Leptospiral pneumonias

PURPOSE OF REVIEW: Pulmonary involvement in leptospirosis has been reported to be increasing in the last few years and is emerging as a serious life threat and the main cause of death due to leptospirosis in some countries. In this review, we present the main clinical and pathological manifestations of pulmonary involvement in leptospirosis, and recent data on the pathophysiology of lung damage and therapeutic implications. RECENT FINDINGS: Although previous reports have emphasized the increasing incidence of pulmonary manifestations in patients with leptospirosis worldwide, pulmonary involvement in leptospirosis is still under-recognized. Experimental models have been used to address new aspects of the pathogenesis of the disease, including determination of novel outer membrane proteins, characterization of dysregulation of sodium transporters of alveolar epithelial cells, and provision of new data on the role of innate immunity in the development of severe disease, thereby making major progress in understanding the mechanisms underlying lung injury. SUMMARY: Pulmonary hemorrhage represents the main cause of death in severe forms of leptospirosis. Although the mechanism of pulmonary impairment is still poorly understood, recent experimental studies have brought new insights to the pathogenesis of lung injury and provide new perspectives on treatment of critically ill patients.     

Obstructive sleep apnea and resistant hypertension: a case-control study

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) has been linked to resistant hypertension, but the magnitude of this association and its independence of confounding have not been established. METHODS: Case patients were 63 patients with resistant hypertension (BP >or= 140/90 mm Hg using at least three BP-lowering drugs, including a diuretic), and control subjects were 63 patients with controlled BP receiving drug treatment. The primary outcome was the frequency of OSAS (apnea-hypopnea index [AHI] >or= 10 episodes per hour) determined with a portable home monitor. The comparison of AHI episodes in patients truly normotensive, truly hypertensive, and in patients with white coat or masked hypertension, based on BP determined at office and by ambulatory BP monitoring (ABPM) was a secondary outcome. RESULTS: Case patients and control subjects were well matched for confounding factors. OSAS was present in 45 case patients (71%) and in 24 control subjects (38%) [p < 0.001]. In a logistic regression model, OSAS was strongly and independently associated with resistant hypertension (odds ratio, 4.8; 95% confidence interval, 2.0 to 11.7). The AHI of case patients with normal BP in ABPM (white coat hypertension) and control subjects with abnormal BP in ABPM (masked hypertension) was intermediate between the AHI of individuals with normal and abnormal BP measures in both settings (p < 0.001). CONCLUSIONS: The magnitude and independence of the risk of OSAS for resistant hypertension strengthen the concept that OSAS is a risk factor for resistant hypertension. Comorbid OSAS should be considered in patients with resistant hypertension.     

Reversible Unilateral Nigrostriatal Pathway Inhibition Induced Through Expression of Adenovirus-mediated Clostridial Light Chain Gene in the Substantia Nigra

Clostridial light chain (LC) inhibits synaptic transmission by digesting a vesicle-docking protein, synaptobrevin, without killing neurons. We here report the feasibility of creating a rat hemiparkinsonism model through LC gene expression in the substantia nigra (SN), inhibiting nigrostriatal transmission. 40 adult Sprague Dawley rats were divided into four groups for SN injections of PBS, 6-hydroxydopamine (6-OHDA), or adenoviral vectors for the expression of LC (AdLC), or GFP (AdGFP). Amphetamine and apomorphine induced rotations were assessed before and after SN injection, revealing significant rotational alterations at 8 or 10 days after injection in both AdLC and 6-OHDA but not PBS and AdGFP groups. Induced rotation recovered by one month in AdLC rats but persisted in 6-OHDA rats. Histological analysis of the SN revealed LC and GFP expression with corresponding synaptobrevin depletion in the LC, but not the GFP groups. Tyrosine hydroxylase (TH) and dopamine transporter (DAT) immunohistochemistry (IHC) showed markedly decreased staining in ipsilateral SN and striatum in 6-OHDA but not AdLC or AdGFP rats. Similarly, compared with contralateral, ipsilateral striatal dopamine level only decreased in 6-OHDA but not AdLC, AdGFP, or PBS treated rats. Thus, LC expression induces nigral synaptobrevin depletion with resulting inhibition of nigrostriatal synaptic transmission. Unlike 6-OHDA, LC expression inhibits synaptic activity without killing neurons. This approach, therefore, represents a potentially reversible means of nigrostriatal pathway inhibition as a model for Parkinson’s disease. Such a model might facilitate transient and controlled nigral inhibition for studying striatal recovery, dopaminergic re-innervation, and normalization of striatal receptors following the recovery of nigrostriatal transmission.     

Exposure to ambient levels of particles emitted by traffic worsens emphysema in mice

Objectives

We investigated effects of chronic exposure (2 months) to ambient levels of particulate matter (PM) on development of protease-induced emphysema and pulmonary remodeling in mice. Methods: Balb/c mice received nasal drop of either papain or normal saline and were kept in two exposure chambers situated in an area with high traffic density. One of them received ambient air and the other had filters for PM. Results: mean concentration of PM10 was 2.68±0.38 and 33.86±2.09 μg/m³, respectively, in the filtered and ambient air chambers (p<0.001). After 2 months of exposure, lungs from papain-treated mice kept in the chamber with ambient air presented greater values of mean linear intercept, an increase in density of collagen fibers in alveolar septa and in expression of 8-isoprostane (p=0.002, p<0.05 and p=0.002, respectively, compared to papain-treated mice kept in the chamber with filtered air). We did not observe significant differences between these two groups in density of macrophages and in amount of cells expressing matrix metalloproteinase-12. There were no significant differences in saline-treated mice kept in the two chambers.

Conclusions

We conclude that exposure to urban levels of PM worsens protease-induced emphysema and increases pulmonary remodeling. We suggest that an increase in oxidative stress induced by PM exposure influences this response. These pulmonary effects of PM were observed only in mice with emphysema.     

Mebendazole disrupts stromal desmoplasia and tumorigenesis in two models of pancreatic cancer

The five-year survival rate for metastatic pancreatic cancer is currently only 3%, which increases to 13% with local invasion only and to 39% with localized disease at diagnosis. Here we evaluated repurposed mebendazole, an approved anthelminthic drug, to determine how mebendazole might work at the different stages of pancreatic cancer formation and progression. We asked if mebendazole could prevent initiation of pancreatic intraepithelial neoplasia precursor lesions, interfere with stromal desmoplasia, or suppress tumor growth and liver metastasis. In both the Kras^LSL.G12D/+; Pdx1-Cre (KC) mouse model of caerulein-induced inflammatory pancreatitis and the Kras^LSL.G12D/+; Tp53^R172H/+; Pdx1-Cre (KPC) mouse model of advanced pancreatic cancer, mebendazole significantly reduced pancreas weight, dysplasia and intraepithelial neoplasia formation, compared to controls. Mebendazole significantly reduced trichrome-positive fibrotic connective tissue and α-SMA-positive activated pancreatic stellate cells that heralds fibrogenesis. In the aggressive KPC model, mebendazole significantly suppressed pancreatic tumor growth, both as an early and late intervention. Mebendazole reduced the overall incidence of pancreatic cancer and severity of liver metastasis in KPC mice. Using early models of pancreatic cancer, treatment with mebendazole resulted in less inflammation, decreased dysplasia, with the later stage model additionally showing a decreased tumor burden, less advanced tumors, and a reduction of metastasis. We conclude that mebendazole should be investigated further as a component of adjuvant therapy to slow progression and prevent metastasis, and well as for primary prevention in the highest risk patients.     

Retinal involvement of Paracoccioidomycosis: A Case Report

Purpose: to describe the clinicopathologic features and treatment of a rare case of systemic paracoccidioidomycosis with choroidal and retinal involvement. Design: retrospective interventional case report. Participant: A 36-year-old young man with visual impairment in left eye with anterior uveitis and presence of whitish perimacular choroidal nodule, multiple underlying whitish spots and mid-periphery exudative retinal detachment. A primary extensive work-up for systemic infectious, autoimmune, neoplasic or inflammatory conditions was performed and high-resolution computer tomography scan demonstrated asymmetric parietal thickening of the trachea and bilateral diffuse multiple lobular opacities. Pulmonary bronchoscopy/biopsy of larynx, trachea and bronchial tube were also performed. Histopathological evaluation showed characteristic of Paracoccidioidomycosis. Intervention: Patient was treated with oral sulphadiazine (1.5 g/day). Main Outcome Measures: Anterior uveitis, retinal examination, histopathological evaluation and primary clinical outcome were observed during systemic treatment. Results: After 3 months of irregular treatment, choroidal lesions decreased in size forming atrophic scars and fibrotic spots; however visual acuity did not show any improvement. Conclusion: We report a rare case of systemic paracoccidioidomycosis with choroidal and retinal involvement treated with oral sulphadiazine.