[Contribution of the maximal exercise test to diagnosis the vascular origin of leg pain in athletes]. / Intérêt de l'épreuve d'effort maximal dans le diagnostic d'une origine artérielle des douleurs des membres inférieurs chez le sportif.

Leg pain is a common debilitating symptom in athletes. Vascular disease is not often proposed as a possible cause. Maximal exercise with measure of the ankle-brachial index after exercise can be an interesting diagnostic test. We report an illustrative case where an athlete presented leg pain revealing arterial disease disclosed by exercise. Interestingly, sub-maximal exercise did not cause pain, causing a delay in diagnosis. The vascular origin of leg pain can be detected with a maximal exercise test that induces the symptomatic pain or at least clinical discomfort.

Does Deep Bradycardia Increase the Risk of Arrhythmias and Syncope in Endurance Athletes?

The aim of this study was to evaluate whether endurance athletes who exhibit deep bradycardia are more prone to arrhythmias and reflex syncope than their non-bradycardic peers. 46 healthy men (ages 19-35) were divided into 3 groups based on whether they were sedentary (SED,<2 h/week) or endurance trained (ET,>6 h/week), and non-bradycardic (NB, resting heart rate (HR)≥60 bpm) or bradycardic (B, resting HR<50 bpm). Resting HR was lower in ETB vs. ETNB and SED (43.8±3.1, 61.3±3.3, 66.1±5.9 bpm, respectively; p<0.001). Thus, 16 SED, 13 ETNB and 17 ETB underwent resting echocardiography, maximal exercise test, tilt test (TT) and 24 h-Holter ECG. Subjects were followed-up during 4.7±1.1 years for training, syncope and cardiac events. Our results showed that incidence of arrhythmias and hypotensive susceptibility did not differ between groups. During follow-up, no episode of syncope or near-syncope was reported. However, cardio-inhibitory syncope occurrence tended to be higher in ETB. Left ventricular end-diastolic diameter index was increased in ETB vs. ETNB and was correlated with resting HR (r=- 0.64; p<0.001). As a result, athletes with deep bradycardia do not present more arrhythmias and more hypotensive susceptibility than their non-bradycardic peers. Cardiac enlargement and autonomic alteration both seem to be involved in an athlete's bradycardia.

Cardiovascular Benefits of Endurance Training in Seniors: 40 is not too Late to Start.

It is unknown whether commencing structured endurance training after 40 years of age is powerful enough to induce beneficial cardiovascular adaptations in later life. 34 men between the ages of 55 and 75 were included: 10 life-long sedentary seniors (SED), 13 endurance master athletes who commenced training≤30 years of age (ET30), and 11 endurance master athletes who commenced training≥40 years of age with no prior physical training (ET40). All performed resting 5-min spectral heart rate (HR) variability analysis, resting and submaximal-exercise echocardiography, and a maximal exercise test. Maximal oxygen uptake was higher and resting HR was lower in both trained groups vs. SED, without difference between ET30 and ET40. Atrial and left ventricle dimensions were greater in ET30 and ET40 vs. SED, without difference between both athletes groups. At rest, total arterial compliance was improved in both ET30 and ET40 compared to SED. During submaximal exercise, improvement in global LV afterload was only observed in ET30 vs. SED. Two powerful markers of health, maximal oxygen uptake and resting HR, did not differ between athletes who commenced training before 30 or after 40 years of age, but were significantly improved compared to their life-long sedentary counterparts.

Continuous engineering of nano-cocrystals for medical and energetic applications.

Cocrystals, solid mixtures of different molecules on molecular scale, are supposed to be tailor made materials with improved employability compared to their pristine individual components in domains such as medicine and explosives. In medicine, cocrystals are obtained by crystallization of active pharmaceutical ingredients with precisely chosen coformers to design medicaments that demonstrate enhanced stability, high solubility, and therefore high bioavailability and optimized drug up-take. Nanoscaling may further advance these characteristica compared to their micronsized counterparts - because of a larger surface to volume ratio of nanoparticles. In the field of energetic materials, cocrystals offer the opportunity to design smart explosives, combining high reactivity with significantly reduced sensitivity, nowadays essential for a safe manipulation and handling. Furthermore, cocrystals are used in ferroelectrics, non-linear material response and electronic organics. However, state of the art batch processes produce low volume of cocrystals of variable quality and only have produced micronsized cocrystals so far, no nano-cocrystals. Here we demonstrate the continuous preparation of pharmaceutical and energetic micro- and nano-cocrystals using the Spray Flash Evaporation process. Our laboratory scale pilot plant continuously prepared up to 8 grams per hour of Caffeine/Oxalic acid 2:1, Caffeine/Glutaric acid 1:1, TNT/CL-20 1:1 and HMX/Cl-20 1:2 nano- and submicronsized cocrystals.

Effect of recombination in the parent populations on the means and combining ability variances in hybrid populations of maize ( Zea mays L.).

Recombination of selected genotypes plays a key role in plant breeding for generating new base populations. We investigated the influence of recombination in two parent populations on the means and combining ability variances of their hybrid population by (1) quantitative genetic theory and (2) experiments with maize. The two parent populations were founded by four early flint and four early dent inbred lines, respectively. Each population was studied in three generations: Syn-0, the four inbred lines themselves; Syn*-1, the six intrapool single crosses (SC); and Syn*-2, the three intrapool double crosses (DC). Four interpool hybrid populations were created: (1) all 16 SC and (2) all 36 DC were produced from generations Syn-0 and Syn*-1, respectively, (3) 168 biparental progenies (BIP) of type flint x dent (female x male), and (4) 168 BIP of type dent x flint were produced according to NC-design I with randomly sampled plants of generation Syn*-2. The half-sib and full-sib families obtained in this manner were evaluated for grain yield, dry matter concentration and plant height. According to theoretical results, differences in the population means of these hybrid populations indicate the presence of various types of epistasis. Changes in combining ability variances from SC to DC reflect different levels of parental inbreeding (F = 1 vs F = 0), whereas changes from DC to BIP only reflect the effects of recombination and are attributable to covariances between additive and dominance effects caused by linkage disequilibrium in the Syn-0 generations. The experimental results showed a significant decline in yield from DC to BIP due to a loss of gene combinations with favourable epistatic effects. Estimates of sigma(2)(GCA) attributable to flint or dent lines decreased or remained unchanged from SC to DC, but generally increased in the BIP populations. The consequences of these trends for developing improved interpool hybrids are discussed.

Reduced expression of junctional adhesion molecule and platelet/endothelial cell adhesion molecule-1 (CD31) at human vascular endothelial junctions by cytokines tumor necrosis factor-alpha plus interferon-gamma Does not reduce leukocyte transmigration under flow.

The combination of tumor necrosis factor (TNF)-alpha plus interferon (IFN)-gamma has been shown previously to promote redistribution of platelet/endothelial cell adhesion molecule-1 (PECAM-1) (CD31), junctional adhesion molecule (JAM), and VE-cadherin away from lateral junctions of human umbilical vein endothelial cell monolayers. In parallel, neutrophil transmigration was significantly reduced. Because PECAM-1 and JAM have been implicated in leukocyte transmigration, the observed redistribution by cytokine activation was presumed to represent the mechanism causing decreased transmigration under static conditions. The current results confirm that culture of human umbilical vein endothelial cells with TNF-alpha plus IFN-gamma caused a decrease in surface-expressed and junctional-localized JAM and PECAM-1, but did not cause decreased leukocyte transmigration in an in vitro flow assay. Furthermore, blocking monoclonal antibody to PECAM-1 still significantly reduced monocyte transmigration, demonstrating that it retains a functional role even though its levels were reduced and redistributed away from junctions, whereas a panel of monoclonal antibodies to JAM failed to reduce leukocyte transmigration. Given the alterations in junction protein location, permeability function was assessed. IFN-gamma alone or TNF-alpha plus IFN-gamma significantly increased permeability, but TNF-alpha alone did not, suggesting lack of correlation between transmigration and loss of permeability. In conclusion, cytokine activation induced loss and redistribution of PECAM-1 and JAM away from lateral junctions, but per se does not negatively regulate either neutrophil or monocyte transmigration under flow.

Junction adhesion molecule is a receptor for reovirus.

Virus attachment to cells plays an essential role in viral tropism and disease. Reovirus serotypes 1 and 3 differ in the capacity to target distinct cell types in the murine nervous system and in the efficiency to induce apoptosis. The binding of viral attachment protein sigma1 to unidentified receptors controls these phenotypes. We used expression cloning to identify junction adhesion molecule (JAM), an integral tight junction protein, as a reovirus receptor. JAM binds directly to sigma1 and permits reovirus infection of nonpermissive cells. Ligation of JAM is required for reovirus-induced activation of NF-kappaB and apoptosis. Thus, reovirus interaction with cell-surface receptors is a critical determinant of both cell-type specific tropism and virus-induced intracellular signaling events that culminate in cell death.

Simultaneous irradiation for prostate cancer: intermediate results with modern techniques.

PURPOSE: In this study of men with early stage prostate cancer we evaluated treatment outcome after modern simultaneous irradiation, comprising transperineal implantation followed by external beam radiation. Disease-free survival rates were calculated according to an undetectable prostate specific antigen (PSA) nadir. MATERIALS AND METHODS: From 1992 to 1996, 689 men with clinical stage T1-T2, N0, Nx prostate cancer were treated with ultrasound guided transperineal 125iodine seed implantation followed 3 weeks later by external beam radiation. Disease-free status was defined as the achievement and maintenance of a PSA nadir of 0.2 ng./ml. or less. Median followup was 4 years (range 3 to 7). None of these men received neoadjuvant or adjuvant hormonal therapy. RESULTS: Overall 5-year disease-free survival was 88%. The 5-year rate according to PSA 4.0 ng./ml. or less, 4.1 to 10.0, 10.1 to 20.0 and greater than 20.0 was 94%, 93%, 75% and 69%, respectively. Multivariate analysis revealed that pretreatment PSA was the strongest indicator of subsequent disease-free status in regard to Gleason score or clinical stage. CONCLUSIONS: Intermediate treatment outcome analysis of modern simultaneous radiation supports the principles of radiation dose intensification for intracapsular disease plus the treatment of potential microscopic capsular penetration.

Human junction adhesion molecule regulates tight junction resealing in epithelia.

Epithelial cells form a highly selective barrier and line many organs. The epithelial barrier is maintained by closely apposed cell-cell contacts containing tight junctions, the regulation of which is incompletely understood. Here we report the cloning, tissue localization and evidence for a role in epithelial barrier regulation of an immunoglobulin superfamily member that likely represents the human homolog of murine junction adhesion molecule (JAM). Analysis of the primary structure of human JAM, cloned from T84 epithelial cells, predicts a transmembrane protein with an extracellular domain that contains two IgV loops. Monoclonal antibodies generated against the putative extracellular domain were reactive with a 35-39 kDa protein from both T84 epithelial cells and human neutrophils. By immunofluorescence, JAM mAbs labeled epithelial cells from intestine, lung, and kidney, prominently in the region of tight junctions (co-localization with occludin) and also along lateral cell membranes below the tight junctions. Flow cytometric studies confirmed predominant JAM expression in epithelial cells but also revealed expression on endothelial and hematopoietic cells of all lineages. Functional studies demonstrated that JAM specific mAbs markedly inhibited transepithelial resistance recovery of T84 monolayers after disruption of intercellular junctions (including tight junctions) by transient calcium depletion. Morphologic analysis revealed that, after disassembly of cell-cell junctions, anti-JAM inhibition of barrier function recovery correlated with a loss of both occludin and JAM, but not ZO-1, in reassembling tight junction structure. Reassembly of the major adherens junction component E-cadherin was not affected by JAM specific mAbs. Our findings suggest that JAM plays an important role in the regulation of tight junction assembly in epithelia. Furthermore, these JAM-mediated effects may occur by either direct, or indirect interactions with occludin.

Post-treatment PSA < or = 0.2 ng/mL defines disease freedom after radiotherapy for prostate cancer using modern techniques.

OBJECTIVES: The prostate-specific antigen (PSA) definition of disease freedom after radiotherapy for prostate cancer is still in dispute. This report focuses on the PSA nadir achieved in men treated by modern radiotherapy techniques. METHODS: From 1984 to 1994, 489 consecutive men with clinical Stage T1 -T2 prostate cancer were treated by simultaneous radiation: prostate iodine-125 implant followed by external beam radiation. A transperineal implant was performed on 143 men with Stage T1-T2NX, the focus of this study; 346 men with Stage T1-T2N0 had a retropubic implant. The median pretreatment PSA was 8.3 ng/mL (range 0.3 to 188). A rising PSA was defined as one that rose on three consecutive occasions above whatever nadir was achieved. A minimum 5-year follow-up (range 5 to 15) was reached by 453 men. RESULTS: After a minimum 5-year follow-up, 336 men had a nonrising PSA, and of this group, 107 had undergone simultaneous radiation by the transperineal implant technique. A PSA nadir of 0.2 ng/mL or less was achieved by 97% of the transperineally implanted men, and 3% had a nadir of 0.3 to 1.0 ng/mL. Of the 489 men, those who had a nadir of 0.2 ng/mL or less had a 92% nonrising PSA rate (P = 0.001) 10 years after treatment compared with a 41% rate for men who had a nadir of 0.3 to 1.0 ng/mL. All men whose nadir was greater than 1.0 ng/mL had recurrence. The median time to achieve the PSA nadir of 0.2 ng/mL was 27 months (range 3 to 102). CONCLUSIONS: Primarily on the basis of the results from men treated with simultaneous radiation using the transperineal technique, the definition of disease freedom for radiotherapy should be men who achieve and maintain a PSA nadir of 0.2 ng/mL or less.

Single-agent paclitaxel in patients with metastatic breast cancer receiving high-dose chemotherapy with peripheral blood stem cell support.

The purpose of this trial was to determine the effects of paclitaxel in patients with newly diagnosed metastatic breast cancer scheduled to receive high-dose chemotherapy with peripheral blood stem cell support. Eighty-four patients received anthracycline-based induction and two doses of paclitaxel at 170 mg/m2 (n = 52) or 250 mg/m2 (n = 32). Eighty-two (98%) received cyclophosphamide and etoposide (n = 50) or paclitaxel and cyclophosphamide (n = 32) with granulocyte colony-stimulating factor for mobilization of peripheral blood stem cells, and 79 (94%) received cyclophosphamide, thiotepa, and carboplatin with peripheral blood stem cell support. One patient (1%) died of infection and 56 (67%) died of progressive disease. For patients with measurable disease, the complete response rate was 21% after induction and 29% after paclitaxel (p = 0.54). Results were compared with those of 125 patients who received the same sequence of therapy without paclitaxel. The complete response rate after high-dose chemotherapy was 54% for patients receiving paclitaxel and 62% for those not receiving paclitaxel (p = 0.60). The probabilities of overall survival and event-free survival at 3 years for patients receiving paclitaxel were 46% and 24%, respectively, compared with 54% and 22%, respectively, for patients not receiving paclitaxel (p = 0.62). Further trials evaluating this dose and schedule of paclitaxel in patients with metastatic breast cancer receiving high-dose chemotherapy are not warranted.

Cell-specific peptide binding by human neutrophils.

Analysis of peptide binding to human neutrophils (PMN) using phage display techniques has revealed cell-specific motifs reactive with the PMN surface. Phage libraries displaying either linear 9-mer or cyclic 10-mer and 6-mer peptides were incubated with normal human neutrophils followed by elution of bound phage with low pH (pH 2.2) and non-ionic detergent. Three rounds of selection generated several related peptide sequences that bound with high avidity to PMN. Using the linear 9-mer library, PMN-binding phage expressed peptides with the motif (G/A)PNLTGRW. The binding of phage bearing this motif was highly specific since no binding was observed on lymphocytes, fibroblasts, epithelial, or endothelial cells. Functional assays revealed that phage bearing the sequence FGPNLTGRW induced a pertussis toxin-sensitive increase in PMN cytosolic calcium analogous to that observed with Galphai coupled receptors. Other prominent motifs identified included phage bearing the consensus DLXTSK(M/L)X(V/I/L), where X represents a non-conserved position. Phage with this motif bound exclusively to a sub population of human PMN that comprised approximately 50% of the total and did not elicit a calcium response. The binding of such phage to PMN was prevented by co-incubation with competing peptides displaying identical or similar sequences (IC50 range from 0.6 micromol/L to 50 micromol/L for DLXTSK and GPNLTG, respectively). We speculate that these techniques will be useful in identifying functional cell-specific binding motifs and contribute to the development of new therapeutic and diagnostic strategies in human disease.

Description of older adults as depicted in magazine advertisements.

Negative attitudes about aging have been widespread and films, television, radio, and print media may serve as an important source of socialization or reflect the current views of older adults. This study focused on examination of the frequency of depictions of older men and women in 765 advertisements appearing in Time and Newsweek national weekly news magazines, and on an analysis of their roles suggested in photographs depicting a total of 2,505 persons. These were collected over a one-year period and coded by three persons. Analysis indicated that older adults, especially older women, were not only presented infrequently but, when presented roles, were often passive or dependent as is consistent with social stereotypes.

Collection of peripheral blood stem cells following administration of paclitaxel, cyclophosphamide, and filgrastim in patients with breast and ovarian cancer.

PURPOSE: To determine the toxicities and efficacy of paclitaxel, cyclophosphamide (Cy), and recombinant human granulocyte-colony stimulating factor (filgrastim) administered for mobilization and collection of peripheral blood stem cells (PBSC) in patients with breast and ovarian cancer. METHODS: One hundred and forty-one patients with breast (n = 115) or ovarian cancer (n = 26) received paclitaxel 170 mg/m2 and Cy 2 gm/m2 (n = 42) or paclitaxel 200 mg/m2, Cy 3 gm/m2 (n = 99), and filgrastim (6 micrograms/kg/day) followed by collection of PBSC by apheresis. RESULTS: The 2 dose levels of paclitaxel and Cy tested were well tolerated. The median yield of CD34+ cells from all patients was 6.53 x 10(6)/kg (range, 0.11-51.76) collected with a median of 2 aphereses (range, 1-8). The target dose of 2.5 x 10(6) CD34+ cells/kg was achieved in 85% of patients. The mean daily collection of CD34+ cells was 5.46 x 10(6)/kg for patients receiving 200 mg/m2 of paclitaxel and 3 gm/m2 of Cy as compared to 2.77 for patients receiving the lower doses (p = 0.0005). Increasing the dose of paclitaxel and Cy did not significantly increase the fraction of patients achieving a target dose of 2.5 x 10(6) CD34+ cells/kg (87% vs 81%, p = 0.367) but did increase the fraction achieving a target of 5.0 x 10(6) CD34+ cells/kg (73% vs 45%, p = 0.002). The mean daily collection of CD34+ cells for patients who had received only 1 prior chemotherapy regimen was 6.59 x 10(6)/kg as compared to 3.47 for patients who had received more than 1 prior chemotherapy regimen (p < 0.0001). Prior radiation therapy (p = 0.003) and patient performance status (p = 0.047) were adverse risk factors for achieving a target dose of > or = 2.5 x 10(6) CD34+ cells/kg. CONCLUSIONS: The combination of paclitaxel, Cy, and filgrastim can be administered with acceptable toxicity, allowing collection of adequate quantities of PBSC from the majority of patients with breast and ovarian cancer. Increasing the doses of paclitaxel and Cy increased the number of CD34+ cells collected and decreased the number of apheresis procedures necessary to collect target cell doses. However, increasing drug doses did not increase the fraction of patients yielding the minimum CD34+ target dose of 2.5 x 10(6)/kg. Collection of PBSC early in the disease course is the best strategy to assure optimal CD34+ cell doses in all patients.

[A program for the rehabilitation of mentally ill students]. / Ein Programm zur Rehabilitation psychisch kranker Studierender.

The rehabilitation of mentally ill undergraduates is a neglected area. The scope and relevance of this problem are confirmed by the epidemiological figures available. A programme aimed at supporting mentally ill undergraduates at Münster university offers such students psychoeducationally oriented group therapy and intensive individual counselling. The report covers 82 students who have expressed interest in this programme since the 1993 summer semester. 57 took part for at least 1 semester, the majority of them (56%) being schizophrenic patients. The main problem is in structuring and coping with required standards of performance, social isolation, excessively high expectations of their own achievement potential, and insecurity with regard to the prospects of success in their degree courses. Experience to date confirms the need for, and the opportunities offered by on-target support of mentally ill undergraduates.

Multiplicative vs. arbitrary gene action in heterosis.

In this article we investigate multiplicative effects between genes in relation to heterosis. The extensive literature on heterosis due to multiplicative effects between characters is reviewed, as is earlier work on the genetic description of heterosis. A two-locus diallelic model of arbitrary gene action is used to derive linear parameters for two multiplicative models. With multiplicative action between loci, epistatic effects are nonlinear functions of one-locus effects and the mean. With completely multiplicative action, the mean and additive effects form similar restrictions for all the rest of the effects. Extensions to more than two loci are indicated. The linear parameters of various models are then used to describe heterosis, which is taken as the difference between respective averages of a cross (F1) and its two parent populations (P). The difference (F2 - P) is also discussed. Two parts of heterosis are distinguished: part I arising from dominance, and part II due to additive x additive (a x a)-epistasis. Heterosis with multiplicative action between loci implies multiplicative accumulation of heterosis present at individual loci in part I, in addition to multiplicative (a x a)-interaction in part II. Heterosis with completely multiplicative action can only be negative (i.e., the F1 values must be less than the midparent), but the difference (F2 - P) can be positive under certain conditions. Heterosis without dominance can arise from multiplicative as well as any other nonadditive action between loci, as is exemplified by diminishing return interaction. The discussion enlarges the scope in various directions: the genetic significance of multiplicative models is considered.(ABSTRACT TRUNCATED AT 250 WORDS)

High-dose 24-hour infusion of 5-fluorouracil in metastatic prostate cancer. A phase II trial of the Piedmont Oncology Association.

Thirty-two patients with metastatic carcinoma of the prostate refractory to endocrine therapy were entered on trial. No patient entered in the study had prior chemotherapy. Patients were treated with 5-fluorouracil given at a dosage of 4 gm/m2 over a 24-hour period every 2 weeks. Of the 27 patients evaluable for response, there were no complete or partial remissions, but 9 (33%) had a stable disease. The 95% confidence interval for complete and partial response in this series (0 of 27 patients) is 0.0-12%. Myelosuppression and gastrointestinal toxicity was moderate. Two patients, however, experienced major but completely reversible neurotoxicity, including 1 with cerebellar ataxia and 1 with memory loss and stroke-like symptoms. These data indicate that high-dose fluorouracil used in this dosage and schedule is ineffective in the therapy of advanced carcinoma of the prostate.

Short Stature in Childhood and Adolescence: Part 1: Medical management.

Childhood short stature is common in family practice. Familial short stature and constitutional growth delay account for most cases, and there are clear guidelines for differentiating these from each other and from less common pathologic conditions. Appropriate investigation, treatment, and referral are delineated, and growth hormone therapy is described. An integrated medical-psychosocial approach to care is recommended.

Short Stature in Childhood and Adolescence: Part 2: Psychological management.

The literature on the psychosocial impact of short stature in childhood and adolescence is reviewed, with particular reference to IQ and educational attainment, personality and psychopathology, and the concept of infantilization. Adult outcome studies are also reviewed with comments on inherent methodological problems. Suggestions are offered for the psychosocial management of short stature.