Highly active antiretroviral therapy reduces the age-associated risk of dementia in a cohort of older HIV-1-infected patients

Historically, older patients have shown a higher risk of HIV-1-associated dementia (HIVD). The objective of this study was to evaluate the association of aging with HIVD and minor cognitive motor disorders (MCMDs) during the late-highly active antiretroviral therapy (HAART) era and to analyze characteristics, predictive factors, and survival of older HIV-1-infected individuals affected by these disorders. A nested longitudinal study was designed for a cohort of HIV-1-infected individuals with neurological diseases. Multiple logistic regression and Cox regression for survival were employed. From 2000 to 2003, 195 patients with HIVD (53%) or MCMD (47%) were enrolled. The cumulative prevalence of these two disorders was 21%, with an increasing rate for calendar year (p < 0.001). Previous antiretroviral exposure occurred in 46% of patients. Mean CD4(+) cell count and plasma HIV-1 RNA were 144 cells/microl and 4.5 log10 copies/ml, respectively. The mean age was 44 years (SD, 9.9), with 35% of patients aged 20-39 years (I), 45% aged 40-49 years (II), and 20% aged >/=50 years (III). Among drug-naive patients, the prevalence of HIVD progressively increased in older subjects: 7.2% (I), 15.3% (II), and 27.3% (III) (p < 0.001), whereas no significant increase in HIVD with older age was observed in drug-treated subjects. Older age was independently associated with an increased risk of HIVD (odds ratio, 6.44; 95% confidence interval, 2.82-14.69) in naive but not in experienced individuals, but had no significant effect on survival. No significant effect of age was observed for MCMD. We conclude that in our cohort, HAART seems to alter the relationship between aging and HIVD, conferring a neuroprotective effect to older patients. These results may have significant implications for the clinical management of the older HIV population.     

Role of the signal peptide in the synthesis and processing of the glucagon-like peptide-1 receptor

Background and purpose:

The glucagon-like peptide-1 receptor (GLP-1R) belongs to Family B of the G protein-coupled receptor superfamily and is a target for treatment of type 2 diabetes. Family B G protein-coupled receptors contain a putative N-terminal signal peptide, but its role in receptor synthesis and trafficking are unclear. Further, the signal peptide is not cleaved in at least one family member.

Experimental approach:

We examined receptor glycosylation and the role of the signal peptide in GLP-1R synthesis and trafficking using constructs containing epitope tags at the N- and/or C-terminus and in which the signal peptide sequence was either present or absent.

Key results:

The signal peptide was absolutely required for GLP-1R synthesis but could be substituted to some extent by increasing positive charge in the N-terminal region of the receptor flanking the signal peptide. The signal peptide is cleaved during synthesis and processing of the receptor. An enhanced GFP-epitope tag at the N-terminus of the receptor permitted synthesis of the receptor but blocked signal peptide cleavage and prevented trafficking to the plasma membrane. Cleavage site mutation allowed synthesis of a full-length receptor, blocked signal peptide cleavage and caused retention within the endoplasmic reticulum.

Conclusions and implications:

Signal peptide cleavage was not essential for receptor synthesis but was obligatory for processing and trafficking of receptors to the plasma membrane. Further, the GLP-1R is subject to N-linked glycosylation and only the mature, fully glycosylated form of the receptor is present in the plasma membrane. Inhibition of glycosylation prevents processing and cell surface expression of the GLP-1R.     

Valerenic acid derivatives as novel subunit-selective GABAA receptor ligands �Cin vitro and in vivo characterization

BACKGROUND AND PURPOSE

Subunit-specific modulators of γ-aminobutyric acid (GABA) type A (GABA_A) receptors can help to assess the physiological function of receptors with different subunit composition and also provide the basis for the development of new drugs. Valerenic acid (VA) was recently identified as a β_2/3 subunit-specific modulator of GABA_A receptors with anxiolytic potential. The aim of the present study was to generate VA derivatives as novel GABA_A receptor modulators and to gain insight into the structure–activity relation of this molecule.

EXPERIMENTAL APPROACH

The carboxyl group of VA was substituted by an uncharged amide or amides with different chain length. Modulation of GABA_A receptors composed of different subunit compositions by the VA derivatives was studied in Xenopus oocytes by means of the two-microelectrode voltage-clamp technique. Half-maximal stimulation of GABA-induced chloride currents (I_GABA) through GABA_A receptors (EC₅₀) and efficacies (maximal stimulation of I_GABA) were estimated. Anxiolytic activity of the VA derivatives was studied in mice, applying the elevated plus maze test.

KEY RESULTS

Valerenic acid amide (VA-A) displayed the highest efficacy (more than twofold greater I_GABA enhancement than VA) and highest potency (EC₅₀= 13.7 ± 2.3 µM) on α₁β₃ receptors. Higher efficacy and potency of VA-A were also observed on α₁β₂γ_2s and α₃β₃γ_2s receptors. Anxiolytic effects were most pronounced for VA-A.

CONCLUSIONS AND IMPLICATIONS

Valerenic acid derivatives with higher efficacy and affinity can be generated. Greater in vitro action of the amide derivative correlated with a more pronounced anxiolytic effect in vivo. The data give further confidence in targeting β₃ subunit containing GABA_A receptors for development of anxiolytics.     

Accuracy of Papanicolaou smears in cervical cancer patients treated with radiochemotherapy followed by radical surgery

Papanicolaou (Pap) smears are part of the follow-up program for patients with cervical cancer treated with radiochemotherapy. After therapy, residual neoplastic cells may be rare, seldom exfoliate, and may demonstrate many alterations, which creates a risk of inaccurate results. We report a study of 65 patients who received radiochemotherapy before radical surgery. For each patient, we compared smear results with results from histologic examination of the whole cervix. The Pap smear was "negative for cancer" in 50 cases, "positive for cancer" in 6 cases, and detected atypical squamous cells of undetermined significance in 9 cases. Histologic examination revealed a complete pathologic response (pR0) in 26 cases and a partial pathologic response (pR1) in 27. In 12 cases, no pathologic response (pR2) was shown. Comparison of these results showed that the Pap test had a sensitivity of 0.16, a specificity of 0.96, a negative predictive value of 0.83, a positive predictive value of 0.42, and an accuracy of 0.46.     

Does laparoscopic management of deep infiltrating endometriosis improve quality of life? A prospective study

Background

Deep infiltrating endometriosis (DIE) can affect importantly patients' quality of life (QOL). The aim of this study is to evaluate the impact of the laparoscopic management of DIE on QOL after six months from treatment.

Methods

It is a prospective cohort study. In a tertiary care university hospital, between April 2008 and December 2009, 100 patients underwent laparoscopic management of DIE and completed preoperatively and 6-months postoperatively a QOL questionnaire, the short form 36 (SF-36).Quality of life was measured through the SF-36 scores. Intra-operative details of disease site, number of lesions, type of intervention, period of hospital stay and peri-operative complications were noted.

Results

Six months postoperatively all the women had a significant improvement in every scale of the SF-36 (p < 0,0005). Among patients with intestinal DIE, significant differences in postoperative scores of SF-36 were not detected between patients submitted to nodule shaving and segmental resection (p > 0.05). There was no significant difference in the SF-36 scores at 6 months from surgery between patients who received postoperative medical treatment and patients who did not (p > 0.05).

Conclusions

Laparoscopic excision of DIE lesions significantly improves general health and psycho-emotional status at six months from surgery without differences between patients submitted to intestinal segmental resection or intestinal nodule shaving.

     

p27Kip1 expression is associated with clinical outcome in advanced epithelial ovarian cancer: multivariate analysis.

Few biological parameters have been shown to have a prognostic role in patients with advanced ovarian cancer. p27Kip1 is a cyclin-dependent kinase inhibitor, and its loss may contribute to tumor progression. We determined whether p27Kip1 protein expression in advanced ovarian cancer could be associated with prognosis. p27Kip1 status was assessed by immunohistochemical analysis of tissue sections from primary tumors of 99 patients with stages III-IV ovarian carcinoma and was analyzed in relation to clinicopathological variables, time to progression (TTP), and overall survival (OS). p27Kip1 expression was detected in 47 (47%) of the 99 patients. p27 expression did not correlate with any of the classical clinicopathological parameters. Loss of p27 protein was significantly associated with a short TTP (P = 0.0004) and decreased OS (P = 0.0302). The 5-year TTP rate in p27-positive patients was 50% versus 11% in p27-negative patients. p27-positive cases showed a 5-year OS rate of 53% compared with 43% of p27-negative cases. In multivariate analysis, p27 expression was an independent predictor of progression of disease (P = 0.0009) and survival (P = 0.0032) when considered together with stage of disease, presence of ascites, and residual tumor at surgery. Loss of p27Kip1 conferred poor prognosis independently of proliferative index, as assessed by proliferating cell nuclear antigen immunostaining. p27 immunoreactivity can be used to predict progression of disease and survival in patients with advanced epithelial ovarian cancer and therefore may represent a new prognostic marker.     

A new method for the automatic mesh generation of bone segments from CT data.

A new procedure for the automatic generation of finite element meshes of bone segments from computed tomography (CT) data sets is described. The new method allows a direct automatic generation from the CT data and produces a very accurate unstructured hexahedral mesh. The accuracy of the method was established using the CT images of an artificial femur showing range of attenuation values comparable to those of a human femur. To establish the optimal values for the parameters controlling the mesh a sensitivity analysis was carried out using mesh-conditioning indicators. Some of the best meshes, with increasing levels of refinement, were used to analyse the stresses induced in the proximal femur by single leg stance posture. The accuracy of the meshes was evaluated using an implicit a posteriori residual-based error estimates. The number of elements with stress residuals larger than 10% of the peak stress was 7.8% using the coarsest mesh and only 1.8% with the finest mesh. The proposed method has been proved able to conjugate full automation with high-quality finite element meshes. The stress predictions obtained using these hexahedral-only meshes have been more accurate than those obtained by any other automatic mesh generation algorithm. Once properly integrated in an easy-to-use application, the described method could finally make feasible many clinical applications of finite element analysis.     

Risk of Recurrence in Uterine Leiomyoma with Bizarre Nuclei: a Systematic Review and Meta-Analysis

Objective Leiomyoma with bizarre nuclei (LBN) is a variant of uterine leiomyoma, which has replaced the previous category of “atypical leiomyoma” and must be distinguished from smooth muscle tumors of uncertain malignant potential (STUMP). However, previously published series of “atypical leiomyoma” might have included both LBN and STUMP, due to the lack of strict diagnostic criteria. Based on such hypothesis, we aimed to define the risk of recurrence in LBN. Study Design A systematic review and meta-analysis was performed by searching 4 electronic databases for all studies assessing the outcome of patients with “atypical leiomyoma” or LBN. The pooled absolute risk of recurrence was calculated. The included studies were subdivided into two subgroups based on the criteria used: “LBN + STUMP” or “LBN-only”. Results Twelve studies with 433 patients were included. The pooled risk of recurrence was 5.5% overall. The funnel plot showed two cluster of studies which superimposed to the two subgroups. In the LBN + STUMP cluster/subgroup, the pooled risk of recurrence was 7.7%. In the LBN-only cluster/subgroup, the pooled risk of recurrence was 1.9%. Statistical heterogeneity was null in all analyses. Conclusion Our results show a risk of recurrence of 1.9% for LBN; higher recurrence rates in older studies are likely due to the inclusion of STUMPs. Key words: prognosis, diagnosis, sarcoma, myoma, leiomyoma, myomata