Toxocara canis infection: Unusual trigger of systemic lupus erythematosus

Infection by Toxocara canis can cause systemic vasculitis. We report here a unique case of systemic lupus erythematosus (SLE) triggered by T. canis infection. An 8‐year‐old girl was treated with albendazole therapy for common toxocariasis, but she developed two weeks later, asthenia, fever, infiltrated maculopapular eruption of the face, peripheral vascular disease with necrosis of the fingers and inflammatory anemia with proteinuria. Anti‐nuclear, anti‐DNA and anti‐Sm antibodies positivity, together with minimal change nephritis with mesangial exclusive IgM deposit on renal biopsy and clinical relapse after initially successful steroid therapy, led to the diagnosis of SLE. T. canis infection can trigger systemic lupus but must also be ruled out of the differential diagnosis given its association with autoimmunity.     

Therapeutic Drug Monitoring of Indinavir in HIV-Infected Patients Undergoing HAART

Background: Therapeutic drug monitoring (TDM) of protease inhibitors (PI) is gaining increasing importance for the management of HIV-infected patients undergoing highly active antiretroviral therapy (HAART). The PI indinavir (IDV) is widely used in HAART regimens. Combinations of IDV with ritonavir (RTV) have been used to increase the plasma concentration of IDV. However, the desirable IDV concentration range in clinical practice remains to be elucidated. Patients and Methods: To study the value of TDM for IDV in clinical practice, a retrospective analysis of 501 plasma samples of patients treated with IDV in various dosages was performed. IDV levels were determined during routine outpatient visits. Analysis was performed by high pressure liquid chromatography (HPLC) with UV detection. Results: A widespread range of IDV plasma concentrations was seen both within and between patients. The mean IDV level during therapy with IDV 2.4 g/d was 3,260 ng/ml (95% CI: 2,903 ng/ml; 3,618 ng/ml). IDV levels at a dose of IDV 1.6 g/d in combination with RTV resulted in a mean IDV plasma concentration of 4,191 ng/ml (95% CI: 3,356 ng/ml; 5,016 ng/ml). There was no significant difference between plasma levels at the doses of 2.4 g/d and 1.6 g/d. 35 of all 130 patients treated with IDV reached only suboptimal IDV plasma concentrations below the limit of 150 ng/ml. There was no statistically significant difference between the number of patients below an IDV plasma concentration of 150 ng/ml in the various dosage regimens. Conclusion: During therapy with IDV in a b.i.d. scheme, similar IDV plasma concentrations and a comparable number of patients with subinhibitory plasma concentrations were observed when compared to a therapeutic regimen with t.i.d. dosing. In this study, even at various times of plasma sampling after oral ingestion, TCM facilitated the surveillance of patients compliance. Received: August 07, 2000 · Revision accepted: August 27, 2001     

Pulmonary dendritic cell development and antigen acquisition

Pulmonary dendritic cells (DCs) constantly sample the tissue and traffic inhaled antigens to the lung-draining lymph node where they normally orchestrate an appropriate immune response. The dynamic ability of these professional antigen-presenting cells to promote tolerance or immunity has been intensively studied by several groups, including ours. Distinct DC subsets in both lymphoid and non-lymphoid tissues have been described based on their surface molecule expression and location. Current efforts to unravel DC development and function are providing insight into the various roles each subset offers the immune system. Elucidating DC functions, particularly in the lung, may then allow use of the inherent ability of these cells for enhanced vaccine strategies and therapeutics for pulmonary infections and diseases.     

Prognostic Significance of Remote Myocardium Alterations Assessed by Quantitative Noncontrast T1 Mapping in ST-Segment Elevation Myocardial Infarction

Objectives

This study assessed the prognostic significance of remote zone native T1 alterations for the prediction of clinical events in a population with ST-segment elevation myocardial infarction (STEMI) who were treated by primary percutaneous coronary intervention (PPCI) and compared it with conventional markers of infarct severity.

Muscles Involved in Naris Dilation and Nose Motion in Rat

In a number of mammals muscle dilator nasi (naris) has been described as a muscle that reduces nasal airflow resistance by dilating the nostrils. Here we show that in rats the tendon of this muscle inserts into the aponeurosis above the nasal cartilage. Electrical stimulation of this muscle raises the nose and deflects it laterally towards the side of stimulation, but does not change the size of the nares. In alert head‐restrained rats, electromyographic recordings of muscle dilator nasi reveal that it is active during nose motion rather than nares dilation. Together these results suggest an alternative role for the muscle dilator nasi in directing the nares for active odor sampling rather than dilating the nares. We suggest that dilation of the nares results from contraction of muscles of the maxillary division of muscle nasolabialis profundus. This muscle group attaches to the outer wall of the nasal cartilage and to the plate of the mystacial pad. Contraction of these muscles exerts a dual action: it pulls the lateral nasal cartilage outward, thus dilating the naris, and drags the plate of the mystacial pad rostrally to produce a slight retraction of the vibrissae. On the basis of these results, we propose that muscle dilator nasi of the rat should be re‐named muscle deflector nasi, and that the maxillary parts of muscle nasolabialis profundus should be referred to as muscle dilator nasi. Anat Rec, 298:546–553, 2015. © 2014 Wiley Periodicals, Inc.     

Epidemiology,pathophysiology and contemporary management of cardiogenic shock – a position statement from the Heart Failure Association of the European Society of Cardiology

Cardiogenic shock (CS) is a complex multifactorial clinical syndrome with extremely high mortality, developing as a continuum, and progressing from the initial insult (underlying cause) to the subsequent occurrence of organ failure and death. There is a large spectrum of CS presentations resulting from the interaction between an acute cardiac insult and a patient's underlying cardiac and overall medical condition. Phenotyping patients with CS may have clinical impact on management because classification would support initiation of appropriate therapies. CS management should consider appropriate organization of the health care services, and therapies must be given to the appropriately selected patients, in a timely manner, whilst avoiding iatrogenic harm. Although several consensus‐driven algorithms have been proposed, CS management remains challenging and substantial investments in research and development have not yielded proof of efficacy and safety for most of the therapies tested, and outcome in this condition remains poor. Future studies should consider the identification of the new pathophysiological targets, and high‐quality translational research should facilitate incorporation of more targeted interventions in clinical research protocols, aimed to improve individual patient outcomes. Designing outcome clinical trials in CS remains particularly challenging in this critical and very costly scenario in cardiology, but information from these trials is imperiously needed to better inform the guidelines and clinical practice. The goal of this review is to summarize the current knowledge concerning the definition, epidemiology, underlying causes, pathophysiology and management of CS based on important lessons from clinical trials and registries, with a focus on improving in‐hospital management.     

Roles of cGMP-dependent protein kinase I (cGKI) and PDE5 in the regulation of Ang II-induced cardiac hypertrophy and fibrosis

Conflicting results have been reported for the roles of cGMP and cGMP-dependent protein kinase I (cGKI) in various pathological conditions leading to cardiac hypertrophy and fibrosis. A cardioprotective effect of cGMP/cGKI has been reported in whole animals and isolated cardiomyocytes, but recent evidence from a mouse model expressing cGKIβ only in smooth muscle (βRM) but not in cardiomyocytes, endothelial cells, or fibroblasts has forced a reevaluation of the requirement for cGKI activity in the cardiomyocyte antihypertrophic effects of cGMP. In particular, βRM mice developed the same hypertrophy as WT controls when subjected to thoracic aortic constriction or isoproterenol infusion. Here, we challenged βRM and WT (Ctr) littermate control mice with angiotensin II (AII) infusion (7 d; 2 mg⋅kg⁻¹⋅d⁻¹) to induce hypertrophy. Both genotypes developed cardiac hypertrophy, which was more pronounced in Ctr animals. Cardiomyocyte size and interstitial fibrosis were increased equally in both genotypes. Addition of sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, in the drinking water had a small effect in reducing myocyte hypertrophy in WT mice and no effect in βRM mice. However, sildenafil substantially blocked the increase in collagen I, fibronectin 1, TGFβ, and CTGF mRNA in Ctr but not in βRM hearts. These data indicate that, for the initial phase of AII-induced cardiac hypertrophy, lack of cardiomyocyte cGKI activity does not worsen hypertrophic growth. However, expression of cGKI in one or more cell types other than smooth muscle is necessary to allow the antifibrotic effect of sildenafil.Cyclic GMP-dependent protein kinase I (cGKI) is expressed in a wide variety of cells including cardiomyocytes (CMs), cardiac myofibroblasts (CMFs), cardiac fibroblasts (CFs), endothelial cells (ECs), and smooth muscle cells (SMCs) (1). Increased cGKI activity has been reported to protect against cardiac hypertrophy induced by pressure overload (2, 3). For example, mice that carry a mutated form of cGKI unable to interact with downstream targets, develop increased pathologic hypertrophy, accelerated mortality, and congestive heart failure when subjected to thoracic aorta constriction (TAC) (4).Hypertrophy induced by angiotensin II (AII) is thought to be attenuated by cGKI, because AII signaling through G_q/11 is abrogated by the regulator of G-protein signaling protein (RGS), a known substrate of cGKI (5). However, selective deletion of the AII receptor 1 (AT-R1) in the kidney ameliorated AII-induced cardiac hypertrophy, suggesting that the cardiac AT-R1 is dispensable for the induction of this response (6), whereas transgenic mice that overexpress the human AT-R1 specifically in CMs develop hypertrophy, fibrosis, dysfunctions, and early death (7). Furthermore, activation of TRPC channels followed by elevated [Ca²⁺]_i may contribute to the induction of the cardiac hypertrophy gene response (8–11). Again, TRPC3 and TRPC6 channels are negatively regulated by cGKI (12–14).It also has been reported that particulate guanylyl cyclase A, the major receptor for atrial natriuretic peptide (ANP) in the heart, couples to and directly activates the TRPC3/C6 channels in chronic cardiac hypertrophy, thus bypassing cGMP and cGKI (15). It was reported that cardiac cGMP can affects cardiac properties by modulating cAMP levels, bypassing again cGKI (16, 17). Thus, the site(s) of action of cGMP/cGKI are not entirely clear (18) and interpretation of cGMP/cGKI effects on cardiac hypertrophy may be quite complicated.Sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, elevates cardiac cGMP at high doses (100 mg⋅kg⁻¹⋅d⁻¹), increases cGKI activity, and has been reported to reverse TAC-induced cardiac hypertrophy (2). This effect is postulated to be caused by an increased activity of RGS2 (19), and in part by the direct regulation of TRPC3/6 conductance by cGKI (11, 14) mentioned above. However, two clinical studies did not report positive therapeutic results after prolonged treatment of diastolic dysfunction with sildenafil (20, 21).We (22) and others (23) have tested the hypothesis that CM-cGKI attenuates cardiac hypertrophy by using the cGKIβ rescue mouse line (βRM). These animals express the cGKIβ isozyme under the SM22α promoter, which is active principally in SMCs and activated CMFs, but do not express cGKIβ in other cell types (24). Chronic infusion of isoproterenol or TAC induced in βRM mice a cardiac hypertrophy that was identical to that of WT littermate controls (22), a result that argues against the hypothesis that CM, EC, or CF cGKI is responsible for the antihypertrophic effects of cGMP in the heart. To examine the role(s) of sildenafil to inhibit cardiac hypertrophy and fibrosis, we now extend these experiments using AII-induced hypertrophy and high concentrations of sildenafil (0.6 mM) in the drinking water. Once again, the lack of cGKI in CM and CF did not cause an increased hypertrophic response as predicted (2). Moreover, little or no antihypertrophic effect of sildenafil was observed in the WT mice and no effect was seen in the βRM mice. However, a large effect of sildenafil was observed on fibrosis in WT but not the βRM mice, suggesting that cGKI present in cardiac SMCs or activated CMFs is an important regulator of cardiac fibrosis.     

Mycophenolate mofetil in steroid-dependent idiopathic nephrotic syndrome

Background

Prospective studies have established the mycophenolate mofetil (MMF) efficiency in childhood idiopathic nephrotic syndrome (INS) but reports on the long-term outcome are lacking. Moreover, the search for factors influencing its efficiency would be useful to define its place among the other treatments.

Methods

We performed a monocentric retrospective study including 96 children with steroid-dependent INS followed for 4.7 years (median) (IQ 3–6) after the onset of MMF treatment. The characteristics of responder patients (n?=?74), as defined by a 50 % decrease of relapse rate and/or a 60 % decrease of steroid dose, and of non-responder patients (n?=?22) were compared by univariate analysis and multivariate logistic regression.

Results

Withdrawal of prednisone was achieved in 48/96 patients after a median duration of 18.1 months (IQ 7.8–30.0) of MMF. Only 26/48 patients did not relapse under MMF alone. After MMF was stopped in these patients, only six remained in remission without any treatment at last follow-up. Responders had a shorter time to remission at the first flare (9.5 vs. 15 days, p?=?0.02), a shorter disease duration prior to the onset of MMF (22.2 vs. 94.5 months, p?=?0.001), and were younger at the MMF initiation (6.7 vs. 10.1 years, p?=?0.02) than non-responder patients. The age of MMF initiation was an independent factor associated with efficiency (OR?=?0.80, 95 % CI [0.69, 0.93], p?<?0.01).

Conclusions

MMF is more efficient in young patients treated early in the disease course. Nevertheless, MMF has no remnant effect while nearly all patients relapsed after withdrawal of the drug.