Cytokine and anti-cytokine therapy for asthma

Cytokines play a critical role in the pathogenesis of asthma. Asthma resolution may depend on the correction of dysregulated cytokine expression, which is a characteristic feature of this chronic inflammatory disease. It is, therefore, not surprising that attempts have been made to either block cytokines present at elevated levels or to substitute cytokines that are insufficiently expressed in asthma. In this article, the results of these studies are discussed, and the obtained insights regarding asthma pathogenesis and new treatment options are summarized.

Correlates of self-reported nonadherence to antiretroviral therapy in HIV-infected patients: the Swiss HIV Cohort Study

BACKGROUND: Adherence is one of the most crucial issues in the clinical management of HIV-infected patients receiving antiretroviral therapy (ART). METHODS: A 2-item adherence questionnaire was introduced into the Swiss HIV Cohort Study in July 2003. All 3607 eligible patients were on ART for > or =6 months and their current regimen for > or =1 month. Three definitions of nonadherence were considered: missing > or =1 dose, missing > or =2 doses, and taking <95% of doses in the past 4 weeks. RESULTS: Over 30% of patients reported missing > or =1 dose, 14.9% missed > or =2 doses, and 7.1% took <95% of doses in the previous 4 weeks. The rate of drug holidays was 5.8%. Whether using more or less conservative definitions of nonadherence, younger age, living alone, number of previous regimens, and boosted protease inhibitor regimens were independent factors associated with nonadherence. There was a significant association between optimal viral suppression and nonadherence as well as a significant linear trend in optimal viral suppression by missed doses. CONCLUSIONS: Younger age, lack of social support, and complexity of therapy are important factors that are related to nonadherence with ART. Investment in behavioral dimensions of HIV is crucial to improve adherence in ART recipients.

Strategies to prevent neuronal damage in paediatric bacterial meningitis

PURPOSE OF REVIEW: The mortality of bacterial meningitis can reach 30%, and up to 50% of survivors suffer from persisting neurological deficits as a consequence of the disease. The incidence of neurological sequelae of bacterial meningitis has not improved over the last decade. Adjunctive therapeutic options are limited, and ongoing research into the pathophysiology of brain damage in bacterial meningitis aims at providing the scientific basis for future development of more efficient adjunctive options. RECENT FINDINGS: In a population with good access to health care, dexamethasone given before or at the time of initiation of antibiotic therapy acts beneficially in paediatric pneumococcal meningitis, but not in meningococcal meningitis. In experimental animal models, brain-derived neurotrophic factor protected against brain injury and improved hearing while melatonin, which has antioxidant properties among other effects, reduced neuronal death. Transgene technology can be used to provide new insights into the pathophysiology of the disease and to identify potential therapeutic targets. SUMMARY: Although dexamethasone improves outcome of bacterial meningitis under defined circumstances, the morbidity of bacterial meningitis still remains unacceptably high. Experimental models may help to identify new therapeutic strategies to further improve the neurological outcome in young children suffering from bacterial meningitis.

Frequency of gynecologic follow-up and cervical cancer screening in the Swiss HIV cohort study

BACKGROUND: According to current recommendations, HIV-infected women should have at least 1 gynecologic examination per year. OBJECTIVES: To analyze factors associated with frequency of gynecologic follow-up and cervical cancer screening among HIV-infected women followed in the Swiss HIV Cohort Study (SHCS). METHODS: Half-yearly questionnaires between April 2001 and December 2004. At every follow-up visit, the women were asked if they had had a gynecologic examination and a cervical smear since their last visit. Longitudinal models were fitted with these variables as outcomes. RESULTS: A total of 2186 women were included in the analysis. Of the 1146 women with complete follow-up in the SHCS, 35.3% had a gynecologic examination in each time period, whereas 7.4% had never gone to a gynecologist. Factors associated with a poor gynecologic follow-up were older age, nonwhite ethnicity, less education, underweight, obesity, being sexually inactive, intravenous drug use, smoking, having a private infectious disease specialist as a care provider, HIV viral load <400 copies/mL, and no previous cervical dysplasia. No association was seen for living alone, CD4 cell count, and positive serology for syphilis. CONCLUSIONS: Gynecologic care among well-followed HIV-positive women is poor and needs to be improved.

Extended CT scale overcomes restoration caused streak artifacts for dental identification in CT--3D color encoded automatic discrimination of dental restorations

OBJECTIVE: Besides DNA, dental radiographs play a major role in the identification of victims in mass casualties or in corpses with major postmortem alterations. Computed tomography (CT) is increasingly applied in forensic investigations and is used to scan the dentition of deceased persons within minutes. We investigated different restoration materials concerning their radiopacity in CT for dental identification purposes. METHODS: Extracted teeth with different filling materials (composite, amalgam, ceramic, temporary fillings) were CT scanned. Radiopacities of the filling materials were analyzed in extended CT scale images. RESULTS: Radiopacity values ranged from 6000-8500HU (temporary fillings), 4500-17000HU (composite fillings) and >30710HU (Amalgam and Gold). The values were used to define presets for a 3D colored volume rendering software. CONCLUSIONS: The effects of filling material caused streak artifacts could be distinctively reduced for the assessment of the dental status and a postprocessing algorithm was introduced that allows for 3D color encoded visualization and discrimination of different dental restorations based on postmortem CT data.

Noninvasive estimation of organ weights by postmortem magnetic resonance imaging and multislice computed tomography

OBJECTIVE: Computed tomography (CT) and magnetic resonance imaging (MRI) are introduced as an alternative to traditional autopsy. The purpose of this study was to investigate their accuracy in mass estimation of liver and spleen. METHODS: In 44 cases, the weights of spleen and liver were estimated based on MRI and CT data using a volume-analysis software and a postmortem tissue-specific density factor. In a blinded approach, the results were compared with the weights noted at autopsy. RESULTS: Excellent correlation between estimated and real weights (r = 0.997 for MRI, r = 0.997 for CT) was found. Putrefaction gas and venous air embolism led to an overestimation. Venous congestion and drowning caused higher estimated weights. CONCLUSION: Postmortem weights of liver and spleen can accurately be assessed by nondestructive imaging. Multislice CT overcomes the limitation of putrefaction and venous air embolism by the possibility to exclude gas. Congestion seems to be even better assessed.

Arterial stiffness assessed by digital volume pulse correlates with comorbidity in patients with ESRD

BACKGROUND: Digital volume pulse (DVP), a noninvasive method for indirect assessment of arterial stiffness, was not tested previously in patients with end-stage renal disease (ESRD). Therefore, we compared the DVP-derived stiffness index (SI(DVP)) with aortic pulse wave velocity (PWV) determined by means of Doppler ultrasonography in 2 groups of patients with ESRD and analyzed the correlation between SI(DVP) and comorbidity. METHODS: Photoplethysmography was performed on the index finger of the dominant hand or the hand from the nonfistula arm in 49 renal transplant (TX) recipients and 48 hemodialysis (HD) patients. Pulse curves were analyzed with computer assistance. Comorbidity was assessed by using an established index. RESULTS: The intrasubject variability of SI(DVP) was 5.7%. SI(DVP) and aortic PWV values correlated significantly (r = 0.66; P = 0.001) in patients with ESRD. SI(DVP) could not be assessed reliably in 25% and 6% of HD patients and TX recipients, respectively. Multivariate regression analyses showed that SI(DVP) increased with age in both HD patients and TX recipients (r = 0.61; P < 0.001) and with systolic blood pressure (r = 0.53; P < 0.025), mean arterial pressure (r = 0.47; P < 0.05), and pulse pressure (r = 0.52; P = 0.02) in TX recipients. Severity of comorbid status was associated highly with individual residuals of age-adjusted SI(DVP) in HD patients and TX recipients (P < 0.001). CONCLUSION: DVP allows the measurement of arterial stiffness in most, but not all, patients with ESRD. SI(DVP) values correlate with comorbidity in HD patients and TX recipients.

Adaptations of intestinal macrophages to an antigen-rich environment

Intestinal macrophages, preferentially located in the subepithelial lamina propria, represent in humans the largest pool of tissue macrophages. To comply with their main task, i.e. the efficient removal of microbes and particulate matter that might have gained access to the mucosa from the intestinal lumen while maintaining local tissue homeostasis, several phenotypic and functional adaptations evolved. Most notably, microbe-associated molecular pattern (MAMP) receptors, including the lipopolysaccharide receptors CD14 and TLR4, but also the Fc receptors for IgA and IgG are absent on most intestinal Mø. Here we review recent findings on the phenotypic and functional adaptations of intestinal Mø and their implications for the pathogenesis of inflammatory bowel diseases.

P450 oxidoreductase deficiency: a new form of congenital adrenal hyperplasia

PURPOSE OF REVIEW: P450 oxidoreductase deficiency--a newly described form of congenital adrenal hyperplasia--typically presents a steroid profile suggesting combined deficiencies of steroid 21-hydroxylase and 17alpha-hydroxylase/17,20-lyase activities. These and other enzymes require electron donation from P450 oxidoreductase. The clinical spectrum of P450 oxidoreductase deficiency ranges from severely affected children with ambiguous genitalia, adrenal insufficiency and the Antley-Bixler skeletal malformation syndrome to mildly affected individuals with polycystic ovary syndrome. We review current knowledge of P450 oxidoreductase deficiency and its broader implications. RECENT FINDINGS: Since the first report in 2004, at least 21 P450 oxidoreductase mutations have been reported in over 40 patients. The often subtle manifestations of P450 oxidoreductase deficiency suggest it may be relatively common. P450 oxidoreductase deficiency, with or without Antley-Bixler syndrome, is autosomal recessive, whereas Antley-Bixler syndrome without disordered steroidogenesis is caused by autosomal dominant fibroblast growth factor receptor 2 mutations. In-vitro assays of P450 oxidoreductase missense mutations based on P450 oxidoreductase-supported P450c17 activities provide excellent genotype/phenotype correlations. The causal connection between P450 oxidoreductase deficiency and disordered bone formation remains unclear. SUMMARY: P450 oxidoreductase mutations cause combined partial deficiency of 17alpha-hydroxylase and 21-hydroxylase. Individuals with an Antley-Bixler syndrome-like phenotype presenting with sexual ambiguity or other abnormalities in steroidogenesis should be analyzed for P450 oxidoreductase deficiency.

Evaluation of p24-based antiretroviral treatment monitoring in pediatric HIV-1 infection: prediction of the CD4+ T-cell changes between consecutive visits

Worldwide, 700,000 infants are infected annually by HIV-1, most of them in resource-limited settings. Care for these children requires simple, inexpensive tests. We have evaluated HIV-1 p24 antigen for antiretroviral treatment (ART) monitoring in children. p24 by boosted enzyme-linked immunosorbent assay of heated plasma and HIV-1 RNA were measured prospectively in 24 HIV-1-infected children receiving ART. p24 and HIV-1 RNA concentrations and their changes between consecutive visits were related to the respective CD4+ changes. Age at study entry was 7.6 years; follow-up was 47.2 months, yielding 18 visits at an interval of 2.8 months (medians). There were 399 complete visit data sets and 375 interval data sets. Controlling for variation between individuals, there was a positive relationship between concentrations of HIV-1 RNA and p24 (P < 0.0001). While controlling for initial CD4+ count, age, sex, days since start of ART, and days between visits, the relative change in CD4+ count between 2 successive visits was negatively related to the corresponding relative change in HIV-1 RNA (P = 0.009), but not to the initial HIV-1 RNA concentration (P = 0.94). Similarly, we found a negative relationship with the relative change in p24 over the interval (P < 0.0001), whereas the initial p24 concentration showed a trend (P = 0.08). Statistical support for the p24 model and the HIV-1 RNA model was similar. p24 may be an accurate low-cost alternative to monitor ART in pediatric HIV-1 infection.