Optical characterization of the impact of 100 keV protons on the optical properties of ZrO2 films prepared by ALD on fused silica substrates.

Atomic layer deposition (ALD)-grown zirconia films underwent irradiation by 100 keV protons at fluences ranging from 1⋅1012 p +/c m 2 through 5⋅1014 p +/c m 2. The induced structural damage was modeled using the stopping and range of ions in matter (SRIM) and compared with the change of the optical properties characterized by ellipsometry, spectrophotometry, and x-ray reflectometry. Proton-induced contamination of the optical surface due to deposition of a carbon-rich layer was determined. Correct estimation of the substrate damage was shown to be critical for reliable evaluation of the optical constants of the irradiated films. The ellipsometric angle Δ is shown to be sensitive to both the presence of the buried damaged zone in the irradiated substrate and the contamination layer on the surface of the samples. The complex chemistry in carbon-doped zirconia accommodating over-stoichiometric oxygen is discussed, along with the impact of the film composition change on the refractive index of the irradiated films.

Dynorphinergic system alterations in the corticostriatal circuitry of neuropathic mice support its role in the negative affective component of pain.

The dynorphinergic system is involved in pain transmission at spinal level, where dynorphin exerts antinociceptive or pronociceptive effects, based on its opioid or non-opioid actions. Surprisingly, little evidence is currently available concerning the supraspinal role of the dynorphinergic system in pain conditions. The present study aimed to investigate whether neuropathic pain is accompanied by prodynorphin (Pdyn) and κ-opioid receptor (Oprk1) gene expression alterations in selected mouse brain areas. To this end, mice were subjected to chronic constriction injury of the right sciatic nerve and neuropathic pain behavioral signs were ascertained after 14 days. At this interval, a marked increase in Pdyn mRNA in the anterior cingulate cortex (ACC) and prefrontal cortex (PFC) was observed. Oprk1 gene expression was increased in the PFC, and decreased in the ACC and nucleus accumbens (NAc). No changes were observed in the other investigated regions. Because of the relationship between dynorphin and the brain-derived neurotrophic factor, and the role of this neurotrophin in chronic pain-related neuroplasticity, we investigated brain-derived neurotrophic factor gene (Bdnf) expression in the areas showing Pdyn or Oprk1 mRNAs changes. Bdnf mRNA levels were increased in both the ACC and PFC, whereas no changes were assessed in the NAc. Present data indicate that the dynorphinergic system undergoes quite selective alterations involving the corticostriatal circuitry during neuropathic pain, suggesting a contribution to the negative affective component of pain. Moreover, parallel increases in Pdyn and Bdnf mRNA at cortical level suggest the occurrence of likely interactions between these systems in neuropathic pain maladaptive neuroplasticity.

N/OFQ system in brain areas of nerve-injured mice: its role in different aspects of neuropathic pain.

Several studies showed that chronic pain causes reorganization and functional alterations of supraspinal brain regions. The nociceptin-NOP receptor system is one of the major systems involved in pain control and much evidence also suggested its implication in stress, anxiety and depression. Therefore, we investigated the nociceptin-NOP system alterations in selected brain regions in a neuropathic pain murine model. Fourteen days after the common sciatic nerve ligature, polymerase chain reaction (PCR) analysis indicated a significant decrease of pronociceptin and NOP receptor mRNA levels in the thalamus; these alterations could contribute to the decrease of the thalamic inhibitory function reported in neuropathic pain condition. Nociceptin peptide and NOP mRNA increased in the anterior cingulate cortex (ACC) and not in the somatosensory cortex, suggesting a peculiar involvement of this system in pain regulating circuitry. Similarly to the ACC, an increase of nociceptin peptide levels was observed in the amygdala. Finally, the pronociceptin and NOP mRNAs decrease observed in the hypothalamus reflects the lack of hypothalamus-pituitary-adrenal axis activation, already reported in neuropathic pain models. Our data indicate that neuropathic pain conditions affect the supraspinal nociceptin-NOP system which is also altered in regions known to play a role in emotional aspects of pain.

Effects of acute ethanol exposure on class I HDACs family enzymes in wild-type and BDNF(+/-) mice.

BACKGROUND: Alterations of brain-derived neurotrophic factor (BDNF) have been associated with the development of addiction to different drugs of abuse, including ethanol (EtOH). EtOH exposure activates the BDNF-signaling cascade in dorsal striatum, which in turn affects further EtOH intake. Different alcohol exposures have been widely demonstrated to modulate chromatin remodeling, affecting histone acetylation/deacetylation balance. Recently, class I histone deacetylases (HDACs) inhibition has been reported to modulate BDNF mRNA expression and to attenuate morphological and behavioral phenomena related to EtOH exposure. However, the role played by different HDAC isoforms in EtOH-induced plasticity is still unclear. METHODS: We investigated the effects induced by acute EtOH exposure on the protein levels of class I HDAC 1-3 isoforms of wild-type (WT) and BDNF heterozygous mice (BDNF(+/-)), in nuclear and cytoplasmic extracts of specific brain regions associated with EtOH addiction. RESULTS: Nuclear HDAC 1-3 levels were markedly reduced after acute EtOH treatment in the caudate putamen (CPu) of WT mice only. Furthermore, CPu basal levels of nuclear HDAC isoforms were significantly lower in BDNF(+/-) mice compared to WT. With the exception of nuclear HDAC 3, no significant changes were observed after acute EtOH treatment in the prefrontal cortex (PFCx) of BDNF(+/-) and WT mice. In this area, the nuclear HDAC basal levels were significantly different between the two experimental groups. CONCLUSIONS: These results provide details about EtOH effects on class I HDAC isoforms and strongly support a correlation between BDNF and class I HDACs, suggesting a possible influence of BNDF on these enzymes.

Impact of chronic viral diseases on semen parameters.

The aim of this study was to assess the effect of human immunodeficiency virus (HIV), hepatitis C (HCV) and B (HBV) virus infection on semen parameters. Semen samples were obtained from 27 HCV, 34 HIV, 30 HBV and 41 HCV-HIV-seropositive patients and compared with those of a control population of healthy seronegative subjects. Tests for detection of HIV, HCV and HBV were performed on seminal samples. The sperm concentration was significantly decreased in HCV- and HBV-seropositive males compared to that of controls (P < 0.001). The mean sperm motility (a + b) was significantly decreased in HCV- and HBV-seropositive (P < 0.001) and in HCV-HIV-seropositive subjects (P < 0.05) compared to that of controls. The sperm viability was significantly lower in HCV- and HBV-seropositive men than in controls (P < 0.001). The normal morphology was significantly reduced in HCV-seropositive and HBV-seropositive men (P < 0.05) with respect to that of controls (P < 0.05). The sperm concentration after sperm wash was significantly higher in controls than in HCV-, HIV-, HBV- and HIV-HCV-seropositive men (P < 0.001). We can conclude that HBV- and HCV-infected men have a significantly impaired sperm quality compared with that of controls. The reason for the better sperm quality in our series of HIV- and HCV-HIV-infected men is still under debate. Further investigations in a larger case series are warranted.

Non-functionalized silver nanoparticles for a localized surface plasmon resonance-based glucose sensor.

The optical properties of non-functionalized silver nanoparticles in ethanol solution have been analyzed and a progressive shift of localized surface plasmon resonances caused by the adding of increasing quantities of glucose has been observed. To understand this occurrence, the interaction of glucose molecules with the silver nanoparticle surface has been investigated using Raman spectroscopy. In addition, high resolution transmission electron microscopy shows the presence of superstructures on the silver nanoparticle surface that can be imputed to the presence of glucose.

Bacillus sonorensis sp. nov., a close relative of Bacillus licheniformis, isolated from soil in the Sonoran Desert, Arizona.

Eight Bacillus strains isolated from Sonoran Desert soil were shown to belong to a previously unidentified species, for which the name Bacillus sonorensis sp. nov. is proposed. The type strain is strain L87-10T (= NRRL B-23154T). On the basis of phenotypic and genetic data, B. sonorensis is most closely related to Bacillus licheniformis. B. sonorensis can be distinguished from B. licheniformis by salt tolerance, pigmentation, multilocus enzyme electrophoresis, reassociation of genomic DNA and sequence differences in protein-coding genes and 16S rRNA.

The pharmacokinetics and pharmacodynamics of irbesartan in heart failure.

Alterations in the pharmacokinetic parameters of a number of medications have been observed in patients with heart failure. Because the angiotensin II receptor antagonist irbesartan has beneficial effects in patients with heart failure, the pharmacokinetics and pharmacodynamics of irbesartan in 10 patients with New York Heart Association (NYHA) class II or III heart failure compared with 10 control subjects matched with respect to race, age, weight, and sex were studied. In a crossover study, participants were randomized to receive open-label irbesartan 75 mg as either an oral capsule or an intravenous (i.v.) infusion in the first treatment period. After a 7- to 10-day washout period, participants were crossed over to the other treatment arm. Single-dose noncompartmental pharmacokinetic parameters, angiotensin II levels, and plasma renin activity (PRA) of irbesartan were determined for each participant. Following oral and i.v. administration, the pharmacokinetics of irbesartan in patients with heart failure was not significantly different from those of matched controls, indicating that there is little influence of potential changes in organ/tissue perfusion and gut edema on the absorption, distribution, and elimination of irbesartan. After dosing with irbesartan, mean increases in angiotensin II and PRA concentrations were higher in patients with heart failure than in the matched controls, but there was more interpatient variability in the patients with heart failure. Given the variability of the data, no definitive conclusions can be made with regard to these pharmacodynamic parameters. The results of this study indicate that the pharmacokinetics of irbesartan following oral and i.v. administration is not altered in patients with heart failure. Therefore, this indicates that no dosage adjustment is needed when prescribing irbesartan in heart failure patients.

Percutaneous absorption and pharmacokinetics of eflornithine HCl 13.9% cream in women with unwanted facial hair.

This article reports the results of an open-label, multiple-dose study to determine percutaneous absorption and pharmacokinetics of eflornithine following topical treatment with eflornithine HCl 13.9% cream (Vaniqa). Ten women with excessive facial hair were treated with two 0.5 g single doses of [14C]-labeled eflornithine HCl 13.9% (w/w) cream (periods A and C) separated by twice-daily application of 0.5 g unlabeled eflornithine HCl 13.9% cream for 7 days (period B). Analysis of radioactivity excreted in urine and feces indicated that percutaneous absorption was minimal. Comparison with urinary excretion of eflornithine in period A suggested that most of absorbed eflornithine was excreted in urine without being metabolized. Radioactivity was not detectable in blood or plasma, but eflornithine concentrations were measurable, with peak concentrations of 4.96 ng/ml in period A and 10.44 ng/ml in period C. Eflornithine was eliminated from plasma with a mean terminal half-life of 11 hours (first application) and 8 hours (final application). Trough plasma concentrations reached steady state (4.61-5.50 ng/ml) after 4 days of twice-daily topical treatment, and multiple dosing had no apparent effect on disposition kinetics. The low degree of percutaneous absorption and low systemic exposure to eflornithine offer a favorable clinical safety profile of eflornithine HCl 13.9% cream.

Human dermal safety studies with eflornithine HCl 13.9% cream (Vaniqa), a novel treatment for excessive facial hair.

Eflornithine HCl 13.9% cream (Vaniqa) is a novel treatment for the management of unwanted facial hair in women. This paper reports the results of four modified open-label, within-subject vehicle-controlled studies evaluating the dermal safety of this topical treatment. In a repeated insult patch test (230 subjects), erythema with oedema occurred in 38.9% of subjects treated with eflornithine HCl 13.9% cream and 4.8% of subjects treated with vehicle cream. Challenge applications at previously untested sites following the three-week induction period produced noticeable erythema or greater on only four sites treated with eflornithine HCl 13.9% cream and one vehicle-treated site. The erythema at these sites subsided substantially within 24 hours. In a three-week cumulative irritation study (30 subjects), the mean irritation score for sites treated with eflornithine HCl 13.9% cream was 1.33, compared with 0.76 at vehicle-treated sites and 3.09 at positive-control (sodium lauryl sulphate-treated) sites (p < 0.001 between all three groups). In a phototoxicity study (25 subjects), irradiated sites showed either no reaction (40% of both sites treated with eflornithine HCl 13.9% cream and vehicle-treated sites), or mild erythema subsiding in all cases but one within 24 hours. No reaction was seen at non-irradiated sites. In a photocontact allergy study (30 subjects), challenge with eflornithine HCl 13.9% cream or its vehicle alone produced either no reaction or mild erythema subsiding within 24 hours at both irradiated and non-irradiated sites. No serious adverse events were reported during the studies, and the only adverse events considered related to treatment were pruritus (three subjects) and dry skin at test site (one subject). These results demonstrate that eflornithine HCl 13.9% cream does not have contact sensitising, photocontact allergic or phototoxic properties. It can cause irritation under exaggerated conditions of use. Eflornithine HCl 13.9% cream, therefore, has a favourable dermal safety profile appropriate for a topical treatment to be applied routinely.

Premature closure of the proximal physis of the humerus in a dog as a result of harvesting a cancellous bone graft.

A 5-month-old castrated male mixed-breed dog was evaluated because of lameness of the right forelimb. Physical examination revealed pain on manipulation of the right elbow joint, and radiography revealed premature closure of the distal physis of the radius with subluxation of the right elbow joint. Corrective osteotomy of the radius was performed to increase the length of the radius and establish congruity of the elbow joint. Cancellous bone was obtained from the proximal portion of the humerus and used as a graft at the osteotomy site. The dog did well after surgery. Four months after surgery, the dog again was lame on the right forelimb. Physical examination revealed instability of the right shoulder, and manipulation of that area elicited signs of pain. Radiography revealed caudomedial subluxation of the right shoulder as well as deformity of the humeral head and hypoplasia of the greater tubercle. It was presumed that these changes were associated with collection of the cancellous bone graft during the initial surgery, which resulted in premature closure of the proximal physis of the humerus. To our knowledge, this is the first report of premature closure of the proximal physis of the humerus as a result of procurement of a bone graft.

Pharmacokinetics and tolerability of formoterol in healthy volunteers after a single high dose of Foradil dry powder inhalation via Aerolizer.

OBJECTIVE: The pharmacokinetics of the long-acting beta2-agonist formoterol fumarate, which is a racemate of the (S,S)- and (R,R)-enantiomers were evaluated in 12 healthy (eight male, four female) volunteers after a single inhaled high dose of 120 microg of formoterol fumarate. The tolerability and safety were also assessed. METHODS: Each volunteer inhaled the single 120-microg dose through the Aerolizer device within 2-5 min, using ten 12-microg dry powder capsules for inhalation. Formoterol, i.e., the sum of both enantiomers, was determined in plasma over 24 h, whereas the separate enantiomers were determined in urine over 48 h. Incidence, seriousness and severity of adverse experiences, electrocardiogram (ECG), including the corrected QT interval (QTc) calculation, systolic blood pressure, heart rate, and plasma potassium levels were recorded. RESULTS: In nine of the 12 volunteers, the peak plasma concentration of formoterol was observed already at 5 min after inhalation. The absorption kinetics were complex, as depicted by multiple peaks or shoulders within 0.5-6 h after inhalation. Mean with (SD; n = 12) of maximum concentration (Cmax) and area under the curve (AUC) of formoterol in plasma were 266 (108) pmol x l(-1) and 1330 (398) pmol x l(-1), respectively. The moderate inter-individual variability in systemic exposure of formoterol reflects the homogeneous pharmacokinetics of the drug. A predominant slow elimination of formoterol from plasma with a mean half-life (t1/2) of 10 h was demonstrated. Assuming linear kinetics in plasma suggested by urinary data, the steady-state trough plasma levels of formoterol for a b.i.d. dosing regimen are predicted to amount to 20% of Cmax. In urine, mean with (SD; n = 10) of the amount excreted over 48 h was 3.61 (0.89)% of dose for the pharmacologically active (R,R)-enantiomer and 4.80 (1.33)% of dose for the (S,S)-enantiomer. The terminal half-lives calculated from the excretion rate-time curves, i.e., 13.9 h and 12.3 h for the (R,R)- and (S,S)-enantiomer, respectively, confirm the slow elimination of formoterol from plasma. The dose inhaled was 10 times the most frequently recommended dose (12 microg) and 5 times the highest recommended dose (24 microg). Ten of 12 subjects experienced mild and transient nervousness. Pulse readings demonstrated the maximum mean increase of 25.8 beats x min(-1) at 6 h. The mean maximum QTc increase was 25 msec at 6 h. Pulse and QTc values returned to baseline or close to baseline values at 24 h or before. Potassium levels in plasma decreased in eight out of 12 subjects; the lowest mean value was 3.53 mmol x l(-1) at 2 h post-dose. The lowest individual potassium measurement was 2.95 mmol x l(-1) between 15 min and 6 h. By 8 h post-dose all values had returned to within the normal ranges. CONCLUSIONS: The extremely fast appearance of formoterol in plasma shows the predominance of airways absorption shortly after inhalation. Due to a terminal elimination half-life of about 10 h, sustained systemic concentrations of formoterol are predicted for a twice daily treatment regimen without noteworthy accumulation. The excreted amounts in percent of dose of the enantiomers in urine and the enantiomer ratio are similar to data reported previously after lower doses and suggest linear kinetics for doses between 12 microg and 120 microg of formoterol fumarate. The expected side effects on heart rate, QTc interval, and plasma potassium were small and had no clinical consequences in spite of the very high dose of 120 microg (5 to 10 times the recommended therapeutic dose of Foradil). It should be noted that the impact of high doses may be greater in patients. Nevertheless these findings provide reassurance on the safety margin of formoterol after accidental and intentional overdosing.

Effect of renal impairment on the pharmacokinetics and pharmacodynamics of desirudin.

OBJECTIVE: To investigate the pharmacokinetics and pharmacodynamics of desirudin in subjects with various degrees of renal impairment in comparison with subjects with normal renal function. METHODS: Eight subjects with normal renal function (creatinine clearance > 90 ml/min) received 0.5 mg/kg desirudin intravenously over 30 minutes. Four subjects with mild renal failure (creatinine clearance between 61 and 90 ml/min) received 0.5 mg/kg. Five subjects with moderate renal failure (creatinine clearance between 31 and 60 ml/min) received 0.25 mg/kg. Six subjects with severe renal failure (creatinine clearance < 31 ml/min) received 0.125 mg/kg. RESULTS: Specific maximum concentration values (maximum concentrations corrected to a dose of 1 mg/kg) increased slightly with decreasing creatinine clearance. Mean specific area under the plasma concentration-time curve increased by a factor of 1.15, 2.83, and 7.0 for subjects with mild, moderate, and severe renal failure, respectively, compared with healthy subjects. Total urinary excretion of desirudin was about 55% to 60% of the dose in all four groups; elimination was delayed for subjects with moderate and severe renal failure. Total and renal clearance of desirudin were proportional to creatinine clearance. Total plasma clearance of desirudin was proportional to renal clearance of the drug. Prolongation of activated partial thromboplastin time was increased among subjects with moderate and severe renal failure despite a dose reduction. Area under the dynamic activated partial thromboplastin time curve for subjects with moderate renal failure remained the same as that for healthy subjects despite a dose reduction by a factor of two. Area under the dynamic curve increased by a factor of about 1.5 for subjects with severe renal failure despite a dose reduction by a factor of four. CONCLUSION: A dose reduction by a factor of six is recommended for persons with severe renal failure.

The effect of valsartan on the angiotensin II pressor response in healthy normotensive male subjects.

OBJECTIVE: Valsartan is an oral antagonist of angiotensin II that competes with angiotensin II for the AT1-receptor and is being developed as an antihypertensive agent. This study assessed the ability of 80 mg valsartan to inhibit the pressor effect of exogenous angiotensin II in healthy normotensive men, first after a single dose and then after multiple doses once daily for 7 days. METHODS: This was a single-center, double-blind, placebo-controlled, randomized crossover study. Six healthy men underwent angiotensin II challenges to determine a suitable dose required to increase their systolic blood pressure by approximately 30 mm Hg. Each subject then received an 80 mg dose of valsartan or matching placebo. The inhibition of the angiotensin II pressor effect was determined by the systolic blood pressure response to repeated angiotensin II challenges at multiple time points. RESULTS: Systolic blood pressure responses to angiotensin II challenges after single and multiple doses of valsartan were significantly lower than placebo, indicating that valsartan blocked the blood pressure response to angiotensin II. The maximum blocking effect was observed within 2 to 3 hours. Mean data suggested that differences in effect between valsartan and placebo were similar after both single and multiple doses and persisted up to 24 hours after administration. The angiotensin II blocking effect was maintained up to this time, despite low plasma valsartan levels and minimal accumulation after multiple doses. CONCLUSION: Valsartan, 80 mg, is a potent angiotensin II antagonist with a rapid onset of action and persistent angiotensin II inhibition up to 24 hours. There is no attenuation of this effect after multiple doses.

[Anatomopathological and clinical aspects of primary gastric lymphoma]. / Aspetti anatomopatologici e clinici del linfoma gastrico primitivo.

The authors utilised several reviews of the literature and own experience based on 6 cases of non Hodgkin's primary gastric lymphoma. They refer about the importance and the difficulties to make differential diagnosis and on the staging. The authors believe that the treatment of choice is a surgical therapy but the role of radiotherapy and chemotherapy is very interesting in several cases.

[Purified human IgG administration, after chemotherapy, to patients with colorectal carcinoma]. / La somministrazione, dopo chemioterapia, di IgG umane purificate in pazienti affetti da carcinoma del colon-retto.

The authors, in the present study try to test the prophylactic effect of human IgG on surgical patients affected by colorectal cancer and undergoing chemotherapy in order to prevent microbial infections, supporting immunological host defences.

The specificity of the cAMP receptor mediating activation of adenylate cyclase in Dictyostelium discoideum.

In Dictyostelium discoideum amoebae, binding of cyclic AMP (cAMP) to surface receptors elicits numerous responses including chemotaxis, cyclic GMP (cGMP) accumulation, and activation of adenylate cyclase. The specificity of the surface cAMP receptor which mediates activation of adenylate cyclase and cAMP secretion was determined by testing the relative effectiveness of a series of 10 cAMP analogs. Each of the 10 analogs elicited cAMP secretion, chemotaxis, and cGMP accumulation in the same dose range. The order of potency for eliciting these responses (cAMP greater than 2'-H-cAMP greater than N1-O-cAMP greater than cAMPS(Sp) greater than 6-Cl-cAMP greater than cAMPN(CH3)2(Sp) greater than 3'-NH-cAMP greater than 8-Br-cAMP greater than cAMPS(Rp) greater than cAMPN(CH3)2(Rp] matches that for binding to the major cell surface cAMP binding sites and differs from that of the cell surface phosphodiesterase and the major intracellular cAMP binding protein.