Lupus mastitis: A rare breast cancer differential diagnosis

Lupus mastitis is an uncommon SLE breast manifestation. Clinically, it can present itself as a malignant‐like mass. Therefore, a tissue biopsy is warranted to confirm the diagnosis. The treatment of this condition is pharmacological and directed to the underlying disease. The rarity of this entity demands a high degree of suspicion.     

Pulmonary changes on HRCT scans in nonsmoking females with COPD due to wood smoke exposure

OBJECTIVE:

To identify and characterize alterations seen on HRCT scans in nonsmoking females with COPD due to wood smoke exposure.

METHODS:

We evaluated 42 nonsmoking females diagnosed with wood smoke-related COPD and 31 nonsmoking controls with no history of wood smoke exposure or pulmonary disease. The participants completed a questionnaire regarding demographic data, symptoms, and environmental exposure. All of the participants underwent spirometry and HRCT of the chest. The COPD and control groups were adjusted for age (23 patients each).

RESULTS:

Most of the patients in the study group were diagnosed with mild to moderate COPD (83.3%). The most common findings on HRCT scans in the COPD group were bronchial wall thickening, bronchiectasis, mosaic perfusion pattern, parenchymal bands, tree-in-bud pattern, and laminar atelectasis (p < 0.001 vs. the control group for all). The alterations were generally mild and not extensive. There was a positive association between bronchial wall thickening and hour-years of wood smoke exposure. Centrilobular emphysema was uncommon, and its occurrence did not differ between the groups (p = 0.232).

CONCLUSIONS:

Wood smoke exposure causes predominantly bronchial changes, which can be detected by HRCT, even in patients with mild COPD.     

PREDIRCAM eHealth Platform for Individualized Telemedical Assistance for Lifestyle Modification in the treatment of Obesity,Diabetes, and Cardiometabolic Risk Prevention: A Pilot Study (PREDIRCAM 1)

Background

Healthy diet and regular physical activity are powerful tools in reducing diabetes and cardiometabolic risk. Various international scientific and health organizations have advocated the use of new technologies to solve these problems. The PREDIRCAM project explores the contribution that a technological system could offer for the continuous monitoring of lifestyle habits and individualized treatment of obesity as well as cardiometabolic risk prevention.

Methods

PREDIRCAM is a technological platform for patients and professionals designed to improve the effectiveness of lifestyle behavior modifications through the intensive use of the latest information and communication technologies. The platform consists of a web-based application providing communication interface with monitoring devices of physiological variables, application for monitoring dietary intake, ad hoc electronic medical records, different communication channels, and an intelligent notification system. A 2-week feasibility study was conducted in 15 volunteers to assess the viability of the platform.

Results

The website received 244 visits (average time/session: 17 min 45 s). A total of 435 dietary intakes were recorded (average time for each intake registration, 4 min 42 s ± 2 min 30 s), 59 exercises were recorded in 20 heart rate monitor downloads, 43 topics were discussed through a forum, and 11 of the 15 volunteers expressed a favorable opinion toward the platform. Food intake recording was reported as the most laborious task. Ten of the volunteers considered long-term use of the platform to be feasible.

Conclusions

The PREDIRCAM platform is technically ready for clinical evaluation. Training is required to use the platform and, in particular, for registration of dietary food intake.     

Blood Pressure-Lowering Efficacy of Amiloride versus Enalapril as Add-On Drugs in Patients with Uncontrolled Blood Pressure Receiving Hydrochlorothiazide

A large proportion of patients with hypertension need a second drug to reach satisfactory control of blood pressure (BP), but there are few well-designed controlled trials comparing the efficacy of drugs added as a second option. In a double-blind randomized clinical trial, 82 patients with uncontrolled BP, receiving hydrochlorothiazide 25 mg daily, were selected to receive amiloride 2.5–5 mg/day (n?=?39) or enalapril 10–20 mg/day (n?=?43). Ambulatory blood pressure monitoring (ABPM) was done before and after 12-weeks of treatment. Office BP was measured in the 4^th, 8^th, and 12^th weeks. The doses of amiloride and enalapril were doubled in the fourth week, and propranolol was added in the 8th week if office BP was above 140/90 mm Hg. There was a greater BP reduction in patients treated with enalapril. The ABPM δ values between the groups were 3.6?±?2.2, 3.9?±?2.2, and 1.1?±?2.7 mmHg for 24-h, daily, and nightly systolic blood pressure, respectively, favoring enalapril. For diastolic blood pressure (DBP), the deltas were 1.7?±?2.0, 3.2?±?1.5, and 1.2?±?1.9 mmHg, respectively (p?=?0.039 for daily DBP). Office SBP decreased more and sooner in patients allocated to enalapril (p?=?0.003). More patients taking amiloride required propranolol to control BP (p?=?0.035). Potassium increased 0.3 mEq/L on the average in both groups. Cough, albeit predominantly mild, was reported more frequently by participants treated with enalapril. We conclude that enalapril is more effective than amiloride to lower BP of patients on hydrochlorothiazide with uncontrolled BP.

Trial registration: ClinicalTrials.gov identifier: NCT00394394.     

DARC (Duffy) and BCAM (Lutheran) reduced expression in thyroid cancer

Duffy or DARC (Duffy Antigen Receptor for Chemokines) is a glycosylated membrane protein that selectively binds angiogenic chemokines. Previous in vivo and in vitro studies of DARC function in cancer have associated DARC over expression with better prognosis, decreased metastatic potential, and inhibition of tumor-associated neovascularization. Another carcinogenesis-associated antigen is Lutheran or BCAM (basal cell adhesion molecule), a surface glycoprotein that acts as a receptor for the extracellular matrix protein, laminin. BCAM is a protein related to tumor progression; and, its over expression is associated with skin, ovarian and pancreatic cancers. We explored DARC and BCAM functions and investigated whether or not their expressions were altered in thyroid cancer. The expression of DARC and BCAM were evaluated by quantitative real-time PCR (qPCR) in a set of 18 normal thyroid tissues (NT), 15 follicular adenomas (FTA), 17 follicular carcinomas (FTC), and 122 papillary thyroid carcinomas (PTC), including 78 classical (CVPTC) and 44 follicular variant (FVPTC). RNA was isolated, reverse transcribed to cDNA, and used in qPCR reactions containing SYBR Green. The relative expression value was calculated using ribosomal protein S8 as an internal control. When we compared benign (NT and FTA) versus malignant samples (FTC, CVPTC and FVPTC) we observed a significant decrease of DARC and BCAM relative expression in malignant cases. Additionally, we correlated clinic-pathological features (tumor size, presence of metastasis, presence of lymphocyte infiltrate) with DARC and BCAM expression. We found a diminished expression of DARC in PTC samples, which was correlated with tumor size and presence of a lymphocyte infiltrate. We, also, found a correlation between decreased BCAM expression and tumor size or presence of metastasis. DARC and BCAM expression was associated with pathogenesis of thyroid carcinoma and correlated with clinical–pathological features.     

Torins are potent antimalarials that block replenishment of Plasmodium liver stage parasitophorous vacuole membrane proteins

Residence within a customized vacuole is a highly successful strategy used by diverse intracellular microorganisms. The parasitophorous vacuole membrane (PVM) is the critical interface between Plasmodium parasites and their possibly hostile, yet ultimately sustaining, host cell environment. We show that torins, developed as ATP-competitive mammalian target of rapamycin (mTOR) kinase inhibitors, are fast-acting antiplasmodial compounds that unexpectedly target the parasite directly, blocking the dynamic trafficking of the Plasmodium proteins exported protein 1 (EXP1) and upregulated in sporozoites 4 (UIS4) to the liver stage PVM and leading to efficient parasite elimination by the hepatocyte. Torin2 has single-digit, or lower, nanomolar potency in both liver and blood stages of infection in vitro and is likewise effective against both stages in vivo, with a single oral dose sufficient to clear liver stage infection. Parasite elimination and perturbed trafficking of liver stage PVM-resident proteins are both specific aspects of torin-mediated Plasmodium liver stage inhibition, indicating that torins have a distinct mode of action compared with currently used antimalarials.The population at risk for developing malaria is vast, comprising some 3.3 billion people particularly in sub-Saharan Africa and Southeast Asia, with mortality estimates ranging from 655,000 to 1,200,000 (1). Widespread resistance has limited the therapeutic utility of most existing antimalarial drugs, and artemisinin, the highly efficacious cornerstone of artemisinin combination therapies, appears to be at risk for the same fate (2). The need for new antimalarial chemotherapeutic strategies is thus acute.Plasmodium spp., the causative agents of malaria, have a complex life cycle with alternating motile-nonreplicative and sessile-replicative forms in both mammal and mosquito. In the mammalian host, Plasmodium invades and replicates inside two very distinct cell types: hepatocytes and red blood cells (RBCs). In mammals, the Plasmodium life cycle is initiated by a motile sporozoite that invades a hepatocyte, where it resides for 2–14 d, multiplying into >10,000 merozoites in a single cycle (3). Once released into the bloodstream, each of these motile merozoites will infect an RBC and, within 1–3 d, generate 10–30 new merozoites, which will contribute to the continuous cycle of blood stage infection that causes the symptoms, morbidity, and mortality of malaria.These two stages of mammalian infection, despite taking place in distinct cell types and having an orders-of-magnitude difference in parasite replication, do share common features. In both, the motile “zoite” invades the host cell through formation of a parasitophorous vacuole (PV). Both stages grow and replicate exclusively within the confines of the PV, and the parasitophorous vacuole membrane (PVM), which is populated with parasite proteins, constitutes the physical host–parasite interface throughout development. Unlike the vacuoles of many intracellular pathogens including Leishmania, Chlamydia, Mycobacteria, and Legionella (4, 5), the Plasmodium vacuole, like that of Toxoplasma gondii, does not fuse with host lysosomes and is not acidified (6). This is not unsurprising in the context of Plasmodium development in an RBC, which lacks endomembrane system trafficking and, indeed, lysosomes. The highly polarized hepatocyte, however, has extensive vesicular transport networks (7) and can target intracellular pathogens residing in a vacuole (8), suggesting that the exoerythrocytic form (EEF) may need to resist host cell attack.Although the PVM is thought to be critical for Plasmodium growth in both the hepatocyte and the RBC contexts, its cellular roles remain elusive. The importance of several Plasmodium PVM-resident proteins, however, has been conclusively demonstrated in both blood and liver stages. Attempts to generate exported (exp)1 and Plasmodium translocon of exported protein (ptex)150 knockout parasites in Plasmodium falciparum failed (9, 10), revealing that these are both essential proteins for the blood stage, whereas Plasmodium berghei and Plasmodium yoelii mutants lacking up-regulated in sporozoites (uis)3 or uis4 fail to complete liver stage development (11, 12). These PVM-resident proteins, and thus the PVM itself, are performing functions that are crucial for Plasmodium growth, but delineating the functions of individual PVM-resident proteins has proven as difficult as identifying the cellular processes mediated by the PVM.The one process in which both the centrality of the PVM is known and evidence for the participation of specific PVM proteins exists is the export of parasite proteins to the RBC. A cohort of parasite proteins that are involved in extensive physiological and structural modifications of the infected RBC (iRBC) is exported into the iRBC cytoplasm and beyond (13). Five proteins have been identified as components of PTEX, the proposed export machinery at the iRBC PVM (9). Although liver stage protein export has been shown for the Circumsporozite (CS) protein (14) and PTEX components are expressed in P. falciparum EEFs (15), a role for parasite protein export into the hepatocyte remains speculative; the host hepatocyte may not require the extensive structural remodeling that the iRBC does.Conversely, however, the hepatocyte, with its extensive vesicular transport network, intuitively constitutes a more hostile host environment than the RBC, and there is evidence that the liver stage PVM may play a crucial role in preventing host cell-mediated parasite killing, as it does in Toxoplasma gondii (16). Support for a protective role for the liver stage PVM comes from knockout parasites that fail in the earliest steps of PVM formation and remodeling. Sporozoites lacking the p52/p36 gene pair invade hepatocytes successfully, but fail in PVM formation (17, 18) and are severely reduced in abundance midway through liver stage development. Parasites lacking slarp/sap (19, 20), a regulator of early liver stage development, fail to express UIS4 and exported protein 1 (EXP-1), along with other parasite proteins, and are also eliminated at the beginning of infection.Acquisition of resources from the host-cell environment, an unambiguous requirement for an obligate intracellular parasite like Plasmodium, is a function ascribed to the PVM in both mammalian stages. The PVM allows the free passage of molecules (21, 22), presumably through proteinaceous pores, which may contribute to acquisition of host nutrients and disposal of parasite waste products. Members of the early transcribed membrane protein (ETRAMP) family, single-pass transmembrane proteins conserved among Plasmodium spp., which are highly expressed and developmentally regulated in both blood and liver stage parasites (23, 24), could be candidates for mediating uptake of host resources. Such a role in lipid uptake has indeed been proposed for the P. berghei ETRAMP UIS3 on the basis of its interaction with host-cell L-FABP (liver fatty acid binding protein) (25).Although Plasmodium parasites must use host resources to support their own growth in both mammalian stages, the single cycle replicative output of the liver stage parasite is vastly greater than that of the blood stage, which may reflect a similarly increased need for host resources. In this respect, the hepatocyte constitutes far superior “raw material” compared with the RBC; hepatocytes are not only metabolically active, but also highly versatile cells, which are capable of altering uptake, storage, production, and degradation of a wide array of macromolecules in response to cellular and organismal requirements. The presence of a growing Plasmodium parasite is sensed by the host hepatocyte, which responds with activation of cellular stress responses and altered metabolism (26, 27). The mammalian target of rapamycin (mTOR) kinase integrates signals from amino acids, stress, oxygen, energy, and growth factors and responds by altering cellular protein and lipid synthesis, as well as autophagy (28). As such, we sought to determine how inhibition of host mTOR signaling would affect Plasmodium liver stage development. Here we show that torins, a single structural class of mTOR inhibitors, are highly potent antiplasmodial compounds targeting both mammalian stages in vitro and in vivo. Independent of host-cell mTOR, torins impair trafficking of Plasmodium liver stage PVM-resident proteins, revealing the fast turnover of these proteins at the liver stage PVM, and provoke elimination of liver stage parasites.     

Anti-CCP in systemic lupus erythematosus patients: a cross sectional study in Brazilian patients

Recently, it has been found that some lupus patients may have anti-cyclic citrullinated peptide antibodies (anti-CCP), although the clinical significance of such finding is not well established. Systemic lupus erythematosus (SLE) patients may have joint complaints that are very similar to those observed in rheumatoid arthritis (RA). In early stages of disease, this form of arthritis can be difficult to differentiate from RA, so it is not rare that some SLE patients are initially misdiagnosed to have this disease. This study aims to investigate the prevalence of anti-CCP in SLE patients from Southern Brazil and its association with clinical and serological profiles. One hundred nine SLE patients were studied for anti-CCP and compared with data of 156 RA patients and 100 healthy volunteers. Comparison of clinical and autoantibody profile of anti-CCP-positive and anti-CCP-negative SLE patients was done. All SLE patients positive of anti-CCP were submitted to hand and feet X-rays. Anti-CCP was positive in 15 of 109 SLE patients, and one of them had confirmed the diagnosis of rhupus. This prevalence was significantly higher than in healthy controls (p?=?0.0004) and lower than in RA patients (p?<?0.0001). No relationship could be found with clinical profile, including joint complaints. SLE patients with anti-CCP had higher prevalence of anti-Ro (p?=?0.02) and anti-La (p?=?0.004) autoantibodies, in comparison with those negative to anti-CCP. We found that 13.7 % of Brazilian patients with SLE have positive anti-CCP. Patients with anti-CCP showed higher prevalence of anti-Ro and anti-La autoantibodies than those negative for anti-CCP. Only a careful and prolonged follow-up will reveal the real clinical value of these markers in each patient individually.     

Analgesic Effect of the Neuropeptide Cortistatin in Murine Models of Arthritic Inflammatory Pain

Objective

To investigate the role of the antiinflammatory neuropeptide cortistatin in chronic pain evoked by joint inflammation.

Methods

Thermal and mechanical hyperalgesia was evoked in mouse knee joints by intraplantar injection of tumor necrosis factor α and intraarticular infusion of Freund's complete adjuvant, and the analgesic effects of cortistatin, administered centrally, peripherally, and systemically, were assessed. In addition, the effects of cortistatin on the production of nociceptive peptides and the activation of pain signaling were assayed in dorsal root ganglion cultures and in inflammatory pain models. The role of endogenous cortistatin in pain sensitization and perpetuation of chronic inflammatory states was evaluated in cortistatin‐deficient mice. Finally, the effect of noxious/inflammatory stimuli in the production of cortistatin by the peripheral nociceptive system was assayed in vitro and in vivo.

Results

Expression of cortistatin was observed in peptidergic nociceptors of the peripheral nociceptive system, and endogenous cortistatin was found to participate in the tuning of pain sensitization, especially in pathologic inflammatory conditions. Results showed that cortistatin acted both peripherally and centrally to reduce the tactile allodynia and heat hyperalgesia evoked by arthritis and peripheral tissue inflammation in mice, via mechanisms that were independent of its antiinflammatory action. These mechanisms involved direct action on nociceptive neurons and regulation of central sensitization. The analgesic effects of cortistatin in murine arthritic pain were linked to binding of the neuropeptide to somatostatin and ghrelin receptors, activation of the G protein subunit G_αi, impairment of ERK signaling, and decreased production of calcitonin gene‐related peptide in primary nociceptors.

Conclusion

These findings indicate that cortistatin is an antiinflammatory factor with potent analgesic effects that may offer a new approach to pain therapy in pathologic inflammatory states, including osteoarthritis and rheumatoid arthritis.