Stochastic transitions: Paths over higher energy barriers can dominate in the early stages.

The time evolution of many physical, chemical, and biological systems can be modeled by stochastic transitions between the minima of the potential energy surface describing the system of interest. We show that in cases where there are two (or more) possible pathways that the system can take, the time available for the transition to occur is crucially important. The well-known results of the reaction rate theory for determining the rates of transitions apply in the long-time limit. However, at short times, the system can, instead, choose to pass over higher energy barriers with a much higher probability, as long as the distance to travel in phase space is shorter. We construct two simple models to illustrate this general phenomenon. We also apply a version of the geometric minimum action method algorithm of Vanden-Eijnden and Heymann [J. Chem. Phys. 128, 061103 (2008)] to determine the most likely path at both short and long times.

Changes in gut microbial metagenomic pathways associated with clinical outcomes after the elimination of malabsorbed sugars in an IBS cohort.

Specific diets to manage sugar malabsorption are reported to reduce clinical symptoms of irritable bowel syndrome (IBS). However, the effects of diets for malabsorbed sugars on gut microbiota signatures have not been studied, and associations with clinical outcomes in IBS have not been characterized. 22 IBS patients positively tested for either lactose-, fructose-, sorbitol- or combined malabsorptions were subjected to 2-weeks sugar elimination and subsequent 4-weeks re-introduction. 7 IBS patients tested negative for sugar malabsorption were used as controls. Nutrition and clinical symptoms were recorded throughout the study. Fecal samples were serially collected for 16S rRNA amplicon and shotgun-metagenome sequencing. Dietary intervention supervised by nutrition counseling reduced IBS symptoms during the elimination and tolerance phases. Varying clinical response rates were observed between subjects, and used to dichotomize our cohort into visual analogue scale (VAS) responders and non-responders. Alpha -and beta-diversity analyzes revealed only minor differences regarding 16S rRNA-based fecal microbiota compositions between responder and non-responder patients during baseline or tolerance phase. In shotgun-metagenome analyzes, however, we analyzed microbial metabolic pathways and found significant differences in pathways encoding starch degradation and complex amino acid biosynthesis at baseline between IBS controls and malabsorbers, and notably, between diet responder and non-responders. Faecalibacterium prausnitzii, Ruminococcus spp. and Bifidobacterium longum largely informed these metabolic pathways. Our study demonstrates that diet interventions for specific, malabsorbed carbohydrates reshaped the metagenomic composition of the gut microbiota, with a small community of bacterial taxa contributing to these changes rather than a single species.

Shoulder arthroscopy combined to hardware removal in proximal humeral fractures: a series of 58 cases with a mean follow-up of 2 years.

BACKGROUND: Proximal humerus fractures are common injuries. Locking plates and anterograde medullary nails are the two most common fixation devices used when open reduction and internal fixation (ORIF) is indicated. Complications related to fracture and to hardware are numerous, especially shoulder stiffness. The goal of this study is to report the clinical outcomes of gleno-humeral arthroscopic arthrolysis combined with hardware removal. METHODS: A total of 58 patients (25 men, 33 women) with a mean age of 58 years (24-79) were reviewed retrospectively. Forty of them were active workers (5 heavy workers), and 18 were retired. A total of 24 fractures were reported after sport accident, 26 after domestic accident, and 8 after high energy trauma. Thirty-four patients with 3 or 4 part fractures (fracture through the anatomic neck and tuberosities), 20 patients with two part (displaced surgical neck) fracture and 4 cases of fracture of the tuberosities were operated. We combined a gleno-humeral arthrolysis by arthroscopy and a removal of the hardware using the previous incision for the plate or by arthroscopy for the nail. RESULTS: The average follow-up was 23 months (range 6-60). Pain in Constant Murley score (CS) increased from 7.3 ± 3.8 points preoperatively to 13 ± 2.76 points post-operatively (p < 0.05). CS increased from 36.8 ± 12.25 points to 68.45 ± 15.24 points. Subjective shoulder value (SSV) score increased from 45.8 ± 16.6 to 78.23 ± 14.74. A gain in all active range of motion was reported (forward flexion: 37.6°, abduction: 39.5°, external rotation: 24.3°, internal rotation: from L5-S1 to T12-L1). CONCLUSIONS: Gleno-humeral arthrolysis by arthroscopy combined with hardware removal after proximal humerus ORIF in one step is safe and beneficial for post-traumatic stiffness of the shoulder. It provides significant pain relief and increase of range of motion and allows to treat associated articular pathology.

Effect of angiotensin II receptor blockers, candesartan, on osteoprotegerin level in hypertensive patients: Link between bone and RAAS.

INTRODUCTION: The renin-angiotensin-aldosterone system (RAAS) has recently been considered as a possible link between bone and vascular disease. The present study was designed to determine the effect of the angiotensin II receptor blocker candesartan on circulating osteoprotegerin (OPG) in hypertensive patients with multiple cardiovascular risk factors. MATERIAL AND METHODS: A total of 69 hypertensive patients were randomized to two groups: Group 1 included patients treated with oral candesartan in doses of 16 mg to 32 mg per day in addition to routine standard of care (routine care + ARB), and Group 2 included patients who received routine standard of care other than ARBs or ACEIs, with no change to their treatment (routine care). Patients were evaluated for lipid profile, HbA1C, insulin, C-peptide, CRP, aldosterone, renin, homeostasis model assessment-insulin resistance (HOMA-IR) and OPG. RESULTS: Baseline OPG levels did not differ significantly by treatment group. Post-treatment serum OPG levels were marginally lower in Group1 compared with Group 2; however, this decrease did not reach statistical significance (p = 0.077). CONCLUSIONS: In the present study, treatment with the ARB candesartan had no significant effect on circulating OPG levels in hypertensive patients with multiple cardiovascular risk factors. To the best of our knowledge, the present study is the first to estimate an effect of candesartan on bone remodeling marker such as OPG.

First 100 cases at a low volume prostate brachytherapy institution: learning curve and the importance of continuous quality improvement.

INTRODUCTION: We report the first 100 patients who underwent prostate brachytherapy as monotherapy with 125I at an institution with moderate volume radical prostatectomy but low volume brachytherapy (<2 cases per month). Learning curve and quality improvement was assessed by way of achieving prescription dose targets. MATERIALS AND METHODS: From May 2002 to August 2006, 100 patients underwent prostate 125I brachytherapy monotherapy via preplanned approach. Preoperative planned dose to 100% of prostate gland (D100) was 145 Gy and postoperative confirmed dose was assessed by computed tomography. The cohort was divided into quartiles and recurrence was assessed using Kaplan-Meier analysis. RESULTS: Patient quartiles were of similar age and Gleason grade, while PSA was slightly higher in the first group. Postoperative D90 increased after the first quartile (p = < 0.0001) reaching targeted values. Kaplan-Meier survival analysis revealed that 5 year recurrence-free survivals by Phoenix definition was 96%-100% in all groups while by ASTRO definition there was a decrease in recurrence for later cases. CONCLUSIONS: At our low volume institution during the first 100 brachytherapy cases, a learning curve for radiation dosimetry was evident, which improved after 25 patients. Preplanned dose-volume parameters were adjusted, enabling the achievement of post-implant goals emphasizing the importance of continuous quality improvement. Although recurrence data is limited by sample size and moderate follow up, there was a discrepancy between the Phoenix and ASTRO definition when evaluating recurrence.

The mental health of female sex workers.

OBJECTIVE: There is limited information available about the mental health of female sex workers. Therefore, we aimed to make a comprehensive assessment of the mental status of female sex workers over different outdoors and indoors work settings and nationalities. METHOD: As the prerequisites of a probability sampling were not given, a quota-sampling strategy was the best possible alternative. Sex workers were contacted at different locations in the city of Zurich. They were interviewed with a computerized version of the World Health Organization Composite International Diagnostic Interview. Additional information was assessed in a structured face-to-face interview. RESULTS: The 193 interviewed female sex workers displayed high rates of mental disorders. These mental disorders were related to violence and the subjectively perceived burden of sex work. CONCLUSION: Sex work is a major public health problem. It has many faces, but ill mental health of sex workers is primarily related to different forms of violence.

Analysis of interfraction prostate motion using megavoltage cone beam computed tomography.

PURPOSE: Determine the degree of interfraction prostate motion and its components measured by using daily megavoltage (MV) cone beam computed tomography (CBCT) imaging. METHODS AND MATERIALS: A total of 984 daily MV CBCT images from 24 patients undergoing definitive intensity-modulated radiotherapy for localized prostate cancer were analyzed retrospectively. Pretreatment couch shifts, based on physician registration of MV CBCT to planning CT data sets, were used as a measure of daily interfraction motion. Off-line bony registration was performed to separate bony misalignment from internal organ motion. Interobserver and intraobserver variation studies were performed on 20 MV CBCT images. RESULTS: Mean interfraction prostate motion was 6.7 mm, with the greatest single-axis deviation in the anterior-posterior (AP) direction. The largest positional inaccuracy was accounted for by systematic deviations in bony misalignment, whereas random deviations occurred from bony misalignment and internal prostate motion. In the aggregate, AP motion did not correlate with days elapsed since beginning therapy or on average with rectal size at treatment planning. Interobserver variation was greatest in the AP direction, decreased in experienced observers, and further decreased in intraobserver studies. Mean interfraction motion during the first 6 days of therapy, when used as a subsequent offset, reduced acceptable AP planning target volume margins by 50%. CONCLUSION: The MV CBCT is a practical direct method of daily localization that shows significant interfraction motion with respect to conventional three-dimensional conformal and intensity-modulated radiotherapy margins, similar to that measured in other modalities.

[Management of autoimmune thrombocytopenic purpura: a prospective study of 147 children from the regional network RHémaP]. / Purpura thrombocytopénique auto-immun: à propos d'une cohorte prospective de 147 enfants pris en charge dans le réseau d'hématologie pédiatrique des régions PACA et Corse (RHémaP).

AIM: Assessment of the impact of guidelines from a regional pediatric network to standardize the management of childhood immune thrombocytopenic purpura (ITP). MATERIALS AND METHODS: Consensus guidelines were drawn up in centers of the pediatric network for hematological diseases, RHémaP, and a cohort of children referred for ITP in these centers was set up. A 1-year follow-up was recorded for each patient over a 43-month period. RESULTS: We report data from a cohort of 147 children. At diagnosis, we recorded severe thrombocytopenia (median=8G/l) and 141 children had hemorrhagic symptoms (96%). Only 23 children had a bone marrow aspiration (BMA) at diagnosis (16.3%), which meant a high level of implementation of the RHémaP recommendations (96%) since indications of BMA were limited to rare indications. For 135 children (91.8%), treatment fulfilled the RHémaP guidelines that were mainly based on the platelet count: 121 received intraveinous immunoglobulin (IVIG) and 14 were not treated. Among those who received IVIG, 110 were good responders (91%) at the 96-h evaluation (platelet count greater than 20G/l), nine (7.4%) were poor responders, and 1 died of intracranial hemorrhage. At 6 months, chronic ITP was observed in 40 children (32.8%). Chronic ITP was associated with a higher platelet count at diagnosis and an older age (p<10(-3) and p=10(-3), respectively). CONCLUSION: The practices recorded over a 43-month period in our cohort fulfilled the RhémaP guidelines and we conclude that we managed to standardize regional practices for children with ITP. We observed conventional epidemiological characteristics in this cohort. Older children and higher platelet count at diagnosis were significantly associated with higher frequency of chronic ITP.

Fruit consumption and seed dispersal of Dimorphandra mollis Benth. (Leguminosae) by the lowland tapir in the cerrado of Central Brazil.

Fruit phenology observations and consumption of Dimorphandra mollis (Leguminosae) were analyzed during seven months in an area of cerrado stricto sensu. We analysed 81 fecal samples collected at six different places of lowland tapirs (Tapirus terrestris) in central Brazilian cerrado. In addition, from the feces of five tapirs at the Brasília Zoo to which fruit had been offered, seeds were collected and used in germination tests. The results suggest that the tapir is an important fruit consumer and a potential seed disperser of D. mollis. In the field, however, fruit consumption was found to be very low, probably because of both fruit palatability and the low density of frugivores, especially tapirs. The possibility that the original dispersal agents of D. mollis seeds belonged to the South American Pleistocene megafauna is discussed.

Fruit consumption and seed ispersal of Dimorphandra mollis Benth. (Leguminosae) by the lowland tapir in the Cerrado of Central Brazil

A frutificação de Dimorphandra mollis e o destino dos frutos foram analisados por 7 meses em uma área de cerrado stricto sensu no Distrito Federal. Analisamos 81 amostras de fezes de anta (Tapirus terrestris) coletadas em 6 áreas de cerrado no Brasil Central e oferecemos frutos a 5 antas no zoológico de Brasília. As fezes foram coletadas e as sementes usadas em testes de germinação. A anta é importante consumidor dos frutos e potencial dispersor das sementes. Contudo, o consumo de frutos no campo foi reduzido provavelmente em razão da palatabilidade dos frutos e da baixa densidade de frugívoros, especialmente antas. Discutimos a possibilidade de os dispersores originais pertencerem à megafauna extinta de mamíferos da América do Sul.

Copper availability in seven Israeli soils incubated with and without biosolids.

Land application is becoming a preferred option for disposal of sewage sludge (biosolids) from wastewater treatment plants. However, it creates potential risks due to the heavy metal contents of these materials, with copper (Cu) being of chief concern. The long-term fate of biosolid metals applied to agricultural soils is not well understood, particularly in the soils of the Middle East. This investigation was conducted to determine whether the availability of Cu changes with time in biosolid-amended and nonamended soils from Israel. Seven soils, typifying the span of properties and formation environments encountered in Israel, were incubated with and without biosolids for 7 yr, and changes in organic carbon (OC) content and labile Cu concentration were determined. Isotopic exchange techniques, using 64Cu, and ion activity measurements, using a Cu2+ ion selective electrode, revealed that the available Cu concentration remained relatively low and stable over the 7-yr incubation. This was despite substantial reductions in OC. This study shows that, with regard to Cu, application of such biosolids to these soils at rates of up to 250 Mg ha(-1) does not pose a threat to the environment in the short to medium term.

The effect of growth hormone on craniofacial growth and dental maturation in Turner syndrome.

Serial cephalometric and panoramic radiographs from a mixed longitudinal group of 28 subjects with Turner syndrome (TS), age 4.4-19.0 years, were evaluated for annualized growth increments of the craniofacial complex and dental development and were compared with a longitudinal control group from the Burlington growth study. The short and retrognathic face characteristic of the syndrome was due largely to the increased cranial base angle, decreased posterior face height, and decreased mandibular length, all of which were significantly different from the controls. Although increases in statural height occurred in the TS children who were treated with human growth hormone (GH), there was little or no effect on growth of the jaws, particularly in the older subjects, and the characteristic facies of the syndrome persisted. Dental development was advanced in all TS subjects, and GH administration had no effect on the rate of dental development.

The safety of newly approved medicines: do recent market removals mean there is a problem?

The removal of 5 pharmaceuticals from the market in a 12-month period because of unexpected adverse events raised concerns about the adequacy of the drug review process at the US Food and Drug Administration (FDA). Specifically, concerns were raised about improvements in drug review efficiency that significantly reduced FDA review times. We have reviewed the circumstances of the 5 removals to determine whether there was any relationship to the increased efficiencies in the drug review process. When the removed drugs were analyzed by date of approval, no increase in the number of drugs taken off the market was seen, demonstrating that reduced review processing time was not the reason for the cluster of removals. We conclude that the agency's drug review procedures and postmarketing surveillance system after a drug has been marketed are currently adequate but must continually adjust to future challenges.

Dental arch asymmetry in children with large overjets.

Little is known about asymmetry of children's dental arches. The purposes of this study were to quantify and describe dental arch asymmetry of 151 children with large overjets, and to determine if a spatial relationship exists between dental landmarks in opposing arches. The median palatal plane (MPP) was the reference for transverse measurements. A computer-constructed transverse palatal plane (TPP) was the reference for anteroposterior measurements. More than 30% of the children had transverse asymmetries > or = 2 mm at the maxillary first permanent molar (paired t-test; p = 0.0001). The highest mean transverse asymmetry (1.59 +/- 1.24 mm) and anteroposterior asymmetry (1.51 +/- 1.23 mm) were at the maxillary first permanent molars. A higher proportion of children with large overjets had clinically significant intra-arch asymmetries (> or = 2 mm) at several bilateral landmarks than norms (99% confidence intervals). Only 3% of these children exhibited interarch molar asymmetries > or = 4 mm. The position of the landmarks in one arch varied with the landmarks in the opposing arch (Pearson's correlation; p = 0.0001). Although many children with large overjets have significant intra-arch asymmetries, few exhibit asymmetric interarch asymmetries.

Approval of new drugs in the United States. Comparison with the United Kingdom, Germany, and Japan.

In a study reported herein, the marketing approval dates of 214 drugs newly introduced into the world market from January 1990 through December 1994 were compared in 4 countries. The analysis reveals that the United States and the United Kingdom have similar patterns of drug availability, although the United States has a number of therapies with significant public health benefits that are not yet available in the United Kingdom. The findings also show that the United States outpaces both Germany and Japan in approving important new drugs. Various strategies adopted by the Food and Drug Administration to expedite its pharmaceutical review process, including the use of industry user fees, are described.

A pilot evaluation of alternating preoperative chemotherapy in the management of patients with locoregionally advanced breast carcinoma.

BACKGROUND: This prospective trial was conducted to evaluate the outcome of patients treated with preoperative and post operative chemotherapy, mastectomy, and irradiation for locoregionally advanced breast carcinoma. METHODS: Between June 1986 and September 1990, 71 patients received 2 cycles of doxorubicin that alternated with 2 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil prior to mastectomy; irradiation was administered when the tumor was not amenable to surgical resection. Additional chemotherapy and tamoxifen, in hormone receptor-positive tumors, was used after mastectomy. Post-operative irradiation was given on a selective basis for patients at high risk for locoregional disease recurrence. RESULTS: Although 5 patients (7%) had disease progression, clinical partial or complete tumor response to preoperative chemotherapy was noted in 46 patients (65%). Sixty-eight patients (96%) underwent mastectomy. With a median follow-up of 52 months, the relapse-free and overall survival rates at 5 years were 42% and 57% respectively. Locoregional tumor recurrence occurred in 14 patients (20%), and 28 patients (39%) developed metastatic disease. Menopausal status, clinical presentation (noninflammatory vs. inflammatory), and American Joint Committee on Cancer clinical stage were independent covariates associated with patient outcome. CONCLUSIONS: Preoperative alternating chemotherapy, with the selective use of irradiation, resulted in significant locoregional disease regression and the successful integration of mastectomy into the therapeutic strategy. Locoregional tumor control and relapse-free and overall survival estimates for the approach described herein compared favorably with other comtemporary reports for this condition.

Leiomyosarcoma of the superior vena cava and azygos vein.

A 40-year-old woman presented with facial swelling and pressure sensation of the ears and sinuses. Chest roentgenography revealed a right paratracheal mass, which was confirmed by a venogram, and transjugular biopsy showed low-grade leiomyosarcoma. The superior vena cava was resected and reconstructed using a spiral vein graft. Pathologic evaluation revealed a low-grade leiomyosarcoma arising from both the superior vena cava and the azygos vein with clear margins.

Patterns of tumor relapse following mastectomy and adjuvant systemic therapy in patients with axillary lymph node-positive breast cancer. Impact of clinical, histopathologic, and flow cytometric factors.

BACKGROUND: This analysis was conducted to evaluate the impact of selected clinical, histopathologic, and flow cytometric factors on sites of initial tumor relapse after postmastectomy adjuvant systemic therapy. METHODS: Five hundred sixty-four patients with axillary node-positive breast cancer were entered in two prospectively randomized trials and received cyclophosphamide, 5-fluorouracil and prednisone with or without tamoxifen as sole adjuvant therapy. These patients were studied to assess the risk of locoregional recurrence and to identify factors that might predict tumor relapse site. RESULTS: With a median follow-up of 9.3 years, the 8-year cumulative incidences of initial locoregional or distant relapse were 20% and 35%, respectively. Pathologic tumor stage, estrogen receptor content, and number of involved axillary nodes were independent predictive factors for an increased risk of locoregional recurrence. With the exception of tumor stage, these factors also were associated with an increased risk of distant relapse so that tumor stage (T3a) remained the sole factor predictive of increased relative risk for initial locoregional (versus distant) recurrence in patients with tumor progression. Clinical and flow cytometric factors were not predictive of initial locoregional or distant relapse. CONCLUSIONS: Exploratory data analysis of two prospective trials of postmastectomy adjuvant systemic therapy has demonstrated a significant risk for initial isolated locoregional recurrence in certain patients with node-positive breast cancer. The benefit of improved locoregional tumor control in appropriately selected patients with axillary node-positive breast cancer who receive adjuvant systemic therapy requires additional investigation.