Xenopus oocytes expressing high voltage-gated calcium channels (Ca(v)) were exposed to formalin (0.5%, v/v, 5 min.) and the oocyte death and Ca(v) currents were studied for up to 10 days. Ca(v) channels were expressed with alpha(1)beta(1)b and alpha(2)delta sub-units and the currents (I(Ba)) were studied by voltage clamp. None of the oocytes was dead during the exposure to formalin. Oocyte death was significant between day 1 and day 5 after the exposure to formalin and was uniform among the oocytes expressing various Ca(v) channels. Peak I(Ba) of all Ca(v) and A(1), the inactivating current component was decreased whereas the non-inactivated R current was not affected by 5 min. exposure to formalin. On day 1 after the exposure to formalin, Ca(v)1.2c currents were increased, 2.1 and 2.2 currents were decreased and 2.3 currents were unaltered. On day 5, both peak I(Ba) and A(1) currents were increased. Ca(v)1.2c, 2.2 and 2.3 currents were increased and Ca(v)2.1 was unaltered on day 10 after the exposure to formalin. Protein kinase C (PKC) may be involved in formalin-induced increase in Ca(v) currents due to the (i) requirement for Ca(v)beta(1)b sub-units;(ii) decreased phorbol-12-myristate,13-acetate potentiation of Ca(v)2.3 currents;(iii) absence of potentiation of Ca(v)2.3 currents following down-regulation of PKC; and (iv) absence of potentiation of Ca(v)2.2 or 2.3 currents with Ser-->Ala mutation of Ca(v)alpha(1)2.2 or 2.3 sub-units. Increased Ca(v) currents and PKC activation may coincide with changes observed in in vivo pain investigations, and oocytes incubated with formalin may serve as an in vitro model for some cellular mechanisms of pain.

We report five cases of possible drug-induced periostitis associated with long-term use of voriconazole therapy after lung transplantation (LT). The diagnosis of periostitis was made by the documentation of bone pain, elevation of serum alkaline phosphatase and characteristic findings on radionuclide bone imaging in the absence of any identifiable rheumatologic disease. This periostitis appears similar to hypertrophic osteoarthopathy (HOA) but does not meet all criteria for HOA. In all patients, the symptoms resolved rapidly after discontinuation of voriconazole therapy. Awareness of this potential syndrome, which manifests as bone pain, elevated serum alkaline phosphatase and a bone scan suggestive of periostitis, is necessary in LT recipients on long-term voriconazole.

The available therapies and prognosis of idiopathic pulmonary fibrosis remain relatively poor, and concurrent pulmonary hypertension further increases the risk of death and complications after lung transplantation. Limited data exist for the treatment of pulmonary hypertension associated with idiopathic pulmonary fibrosis. We describe a case where intravenous treprostinil was used to bridge an elderly patient with idiopathic pulmonary fibrosis with severe pulmonary hypertension to successful single-lung transplantation.

BACKGROUND AND PURPOSE: Patients with stroke and patients with transient ischemic attack (TIA) are at high risk for vascular events and may not exhibit the signs and symptoms of peripheral arterial disease (PAD). We investigated if asymptomatic PAD detected by ankle brachial index <0.9 is independently associated with recurrent vascular events in patients with stroke or TIA. METHODS: In this prospective longitudinal hospital-based cohort study, asymptomatic PAD was detected by ankle brachial index measurement in consecutive patients with stroke and patients with TIA. They were assessed for stroke risk factors, ankle brachial index measurement, and laboratory parameters known to be associated with stroke risk. These patients were followed for composite vascular events, including stroke, TIA, myocardial infarction, and vascular death. RESULTS: In a 1-year period, 102 patients were evaluated, of whom 26% had asymptomatic PAD. All patients were followed for a median period of 2.1 years from the index stroke/TIA (range, 1.0 to 2.7 years) for vascular events. Kaplan-Meier curve showed fewer patients with asymptomatic PAD remained free of composite vascular events (48% compared with 84% in the no-PAD group; log rank, P=0.0001). Asymptomatic PAD was significantly associated with composite vascular events before (hazard ratio, 4.2; 95% CI, 1.9 to 9.3; P=0.0003) and after adjustment for confounders (hazard ratio, from Model 1, 2.8; 95% CI, 1.1 to 7.2; P=0.03 and Model 2, 3.4; 95% CI, 1.4 to 8.2, P=0.006). Asymptomatic PAD was also significantly associated with stroke before (hazard ratio, 6.5; 95% CI, 2.1 to 19.9; P=0.001) and after adjustment for confounders (hazard ratio from Model 1, 4.8; 95% CI, 1.5 to 15.3; P=0.009 and Model 2, 5.2; 95% CI, 1.5 to 17.6; P=0.008). CONCLUSIONS: In patients with stroke or TIA, asymptomatic PAD is independently associated with recurrent vascular events and stroke.

Multiple infections have been linked with the development of bronchiolitis obliterans syndrome (BOS) post-lung transplantation. Lung allograft airway colonization by Aspergillus species is common among lung transplant recipients. We hypothesized that Aspergillus colonization may promote the development of BOS and may decrease survival post-lung transplantation. We reviewed all lung transplant recipients transplanted in our center between January 2000 and June 2006. Bronchoscopy was performed according to a surveillance protocol and when clinically indicated. Aspergillus colonization was defined as a positive culture from bronchoalveolar lavage or two sputum cultures positive for the same Aspergillus species, in the absence of invasive pulmonary Aspergillosis. We found that Aspergillus colonization was strongly associated with BOS and BOS related mortality in Cox regression analyses. Aspergillus colonization typically preceded the development of BOS by a median of 261 days (95% CI 87-520). Furthermore, in a multivariate Cox regression model, Aspergillus colonization was a distinct risk factor for BOS, independent of acute rejection. These data suggest a potential causative role for Aspergillus colonization in the development of BOS post-lung transplantation and raise the possibility that strategies aimed to prevent Aspergillus colonization may help delay or reduce the incidence of BOS.

Over the past 3 decades, antimicrobial resistance among Streptococcus pneumoniae, the most common cause of community-acquired pneumonia (CAP), has escalated dramatically worldwide. In the late 1970s, strains of pneumococci displaying resistance to penicillin were described in South Africa and Spain. By the early 1990s, penicillin-resistant clones of S. pneumoniae spread rapidly across Europe and globally. Additionally, resistance to macrolides and other antibiotic classes escalated in tandem with penicillin resistance. Six international clones (serotypes 6A, 6B, 9V, 14, 19F, 23F) were responsible for most of these resistant isolates. Currently, 15 to 30% of S. pneumoniae worldwide are multidrug-resistant (MDR)(i.e., resistant to > or = 3 classes of antibiotics). Despite the dramatic escalation in the rate of antimicrobial resistance among pneumococci worldwide, the clinical impact of antimicrobial resistance is difficult to define. Treatment failures due to antibiotic-resistant pneumococci have been reported with meningitis, otitis media, and lower respiratory tract infections, but the relation between drug resistance and treatment failures has not been convincingly established. Clinical failures often reflect factors independent of antimicrobial susceptibility of the infecting organisms. Host factors (e.g., extremes of age; underlying immunosuppressive or debilitating disease; comorbidities), or factors that affect intrinsic virulence of the organisms (e.g., capsular subtype) strongly influence prognosis. Mortality rates are higher in the presence of: multilobar involvement, renal insufficiency, need for intensive care unit (ICU) care, hypoxemia, severe derangement in physiological parameters, and comorbidities. Given these confounding factors, dissecting out the impact of antimicrobial resistance on clinical outcomes is difficult, if not impossible. Prospective, randomized trials designed to assess the clinical significance of antimicrobial resistance among pneumococci are lacking, and for logistical reasons, will never be done. Does in vitro resistance translate into clinical failures? Should changing resistance patterns modify our choice of therapy for CAP or for suspected pneumococcal pneumonia? In this review, we discuss several facets, including mechanisms of antimicrobial resistance among specific antibiotic classes, epidemiology and spread of antimicrobial resistance determinants regionally and worldwide, risk factors for acquisition and dissemination of resistance, the impact of key international clones displaying multidrug resistance, the clinical impact of antimicrobial resistance, and strategies to limit or curtail antimicrobial resistance among this key respiratory tract pathogen.

Streptococcus pneumoniae is the most common cause of community-acquired pneumonia, meningitis, and bacteremia in children and adults. Invasive pneumococcal disease (IPD) primarily affects young children, older adults (> 65 years of age), and individuals with comorbidities or impaired immune systems. Case fatality rates range from 10 to 30% in adults with IPD but are much lower (< 3%) in children. In this article, we describe the epidemiology of IPD, risk factors, and the influence of host- and organism-specific factors on outcomes. Most cases of IPD are caused by a limited number of serotypes that vary in infectivity and virulence. Vaccinating adults and high-risk patients with the pneumococcal polysaccharide vaccine reduces the incidence of IPD in populations at risk but does not affect nasopharyngeal colonization and has had limited benefit in the population at large. Use of the heptavalent pneumococcal conjugate vaccine (PCV7) in children in the United States since 2000 has resulted in a substantial decline of IPD in both children and adults (by herd immunity), but has facilitated the emergence of serotypes not encompassed in the PCV7 vaccine. Recent reports of "replacement" serotypes that have heightened virulence are worrisome. In this chapter, we discuss the role of vaccines (both polysaccharide and conjugate) and other preventive strategies to limit this important and potentially lethal disease.

Lung transplantation is a therapeutic option for patients with end-stage pulmonary disorders. Unfortunately, due to post-lung transplant complications, both infectious and noninfectious, it is only a treatment and not a cure. Importantly, despite induction combined with triple or quadruple maintenance immunosuppressive therapy, chronic lung rejection, in the form of obliterative bronchiolitis or its clinical correlate bronchiolitis obliterans syndrome (BOS), continues to be highly prevalent and is the major limitation to long-term survival. In this review we evaluate the presentation, diagnosis, histopathology, pathologic mechanisms, risk factors, and prevention/treatment options for BOS. A better understanding of the risk factors and how it relates to the pathologic mechanisms of chronic lung allograft rejection should lead to better pharmacologic targets to prevent/treat this syndrome without increasing the recipient's risk for infections.