Statins withdrawal, vascular complications, rebound effect and similitude

Hahnemann considered the secondary action of medicines to be a law of nature and reviewed the conditions under which it occurs. It is closely related to the rebound effects observed with many modern drugs. I review the evidence of the rebound effect of statins that support the similitude principle. In view of their indications in primary and secondary prevention of cardiovascular diseases, statins are widely prescribed. Besides reducing cholesterol biosynthesis, they provide vasculoprotective effects (pleiotropic effects), including improvement of endothelial function, increased nitric oxide bioavailability, antioxidant properties, inhibition of inflammatory and thrombogenic responses, stabilisation of atherosclerotic plaques, and others. Recent studies suggest that suspension of statin treatment leads to a rebound imparing of vascular function, and increasing morbidity and mortality in patients with vascular diseases. Similarly to other classes of modern palliative drugs, this rebound effect is the same as a secondary action or vital reaction described by Samuel Hahnemann, and used in homeopathy in a therapeutic sense. Homeopathy (2010) 99, 255-262.

Anaphylactic reaction induced by a polysulfone/polyvinylpyrrolidone membrane in the 10th session of hemodialysis with the same dialyzer

The majority of severe hypersensitivity reactions in hemodialysis patients have occurred due to sensitization to ethylene oxide or to nonbiocompatible membrane dialyzers. The use of polysulfone dialyzers rarely causes hypersensitivity reactions. In the present study, we describe a case of severe life-threatening reactions induced by polysulfone dialyzers (from different manufacturers subjected to a variety of sterilization methods), which occurred after 9 sessions of hemodialysis with the same prescription, exemplifying the complexity of such reactions.

Antidepressants, suicidality and rebound effect: evidence of similitude?

Background: Samuel Hahnemann noticed that palliative treatments for the symptoms of chronic diseases, after an initial improvement, provoked symptoms similar but stronger symptoms to those initially suppressed. He regarded this as a consequence of the vital reaction of the organism: an automatic and instinctive capacity to return to the initial health condition altered by medicines. Using this homeostatic conception of the organism as a treatment rationale, Hahnemann proposed the therapy of similarity, administering to the patients medicines capable of causing, in healthy individuals, similar symptoms to the natural disease. Based on experimental observations, he proposed that the primary action of the drug was followed by the secondary and opposite action of the organism, inaugurating homeopathic pharmacology, and alerting to the harmful consequences of palliative medicines in susceptible individuals. Such liatrogenic events can be observed in contemporary medicine, after the withdrawal of modern enantiopathic medicines, according to the study of the rebound effect or paradoxical reaction of the organism. Method. This study reviews the recent studies which describe suicidallity after the suspension or discontinuation of second generation antidepressants according to the hypothesis of the paradoxical reaction of the organism. Conclusions: Rebound and withdrawal effects, including suicidality occur with antidepressant drugs. They are relatively rare but more intense than the primary action of the drug. The probability of such effects is influenced by patient factors including age and diagnosis, and drug factors including half-life. Homeopathy (2009) 98, 114-121.

Polymerase chain reaction compared to other laboratory findings and to clinical evaluation in the diagnosis of cutaneous tuberculosis and atypical mycobacteria skin infection

Cutaneous tuberculosis has re-emerged in the last 15 years together with the higher incidence of pulmonary tuberculosis and multidrug resistance. The choice for a single diagnostic tool among the many available today is a challenge. Our objective was to compare polymerase chain reaction (PCR) with other exams in the diagnosis of cutaneous tuberculosis and atypical mycobacteria skin infection. PCR and a set of five different exams were performed in 32 patients (34 samples of paraffin-embedded tissue) evaluated for 3 years in a university hospital, considering the response to mycobacterial infection treatment as a positive case. PCR was the most sensitive (88%) and specific (83%) exam. Culture, immunohistochemistry and acid-fast bacilli were not in agreement with clinical response to treatment. Although PCR is a useful tool, careful clinical exam is still the gold standard for the evaluation and treatment of cutaneous tuberculosis and mycobacteria skin infection.

Haemophilus ducreyi detection by polymerase chain reaction in oesophageal lesions of HIV patients

HIV patients frequently have opportunistic oesophageal infections. We report Haemophilus ducreyi genetic material detected by polymerase chain reaction in biopsies of oesophageal lesions in three HIV-1-infected patients. This finding may be an indication of its aetiopathological role in oesophageal lesions of HIV patients.

Genetic polymorphisms involved in folate metabolism and concentrations of methylmalonic acid and folate on plasma homocysteine and risk of coronary artery disease

Objectives Alterations in the enzymes involved in homocysteine (Hcy) metabolism or vitamin deficiency could play a role in coronary artery disease (CAD) development. This study investigated the influence of MTHFR and MTR gene polymorphisms, plasma folate and MMA on Hcy concentrations and CAD development. MMA and folate concentrations were also investigated according to the polymorphisms. Methods Two hundred and eighty-three unrelated Caucasian individuals undergoing coronary angiography (175 with CAD and 108 non-CAD) were assessed in a case-control study. Plasma Hcy and MMA were measured by liquid chromatography/tandem mass spectrometry. Plasma folate was measured by competitive immunoassay. Dietary intake was evaluated using a nutritional questionnaire. Polymorphisms MTHFR and MTR were investigated by polymerase chain reaction (PCR) followed by enzyme digestion or allele-specific PCR. Results Hcy mean concentrations were higher in CAD patients compared to controls, but below statistical significance (P = 0.246). Increased MMA mean concentrations were frequently observed in the CAD group (P = 0.048). Individuals with MMA concentrations > 0.5 mu mol/l (vitamin B(12) deficiency) were found only in the CAD group (P = 0.004). A positive correlation between MMA and Hcy mean concentrations was observed in both groups, CAD (P = 0.001) and non-CAD (P = 0.020). MMA mean concentrations were significantly higher in patients with hyperhomocysteinemia in both groups, CAD and non-CAD (P = 0.0063 and P = 0.013, respectively). Folate mean concentration was significantly lower in carriers of the wild-type MTHFR 1298AA genotype (P = 0.010). Conclusion Our results suggest a correlation between the MTHFR A1298C polymorphism and plasma folate concentration. Vitamin B(12) deficiency, reflected by increased MMA concentration, is an important risk factor for the development both of hyperhomocysteinemia and CAD.

Endothelins modulate inflammatory reaction in zymosan-induced arthritis: participation of LTB4, TNF-alpha, and CXCL-1

Endothelins (ETs) are involved in inflammatory events, including pain, fever, edema, and cell migration. ET-1 levels are increased in plasma and synovial membrane of rheumatoid arthritis (RA) patients, but the evidence that ETs participate in RA physiopathology is limited. The present study investigated the involvement of ETs in neutrophil accumulation and edema formation in the murine model of zymosan-induced arthritis. Intra-articular (i.a.) administration of selective ETA or ETB receptor antagonists (BQ-123 and BQ-788, respectively; 15 pmol/cavity) prior to i.a. zymosan injection (500 mu g/cavity) markedly reduced knee-joint edema formation and neutrophil influx to the synovial cavity 6 h and 24 h after stimulation. Histological analysis showed that ETA or ETB receptor blockade suppressed zymosan-induced neutrophil accumulation in articular tissue at 6 h. Likewise, dual blockade of ETA/ETB with bosentan (10 mg/kg, i.v.) also reduced edema formation and neutrophil counts 6 h after zymosan stimulation. Pretreatment with BQ-123 or BQ-788 (i.a.; 15 pmol/cavity) also decreased zymosan-induced TNF-alpha production within 6 h, keratinocyte-derived chemokine/CXCL1 production within 24 h, and leukotriene B-4 at both time-points. Consistent with the demonstration that ET receptor antagonists inhibit zymosan-induced inflammation, i.a. injection of ET-1 (1-30 pmol/cavity) or sarafotoxin S6c (0.1-30 pmol/cavity) also triggered edema formation and neutrophil accumulation within 6 h. Moreover, knee-joint synovial tissue expressed ETA and ETB receptors. These findings suggest that endogenous ETs contribute to knee-joint inflammation, acting through ETA and ETB receptors and modulating edema formation, neutrophil recruitment, and production of inflammatory mediators.

Role of olfaction and vision cues in feeding behavior and alarm reaction in the catfish pintado, Pseudoplatystoma corruscans

Experiments were performed to investigate senses that are essential for mediating fright reaction and food behavior in Pseudoplatystoma corruscans, pintado. The dilemma ""to feed or to flee"" was also analyzed in fishes with intact and sectioned olfactory tracts, stimulated by alarm substance extracts and food. Fishes were arranged into five groups: fish with intact lateral olfactory tracts (LOT), fish with intact medial olfactory tract (MOT), fish with tracts totally sectioned (TOTAL, both LOT and MOT), sham operated, and nonoperated fish. The five groups were submitted to either alarm substance extract and food stimulus or to distilled water (control) and food stimulus. Fish reacted to food independently of which tract (LOT, MOT or TOTAL) was sectioned; vision seems necessary and elemental to detect and deflagrate food response. Latency of the responses to each reaction was different between groups. None of the fish with sectioned tracts reacted to alarm substance extract, while sham- and nonoperated fish showed the typical alarm behavior response, leading to the conclusion that olfaction is essential for mediating alarm response. These results indicate that others sense systems (e.g., vision) are sufficient to trigger and elicit feeding behavior and that olfaction is not necessary to fully maintain food detection to qualitative and quantitative extent. However, olfactory tract integrity seems to be required for mediation of alarm reaction in P. corruscans.

Advantages and Pitfalls of the Polymerase Chain Reaction in the Diagnosis of Esophageal Ulcers in AIDS Patients

HIV-1-infected patients frequently have opportunistic esophageal infections which, when associated with severe immunodeficiency, can be attributed to unusual pathogens. The clinical presentation of several esophageal diseases is similar and the best method for a specific diagnosis of these patients has not been well defined. To evaluate the role of the polymerase chain reaction (PCR) in the etiologic definition of esophageal ulcers in HIV-1-infected patients, 96 esophageal biopsies from 79 HIV-1-infected patients were processed by PCR using specific primers for cytomegalovirus (CMV), herpes virus (HSV), human papilloma virus (HPV), HIV-1, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Treponema pallidum, and Haemophilus ducreyi. The PCR results were compared to the histopathologic results. Seventy-nine patients were studied (mean age: 34 years; 62% men; median CD4 + T cell = 103.59 cells/mu l (range 1-795.2 cells/mu l). The most common endoscopic findings were as follows: esophageal candidiasis (37.1%), esophageal ulcers (24.7%), esophagitis (11.2%), and lugol-negative areas (10.1%). The histopathologic findings in the esophageal ulcers (22 biopsies) were non-specific inflammation (31.8%), HSV (36.4%), Candida (13.6%), CMV (13.6%), or HPV disease (4.5%). In the esophageal ulcer biopsies, the PCR results were negative in 27.6% of cases, and positive for HIV (65.5%), CMV (31%), HPV (20.7%), HSV (10.3%), and H. ducreyi (6.9%). The histopathologic examination did not identify a pathogen or identified only Candida in 15 biopsies of esophageal ulcers. PCR was positive in ten (66.7%) and negative in five (33.3%) of these biopsies (idiopathic ulcers). PCR detected: HIV (53.3%), CMV (20%), HPV (13.3%), and H. ducreyi (6,7%). PCR detected more etiologic agents in esophageal ulcers than histopathology and was able to detect unusual pathogens. On the other hand, sometimes more than one pathogen was detected in the esophageal ulcers, making it difficult to reach an accurate diagnosis. This finding indicates the need for more studies to evaluate the benefit of this method in the routine evaluation of esophageal ulcer biopsies in HIV-1-infected patients.

Inhibition of COX 1 and 2 prior to Renal Ischemia/Reperfusion Injury Decreases the Development of Fibrosis

Ischemia and reperfusion injury (IRI) contributes to the development of chronic interstitial fibrosis/tubular atrophy in renal allograft patients, Cyclooxygenase (COX) 1 and 2 actively participate in acute ischemic injury by activating endothelial cells and inducing oxidative stress. Furthermore, blockade of COX I and 2 has been associated with organ improvement after ischemic damage. The aim of this study was to evaluate the role of COX I and 2 in the development of fibrosis by performing a COX I and 2 blockade immediately before IRI We subjected C57BI/6 male mice to 60 min of unilateral renal pedicle occlusion, Prior to surgery mice were either treated with indomethacin (IMT) at days -1 and 0 or were untreated. Blood and kidney samples were collected 6 wks after IRI. Kidney samples were analyzed by real-time reverse transcription-poly me rase chain reaction for expression of transforming growth factor beta (TGF-beta), monocyte chemoattractant protein 1 (MCP-1), osteopontin (OPN), tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1 beta, IL-10, heme oxygenose 1 (HO-1), vimentin, connective-tissue growth factor (CTGF), collagen 1, and bone morphogenic protein 7 (BMP-7), To assess tissue fibrosis we performed morphometric analyses and Sirius red staining. We also performed immunohistochemical analysis of anti-actin smooth muscle, Renal function did not significantly differ between groups. Animals pretreated with IMT showed significantly less interstitial fibrosis than nontreated animals. Gene transcript analyses showed decreased expression of TGF-beta, MCP-1,TNF-alpha, IL-1-beta, vimentin, collagen 1, CTGF and IL-10 mRNA (all P < 0.05), Moreover, HO-I mRNA was increased in animals pretreated with IMT (P < 0.05) Conversely, IMT treatment decreased osteopontin expression and enhanced BMP-7 expression, although these levels did rot reach statistical significance when compared with control expression levels, I he blockade of COX 1 and 2 resulted in less tissue fibrosis, which was associated with a decrease in proinflammatory cytokines and enhancement of the protective cellular response.

Stability improvement of the fatty acid binding protein Sm14 from S. mansoni by Cys replacement: Structural and functional characterization of a vaccine candidate

The Schistosoma mansoni fatty acid binding protein (FABP), SmA, is a vaccine candidate against, S. mansoni and F hepatica. Previously, we demonstrated the importance of a correct fold to achieve protection in immunized animals after cercariae challenge [[10]. C.R.R. Ramos, R.C.R. Figueredo, T.A. Pertinhez, M.M. Vilar, A.L.T.O. Nascimento, M. Tendler, I. Raw, A. Spisni, P.L. Ho, Gene structure and M20T polymorphism of the Schistosoma mansoni Sm14 fatty acid-binding protein: structural, functional and immunoprotection analysis. J. Biol. Chem. 278 (2003) 12745-12751]. Here we show that the reduction of vaccine efficacy over time is due to protein dimerization and subsequent aggregation. We produced the mutants Sm14-M20(C62S) and Sm14M20(C62V) that, as expected, did not dimerize in SDS-PAGE. Molecular dynamics calculations and unfolding experiments highlighted a higher structural stability of these mutants with respect to the wild-type. In addition, we found that the mutated proteins, after thermal denaturation, refolded to their active native molecular architecture as proved by the recovery of the fatty acid binding ability. Sm14-M20(C62V) turned out to be the more stable form over time, providing the basis to determine the first 3D solution structure of a Sm14 protein in its apo-form. Overall, Sm14-M20(C62V) possesses an improved structural stability over time, an essential feature to preserve its immunization capability and, in experimentally immunized animals, it exhibits a protection effect against S. mansoni cercariae infections comparable to the one obtained with the wild-type protein. These facts indicate this protein as a good lead molecule for large-scale production and for developing an effective Sm14 based anti-helminthes vaccine. (C) 2008 Elsevier B.V. All rights reserved.

The improvement of care for paediatric and congenital cardiac disease across the World: a challenge for the World Society for Pediatric and Congenital Heart Surgery

The diagnosis and treatment for paediatric and congenital cardiac disease has undergone remarkable progress over the last 60 years. Unfortunately, this progress has been largely limited to the developed world. Yet every year approximately 90% of the more than 1,000,000 children who are born with congenital cardiac disease across the world receive either suboptimal care or are totally denied care. While in the developed world the focus has changed from an effort to decrease post-operative mortality to now improving quality of life and decreasing morbidity, which the focus of this Supplement, the rest of the world still needs to develop basic access to congenital cardiac care. The World Society for Pediatric and Congenital Heart Surgery [http://www.wspchs.org/] was established in 2006. The Vision of the World Society is that every child born anywhere in the world with a congenital heart defect should have access to appropriate medical and surgical care. The Mission of the World Society is to promote the highest quality comprehensive care to all patients with pediatric and/or congenital heart disease, from the fetus to the adult, regardless of the patient`s economic means, with emphasis on excellence in education, research and community service. We present in this article an overview of the epidemiology of congenital cardiac disease, the current and future challenges to improve care in the developed and developing world, the impact of the globalization of cardiac surgery, and the role that the World Society should play. The World Society for Pediatric and Congenital Heart Surgery is in a unique position to influence and truly improve the global care of children and adults with congenital cardiac disease throughout the world [http://www.wspchs.org/].

Detection of Leptospira spp. in semen and vaginal fluids of goats and sheep by polymerase chain reaction

Thirteen goat herds and seven sheep flocks in the state of Rio de Janeiro, Brazil were screened for leptospirosis. From the three herds and three flocks with greatest seroreactivity, 19 goats (16 females and three bucks) and 40 sheep (26 ewes and 14 rams) that were seropositive (specific anti-Leptospira titres >= 400, based on a microscopic agglutination test), were selected for more detailed studies. From those animals, samples of vaginal fluids or semen were collected for bacteriological and molecular assays. For both species of animals, the most prevalent reactions were to serovars Hardjo, Shermani, and Grippotyphosa. Although leptospires were detected by darkfield microscopy in three vaginal fluid samples (from two goats and one ewe), pure isolates were not obtained by bacteriological culture of vaginal fluids or semen. However, seven vaginal fluid samples (from four goats and three ewes) and six semen samples (all from rams) were positive on polymerase chain reaction (PCR). Based on these findings, in addition to analogous findings in cattle, we inferred that there is potential for venereal transmission of leptospirosis in small ruminants. (c) 2008 Elsevier Inc. All rights reserved.

Photoinitiator content in restorative composites: Influence on degree of conversion, reaction kinetics, volumetric shrinkage and polymerization stress

Purpose: To determine the influence of rate of polymerization, degree of conversion and volumetric shrinkage on stress development by varying the amount of photoinitiators in a model composite. Methods: Volumetric shrinkage (with a mercury dilatometer), degree of conversion, maximum rate of reaction (RP(max)) (with differential scanning calorimetry) and polymerization stress (with a controlled compliance device) were evaluated. Bis-GMA/TEGDMA (equal mass ratios) were mixed with a tertiary amine (EDMAB) and camphorqpinone, respectively, in three concentrations (wt%): high= 0.8/1.6; intermediate= 0.4/0.8 and low= 0.2/0.4. 80 wt% filler was added. Composites were photoactivated (400 mW/cm(2) x 40 seconds; radiant exposure=16J/cm(2)). A fourth experimental group was included in which the low concentration formulation was exposed for 80 seconds (32 J/cm(2)). Results: For the same radiant exposure, conversion, RP(max) and stress increased with photoinitiator concentration (P< 0.001). When the low concentration group exposed to 32 J/cm(2) was compared with the high and intermediate groups (exposed to 16 J/cm(2)), RPmax Still increased with the photoinitiator concentration between all levels (P< 0.001) but conversion and stress did not vary (P> 0.05). Shrinkage did not vary regardless of the photoinitiator concentration or radiant exposure. For the photoinitiator concentrations used in this study. Polymerization stress was influenced by conversion but not by rate of reaction. (Am J Dent 2009;22:206-210).

The Potential Role of Suppressors of Cytokine Signaling in the Attenuation of Inflammatory Reaction and Alveolar Bone Loss Associated with Apical Periodontitis

Inflammatory cytokines contribute to periapical tissue destruction. Their activity is potentially regulated by suppressors of cytokine signaling (SOCS), which down-regulate signal transduction as part of an inhibitory feedback loop. We investigated the expression of the cytokines tumor necrosis factor alpha (TNF-alpha); interleukin (IL)-10 and RANKL; and SOCS-1, -2, and -3 by real-time polymerase chain reaction in 57 periapical granulomas and 38 healthy periapical tissues. Periapical granulomas exhibited significantly higher SOCS-1, -2, and -3, TNF-alpha, IL-10, and RANKL messenger RNA levels when compared with healthy controls. Significant positive correlations were found between SOCS1 and IL-10 and between SOCS3 and IL-10. Significant inverse correlations were observed between SOCS1 and TNF-alpha, SOCS1 and RANKL, and SOCS3 and TNF-alpha. Increased SOCS-1, -2, and -3 messenger RNA levels in periapical granulomas may be related to the downregulation of inflammatory cytokines in these lesions; therefore, SOCS molecules may play a role in the dynamics of periapical granulomas development. (J Endod 2008;34:1480-1484)