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Gender violence is a human rights violation and a serious public health problem that should be addressed with an inter-sector and interdisciplinary focus. Collaboration and coordination between sectors, including the health sector, is essential for guaranteeing such approach. The study aimed to learn which actors address gender violence in the communities and to study the communities' opinions concerning the public health system's role in (and approach to) this problem. A qualitative action-research project was conducted with local community self-diagnosis workshops, using various qualitative techniques and thematic analysis. The results pointed to various local actors that address the problem and showed that primary healthcare plays a relevant role, due mainly to its proximity to the population and interdisciplinary approach. The obstacles identified by the communities for the health system approach mainly involved the biomedical model of care, decentralization, and lack of resources, training, and integrated policies. In conclusion, the workshops facilitated the development of collective knowledge on the local reality, underlining the role of primary healthcare and the need to link action and approaches between sectors and communities.

Background: Although surgical resection is the only potentially curative treatment for pancreatic cancer (PC), long-term outcomes of this treatment remain poor. The aim of this study is to describe the feasibility of a neoadjuvant treatment with induction polychemotherapy (IPCT) followed by chemoradiation (CRT) in resectable PC, and to develop a machine-learning algorithm to predict risk of relapse., Methods: Forty patients with resectable PC treated in our institution with IPCT (based on mFOLFOXIRI, GEMOX or GEMOXEL) followed by CRT (50 Gy and concurrent Capecitabine) were retrospectively analyzed. Additionally, clinical, pathological and analytical data were collected in order to perform a 2-year relapse-risk predictive population model using machine-learning techniques., Results: A R0 resection was achieved in 90% of the patients. After a median follow-up of 33.5 months, median progression-free survival (PFS) was 18 months and median overall survival (OS) was 39 months. The 3 and 5-year actuarial PFS were 43.8% and 32.3%, respectively. The 3 and 5-year actuarial OS were 51.5% and 34.8%, respectively. Forty-percent of grade 3-4 IPCT toxicity, and 29.7% of grade 3 CRT toxicity were reported. Considering the use of granulocyte colony-stimulating factors, the number of resected lymph nodes, the presence of perineural invasion and the surgical margin status, a logistic regression algorithm predicted the individual 2-year relapse-risk with an accuracy of 0.71 (95% confidence interval [CI] 0.56-0.84, p = 0.005). The model-predicted outcome matched 64% of the observed outcomes in an external dataset., Conclusion: An intensified multimodal neoadjuvant approach (IPCT + CRT) in resectable PC is feasible, with an encouraging long-term outcome. Machine-learning algorithms might be a useful tool to predict individual risk of relapse. A small sample size and therapy heterogeneity remain as potential limitations.

Introduction: The management of urinary clot retention and hematuria involves manual irrigation with sterile water or normal saline via a Foley catheter followed by continuous bladder irrigation. Irrigation may become difficult because of the formation of dense blood clots. Tissue plasminogen activator (t-PA/Alteplase) may be a useful pharmacological agent to improve the efficacy of manual irrigation of large, dense clots. The goal of the current study was to compare t-PA to sterile water for clot irrigation in an in vitro model., Materials and Methods: In vitro models of clot retention were created using 500-cc urinary leg bags each filled with 80 cc of unpreserved whole blood from a healthy volunteer. Each model was incubated at 25 degrees C for 24 hours to allow clot formation. Four models each with 25 mL solution of t-PA at concentrations of 2, 1, 0.5, and 0.25 mg/mL were evaluated and compared to a control (25 mL sterile water). Models were instilled with solution (t-PA or control) and incubated for 30 minutes at 37 degrees C, and then irrigated with sterile water via 18F Foley by a blinded investigator. Three separate experiments were conducted, and statistical analysis was performed comparing various irrigation parameters., Results: Clot evacuation with 25 mL of t-PA at a concentration of 2 mg/mL (50 mg) was significantly easier (p = 0.05) and faster (p < 0.05) than the sterile water control. The mean time for clot evacuation in this model was 2.7 minutes for t-PA solution 2 mg/mL versus 7.3 minutes for the control (p < 0.05). Compared to the control, irrigation with t-PA solution 2 mg/mL also required less irrigant (180 mL vs. 500 mL) (p < 0.05) for complete evacuation. There was a similar trend in efficacy for the lower doses of t-PA, but this was not statistically significant., Conclusion: In this in vitro study, a single 25 mL instillation of t-PA solution 2 mg/mL is significantly better than sterile water alone for clot evacuation. In vivo animal studies are pending.

Background: Neurotoxicity of long-term exposure to toluene is known at higher levels than 50 ppm and is suspected at lower levels., Methods: A cross-sectional study carried out in two printing plants on 129 blue collar workers explored such a low level exposure of toluene. With 231 samples of ambient air, toluene concentration was estimated from 0 to 18 ppm in Plant A (offset) and from 2 to 27 ppm in Plant B (heliogravure). Outside any period of acute exposure, the workers answered a self-administered questionnaire on neurotoxic symptoms, EUROQUEST, and performed six psychometric tests on a computer-assisted version of battery NES., Results: After adjustment for confounders, we found significant relationships only between present exposure and Digit Span Forwards (DSF) performance (decrement is 1 digit for 40 ppm, P=0.04) and Digit Span Backwards (DSB) performance (decrement is 1 digit for 25 ppm, P=0.01). Neurotoxic symptoms were not significantly correlated with current exposure. No association was found between estimated cumulative exposure and either psychometric performances or neurotoxic symptoms., Conclusion: In this study, low present exposure levels to toluene were associated with decrements of memory test performances., (Copyright 2002 Wiley‐Liss, Inc.)

The purpose of this study was to establish a basis for the use of a device for measuring vibrotactile perception thresholds for epidemiological purposes on a series of non-exposed populations. Vibrotactile perception thresholds (VPTs) were measured with a vibrometer in 218 men and 160 women belonging to two non-exposed male blue collar populations, one white-collar population and one age and gender stratified sample of the general population. VPTs were measured on the middle and the little finger of the dominant hand at 31.5 and 125 Hz. The VPTs were expressed in dB and the effect of a series of factors including the population, age, gender and digital temperature was assessed in a regression analysis weighted by the inverse variance of the measurements. Adjusted for age, no significant difference between the VPTs in the four male populations was observed. At frequency 125 Hz, the effect of age (0.3 dB per year) was more important than at frequency 31.5 Hz (0.2 dB per year). In the two female populations, the results were less stable than among males and the VPTs were higher than among males. However, the age-dependence was similar among males and females. The within-test variance is a valuable indicator of the quality of the VPT measurements. Weighting by its inverse improved the fit of the regression models. Normal values for VPTs in non-exposed populations were obtained, which were reproducible in four separate populations.

One of the main difficulties with blood substitutes based on hemoglobin (Hb) solutions is the auto-oxidation of the hemes, a problem aggravated by the dimerization of Hb tetramers. We have employed a method to study the oxyHb tetramer-dimer equilibrium based on the rate of auto-oxidation as a function of protein concentration. The 16-fold difference in dimer and tetramer auto-oxidation rates (in 20 mM phosphate buffer at pH 7.0, 37 degrees C) was exploited to determine the fraction dimer. The results show a transition of the auto-oxidation rate from low to high protein concentrations, allowing the determination of the tetramer-dimer dissociation coefficient K4,2 = [Dimer] 2/[Tetramer]. A 14-fold increase in K4,2 was observed for addition of 10 mM of the allosteric effector inositol hexaphosphate (IHP). Recombinant hemoglobins (rHb) were genetically engineered to obtain Hb with a lower oxygen affinity than native Hb (Hb A). The rHb alpha2beta2 [(C7) F41Y/(G4) N102Y] shows a fivefold increase in K4,2 at pH 7.0, 37 degrees C. An atmosphere of pure oxygen is necessary in this case to insure fully oxygenated Hb. When this condition is satisfied, this method provides an efficient technique to characterize both the tetramer-dimer equilibrium and the auto-oxidation rates of various oxyHb. For low oxygen affinity Hb equilibrated under air, the presence of deoxy subunits accelerates the auto-oxidation. Although a full analysis is complicated, the auto-oxidation studies for air equilibrated samples are more relevant to the development of a blood substitute based on Hb solutions. The double mutants, rHb alpha2beta2 [(C7) F41Y/(G4) N102A] and rHb alpha2beta2 [(C7) F41Y/(E10) K66T], show a lower oxygen affinity and a higher rate of oxidation than Hb A. Simulations of the auto-oxidation rate versus Hb concentration indicate that very high protein concentrations are required to observe the tetramer auto-oxidation rate. Because the dimers oxidize much more rapidly, even a small fraction dimer will influence the observed oxidation rate.

We have engineered alpha2beta2 [Phe63]hemoglobin by changing the highly conserved distal histidine of the beta chains to a phenylalanine. The mutant tetramer binds four high-affinity ligands, such as CO or NO, to the ferrous form, or CN to the oxidized iron; however, it binds only two low-affinity ligands, oxygen and azide. The absorption spectrum of the ferrous deoxy or ferric forms are not normal, displaying an enhanced absorption of the visible band near 560 nm. Half of the autooxidation process, attributed to the mutated beta subunits, is over 1000-fold faster than for Hb A. The mutant Hb exhibits non-cooperative binding of two oxygens with an affinity about fivefold lower than those of HbA valency hybrids (alpha met beta)2. Functional properties of this mutant Hb resemble those of Hb Saskatoon ([Tyr63]Hb) [Suzuki, T., Hayashi, A., Shimizu, A. & Yamamura, Y. (1966) Biochim. Biophys. Acta 127, 280-282]. Flash-photolysis experiments also indicate non-cooperative behaviour: the CO-recombination kinetics were independent of the fraction dissociated. Furthermore, the amplitude of the CO bimolecular phase was the same for the (alpha(CO)metbeta)2 valency hybrid or the (alphaCO betaCO)2 form, suggesting mainly geminate CO-recombination kinetics to the beta chains. EPR and Resonance Raman spectra did not show evidence for a hemichrome, normally considered as a six-coordinated iron with low-spin character. The EPR and resonance Raman spectra for the mutated beta subunits demonstrate the presence of a high-spin compound in the ferric and deoxy ferrous forms. In particular, the ferrous mutated beta subunits are penta-coordinated. The abnormal absorption spectra are possibly due to an interaction between the porphyrin and the phenyl ring in the distal position rather than to direct binding to the iron.

The replacement of beta 5(A2)Pro by Arg in Hb Warwickshire appears to be without an effect on the functional properties of human Hb A, despite adding two external positive charges close to the central cavity of the hemoglobin tetramer, along the dyad axis. To clarify the role of this portion of the molecule involved in oxygen-linked anion binding, we have engineered the recombinant hemoglobin alpha 2 beta (2)5(A2)Pro-->Ala[rHb beta 5(A2)Pro-->Ala]. The rHb beta 5(A2)Pro-->Ala exhibits an increased oxygen affinity compared to Hb A, with normal heterotropic effects in standard conditions. The increased oxygen affinity may be attributed to the absence of proline, which would render the A helix more flexible, thus destabilizing the T structure. The normal functional properties of Hb Warwickshire may be due to the regulation of oxygen affinity by electrostatic effects involving diffusible anions not bound to any specific site.

Bovine hemoglobin (Hb) has been proposed as a potential blood substitute because of its low intrinsic oxygen affinity in the absence of chloride anions and 2,3-diphosphoglycerate. The use of bovine blood as a source of Hb does not eliminate the risks of viral infections. Biotechnology techniques allow to produce modified recombinant Hbs. We have engineered human Hb mutants with the aim of mimicking the functional properties of bovine Hb. The argument for this work resides in the crystallographic studies and in the comparison of human and bovine beta globin sequences. The mutant recombinant Hbs exhibit the heterotropic effects of bovine Hb do not exhibit the low intrinsic oxygen affinity of bovine Hb.

The search for human Hb variants exhibiting a low oxygen affinity without requiring 2,3-diphosphoglycerate, together with a low oxygation rate, is of an increased interest in the view of producing an artificial oxygen carrier. We have synthesized the recombinant Hb beta 41Phe-->Tyr (rHb beta F41Y) which exhibits a low oxygen affinity due to the stabilization of the deoxy state of tetrameric Hb [1]. Interestingly, the autooxydation rate for this mutant is similar to that for Hb A. We have associated the mutation beta F41Y with the naturally occurring beta 82Lys-->Asp substitution (Hb Providence) known to be responsible for a low oxygen affinity [2]. The second-site mutation further decreases the oxygen affinity of the rHb beta F41Y. The effects of the beta F41Y and K82D mutations are additive, resulting in a four fold decrease in oxygen affinity of the artificial mutant Hb beta F41Y-K82D, compared to Hb A. In spite of the marked decrease in oxygen affinity, the autooxydation rate is 2- to 3 fold larger than that of Hb A. These data show that it is possible to adjust the oxygen binding properties of human Hb by using protein engineering methods. Because of the low oxygen affinity coexisting with a moderately increased autooxydation rate, this variant is a good candidate for the development of a Hb-based oxygen carrier.

During the 28th Meeting of the Collège Français de Pathologie Vasculaire, twelve experts, six angiologists and six surgeons were asked to choose a first intention treatment for 32 case reports of patients with varicose veins based on physical examinations and écho-Doppler findings. The audience made their choice simultaneously by an electronic voting system. In a large number of cases, several therapeutic options were possible. The greater saphenous vein can often be retained in first intention situations with the possibility that several years later the prognosis of the limb may depend on the presence of this vein, particularly in life threatening cases where it is needed for arterial bypass surgery. In some cases it is clear that the greater saphenous vein does not need to be removed and in others, deterioration is clearly sufficient to justify removal. In many cases, the choice between the two options is a decision to be made. Indications depend on the clinical presentation and echo-Doppler findings. The caliber of the greater saphenous vein must be determined for the entire length of the vein. Whenever possible, veins with a diameter below 8 mm should be preserved and the patients should be informed on why the choice was made. Whatever treatment has been chosen, recurrence may be observed and periodic follow-up is required.

Our goal was to design a single hemoglobin subunit able to assemble into a stable tetrameric structure with cooperative O2 binding and low oxygen affinity. We have synthesized in E. coli a chimeric beta/alpha globin subunit composed of the first 73 residues of the beta chain and the last 73 residues of the alpha chain. Molecular building indicated that this construction could result in Hb homotetramers possessing the alpha 1 beta 2 interface, responsible for the heme-heme interaction in Hb heterotetramers. The results show that the chimeric subunits assemble into tetramers which bind oxygen reversibly without cooperativity but with an oxygen affinity slightly lower than observed for human Hb. The strong effector RSR 4 lowers the oxygen affinity. Kinetics of CO recombination in the presence of RSR 4 reveal a biphasic bimolecular rebinding. Functional studies suggest that the quaternary structure of the oligomer is intermediary between R-and T-state.

Bovine Hb (hemoglobin) has a low oxygen affinity in the absence of chloride ions and DPG. Because of the increasing interest of this Hb as a potential blood substitute we have engineered a human Hb mutant with the aim of mimicking the functional properties of bovine Hb. This was achieved by deleting residue beta NA1 Val and substituting a methionine for histidine at the beta NA2 position as previously suggested by Perutz and Imai in 1980. Our results show that the artificial mutant exhibits some of the characteristics of bovine Hb but does not show the low oxygen affinity which is measured in bovine blood.

The Hb S (beta 6 Glu-->Val) fiber is formed by the packing of double strands which constitute the basic unit of the deoxyHb S polymer. The specific interaction responsible for the stabilization of the double strand involves the mutated beta 6 Val side chain (lateral contact). Recombinant Hb beta 6 Glu-->Ala and the double mutant beta 6 Glu-->Ala, 23 Val-->Ile exhibit a decreased solubility compared to Hb A. While the Hb beta 6 Ala does not polymerize, the association of the beta 23 Val-->Ile mutation at the axial contact allows the double mutant to polymerize. These results show that: (1) the hydrophobic interactions between donor and acceptor sites depend on both the hydrophobicity and the stereospecificity of the amino acid side chain at the beta 6 position; (2) increasing the hydrophobic interactions at the axial contact (connecting molecules along the same strand) result in an increased stability of the lateral contact between filaments.