The study on bacterial infection in chronic lower respiratory tract infection--from the viewpoints of acute and chronic infection]

Using mainly changes in the amount of sputum as an index of the infectious course of chronic lower respiratory tract infection associated with purulent sputum over years, the disease was divided into stable and acute exacerbated phases and a bacteriological investigation using transtracheal aspiration (TTA) conducted. TTA was performed 107 and 45 episodes during stable phases and acute exacerbated phases respectively. Monomicrobial and polymicrobial infection were detected most frequently during the stable and acute exacerbated phases respectively (p less than 0.01). During the stable phases, the single organisms detected most frequently were H. influenzae (26 episodes) and P. aeruginosa (20 episodes), while in the cases in which multiple organisms were detected during stable phases, combination including H. influenzae were most common (19 episodes). H. influenzae was the most frequently detected organism in cases showing single organisms during acute exacerbated phases (7 episodes). In the cases in which multiple organisms were detected as well, H. influenzae was the most commonly detected organism assumed to predispose to exacerbation (7 episodes), while P. aeruginosa was not found. These results suggest that in chronic lower respiratory tract infection. H. influenzae and P. aeruginosa are important as persistent infective organisms, while H. influenzae are important in acute exacerbation.     

A case of endocapillary proliferative glomerulonephritis with macrophages phagocytosing monoclonal immunoglobulin lambda light chain

Multiple myeloma (MM) is a plasma‐cell neoplasm that can cause renal disorders. Renal lesions in MM can present with a very rare pathological manifestation involving a specific monoclonal immunoglobulin (Ig). We report the case of a 33‐year‐old woman who had edema, fatigue, elevated serum creatinine levels, hypoalbuminemia, and hypercholesterolemia. She had persistent hematuria and proteinuria lasting 3 years. Serum protein electrophoresis showed an M‐spike, and serum immunofixation demonstrated the presence of monoclonal IgG λ. She had proteinuria in the nephrotic range, and a monoclonal λ fragment was present on urine immunofixation. Renal biopsy showed proliferative glomerulonephritis with λ light chain and C3c deposition and inflammatory cell infiltration with CD68. Macrophage lysosomes contained λ light chains, suggesting their partial phagocytosis. She was diagnosed with symptomatic MM and was treated with bortezomib and dexamethasone and an autologous peripheral stem cell transplant conditioned with intravenous melphalan. She achieved a partial response with decreased serum monoclonal protein and improved renal function. This case may be categorized as a monoclonal gammopathy‐associated proliferative glomerulonephritis. The biopsy finding of partially phagocytosed Ig λ light chains by macrophages is very rare; this pathological condition is similar to crystal‐storing histiocytosis.     

κ Opioid receptor ligands regulate angiogenesis in development and in tumours

Opioid systems mainly regulate physiological functions such as pain, emotional tone and reward circuitry in neural tissues (brain and spinal cord). These systems are also found in extraneural tissues (ganglia, gut, spleen, stomach, lung, pancreas, liver, heart, blood and blood vessels), and recent studies have elucidated their roles in various organs. The current review focuses on the roles of opioid systems in blood vessels, especially angiogenesis, during development and tumour malignancy. The balance between endogenous activators and inhibitors of angiogenesis delicately maintains a normally quiescent vasculature to sustain homeostasis. Disturbance of this balance causes pathogenic angiogenesis and, especially in tumours, several activators such as VEGF are highly expressed in the tumour microenvironment and strongly induce tumour angiogenesis, the so-called angiogenic switch. Recently, we demonstrated that κ opioid receptor agonists function as anti-angiogenic factors, which impede the angiogenic switch, in vascular development and tumour angiogenesis by inhibiting the expression of receptors for VEGF. In clinical medicine, angiogenesis inhibitors that target VEGF signalling such as bevacizumab are used as anti-cancer drugs. Although therapies that inhibit tumour angiogenesis have been highly successful for tumour therapy, most patients eventually develop resistance to this anti-angiogenic therapy. Thus, we must identify novel targets for anti-angiogenic agents to sustain inhibition of angiogenesis for tumour therapy. The regulation of responses to κ opioid receptor ligands could be useful for controlling vascular formation under physiological conditions and in cancers, and thus could offer therapeutic benefits beyond the relief of pain.

LINKED ARTICLES

This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2     

Redistribution of the Lamin B1 genomic binding profile affects rearrangement of heterochromatic domains and SAHF formation during senescence

Senescence is a stress-responsive form of stable cell cycle exit. Senescent cells have a distinct gene expression profile, which is often accompanied by the spatial redistribution of heterochromatin into senescence-associated heterochromatic foci (SAHFs). Studying a key component of the nuclear lamina lamin B1 (LMNB1), we report dynamic alterations in its genomic profile and their implications for SAHF formation and gene regulation during senescence. Genome-wide mapping reveals that LMNB1 is depleted during senescence, preferentially from the central regions of lamina-associated domains (LADs), which are enriched for Lys9 trimethylation on histone H3 (H3K9me3). LMNB1 knockdown facilitates the spatial relocalization of perinuclear H3K9me3-positive heterochromatin, thus promoting SAHF formation, which could be inhibited by ectopic LMNB1 expression. Furthermore, despite the global reduction in LMNB1 protein levels, LMNB1 binding increases during senescence in a small subset of gene-rich regions where H3K27me3 also increases and gene expression becomes repressed. These results suggest that LMNB1 may contribute to senescence in at least two ways due to its uneven genome-wide redistribution: first, through the spatial reorganization of chromatin and, second, through gene repression.     

Long-term outcome of complete cardiovascular implantable electronic device removal with cardiopulmonary bypass

Definitive endovascular techniques have been developed for pacemaker lead extraction; however, a few patients require immediate secondary open heart surgery because of incomplete transvenous lead extraction. This study examined the safety, effectiveness, and long-term outcome of the removal of cardiovascular implantable electronic device (CIED) via median sternotomy under cardiopulmonary bypass. The removal of CIED was performed in 6 patients (mean age 57 ± 16 years, 5 males and 1 female), from September 2000 to April 2011. The reasons for removal included eradication of an infection in 5 patients and elimination of pacemaker component allergy in 1. Positive culture results, including methicillin-sensitive Staphylococcus aureus (MSSA, n = 2), methicillin-resistant S. aureus (MRSA, n = 1), coagulase-negative staphylococci (CNS, n = 1), and methicillin-resistant S. epidermidis (MRSE, n = 1) were observed in all 5 infected patients. Mitral annuloplasty (n = 1), mitral valvuloplasty (n = 1), tricuspid annuloplasty (n = 3). Implantation of myocardial pacing leads (n = 5) were performed concomitantly (n = 4), or secondarily (n = 1). All 6 patients were alive in good condition at 72 ± 55 months following CIED removal. New device infection occurred in 1 patient during long-term follow up. Complete surgical removal of pacing systems via median sternotomy with cardiopulmonary bypass is, therefore, considered to be safe and feasible with acceptable long term results.     

Successful remission using metyrapone in an elderly patient with Cushing disease accompanied by generalized edema

An 82-year-old woman was referred to our hospital because of hypoalbuminemia and generalized edema. Hypercortisolemia was subsequently found as the levels of serum cortisol and plasma adrenocorticotropic hormone (ACTH) sampled in a fasting morning were 140 pg/mL and 41.9 μg/dL, respectively. These hormones were not suppressed after taking low-dose dexamethasone the previous night and increased to a mild extent in response to administration of corticotrophin-releasing hormone, suggesting presence of pituitary adenoma producing ACTH (Cushing's disease). However, intrasella localization of pituitary adenoma could not be determined by magnetic resonance imaging. Soon after administration of metyrapone was started in an attempt to reduce her cortisol levels, the patient suffered from severe pneumonia. The pulmonary infection and peripheral edema were improved with decreases in cortisol levels by continuing metyrapone administration with antibiotics and finally she was discharged from the hospital on foot. Metyrapone is a useful therapeutic choice to achieve a remission of cortisol levels in the elderly patients with Cushing's disease in association with serious hypercortisolemia impending severe infection.     

Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria

Cytochrome c release and the mitochondrial permeability transition (PT), including loss of the transmembrane potential (Δψ), play an important role in apoptosis. Using isolated mitochondria, we found that recombinant Bax and Bak, proapoptotic members of the Bcl-2 family, induced mitochondrial Δψ loss, swelling, and cytochrome c release. All of these changes were dependent on Ca²⁺ and were prevented by cyclosporin A (CsA) and bongkrekic acid, both of which close the PT pores (megachannels), indicating that Bax- and Bak-induced mitochondrial changes were mediated through the opening of these pores. Bax-induced mitochondrial changes were inhibited by recombinant Bcl-x_L and transgene-derived Bcl-2, antiapoptotic members of the Bcl-2 family, as well as by oligomycin, suggesting a possible regulatory effect of F₀F₁-ATPase on Bax-induced mitochondrial changes. Proapoptotic Bax- and Bak-BH3 (Bcl-2 homology) peptides, but not a mutant BH3 peptide nor a mutant Bak lacking BH3, induced the mitochondrial changes, indicating an essential role of the BH3 region. A coimmunoprecipitation study revealed that Bax and Bak interacted with the voltage-dependent anion channel, which is a component of PT pores. Taken together, these findings suggest that proapoptotic Bcl-2 family proteins, including Bax and Bak, induce the mitochondrial PT and cytochrome c release by interacting with the PT pores.