Amphiphilic Antimony(V) Complexes for Oral Treatment of Visceral Leishmaniasis

The need for daily parenteral administration is an important limitation in the clinical use of pentavalent antimonial drugs against leishmaniasis. In this study, amphiphilic antimony(V) complexes were prepared from alkylmethylglucamides (L8 and L10, with carbon chain lengths of 8 and 10, respectively), and their potential for the oral treatment of visceral leishmaniasis (VL) was evaluated. Complexes of Sb and ligand at 1:3 (SbL8 and SbL10) were obtained from the reaction of antimony(V) with L8 and L10, as evidenced by elemental and electrospray ionization-tandem mass spectrometry (ESI-MS) analyses. Fluorescence probing of hydrophobic environment and negative-staining transmission electron microscopy showed that SbL8 forms kinetically stabilized nanoassemblies in water. Pharmacokinetic studies with mice in which the compound was administered by the oral route at 200 mg of Sb/kg of body weight indicated that the SbL8 complex promoted greater and more sustained Sb levels in serum and liver than the levels obtained for the conventional antimonial drug meglumine antimoniate (Glucantime [Glu]). The efficacy of SbL8 and SbL10 administered by the oral route was evaluated in BALB/c mice infected with Leishmania infantum after a daily dose of 200 mg of Sb/kg for 20 days. Both complexes promoted significant reduction in the liver and spleen parasite burdens in relation to those in the saline-treated control group. The extent of parasite suppression (>99.96%) was similar to that achieved after Glu given intraperitoneally at 80 mg of Sb/kg/day. As expected, there was no significant reduction in the parasitic load in the group treated orally with Glu at 200 mg of Sb/(kg day). In conclusion, amphiphilic antimony(V) complexes emerge as an innovative and promising strategy for the oral treatment of VL.     

Pro-epileptic effect of alfentanil in rats subjected to pilocarpine-induced chronic epilepsy

Pharmacological induction of epileptiform activity is a complementary method to study the epileptogenic area in drug-resistant epileptic patients. Among the different activation methods, fentanyl derivatives (e.g. alfentanil) provide one of the most efficient tools in triggering epileptiform abnormalities in surgical candidates. In this study, we tested the pro-epileptic effect of different concentrations of alfentanil in hippocampal slices obtained from control and pilocarpine-treated chronic epileptic rats. The pro-convulsant action of alfentanil was also studied in control and pilocarpine-treated epileptic rats implanted with subdural and hippocampal electrodes for electroencephalographic recordings. In 90% of slices from control animals, application of alfentanil (0.1-5 microM) induced a significant enhancement in amplitude and number of population spikes recorded in the hippocampal CA1 region. In contrast, alfentanil produced a significant reduction in the amplitude of population spikes in slices from pilocarpine-treated epileptic rats. These changes were accompanied by a significant increase in the number of population spikes in the form of epileptiform multispike responses of epileptic slices. Naloxone (20 microM) antagonized the effect of alfentanil in both control and epileptic slices, reducing the number of population spikes in slices from epileptic rats. In control rats, alfentanil induced epileptiform abnormalities in the hippocampal and cortical electroencephalographic recordings but only at concentrations higher than 200 microg/kg (e.g. 350 microg/kg). Lower doses of alfentanil (25 microg/kg) elicited epileptiform abnormalities only in chronic epileptic rats. The potent action of a minimal dose of alfentanil in inducing epileptiform activity suggests an enhancement of the pro-convulsant action of mu-receptor opioids in chronic temporal lobe epilepsy.     

Estrogen and its receptors in efferent ductules and epididymis

Estrogens play key roles in the development and maintenance of male reproductive function and fertility. In this review, we briefly describe the localization and function of estrogen receptors ESR1 and ESR2 (also known as ERα and ERβ, respectively) and the expression of G protein-coupled estrogen receptor-1 (GPER, formerly known as GPR30) in efferent ductules and epididymis. The efferent ductules present the highest levels of ESR1 and ESR2 in the male reproductive system, and represent a major target of estrogen action. In efferent ductules, ESR1 has a crucial role in the regulation of fluid reabsorption, and in the epididymis the receptor helps to maintain fluid osmolality and pH. ESR1 expression in the epididymal epithelium shows considerable variation among species, but differences in laboratory techniques may also contribute to this variation. Here we report that Esr1 mRNA and protein are higher in corpus than in other regions of the rat epididymis. The mRNA level for Gper was also higher in corpus. Although ESR1 is expressed constitutively in efferent ductules and down-regulated by estrogen, in the epididymis, both testosterone (T) and estradiol (E2) may regulate its expression. T and E2 are, respectively, higher and lower in the corpus than in the initial segment/caput and cauda regions. It is important to determine the expression of GPER, ESR1, androgen receptor, and their respective cofactors in specific cell types of this tissue, as well as the intracellular signaling pathways involved in efferent ductules and epididymis. These studies will help to explain the consequences of exposures to environmental endocrine disruptors and provide potential targets for the development of a male contraceptive.     

Effects of low-level laser therapy on expression of TNF-α and TGF-β in skeletal muscle during the repair process

The aim of the present study was to determine the effect of low-level laser therapy (LLLT) on the expression of TNF-α and TGF-β in the tibialis anterior muscle of rats following cryoinjury. Muscle regeneration involves cell proliferation, migration and differentiation and is regulated by growth factors and cytokines. A growing body of evidence suggests that LLLT promotes skeletal muscle regeneration by reducing the duration of acute inflammation and accelerating tissue repair. Adult male Wistar rats (n = 35) were randomly divided into three groups: control group (no lesion, untreated, n = 5), cryoinjury without LLLT group (n = 15), and cryoinjury with LLLT group (n = 15). The injured region was irradiated three times a week using an AlGaInP laser (660 nm; beam spot 0.04 cm², output power 20 mW, power density 500 mW/cm², energy density 5 J/cm², exposure time 10 s). Muscle remodeling was evaluated at 1, 7 and 14 days (long-term) following injury. The muscles were removed and total RNA was isolated using TRIzol reagent and cDNA synthesis. Real-time polymerase chain reactions were performed using TNF-α and TGF-β primers; GAPDH was used to normalize the data. LLLT caused a decrease in TNF-α mRNA expression at 1 and 7 days following injury and in TGF-β mRNA expression at 7 days following cryoinjury in comparison to the control group. LLLT modulated cytokine expression during short-term muscle remodeling, inducing a decrease in TNF-α and TGF-β.     

Laparoendoscopic single-site (LESS) sacrocolpopexy: feasibility and efficacy of knotless procedure performed with conventional instruments

The aim of this paper was to report a case of a patient with stage IV vaginal vault prolapse treated by laparoendoscopic single-site (LESS) sacrocolpopexy using an Alexis retractor and a surgical glove attached to three trocars through a 3.5-cm umbilical incision. Only conventional laparoscopic instruments were used for intrabdominal dissection of vagina and peritoneum. The mesh was fixed to the vaginal fornix and to the sacral periosteum from the promontory using running sutures hold in the extremities by polymer clips. The posterior peritoneum was closed over the mesh. LESS sacrocolpopexy performed with conventional instruments is a difficult but feasible and efficient technique to treat vaginal vault prolapse that respects the principles of conventional laparoscopic or open repairs. Alexis retractor associated with knotless sutures are technical options that simplify LESS reconstructive surgical maneuvers.     

Elastic stable intramedullary nailing for displaced proximal humeral fractures in older children

Purpose To demonstrate the effectiveness of intramedullary fixation of severely displaced proximal humeral physeal fractures in skeletally immature children using the elastic stable intramedullary nail (ESIN). Methods Retrospective recruitment of 14 patients aged 10–15-years old with severely displaced proximal humeral physeal fractures between 1999 and 2004 in a single regional specialist paediatric orthopaedic hospital. The fractures were graded using the Neer classification; severe displacement constituted Neer II–IV or displacement >1 cm and angulation >45°. Patients were followed up and assessed using the Disabilities of the Arm, Shoulder and Hand score (DASH) and the Neer Shoulder score. Radiographs were assessed for deformity. Subjective satisfaction was assessed. Results Fourteen patients with mean follow-up of 30 months (12–66 m) from surgery. All fractures were radiologically united at a median time of eight weeks (7–10 weeks). At follow-up, Neer Shoulder mean score was 96.79 (range 83–100) and DASH mean score 2.26 (0–7.5). Subjectively 71% were very satisfied and 29% were satisfied. Conclusions We commend stabilisation using ESIN in the management of the displaced proximal humeral physeal fracture in older children, once reduction of the fracture has been achieved by either closed or open means. ESIN is safe and allows early return to pre-injury function.