Prolongation of the ejaculation latency in the male rat by thioridazine and chlorimipramine

Thioridazine (3 mg/kg) and chlorimipramine (1.5–6.0 mg/kg) prolonged the ejaculation latency and increased the number of mounts but did not change the number of intromissions preceding ejaculation. Blockade of peripheral and central noradrenaline receptors by phentolamine and phenoxybenzamine respectively resulted in a suppression of all aspects of the sexual behavior with increasing doses. dl-5-HTP (25–100 mg/kg) in combination with an inhibitor of peripheral 5-HTP decarboxylase (benserazide, 25 mg/kg) produced, like chlorimipramine and thioridazine, a prolongation of ejaculation latency and an increase in the number of mounts preceding ejaculation. Selective inhibition of 5-HT reuptake however, by zimelidine (0–20 mg/kg) or alaproclate (0–20 mg/kg) did not affect the mating behavior. At higher doses of these drugs some animals failed to initiate sexual activities. There was an increase in the postejaculatory interval but no change in the ejaculatory latency.It is concluded that the prolonged ejaculation latencies observed following treatment with thioridazine or chlorimipramine is not due to a blockade of central or peripheral adrenergic -receptors.     

Acute effects of rapamycin on glomerular dynamics: a micropuncture study in the rat

The acute effects of cyclosporin (CsA, 20 mg(kg i.v.) and rapamycin (RAPA, 5 mg(kg i.v.) on glomerular dynamics were separately investigated by renal micropuncture in two groups of intact rats (group CsA and RAPA, respectively) and compared with vehicle-treated rats, used as controls (group CON). Left kidney glomerular filtration rate (GFR) was decreased by CSA (-35% vs. CON, P<0.05), but was not affected by RAPA (-14% vs. CON, NS), whereas the single-nephron GFR (SNGFR) was significantly decreased in both groups (-40% in CsA, P<0.01 and -26% in RAPA, P<0.05 vs. CON). In both groups glomerular plasma flow (GPF) was significantly reduced vs. CON (CsA: -48%, and RAPA: -25%) due to the increase in both afferent (Ra) and efferent (Re) glomerular resistances: group CSA showed a prevalent rise in Re (+98% vs. CON, P<0.001) than in Ra (+66%, P<0.001); in group RAPA the increment was modest and similar in Ra and Re (+33 and +32%, respectively, NS versus CON). A further group of rats was studied in which L-Arginine (ARG), the precursor of nitric oxide (NO), was administered (2.5 mg/Kg/min iv) with RAPA (group ARG). ARG limited the rise in Ra and Re, thereby preserving GPF; nevertheless, SNGFR remained low (-26% vs. CON, P<0.05) due to the decrease in the effective filtration pressure (-26% vs. CON). These data demonstrate that: (1) CsA is nephrotoxic at immunosuppressive doses; (2) RAPA, even at huge doses, has marginal effects on renal and glomerular dynamics; (3) the ARG-NO pathway is only partially involved in the vasoconstriction of superficial nephrons after RAPA administration.     

Intensity modulated radiation therapy with electrons using algorithm based energy/range selection methods.

BACKGROUND AND PURPOSE: In recent years photon intensity modulated radiation therapy (IMRT) has gained attention due to its ability to improve conformity of dose distributions. A potential advantage of electron-IMRT is that the dose fall off in the depth dose curve makes it possible to modulate the dose distribution in the direction of the beam by selecting different electron energies. This paper examines the use of a computer based energy selection in combination with the IMRT technique to optimise the electron dose distribution. MATERIALS AND METHODS: One centimetre square electron beamlets ranging from 2.5 to 50 MeV were pre-calculated in water using Monte Carlo methods. A modified IMRT optimisation tool was then used to find an optimum mix of electron energies and intensities. The main principles used are illustrated in some simple geometries and tested on two clinical cases of post-operated ca. mam. RESULTS: It is clearly illustrated that the energy optimisation procedure lowers the dose to lung and heart and makes the dose in the target more homogeneous. Increasing the energy at steep gradients compensates for lack of target coverage at beam edges and steep gradients. Comparison with a clinically acceptable four segment plan indicates the advantage of the used electron IMRT technique. CONCLUSIONS: Using an intensity optimised mix of computer selected electron energies has the potential to improve electron treatments for mastectomy patients with good target coverage and reduced dose to normal tissue such as lung and heart.     

Cholecystectomy: costs and health-related quality of life: a comparison of two techniques.

BACKGROUND: Outcomes of previous health economic evaluations comparing minilaparotomy cholecystectomy and laparoscopic cholecystectomy have been inconsistent. OBJECTIVE: To compare costs for minilaparotomy cholecystectomy and laparoscopic cholecystectomy and to study changes in quality of life induced by these operations. DESIGN: Single-blind, randomized controlled trial, run from 1 March 1997 to 30 April 1999. SETTING: One university hospital and four non-university hospitals in Sweden. MAIN MEASURE: : Cost and perceived health estimation according to the global quality of life instrument EuroQol-5D. RESULTS: Of 1719 cholecystectomy patients at five centres, 724 entered the trial and were treated with minilaparotomy cholecystectomy or laparoscopic cholecystectomy, 362 in each group. Total health care costs were less for minilaparotomy cholecystectomy than for laparoscopic cholecystectomy (median values US$2428 for minilaparotomy cholecystectomy versus US$2613 or US$3006 for laparoscopic cholecystectomy with 100 operations per year and reusable trocars or 50 operations per year and disposable trocars, respectively). There was no significant difference in total costs (including costs due to loss of production) between minilaparotomy cholecystectomy and laparoscopic cholecystectomy with 100 operations per year and reusable trocars in laparoscopic cholecystectomy (US$3731 versus US$3649, respectively). However, in calculations assuming 50 operations per year and disposable trocars in laparoscopic cholecystectomy, this technique was more expensive than minilaparotomy cholecystectomy (US$4042 versus US$3731). Health-related quality of life was slightly but significantly lower for the minilaparotomy cholecystectomy group 1 week after surgery. One month and 1 year postoperatively no difference between the randomized groups was found. CONCLUSION: Total costs did not differ between minilaparotomy cholecystectomy and laparoscopic cholecystectomy with high-volume surgery and disposable trocars, whereas laparoscopic cholecystectomy was more expensive with fewer operations and disposable trocars. The gain in health-related quality of life with laparoscopic cholecystectomy compared with minilaparotomy cholecystectomy was small and of limited duration.     

Wound ventilation with ultraclean air for prevention of direct airborne contamination during surgery.

BACKGROUND AND OBJECTIVE: Despite the novelties in operating room ventilation, airborne bacteria remain an important source of surgical wound contamination. An ultraclean airflow from the ceiling downward may convey airborne particles from the surgical team into the wound, thus increasing the risk of infection. Therefore, similar ventilation from the wound upward should be considered. We investigated the effect of wound ventilation on the concentration of airborne particles in a wound model during simulated surgery. DESIGN: Randomized experimental study simulating surgery with a wound cavity model. SETTING: An operating room of a university hospital ventilated with ultraclean air directed downward. INTERVENTIONS: Particles 5 microm and larger were counted with and without a 5-cm deep cavity and with and without the insufflation of ultraclean air. RESULTS: With the surgeon standing upright, no airborne particles could be detected in the wound model. In contrast, during simulated operations, the median number of particles per 0.1 cu ft reached 18 (25th and 75th percentiles, 12 and 22.25) in the model with a cavity and 15.5 (25th and 75th percentiles, 14 and 21.5) without. With a cavity, wound ventilation markedly reduced the median number of particles to 1 (range, 0 to 1.25; P < .001). CONCLUSIONS: To protect a surgical wound against direct airborne contamination, air should be directed away from the wound rather than toward it. This study provides supportive evidence to earlier studies that operating room ventilation with ultraclean air is imperfect during surgical activity and that wound ventilation may be a simple complement. Further clinical trials are needed.     

The effect of extracts of Searsia species on epileptiform activity in slices of the mouse cerebral cortex

ETHNOPHARMACOLOGICAL RELEVANCE: Searsia dentata and Searsia pyroides are used in traditional South African medicine to treat convulsions and epilepsy. Previous studies have demonstrated that extracts of these plants comprise compounds that bind to the flumazenil-sensitive site on the GABA(A) receptor. However, their use as anticonvulsant medicinal plants cannot be adequately explained by these findings. AIMS: The aim of this study was to examine the possible involvement of the glutamatergic system of extracts from the plants. MATERIALS AND METHODS: The mouse cortical wedge preparation was used for functional characterization of the extracts. The affinity towards the NMDA and the AMPA receptor was investigated using classical [(3)H]-GP39653 and [(3)H]-AMPA binding assays, respectively. RESULTS: The extracts of Searsia dentata and Searsia pyroides inhibited the spontaneous epileptiform discharges in mouse cerebral cortical slices with ED(50) of 0.62 and 1.67mg dry extract/mL, respectively. Both extracts displaced [(3)H]-GP39653 binding and significantly inhibited the NMDA-induced response during co-administration in cortical slices. CONCLUSION: In this study, the NMDA receptor antagonistic effect of the crude ethanolic extracts of these two South African medicinal plants was demonstrated.     

Physicochemical classification of organisms

The hypervariable residues that compose the major part of proteins’ surfaces are generally considered outside evolutionary control. Yet, these “nonconserved” residues determine the outcome of stochastic encounters in crowded cells. It has recently become apparent that these encounters are not as random as one might imagine, but carefully orchestrated by the intracellular electrostatics to optimize protein diffusion, interactivity, and partner search. The most influential factor here is the protein surface-charge density, which takes different optimal values across organisms with different intracellular conditions. In this study, we examine how far the net-charge density and other physicochemical properties of proteomes will take us in terms of distinguishing organisms in general. The results show that these global proteome properties not only follow the established taxonomical hierarchy, but also provide clues to functional adaptation. In many cases, the proteome–property divergence is even resolved at species level. Accordingly, the variable parts of the genes are not as free to drift as they seem in sequence alignment, but present a complementary tool for functional, taxonomic, and evolutionary assignment.

Recent studies of live cells reveal that cytosolic crowding imposes some unique functional challenges that have previously been unconsidered. Essentially, the cytosolic proteins are not just sterically obstructive, but also interact electrostatically with one another through repulsive and attractive forces (1). These diffusive interactions are commonly referred to as “quinary interactions” (2), and their effect on the proteins largely exceeds that predicted from simplistic hard-sphere crowding models (3). The most dramatic effect of altering the quinary interactions is observed for the protein motions. A protein that normally diffuses relatively freely in the cytosolic compartment can be changed to get stuck to the intracellular surrounding by a single surface mutation (4). The principal determinant behind this effect is the protein-surface charge (4, 5). To maintain the cytosolic components suitably fluid, most biological macromolecules, like proteins, nucleic acids, and membranes, carry repulsive net-negative charge, and complete loss of this repulsion will naturally promote aggregation and functional arrest (1). However, the role of the protein charge has turned out to be more subtle than that: It modulates in detail the functional protein–protein encounters (1, 5–8). Because the strength and duration of these dynamic encounters need to be kept within certain limits for the cell to function optimally, the protein-charge decoration itself has been suggested to be under biological control (1, 4, 9–11). This very idea challenges the notion that the composition of the variable protein surfaces drifts freely and adds another dimension to protein evolution and organism fitness (12). Attention then shifts from the relatively small and highly conserved binding interfaces and active sites visible in crystal structures to the least-conserved parts of the protein surfaces exposed to the cytosolic surrounding. Proteome-wide studies of Escherichia coli confirm that there is indeed a systematic bias toward negative charge density and show also that not any negative charge density is acceptable: Proteins distribute around a moderately negative value, away from which few deviations are observed (1, 13) (Fig. 1). Similar results are obtained from measurements of isoelectric points, leading to the conclusion that the majority of soluble proteins are acidic and that the degree of this acidity varies across organisms (14–17). Classical examples are the proteomes of some halophilic archaea, with net-charge densities 10 times more negative than observed for most other organisms (18–23). Together, these findings show that the variable protein surfaces contain previously unrecognized evolutionary cues, which can be captured in terms of specific sets of physicochemical properties. The question is then whether organism identity can be deduced from physicochemical observables alone. To explore this possibility, we map here the divergence of proteome properties across organisms against the established taxonomic classification and demonstrate that the resolving power is indeed remarkably high. The results show that distinct clustering and separations of proteome properties not only follow taxonomic divisions, but also reflect their adaptation to various biotopes and functional specializations. Given that the data cover ∼18,000 organisms in all kingdoms of life, we focus below on a few representative examples of divergent optimizations and refer the specialist readers to our proteome explorer website for more specific analysis (https://proteome-explorer.herokuapp.com/).Open in a separate windowFig. 1.Outline of approach. (A) The UniProt Proteomes of Archaea, Bacteria, and Eukaryota were sampled and the physicochemical properties of each of their proteins calculated (Methods). From this dataset, containing ∼10,000 proteomes, any species can be further analyzed with respect to its detailed protein properties. (B) The distributions of protein MW and protein NCD for the proteomes of H. salinarum, E. coli, and H. sapiens. (C) Plot of the average MW and NCD values, derived from the protein distributions in B. This two-dimensional representation shows clear separation of the three species. Corresponding plots can be obtained for all UniProt Proteomes and, similarly, for all NCBI Assemblies (Methods; SI Appendix, Fig. S1; and Fig. 2). (D–F) Generally, the protein-surface charge of individual proteins follows closely that of the proteome average (SI Appendix, Fig. S19). Shown are surface charge potentials in vacuum (red for negative and blue for positive) of ribonucleotide reductase orthologs in H. salinarum (UniProt {"type":"entrez-protein","attrs":{"text":"Q9HMU3","term_id":"74568776","term_text":"Q9HMU3"}}Q9HMU3 modeled on PDB 5im3), E. coli (PDB 2xap), and H. sapiens (PDB 3hnc).     

Management of respiratory complications and rehabilitation in individuals with muscular dystrophies: 1st Consensus Conference report from UILDM - Italian Muscular Dystrophy Association (Milan,January 25-26, 2019)

Respiratory complications are common in the patient with muscular dystrophy. The periodic clinical and instrumental respiratory evaluation is extremely important. Despite the presence in the literature of updated guidelines, patient associations often report lack of knowledge of these pathologies, particularly in peripheral hospitals. The purpose of this work, inspired by the Italian Muscular Dystrophy Association (UILDM) is to improve management of respiratory problems necessary for the management of these patients complex. To this end, the main items that the specialist can meet in the follow-up of these pathologies have been analyzed and discussed, among which the respiratory basal evaluation, the criteria of adaptation to non-invasive ventilation, management of bronchial secretions, situations of respiratory emergency, indications for tracheostomy and the subject of advance directives of treatment (DAT).Key words: respiratory failure, muscular dystrophy, cough efficacy, spirometry, polygraphy, non-invasive ventilation, arterial blood gases, cough machine, invasive ventilation, tracheostomy, mechanical ventilation