Effects of a selective histamine H4R antagonist on inflammation in a model of carrageenan-induced pleurisy in the rat.

The histamine H4 receptor (H4R), recently cloned and identified, is a G-protein coupled histamine receptor family expressed in immune cells which plays an important role in inflammation. Recent data evidentiated that H4R antagonists can decrease airway inflammation and hyperreactivity in animal models of asthma. In the present study we evaluated the effect of the selective H4R antagonist JNJ7777120 (JNJ) in carrageenan-induced pleurisy, an in vivo model of inflammation, well characterized for cellular and molecular mechanisms. Intra-pleural administration of λ-carrageenan (1% w/v in 0.2 ml sterile saline) determined an intense recruitment of leucocytes in pleural exudates and in lung tissues, activated inducible nitric oxide (NO) synthase and cyclooxygenase-2, thus increasing the generation of harmful autacoids such as NO and pro-inflammatory prostaglandins, PgE2 and 6-ketoPgF(1α), increased cellular and DNA oxidative stress, measured as malondialdehyde and 8-OH-deoxyguanosine and the local generation of IL-1ß and TNF-α. Moreover, the activity of caspase-3, an early marker of apoptosis was also activated by λ-carrageenan injection. The pre-treatment with JNJ (5-10 mg Kg⁻¹ b.wt., given intrapleurally), 60 min before carrageenan markedly reduced all the studied parameters. This study clearly demonstrated that histamine H4R antagonists have anti-inflammatory effects and could have potential therapeutic application for the treatment of inflammatory diseases.

A selective antagonist of histamine H4 receptors prevents antigen-induced airway inflammation and bronchoconstriction in guinea pigs: involvement of lipocortin-1.

BACKGROUND AND PURPOSE: Among the pathogenic mechanisms of asthma, a role for oxidative/nitrosative stress has been well documented. Recent evidence suggests that histamine H4 receptors play a modulatory role in allergic inflammation. Here we report the effects of compound JNJ 7777120 (JNJ), a selective H4 receptor antagonist, on antigen-induced airway inflammation, paying special attention to its effects on lipocortin-1 (LC-1/annexin-A1), a 37 kDA anti-inflammatory protein that plays a key role in the production of inflammatory mediators. EXPERIMENTAL APPROACH: Ovalbumin (OA)-sensitized guinea pigs placed in a respiratory chamber were challenged with antigen. JNJ (5, 7.5 and 10 mg.kg⁻¹) was given i.p. for 4 days before antigen challenge. Respiratory parameters were recorded. Bronchoalveolar lavage (BAL) fluid was collected and lung specimens taken for further analyses 1 h after antigen challenge. In BAL fluid, levels of LC-1, PGD2 , LTB4 and TNF-α were measured. In lung tissue samples, myeloperoxidase, caspase-3 and Mn-superoxide dismutase activities and 8-hydroxy-2-deoxyguanosine levels were measured. KEY RESULTS: OA challenge decreased LC-1 levels in BAL fluid, induced cough, dyspnoea and bronchoconstriction and increased PGD2 , LTB4 and TNF-α levels in lung tissue. Treatment with JNJ dose-dependently increased levels of LC-1, reduced respiratory abnormalities and lowered levels of PGD2 , LTB4 and TNF-α in BAL fluid. CONCLUSIONS AND IMPLICATIONS: Antigen-induced asthma-like reactions in guinea pigs decreased levels of LC-1 and increased TNF-α and eicosanoid production. JNJ pretreatment reduced allergic asthmatic responses and airway inflammation, an effect associated with LC-1 up-regulation.

Word recall correlates with sleep cycles in elderly subjects.

Morning recall of words presented before sleep was studied in relation to intervening night sleep measures in elderly subjects. Night sleep of 30 elderly subjects aged 61-75 years was recorded. Before sleep, subjects were presented with a list of paired non-related words and cued recall was asked immediately after the morning awakening. Recall positively correlated with average duration of NREM/REM cycles, and with the proportion of time spent in cycles (TCT) over total sleep time (TST). No significant correlations were found with other sleep or wake measures. These results suggest the importance of sleep structure for sleep-related memory processes in elderly adults.

Slow wave sleep (SWS) distribution across night sleep episode in the elderly.

Slow wave sleep (SWS) distribution across night sleep was shown to be different between infants and young adults. The present research aimed at studying the SWS distribution across night sleep in elderly subjects. Nine healthy elderly subjects, 61-71 years old, were submitted to nocturnal polygraphic sleep recording. Eleven young subjects, 21-23 years old, were the control group. Recordings were visually analyzed according to Rechtschaffen and Kales rules; the method proposed by Webb and Dreblow was used for scoring SWS. An NREM-REM cycle was defined as a sequence of NREM and REM sleep not interrupted by a waking period longer than 15 minutes. SWS percentage was calculated for each successive NREM episode. No significant association between SWS percentage and cycle rank was shown in elderly subjects, whereas a significant association was observed in the young ones. This kind of SWS distribution could be interpreted as reflecting the restructuring of internal organization of sleep in the elderly.

Functional uncertainty, aging and memory processes during sleep.

Disorganized sleep patterns, can be found both during normal development and in pathological conditions. Aging could also be accompanied by a disorganization of the night sleep episode; sleep could be interrupted by spontaneous awakening, sleep cycle could be shortened or incomplete, sleep states modified. These patterns suggest an inability to sustain a stable condition, i.e. a condition of functional uncertainty. Biological and cognitive implications of functional uncertainty conditions are discussed. In particular, the hypothesis has been put forward that disturbances of sleep could have a detrimental role on memory. Recent results obtained in our lab support this hypothesis: recall is correlated with NREM-REM cycles proportion. Future research should ascertain the role of the functional uncertainty with respect to the kind of memory being involved during sleep, and establish how much and for which cognitive processes (including those involved in dream production) the inability to sustain a steady condition impairs the functioning during sleep. The duration of the functional uncertainty condition is also important. The long-term study of the link between functional uncertainty and cognitive resources, could be important for the understanding of the night life and for an adequate treatment of patients.

[Cefoxitin in emergency surgery]. / La cefoxitina in chirurgia d'urgenza.

In basic pharmacological studies, sodium cefoxitin has proved to possess the following features: a broad action spectrum, resistance to bacterial beta-lactamase, activity against anaerobic species, rapid distribution, rapid serum and bile concentration, rapid, elevated excretion in the urine in active form, and low local and general toxicity. Patients in an Emergency Surgery Department often present the following conditions: highly compromised general situation, serious, often polymicrobic sepsis with aerobic and anaerobic flora, prior treatment without result with various cycles of chemo-antibiotic treatment. The theoretical conditions therefore exist to assess the effectiveness of sodium cefoxitin in patients admitted to an emergency surgery department and presenting serious post-surgical or post-traumatic sepsis, or sepsis due to pathology that can be corrected surgically. A study of 14 patients (3 g i.v. or i.m. for 6 days) showed 71% complete cure, 21% definite improvements and one death (treatment commenced 36 hours prior to death). It is therefore maintained that sodium cefoxitin is particularly indicated as first-choice antibiotic in emergency surgery situations.