Neuropeptide Y acts within the rat testis to inhibit testosterone secretion

The factors that influence Leydig cell activity currently include peptides such as neuropeptide Y (NPY). In this work we investigated the ability of this compound, injected directly into the testes of adult male rats, to alter testosterone (T) release into the general circulation. At a 5μg/kg dose administered 1h prior to challenge with human chorionic gonadotropin (hCG, 1.0 U/kg, iv), NPY significantly (P<0.01) blunted the T response to this gonadotropin. The inhibitory effect of NPY was observed in animals pretreated with an antagonist to gonadotropin-releasing hormone or not, indicating that the decrease in plasma T found was most likely independent of pituitary luteinizing hormone. However, testicular levels of steroidogenic acute regulatory (STAR) protein or translocator protein (TSPO) in the Leydig cells did not exhibit consistent changes, which suggested that other mechanisms mediated the blunted T response to hCG. We therefore used autoradiography and immunohistochemistry methodologies to identify NPY receptors in the testes, and found them primarily located on blood vessels. Competition studies further identified these receptors as being Y(1), a subtype previously reported to modulate the vasoconstrictor effect of NPY. The absence of significant changes in STAR and TSPO levels, as well as the absence of Y(1) receptors on Leydig cells, suggest that NPY-induced decreases in T release is unlikely to represent a direct effect of NPY on these cells. Rather, the very high expression levels of Y(1) found in testicular vessels supports the concept that NPY may alter gonadal activity, at least in part, through local vascular impairment of gonadotropin delivery to, and/or blunted T secretion from, Leydig cells.

An interactive surgical planning tool for acetabular fractures: initial results

Background Acetabular fractures still are among the most challenging fractures to treat because of complex anatomy, involved surgical access to fracture sites and the relatively low incidence of these lesions. Proper evaluation and surgical planning is necessary to achieve anatomic reduction of the articular surface and stable fixation of the pelvic ring. The goal of this study was to test the feasibility of preoperative surgical planning in acetabular fractures using a new prototype planning tool based on an interactive virtual reality-style environment. Methods 7 patients (5 male and 2 female; median age 53 y (25 to 92 y)) with an acetabular fracture were prospectively included. Exclusion criterions were simple wall fractures, cases with anticipated surgical dislocation of the femoral head for joint debridement and accurate fracture reduction. According to the Letournel classification 4 cases had two column fractures, 2 cases had anterior column fractures and 1 case had a T-shaped fracture including a posterior wall fracture. The workflow included following steps: (1) Formation of a patient-specific bone model from preoperative computed tomography scans, (2) interactive virtual fracture reduction with visuo-haptic feedback, (3) virtual fracture fixation using common osteosynthesis implants and (4) measurement of implant position relative to landmarks. The surgeon manually contoured osteosynthesis plates preoperatively according to the virtually defined deformation. Screenshots including all measurements for the OR were available. The tool was validated comparing the preoperative planning and postoperative results by 3D-superimposition. Results Preoperative planning was feasible in all cases. In 6 of 7 cases superimposition of preoperative planning and postoperative follow-up CT showed a good to excellent correlation. In one case part of the procedure had to be changed due to impossibility of fracture reduction from an ilioinguinal approach. In 3 cases with osteopenic bone patient-specific prebent fixation plates were helpful in guiding fracture reduction. Additionally, anatomical landmark based measurements were helpful for intraoperative navigation. Conclusion The presented prototype planning tool for pelvic surgery was successfully integrated in a clinical workflow to improve patient-specific preoperative planning, giving visual and haptic information about the injury and allowing a patient-specific adaptation of osteosynthesis implants to the virtually reduced pelvis.

Attacks on German public figures, 1968-2004: warning behaviors, potentially lethal and non-lethal acts, psychiatric status, and motivations

Fourteen non-terrorist attackers of public figures in Germany between 1968 and 2004 were intensively studied, with a particular focus on warning behaviors, attack behaviors, and the relationship between psychiatric diagnosis, symptoms, and motivations for the assault. A large proportion of the attackers were severely mentally ill, and most likely to be in the potentially lethal rather than the non-lethal group. A new typology of seven warning behaviors was applied to the data, and all were present, most frequently fixation and pathway warning behavior, and least frequently a direct threat. Psychiatric diagnosis could be closely linked to motivation when analyzed at the level of symptom and content of thought, often delusional. Most of the attacks were directed at political figures, and the majority occurred after 1995.

Disabling c-Myc in childhood medulloblastoma and atypical teratoid/rhabdoid tumor cells by the potent G-quadruplex interactive agent S2T1-6OTD

We investigated here the effects of S2T1-6OTD, a novel telomestatin derivative that is synthesized to target G-quadruplex-forming DNA sequences, on a representative panel of human medulloblastoma (MB) and atypical teratoid/rhabdoid (AT/RT) childhood brain cancer cell lines. S2T1-6OTD proved to be a potent c-Myc inhibitor through its high-affinity physical interaction with the G-quadruplex structure in the c-Myc promoter. Treatment with S2T1-6OTD reduced the mRNA and protein expressions of c-Myc and hTERT, which is transcriptionally regulated by c-Myc, and decreased the activities of both genes. In remarkable contrast to control cells, short-term (72-hour) treatment with S2T1-6OTD resulted in a dose- and time-dependent antiproliferative effect in all MB and AT/RT brain tumor cell lines tested (IC(50), 0.25-0.39 micromol/L). Under conditions where inhibition of both proliferation and c-Myc activity was observed, S2T1-6OTD treatment decreased the protein expression of the cell cycle activator cyclin-dependent kinase 2 and induced cell cycle arrest. Long-term treatment (5 weeks) with nontoxic concentrations of S2T1-6OTD resulted in a time-dependent (mainly c-Myc-dependent) telomere shortening. This was accompanied by cell growth arrest starting on day 28 followed by cell senescence and induction of apoptosis on day 35 in all of the five cell lines investigated. On in vivo animal testing, S2T1-6OTD may well represent a novel therapeutic strategy for childhood brain tumors.

Magnetic resonance imaging based determination of body compartments with the versatile, interactive sparse sampling (VISS) method

To investigate the inhomogeneity of radiofrequency fields at higher field strengths that can interfere with established volumetric methods, in particular for the determination of visceral (VAT) and subcutaneous adipose tissue (SCAT). A versatile, interactive sparse sampling (VISS) method is proposed to determine VAT, SCAT, and also total body volume (TBV).

A new model of interactive effects of alcohol and high-fat diet on hepatic fibrosis

Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) are the most frequent conditions leading to elevated liver enzymes and liver cirrhosis, respectively, in the Western world. However, despite strong epidemiological evidence for combined effects on the progression of liver injury, the mutual interaction of the pathophysiological mechanisms is incompletely understood. The aim of this study was to establish and analyze an experimental murine model, where we combined chronic alcohol administration with a NASH-inducing high-fat (HF) diet.

The major central endocannabinoid directly acts at GABA(A) receptors

GABA(A) receptors are the major ionotropic inhibitory neurotransmitter receptors. The endocannabinoid system is a lipid signaling network that modulates different brain functions. Here we show a direct molecular interaction between the two systems. The endocannabinoid 2-arachidonoyl glycerol (2-AG) potentiates GABA(A) receptors at low concentrations of GABA. Two residues of the receptor located in the transmembrane segment M4 of β(2) confer 2-AG binding. 2-AG acts in a superadditive fashion with the neurosteroid 3α, 21-dihydroxy-5α-pregnan-20-one (THDOC) and modulates δ-subunit-containing receptors, known to be located extrasynaptically and to respond to neurosteroids. 2-AG inhibits motility in CB(1)/CB(2) cannabinoid receptor double-KO, whereas β(2)-KO mice show hypermotility. The identification of a functional binding site for 2-AG in the GABA(A) receptor may have far-reaching consequences for the study of locomotion and sedation.