Sexual motivation is demasculinized, but not feminized, in prenatally stressed male rats

Sexual motivation and copulation in male rats are associated with dopamine release in the nucleus accumbens. Demasculinized copulatory behavior has been demonstrated in prenatally stressed adult male rats. We have previously reported that approximately 80% of prenatally stressed male rats do not exhibit copulation and that no significant changes in nucleus accumbens dopamine release are seen during exposure to estrous females. In the present study, we investigated whether prenatal stress affects sexual motivation in these animals as adults. Pregnant Wistar rats were subjected to immobilization stress for two hours daily from day 15-19 of gestation. The prenatally stressed male offspring at the age of 3 months were allowed contact with receptive female rats for a 30 min period per week for 10 weeks; then, between the age of 5 and 6 months, their sexual motivation and copulatory activity were measured. Sexual motivation was measured in terms of sexual partner preference. The number of visits and the duration of each visit to an estrous female (stimulus female) or to a sexually active male rat (stimulus male) were recorded. Compared with control males, prenatally stressed male rats showed a significantly lower number of visits and a shorter duration of each visit to stimulus females. Prenatally stressed males showed no preference for male or female stimulus rats in terms of the number of visits and the duration of each visit, whereas control rats showed a significantly higher number of visits and duration of visits to female stimulus rats than male stimulus rats. A significant decrease in copulatory activity was observed in the prenatally stressed male offspring compared with control male rats, with most of the prenatally stressed males failing to show copulation. In vivo microdialysis experiments were performed on the nucleus accumbens with concurrent observation of sexual behavior. The prenatally stressed rats that did not exhibit copulation showed no significant changes in nucleus accumbens dopamine release during exposure to a stimulus male behind a wire-mesh barrier and the amount of dopamine release remained at the basal levels during actual physical contact. These results, combined with those of our previous report, indicate that sexual motivation in prenatally stressed male rats is demasculinized, but not feminized.     

N-Methyl-D-aspartate receptor antagonist MK-801 attenuates morphine tolerance and associated glial fibrillary acid protein up-regulation: a proteomic approach

Background: It is well known that long-term morphine administration results in tolerance, which limits the clinical use of this drug in pain management.
Methods: Male Wistar rats were randomly assigned to receive one of four different infusions: morphine [15 μg/h, intrathecal (i.t.)], saline, MK-801 (5 μg/h, i.t.) plus morphine (15 μg/h, i.t.), or MK-801 (5 μg/h, i.t.) alone.
Results: Morphine infusion induced a maximal antinociceptive effect on day 1 and tolerance on day 3, and the maximal anti-receptive tolerance was observed on day 5. Co-infusing MK-801 with morphine attenuated morphine's anti-receptive tolerance. Two-dimensional gel electrophoretic analysis of spinal proteins revealed that eight protein spots were up-regulated in morphine-tolerant rats, and that they were significantly inhibited by MK-801 co-infusion. Among the up-regulated proteins, glial fibrillary acid protein (GFAP), a glial-specific maker, was identified by mass spectrometry. This finding was also confirmed by Western blot analysis.
Conclusion: Using proteomic analysis, we identified eight GFAP protein spots that were up-regulated in the dorsal horn of morphine-tolerant rat spinal cords. This up-regulation was partly inhibited by N -methyl- d -aspartate receptor antagonist MK-801 co-infusion, which suggests that GFAP protein can be considered to be a pathogenesis marker of morphine tolerance.     

Efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients: 24-week results of POWER 1

BACKGROUND: The ongoing phase IIb POWER 1 (TMC114-C213) trial is designed to assess efficacy and safety of the protease inhibitor (PI) TMC114 (darunavir) in treatment-experienced HIV-1-infected patients. DESIGN: This randomized, partially blinded, 24-week dose-finding study compared efficacy and safety of four doses of TMC114 plus low-dose ritonavir (TMC114/r) with investigator-selected control PI(s) (CPI[s]). METHODS: Patients with one or more primary PI mutation and HIV RNA > 1000 copies/ml received optimized background therapy, plus TMC114/r 400/100 mg once daily, 800/100 mg once daily, 400/100 mg twice daily or 600/100 mg twice daily, or CPI(s). The primary endpoint (intent-to-treat) compared proportions of patients achieving viral load reduction >or= 1.0 log10 copies/ml from baseline. RESULTS: In total, 318 patients were treated. Baseline mean viral load was 4.48 log10 copies/ml; median CD4 cell count was 179 cells/microl. In the CPI arm 62% of patients discontinued (virological failure: 54%); 10% of TMC114/r patients discontinued. More TMC114/r (69-77%) than CPI patients (25%) reached the primary endpoint (P < 0.001); 43-53% of TMC114/r patients and 18% of the CPI arm achieved viral load < 50 copies/ml (P < 0.001). TMC114/r demonstrated greater mean CD4 cell count increases versus CPI(s) (68-124 versus 20 cells/microl; P < 0.05). TMC114/r 600/100 mg twice daily demonstrated the highest virological and immunological responses. Adverse event incidence was similar between treatments; headache and diarrhoea were more common with CPI(s). CONCLUSIONS: TMC114/r demonstrated statistically higher 24-week virological response rates and CD4 cell count increases than CPI(s). TMC114/r 600/100 mg twice daily has received regulatory approval in treatment-experienced patients.     

Oncogenic PIK3CA mutations occur in epidermal nevi and seborrheic keratoses with a characteristic mutation pattern

Activating mutations of the p110 alpha subunit of PI3K (PIK3CA) oncogene have been identified in a broad spectrum of malignant tumors. However, their role in benign or preneoplastic conditions is unknown. Activating FGF receptor 3 (FGFR3) mutations are common in benign skin lesions, either as embryonic mutations in epidermal nevi (EN) or as somatic mutations in seborrheic keratoses (SK). FGFR3 mutations are also common in low-grade malignant bladder tumors, where they often occur in association with PIK3CA mutations. Therefore, we examined exons 9 and 20 of PIK3CA and FGFR3 hotspot mutations in EN (n = 33) and SK (n = 62), two proliferative skin lesions lacking malignant potential. Nine of 33 (27%) EN harbored PIK3CA mutations; all cases showed the E545G substitution, which is uncommon in cancers. In EN, R248C was the only FGFR3 mutation identified. By contrast, 10 of 62 (16%) SK revealed the typical cancer-associated PIK3CA mutations E542K, E545K, and H1047R. The same lesions displayed a wide range of FGFR3 mutations. Corresponding unaffected tissue was available for four EN and two mutant SK: all control samples displayed a WT sequence, confirming the somatic nature of the mutations found in lesional tissue. Forty of 95 (42%) lesions showed at least one mutation in either gene. PIK3CA and FGFR3 mutations displayed an independent distribution; 5/95 lesions harbored mutations in both genes. Our findings suggest that, in addition to their role in cancer, oncogenic PIK3CA mutations contribute to the pathogenesis of skin tumors lacking malignant potential. The remarkable genotype-phenotype correlation as observed in this study points to a distinct etiopathogenesis of the mutations in keratinocytes occuring either during fetal development or in adult life.     

Correlation of sonographic severity with biochemical markers of synovium and cartilage in knee osteoarthritis patients

OBJECTIVE: Ultrasonography can be used to detect soft tissue abnormalities within the joints that cannot be assessed using conventional X-rays. This study investigated the relationship between soft tissue and/or bony abnormalities on ultrasonography and the biochemical markers of the synovium and cartilage in the knee of osteoarthritis (OA) patients. METHODS: The knees from 51 OA patients who fulfilled the ACR criteria were enrolled in this study. Knee ultrasonography was performed in the affected knee joints using a 12 MHz linear probe to assess the presence of effusion, synovial proliferation, capsular distention, the length of osteophytes and the cartilage thickness. At the same time, the serum hyaluronic acid (HA) and the cartilage oligomeric protein (COMP) levels were measured by ELISA, and RIA was used to determine the serum osteocalcin levels. RESULTS: The patients with a longer medial osteophyte showed higher serum HA and COMP levels than those with a shorter one. The serum HA levels were significantly higher in those patients with a larger amount of effusion and/or synovial proliferation, which indicated inflammatory changes, than in those without. In addition, the severity of the capsular distention also correlated well with the serum HA and COMP levels. However, the length of the lateral osteophytes and the thickness of the femoral cartilage showed no correlation with the serum HA or COMP levels. In addition, the serum osteocalcin levels did not show any association with the above ultrasonographic parameters. CONCLUSION: This study demonstrated that the serum HA and COMP levels were elevated in the more severe OA patients by knee ultrasonography than in the less severe patients. This suggests that the detailed pathological changes in the soft tissue and/or bone of the OA joints on ultrasonography are directly reflected by the biochemical markers measured in the peripheral blood.     

Near-total splenectomy for hereditary spherocytosis: clinical prospects in relation to disease severity

We prospectively studied the efficacy of near total splenectomy (NTS) for managing hereditary spherocytosis (HS) based on haemoglobin (Hb), total bilirubin and splenic remnant regrowth in 30 children receiving NTS for HS between November 1996 and December 2004 (mean followup 3.6 years). Patients were classified into three severity groups. At followup, mean Hb had increased by 2.9-5.0 g/dl (P = 0.110) and bilirubin dropped by 15.4-56.4 mumol/l. Remnant regrowth was moderate, within the weight-specific norm. Amongst spleen-preserving techniques, NTS shows markedly lower rates of recurrent haemolysis, remnant regrowth and secondary operations, thus potentially benefiting all clinical forms of HS.     

Evaluation of prognostic factors and two radiation techniques in patients treated with surgery followed by radio(chemo)therapy or definitive radio(chemo)therapy for locally advanced head-and-neck cancer

BACKGROUND AND PURPOSE: Conventional radiotherapy (RT) still is the standard technique for head-and-neck cancer in many centers worldwide, whereas other centers replaced this technique by 3-D conformal RT, which is associated with more appropriate dose distributions. Comparative studies regarding outcome and toxicity are lacking. This study compared both techniques for overall survival (OS), metastases-free survival (MFS), loco-regional control (LC), and toxicity in stage III/IV head-and-neck cancer. PATIENTS AND METHODS: Data of 345 patients irradiated for stage III/IV squamous cell head-and-neck cancer were retrospectively analyzed. Patients received conventional RT (group A, n = 166) or 3-D conformal RT (group B, n = 179). Both techniques were compared for outcomes and toxicity. Eleven further potential prognostic factors were investigated: age, gender, performance status, tumor site, grading, T-stage, N-stage, AJCC-stage, chemotherapy, surgery, pre-RT hemoglobin. RESULTS: 3-year-OS was 62% in group A and 57% in group B (p = 0.15). 3-year-MFS was 67% and 76% (p = 0.46), 3-year-LC was 65% and 68%, respectively (p = 0.71). On multivariate analysis, gender (p = 0.005), performance status (p < 0.001), T-stage (p = 0.002), and N-stage (p < 0.001) were associated with OS. MFS was influenced by performance status (p < 0.001) and N-stage (p < 0.001), LC by gender (p = 0.021), T-stage (p < 0.001), and pre-RT hemoglobin level (>or= 12 better than < 12 g/dl, p = 0.004). Grade 2-3 xerostomia was less frequent with 3-D conformal RT (43% vs. 58%, p = 0.06). Otherwise, toxicities were similar. CONCLUSION: Both RT techniques resulted in similar treatment outcomes. Because xerostomia was less with 3-D conformal RT, this technique appeared beneficial for patients, in whom one parotid gland can be spared. Outcome was associated with gender, performance status, tumor stage, and pre-RT hemoglobin.