Sprouted innervation into uterine transplants contributes to the development of hyperalgesia in a rat model of endometriosis

Endometriosis is an enigmatic painful disorder whose pain symptoms remain difficult to alleviate in large part because the disorder is defined by extrauteral endometrial growths whose contribution to pain is poorly understood. A rat model (ENDO) involves autotransplanting on abdominal arteries uterine segments that grow into vascularized cysts that become innervated with sensory and sympathetic fibers. ENDO rats exhibit vaginal hyperalgesia. We used behavioral, physiological, and immunohistochemical methods to test the hypothesis that cyst innervation contributes to the development of this hyperalgesia after transplant. Rudimentary sensory and sympathetic innervation appeared in the cysts at two weeks, sprouted further and more densely into the cyst wall by four weeks, and matured by six weeks post-transplant. Sensory fibers became abnormally functionally active between two and three weeks post-transplant, remaining active thereafter. Vaginal hyperalgesia became significant between four and five weeks post-transplant, and stabilized after six to eight weeks. Removing cysts before they acquired functional innervation prevented vaginal hyperalgesia from developing, whereas sham cyst removal did not. Thus, abnormally-active innervation of ectopic growths occurs before hyperalgesia develops, supporting the hypothesis. These findings suggest that painful endometriosis can be classified as a mixed inflammatory/neuropathic pain condition, which opens new avenues for pain relief. The findings also have implications beyond endometriosis by suggesting that functionality of any transplanted tissue can be influenced by the innervation it acquires.     

Retinoic acid in alveolar development, maintenance and regeneration

Recent data suggest that exogenous retinoic acid (RA), the biologically active derivative of vitamin A, can induce alveolar regeneration in a rat model of experimental emphysema. Here, we describe a mouse model of disrupted alveolar development using dexamethasone administered postnatally. We show that the effects of dexamethasone are concentration dependent, dose dependent, long lasting and result in a severe loss of alveolar surface area. When RA is administered to these animals as adults, lung architecture and the surface area per unit of body weight are completely restored to normal. This remarkable effect may be because RA is required during normal alveolar development and administering RA re-awakens gene cascades used during development. We provide evidence that RA is required during alveologenesis in the mouse by showing that the levels of the retinoid binding proteins, the RA receptors and two RA synthesizing enzymes peak postnatally. Furthermore, an inhibitor of RA synthesis, disulphiram, disrupts alveologenesis. We also show that RA is required throughout life for the maintenance of lung alveoli because when rats are deprived of dietary retinol they lose alveoli and show the features of emphysema. Alveolar regeneration with RA may therefore be an important novel therapeutic approach to the treatment of respiratory diseases characterized by a reduced gas-exchanging surface area such as bronchopulmonary dysplasia and emphysema for which there are currently no treatments.     

Retinoic acid in the development, regeneration and maintenance of the nervous system

Retinoic acid (RA) is involved in the induction of neural differentiation, motor axon outgrowth and neural patterning. Like other developmental molecules, RA continues to play a role after development has been completed. Elevated RA signalling in the adult triggers axon outgrowth and, consequently, nerve regeneration. RA is also involved in the maintenance of the differentiated state of adult neurons, and disruption of RA signalling in the adult leads to the degeneration of motor neurons (motor neuron disease), the development of Alzheimer's disease and, possibly, the development of Parkinson's disease. The data described here strongly suggest that RA could be used as a therapeutic molecule for the induction of axon regeneration and the treatment of neurodegeneration.     

Effects of low frequency vibrations on the human spine

There is a general agreement in literature about effects of low frequency vibrations on spine in tractor drivers. Tractor drivers are exposed to noxious vibrations transmitted mostly by the seat. Spine generally presents a picture of degenerative lesions with higher incidence than in control groups. A statistical relation to the precocity of tractor driving can be shown.     

Dynamics within mutualism and the maintenance of diversity: inference from a model of interguild frequency dependence

Numerical models have suggested that the dynamics within mutualisms are not important for the maintenance of diversity. In this study it is demonstrated that the dynamics within mutualism can contribute to the maintenance of diversity within its participants, using a general model of frequency dependence between two mutualistically interacting guilds. Specifically, it is demonstrated that while mutualisms may exhibit positive feedback in density, there may be a negative feedback within a mutualism as a result of the change in composition within the interacting guild. Such a negative feedback results from an asymmetry in the delivery of benefit between participants of the mutualism that generates a negative interguild frequency dependence. This dynamic contributes to the maintenance of diversity within the interacting guilds. Conditions are identified for the maintenance of diversity and the maximization of benefit from mutualism within the context of the model. The utility of these conditions for testing hypotheses using data from the mutualistic interaction between plants and mycorrhizal fungi is then demonstrated.     

Effects of UV-irradiation on the SCE frequency in human lymphocyte cultures

UV-irradiation (254 nm) was found to induce a smaller increase of SCE in human lymphocytes than in human fibroblasts and CHO cells. The UV-induced SCE frequency in human lymphocytes was not influenced by the duration between irradiation and the subsequent S-phase. UV-irradiated lymphocytes showed a slightly more than additive response to the SCE-inducing effect of HN2 and acetaldehyde in comparison with non-irradiated cells. The UV-induced SCE frequency was similar in lymphocyte cultures containing 20 and 100 microM of BrdUrd. The results suggest that human lymphocytes are relatively insensitive to the SCE-inducing effect of UV-irradiation, and that SCE-inducing damage caused by UV is not removed during the G1 phase in these cells.     

Effects of in-season strength maintenance training frequency in professional soccer players

The aim of the present study was to examine the effect of in-season strength maintenance training frequency on strength, jump height, and 40-m sprint performance in professional soccer players. The players performed the same strength training program twice a week during a 10-week preparatory period. In-season, one group of players performed 1 strength maintenance training session per week (group 2 + 1; n = 7), whereas the other group performed 1 session every second week (group 2 + 0.5; n = 7). Only the strength training frequency during the in-season differed between the groups, whereas the exercise, sets and number of repetition maximum as well as soccer sessions were similar in the 2 groups. The preseason strength training resulted in an increased strength, sprint, and jump height (p < 0.05). During the first 12 weeks of the in-season, the initial gain in strength and 40-m sprint performance was maintained in group 2 + 1, whereas both strength and sprint performance were reduced in group 2 + 0.5 (p < 0.05). There was no statistical significant change in jump height in any of the 2 groups during the first 12 weeks of the in-season. In conclusion, performing 1 weekly strength maintenance session during the first 12 weeks of the in-season allowed professional soccer players to maintain the improved strength, sprint, and jump performance achieved during a preceding 10-week preparatory period. On the other hand, performing only 1 strength maintenance session every second week during the in-season resulted in reduced leg strength and 40-m sprint performance. The practical recommendation from the present study is that during a 12-week period, 1 strength maintenance session per week may be sufficient to maintain initial gain in strength and sprint performance achieved during a preceding preparatory period.     

The effect of levofloxacin concentration on the development and maintenance of antibiotic-resistant clones of Escherichia coli in chemostat culture

A levofloxacin-sensitive strain of Escherichia coli (broth MIC: 0.0625 mg l⁻¹) was grown in carbon-limited chemostat culture for 316 h (D=0.294 h⁻¹). Hyperresistant strains isolated after 58 and 91 generations of culture retained a 16- to 47-fold increase in tolerance to levofloxacin during antibiotic-free serial batch and continuous culture (20 generations, glucose-limited, D=0.2 h⁻¹). Isolates differed from the original strain in their maximum growth rates in the presence and absence of subinhibitory levels of levofloxacin, protein-banding profiles, and resistance to a range of antibiotics. Competition between resistant isolates and the original sensitive strain was studied in glucose-limited chemostat cultures (D=0.2 h⁻¹). At levofloxacin concentrations less than 0.03 mg l⁻¹, the sensitive strain outcompeted resistant isolates and displaced them from the culture, whereas the reverse was true at higher concentrations. These results have clinical and environmental implications for those administering levofloxacin. Journal of Industrial Microbiology & Biotechnology (2002) 29, 155–162 doi:10.1038/sj.jim.7000295 Received 26 September 2001/ Accepted in revised form 13 June 2002     

Effects of cholinergic stimulation on human esophageal peristalsis.

The effects of cholinergic stimulation on esophageal peristalsis were studied in normal subjects. An intraesophageal transducer assembly was used to measure the dynamics of esophageal peristalsis before and after edrophonium chloride, 80 mug/kg intravenously. Following endrophonium, there was a marked increase in amplitude of esophageal persistalsis associated with a significant reduction in velocity of esophageal peristalsis and a significant increase in width and time of appearance of the contraction wave following a swallow. Graded doses of endrophonium all resulted in significant increases in peristaltic amplitude with the maximal response occurring at doses of 80 and 160 mug/kg. Similar results were obtained with a more direct-acting cholinergic agent, bethanechol, 80 mug/kg subcutaneously. The relevance of these results as an indication of the importance of cholinergic innervation in regulating esophageal motility are discussed.     

Site-specific amino acid frequency, fitness and the mutational landscape model of adaptation in human immunodeficiency virus type 1

Analysis of the intensely studied HIV-1 gp120 V3 protein region reveals that the among-population mean site-specific frequency of an amino acid is a measure of its relative marginal fitness. This surprising result may arise if populations are displaced from mutation-selection equilibrium by fluctuating selection and if the probability of fixation of a beneficial amino acid is proportional to its selection coefficient.     

Effects of TRH on gastric acid secretion: A model for human study

The possible effects of TRH administration on different parameters of gastric function were studied in 10 patients with different gastrointestinal complaints. Basal (BAO) and pentagastrin stimulated (6 μg pentagastrin/kg bw sc) maximal (MAO) acid output were determined and serum levels of TSH, total and free thyroxine (T4 and FT4), triiodothyronine (T3) were measured. After determinations of BAO and MAO and the hormones indicated above, one group of patients received a TRH injection (0.2 mg protirelin) intravenously. The second group of patients was injected with atropine (atropinum sulfuricum, 1 mg, iv). At different times following the injections in both groups of patients BAO, MAO and serum levels of TSH, total and free T4, T3, gastrin were determined. Injection of TRH resulted in an increase in TSH and with some delay in thyroxine and gastric acid levels. Atropine treatment was followed by a decrease in gastric acid secretion and a small decrease in TSH and no changes in the values of the other studied hormones. The results suggest a complex interrelationship between TRH, vagal system and pentagastrin-dependent gastric acid secretion operating in human subjects.     

Individual and combined effects of ph and lactic acid concentration on Listeria innocua inactivation: development of a predictive model and assessment of experimental variability

In food technology, organic acids (e.g., lactic acid, acetic acid, and citric acid) are popular preservatives. The purpose of this study was to separate the individual effects of the influencing factors pH and undissociated lactic acid on Listeria innocua inactivation. Therefore, the inactivation process was investigated under controlled, initial conditions of pH (pH0) and undissociated lactic acid ([LaH]0). The resulting inactivation curves consisted of a (sometimes negligible) shoulder period followed by a descent phase. In a few cases, a tailing phase was observed. Depending on the conditions, the descent phase contained one or two log-linear parts or had a convex or concave shape. In addition, the inactivation process was characterized by a certain variability, dependent on the severity of the conditions. Furthermore, in the neighborhood of the growth/no growth interface sometimes contradictory observations occurred. Overall, the individual effects of the influencing factors pH and undissociated lactic acid could clearly be distinguished and were also apparent based on fluorescence microscopy. Appropriate model types were developed and enabled prediction of which conditions of pH0 and [LaH]0 are necessary to obtain a predetermined inactivation (number of decimal reductions) within a predetermined time range.     

Optimizing the concentration and bolus of a drug delivered by continuous infusion

We consider treatment regimes in which an agent is administered continuously at a specified concentration until either a response is achieved or a predetermined maximum infusion time is reached. Response is an event defined to characterize therapeutic efficacy. A portion of the maximum planned total amount administered is given as an initial bolus. For such regimes, the amount of the agent received by the patient depends on the time to response. An additional complication when response is evaluated periodically rather than continuously is that the response time is interval censored. We address the problem of designing a clinical trial in which such response time data and a binary indicator of toxicity are used together to jointly optimize the concentration and the size of the bolus. We propose a sequentially adaptive Bayesian design that chooses the optimal treatment for successive patients by maximizing the posterior mean utility of the joint efficacy-toxicity outcome. The methodology is illustrated by a trial in which tissue plasminogen activator is infused intraarterially as rapid treatment for acute ischemic stroke.