AimsTo Assess changes in infective endocarditis (IE) epidemiology over the last 5 decades. Methods and ResultsWe searched the published literature using PubMed, MEDLINE, and EMBASE from inception until December 2011. Data FromEinstein Medical Center, Philadelphia, PA were also included. Criteria for inclusion in this systematic review included studies with reported IE microbiology, IE definition, description of population studied, and time frame. Two authors independently extracted data and assessed manuscript quality. One hundred sixty studies (27,083 patients) met inclusion criteria. Among hospital-based studies (n=142; 23,606 patients) staphylococcal IE percentage increased over time, with coagulase-negative staphylococcus (CNS) increasing over each of the last 5 decades (p<0.001) and Staphylococcus aureus (SA) in the last decade (21% to 30%; p<0.05). Streptococcus viridans (SV) and culture negative (CN) IE frequency decreased over time (p<0.001), while enterococcal IE increased in the last decade (p<0.01). Patient age and male predominance increased over time as well. In subgroup analysis, SA frequency increased in North America, but not the rest of the world. This was due, in part, to an increase in intravenous drug abuse IE in North America (p<0.001). Among population-based studies (n=18; 3,477 patients) no significant changes were found. ConclusionImportant changes occurred in IE epidemiology over the last half-century, especially in the last decade. Staphylococcal and enterococcal IE percentage increased while SV and CN IE decreased. Moreover, mean age at diagnosis increased together with male:female ratio. These changes should be considered at the time of decision-making in treatment of and prophylaxis for IE.

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The lung is both the conduit for oxygen uptake and is also affected by hypoxia and hypoxia signaling. Decreased ventilatory drive, airway obstructive processes, intra-alveolar exudates, septal thickening by edema, inflammation, fibrosis, or damage to alveolar capillaries will all interpose a significant and potentially life-threatening barrier to proper oxygenation, therefore enhancing the alveolar/arterial pO 2 gradient. These processes result in decreased blood and tissue oxygenation. This review addresses the relationship of hypoxia with lung development and with lung diseases. We particularly focus on molecular mechanisms underlying hypoxia-driven physiological and pathophysiological lung processes, specifically in the infant lung, pulmonary hypertension, and chronic obstructive pulmonary disease.Keywords Hypoxia . Lung . Pathology . HIF Air, containing oxygen at approximately 21% partial pressure at sea level (140-150 mmHg), travels through up to 20 generations of airways by mass flow and then diffuses into the gas exchange units (alveoli) in the lung with a partial pressure of approximately 105-110 mmHg. The human lung contains approximately 480 million alveoli, which represent 64% of total lung structure. These alveoli are elegantly packed in only 1.3-2.6 L of total lung volume, providing a surface area of 120-150 m 2 , equivalent to the dimensions of a "tennis court" dedicated for gas exchange. Although the molecular determinants of lung size are not known, oxygen diffusion constant and gas exchange surface area are roughly proportional to body weight and oxygen consumption in different species [1]. Physical hyperactivity and exposure to a cold environment or high altitude lead to increased oxygen diffusion capacity, in proportion to enhanced oxygen consumption [1].Decreased ventilatory drive, airway obstructive processes, intraalveolar exudates, septal thickening by edema, inflammation, fibrosis, or damage to alveolar capillaries will all interpose a significant and potentially life-threatening barrier to proper oxygenation, therefore enhancing the alveolar/ arterial pO 2 gradient. This review addresses the contribution of hypoxia to lung diseases and the potential molecular mechanisms involved in hypoxia-driven physiological and pathophysiological lung processes (Fig. 1), particularly in the infant lung, pulmonary hypertension, and chronic obstructive pulmonary disease. The fundamental concepts underlying hypoxia-induced gene expression and the molecular regulation of HIF(s) also apply to the lung, and they will be cited in relation to their demonstrated role in lung physiology or pathophysiology.

Background: Generalized granuloma annulare (GGA) is a benign skin disorder of an unknown etiology. Though some cases of GGA have been reported, few systemic reviews of the clinical and pathological features of GGA have been performed. Objective: The purpose of this study is to analyze and correlate the clinical and pathological characteristics of GGA in Korean patients. Methods: We conducted a retrospective study that included 54 biopsy specimens of Korean GGA patients, and the clinical and pathological features of GGA were reviewed and analyzed for their correlation. Results: The cutaneous lesions could be divided into the annular (24, 44%) and nonannular types (30, 56%), and the lesions were more common in males than in females (29 males and 25 females). The incidence of GGA showed a bimodal age distribution. The number of patients who presented within the first decade was 24 cases (44%), and 24 cases (44%) were over the fifth decade. Eight patients (15%) had systemic diseases. Especially, diabetes mellitus (DM) occurred only in the adult GGA patients over forty years old. The pathological findings showed dermal granulomatous lesions that consisted of either a palisading pattern (28, 52%) or an interstitial pattern (26, 48%). Conclusion: In contrast to the previously reported studies, the age of GGA onset showed a bimodal distribution, and GGA was observed more often in males. The prevalence of DM in the GGA affected individuals was higher than that found in the general Korean population. Therefore, it is recommended to perform a work-up for DM in the GGA affected patients who are over forty years old. (Ann Dermatol 21(2) 113∼119, 2009)

Genetic variants in Hedgehog interacting protein (HHIP) have consistently been associated with the susceptibility to develop chronic obstructive pulmonary disease and pulmonary function levels, including the forced expiratory volume in 1 s (FEV1), in general population samples by genome-wide association studies. However, in vivo evidence connecting Hhip to age-related FEV1 decline and emphysema development is lacking. Herein, using Hhip heterozygous mice (Hhip+/−), we observed increased lung compliance and spontaneous emphysema in Hhip+/− mice starting at 10 mo of age. This increase was preceded by increases in oxidative stress levels in the lungs of Hhip+/− vs. Hhip+/+ mice. To our knowledge, these results provide the first line of evidence that HHIP is involved in maintaining normal lung function and alveolar structures. Interestingly, antioxidant N-acetyl cysteine treatment in mice starting at age of 5 mo improved lung function and prevented emphysema development in Hhip+/− mice, suggesting that N-acetyl cysteine treatment limits the progression of age-related emphysema in Hhip+/− mice. Therefore, reduced lung function and age-related spontaneous emphysema development in Hhip+/− mice may be caused by increased oxidative stress levels in murine lungs as a result of haploinsufficiency of Hhip.

BackgroundCigarette smoking is the leading modifiable risk factor for disease and death worldwide. Previous studies quantifying gene-level expression have documented the effect of smoking on mRNA levels. Using RNA sequencing, it is possible to analyze the impact of smoking on complex regulatory phenomena (e.g. alternative splicing, differential isoform usage) leading to a more detailed understanding of the biology underlying smoking-related disease.MethodsWe used whole-blood RNA sequencing to describe gene and exon-level expression differences between 229 current and 286 former smokers in the COPDGene study. We performed differential gene expression and differential exon usage analyses using the voom/limma and DEXseq R packages. Samples from current and former smokers were compared while controlling for age, gender, race, lifetime smoke exposure, cell counts, and technical covariates.ResultsAt an adjusted p-value <0.05, 171 genes were differentially expressed between current and former smokers. Differentially expressed genes included 7 long non-coding RNAs that have not been previously associated with smoking: LINC00599, LINC01362, LINC00824, LINC01624, RP11-563D10.1, RP11-98G13.1, AC004791.2. Secondary analysis of acute smoking (having smoked within 2-h) revealed 5 of the 171 smoking genes demonstrated an acute response above the baseline effect of chronic smoking. Exon-level analyses identified 9 exons from 8 genes with significant differential usage by smoking status, suggesting smoking-induced changes in isoform expression.ConclusionsTranscriptomic changes at the gene and exon levels from whole blood can refine our understanding of the molecular mechanisms underlying the response to smoking.Electronic supplementary materialThe online version of this article (10.1186/s12920-017-0295-9) contains supplementary material, which is available to authorized users.

The discovery of vascular endothelial growth factor (VEGF) changed the field of angiogenesis. We have learned that VEGF has broader actions than merely a driver of tumor angiogenesis, particularly that VEGF controlled several fundamental functions and properties of endothelial cells and nonendothelial cells. The lung is one of the main organs where VEGF controls several crucial physiological functions. These actions rely on tightly regulated temporal and concentration gradients of VEGF and VEGF receptor expression in the lung. Excessive or diminished VEGF have been linked to abnormal lung phenotypes and, in humans, linked to several diseases. The beneficial and detrimental actions of VEGF underscore that therapeutic targeting of VEGF in disease has to carefully consider the lung biology of VEGF.

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