Humidification during high-frequency oscillation ventilation is affected by ventilator circuit and ventilatory setting

Background:  High-frequency oscillation ventilation (HFOV) is an accepted ventilatory mode for acute respiratory failure in neonates. As conventional mechanical ventilation, inspiratory gas humidification is essential. However, humidification during HFOV has not been clarified. In this bench study, we evaluated humidification during HFOV in the open circumstance of ICU. Our hypothesis is that humidification during HFOV is affected by circuit design and ventilatory settings.
Methods/Materials:  We connected a ventilator with HFOV mode to a neonatal lung model that was placed in an infant incubator set at 37°C. We set a heated humidifier (Fisher & Paykel) to obtain 37°C at the chamber outlet and 40°C at the distal temperature probe. We measured absolute humidity and temperature at the Y-piece using a rapid-response hygrometer. We evaluated two types of ventilator circuit: a circuit with inner heating wire and another with embedded heating element. In addition, we evaluated three lengths of the inspiratory limb, three stroke volumes, three frequencies, and three mean airway pressures.
Results:  The circuit with embedded heating element provided significantly higher absolute humidity and temperature than one with inner heating wire. As an extended tube lacking a heating wire was shorter, absolute humidity and temperature became higher. In the circuit with inner heating wire, absolute humidity and temperature increased as stroke volume increased.
Conclusion:  Humidification during HFOV is affected by circuit design and ventilatory settings.     

Does dispositional optimism predict psychological responses to counseling for familial breast cancer?

OBJECTIVE: The present study sought to assess the ability of dispositional optimism to predict the psychological responses of women with a family history of breast cancer who had been referred to counseling for familial breast cancer. METHODS: Women completed questionnaires prior to (n=735), immediately after (n=655), and 9 months after (n=545) attending counseling. Breast cancer risk status was assessed and communicated to the women in the clinics. RESULTS: Dispositional optimism was found to predict lower levels of anxiety and breast cancer worries immediately following counseling as well as lower levels of anxiety and perceived risk at 9-month follow-up, controlling for corresponding baseline scores. In addition, risk status moderated the optimism-perceived risk relationship, such that optimism was only predictive of lower risk perceptions among women at high risk. CONCLUSIONS: Low levels of dispositional optimism may be considered to be a risk factor for adverse reactions to high breast cancer risk information. The implications of the findings for the clinical management of such reactions are discussed.     

Alarin is a vasoactive peptide

Galanin-like peptide (GALP) is a hypothalamic neuropeptide belonging to the galanin family of peptides. The GALP gene is characterized by extensive differential splicing in a variety of murine tissues. One splice variant excludes exon 3 and results in a frame shift leading to a novel peptide sequence and a stop codon after 49 aa. In this peptide, which we termed alarin, the signal sequence of the GALP precursor peptide and the first 5 aa of the mature GALP are followed by 20 aa without homology to any other murine protein. Alarin mRNA was detected in murine brain, thymus, and skin. In accordance with its vascular localization, the peptide exhibited potent and dose-dependent vasoconstrictor and anti-edema activity in the cutaneous microvasculature, as was also observed with other members of the galanin peptide family. However, in contrast to galanin peptides in general, the physiological effects of alarin do not appear to be mediated via the known galanin receptors. Alarin adds another facet to the surprisingly high-functional redundancy of the galanin family of peptides.     

Neuroeffector Ca2+ transients for the direct measurement of purine release and indirect measurement of cotransmitters in rodents

Determining whether ATP and noradrenaline are released from the same vesicle at mature autonomic neuroeffector junctions is challenging because of the difficulty of simultaneously detecting the packeted release of these neurotransmitters. Contraction, overflow and electrophysiology experiments all show that both ATP and noradrenaline are released following field stimulation (although the ratio might vary) from autonomic nerves in tissues including the vas deferens, rat tail artery and mesenteric artery. The occurrence of purinergic neuroeffector Ca(2+) transients (NCTs) has been used to detect the packeted release of the neurotransmitter ATP acting on postjunctional P2X receptors to cause Ca(2+) influx. Neuroeffector Ca(2+) transients can also be used to detect the local effects of noradrenaline through its alpha(2)-adrenoceptor-mediated prejunctional autoinhibitory effects on nerve terminal Ca(2+) concentration and the probability of exocytosis (measured by counting NCTs). Evidence is presented that exocytosis from sympathetic varicosities does not occur in a manner independent of the history of that varicosity, but rather that the release of a packet of ATP transiently suppresses (or predicts the transient suppression of) subsequent release. This could arise by autoinhibition (by the prejunctional action of noradrenaline or purines) or due to a transient shortage of vesicles readily available for release. In summary, two high-resolution approaches are proposed to measure the intermittent release of packets of neurotransmitter: (1) local transient suppression of nerve terminal Ca(2+) transients; and (2) the local and transient inhibition of NCTs to infer local autoinhibition, hence transmitter release. Such approaches may allow the packeted corelease of ATP and noradrenaline to be investigated without the need to measure both neurotransmitters directly.     

Confounding and interaction effect of Treponema denticola salivary carriage in chronic periodontitis

Oral Diseases (2010) 16 , 278–285 Aim: To evaluate the salivary carriage of Treponema denticola and its association with demographic variables in the etiopathogenesis of chronic periodontitis. Subjects and methods: Ninety‐seven chronic periodontitis (CP) patients and a control group of 51 healthy subjects (HC) were selected. Periodontal status was assessed by criteria based on probing depth, attachment loss, extent, and severity of periodontal breakdown. A polymerase chain reaction method was used to determine the occurrence of T. denticola in saliva samples. Risk indicators for CP were assessed individually and adjusted for confounding and/or interaction using a logistic regression model. Results: Although univariate analysis revealed a positive association of age ≥30 years, smoking, and salivary carriage of T. denticola with CP, after logistic regression analysis, the association between age ≥30 years/smoking and CP persisted, whereas salivary carriage of T. denticola failed to achieve statistical significance. An interaction effect was significantly detected between these three variables. Conclusion: Although salivary carriage of T. denticola may be a risk indicator for CP, its pathogenicity should not be exclusively endorsed to its detection in saliva, but it might be associated with the synergistic biological interaction of the bacterium with some demographic characteristics of the susceptible host.     

Identification and structural elucidation of process impurities generated in the end-game synthesis of taranabant (MK-0364) via cyanuric chloride

Taranabant (MK-0364) is a highly potent and selective cannabinoid-1 receptor (CB-1R) inverse agonist. It is being developed at Merck & Company to treat obesity. The chemical synthesis of MK-0364 drug substance involved the direct coupling of chiral amine and pyridine acid side chains mediated by cyanuric chloride. Four major process impurities were observed and characterized using high performance liquid chromatography (HPLC) coupled with ultraviolet (UV) and electrospray ionization (ESI) mass spectrometry (MS) detectors. The exact mass data was used for structural elucidation which suggests that the impurities are derivatives of cyanuric chloride formed in the coupling step. Owing to the reactive nature of these impurities, an interesting degradation phenomenon was observed during stability testing of MK-0364 drug substance when stored at 40 °C/75% RH and 25 °C/60% RH conditions. Degradation pathways were proposed to explain the changes observed in the HPLC impurity profile. Forced degradation experiments were also conducted to confirm the degradation pathways and assess the stability of the impurities. Finally, the complete stability data of the bulk drug are reported to support the hypothesis.     

Pharmacogenetic characterization of indacaterol,a novel β2-adrenoceptor agonist

Background and purpose:

Indacaterol is a novel β₂-adrenoceptor agonist in development for the treatment of chronic obstructive pulmonary disease. The aim of this study was to investigate the comparative pharmacology of indacaterol in recombinant cells expressing the common polymorphic variants of the human β₂-adrenoceptor and in human primary airway smooth muscle (ASM) cells.

Experimental approach:

Chinese hamster ovarian-K1 cell lines expressing high and low levels of the common human β₂-adrenoceptor variants were generated [Gly16-Glu27-Val34-Thr164(GEVT), RQVT, GQVT] and also the rare GQVI variant. Human primary ASM cells were isolated from explants of trachealis muscle. Adenosine-3′,5′-cyclic-monophosphate production was used as an outcome measure.

Key results:

In both the low- and high-expression recombinant GEVT ‘wild type’ cell lines indacaterol is a high-efficacy agonist. Salmeterol and formoterol were identified as low- and high-efficacy agonists, respectively, and showed similar potencies to indacaterol irrespective of the β₂-adrenoceptor genotype. The I164 variant cell line was associated with a reduced capacity to generate adenosine-3′,5′-cyclic-monophosphate in response to β₂-adrenoceptor agonist. In the human primary ASM cells indacaterol gave a maximal response intermediate between that of salmeterol and formoterol.

Conclusions and implications:

These data demonstrate that indacaterol is a high-efficacy agonist in recombinant cell systems but acts with lower efficacy in human primary ASM cells. No marked genotype-dependent effects were observed for common variants; however, changes in I164 receptor activity were identified, which were dependent on the level of expression of β₂-adrenoceptors.     

Targeted Disruption of the Galanin Gene Attenuates Inflammatory Responses in Murine Skin

The release of neuropeptides from primary sensory nerve fibers has been implicated in the modulation of local immune responses in surface tissues, such as the skin and the gastrointestinal mucosa, thereby inducing neurogenic inflammation, which is characterized by plasma extravasation and vasodilatation. In addition, cytokines, either alone or in conjunction with neuropeptides, initiate recruitment of immunocompetent cells such as neutrophils during the initial phases of inflammation. Growing evidence suggests that the neuropeptide galanin plays an important role in skin immune defense and pathophysiology. In this paper, we report that adult mice carrying a loss-of-function mutation in the galanin gene (galanin knockout, Gal KO) demonstrate an absence of the normal neurogenic inflammatory response, upon treatment of the skin either with the vanilloid receptor 1 agonist capsaicin or noxious heat. Furthermore, a lack of an acute inflammatory edema induced by coinjection of substance P and calcitonin gene-related peptide was observed. In addition, Gal KO animals also exhibit a deficit in neutrophil accumulation in the skin after exposure to noxious heat, carrageenin, or tumor necrosis factor alpha. These data indicate that Gal KO mice demonstrate abnormal neurogenic inflammatory responses in murine skin compared to strain-matched wild-type mice.     

Variations in schedules of ifosfamide administration: a better understanding of its implications on pharmacokinetics through a randomized cross-over study

Feline soft tissue sarcomas are spontaneous, rapidly growing, and aggressive neoplasms that mimic their human counterpart. The purpose of this study was to evaluate the feasibility and efficacy of electrochemotherapy (ECT) in an adjuvant fashion for the treatment of feline sarcomas, and the possibility of repeated treatments in the case of recurrence. Cats with fibrosarcoma (FSA) were assigned to receive surgery or surgery plus ECT. Feline patients recruited in the ECT study were enrolled in a microscopic arm (39 patients) or a macroscopic arm (19 patients) on the basis of their tumor status (absence or presence of gross disease). Patients received local injection of bleomycin followed by bursts of eight biphasic pulses at a voltage of 1,300 V/cm for postoperative and of 800 V/cm for intraoperative treatments. The median time to recurrence was 4 months for cats treated with surgery alone, 19 months for the postoperative cohort, and 12 months for the intraoperative group. Moreover, ten patients with recurring neoplasms were retreated and experienced responses lasting 6 to 28+ months. Side effects were minimal. Of interest, the metastatic rate (1.7%) in our patients was negligible: only one cat had distant spread. The results suggest that ECT is a well tolerated and potentially useful addition to surgery in controlling high-grade sarcomas. On the basis of these results, additional evaluations are warranted in pets and in humans.