Hyperpolarization moves S4 sensors inward to open MVP,a methanococcal voltage-gated potassium channel

MVP, a Methanococcus jannaschii voltage-gated potassium channel, was cloned and shown to operate in eukaryotic and prokaryotic cells. Like pacemaker channels, MVP opens on hyperpolarization using S4 voltage sensors like those in classical channels activated by depolarization. The MVP S4 span resembles classical sensors in sequence, charge, topology and movement, traveling inward on hyperpolarization and outward on depolarization (via canaliculi in the protein that bring the extracellular and internal solutions into proximity across a short barrier). Thus, MVP opens with sensors inward indicating a reversal of S4 position and pore state compared to classical channels. Homologous channels in mammals and plants are expected to function similarly.     

Sarcopenia and Appendicular Muscle Mass as Predictors of Impaired Fasting Glucose/Type 2 Diabetes in Elderly Women

Elderly women exhibit a high risk of type 2 diabetes (T2D), but no definitive data exist about the possible role of postmenopausal increases in visceral adiposity, the loss of lean body mass, or decreases in the sum of the lean mass of arms and legs (appendicular skeletal muscle mass (ASMM)). This retrospective, longitudinal study investigated whether body composition (bioelectrical impedance analysis) predicted the development of impaired fasting glucose (IFG) or T2D in a cohort of 159 elderly women (age: 71 ± 5 years, follow-up: 94 months) from southern Italy (Clinical Nutrition and Geriatric Units of the “Mater Domini” University Hospital in Catanzaro, Calabria region, and the “P. Giaccone ”University Hospital in Palermo, Sicily region). Sarcopenia was defined in a subgroup of 128 women according to the EWGSOP criteria as the presence of low muscle strength (handgrip strength <16 kg) plus low muscle mass (reported as appendicular skeletal muscle mass <15 kg). Participants with a low ASMM had a higher IFG/T2D incidence than those with a normal ASMM (17% vs. 6%, p-adjusted = 0.044); this finding was independent of BMI, fat mass, waist circumference, and habitual fat intake (OR = 3.81, p = 0.034). A higher incidence of IFG/T2D was observed in the subgroup with sarcopenia than those without sarcopenia (33% vs. 7%, p-adjusted = 0.005) independent of BMI and fat mass (OR = 6.75, p = 0.007). In conclusion, this study demonstrates that elderly women with low ASMM had a higher probability of developing IFG/T2D. Further studies are needed to confirm these results in men and in other age groups.     

Insulin receptor substrate (IRS) transduction system: distinct and overlapping signaling potential

Insulin receptor substrate (IRS) proteins play a central role in maintaining basic cellular functions such as growth and metabolism. They act as an interface between multiple growth factor receptors possessing tyrosine kinase activity, such as the insulin receptor, and a complex network of intracellular signalling molecules containing Src homology 2 (SH2) domains. Four members (IRS-1, IRS-2, IRS-3, IRS-4) of this family have been identified which differ in their subcellular distribution and interaction with SH2 domain proteins. In addition, differential IRS tissue- and developmental-specific expression patterns may contribute to specificity in their signaling potential.     

From microbiota toward gastro-enteropancreatic neuroendocrine neoplasms: Are we on the highway to hell?

Gut microbiota is represented by different microorganisms that colonize the intestinal tract, mostly the large intestine, such as bacteria, fungi, archaea and viruses. The gut microbial balance has a key role in several functions. It modulates the host’s metabolism, maintains the gut barrier integrity, participates in the xenobiotics and drug metabolism, and acts as protection against gastro-intestinal pathogens through the host’s immune system modulation. The impaired gut microbiota, called dysbiosis, may be the result of an imbalance in this equilibrium and is linked with different diseases, including cancer. While most of the studies have focused on the association between microbiota and gastrointestinal adenocarcinomas, very little is known about gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs). In this review, we provide an overview concerning the complex interplay between gut microbiota and GEP NENs, focusing on the potential role in tumorigenesis and progression in these tumors.

     

Human papillomavirus (HPV) testing in the management of women with abnormal Pap smears. Experience of a colposcopy referral clinic

BACKGROUND AND OBJECTIVES: Several detailed algorithms for the appropriate use of human papillomavirus (HPV) testing in the management of women with abnormal Pap (Papanicolaou) smears have been launched, but their direct country-to-country adoption is difficult. This necessitates their testing in individual settings, which is ongoing in our colposcopy referral clinic. METHODS: A series of 224 consecutive women attending the clinic with the usual referral indications (ASC-US or higher in Pap) were examined by the conventional diagnostic tools (PAP smear, colposcopy, punch biopsy) and subjected to HPV testing and viral typing for both low-risk (L-R) and high-risk (H-R) types by nested PCR-based techniques. Predictors of the high-grade diagnostic categories were analysed using both univariate- and multivariate modelling, and the performance characteristics (sensitivity, specificity, NPV, PPV) of all tests in detecting high-grade CIN were calculated. RESULTS: In the PAP test, ASC-US smears were most common (37.9%), followed by low-grade squamous intraepithelial lesions (LSIL) (26.3%) and high-grade SIL (HSIL) (4.9%). Colposcopy was performed for 180 women, of whom 48.3% had a normal transformation zone (TZ), 40.6% had ATZ1 (abnormal TZ grade 1), and 5.6% had ATZ2. In biopsy (n = 71), 49.3% had CIN1, 5.6% CIN2, and 16.9% CIN3. The HPV test was positive in 64 (28.8%) women, more often in those aged < 35 years (p = 0.025). High-grade colposcopy (ATZ2) was significantly associated with HSIL in the Pap test (OR 20.5; 95% CI: 4.34-96.47), and with HPV test positivity (OR 6.37; 95% CI: 1.58-25.73). The most significant predictors of CIN3 were HSIL in the PAP, HPV test positivity, and high-grade colposcopy. HSIL and HPV test (for H-R types), but not colposcopy, retained their significance as independent predictors of CIN3 also in adjusted multivariate models: OR 88.27; 95% CI 4.17-1867.04, and OR 19.46; 95% CI 2.01-187.75, for the HSIL and H-R HPV test, respectively. Changing the cut-off level of the Pap test from ASC-US to HSIL increased the specificity of the test up to 96.4%, with the loss in sensitivity from 87.5% to 43.8%. Colposcopy (ATZ2) had 92% specificity, and NPV competing with that of the Pap test. The sensitivity of HPV test exceeds that of the Pap test at HSIL cut-off level, but the specificity of the PAP test is clearly superior. CONCLUSIONS: Accurate predictors of significant cervical pathology (CIN3) are well defined, but the problem is the different performance of the diagnostic tools in clinical practice. A proficient combination of the tests is likely to result in the most satisfactory clinical practice in the management of women with abnormal Pap tests (MAPS).     

Assessment of risk factors and human papillomavirus (HPV) related pathogenetic mechanisms of CIN in HIV-positive and HIV-negative women. Study design and baseline data of the HPV-PathogenISS study

OBJECTIVES: In women with HIV-associated immunosuppression, HPV infections have an increased risk of progression to high-grade cervical intraepithelial neoplasia (CIN). With the HAART-induced prolonged survival and more protracted clinical course of AIDS, progression of CIN to cervical cancer (CC) has become a clinically relevant issue, and the mechanisms responsible for HIV-HPV interactions need further elucidation. The study design and analysis of the baseline data of our new project are presented. MATERIAL AND METHODS: This project is a combination of a prospective cohort study of HIV- and HIV+ women, and a retrospective analysis of CIN lesions and cervical cancer. Up to the present, 244 women have been enrolled (17 HIV+) and subjected to epidemiological interview, colposcopic examination, sampling for HPV testing and typing (PCR, InnoLiPA), and HPV serology. The retrospective series of biopsies were analysed for 13 biomarkers (monitoring key molecular events) using immunohistochemistry and tested for HPV by PCR and TaqMan. RESULTS: HIV- and HIV+ women differ in their exposure status to many of the key epidemiological risk factors of cervical cancer, the most significant ones being number of sexual partners (p = 0.0001), age at onset of sexual activity (p = 0.002), and contraception (yes-no) (p = 0.009). The differences in the baseline clinical observations are less dramatic; HIV-positive women had more frequent HSIL PAP tests (p = 0.040), CIN2 or higher in cervical biopsy (p = 0.049), and external genital warts (p = 0.019). The factors predicting intermediate endpoint markers of cervical cancer, i.e., HSIL PAP smear, ATZ2 in colposcopy, and high-grade CIN in biopsy were analysed in univariate and multivariate regression models. All factors significant in univariate analysis were entered in the multivariate model; HIV-status and Pap smear history maintained their independent predictive power of the HSIL Pap test. The most powerful predictor of ATZ2 colposcopy was HSIL in Pap test. Only the HSIL Pap test and ATZ2 colposcopy remained significant independent predictors of high-grade CIN (p = 0.0001 and p = 0.008, respectively) in the multivariate model. CONCLUSIONS: The three intermediate endpoint markers are closely interrelated, but predicted in part by different covariantes in the causal pathway to cervical cancer. To elucidate whether the increased risk of HIV-positive women to high-grade CIN is due a) to their different exposure status to the risk factors, b) to the direct effects of HIV, or c) to molecular interactions between HIV and HPV, we need to complete these analyses separately in HIV+ and HIV- women.     

Multiple leiomyomas of the vagina in a premenopausal woman

Case report A 32-year-old multiparous woman was seen for a history of dyspareunia and vaginal pain. She presented with two firm masses on the lower-medium left lateral wall of the vagina. Transvaginal ultrasonography showed two spherical smooth-walled masses, respectively of 33 and 35 mm in diameter. A transvaginal approach was used to remove the two tumors en bloc.Conclusion Histologically, the tumors were leiomyomas.