The effects of axotomy on neurons and satellite glial cells in mouse trigeminal ganglion

Damage to peripheral nerves induces ectopic firing in sensory neurons, which can contribute to neuropathic pain. As most of the information on this topic is on dorsal root ganglia we decided to examine the influence of infra-orbital nerve section on cells of murine trigeminal ganglia. We characterized the electrophysiological properties of neurons with intracellular electrodes. Changes in the coupling of satellite glial cells (SGCs) were monitored by intracelluar injection of the fluorescent dye Lucifer yellow. Electrophysiology of SGCs was studied with the patch-clamp technique. Six to eight days after axotomy, the percentage of neurons that fire spontaneously increased from 1.6 to 12.8%, the membrane depolarized from -51.1 to -45.5 mV, the percentage of cells with spontaneous potential oscillations increased from 19 to 37%, the membrane input resistance decreased from 44.4 to 39.5 MOmega, and the threshold for firing an action potential decreased from 0.61 to 0.42 nA. These changes are consistent with increased neuronal excitability. SGCs were mutually coupled around a given neuron in 21% of the cases, and to SGCs around neighboring neurons in only 4.8% of the cases. After axotomy these values increased to 37.1 and 25.8%, respectively. After axotomy the membrane resistance of SGCs decreased from 101 MOmega in controls to 40 MOmega, possibly due to increased coupling among these cells. We conclude that axotomy affects both neurons and SGCs in the trigeminal ganglion. The increased neuronal excitability and ectopic firing may play a major role in neuropathic pain.     

Interaction pharmacokinetics of pegylated liposomal doxorubicin (Caelyx) on coadministration with paclitaxel or docetaxel

Purpose To investigate the pharmacokinetics of polyethylene glycol-coated liposomal doxorubicin (PLD, Caelyx) when given as a single agent and in combination with the taxanes paclitaxel or docetaxel in humans.Methods The plasma kinetics of PLD were studied in 19 cancer patients treated with PLD every 4 weeks combined with either paclitaxel (on a weekly basis in seven and as a single infusion in three patients) or docetaxel (weekly in seven and as a single infusion in two). Plasma concentrations of PLD were quantified in two sets of samples per patient to compare the same pharmacokinetic parameters in each subject when treated with single-agent PLD and again with the combination. Total doxorubicin concentrations in plasma were quantified by HPLC. Pharmacokinetics were evaluated by noncompartmental analysis and the data obtained were compared for differences by a matched-pairs nonparametric test.Results Coadministration of paclitaxel produced a median/mean 54/80% increase in PLD AUC_inf (95% confidence interval 23% to 136%, P=0.002). The observed increase was consistent among all subjects. PLD clearance was also decelerated in the presence of paclitaxel (P=0.013) while other pharmacokinetic parameters were affected modestly. A small increase in the AUC of PLD was observed in the docetaxel/PLD arm (mean increase 12%, P=0.039) while PLD clearance decreased marginally and other pharmacokinetic parameters remained unaffected. AUC extrapolated to infinity was below 8% in both arms.Conclusions This study showed the presence of a pharmacokinetic interaction that led to higher plasma concentrations of PLD when combined with paclitaxel and to a minor extent when combined with docetaxel. This pharmacokinetic information may be of value when planning combination therapies of PLD with taxanes.     

Efficacy, safety, and tolerability of sertraline in patients with late-life depression and comorbid medical illness

OBJECTIVES: To report on the efficacy, safety, and tolerability of sertraline in the treatment of elderly depres-sed patients with and without comorbid medical illness. SETTING: Multicenter. DESIGN: Randomized, double-blind, placebo-controlled study. PARTICIPANTS: A total of 752 patients aged 60 and older with diagnosis of major depressive disorder according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis. MEASUREMENTS: Outcome measures included the 17-item Hamilton Depression Scale (HAMD); the Clinical Global Depression-Severity/Improvement (CGI-S/CGI-I); efficacy and safety/adverse event assessments; Quality of Life, Enjoyment, and Satisfaction Questionnaire; and the Medical Outcomes Study 36-Item Short-Form Health Status Survey. RESULTS: In the overall sample, sertraline was superior to placebo on all three primary outcome measures, HAMD, and overall clinical severity and change (CGI-S/CGI-I). Furthermore, therapeutic response to sertraline was comparable in those with or without medical comorbidity, and there were no treatment-by-comorbidity group interactions. Sertraline was also associated with a faster time to response than placebo in the comorbid group (P<.006). Sertraline-treated patients in the comorbid group had similar adverse events and discontinuations when compared to those in the noncomorbid group. CONCLUSION: Sertraline was efficacious in reducing depressive symptomatology, regardless of the presence of comorbid medical illness. Sertraline was safe and well tolerated by patients with or without medical illness.     

CD81-induced behavioural changes during chronic cocaine administration: in vivo gene delivery with regulatable lentivirus

CD81, a tetraspanin transmembrane protein involved in cell adhesion, is up-regulated in the mesolimbic dopaminergic pathway 24 h following acute administration of high doses of cocaine [Brenz-Verca et al., (2001) Mol. Cell. Neurosci., 17, 303-316]. Further evidence consecutive with this observation and based on microarray analysis are presented here. In addition, a regulatable lentivirus was developed bearing the rat CD81 gene under the control of a tetracycline inducible system. This lentivirus vector was stereotaxically injected into the ventral tegmental area (VTA) of two groups of animals, one fed water (expressing CD81) and the other Doxycycline solution (which down-regulates CD81 expression) and locomotor activity after chronic cocaine administration (10 mg/kg daily) was monitored. After 2 weeks, the groups were inverted, animals receiving water were placed on Doxycycline and the second group was placed on water. In all cases highly a significant increase (3.2-fold) in locomotor activity was observed in animals expressing CD81 in the VTA vs. animals placed on Doxycycline. Similar studies where CD81 was delivered into the nucleus accumbens (NAcc) resulted in significantly higher effects (30%), in accordance with microarray data and our previous reports, yielding a 4.2-fold increase in locomotor activity. No change was observed under similar conditions in control animals, which were injected a regulatable lentivirus expressing GFP. These findings suggest that CD81 expression in the mesolimbic dopaminergic pathway contributes to behavioural changes associated with cocaine sensitization. This study provides a powerful approach for evaluating a gene function in vivo in a single animal under various paradigms, even on gene candidates, which display small changes of expression.     

Long-term nutritional and digestive consequences of pelvic radiation

OBJECTIVE: To study long-term changes in nutritional status and gastrointestinal (GI) functions of 15 women previously treated with radiotherapy for gynecological cancer. Two years prior to this research, these patients had been assessed twice: before external radiotherapy and 5 weeks later, at the completion of the external dose (45-50 Gy). METHODS: Each patient was given complete clinical evaluation, consisting of dietary, physical activity and digestive symptoms questionnaires. Blood was drawn for routine clinical laboratory tests (hemoglobin, white blood cell count, creatinine, lipoproteins, glucose, total proteins, albumin, and C reactive protein). Body composition was assessed by classical anthropometric indicators and double beam X-ray absorptiometry (DEXA), while muscle strength was measured through a hand dynamometer. Resting energy expenditure (REE), obtained by indirect calorimetry, was subtracted from energy ingestion, derived from dietary records, to calculate energy balance. RESULTS: This third evaluation included fifteen patients. A significant increase in body mass index (BMI), % body fat and waist circumference were observed in comparison to earlier evaluations. The lean compartment decreased significantly, and REE descended in parallel. Meanwhile, total energy, fat and protein intake increased, compared to previous measurements. The changes in bowel habits observed during radiotherapy persisted at this third evaluation, with the exception of diarrhea, which was less reported. Abdominal bloating and rectal symptoms were the most prevalent complaints. CONCLUSIONS: After radiation treatment for gynecological cancer, patients gained more body fat than expected in Chilean women around menopause. In spite of high protein ingestion, the loss of fat-free mass observed during radiation treatment was not recovered along with weight increase. This is probably associated with infrequent physical activity, both during and after treatment, and hyperphagia.     

Do oral contraceptives improve vocal quality? Limited trial on low-dose formulations

OBJECTIVE: To evaluate the effect of low-dose monophasic oral contraceptives on female vocal quality. METHODS: Acoustic voice parameters of six women who use oral contraceptives and six women who do not were evaluated repeatedly during the menstrual cycle. Frequency and amplitude variations were measured using a computerized voice analysis program. Repeated-measures analysis of variance was performed to test differences between groups for each acoustic voice parameter. RESULTS: Vocal stability among the women who use oral contraceptives was significantly better than among those who did not use oral contraceptives (P <.05). Specifically, amplitude and frequency variations between successive vocal cycles were smaller in women using oral contraceptives in comparison with the control group (.24 dB versus.37 dB and.86% versus 1.27% for amplitude and frequency variations, respectively). CONCLUSION: Contrary to the reports of adverse effects that high-dose pills have on voice, low-dose oral contraceptives show a favorable influence on voice in young women.     

Ovarian response to gonadotropin stimulation in repeated IVF cycles after unilateral salpingectomy

Purpose : This study aimed to examine ovarian response to gonadotrpoin stimulation after repeated IVF treatment cycles in patients who underwent previous unilateral salpingectomy for tubal pregnancy. Methods : The study group included 26 patients who underwent unilateral salpingectomy for tubal pregnancy 1–9 years prior to starting IVF treatment. A control group of 52 patients with anatomically intact pelvis was treated during the same time period by ICSI. The two groups were matched for age, number of gonadotropin ampules, and length of stimulation. End point measurements included number of follicles, oocytes, and cleaved embryos in consecutive treatment cycles of each group. Results : There were 98 cycles in the study group and 154 cycles in the control group. The mean number of follicles, retrieved oocytes, and cleaved embryos were not different in the two groups, and no reductions in these parameters were noted up to 10 cycles of treatment. The mean number of follicles ipsilateral to the operated side was similar to the number of follicles of the contralateral ovary and was not different whether salpingectomy was by laparoscopy or laparotomy. Conclusions : Unilateral salpingectomy does not affect ipsilateral ovarian response to gonadotropin stimulation even after repeated IVF treatment cycles.     

Supplementing with beta-hydroxy-beta-methylbutyrate (HMB) to build and maintain muscle mass: a review

Beta-hydroxy-beta-methylbutyrate, more commonly referred to as HMB, is derived from the amino acid, leucine, and its keto acid, alpha-ketoisocaproate. In several studies combining HMB supplementation and resistance exercise, researchers have concluded that HMB may play an important role in reducing protein degradation and/or increasing recovery of damaged muscle cells. These actions could be advantageous to all individuals participating in exercise programs and improve the lives of many by overcoming weakness or frailty.