/s for some of the retrofit schemes. However, conventional braces are observed to deteriorate rapidly. Hence, if a braced-frame that employs conventional braces survives a large earthquake, it is questionable how much service the braces provide in potential aftershocks.