Puberty, as the end-point of a complex series of maturational events affecting the components of the hypothalamic-pituitary-gonadal (HPG) axis, is gated by the state of body energy reserves and sensitive to different metabolic cues; conditions of severe metabolic stress and energy unbalance (from anorexia to morbid obesity) being commonly linked to perturbation of the onset of puberty. In the last two decades, the neuroendocrine mechanisms responsible for the tight coupling between energy homeostasis and puberty onset have begun to be deciphered. These seemingly involve a plethora of metabolic hormones and neuropeptides, which impinge and integrate (mostly) at the hypothalamic centers governing reproduction. Yet, characterization of the mechanisms of action of such regulators (and even their nature and physiological relevance) still remains incomplete. In this review, we will summarize some recent developments in our knowledge of the effects and mechanisms of action of two key metabolic hormones, leptin and ghrelin, in the control of puberty onset. In addition, the roles of the hypothalamic Kiss1 system in the metabolic gating of puberty will be reviewed, with special attention to its regulation by leptin and the recent identification of the putative roles of Crtc1 and mTOR signaling as molecular conduits for the metabolic control of Kiss1 expression. Elucidation of these novel players and regulatory mechanisms will help for a better understanding of the determinants of the timing of puberty, and its eventual alterations in adverse metabolic conditions.

Alzheimer's disease is a progressive neurodegenerative brain disorder that leads to major debilitating cognitive deficits. It is believed that the alterations capable of causing brain circuitry dysfunctions have a slow onset and that the full blown disease may take several years to develop. Therefore, it is important to understand the early, asymptomatic and possible reversible states of the disease with the aim of proposing preventive and disease modifying therapeutic strategies. It is largely unknown how amyloid beta-peptide (Abeta), a principal agent in Alzheimer's disease, affects synapses in brain neurons. In this study, we found that similar to other pore-forming neurotoxins, Abeta induced a rapid increase in intracellular calcium and miniature currents indicating an enhancement in vesicular transmitter release. Significantly, blockade of these effects by low extracellular calcium and a peptide known to act as an inhibitor of the Abeta induced pore, prevented the delayed failure indicating that Abeta blocks neurotransmission by causing vesicular depletion. This new mechanism for Abeta synaptic toxicity should provide an alternative pathway to search for small molecules that can antagonize these effects of Abeta.

An atmospheric neutrino oscillation tool that uses full three-neutrino oscillation probabilities and a full three-neutrino treatment of the Mikheyev-Smirnov-Wolfenstein effect, together with an analysis of the K2K, MINOS, and CHOOZ data, is used to examine the bounds on theta_{13}. The recent, more finely binned, Super-K atmospheric data are employed. For L/E_{nu} greater, similar 10;{4} km/GeV, we previously found significant linear in theta_{13} terms. This analysis finds theta_{13} bounded from above by the atmospheric data while bounded from below by CHOOZ. The origin of this result arises from data in the previously mentioned very long baseline region; here, matter effects conspire with terms linear in theta_{13} to produce asymmetric bounds on theta_{13}. Assuming CP conservation, we find theta_{13}=-0.07_{-0.11};{+0.18}(90% C.L.).

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that operates as sensor of cellular energy status and effector for its coupling to cell growth and proliferation. At the hypothalamic arcuate nucleus, mTOR signaling has been recently proposed as transducer for leptin effects on energy homeostasis and food intake. However, whether central mTOR also participates in metabolic regulation of fertility remains unexplored. We provide herein evidence for the involvement of mTOR in the control of puberty onset and LH secretion, likely via modulation of hypothalamic expression of Kiss1. Acute activation of mTOR by L-leucine stimulated LH secretion in pubertal female rats, whereas chronic L-leucine infusion partially rescued the state of hypogonadotropism induced by food restriction. Conversely, blockade of central mTOR signaling by rapamycin caused inhibition of the gonadotropic axis at puberty, with significantly delayed vaginal opening, decreased LH and estradiol levels, and ovarian and uterine atrophy. Inactivation of mTOR also blunted the positive effects of leptin on puberty onset in food-restricted females. Yet the GnRH/LH system retained their ability to respond to ovariectomy and kisspeptin-10 after sustained blockade of mTOR, ruling out the possibility of unspecific disruption of GnRH function by rapamycin. Finally, mTOR inactivation evoked a significant decrease of Kiss1 expression at the hypothalamus, with dramatic suppression of Kiss1 mRNA levels at the arcuate nucleus. Altogether our results unveil the role of central mTOR signaling in the control of puberty onset and gonadotropin secretion, a phenomenon that involves the regulation of Kiss1 and may contribute to the functional coupling between energy balance and gonadal activation and function.

BACKGROUND AND OBJECTIVES: The goal of this study was to evaluate a series of patients with early gallbladder cancer, focusing on the selection of treatment and the role of Rokitansky Aschoff sinus infiltration. METHODS: We performed a retrospective analysis of a prospective series of 371 patients with gallbladder cancer. Specimens were reviewed by an independent pathologist to confirm the diagnosis and depth of infiltration and to evaluate the presence of Rokitansky Aschoff sinus involvement. RESULTS: Forty-nine and 45 patients with muscular (pT1b) and mucosal (pT1a) infiltration gallbladder cancer tumors were studied respectively. Simple cholecystectomy was the treatment in all patients, with the exception of 11 patients who underwent further surgery. Rokitansky Aschoff sinus invasion was seen in seven patients with mucosa (pT1a) and three with muscular (pT1b) compromise. The 5-year survival rates of patients with muscular (pT1b) and mucosal (pT1a) infiltration were 87.6% and 86.4%, respectively. Patients with Rokitansky Aschoff involvement had a lower survival rate than those with no involvement in both categories. CONCLUSIONS: Early gallbladder cancer is associated with a favorable prognosis and cholecystectomy should be the standard treatment. Despite some patients having a worse prognosis, there are no data to support more aggressive treatment. J. Surg. Oncol.(c) 2009 Wiley-Liss, Inc.

The concomitant presence of a primary gastric adenocarcinoma and a gastrointestinal stromal tumor in the stomach is uncommon. We report a 68-year-old male with an advanced gastric adenocarcinoma. During gastrectomy, a nodular intramural lesion was found. The pathological study, revealed a gastrointestinal stromal tumor, positive form CD117. After six months of follow up, there is no evidence of recurrence of either tumor).

Goldin R D & Roa J C (2009) Histopathology Gallbladder cancer: a morphological and molecular updateGallbladder cancer (GBC) shows a marked geographical variation in its incidence, with the highest figures being seen in India and Chile and relatively low levels in many Western countries. Risk factors for its development include the presence of gallstones, infection and the presence of an anomalous pancreatobiliary ductal junction. It can arise from either a pathway involving metaplasia or dysplasia or one in which there is a pre-existing adenoma. The former is the more common and, because it is often not associated with a macroscopically recognizable lesion, leads to the recommendation that all gallbladders need to be examined microscopically. Accurate staging of invasive cancers is essential to determine prognosis and treatment, and this requires extensive tumour sampling. A number of genetic alterations have been identified in the preinvasive and invasive stages of GBC and they support the morphological evidence of there being two pathways by which tumours develop. Some of these genetic changes are associated with particular risk factors. For example, cases with anomalous pancreatobiliary ductal junction show a higher frequency of K-ras mutations. Some changes are associated with differences in prognosis. For example, cancers without expression of p21 but with expression for p27 have a better prognosis, whereas those that express c-erb-B2 have a worse one. Work has also been done on identifying clinical, imaging and other factors that indicate that patients have a higher risk of having GBC. This is particularly important in high-incidence areas in which GBC is a significant public health problem.

Kisspeptins, the natural ligands of the G protein-coupled receptor KISS1R, comprise a family of related peptides derived from the proteolytic processing of a common precursor encoded by the KISS1 gene. Among those, Kisspeptin-10 (Kp-10) contains the basic residues to retain full functional activity, and exhibits higher receptor affinity and biopotency than longer forms of the peptide. Although kisspeptins were first characterized by their ability to inhibit tumor metastasis, recent studies have revealed that the KISS1/KISS1R system plays an essential role in the neuroendocrine control of the reproductive axis. In this context, development and functional analysis of Kp-10 analogs may help searching new agonists and antagonists, as valuable tools to manipulate the KISS1/KISS1R system and, hence, fertility. We report herein functional and structural analyses of a series of Ala-substituted rat kp-10 analogs, involving [Ca(2+)]i responses in rat kiss1r-transfected CHO cells, dynamic LH responses in vivo, and NMR structural studies. In vitro assays revealed that Ala-substitutions in positions 6 or 10 of kp-10 resulted in a significant increase in EC50 values (> 6.46x10(-6)M vs. 1.54-2.6x10(-8)M for rat and human Kp-10), and a substantial decrease in the proportion of responsive cells coupled to a marked increase in the time required to reach maximal response. In vivo assays showed that Ala(6) substitution diminished, and Ala10 substitution eliminated, LH secretory responses, whereas co-administration of each analog failed to affect the LH-releasing ability of kp-10. Molecular modeling under NMR restraints revealed that kp-10 exhibits a helicoidal structure between the Asn(4) and Tyr(10) residues, with mixed alpha- and 310 characteristics. Ala(6) substitution induced limited destabilization of the helix around the position of the substitution. Ala(10) substitution was found to totally disrupt the helical structure in the C-terminal region of the molecule. Taken together, our results indicate that positions 6 and 10 are critical for kp-10 action at kiss1r, and suggest that modifications in these positions could lead to the generation of new kisspeptin agonists and/or antagonists with altered binding and perhaps functional properties. Further, they emphasize the importance of using combined, multidisciplinary approaches, including in vivo studies, to reliably evaluate structure function properties of novel kisspeptin analogs.

BACKGROUND: Human papillomavirus (HPV) infection is the most common sexually transmitted disease. AIM: To determine prevalence of HPV genital infection in voluntary asymptomatic male university students. MATERIAL AND METHODS: A cross-sectional study in 62 asymptomatic, sexually active male students. Exfoliated cells were obtained from the penile shaft and coronal sulcus. Samples were analyzed for HPV DNA detection and genotyping by polymerase chain reaction and Reverse Line Blot. RESULTS: The prevalence of HPV infection was 84%. HPV detection was 77% in penile shaft and 66% in coronal sulcus. The most commonly detected types were HPV-16 (45%), HPV-11 (19%), HPV-6 (10%) and HPV-18 (9%). Multiple infection was found in 54%. The most frequent combinations were VPH11/16 (18%) and VPH16/18 (5%). CONCLUSIONS: HPV infection is highly frequent in asymptomatic male university students, high risk HPV types were greatly predominant.

PURPOSE: Biliary tract cancers (BTC) are uncommon in the United States, but are endemic in parts of South America and Asia. BTCs are aggressive tumors associated with poor survival. Activation of HER-2/neu (erbB2) and/or epidermal growth factor receptor (EGFR) are important in breast, colon, and lung cancers. Tumor specimens from patients from the United States and Chile were examined for expression of HER-2/neu, EGFR, and their activated forms (p-erbB2, p-EGFR). MATERIALS AND METHODS: Specimens from 77 gallbladder cancers (GBC), 16 extrahepatic bile duct cancers (EHBDC), 21 intrahepatic bile duct cancers (IHBDC), 11 cases of cholecystitis (CHOLE), and 8 normal gallbladders (NGB) were examined for HER-2/neu, p-erbB2, EGFR, and p-EGFR expression by immunohistochemistry (IHC), with scores of 2+ or 3+ defined as positive. HER-2/neu gene amplification was analyzed by double color HER-2/neu gene/chromosome 17 centromere (CEP17) fluorescence in situ hybridization (FISH) assays RESULTS: HER-2/neu-positive IHC staining was found in 31.2% of GBC, 31.3%, of EHBDC, and 33.3% of IHBDC; 12.5% of CHOLE specimens showed 2+ staining and the remaining CHOLE and NGB were negative. HER-2/neu gene amplification was detected in 20.9% of GBC, 21.4% of EHBDC, and none of IHBDC. There was a significant correlation between IHC 2+ and 3+ and gene amplification (P =.0001). CONCLUSIONS: HER-2/neu amplification was identified in more than 20% of GB and EHBDC. There was strong correlation between HER-2/neu IHC and FISH positivity. These findings indicate a role for HER-2/neu in some subsets of BTC, and provide a rationale for study of HER-2/neu-directed therapies in this setting.