Effects of systemic and local CXC chemokine administration on the ethanol-induced suppression of pulmonary neutrophil recruitment

BACKGROUND: Acute alcohol intoxication impairs the neutrophil response to intrapulmonary infection, resulting in impaired host defense and increased patient morbidity and mortality. We recently showed that intratracheal (IT) chemokine administration promotes pulmonary neutrophil migration in rats and that this process is enhanced by systemic administration of the Glu-Leu-Arg (ELR+) and CXC chemokine cytokine-induced neutrophil chemoattractant (CINC). Here we hypothesized that exogenous chemokine administration would mitigate the suppressive effect of alcohol on neutrophil recruitment into the lung. METHODS: Macrophage inflammatory protein-2 (MIP-2), a rat ELR+ CXC chemokine, or live Klebsiella pneumoniae (K. pneumoniae) was administered it to induce alveolar neutrophil migration in the absence or presence of acute ethanol intoxication. Depending on the experimental protocol, rats received either intravenous (IV) CINC or IT chemokines (CINC and MIP-2) 20 min after it MIP-2 or K. pneumoniae. Rats were euthanized 90 min or four hr after the first IT injection for sample collection. RESULTS: Neutrophil counts were significantly elevated in bronchoalveolar lavage fluid (BALF) of rats receiving IT MIP-2 compared with vehicle-treated rats, and this response was significantly decreased in animals pretreated with ethanol. CINC IV enhanced the neutrophil response to IT MIP-2 in both the absence and presence of acute ethanol intoxication. In rats challenged with K. pneumoniae, ethanol pretreatment significantly reduced BALF levels of CINC and MIP-2, suppressed alveolar neutrophil recruitment, and decreased whole-lung myeloperoxidase activity. CINC IV did not alter BALF neutrophil counts in the absence or presence of ethanol administration 4 hr after IT K. pneumoniae. Alternatively, IT chemokine instillation partially restored BALF neutrophil recruitment but not whole-lung myeloperoxidase activity in ethanol-treated rats. CONCLUSIONS: Ethanol significantly inhibits the pulmonary inflammatory responses to both MIP-2 and K. pneumoniae. Exogenous chemokine administration may be a useful means to enhance host defenses in the ethanol-intoxicated host, although the results of this study also indicate that ethanol intoxication can impair neutrophil recruitment, independent of its effects on local chemotactic gradients.     

Fenestrated ASD Closure in a Child with Idiopathic Pulmonary Hypertension and Exercise Desaturation

Pulmonary arterial hypertension is a progressive disorder that may result in right heart failure and death. Atrial level shunts in the presence of pulmonary hypertension may allow right‐to‐left mixing with maintenance of cardiac output and improved survival. However, excessive mixing at the atrial level can cause undue systemic desaturation, increased fatigue and decreased exercise tolerance even in the presence of adequate cardiac output. A 5½‐year‐old was diagnosed with pulmonary hypertension, a large atrial septal defect and right‐to‐left shunting. Medical therapy over an 18‐month period was successful in decreasing pulmonary artery pressure and pulmonary vascular resistance. However, because of the size and position of the intracardiac defect, symptoms of fatigue, and severe systemic desaturation with only minor activities persisted. Fenestrated surgical closure of the defect was thus undertaken to decrease the degree of atrial mixing, but still allow atrial decompression if necessary. Subsequent hemodynamic evaluation has demonstrated continued improvement, and all previous symptoms have resolved. Repeated echocardiography has confirmed patency of the atrial fenestration with left‐to‐right atrial flow.     

International Headache Society classification: interobserver reliability in the diagnosis of primary headaches

We assessed interobserver reliability of the International Headache Society (IBIS) classification for diagnosis of primary headaches. The study was performed on 103 patients consecutively seen at two Headache Centres. Each patient was given a structured interview recorded on videotape. Four experienced clinicians then reviewed the interviews separately and made a diagnosis of headache according to IHS criteria at the one- and two-digit levels. At both the one- and the two-digit level the agreement was substantial (Kappa = 0.74 and 0.65, respectively). The analysis of reliability for each of nine items necessary for diagnosis showed an agreement ranging from substantial (Kappa = 0.69) to almost perfect (Kappa = 0.89). Our results indicate that the IHS classification has a good reliability for the diagnosis of primary headaches at the one- and two-digit levels.     

Host defense and bacterial pneumonia

Despite advances in antibiotic therapy, bacterial pneumonia remains a significant cause of morbidity and mortality. Pulmonary host defense has both an innate component, consisting of nonspecific antimicrobial factors, as well as an acquired component, which is pathogen-specific. Defects in either arm of the immune system can have a profound impact on the other because these are highly interactive systems. From the upper airway to the respiratory alveolus, defense mechanisms are in place to maintain sterility of the lower respiratory tract. These features include anatomical barriers, nonspecific antimicrobial peptides, the mucociliary escalator, and the airway lining fluid. In the airspaces, the alveolar macrophage is the cell responsible for early pathogen clearance and subsequent initiation of the acute inflammatory response. Neutrophil recruitment and acquired immune responses are dependent on cytokine secretion by these resident tissue phagocytes. This article reviews the salient features of innate and acquired immunity against bacterial pathogens and how host factors (such as alcoholism) undermine these antibacterial defenses.     

Interferon-gamma-induced apoptotic responses of Fanconi anemia group C hematopoietic progenitor cells involve caspase 8-dependent activation of caspase 3 family members

Hematopoietic progenitor cells (HPC) from mice nullizygous at the Fanconi anemia (FA) group C locus and children with Fanconi anemia group C (FA-C) are hypersensitive to interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha. This hypersensitivity results, in part, from the capacity of these cytokines to prime the fas pathway. Because fas-mediated programmed cell death in many cells involves sequential activation of specific caspases, we tested the hypothesis that programmed cell death in FA HPC involves the ordered activation of specific caspase molecules. Lysates from lymphoblasts treated with both agonistic anti-fas antibody and IFN-gamma contained activated caspase 3 family members (caspases 3, 6, and 7), as well as caspase 8, whereas activation of caspases 1, 2, 4, 9, and 10 was not detected. The apoptotic effects of fas agonists in IFN-gamma-treated human and murine FA-C cells were blocked when pretreated with inhibitors (ac-DEVD-cho, CP-DEVD-cho, Z-DEVD-FMK) of the caspase 3 protease. Inhibitors (ac-YVAD-cho, CP-YVAD-cho, Z-YVAD-FMK) of caspase 1 did not block apoptosis or caspase 3 activation. Treatment of FA cells with the fluoromethyl ketone tetrapeptide caspase 8 inhibitor (ac-IETD-FMK) did suppress caspase 3 activation. A 4-fold greater fraction of IFN-induced FA-C cells expressed caspase 3 than FA-C cells complemented by retroviral-mediated transfer of FANCC. Therefore fas-induced apoptosis in Fanconi anemia cells of the C type involves the activation of caspase 8, which controls activation of caspase 3 family members and one direct or indirect function of the FANCC protein is to suppress apoptotic responses to IFN-gamma upstream of caspase 3 activation. (Blood. 2000;96:4204-4211)     

Patient satisfaction with alosetron for the treatment of women with diarrhea-predominant irritable bowel syndrome

OBJECTIVE: The efficacy and tolerability of alosetron in women with diarrhea-predominant irritable bowel syndrome (IBS) have been established in double-blind, placebo-controlled trials. However, the degree to which alosetron fulfills the needs of those suffering from IBS has not been thoroughly examined from the patient's perspective. This randomized, double-blind, placebo-controlled study conducted in women with diarrhea-predominant IBS evaluated patients' overall satisfaction with treatment as well as their satisfaction with respect to several specific medication attributes. METHODS: Patients randomized to receive either alosetron 1 mg b.id. (n = 532) or placebo (n = 269) were administered a questionnaire on which they rated on 7-point Likert scales their prestudy IBS treatment (at the screening visit) or study medication (on wk 12 or final study visit) with respect to overall satisfaction and 11 specific medication attributes. RESULTS: Whereas approximately 10% of patients were satisfied or very satisfied overall with prestudy IBS medication, 69% of patients were satisfied or very satisfied overall with alosetron and 46% with placebo (p < 0.001) at the end of 12 wk of therapy. The majority of alosetron-treated patients (61-87%) were satisfied or very satisfied with each of 11 specific medication attributes (p < 0.001 vs placebo for each attribute). Favorable satisfaction ratings for alosetron were assigned to the five medication attributes that patients considered to be most important, including relief of urgency (68% alosetron vs 41% placebo), speed of relief (71% vs 40%), time to return to normal activities (75% vs 49%), relief of abdominal pain (62% vs 44%), and prevention of return of urgency (68% vs 42%). CONCLUSIONS: Women with diarrhea-predominant IBS are satisfied with alosetron 1 mg b.i.d. treatment overall and also with respect to specific attributes of IBS medication they consider most important.     

Effects of staphylococcus toxoid vaccine on pain and fatigue in patients with fibromyalgia/chronic fatigue syndrome

Positive results of pilot studies of the effect of staphylococcus toxoid vaccine in patients with fibromyalgia and chronic fatigue syndrome were the incitement to the present, placebo-controlled study. It included 28 patients who fulfilled the criteria for both fibromyalgia and chronic fatigue syndrome. The effect of vaccination with a staphylococcus toxoid was compared with the effect of injections of sterile water. Psychometric assessment was made using 15 items from the comprehensive psychopathological rating scale (CPRS), Zung's self-rating depression scale and clinical global impressions (CGI). The visual analogue scale (VAS) was used to measure pain levels, and a hand-held electronic pressure algometer was used to measure pressure pain thresholds. Significant improvement was seen in seven of the 15 CPRS items in the vaccine group when pretreatment values were compared to post-treatment values. In CPRS ‘fatiguability';, there were significant intergroup differences, and in CPRS ‘pain'; intergroup differences bordered on significance. There was no significant improvement in CPRS items in the placebo group. Clinical global impressions showed significant improvement in the vaccine-treated group, and VAS did so in both groups. In a follow-up study of 23 patients, the vaccine treatment was continued for 2–6 years. Fifty percent were rehabilitated successfully and resumed half-time or full-time work. The results of this study support the authors' hypothesis that treatment with staphylococcus toxoid may be a fruitful strategy in patients with fibromyalgia and chronic fatigue syndrome.     

Alcohol Consumption in Rats Potentiates the Deleterious Effect of Gram-Negative Sepsis on Hepatic Hyaluronan Uptake

The role of hepatic sinusoidal endothelial cells (SECs) in the pathologic changes of the liver associated with alcohol consumption is not fully understood. The measurement of hyaluronan (HA) uptake by the SECs provides a useful means for assessing the functional state of these cells. In this study, we determined the effect of acute and chronic exposure to alcohol in rats in the absence and presence of subcutaneous Escherichia co/i-induced sepsis on plasma HA concentration and HA uptake by the isolated, perfused liver. Rats were administered ethanol (two doses of 0.2 g/100 g body weight, intraperitoneal, 24 and 15 hr before killing) or fed a liquid diet for 8–10 weeks, containing alcohol (36% of the total calories) or dextrin (in isocaloric amounts). Twenty-one hr before euthanizing for liver perfusion, animals were injected subcutaneously with live E. coli (sepsis) or sterile saline (control). Neither acute nor chronic alcohol exposure by themselves altered plasma HA levels. However, both treatments exacerbated the hyperhyaluronanemic effect of sepsis. Thus, in acutely alcohol-treated rats, sepsis induced a 187% (p &< 0.05) increase in plasma levels of HA, whereas in nonalcohol septic rats, the increase was only 54% (p &< 0.05). Likewise, sepsis resulted in a greater increase in the plasma levels of HA (871%) in alcohol-fed rats than it did in liquid diet, control-fed rats (323%, p &< 0.05). The rate of HA uptake by the isolated, perfused liver was not altered by either acute or chronic alcohol exposure. However, alcohol exposure markedly potentiated the inhibitory effect of sepsis on the capacity of the liver to take up HA. Thus, in acutely alcohol-treated rats, sepsis decreased HA uptake (60-80%, p &< 0.05), whereas in the corresponding nonalcoholic control group the decrease was evident only at the beginning of HA infusion. In chronically alcohol-fed rats, sepsis induced an 80% (p &< 0.05) inhibition of HA uptake, whereas in diet-fed control rats the inhibition was only 60% (p &< 0.05). The inhibition by sepsis of HA uptake by the isolated, perfused liver provides an explanation for the previously observed hyperhy-aluronanemia in septic humans and animals. Because alcohol alone does not alter HA metabolism, the results suggest that acute and chronic alcohol exposure influences the communication between liver cells leading to downregulation of HA clearance by SECs.