Tight open knots.

The tightest open conformations of a few prime knots (3(1), 4(1), 5(1), 5(2), and 6(3)) found with the use of the SONO algorithm are presented and discussed. The conformations are obtained from the tightest closed conformations of the knots by cutting and opening them at different locations. The length of the rope engaged in each of the open conformations is calculated. The curvature and torsion profiles of the unique tightest conformations of the 3(1) and 4(1) open knots are presented and discussed. In particular, symmetry properties of the knots reflected within their curvature and torsion profiles are analysed. Connections with the physics of polymers are discussed.

Paclitaxel-eluting biodegradable synthetic vascular prostheses: a step towards reduction of neointima formation?

BACKGROUND: Clinical small-caliber vascular prostheses are unsatisfactory. Reasons for failure are early thrombosis and late intimal hyperplasia. We thus prepared biodegradable small-caliber vascular prostheses using electrospun polycaprolactone (PCL) with slow-releasing paclitaxel (PTX), an antiproliferative drug. METHODS AND RESULTS: PCL solutions containing PTX were used to prepare nonwoven nanofibre-based 2-mm ID prostheses. Mechanical morphological properties and drug loading, distribution, and release were studied in vitro. Infrarenal abdominal aortic replacement was carried out with nondrug-loaded and drug-loaded prostheses in 18 rats and followed for 6 months. Patency, stenosis, tissue reaction, and drug effect on endothelialization, vascular remodeling, and neointima formation were studied in vivo. In vitro prostheses showed controlled morphology mimicking extracellular matrix with mechanical properties similar to those of native vessels. PTX-loaded grafts with suitable mechanical properties and controlled drug-release were obtained by factorial design. In vivo, both groups showed 100% patency, no stenosis, and no aneurysmal dilatation. Endothelial coverage and cell ingrowth were significantly reduced at 3 weeks and delayed at 12 and 24 weeks in PTX grafts, but as envisioned, neointima formation was significantly reduced in these grafts at 12 weeks and delayed at 6 months. CONCLUSIONS: Biodegradable, electrospun, nanofibre, polycaprolactone prostheses are promising because in vitro they maintain their mechanical properties (regardless of PTX loading), and in vivo show good patency, reendothelialize, and remodel with autologous cells. PTX loading delays endothelialization and cellular ingrowth. Conversely, it reduces neointima formation until the end point of our study and thus may be an interesting option for small caliber vascular grafts.

Clinical benefits of an adherence monitoring program in the management of secondary hyperparathyroidism with cinacalcet: results of a prospective randomized controlled study.

BACKGROUND/AIMS: One of the causes of uncontrolled secondary hyperparathyroidism (sHPT) is patient's poor drug adherence. We evaluated the clinical benefits of an integrated care approach on the control of sHPT by cinacalcet. METHODS: Prospective, randomized, controlled, multicenter, open-label study. Fifty hemodialysis patients on a stable dose of cinacalcet were randomized to an integrated care approach (IC) or usual care approach (UC). In the IC group, cinacalcet adherence was monitored using an electronic system. Results were discussed with the patients in motivational interviews, and drug prescription adapted accordingly. In the UC group, drug adherence was monitored, but results were not available. RESULTS: At six months, 84% of patients in the IC group achieved recommended iPTH targets versus 55% in the UC group (P = 0.04). The mean cinacalcet taking adherence improved by 10.8% in the IC group and declined by 5.3% in the UC group (P = 0.02). Concomitantly, the mean dose of cinacalcet was reduced by 7.2 mg/day in the IC group and increased by 6.4 mg/day in the UC group (P = 0.03). CONCLUSIONS: The use of a drug adherence monitoring program in the management of sHPT in hemodialysis patients receiving cinacalcet improves drug adherence and iPTH control and allows a reduction in the dose of cinacalcet.

Tenofovir use is associated with a reduction in calculated glomerular filtration rates in the Swiss HIV Cohort Study.

BACKGROUND: A growing number of case reports have described tenofovir (TDF)-related proximal renal tubulopathy and impaired calculated glomerular filtration rates (cGFR). We assessed TDF-associated changes in cGFR in a large observational HIV cohort. METHODS: We compared treatment-naive patients or patients with treatment interruptions > or = 12 months starting either a TDF-based combination antiretroviral therapy (cART) (n = 363) or a TDF-sparing regime (n = 715). The predefined primary endpoint was the time to a 10 ml/min reduction in cGFR, based on the Cockcroft-Gault equation, confirmed by a follow-up measurement at least 1 month later. In sensitivity analyses, secondary endpoints including calculations based on the modified diet in renal disease (MDRD) formula were considered. Endpoints were modelled using pre-specified covariates in a multiple Cox proportional hazards model. RESULTS: Two-year event-free probabilities were 0.65 (95% confidence interval [CI] 0.58-0.72) and 0.80 (95% CI 0.76-0.83) for patients starting TDF-containing or TDF-sparing cART, respectively. In the multiple Cox model, diabetes mellitus (hazard ratio [HR] = 2.34 [95% CI 1.24-4.42]), higher baseline cGFR (HR = 1.03 [95% CI 1.02-1.04] by 10 ml/min), TDF use (HR = 1.84 [95% CI 1.35-2.51]) and boosted protease inhibitor use (HR = 1.71 [95% CI 1.30-2.24]) significantly increased the risk for reaching the primary endpoint. Sensitivity analyses showed high consistency. CONCLUSION: There is consistent evidence for a significant reduction in cGFR associated with TDF use in HIV-infected patients. Our findings call for a strict monitoring of renal function in long-term TDF users with tests that distinguish between glomerular dysfunction and proximal renal tubulopathy, a known adverse effect of TDF.

Liver kidney microsomes type 1 antibodies are associated with 80% reduction of the CYP2D6 activity in patients with chronic hepatitis C

Introduction Liver kidney microsomal type 1 (LKM-1) antibodies have been shown to decrease CYP2D6 activity in vitro. We investigated whether LKM-1 antibodies might reduce CYP2D6 activity also in vivo.Materials and Methods All patients with chronic hepatitis C and LKM-1 antibodies enrolled in the Swiss Hepatitis C Cohort Study (SCCS) were assessed: ten were eligible and fi tted to patients without LKM-1 antibodies. Patients were genotyped for CYP2D6 variants to exclude individuals with a poor metabolizer genotype. CYP2D6 activity was measured by a specifi c substrate using the dextromethorphan/dextrorphan (DEM/DOR) metabolic ratio to classify patients into four activity phenotypes (i.e. ultrarapid, extensive, intermediate and poor metabolizers). The concordance between phenotype based on DEM/DOR ratio and phenotype expected from genotype was examined in LKM-1 positive and negative patients. Groups were compared with respect to the DEM/DOR metabolic ratio.Results All patients had a CYP2D6 extensive metabolizer genotype. The observed phenotype was concordant with CYP2D6 genotype in most LKM-negative patients, whereas only three (30%) LKM-1 positive patients had a concordant phenotype (six presented an intermediate and one a poor metabolizer phenotype). The median DEM/DOR ratio was six-fold higher in LKM-1 positive than in LKM-1 negative patients (0.096 vs. 0.016, p = 0.004), indicating that CYP2D6 metabolic function was significantly reduced in the presence of LKM-1 antibodies.Conclusion In chronic hepatitis C patients with LKM-1 antibodies, the CYP2D6 metabolic activity was on average reduced by 80%. The impact of LKM-1 antibodies on CYP2D6-mediated drug metabolism pathways warrants further translational studies in the setting of new protease inhibitor therapies

Proximale Humerusmehrfragmentfrakturen--Misserfolge nach T-Platten-Osteosynthesen [Proximal humeral multiple fragment fractures--failures after T-plate osteosynthesis].

Dislocated compound fractures of the proximal humerus are often difficult to treat. The choice of treatment influences the final functional result. From 1984-1991 108 patients with dislocated compound fractures of the proximal humerus were operated with a T-plate osteosynthesis, retrospectively examined and classified according to the Neer-Classification. At an average follow up time of 5 years 72 patients had a clinical and radiological examination. 68% of these patients with 3-fragment fractures and 80% with 4-fragment fractures showed a modest to unsatisfactory result caused by fracture biology, imprecise fracture reduction or poor surgical procedure. Incorrect position of T-plates and inadequate material were distinguishable. The T-plate which was widely used in the late eighties for internal fixation has to be considered a failure for these particular types of fractures and should be limited for Collum chirurgicum fractures.

Assessment of total energy expenditure in free-living patients with cystic fibrosis.

The increase in resting energy expenditure (REE) reported in patients with cystic fibrosis (CF) does not necessarily imply an increase in total energy expenditure (TEE). In this study REE was assessed with open-circuit indirect calorimetry, and free-living 24-hour TEE with the heart rate method. Thirteen patients with CF, aged 8 to 24 years, with adequate nutritional status and moderately decreased pulmonary function, were studied. They were compared with 13 healthy control subjects matched for gender, age, height, and nutritional status. Resting energy expenditure was higher in patients with CF (1512 +/- 88 kcal/day) than in control subjects (1339 +/- 76 kcal/day; p less than 0.01), whereas free-living 24-hour TEE (2345 +/- 127 kcal/day and 2358 +/- 256 kcal/day, respectively) and net mechanical work efficiency of walking on a treadmill (20.4 +/- 0.7% and 19.8 +/- 0.6%, respectively) were similar. Respiratory quotient was higher in patients with CF than in control subjects at rest (0.834 +/- 0.009 vs 0.797 +/- 0.008; p less than 0.05), and tended to remain so during physical exercise, indicating a higher contribution of carbohydrate oxidation to energy expenditure. We conclude that in free living conditions, patients with CF can compensate for their increase in REE by a reduction in spontaneous physical activities or other yet undefined mechanisms.

Maps as risk mitigation tools. Adaptation of the Swiss hazard assessment and mapping methodology to a Moroccan site: Beni Mellal

Dans le contexte climatique actuel, les régions méditerranéennes connaissent une intensification des phénomènes hydrométéorologiques extrêmes. Au Maroc, le risque lié aux inondations est devenu problématique, les communautés étant vulnérables aux événements extrêmes. En effet, le développement économique et urbain rapide et mal maîtrisé augmente l'exposition aux phénomènes extrêmes. La Direction du Développement et de la Coopération suisse (DDC) s'implique activement dans la réduction des risques naturels au Maroc. La cartographie des dangers et son intégration dans l'aménagement du territoire représentent une méthode efficace afin de réduire la vulnérabilité spatiale. Ainsi, la DDC a mandaté ce projet d'adaptation de la méthode suisse de cartographie des dangers à un cas d'étude marocain (la ville de Beni Mellal, région de Tadla-Azilal, Maroc). La méthode suisse a été adaptée aux contraintes spécifiques du terrain (environnement semi-aride, morphologie de piémont) et au contexte de transfert de connaissances (caractéristiques socio-économiques et pratiques). Une carte des phénomènes d'inondations a été produite. Elle contient les témoins morphologiques et les éléments anthropiques pertinents pour le développement et l'aggravation des inondations. La modélisation de la relation pluie-débit pour des événements de référence, et le routage des hydrogrammes de crue ainsi obtenus ont permis d'estimer quantitativement l'aléa inondation. Des données obtenues sur le terrain (estimations de débit, extension de crues connues) ont permis de vérifier les résultats des modèles. Des cartes d'intensité et de probabilité ont été obtenues. Enfin, une carte indicative du danger d'inondation a été produite sur la base de la matrice suisse du danger qui croise l'intensité et la probabilité d'occurrence d'un événement pour obtenir des degrés de danger assignables au territoire étudié. En vue de l'implémentation des cartes de danger dans les documents de l'aménagement du territoire, nous nous intéressons au fonctionnement actuel de la gestion institutionnelle du risque à Beni Mellal, en étudiant le degré d'intégration de la gestion et la manière dont les connaissances sur les risques influencent le processus de gestion. L'analyse montre que la gestion est marquée par une logique de gestion hiérarchique et la priorité des mesures de protection par rapport aux mesures passives d'aménagement du territoire. Les connaissances sur le risque restent sectorielles, souvent déconnectées. L'innovation dans le domaine de la gestion du risque résulte de collaborations horizontales entre les acteurs ou avec des sources de connaissances externes (par exemple les universités). Des recommandations méthodologiques et institutionnelles issues de cette étude ont été adressées aux gestionnaires en vue de l'implémentation des cartes de danger. Plus que des outils de réduction du risque, les cartes de danger aident à transmettre des connaissances vers le public et contribuent ainsi à établir une culture du risque. - Severe rainfall events are thought to be occurring more frequently in semi-arid areas. In Morocco, flood hazard has become an important topic, notably as rapid economic development and high urbanization rates have increased the exposure of people and assets in hazard-prone areas. The Swiss Agency for Development and Cooperation (SADC) is active in natural hazard mitigation in Morocco. As hazard mapping for urban planning is thought to be a sound tool for vulnerability reduction, the SADC has financed a project aimed at adapting the Swiss approach for hazard assessment and mapping to the case of Morocco. In a knowledge transfer context, the Swiss method was adapted to the semi-arid environment, the specific piedmont morphology and to socio-economic constraints particular to the study site. Following the Swiss guidelines, a hydro-geomorphological map was established, containing all geomorphic elements related to known past floods. Next, rainfall / runoff modeling for reference events and hydraulic routing of the obtained hydrographs were carried out in order to assess hazard quantitatively. Field-collected discharge estimations and flood extent for known floods were used to verify the model results. Flood hazard intensity and probability maps were obtained. Finally, an indicative danger map as defined within the Swiss hazard assessment terminology was calculated using the Swiss hazard matrix that convolves flood intensity with its recurrence probability in order to assign flood danger degrees to the concerned territory. Danger maps become effective, as risk mitigation tools, when implemented in urban planning. We focus on how local authorities are involved in the risk management process and how knowledge about risk impacts the management. An institutional vulnerability "map" was established based on individual interviews held with the main institutional actors in flood management. Results show that flood hazard management is defined by uneven actions and relationships, it is based on top-down decision-making patterns, and focus is maintained on active mitigation measures. The institutional actors embody sectorial, often disconnected risk knowledge pools, whose relationships are dictated by the institutional hierarchy. Results show that innovation in the risk management process emerges when actors collaborate despite the established hierarchy or when they open to outer knowledge pools (e.g. the academia). Several methodological and institutional recommendations were addressed to risk management stakeholders in view of potential map implementation to planning. Hazard assessment and mapping is essential to an integrated risk management approach: more than a mitigation tool, danger maps represent tools that allow communicating on hazards and establishing a risk culture.

Reduction of the hand representation in the ipsilateral primary motor cortex following unilateral section of the corticospinal tract at cervical level in monkeys.

BACKGROUND: After sub-total hemi-section of cervical cord at level C7/C8 in monkeys, the ipsilesional hand exhibited a paralysis for a couple of weeks, followed by incomplete recovery of manual dexterity, reaching a plateau after 40-50 days. Recently, we demonstrated that the level of the plateau was related to the size of the lesion and that progressive plastic changes of the motor map in the contralesional motor cortex, particularly the hand representation, took place following a comparable time course. The goal of the present study was to assess, in three macaque monkeys, whether the hand representation in the ipsilesional primary motor cortex (M1) was also affected by the cervical hemi-section.¦RESULTS: Unexpectedly, based on the minor contribution of the ipsilesional hemisphere to the transected corticospinal (CS) tract, a considerable reduction of the hand representation was also observed in the ipsilesional M1. Mapping control experiments ruled out the possibility that changes of motor maps are due to variability of the intracortical microstimulation mapping technique. The extent of the size reduction of the hand area was nearly as large as in the contralesional hemisphere in two of the three monkeys. In the third monkey, it represented a reduction by a factor of half the change observed in the contralesional hemisphere. Although the hand representation was modified in the ipsilesional hemisphere, such changes were not correlated with a contribution of this hemisphere to the incomplete recovery of the manual dexterity for the hand affected by the lesion, as demonstrated by reversible inactivation experiments (in contrast to the contralesional hemisphere). Moreover, despite the size reduction of M1 hand area in the ipsilesional hemisphere, no deficit of manual dexterity for the hand opposite to the cervical hemi-section was detected.¦CONCLUSION: After cervical hemi-section, the ipsilesional motor cortex exhibited substantial reduction of the hand representation, whose extent did not match the small number of axotomized CS neurons. We hypothesized that the paradoxical reduction of hand representation in the ipsilesional hemisphere is secondary to the changes taking place in the contralesional hemisphere, possibly corresponding to postural adjustments and/or re-establishing a balance between the two hemispheres.

Reduction in the expression of glucose transporter protein GLUT 2 in preneoplastic and neoplastic hepatic lesions and reexpression of GLUT 1 in late stages of hepatocarcinogenesis.

Expression of two important glucose transporter proteins, GLUT 2 (which is the typical glucose transporter in hepatocytes of adult liver) and the erythroid/brain type glucose transporter GLUT 1 (representing the typical glucose transporter in fetal liver parenchyma), was studied immunocytochemically during hepatocarcinogenesis in rats at different time points between 7 and 65 wk after cessation of 7-wk administration of 12 mg/kg of body weight of N-nitrosomorpholine p.o. (stop model). Foci of altered hepatocytes excessively storing glycogen (GSF) and mixed cell foci (MCF) composed of both glycogenotic and glycogen-poor cells were present at all time points studied. Seven wk after withdrawal of the carcinogen, GSF were the predominant type of focus of altered hepatocytes. Morphometrical evaluation of the focal lesions revealed that the number and volume fraction of GSF increased steadily until Wk 65. MCF were rare at 7 wk, increased slightly in number and size until Wk 37, but showed a pronounced elevation in their number and volume fraction from Wk 37 to Wk 65. In both GSF and MCF, GLUT 2 was generally decreased or partially absent at all time points. Consequently, foci of decreased GLUT 2 expression showed a steady increase in number and volume fraction from Wk 7 to Wk 65. GLUT 1 was lacking in GSF but occurred in some MCF from Wk 50 onward. The liver type glucose transporter GLUT 2 was decreased in all adenomas and hepatocellular carcinomas (HCC). In three of seven adenomas and 10 of 12 carcinomas, expression of GLUT 1 was increased compared with normal liver parenchyma. In two cases of adenoid HCC, cells of ductular formations coexpressed GLUT 2 and GLUT 1. In contrast, normal bile ducts, bile duct proliferations, and cystic cholangiomas expressed only GLUT 1. Seven of 12 HCC contained many microvessels intensely stained for GLUT 1, a phenomenon never observed in normal liver. Whenever adenoid tumor formations occurred, GLUT 1-positive microvessels were located in the immediate vicinity of these formations. Only in one HCC were such microvessels found in the absence of adenoid formations. Our studies indicate that a reduction of GLUT 2 expression occurs already in early preneoplastic hepatic foci and is maintained throughout hepatocarcinogenesis, including benign and malignant neoplasms. Reexpression of GLUT 1, however, appears in a few MCF and in the majority of adenomas and carcinomas.

Laparoscope use and surgical site infections in digestive surgery.

OBJECTIVE: To compare surgical site infection (SSI) rates in open or laparoscopic appendectomy, cholecystectomy, and colon surgery. To investigate the effect of laparoscopy on SSI in these interventions. BACKGROUND: Lower rates of SSI have been reported among various advantages associated with laparoscopy when compared with open surgery, particularly in cholecystectomy. However, biases such as the lack of postdischarge follow-up and confounding factors might have contributed to the observed differences between the 2 techniques. METHODS: This observational study was based on prospectively collected data from an SSI surveillance program in 8 Swiss hospitals between March 1998 and December 2004, including a standardized postdischarge follow-up. SSI rates were compared between laparoscopic and open interventions. Factors associated with SSI were identified by using logistic regression models to adjust for potential confounding factors. RESULTS: SSI rates in laparoscopic and open interventions were respectively 59/1051 (5.6%) versus 117/1417 (8.3%) in appendectomy (P = 0.01), 46/2606 (1.7%) versus 35/444 (7.9%) in cholecystectomy (P < 0.0001), and 35/311 (11.3%) versus 400/1781 (22.5%) in colon surgery (P < 0.0001). After adjustment, laparoscopic interventions were associated with a decreased risk for SSI: OR = 0.61 (95% CI 0.43-0.87) in appendectomy, 0.27 (0.16-0.43) in cholecystectomy, and 0.43 (0.29-0.63) in colon surgery. The observed effect of laparoscopic techniques was due to a reduction in the rates of incisional infections, rather than in those of organ/space infections. CONCLUSION: When feasible, a laparoscopic approach should be preferred over open surgery to lower the risks of SSI.

Reduction in the proportion of fevers associated with Plasmodium falciparum parasitaemia in Africa: a systematic review.

BACKGROUND: Malaria is almost invariably ranked as the leading cause of morbidity and mortality in Africa. There is growing evidence of a decline in malaria transmission, morbidity and mortality over the last decades, especially so in East Africa. However, there is still doubt whether this decline is reflected in a reduction of the proportion of malaria among fevers. The objective of this systematic review was to estimate the change in the Proportion of Fevers associated with Plasmodium falciparum parasitaemia (PFPf) over the past 20 years in sub-Saharan Africa. METHODS: Search strategy. In December 2009, publications from the National Library of Medicine database were searched using the combination of 16 MeSH terms.Selection criteria. Inclusion criteria: studies 1) conducted in sub-Saharan Africa, 2) patients presenting with a syndrome of 'presumptive malaria', 3) numerators (number of parasitologically confirmed cases) and denominators (total number of presumptive malaria cases) available, 4) good quality microscopy.Data collection and analysis. The following variables were extracted: parasite presence/absence, total number of patients, age group, year, season, country and setting, clinical inclusion criteria. To assess the dynamic of PFPf over time, the median PFPf was compared between studies published in the years ≤2000 and > 2000. RESULTS: 39 studies conducted between 1986 and 2007 in 16 different African countries were included in the final analysis. When comparing data up to year 2000 (24 studies) with those afterwards (15 studies), there was a clear reduction in the median PFPf from 44% (IQR 31-58%; range 7-81%) to 22% (IQR 13-33%; range 2-77%). This dramatic decline is likely to reflect a true change since stratified analyses including explanatory variables were performed and median PFPfs were always lower after 2000 compared to before. CONCLUSIONS: There was a considerable reduction of the proportion of malaria among fevers over time in Africa. This decline provides evidence for the policy change from presumptive anti-malarial treatment of all children with fever to laboratory diagnosis and treatment upon result. This should insure appropriate care of non-malaria fevers and rationale use of anti-malarials.