A second Candida albicans resistance gene (Carg2) regulates tissue damage, but not fungal clearance, in sub-lethal murine systemic infection

The severity of systemic infection with the yeast Candida albicans has been shown to be under complex genetic control. C57/L mice carry an allele that is associated with an increase in tissue destruction when compared with C57BI/6 mice; however, the gene affects only the severity of tissue lesions, and does not influence the magnitude of the fungal burden in either kidney or brain. Studies in [C57/L x C57BI/6]F1 hybrid mice, and [C57/L x C57BI/6]F1 x C57/L backcross mice, demonstrated that the gene behaves as a simple Mendelian co-dominant. (C) 1998 Academic Press.

Both CD4(+) and CD8(+) lymphocytes reduce the severity of tissue lesions in murine systemic candidiasis, and CD4(+) cells also demonstrate strain-specific immunopathological effects

The role of T lymphocytes in host responses to sublethal systemic infection with Candida albicans was evaluated by mAb depletion of CD4(+) and CD8(+) cells from BALB/c and CBA/CaH mice, which develop mild and severe tissue damage, respectively. Depletion of CD4(+) lymphocytes from BALB/c mice markedly increased tissue damage, but did not alter the course of infection. In CBA/CaH mice, depletion of CD4+ cells abrogated tissue destruction in both brain and kidney at day 4 after infection, and significantly decreased fungal colonization in the brain. However, the severity of tissue lesions increased relative to controls from day 8 onwards. A small increase in tissue damage was evident in both mouse strains after depletion of CD8(+) cells. There were no major differences between days 4 end 8 after infection in cDNA cytokine profiles of CD4(+) lymphocytes from either BALB/c or CBA/CaH mice. After passive transfer into infected syngeneic recipients, spleen cells from infected CBA/CaH mice markedly increased tissue damage when compared to controls, and also caused a significant increase in fungal colonization in the brain. A similar transfer in BALB/c mice increased the number of inflammatory cells in and around the lesions, but had no effect on the fungal burden in brain and kidney. The data demonstrate that both CD4(+) and CD8(+) lymphocytes contribute to the reduction of tissue damage after systemic infection with C. albicans, and that the development and expression of CD4(+) lymphocyte effector function is influenced by the genetic background of the mouse.

Systemic coadministration of chloramphenicol with intravenous but not intracerebroventricular morphine markedly increases morphine antinociception and delays development of antinociceptive tolerance in rats

Chloramphenicol, an in vitro inhibitor of the glucuronidation of morphine to its putative antianalgesic metabolite, morphine-3-glucuronide (M3G), was coadministered with morphine in adult male Sprague-Dawley rats to determine whether it inhibited the in vivo metabolism of morphine to M3G, thereby enhancing morphine antinociception and/or delaying the development of antinociceptive tolerance. Parenteral chloramphenicol was given acutely (3-h studies) or chronically (48-h studies). Morphine was administered by the i.v. or i.c.v. route. Control rats received chloramphenicol and/or vehicle. Antinociception was quantified using the hotplate latency test. Coadministration of chloramphenicol with i.v. but not i.cv. morphine increased the extent and duration of morphine antinociception by approximate to 5.5-fold relative to rats that received i.v. morphine alone. Thus, the mechanism through which chloramphenicol enhances i.v. morphine antinociception in the rat does not directly involve supraspinal opioid receptors. Acutely, parenteral coadministration of chloramphenicol and morphine resulted in an approximate to 75% increase in the mean area under the serum morphine concentration-time curve but for chronic dosing there was no significant change in this curve, indicating that factors other than morphine concentrations contribute significantly to antinociception. Antinociceptive tolerance to morphine developed more slowly in rats coadministered chloramphenicol, consistent with our proposal that in vivo inhibition of M3G formation would result in increased antinociception and delayed development of tolerance. However, our data also indicate that chloramphenicol inhibited the biliary secretion of M3G. Whether chloramphenicol altered the passage of M3G and morphine across the blood-brain barrier remains to be investigated.

Systemic administration of antisense p75(NTR) oligodeoxynucleotides rescues axotomised spinal motor neurons

The 75 kD low-affinity neurotrophin receptor (p75(NTR)) is expressed in developing and axotomised spinal motor neurons. There is now convincing evidence that p75NTR can, under some circumstances, become cytotoxic and promote neuronal cell death. We report here that a single application of antisense p75(NTR) oligodeoxynucleotides to the proximal nerve stumps of neonatal rats significantly reduces the loss of axotomised motor neurons compared to controls treated with nonsense oligodeoxynucleotides or phosphate-buffered saline. Our investigations also show that daily systemic intraperitoneal injections of antisense p75(NTR) oligodeoxynucleotides for 14 days significantly reduce the loss of axotomised motor neurons compared to controls. Furthermore, we found that systemic delivery over a similar period continues to be effective following axotomy when intraperitoneal injections were 1) administered after a delay of 24 hr, 2) limited to the first 7 days, or 3) administered every third day. In addition, p75(NTR) protein levels were reduced in spinal motor neurons following treatment with antisense p75(NTR) oligodeoxynucleotides. There were also no obvious side effects associated with antisense p75(NTR) oligodeoxynucleotide treatments as determined by behavioural observations and postnatal weight gain. Our findings indicate that antisense-based strategies could be a novel approach for the prevention of motor neuron degeneration associated with injuries or disease. (C) 2001 Wiley-Liss, Inc.

Diagnosis of Organizational Soft Problems in a Peruvian Financial Institution by Systemic Thinking

Managing financial institutions in an underdeveloped economic context has become a real challenge nowadays. In order to reach the organization`s planned goals, they have to deal with structural, behavioral and informational problems. From the systemic point of view, this situation gets even worse when the company does not present organizational boundaries and a cohesive identification for their stakeholders. Thus, European countries have some special financial lines in order to help the development of micro credit in Latin communities in an attempt to help the local economy. However, institutions like Caixa dos Andes in Peru present management problems when dealing with this complexity. Based on this, how can the systemic eye help in the diagnosis of soft problems of a Peruvian financial company? This study aims to diagnose soft problems of a Peruvian financial company based on soft variables like identity, communication and autonomy and also intends to identify possible ways to redesign its basic framework. The (VSM--Viable System Model) method from Beer (1967), applied in this diagnostic study, was used in a practical way as a management tool for organizations` analysis and planning. By describing the VSM`s five systems, the creation of a systemic vision or a total vision is possible, showing the organization`s complexity from the inside. Some company`s soft problems like double control, inefficient use of physical and human resources, low information flows, slowness, etc. The VSM presented an organizational diagnosis indicating effective solutions that do integrate its five systems.

Systemic Model for Diagnosis of the Micro, Small and Medium Enterprises from Two Cities from the Countryside of the State of So Paulo in Brazil

This article presents a proposal of a systemic model composed for the micro and small companies (MSE) of the region of Ribeiro Preto and the agents which influenced their environment. The proposed model was based on Stafford Beer`s (Diagnosing the system for organizations. Chichester, Wiley, 1985) systemic methodologies VSM (Viable System Model) and on Werner Ulrich`s (1983) CSH (Critical Systems Heuristics). The VSM is a model for the diagnosis of the structure of an organization and of its flows of information through the application of the cybernetics concepts (Narvarte, In El Modelo del Sistema Viable-MSV: experiencias de su aplicacin en Chile. Proyecto Cerebro Colectivo del IAS, Santiago, 2001). On the other hand, CSH focus on the context of the social group applied to the systemic vision as a counterpoint to the organizational management view considered by the VSM. MSE of Ribeiro Preto and Sertozinho had been analyzed as organizations inserted in systems that relate and integrate with other systems concerning the public administration, entities of representation and promotion agencies. The research questions: which are the bonds of interaction among the subsystems in this process and who are the agents involved? The systemic approach not only diagnosed a social group, formed by MSE of Ribeiro Preto and Sertozinho, public authorities and support entities, but could also delineate answers that aimed the clarification of obscure questions generating financial assistance to the formularization of efficient actions for the development of this system.

Hepatic Steatosis, Obesity, and the Metabolic Syndrome Are Independently and Additively Associated With Increased Systemic Inflammation

Objective-The goal of this study was to assess the independent and collective associations of hepatic steatosis, obesity, and the metabolic syndrome with elevated high-sensitivity C-reactive protein (hs-CRP) levels. Methods and Results-We evaluated 2388 individuals without clinical cardiovascular disease between December 2004 and December 2006. Hepatic steatosis was diagnosed by ultrasound, and the metabolic syndrome was defined using National Heart, Lung, and Blood Institute criteria. The cut point of >= 3 mg/L was used to define high hs-CRP. Multivariate logistic regression was used to assess the independent and collective associations of hepatic steatosis, obesity, and the metabolic syndrome with high hs-CRP. Steatosis was detected in 32% of participants, 23% met criteria for metabolic syndrome, and 17% were obese. After multivariate regression, hepatic steatosis (odds ratio [OR] 2.07; 95% CI 1.68 to 2.56), obesity (OR 3.00; 95% CI 2.39 to 3.80), and the metabolic syndrome (2.39; 95% CI 1.88 to 3.04) were all independently associated with high hs-CRP. Combinations of these factors were associated with an additive increase in the odds of high hs-CRP, with individuals with 1, 2, and 3 factors having ORs for high hs-CRP of 1.92 (1.49 to 2.48), 3.38 (2.50 to 4.57), and 4.53 (3.23 to 6.35), respectively. Conclusion-Hepatic steatosis, obesity, and the metabolic syndrome are independently and additively associated with increased odds of high hs-CRP levels. (Arterioscler Thromb Vasc Biol. 2011; 31: 1927-1932.)

Degos` disease as a cutaneous manifestation of systemic lupus erythematosus

Degos` disease or malignant atrophic papulosis is a rare vasculopathy characterized by the presence of a typical skin lesion and visceral vascular involvement of small vessels, mainly of the digestive tract or central nervous system. The most interesting fact in this disease is the benign appearance of cutaneous lesion, hiding the occlusion of skin and visceral vessels. The author reports the case of a female patient with systemic lupus erythematosus for eight years. During her follow up, generalized skin papules were observed on the trunk and limbs, sparing her face, hands and feet, compatible with Degos` disease. Additional. imaging investigation excluded systemic involvement of the disease. Treatment with acetylsalicylic acid prevented the appearance of new cutaneous manifestations and the patient remains clinically stable on the Outpatient Clinic without complications, until this moment. Malign atrophic papulosis is a rare disease with a poor prognosis. However, its association with systemic lupus erythematosus seems to follow a more benign course, without the typical visceral involvement.

Mode of action of back-line application of spinosad, a non-systemic parasiticide, on sheep

Spinosad, applied as a jetting solution or dip is an efficacious, non-systemic treatment for the control of Bovicola ovis in sheep. This paper describes the effect of back-line treatment width and group housing of animals on the efficacy of spinosad for the control of lice. A 0.4 mg/kg liveweight dose was found to be the suboptimal dose of spinosad for the control of body lice in a dose titration study and was used to investigate application and housing effects in a second study. Lousy Merino sheep were treated with either a narrow 3-cm application of spinosad or with a wider 25-cm swathe. After treatment they were either kept alone or in groups of 6 sheep per pen. Lice were counted at day 0 and every 14 days to 70 days after treatment before estimation of the percentage of lice control and analysis of treatment effects. A much higher percentage of lice control was achieved with 0.4 mg/kg in the second study than in the first, possibly because of differences in formulation used. The wider application width gave significantly higher (P < 0.05) control of lice than the narrow application when sheep were either housed alone or in groups up to day 42 post-treatment. Greater control of lice was seen in group-housed sheep compared with sheep housed individually (P < 0.05) up to day 70. Using broader application widths combined with holding the animals together after treatment with pour-on formulations may optimise the delivery and efficacy of ectoparasiticides for livestock.

Neutrophil depletion increases susceptibility to systemic and vaginal candidiasis in mice, and reveals differences between brain and kidney in mechanisms of host resistance

Infections caused by the yeast Candida albicans represent an increasing threat to debilitated and immunosuppressed patients, and neutropenia is an important risk factor. Monoclonal antibody depletion of neutrophils in mice was used to study the role of these cells in host resistance. Ablation of neutrophils increased susceptibility to both systemic and vaginal challenge. The fungal burden in the kidney increased threefold on day 1, and 100-fold on day 4, and infection was associated with extensive tissue destruction. However, a striking feature of the disseminated disease in neutrophil-depleted animals was the altered pattern of organ involvement. The brain, which is one of the primary target organs in normal mice, was little affected. There was a threefold increase in the number of organisms recovered from the brains of neutrophil-depleted mice on day 4 after infection, but detectable abscesses were rare. In contrast, the heart, which in normal mice shows only minor lesions, developed severe tissue damage following neutrophil depletion. Mice deficient in C5 demonstrated both qualitative and quantitative increases in the severity of infection after neutrophil depletion when compared with C5-sufficient strains. The results are interpreted as reflecting organ-specific differences in the mechanisms of host resistance.

Severe and refractory myositis in mixed connective tissue disease: a description of a rare case

Mixed connective tissue disease (MCTD) is a rare disease that includes clinical and laboratorial manifestations of systemic lupus erythematosus, scleroderma and polymyositis that is associated with high titers of anti-U1RNP antibodies. In general, muscle involvement is subclinical, usually appearing as an increase in muscle enzyme levels that tends to be a characteristic of the initial phases of the disease. Severe clinical muscle weakness is not observed in this disease. The objective of this study is to report a rare case of a patient who presented a severe onset of myositis characterized by dysphagia, an increase in myopathy and a weakening of the cervical musculature. While there was no response to the administration of an initial dose of corticosteroids, improvement was observed after increasing the dose of corticosteroids, in addition to the initiation of pulse therapy with methylprednisolone accompanied by methotrexate treatment. The authors emphasize that there is only one previously reported case regarding a child with MCTD and severe clinical myopathy on electromyography and muscle biopsy, and they report in this article one adult female patient who presented severe myositis and was refractive to corticotherapy. Lupus (2010) 19, 1659-1661.

Digital vasculitis in systemic lupus erythematosus: a minor manifestation of disease activity?

The objective of this study is to determine if digital vasculitis (DV), a clinical manifestation with a high systemic lupus erythematosus disease activity index (SLEDAI) score, is associated with lupus severity. DV and other clinical manifestations defined according to the SLEDAI were evaluated in 168 consecutive patients with systemic lupus erythematosus (SLE). Two groups were defined according to presence (DV+, n = 27) or absence of DV (DV-, n = 141) at the time of evaluation. The exclusion criterion was the presence of antiphospholipid syndrome (Sapporo`s criteria). The two groups were comparable with regard to age (P = 0.09), gender (P = 1.00), white race (P = 0.81), and disease duration (P = 0.78). Compared to the DV-group, the DV+ group had a significantly higher frequency of mucocutaneous manifestations (66.7 vs. 39.0%, P = 0.01), haematological abnormalities (22.2 vs. 6.4%, P = 0.02) and constitutional symptoms (11.1 vs. 0.7%, P = 0.01). Renal and neurological involvements were similar in both groups ( P = 0.57 and P = 1.00, respectively). The evaluation of each SLEDAI parameter confirmed that the DV+ group had higher frequencies of mild manifestations, such as new rash (P = 0.02), alopecia (P = 0.02), oral ulcers (P = 0.045), fever (P = 0.01) and leucopenia (P = 0.005). In contrast, both groups had similarly increased anti-dsDNA (P = 0.78) and decreased complement levels (P = 0.29). In conclusion, DV in patients with SLE identifies a subgroup of a mild disease. The high `weighted` index attributed to this alteration in the SLEDAI score should therefore be revised. Lupus (2009) 18, 990-993.

Macrophage Activation Syndrome Associated with Etanercept in a Child with Systemic Onset juvenile Idiopathic Arthritis

Fundacao de Amparo a Pesquisa do Estado de Sao Paulo - FAPESP[06/61303-7]

Juvenile onset systemic lupus erythematosus thyroid dysfunction: A subgroup with mild disease?

The aim of this study was to evaluate the frequency of thyroid dysfunction and thyroid antibodies in patients with juvenile onset Systemic Lupus Erythematosus (JOSLE) and its association with clinical and immunological features. Seventy-seven patients with JOSLE, 64 females, median age 19 years, were consecutively enrolled from March to December 2007. Clinical data related to thyroid dysfunction and lupus were obtained by chart review and patient interview. Serum levels of TSH, free T4, anti-thyroglobulin (TgAb), anti-thyroperoxidase (TPOAb), TRAb and lupus related autoantibodies were analyzed by standard techniques. Nine patients were diagnosed as hypothyroidism and 4 hyperthyroidism. 28% JOSLE patients had moderate/high titer of thyroid antibodies: 23% TgAb, 2.6% TPOAb and 3.9% TRAb. JOSLE patients with positive thyroid autoantibodies had higher frequency of anti-U1RNP antibodies than patients without these antibodies (40.9 vs. 14.5%, OR:0.25, CI:0.08-0.76, p = 0.017). Furthermore, renal/neurological/hematological involvement was less frequently observed in patients with hypothyroidism (55.6 vs. 87.5%, OR:0.18, CI:0.04-0.81, p = 0.035) and with thyroid antibodies (68.4 vs. 90.9%, OR:0.22, CI:0.06-0.82. p = 0.027) than in patients without these alterations. No association with PTPN22 polymorphism was found. In conclusion, JOSLE patients have high prevalence of subclinical hypothyroidism. The novel association of anti-thyroid antibodies with anti-U1RNP antibodies in JOSLE seems to identify a subgroup of patients with less life-threatening organ involvement. (C) 2009 Elsevier Ltd. All rights reserved.