Physical Model for Investigating Intracranial Pressure with Clinical Pressure Sensors and Diagnostic Ultrasound: Preliminary Results.

Introduction: Intracranial pressure (ICP) is a commonly collected neurocritical parameter, but accurate signal modelling remains challenging. The goal of this project was to mimic clinical ICP waveforms using a physical model.

Materials And Methods: A physical head model was developed.

Polycomb regulation is coupled to cell cycle transition in pluripotent stem cells.

When self-renewing pluripotent cells receive a differentiation signal, ongoing cell duplication needs to be coordinated with entry into a differentiation program. Accordingly, transcriptional activation of lineage specifier genes and cell differentiation is confined to the G phase of the cell cycle by unknown mechanisms. We found that Polycomb repressive complex 2 (PRC2) subunits are differentially recruited to lineage specifier gene promoters across cell cycle in mouse embryonic stem cells (mESCs).

The Chemogenetic Receptor Ligand Clozapine N-Oxide Induces Neuroreceptor Occupancy and Reduces Striatal Glutamate Levels.

Chemogenetic studies with the ligand clozapine N-oxide (CNO) are predicated upon the assumption that CNO is devoid of actions at natural neuroreceptors. However, recent evidence shows that CNO may be converted back to clozapine (CLZ) , which could yield plasma concentrations that may be sufficient to occupy inter alia dopamine D and serotonin 5HT receptors in living brain. To test this phenomenon, we measured striatal dopamine D receptor occupancy with [F]fallypride PET and serotonin 5HT occupancy using [F]MH.

Ensemble theory for slightly deformable granular matter.

Given a granular system of slightly deformable particles, it is possible to obtain different static and jammed packings subjected to the same macroscopic constraints. These microstates can be compared in a mathematical space defined by the components of the force-moment tensor (i.e.

Impact of the timestep in some molecular dynamics simulations on compression of granular systems.

We conduct two-dimensional molecular dynamics simulations to study the statistical distribution of the force-moment (defined as stress multiplied by volume) of static granular packings under external isotropic compression. To that end, we generate packings by compressing initially ordered lattices using irregular, randomly generated, walls. Velocity-Verlet algorithm and linear spring-dashpot interactions are employed.

Population pharmacokinetics of prophylactic cefoxitin in patients undergoing colorectal surgery.

Purpose: To elucidate whether a dose of 2 g cefoxitin as a prophylactic agent in patients undergoing elective colorectal surgery is able to maintain free drug concentrations above the minimum inhibitory concentration of the microorganisms involved in surgical site infection.

Methods: This was a prospective study involving 56 patients electively undergoing rectal or colon surgery. All plasma concentration-time data were analyzed simultaneously using the population approach to estimate population pharmacokinetic parameters and study the influence of the subjects' demographic characteristics, disease status, surgical procedure, and clinical laboratory values on the pharmacokinetic properties of cefoxitin.

Inhibition of vascular endothelial growth factor (VEGF)-induced endothelial proliferation, arterial relaxation, vascular permeability and angiogenesis by dobesilate.

Vascular endothelial growth factor (VEGF) is a key factor in angiogenesis and vascular permeability which is associated with many pathological processes. 2,5-hydroxybenzene sulfonate (DHBS; dobesilate) is a small molecule with anti-angiogenic activity that has been described as an inhibitor of fibroblast growth factors (FGF). The aim of the present study was to evaluate the effects of DHBS on VEGF-induced actions.

The novel antioxidant, AC3056 (2,6-di-t-butyl-4-((dimethyl-4-methoxyphenylsilyl)methyloxy)phenol), reverses erectile dysfunction in diabetic rats and improves NO-mediated responses in penile tissue from diabetic men.

Introduction: Diabetes is associated with a high incidence of erectile dysfunction (ED) and poor response to standard treatments. Oxidative stress could be relevant in the pathophysiology of diabetic ED.

Aim: To evaluate the effects of the antioxidant, AC3056 (2,6-di-t-butyl-4-((dimethyl-4-methoxyphenylsilyl)methyloxy)phenol), on diabetic ED.

Integrating partners into erectile dysfunction treatment: improving the sexual experience for the couple.

Introduction: Erectile dysfunction (ED) is a common condition estimated to affect more than 150 million men worldwide. ED should be regarded as a shared sexual problem which has significant detrimental effects both on the men who experience this condition and on their partners.

Evidence To Support Partner Involvement In Ed Therapy: Evidence shows that the partner plays a key supportive role in the man's ED treatment and in successful long-term ED therapy.

Antidepressant-induced inhibition of genital vascular responses is reversed by vardenafil in female rabbits.

Introduction: Administration of serotonin reuptake inhibitors (SRI) or serotonin and norepinephrine reuptake inhibitors (SNRI) relieves depressive symptoms but may cause sexual dysfunction in women and men.

Aim: The aim of the present study was to evaluate the effects of the phosphodiesterase type 5 (PDE5) inhibitor, vardenafil, on inhibition of genital vascular responses (GVR) induced by SRI or SNRI administration in female rabbits.

Methods: Vaginal and clitoral vasodilatory responses to pelvic nerve electrical stimulation were measured by laser Doppler flow needle probes.

Enhanced thromboxane receptor-mediated responses and impaired endothelium-dependent relaxation in human corpus cavernosum from diabetic impotent men: role of protein kinase C activity.

We have evaluated the influence of protein kinase C (PKC) activity on penile smooth muscle tone in tissues from diabetic and nondiabetic men with erectile dysfunction. Human corpus cavernosum (HCC) strips were obtained from impotent diabetic and nondiabetic men at the time of penile prosthesis implantation and studied in organ chambers. Contractility responses to a prostanoid precursor, to prostanoids, and to the endothelium-dependent vasodilator acetylcholine were studied.

[Hepatic portal venous gas. Clinical significance and review of the literature].

Hepatic portal venous gas in adults is a rare entity. The most frequent cause is intestinal ischemia. However, an increasing number of cases associated with benign conditions suitable for conservative treatment are being reported.

Synthesis and structure-activity relationships of a new model of arylpiperazines. 8. Computational simulation of ligand-receptor interaction of 5-HT(1A)R agonists with selectivity over alpha1-adrenoceptors.

We have designed and synthesized a new series of arylpiperazines V exhibiting high 5-HT(1A)R affinity and selectivity over alpha(1)-adrenoceptors. The new selective 5-HT(1A)R ligands contain a hydantoin (m = 0) or diketopiperazine (m = 1) moiety and an arylpiperazine moiety separated by one methylene unit (n = 1). The aryl substituent of the piperazine moiety (Ar) consists of different benzofused rings mimicking the favorable voluminous substituents at ortho and meta positions predicted by 3D-QSAR analysis in the previously reported series I.

Localization of MRX82: a new nonsyndromic X-linked mental retardation locus to Xq24-q25 in a Basque family.

Clinical and molecular studies are reported on a Basque family (MRX82) with nonsyndromic X-linked mental retardation (XLMR) in five affected males. A total of 38 microsatellite markers were typed. The XLMR locus has been linked to DXS8067, DXS1001, DXS425, DXS7877, and DXS1183 with a maximum LOD score of 2.

Benzimidazole derivatives. Part 5: design and synthesis of new benzimidazole-arylpiperazine derivatives acting as mixed 5-HT1A/5-HT3 ligands.

A series of new mixed benzimidazole-arylpiperazine derivatives were designed by incorporating in general structure III the pharmacophoric elements of 5-HT(1A) and 5-HT(3) receptors. Compounds 1-11 were synthesized and evaluated for binding affinity at both serotoninergic receptors, all of them exhibiting high 5-HT(3)R affinity (K(i)=10-62nM), and derivatives with an o-alkoxy group in the arylpiperazine ring showing nanomolar affinity for the 5-HT(1A)R (K(i)=18-150nM). Additionally, all the synthesized compounds were selective over alpha(1)-adrenergic and dopamine D(2) receptors (K(i)>1000-10,000nM).

Therapeutic strategies for optimizing PDE-5 inhibitor therapy in patients with erectile dysfunction considered difficult or challenging to treat.

Phosphodiesterase 5 (PDE5) inhibitors prevent the normal hydrolysis of cGMP. As the resulting cGMP accumulation facilitates penile smooth muscle relaxation, PDE5 inhibitors can partially reverse deficiencies in the nitric oxide (NO)/cGMP pathway to treat erectile dysfunction (ED). However, approximately 30-40% of men with ED do not respond to drug therapy.

Design and synthesis of new benzimidazole-arylpiperazine derivatives acting as mixed 5-HT1A/5-HT3 ligands.

A series of new benzimidazole-arylpiperazine derivatives III were designed, synthesized and evaluated for binding affinity at serotoninergic 5-HT(1A) and 5-HT(3) receptors. Compound IIIc was identified as a novel mixed 5-HT(1A)/5-HT(3) ligand with high affinity for both serotonin receptors and excellent selectivity over alpha(1)-adrenergic and dopamine D(2) receptors. This compound was characterized as a partial agonist at 5-HT(1A)Rs and a 5-HT(3)R antagonist, and was effective in preventing the cognitive deficits induced by muscarinic receptor blockade in a passive avoidance learning test.

Design and synthesis of S-(-)-2-[[4-(napht-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-a]pyrazine (CSP-2503) using computational simulation. A 5-HT1A receptor agonist.

Based on a computational model for 5-HT(1A)R-ligand interaction and QSAR studies, we have designed and synthesized a new series of arylpiperazines 2-8 which exhibit high 5-HT(1A)R affinity and selectivity over alpha(1)-adrenergic receptors. Among them, compound CSP-2503 (4) has been pharmacologically characterized as a 5-HT(1A)R agonist at somatodendritic and postsynaptic sites, endowed with anxiolytic properties.

Development of explicit criteria for cholecystectomy.

Objective: Consensus development techniques were used in the late 1980s to create explicit criteria for the appropriateness of cholecystectomy. New diagnostic and treatment techniques have been developed in the last decade, so an updated appropriateness of indications tool was developed for cholecystectomy in patients with non-malignant diseases. The validity and reliability of panel results using this tool were tested.

Benzimidazole derivatives. 2. Synthesis and structure-activity relationships of new azabicyclic benzimidazole-4-carboxylic acid derivatives with affinity for serotoninergic 5-HT(3) receptors.

A new series of azabicyclic benzimidazole-4-carboxamides 2-21 and -carboxylates 22-30 were synthesized and evaluated for binding affinity at serotoninergic 5-HT(3) and 5-HT(4) receptors in the CNS. Most of the synthesized compounds exhibited high or very high affinity for the 5-HT(3) binding site and low to no significant affinity for the 5-HT(4) receptor. SAR observations indicated that a halogen atom at the 6-position and a nitro group at the 7-position of the benzimidazole ring is the best substitution pattern for 5-HT(3) affinity and 5-HT(3)/5-HT(4) selectivity, as well as no substitution in this ring.

Design and evaluation of nitrosylated alpha-adrenergic receptor antagonists as potential agents for the treatment of impotence.

We designed and evaluated a new class of molecules, nitrosylated alpha-adrenergic receptor antagonists, as potential agents for the treatment of impotence. In in vitro studies with human and rabbit corpus cavernosum strips in organ chambers, the alpha-adrenergic receptor antagonists (alpha-ARAs) moxisylyte and yohimbine and their corresponding nitrosylated compounds, SNO-moxisylyte (NMI-221) and SNO-yohimbine (NMI-187), concentration-dependently relaxed endothelin-induced contraction. The nitrosylated compounds were significantly more potent than the parent alpha-ARA.

Buckling of cylinders may cause prolonged penile pain after prosthesis implantation: a case control study using magnetic resonance imaging of the penis.

Purpose: We identify risk factors associated with chronic postoperative penile pain after inflatable prosthesis insertion.

Materials And Methods: We performed a case control study to determine the incidence of prolonged penile pain in 65 men who underwent prosthesis insertion. The association of various potential risk factors, including diabetes mellitus, incision site, prosthesis type, patient age and history of pelvic surgery, was assessed.

Prostanoid production in rabbit corpus cavernosum: I. regulation by oxygen tension.

Purpose: To investigate the effects of oxygen tension on prostanoid synthesis in rabbit penile corpus cavernosum tissue (RCC) in organ culture.

Materials And Methods: Strips of rabbit corpus cavernosum were incubated in organ culture media under varying oxygen conditions (0%, 12% and 21% oxygen), in the presence or absence of acetylcholine and arachidonate stimulation. Prostanoids were measured in collected media by radioimmunoassay.