Conformational Analysis of the Mannosidase Inhibitor Kifunensine: A Quantum Mechanical and Structural Approach

The varied yet family‐specific conformational pathways used by individual glycoside hydrolases (GHs) offer a tantalising prospect for the design of tightly binding and specific enzyme inhibitors. A cardinal example of a GH‐family‐specific inhibitor, and one that finds widespread practical use, is the natural product kifunensine, which is a low‐nanomolar inhibitor that is selective for GH family 47 inverting α‐mannosidases. Here we show, through quantum‐mechanical approaches, that kifunensine is restrained to a “ring‐flipped” ¹C₄ conformation with another accessible, but higher‐energy, region around the ^1,4B conformation. The conformations of kifunensine in complex with a range of GH47 enzymes—including an atomic‐level resolution (1 Å) structure of kifunensine with Caulobacter sp. CkGH47 reported herein and with GH family 38 and 92 α‐mannosidases—were mapped onto the kifunensine free‐energy landscape. These studies revealed that kifunensine has the ability to mimic the product state of GH47 enzymes but cannot mimic any conformational states relevant to the reaction coordinate of mannosidases from other families.     

Individual and contextual effects in injury morbidity in Barcelona (Spain)

OBJECTIVE: To determine the relationship between socioeconomic level (measured through individual educational level and material deprivation in the areas of residence) and injury morbidity in different age groups and in males as well as in females. DESIGN: Cross-sectional survey. SETTING: Barcelona (Spain). METHODS: The study population included all cases over the age of 19 who, as a result of an injury (motor vehicles injuries, falls, hits and cuts), were admitted to the emergency departments of the six main hospitals of the city during the years 1990-1991. Age- and sex-specific morbidity rates were calculated for each educational level and each cause of injury. The contextual variable included was the proportion of unemployment in each neighbourhood. Multilevel Poisson regression models were fitted. RESULTS: Morbidity rates were higher in males, in young people and for lower educational levels. Results from the multilevel models show that, at contextual level, neighbourhoods with more unemployment present a higher risk of injuries. At individual level, after adjusting for contextual variables, the risk of sustaining injuries was higher among young men and women for all injury causes except falls among women where the risk was higher in the elderly; among both men and women, the risk of sustaining injury was higher in the population with lower educational level (RR = 1.79, 95% CI = 1.73-1.86 in men; RR = 2.12, 95% CI = 2.04-2.21 in women). This trend was also observed separately for traffic injuries, falls, hits and cuts. CONCLUSION: Our results provide information about individual and contextual social inequalities in injury morbidity, the highest risks of injury occur in individuals of lower educational level and who reside in the more private neighbourhoods. These results underscore the need to implement injury prevention strategies not only at the individual level, but also to tailor them to the socioeconomic position of the population.     

Chromatic parameters and oxidation indices for edible vegetable oils submitted to thermal oxidation

Peroxide values, TBA numbers and chromatic parameters of edible vegetable oils (olive, sunflower, corn oils) thermally oxidised (75°C, 100°C, 180°C) during 5 days were determined. For calculating chromatic parameters the recommended standard CIE methods and several simplified methods were employed. With olive oil a remarkable change in spectral characteristics occurred as the temperature and time of heating were increased. Thermal autoxidation, as assessed by peroxide value and TBA number, was only observed at 75°C (Schaal oven test). In none of the three types of vegetable oil was the dominant wavelength modified during the course of the heating process. Luminosity and hue angle showed slight increases in olive and sunflower oils. Colour saturation underwent a remarkable decrease in olive oil. From a comparison and a correlation study it is concluded that the simplified methods could be applied only for certain chromatic parameters and types of vegetable oil. For a comprehensive study of the diverse chromatic parameters the standard CIE methods should be applied.     

Changes in cigarette smoking among adults in 35 populations in the mid-1980s

OBJECTIVE—To examine changes in the prevalence of cigarette smoking in 35 study populations of the World Health Organisation's MONICA Project.
DESIGN—Data from two independent, community-based surveys conducted, on average, five years apart.
SETTING—Geographically defined populations in 21 countries mainly in eastern and western Europe.
SUBJECTS—Randomly selected men and women aged 25-64 years. Numbers of participants in each study population ranged from 586 to 2817 in each survey.
MAIN OUTCOME MEASURES—Changes in proportions of current smokers, ex-smokers, and never-smokers by age and sex using data collected by standardised methods.
RESULTS—Among men, smoking prevalence decreased in most populations, by three to four percentage points over five years. In Beijing, however, it increased in all age groups—overall by 11 percentage points. Among women there were increases in smoking in about half the populations. The increases were mainly in the age group 35-54 years and often in those populations where smoking prevalence among women has been relatively low.
CONCLUSIONS—Smoking initiation by middle-aged women in parts of southern and eastern Europe and among men of all ages in Beijing is a matter of concern. The various public health measures that have helped to reduce smoking among men in developed countries should be vigorously extended to these other groups now at growing risk of smoking-related disease.


Keywords: cigarette smoking; prevalence; World Health Organisation MONICA Project     

Effect of the Machining Method on the Catalycity and Emissivity of ZrB2 and ZrB2–HfB2-Based Ceramics

The emissivity and the catalytic efficiency related to atomic oxygen recombination were investigated experimentally in the range 1000–2000 K for ZrB₂ and ZrB₂–HfB₂-based ceramics. In order to evaluate the effect of the machining method, two series of samples, one prepared by electrical discharge machining and the other machined by diamond-loaded tools, were tested. High emissivity (about 0.7 at 1700 K) and low recombination coefficients (on average 0.08 at 1800 K) were found for all the materials. The experimental data showed an effect of the surface machining on the catalytic behavior only on the ZrB₂-based composite; conversely, small variations were found in the recombination coefficients of ZrB₂–HfB₂-based samples for the different machining processes. The surface finish affected the emissivity at lower temperatures in both compositions, with the effect becoming negligible at temperatures above 1500 K.     

The Experiences of Retired Managers Acting as Volunteers in an Entrepreneurial Mentoring Organization

Volunteering in later life is an important way of staying involved in one’s community and engaging in a meaningful activity that has a positive impact on others. Previous research has mainly described the antecedents and consequences of volunteering; the process and experiences associated with performing this role has been less studied. The aim of this study was to assess the positive and negative experiences of older managers involved in an entrepreneurial mentoring organization. Fourteen older male volunteers were administered a semi-structured interview and the data obtained were analyzed thematically. The themes that emerged were the importance of the final result as a filter to assess the whole mentoring experience, the mentor-mentee bond, and the self-attribution of successes and failures. These themes were discussed using the generativity theory as a framework to understand the experiences of older adults keen to pass on their skills and knowledge to a younger generation.     

Domiciliary oxygen therapy. Study of use in a rural area

OBJECTIVE: To assess use of long-term oxygen therapy (LTOT) in a rural community we conducted a transversal study. METHOD: Data was collected in patients' homes, and based on the total number of patients with LTOT, with reference to indication, follow-up and correct completion; two oximetries were carried out, breathing room air, and after breathing oxygen. Of the 70 patients with LTOT, 7 were considered not eligible, the prevalence was found to be: 179/100,000 inhabitants. Sixteen patients were excluded, 6 with exacerbation, and 10 who were unable to be contacted at their home address. The sample was composed of 45 patients. The most frequent diagnosis was COPD (34/45). Indication of LTOT was carried out in the hospital in 40 (89%) patients, and in the health centre in 5 (11%). RESULTS: In 22 (49%) the treatment could be considered acceptable, and only in 21 (46%), the indication of LTOT was correct. Oxygen was administered at least 15 hours/day in 42% of cases (19/45). Patients with periodical check-ups, maintained better pharmacological treatment, although there were no significant differences in the carrying out of LTOT. Using oximetry, it was shown that in 27 patients the SaO2 was lesser than or equal to 88%, and that in 23 cases (85%) administration of oxygen, corrected the saturation. Only in 11 (24%) the indication criteria and adequate administration of LTOT were carried out, as well as correction of the hypoxemia following administration of oxygen. CONCLUSIONS: The prevalence was found to be very high. The results show this form of treatment as being very badly controlled. In a rural community, the pulse oximetry is useful in the follow-up of TLOT.     

Determining Criteria for Selecting Software Components: Lessons Learned

Software component selection is growing in importance. Its success relies on correctly assessing the candidate components' quality. For a particular project, you can assess quality by identifying and analyzing the criteria that affect it. Component selection is on the suitability and completeness of the criteria used for evaluation. Experiences from determining criteria for several industrial projects provide important lessons. For a particular selection process, you can organize selection criteria into a criteria catalog. A CC is built for a scope, which can be either a domain (workflow systems, mail servers, antivirus tools, and so on) or a category of domains (communication infrastructure, collaboration software, and so on). Structurally, a CC arranges selection criteria in a hierarchical tree-like structure. The higher-level selection criteria serve to classify more concrete selection criteria, usually allowing some overlap. They also serve to leverage the CC     

Usefulness of ultrasonography and computerized tomography in predicting resectability of pancreatic carcinoma

BACKGROUND: Surgical resection is the only curative treatment of pancreatic carcinoma (PC). An accurate assessment of the extension of PC is mandatory to select appropriate patients to this therapeutic option. This study was aimed at assessing the usefulness of abdominal ultrasonography (US) and computed tomography (CT) to establish tumoral staging and to predict tumor resectability. PATIENTS AND METHODS: Between January 1990 and December 1995, 84 PC patients were submitted to surgical procedures (potentially curative resection in 30%, biliodigestive anastomosis in 51% and exploratory laparotomy in 13%). Preoperative staging was carried out by means of abdominal US and/or CT. Definitive staging was established according to surgical findings, using the TNM classification. RESULTS: Accuracy of preoperative evaluation with regard to tumoral staging was 65%, being underestimated in 29 (35%) patients. This underestimation was mainly due to lesions in stage I. In addition, preoperative staging predicted tumor unresectability with a 50% sensitivity and a 83% specificity. CONCLUSIONS: US and CT have a good specificity in the staging and unresectability prediction of pancreatic cancer. However, their usefulness is limited by their low sensitivity.     

A role for BDNF in early postnatal rat vestibular epithelia maturation: implication of supporting cells

The early development of the inner ear is largely determined by two members of the neurotrophic family: brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3). Little information is available on the role of these neurotrophins during the late stages of vestibular development in the rat which take place during the first postnatal weeks. At this period where terminal synaptogenesis and maturation occur, we have investigated the expression and the activity of BDNF, the most important neurotrophin in the vestibular system. Using different experimental approaches, we show that BDNF is released by vestibular epithelia on postnatal day 3 (P3) and continues to have a trophic effect on vestibular neurones in vitro. Immunocytochemistry coupled to confocal microscopy revealed a remarkable evolution in BDNF localization during later stages of development. Whereas BDNF is present in both supporting cells and hair cells at P3, its distribution gradually changed and is highly compartmentalized within the upper part of supporting cells at P8 and P15. In parallel, we observed the presence of a truncated form of the BDNF receptor in sensory hair cells. These results suggest an original role for supporting cells, which could be involved in the release of BDNF during the late stages of synaptogenesis in mammalian vestibular epithelia. In particular, BDNF could participate to the set up of the calyx, a specific nerve structure surrounding type I vestibular hair cells.