Preparation of novel apigenin‐enriched,liposomal and non‐liposomal,antiinflammatory topical formulations as substitutes for corticosteroid therapy

Two oil‐in‐water formulations, containing equal amounts of apigenin‐enriched chamomile flower extracts, for potential use as topical antiinflammatory agents, were prepared and their physicochemical properties evaluated. A pilot clinical study was then carried out to assess patient acceptability and efficacy. The creams were either non‐liposomal or liposomal. The liposomal formulations were more viscous, thus producing superior release characteristics in vitro. The clinical study also showed that the liposomal creams were, as antiinflammatory agents, slightly more effective in vivo than the non‐liposomal formulations. These results suggest that there is scope for the further development of even more effective and safer alternatives to corticosteroids. Copyright © 2010 John Wiley & Sons, Ltd.     

Dilated Cardiomyopathies as a Cause of Congestive Heart Failure

DEFINITION AND CLASSIFICATION: Cardiomyopathies are disorders affecting the heart muscle that frequently result in congestive heart failure. Five major forms are recognized: dilated, hypertrophic, restrictive, right ventricular, and nonclassifiable cardiomyopathies with distinct hemodynamic properties. Furthermore, the new WHO/WHF definition also comprises inflammatory cardiomyopathy, defined as myocarditis in association with cardiac dysfunction. Idiopathic, autoimmune, and infectious forms of inflammatory cardiomyopathy were recognized. Viral cardiomyopathy is defined as viral persistence in a dilated heart. It may be accompanied by myocardial inflammation and then termed inflammatory viral cardiomyopathy (or viral myocarditis with cardiomegaly). If no inflammation is observed in the biopsy of a dilated heart (< 14 lymphocytes and macrophages/mm2), the term viral cardiomyopathy or viral persistence in dilated cardiomyopathy should be applied. DIAGNOSIS AND TREATMENT: In recent years, there have been breakthroughs in understanding the molecular and genetic mechanisms involved in this group of conditions, enabling improvement of diagnostic strategies and introduction of new therapies. Ongoing evaluation of antiviral, immunoglobulin, and immunosuppressive therapies including the European Study of Epidemiology and Treatment of Cardiac Inflammatory Diseases (ESETCID), removal of antibodies by immunoadsorption, anticytokine and gene therapy, as well as the mechanical support devices may provide new treatment options.     

Treatment failure rates and health care utilization and costs among patients with community-acquired pneumonia treated with levofloxacin or macrolides in an outpatient setting: a retrospective claims database analysis

Background: Macrolide antibiotics and fluoroquinolones are extensively used in the treatment of community-acquired pneumonia (CAP). Objective: This analysis was conducted to compare treatment failure rates and health care utilization and cost outcomes among patients with CAP treated with levo-floxacin (500 or 750 mg) or macrolides (azithromycin, clarithromycin, or erythromycin) in an outpatient setting. Methods: This was a retrospective analysis of claims data from a large US health plan. Patients were aged >/=18 years and had a primary diagnosis of CAP that was treated with oral levofloxacin or a macrolide in an outpatient setting (including physicians' offices, outpatient clinics, urgent care centers, and large ambulatory health centers). Patients were followed for 30 days after the index drug date to measure study outcomes. Multivariate regression analysis and a propensity score technique were used to compare rates of treatment failure and CAP-related health care utilization and costs. Two post hoc subgroup analyses were conducted in patients aged >/=50 and >/=65 years. Results: Of the 7526 patients meeting the inclusion criteria, 2968 (39.4%) were treated with levofloxacin and 4558 (60.6%) with a macrolide. Unadjusted rates of treatment failure were 21.1% and 22.7% in the levofloxacin and macrolide cohorts, respectively. After adjustment for demographic characteristics, baseline comorbidities, and severity of illness, levofloxacin recipients were significantly less likely to experience treatment failure than macrolide recipients (odds ratio [OR] = 0.84; 95% CI, 0.75-0.94, P = 0.003). The likelihood of treatment failure was significantly lower in levofloxacin recipients aged >/=50 years (OR = 0.79; 95% CI, 0.66-0.94; P = 0.007) and >/=65 years (OR = 0.65; 95% CI, 0.43-1.00; P = 0.049) compared with the corresponding subgroups of macrolide recipients. The magnitude of this difference was greatest in the subgroup aged >/=65 years, which had a 35% reduced risk of treatment failure compared with the corresponding group of macrolide-treated patients. The rate of CAP-related emergency department visits was significantly lower among patients receiving levofloxa-cin (OR = 0.68; 95% CI, 0.51-0.91; P = 0.009); there were no differences in CAP-related hospitalizations or total CAP-related health care costs between levofloxa-cin and macrolide recipients. Conclusions: Multivariate-adjusted rates of treatment failure in outpatients with CAP were significantly lower in those treated with levofloxacin relative to those treated with a macrolide. The lower rates of treatment failure with levofloxacin were consistently observed across all patients and in the subgroups aged >/=50 and >/=65 years. Rates of emergency department visits were also significantly lower among levofloxacin-treated patients, whereas overall CAP-related hospitali-zations and costs did not differ significantly between the 2 treatment groups.     

Uncertainty in predictions of disease spread and public health responses to bioterrorism and emerging diseases

Concerns over bioterrorism and emerging diseases have led to the widespread use of epidemic models for evaluating public health strategies. Partly because epidemic models often capture the dynamics of prior epidemics remarkably well, little attention has been paid to how uncertainty in parameter estimates might affect model predictions. To understand such effects, we used Bayesian statistics to rigorously estimate the uncertainty in the parameters of an epidemic model, focusing on smallpox bioterrorism. We then used a vaccination model to translate the uncertainty in the model parameters into uncertainty in which of two vaccination strategies would provide a better response to bioterrorism, mass vaccination, or vaccination of social contacts, so-called "trace vaccination." Our results show that the uncertainty in the model parameters is remarkably high and that this uncertainty has important implications for vaccination strategies. For example, under one plausible scenario, the most likely outcome is that mass vaccination would save approximately 100,000 more lives than trace vaccination. Because of the high uncertainty in the parameters, however, there is also a substantial probability that mass vaccination would save 200,000 or more lives than trace vaccination. In addition to providing the best response to the most likely outcome, mass vaccination thus has the advantage of preventing outcomes that are only slightly less likely but that are substantially more horrific. Rigorous estimates of uncertainty thus can reveal hidden advantages of public health strategies, suggesting that formal uncertainty estimation should play a key role in planning for epidemics.     

Platelet count, mean platelet volume and smoking status in stable chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD), an increasing global health problem, may be complicated by acute atherothrombotic events. Although systemic inflammation plays the leading role in atherothrombotic processes, platelet activation and increased coagulation together with oxidative stress can significantly exacerbate atherosclerosis in COPD patients. In this study we determined platelet count, mean platelet volume (MPV) and classical markers of systemic inflammation - serum C-reactive protein (CRP), white blood cell (WBC) count and the relative proportion of segmented neutrophils in COPD patients, and compared them to those from the healthy controls. The most important and novel finding of this study was that patients with COPD had a significantly increased platelet count, along with a reduced MPV when compared to healthy controls (286 vs. 260 ×?10(9)/l; 9.6 vs. 8.7?fL, respectively). Cigarette smoking had no influence on these results. The presence of systemic inflammation was clearly proved by the increase in classical inflammatory markers (CRP, WBC and segmented neutrophil count).     

Pericardial Disease in Pregnancy

Background: There is no evidence that pregnancy affects susceptibility to pericardial disease. However, when such a condition occurs, its proper diagnosis and management may be crucial for the outcome of the pregnancy. Incidence and Diagnosis: Hydropericardium is the most frequent form of pericardial involvement in pregnancy. It is typically a small, clinically silent pericardial effusion present in the third trimester in approximately 40% of healthy pregnant women. Small amounts of fetal pericardial fluid (< 2 mm in echocardiography, in diastole) can be detected after 20 weeks of gestation. Larger effusions should raise clinical concern for hydrops fetalis, Rh disease, hypoalbuminemia, and infectious or autoimmune disorder. Wide varieties of etiologic forms of pericardial diseases occur sporadically in pregnant women. Significant symptoms, electrocardiographic changes, or physiologic impairment warrant hospitalization. Treatment: Most pericardial disorders are managed during pregnancy as in nonpregnant patients (i.e., nonsteroidal antiinflammatory drugs for acute, antibiotics and drainage for purulent pericarditis, and corticosteroids for systemic autoimmune disorders). However, colchicine is contraindicated in pregnancy, and pericardiocentesis should be performed only for very large effusions causing clinical signs of cardiac tamponade or if presence of suppurative, tuberculous or neoplastic pericardial effusion is suspected. Echocardiographic guidance of pericardiocentesis is preferred to fluoroscopic guidance in order to avoid fetal X-ray exposure. Pericardiectomy should be reserved for significant pericardial constriction and resistant bacterial infections. Delivery of normal infants in term after pericardiocentesis or pericardiectomy is expected, whenever natural history of causative disease allows. Pericardiectomy itself is not a contraindication for subsequent successful pregnancies. Zusammenfassung. Hintergrund: Hinweise dafür, dass eine Schwangerschaft zur Entstehung von Perikarderkrankungen prädisponiert oder deren Ausbildung beeinflusst, gibt es nicht. Wenn aber während der Schwangerschaft eine Perikarderkrankung auftritt, sind eine schnelle Diagnose und die richtige Behandlung von großer Bedeutung. Inzidenz und Diagnose: Die häufigste Form eines Perikardergusses während der Schwangerschaft ist das "Hydroperikard". Es handelt sich typischerweise um das Auftreten eines kleinen, klinisch nicht relevanten Perikardergusses im dritten Trimenon der Schwangerschaft. Bei ca. 40% aller gesunden Schwangeren ist ein solcher minimaler Erguss nachweisbar. In der 20. Schwangerschaftswoche kann auch bei den Feten ein kleiner Perikarderguss nachgewiesen werden, der in der fetalen Echokardiographie eine Separation von < 2 mm zeigen sollte. Größere Ergüsse sind meist das erste klinische Zeichen für einen Hydrops fetalis, eine Rhesus-Blutgruppenunverträglichkeit, eine Hypoalbuminämie bzw. infektiöse oder autoimmune Erkrankungen des Fetus und/oder der Mutter. Die Ätiologie der Perikarderkrankungen der Mutter während der Schwangerschaft ist vielfältig, wobei die akute virale Perikarditis und Perikardergüsse im Rahmen systemischer autoimmuner Erkrankungen die häufigsten Ursachen darstellen. Selten findet man auch Perikardergüsse bei Schwangeren im Rahmen von Tumorerkrankungen oder einer Tuberkulose. Wenn starke präkordiale Schmerzen, Veränderungen im EKG und eine deutliche Beeinträchtigung der Belastungsfähigkeit auftreten, ist eine Klinikeinweisung unumgänglich. Therapie: Die meisten Perikarderkrankungen bei Schwangeren werden behandelt wie die von Nichtschwangeren, d.h. mit nichtsteroidalen antiinflammatorischen Medikamenten bei akuter Perikarditis, mit Antibiotika und ggf. einer Drainage bei eitrigen Perikardergüssen bzw. der Gabe von Kortikosteroiden bei autoimmunen Systemerkrankungen. Die Gabe von Colchicin ist während der Schwangerschaft kontraindiziert. Eine Perikardpunktion wird nur bei großen Perikardergüssen mit den klinischen Zeichen einer akuten Tamponade bzw. bei Verdacht auf Tuberkulose, infektiösen Erguss oder Tumorerkrankung durchzuführen sein. In diesen wenigen Fällen ist eine echokardiographisch gesteuerte Punktion angebracht, um eine Strahlenbelastung des Ungeborenen zu vermeiden. Eine Perikardektomie sollte nur bei perikardialer Konstriktion und schwerer bakterieller Infektion durchgeführt werden. Die Prozeduren Perikardpunktion und Perikardektomie allein haben, vom Interventions- bzw. Operationsrisiko abgesehen, keinen negativen, sondern eher einen günstigen prognostischen Einfluss auf die Schwangerschaft. Es gibt bislang keine ausreichenden Daten dafür, dass eine Perikardergussbildung in einer vorausgegangenen Schwangerschaft bei erneuter Gravidität zu einem Rezidiv führt. Liegen gleichzeitig allerdings eine linksventrikuläre Dilatation und Dysfunktion vor, ist, wie im Beitrag "Schwangerschaft und Kardiomyopathie" ausgeführt, nach den Empfehlungen der European Society of Cardiology (ESC) von einer erneuten Schwangerschaft abzuraten.     

Pericardial syndromes: an update after the ESC guidelines 2004

Despite a myriad of causes, pericardial diseases present in few clinical syndromes. Acute pericarditis should be differentiated from aortic dissection, myocardial infarction, pneumonia/pleuritis, pulmonary embolism, pneumothorax, costochondritis, gastroesophageal reflux/neoplasm, and herpes zoster. High-risk features indicating hospitalization are: fever >38 °C, subacute onset, large effusion/tamponade, failure of non-steroidal anti-inflammatory drugs (NSAIDs), previous immunosuppression, trauma, anticoagulation, neoplasm, and myopericarditis. Treatment comprises 10–14-days NSAID plus 3 months colchicine (2 × 0.5 mg; 1 × 0.5 mg in patients <70 kg). Corticosteroids are avoided, except for autoimmunity, as they facilitate the recurrences. Echo-guided pericardiocentesis (±fluoroscopy) is indicated for tamponade and effusions >2 cm. Smaller effusions are drained if neoplastic, purulent or tuberculous etiology is suspected. In recurrent pericarditis, repeated testing for autoimmune and thyroid disease is appropriate. Pericardioscopy and pericardial/epicardial biopsy may clarify the etiology. Familial clustering was recently associated with tumor necrosis factor receptor-associated periodic syndrome (TNFRSF1A gene mutation). Treatment includes 10–14 days NSAIDs with colchicine 0.5 mg bid for up to 6 months. In non-responders, low-dose steroids, intrapericardial steroids, azathioprine, and cyclophosphamide can be tried. Successful management with interleukin-1 receptor antagonist (anakinra) was recently reported. Pericardiectomy remains the last option in >2 years severely symptomatic patients. In constriction, expansion of the heart is impaired by the rigid, chronically inflamed/thickened pericardium (no thickening ~20 %). Chest radiography, echocardiography, computerized tomography, magnetic resonance imaging, hemodynamics, and endomyocardial biopsy indicate the diagnosis. Pericardiectomy is the only treatment for permanent constriction. Predictors of poor survival are prior radiation, renal dysfunction, high pulmonary artery pressures, poor left ventricular function, hyponatremia, age, and simultaneous HIV and tuberculous infection.     

Adult stem cell maintenance and tissue regeneration around the clock: do impaired stem cell clocks drive age-associated tissue degeneration?

Human adult stem cell research is a highly prolific area in modern tissue engineering as these cells have significant potential to provide future cellular therapies for the world’s increasingly aged population. Cellular therapies require a smart biomaterial to deliver and localise the cell population; protecting and guiding the stem cells toward predetermined lineage-specific pathways. The cells, in turn, can provide protection to biomaterials and increase its longevity. The right combination of stem cells and biomaterials can significantly increase the therapeutic efficacy. Adult stem cells are utilised to target many changes that negatively impact tissue functions with age. Understanding the underlying mechanisms that lead to changes brought about by the ageing process is imperative as ageing leads to many detrimental effects on stem cell activation, maintenance and differentiation. The circadian clock is an evolutionarily conserved timing mechanism that coordinates physiology, metabolism and behavior with the 24 h solar day to provide temporal tissue homeostasis with the external environment. Circadian rhythms deteriorate with age at both the behavioural and molecular levels, leading to age-associated changes in downstream rhythmic tissue physiology in humans and rodent models. In this review, we highlight recent advances in our knowledge of the role of circadian clocks in adult stem cell maintenance, driven by both cell-autonomous and tissue-specific factors, and the mechanisms by which they co-opt various cellular signaling pathways to impose temporal control on stem cell function. Future research investigating pharmacological and lifestyle interventions by which circadian rhythms within adult stem niches can be manipulated will provide avenues for temporally guided cellular therapies and smart biomaterials to ameliorate age-related tissue deterioration and reduce the burden of chronic disease.     

Influence of HLA-DRB-1 alleles on the production of antibody against CSP, MSP-1, AMA-1, and DBP in Brazilian individuals naturally infected with Plasmodium vivax

We evaluated the influence of allelic frequency of the human leukocyte antigen (HLA) -DRB1 on the acquisition of antibody response against malaria sporozoite and merozoite peptides in patients with Plasmodium vivax malaria acquired in endemic areas of Brazil. IgG antibodies were detected by enzyme-linked immunosorbent assay against four peptides of circumsporozoite protein (CSP) (amino, carboxyl, and VK210 and VK247 repeats) and peptides of merozoite surface protein 1 (MSP-1), apical membrane antigen 1 (AMA-1), and Duffy-binding protein (DBP). We found an association between HLA-DR3 and HLA-DR5 alleles and lack of antibody response to CSP amino terminal, as well as an association between HLA-DR3 and the highest antibody response to MSP1 (Pv200L). In conclusion, we suggest a potential regulatory role of the HLA-DRB1 alleles in the production of antibodies to a conserved region of P. vivax CSP and MSP1 in Brazilian population exposed to malaria.