Same Story, Different Story.

Differences in people's beliefs can substantially impact their interpretation of a series of events. In this functional MRI study, we manipulated subjects' beliefs, leading two groups of subjects to interpret the same narrative in different ways. We found that responses in higher-order brain areas-including the default-mode network, language areas, and subsets of the mirror neuron system-tended to be similar among people who shared the same interpretation, but different from those of people with an opposing interpretation. Furthermore, the difference in neural responses between the two groups at each moment was correlated with the magnitude of the difference in the interpretation of the narrative. This study demonstrates that brain responses to the same event tend to cluster together among people who share the same views.

Oxazoline-Promoted Rh-Catalyzed C-H Amidation of Benzene Derivatives with Sulfonamides and Trifluoroacetamide. A Comparative Study.

A Rh-catalyzed ortho-amidation of 2-aryloxazolines offers an efficient and direct route to a range of sulfonamides. The scope of the reaction is very broad with respect to sulfonamide substrate, but the position and electronic nature of the substituents on the aryl moiety of the oxazoline lead to a surprising modulation of reactivity. The reactivity of sulfonamides in comparison to trifluoroacetamide is compared, the latter undergoing Rh-catalyzed amidation more rapidly.

Albendazole therapy and enteric parasites in United States-bound refugees.

BACKGROUND: Beginning on May 1, 1999, the Centers for Disease Control and Prevention (CDC) recommended presumptive treatment of refugees for intestinal parasites with a single dose of albendazole (600 mg), administered overseas before departure for the United States. METHODS: We conducted a retrospective cohort study involving 26,956 African and Southeast Asian refugees who were screened by means of microscopical examination of stool specimens for intestinal parasites on resettlement in Minnesota between 1993 and 2007. Adjusted prevalence ratios for intestinal nematodes, schistosoma species, giardia, and entamoeba were calculated among refugees who migrated before versus those who migrated after the CDC recommendation of presumptive predeparture albendazole treatment. RESULTS: Among 4370 untreated refugees, 20.8% had at least one stool nematode, most commonly hookworm (in 9.2%). Among 22,586 albendazole-treated refugees, only 4.7% had one or more nematodes, most commonly trichuris (in 3.9%). After adjustment for sex, age, and region, albendazole-treated refugees were less likely than untreated refugees to have any nematodes (prevalence ratio, 0.19), ascaris (prevalence ratio, 0.06), hookworm (prevalence ratio, 0.07), or trichuris (prevalence ratio, 0.27) but were not less likely to have giardia or entamoeba. Schistosoma ova were identified exclusively among African refugees and were less prevalent among those treated with albendazole (prevalence ratio, 0.60). After implementation of the albendazole protocol, the most common pathogens among 17,011 African refugees were giardia (in 5.7%), trichuris (in 5.0%), and schistosoma (in 1.8%); among 5575 Southeast Asian refugees, only giardia remained highly prevalent (present in 17.2%). No serious adverse events associated with albendazole use were reported. CONCLUSIONS: Presumptive albendazole therapy administered overseas before departure for the United States was associated with a decrease in the prevalence of intestinal nematodes among newly arrived African and Southeast Asian refugees.

A mild and regioselective route to functionalized quinazolines.

A Rh-catalyzed ortho-amidation cyclocondensation sequence gave a range of 4-aminoquinazolines in high yield. The method features a remarkably mild C(sp(2) )H activation step and can be exploited to rapidly access compounds with established biological activity.

Studies on the stereochemical assignment of 3-acylidene 2-oxindoles.

The designation of E/Z-geometrical isomers in 3-acylidene 2-oxindoles by NMR spectroscopy can lead to erroneous assignment of alkene stereochemistry because of the narrow chemical shift range observed over a large series of analogues. In contrast, UV-Vis spectroscopy offers a convenient and more reliable method for alkene stereochemical assignment. A combination of X-ray crystallography and theoretical studies shows that the observed differences in UV-Vis spectroscopic behaviour relate to the twisted conformation of the Z-isomers that provides reduced conjugation and weaker hypsochromic (blue-shifted) absorbances relative to those of the E-isomers.

Every breath counts: Lessons learned in developing a training NICU in Northern Tanzania.

Introduction: Neonatal mortality rates in resource-limited hospitals of Sub-Saharan Africa (SSA) remain disproportionately high and are likely underestimated due to misclassification of extremely preterm births as "stillbirths" or "abortions", incomplete death registries, fear of repercussions from hospital and governmental authorities, unrecorded village deaths, and cultural beliefs surrounding the viability of premature newborns. While neonatology partnerships exist between high income countries and hospitals in SSA, efforts have largely been directed toward improving newborn survival through neonatal resuscitation training and provision of equipment to nascent neonatal intensive care units (NICUs). These measures are incomplete and fail to address the challenges which NICUs routinely face in low-resource settings. We draw on lessons learned in the development of a low-technology referral NICU in Tanzania that achieved an overall 92% survival rate among infants. Lessons learned: Achieving high survival rates among critically ill and preterm neonates in SSA is possible without use of expensive, advanced-skill technologies like mechanical ventilators. Evidence-based protocols adapted to low-resource hospitals, mentorship of nurses and physicians, changes in hierarchal culture, improved nurse-infant staffing ratios, involvement of mothers, improved procurement of consumables and medications, and bedside diagnostics are necessary steps to achieving high survival rates. Our NICU experience indicates that low-technology solutions of thermoregulation, respiratory support via continuous positive airway pressure, feeding protocols and infection control measures can ensure that infants not only survive, but thrive. Conclusions: Neonatal mortality and survival of preterm newborns can be improved through a long-term commitment to training NICU staff, strengthening basic neonatal care practices, contextually appropriate protocols, and limited technology.

Multidrug-resistant Salmonella enterica serotype Typhimurium associated with pet rodents.

BACKGROUND: An estimated 1.4 million salmonella infections occur annually in the United States. The majority of these infections are foodborne, but many are acquired by contact with animals. In August 2004, isolates of Salmonella enterica serotype Typhimurium, which were indistinguishable from one another by pulsed-field gel electrophoresis (PFGE), were obtained from eight hamsters from a Minnesota pet distributor. We conducted an investigation to determine whether human cases of salmonella could be linked to this rodent-borne strain. METHODS: To identify cases of human infection with S. enterica serotype Typhimurium potentially related to pet rodents, we reviewed salmonella PFGE patterns submitted to the National Molecular Subtyping Network for Foodborne Disease Surveillance. Patients with isolates matching the hamster strain were interviewed about exposure to pet rodents. Implicated rodents were traced to pet stores, distributors, and breeders. RESULTS: We identified matching S. enterica serotype Typhimurium isolates from 28 patients in whom the onset of illness occurred between December 2003 and September 2004. Of 22 patients (or in the case of children, their parents) interviewed, 13 patients (59%) in 10 states reported exposure to pet hamsters, mice, or rats, and 2 (9%) had secondary infections. The median age of the 15 patients with primary or secondary rodent exposure was 16 years, and 6 patients (40%) were hospitalized. Thirteen associated pet stores supplied by seven distributors were identified in 10 states. No single source of the rodents was identified. The outbreak strain of S. enterica serotype Typhimurium was cultured from a patient's pet mouse and from seven hamsters from pet stores. Closely related S. enterica serotype Typhimurium isolates were cultured from rodent cages and reusable transport containers at a pet distributor. Human, rodent, and environmental isolates were resistant to ampicillin, chloramphenicol, streptomycin, sulfisoxazole, and tetracycline. CONCLUSIONS: Pet rodents probably are an underrecognized source of human salmonella infection.

Quantification of Intracellular Accumulation and Retention of Lysosomotropic Macrocyclic Compounds by High-Throughput Imaging of Lysosomal Changes.

Many marketed pharmaceuticals reach extremely high tissue concentrations due to accumulation in lysosomes (lysosomotropism). Quantitative prediction of intracellular concentrations of accumulating drugs is challenging, especially for macrocyclic compounds that mainly do not fit in current in silico models. We tested a unique library of 47 compounds (containing 39 macrocycles) specifically designed to cover the entire range of accumulation intensities observed with pharmaceuticals so far. For the first time, we show that intracellular concentration of compounds measured by liquid chromatography with tandem mass spectrometry correlates with the induction of phospholipidosis and inhibition of autophagy, but the highest correlation was observed with the increase of lysosomal volume (R = 0.95), all measured by high-throughput imaging assays. Based only on imaging data, we developed a 5-class in vitro model for the prediction of compound accumulation with the accuracy of 81%. The measured change of total lysosomal volume can thus be used in high-throughput screening for determination of the actual intensity of intracellular accumulation of new macrocyclic compounds. The models are largely based on macrocycles, greatly improving the screening and prediction of intracellular accumulation of this challenging class. However, all tested nonmacrocyclic compounds fitted well in the models, indicating potential use of the models in broader chemical space.

Tibolone for the treatment of moderate to severe vasomotor symptoms and genital atrophy in postmenopausal women: a multicenter, randomized, double-blind, placebo-controlled study.

OBJECTIVE: To demonstrate the safety and efficacy of tibolone (1.25 and 2.5 mg) in the treatment of moderate to severe vasomotor symptoms and symptoms associated with vaginal atrophy. DESIGN: A placebo-controlled, double-blind, randomized, multicenter study was conducted on 396 healthy postmenopausal women experiencing a minimum of 7 moderate to severe hot flashes per day (60 per week). Participants were randomized to receive tibolone 1.25 or 2.5 mg or placebo once daily for 12 weeks. Assessments were done at weeks 4, 8, and 12. The severity and frequency of hot flashes were recorded in patient diaries on a daily basis. RESULTS: Tibolone 2.5 mg significantly (P < 0.001) reduced the average number of hot flashes compared with placebo at week 4 (-7.82 vs -5.27), week 8 (-9.71 vs -5.86), and week 12 (-10.14 vs -5.85). The difference between tibolone 1.25 mg and placebo was significant (P < 0.001) at week 8 (-7.96) and week 12 (-8.32). Findings for the average daily severity of hot flashes were similar, with significantly greater reductions at week 4 (P < 0.05) and weeks 8 and 12 (P < 0.001) for tibolone 2.5 mg versus placebo and at weeks 8 and 12 for tibolone 1.25 mg versus placebo (P < 0.001). A menopausal atrophic symptom questionnaire revealed that tibolone 2.5 mg significantly (P < 0.05) reduced nocturia compared with placebo at weeks 4, 8, and 12 and urinary urgency at week 4. Compared with placebo, both doses of tibolone also significantly (P < 0.001) increased the vaginal maturation value from baseline. The overall incidence of adverse events was similar in all treatment groups. CONCLUSIONS: Tibolone is effective and well tolerated for the treatment of moderate to severe vasomotor symptoms and the effects of vaginal atrophy associated with menopause.

Synthesis of Functionalized Pyridines via a Regioselective Oxazoline Promoted C-H Amidation Reaction.

The first Rh-catalyzed C-H amidation of pyridines is reported. The incorporation of a substituent at the C2 position both is crucial to the success of this transformation and provides considerable scope for further elaboration of the resulting products. Among these compounds, 2-chloropyridines allow access to a selection of intermediates including a versatile azaquinazoline scaffold.

Combined esterified estrogens and methyltestosterone versus esterified estrogens alone in the treatment of loss of sexual interest in surgically menopausal women.

OBJECTIVE: To compare the effect of esterified estrogens and methyltestosterone versus esterified estrogens alone on diminished sexual interest in surgically menopausal women. DESIGN: This randomized, double-blind study compared the effect of combined esterified estrogens (1.25 mg) and methyltestosterone (2.5 mg) (EE/MT) versus esterified estrogens (1.25 mg) alone (EE) for 8 weeks. Several different sexual function questionnaires were used to measure response to therapy. Changes from baseline in sexual interest/function and hormone levels were evaluated after 4 and 8 weeks of treatment. RESULTS: A total of 102 women were randomized into the study; 52 (age range, 32-61 years) to EE/MT and 50 (age range, 33-62 years) to EE. After 8 weeks, significant differences between treatments were not seen in the Changes in Sexual Functioning Questionnaire (CSFQ-F-C) sexual desire/interest subscale score, the primary efficacy variable. In contrast statistically significant between-treatment differences were found for several secondary efficacy variables including Menopausal Sexual Interest Questionnaire (MSIQ) sexual interest/desire score, CSFQ-F-C arousal/erection subscale score and Women's Health Questionnaire sexual functioning subscale score. The mean serum concentration of bioavailable and free testosterone significantly increased, approximately doubling between baseline and the end of the study in patients receiving EE/MT, with a significant (P < 0.001) between-treatment difference. The mean serum concentration of sex hormone-binding globulin significantly decreased to less than one third of the pretreatment levels in patients receiving EE/MT (P < 0.001). Both treatments were well tolerated. CONCLUSIONS: The mixed results seen with the different sexual function questionnaires may be due to the CSFQ-F-C's lack of specificity for this population. Increased levels of bioavailable and free testosterone paralleled the improved MSIQ item scores. Both the EE and EE/MT treatments were well tolerated.

Simulation of biceps femoris musculotendon mechanics during the swing phase of sprinting.

INTRODUCTION/PURPOSE: Characterization of hamstring mechanics during sprinting is fundamental to understanding musculotendon injury mechanisms. The objective of this study was to use muscle-actuated forward dynamic simulations to investigate musculotendon mechanics of the biceps femoris long head during the swing phase of sprinting. METHODS: We used a three-dimensional linked segment model with 26 Hill-type musculotendon actuators to simulate swing phase dynamics. Muscle excitations were computed that drove the linked segment model to track measured hip and knee motion of an individual sprinting on a treadmill. The simulations were used to investigate the effect of tendon compliance on the excursions and power development of the muscle and tendinous components of the biceps femoris. RESULTS: The biceps femoris musculotendon complex underwent a stretch-shortening cycle over the latter half of swing phase, with the shortening portion occurring in the final 10% of the gait cycle. Biceps femoris excitation increased markedly between 70 and 80% of the gait cycle and continued through the end of swing. Following the onset of excitation, stretch of the muscle component slowed considerably while the tendon lengthened and stored elastic energy. Simulating the sprinting movement with a more compliant tendon increased tendon elastic energy storage, thereby reducing peak muscle stretch and negative muscle work. CONCLUSIONS: Muscle-actuated forward dynamic simulation provides a powerful approach for investigating biomechanical factors that may contribute to the occurrence of hamstring musculotendon injuries.

Hamstring muscle kinematics during treadmill sprinting.

INTRODUCTION/PURPOSE: The objective of this study was to characterize hamstring muscle kinematics during sprinting, so as to provide scientific data to better understand injury mechanisms and differences in injury rates between muscles. METHODS: We conducted three-dimensional motion analyses of 14 athletes performing treadmill sprinting at speeds ranging from 80 to 100% of maximum. Scaled musculoskeletal models were used to estimate hamstring muscle-tendon lengths throughout the sprinting gait cycle for each speed. We tested the hypothesis that the biceps femoris (BF) long head would be stretched a greater amount, relative to its length in an upright posture, than the semitendinosus (ST) and semimembranosus (SM). We also tested the hypothesis that increasing from submaximal to maximal sprinting speed would both increase the magnitude and delay the occurrence of peak muscle-tendon length in the gait cycle. RESULTS: Maximum hamstring lengths occurred during the late swing phase of sprinting and were an average of 7.4% (SM), 8.1% (ST), and 9.5% (BF) greater than the respective muscle-tendon lengths in an upright configuration. Peak lengths were significantly larger in the BF than the ST and SM (P < 0.01), occurred significantly later in the gait cycle at the maximal speed (P < 0.01), but did not increase significantly with speed. Differences in the hip extension and knee flexion moment arms between the biarticular hamstrings account for the intermuscle variations in the peak lengths that were estimated. CONCLUSIONS: We conclude that intermuscle differences in hamstring moment arms about the hip and knee may be a factor contributing to the greater propensity for hamstring strain injuries to occur in the BF muscle.

Identifying the time of occurrence of a hamstring strain injury during treadmill running: a case study.

BACKGROUND: While hamstring strain injuries are common during sprinting, the mechanisms of injury are not well understood. In this study, we analyzed the running kinematics of an athlete obtained at the time of an acute hamstring strain injury. The purpose was to identify the period of the gait cycle during which the hamstring was likely injured, as well as to characterize the biomechanical conditions associated with the injury. METHODS: A male professional skier injured his right biceps femoris long head while running at 5.36 m/s on a treadmill with a 15% incline. Whole body kinematics were recorded at the time of injury. A linear periodic prediction model was used to determine when individual marker trajectories deviated from a cyclic periodic pattern, indicating the mechanical response to injury. A three-dimensional musculoskeletal model was used to compute joint angles and hamstring musculotendon lengths during the injurious running trial. These data were used with estimates of neuromuscular latencies and electromechanical delays to identify the most likely time period of injury. FINDINGS: Based upon the earliest indications in marker trajectories, a 130 ms period during the late swing phase of the gait cycle was identified as the period of injury. During this period, the biceps femoris reached a peak musculotendon length that was estimated to be 12% beyond the length seen in an upright posture and exceeded the normalized peak length of the medial hamstrings. INTERPRETATION: This case provides quantitative data suggesting that the biceps femoris muscle is susceptible to an lengthening contraction injury during the late swing phase of the running gait cycle.

2-Iodoisatogens: versatile intermediates for the synthesis of nitrogen heterocycles.

A Cu-promoted cyclization of 2-nitrophenyl iodoacetylenes provides a direct route to a range of 2-iodoisatogens. These compounds represent useful intermediates for the late-stage elaboration of the C-I bond to furnish isatins and a range of alternative heterocyclic products.

A practical drug discovery project at the undergraduate level.

In this article, we describe a practical drug discovery project for third-year undergraduates. No previous knowledge of medicinal chemistry is assumed. Initial lecture workshops cover the basic principles; then students, in teams, seek to improve the profile of a weakly potent, insoluble phosphatidylinositide 3-kinase delta (PI3Kδ) inhibitor (1) through compound array design, molecular modelling, screening data analysis and the synthesis of target compounds in the laboratory. The project benefits from significant industrial support, including lectures, student mentoring and consumables. The aim is to make the learning experience as close as possible to real-life industrial situations. In total, 48 target compounds were prepared, the best of which (5b, 5j, 6b and 6ap) improved the potency and aqueous solubility of the lead compound (1) by 100-1000 fold and ≥tenfold, respectively.

Pediatric travelers visiting friends and relatives (VFR) abroad: illnesses, barriers and pre-travel recommendations.

Global mobility has shown a steady rise in recent years, with increased immigration and international travel. The VFR traveler is a traveler whose primary purpose of travel is to visit friends and relatives (VFR), where there is a gradient of risk between home and destination. Children are more likely to be VFR travelers than adults. Pediatric VFR travelers have higher risks for certain infectious travel-related illnesses and face multiple barriers in receiving comprehensive pre-travel care. This review focuses on the current state of knowledge of the pediatric VFR traveler, including epidemiological risks, barriers to adequate pre-travel services, and specific recommendations for disease prevention.

Safety and efficacy of low-dose esterified estrogens and methyltestosterone, alone or combined, for the treatment of hot flashes in menopausal women: a randomized, double-blind, placebo-controlled study.

This study evaluated safety and efficacy of esterified estrogens and methyltestosterone administered alone or in combination for the treatment of hot flashes in menopausal women. The 0.30-mg esterified estrogens and 0.30-mg methyltestosterone combination was the lowest effective dose, and our results are consistent with the known safety profile of estrogen and androgen combination products.

Surgical correction of limb malalignment for instability of the patella: a comparison of 2 techniques.

BACKGROUND: Although patients considered "successful" at longer-term follow-up no longer exhibited patellar instability, those with more severe malalignment issues had other, gradually worsening symptoms such as activity-related pain, crepitation, swelling with activities, and pain with weather changes. HYPOTHESIS: Improvement of patellar tracking by correction of the tubercle-sulcus angle and related ligament deficiencies will result in good to excellent results, regardless of the technique employed. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Twenty-five patients with dislocating patellae and significant lower leg deformity were treated; 12 patients (group 1) underwent a derotational high tibial osteotomy and 13 patients (group 2) underwent an Elmslie-Trillat-Fulkerson proximal-distal realignment. All were prospectively evaluated a minimum of 24 months postoperatively with a physical examination, validated outcome questionnaires, radiographs, and computerized axial tomography scans. Postoperative 3-dimensional bilateral gait analyses were performed on all subjects walking on a 3-dimensional force treadmill to measure stance kinematics, foot progression angle, knee flexion, knee valgus-varus, hip flexion, and patella angle. Contralateral limbs with similar preoperative alignment were used as controls. RESULTS: Group 1 patients significantly improved over their preoperative status in all primary subjective and functional outcome parameters, and were significantly better than group 2 patients. Group 2 patients improved, but not to the degree of group 1 patients. Gait analysis revealed group 1 patients had more symmetrical gait patterns, with less variability and less compensatory gait changes, than group 2 patients. CONCLUSION: The original hypothesis proved to be incorrect. The simultaneous correction of ligament imbalance, excessive tubercle-sulcus angle, and lower limb torsional deformity produced significantly better results than conventional proximal-distal realignment.

Coinfections acquired from ixodes ticks.

The pathogens that cause Lyme disease (LD), human anaplasmosis, and babesiosis can coexist in Ixodes ticks and cause human coinfections. Although the risk of human coinfection differs by geographic location, the true prevalence of coinfecting pathogens among Ixodes ticks remains largely unknown for the majority of geographic locations. The prevalence of dually infected Ixodes ticks appears highest among ticks from regions of North America and Europe where LD is endemic, with reported prevalences of < or =28%. In North America and Europe, the majority of tick-borne coinfections occur among humans with diagnosed LD. Humans coinfected with LD and babesiosis appear to have more intense, prolonged symptoms than those with LD alone. Coinfected persons can also manifest diverse, influenza-like symptoms, and abnormal laboratory test results are frequently observed. Coinfecting pathogens might alter the efficiency of transmission, cause cooperative or competitive pathogen interactions, and alter disease severity among hosts. No prospective studies to assess the immunologic effects of coinfection among humans have been conducted, but animal models demonstrate that certain coinfections can modulate the immune response. Clinicians should consider the likelihood of coinfection when pursuing laboratory testing or selecting therapy for patients with tick-borne illness.