La inflamación como el nexo entre la enfermedad periodontal y la enfermedad cardiovascular / Inflammation as a link between periodontal disease and cardiovascular disease

La periodontitis es una enfermedad no transmisible, con una alta prevalencia, que oscila entre el 45% y el 50% de la población mundial, ocupando el sexto lugar entre las enfermedades más frecuentes de la huma-nidad. Existe suficiente evidencia que avala la relación entre la enfermedad periodontal y la enfermedad car-diovascular, responsable de aproximadamente el 45% de las muertes en países desarrollados, compren-diendo en su causalidad al infarto de miocardio, el accidente cerebrovascular, la insuficiencia cardíaca y las arritmias, que causan alrededor del 95 % de las muertes relacionadas con la enfermedad cardiovas-cular. Ambas patologías presentan factores de riesgo comunes ampliamente reconocidos, como la diabetes y el tabaquismo, pero además manifiestan caracte-rísticas genéticas y epigenéticas que avalan distintos mecanismos etiopatológicos. Más allá de los factores de riesgo comunes, se han propuesto dos mecanis-mos para explicar la relación entre la enfermedad periodontal y las cardiovasculares. Uno de ellos, constituye la invasión directa de patógenos periodontales en las células endoteliales. El otro mecanismo sugerido (vía indirecta), ocasionado por la respuesta inflamatoria sistémica que resulta en niveles cróni-camente elevados de diferentes citoquinas, también relacionadas con la enfermedad vascular aterosclerotica como IL-1ß, IL-6, IL-8, TNF-α, PCR y la proteína quimioatrayente de monocitos, podría estar mediado por productos bacterianos, como los lipopolisacári-dos que alcanzarían la circulación induciendo una potente respuesta inmunitaria. Estos mecanismos pueden actuar inflamando las células endoteliales, modulando el metabolismo de los lípidos y aumentan-do el estrés oxidativo, favoreciendo la aterosclerosis, conformando la expresión de un fenotipo arterial in-flamatorio, generando el nexo entre la enfermedad periodontal y las patologías cardiovasculares (AU))

Periodontitis is a non-communicable disease which is highly prevalent worldwide. It was reported to range from 45% to 50% around the world and it was the sixth most prevalent condition of humanity. Consistent body of evidence explains the relationship between periodontal disease and other common systemic conditions such as cardiovascular disease. Periodontitis is likely to cause a 45% of deaths in developed countries, including myocardial infarction, stroke, heart failure and arrhythmias that cause about a 95% of deaths related to cardiovascular disease.Both diseases share many risk factors, such as diabetes and smoking; but also, genetic, and epigenetic characteristics support several etiopathological mechanisms. Beyond the common risk factors, two mechanisms have been proposed to elucidate the relationship between the periodontal disease and cardiovascular diseases. One of them supports the concept that periodontal pathogens are capable of the direct invasion of endothelial cells. The other mechanism suggested (indirect pathway), caused by the disease resulting in chronically elevation of CRP, inflammatory cytokines, the monocyte chemoattractant protein, could be mediated by bacterial products, such as lipopolysaccharides, wich induce a potent immune response and can accelerate endothelial dysfunction. These mechanisms may act by inflaming endothelial cells, modulating lipid metabolism and increasing oxidative stress, favoring atherosclerosis, determining the expression of an inflammatory arterial phenotype, generating the link between periodontal disease and cardiovascular pathologies (AU)

Co-managed care for fragility hip fractures (Rochester model).

Hip fractures in older adults are a common event with a high risk of morbidity and mortality. Patients who sustain a hip fracture often present with multiple co-morbid conditions that can benefit from co-management by orthopedic surgeons and geriatricians. This manuscript describes a co-managed model of care for patients with hip fractures. This model of care will be explained, and the benefits and results will be described. Retrospective review of the care of all native non-pathological hip fracture patients aged 60 years and older admitted between April 2005 and March 2009 to a 261-bed community teaching hospital. The outcome measures include patient characteristics, length of stay, mortality, 30-day readmission, re-operation, and costs of care. Seven hundred fifty-eight patients were identified with an average age of 84.8 (SD 8.4); 77.8% of the patients were female, 94.7% Caucasian, and 37.3% from nursing homes, and the mean Charlson score is 2.9 (SD 2.1). The length of stay was 4.3 days, 30-day readmission rate was 10.4%, 17-month re-operation rate was 1.9%, and costs of care to the system were $15,188. The 1-year mortality rate was 21.2%. This model of care resulted in improvements in all measures studied. Previous studies have shown reduction in in-hospital complications. Additional studies are needed to show if this model of care can be translated to other systems or to other surgical conditions. Wide application of this model care could substantially improve the quality of care and cost of caring for frail elders with hip fractures.

Ortho-geriatric service--a literature review comparing different models.

In the fast-growing geriatric population, we are confronted with both osteoporosis, which makes fixation of fractures more and more challenging, and several comorbidities, which are most likely to cause postoperative complications. Several models of shared care for these patients are described, and the goal of our systematic literature research was to point out the differences of the individual models. A systematic electronic database search was performed, identifying articles that evaluate in a multidisciplinary approach the elderly hip fracture patients, including at least a geriatrician and an orthopedic surgeon focused on in-hospital treatment. The different investigations were categorized into four groups defined by the type of intervention. The main outcome parameters were pooled across the studies and weighted by sample size. Out of 656 potentially relevant citations, 21 could be extracted and categorized into four groups. Regarding the main outcome parameters, the group with integrated care could show the lowest in-hospital mortality rate (1.14%), the lowest length of stay (7.39 days), and the lowest mean time to surgery (1.43 days). No clear statement could be found for the medical complication rates and the activities of daily living due to their inhomogeneity when comparing the models. The review of these investigations cannot tell us the best model, but there is a trend toward more recent models using an integrated approach. Integrated care summarizes all the positive features reported in the various investigations like integration of a Geriatrician in the trauma unit, having a multidisciplinary team, prioritizing the geriatric fracture patients, and developing guidelines for the patients' treatment. Each hospital implementing a special model for geriatric hip fracture patients should collect detailed data about the patients, process of care, and outcomes to be able to participate in audit processes and avoid peerlessness.

Indoleamine 2,3-dioxygenase, an emerging target for anti-cancer therapy.

The inability of the host immune system to control tumor growth appears to result from dominant mechanisms of immune suppression that prevent the immune system from effectively responding in a way that consistently results in tumor rejection. Among the many possible mediators of tumoral immune escape, the immunoregulatory enzyme, indoleamine 2,3-dioxygenase (IDO), has recently gained considerable attention. IDO is a heme-containing, monomeric oxidoreductase that catalyzes the first and rate-limiting step in the degradation of the essential amino acid tryptophan to N formyl-kynurenine. Tryptophan depletion as well as the accumulation of its metabolites results in a strongly inhibitory effect on the development of immune responses by blocking T cell activation, inducing T cell apoptosis and promoting the differentiation of naïve T cells into cells with a regulatory phenotype (T(regs)). Recent data obtained from preclinical tumor models demonstrate that IDO inhibition can significantly enhance the antitumor activity of various chemotherapeutic and immunotherapeutic agents. These results, coupled with data showing that increased IDO expression is an independent prognostic variable for reduced overall survival in cancer patients, suggest that IDO inhibition may represent an effective strategy to treat malignancies, either alone or in combination with chemotherapeutics or other immune based therapies. This review will focus on the role of IDO as a mediator of peripheral immune tolerance, evidence that IDO becomes dysregulated in human cancers, and the latest progress on the development of IDO inhibitors as a novel anti-cancer therapy.

Dietas desequilibradas en niños preescolares: estudio en un jardín integral de la provincia de Buenos Aires, Argentina / Imbalance diets in preschool children: study in a day-care center in the Province of Buenos Aires, Argentina

The purpose of this study was to investigate the impact of low fat diets in children aged 2 to 5. Eighty two children (40 females and 42 males) attending a school cafeteria (Province of Buenos Aires, Argentina), in a cross sectional study, were evaluated. Body weight (W), height (H) and body composition (BC) by bioimpedance were recorded. The anthropometric raw data were processed as Z-score of the weight-for-age (WEZ) and of the height-for-age (HAZ). Serum insulin-like growth factor 1 (IGF-1) and Zinc/haemoglobin ratio (Zn/Hb) were also measured. Results showed that 73.2 per cent of children were adequate (A) according WEZ, 13.4 per cent were lean (L) and 13.4 per cent overweight (O). 8.5 per cent presented simultaneously impairment in WEZ and HAZ. Body fat percentage and energy metabolism were higher in O than in L and A (p < 0.05). Serum IGF-1's children--aged 4 to 5 years--with HAZ deficit were low than adequate HAZ ones. No statistical differences in Zn/Hb ratio between A, L and O were found. This cross sectional study suggests metabolic disorders in young children attending school cafeterias. These conclusions will allow to design balanced diets in order to optimize the resources, promote optimal growth and development and prevent adult diseases through dietary practices in childhood.

Role of crevice in the occurrence of hemoglobin in saliva

The aim of the present study was to analyze the role of the gingival-periodontal component in the presence of blood in saliva. We studied a population of 184 adult patients composed of 101 totally edentulous patients with no oral mucosa lesions and 83 dentulous patients with clinically healthy gums. Saliva samples obtained by spontaneous salivation were collected in sterile containers. Qualitative and quantitative evaluation of each of the samples was performed. 67

of the dentulous patients tested positive for hemoglobin in saliva. None of the patients in the totally edentulous group exhibited hemoglobin in saliva. These data suggest that the periodontal condition is an essential factor for the presence of hemoglobin in saliva.

Photochemically enhanced binding of small molecules to the tumor necrosis factor receptor-1 inhibits the binding of TNF-alpha.

The binding of tumor necrosis factor alpha (TNF-alpha) to the type-1 TNF receptor (TNFRc1) plays an important role in inflammation. Despite the clinical success of biologics (antibodies, soluble receptors) for treating TNF-based autoimmune conditions, no potent small molecule antagonists have been developed. Our screening of chemical libraries revealed that N-alkyl 5-arylidene-2-thioxo-1,3-thiazolidin-4-ones were antagonists of this protein-protein interaction. After chemical optimization, we discovered IW927, which potently disrupted the binding of TNF-alpha to TNFRc1 (IC(50) = 50 nM) and also blocked TNF-stimulated phosphorylation of Ikappa-B in Ramos cells (IC(50) = 600 nM). This compound did not bind detectably to the related cytokine receptors TNFRc2 or CD40, and did not display any cytotoxicity at concentrations as high as 100 microM. Detailed evaluation of this and related molecules revealed that compounds in this class are "photochemically enhanced" inhibitors, in that they bind reversibly to the TNFRc1 with weak affinity (ca. 40-100 microM) and then covalently modify the receptor via a photochemical reaction. We obtained a crystal structure of IV703 (a close analog of IW927) bound to the TNFRc1. This structure clearly revealed that one of the aromatic rings of the inhibitor was covalently linked to the receptor through the main-chain nitrogen of Ala-62, a residue that has already been implicated in the binding of TNF-alpha to the TNFRc1. When combined with the fact that our inhibitors are reversible binders in light-excluded conditions, the results of the crystallography provide the basis for the rational design of nonphotoreactive inhibitors of the TNF-alpha-TNFRc1 interaction.

Differential regulation of IL-1beta and TNF-alpha RNA expression by MEK1 inhibitor after focal cerebral ischemia in mice.

Activation of the extracellular-signal-responsive kinase (ERK 1/2) by MAP kinase/ERK kinase (MEK1/2) following ischemia/reperfusion in the brain has been associated with cell death since inhibition of MEK1/2 provides neuroprotection in cerebral ischemia injury. Since inflammation has been implicated in ischemic brain injury, the present study investigated whether MEK1/2 modifies expression of two key inflammatory cytokines, IL-1beta and TNFalpha, that have been shown to exacerbate ischemic brain injury. A mouse model of transient cerebral ischemia was deployed to test the effect of selective MEK1/2 inhibitor (SL327) on infarct size and cytokine expression. SL327 (100 mg/kg, i.p.) administered 15 min prior to ischemia resulted in 64% reduction in infarct size over controls (n = 8, P < 0.01). Under the same condition, SL327 significantly reduced peak expression of IL-1beta mRNA (59% reduction compared to vehicle, P < 0.01, n = 4) but not TNF-alpha mRNA. A parallel reduction in IL-1beta protein (67%, P < 0.05, n = 6) was also observed using ELISA analysis. These data suggest that the neuroprotective effect of MEK1/2 inhibition may be mediated by suppression of IL-1beta. The study also demonstrates for the first time that these two cytokines are differentially regulated by kinase mediated signaling pathways.

Biology of TACE inhibition.

Studies conducted over the past decade have demonstrated a central role for tumour necrosis factor alpha (TNFalpha) in inflammatory diseases. As a result of this work, a number of biological agents that neutralise the activity of this cytokine have entered the clinic. The recent clinical data obtained with etanercept and infliximab highlight the relevance of this strategy. TNFalpha converting enzyme (TACE) is the metalloproteinase that processes the 26 kDa membrane bound precursor of TNFalpha (proTNFalpha) to the 17 kDa soluble component. Although a number of proteases have been shown to process proTNFalpha, none do so with the efficiency of TACE. A series of orally bioavailable, selective, and potent TACE inhibitors are currently in clinical development. These inhibitors effectively block TACE mediated processing of proTNFalpha and can reduce TNF production by lipopolysaccharide stimulated whole blood by >95%. Through a series of studies it is shown here that >80% of the unprocessed proTNFalpha is degraded intracellularly. The remainder appears to be transiently expressed on the cell surface. Although, in vitro, TACE inhibition has also been implicated in shedding of p55 and p75 surface TNFalpha receptors, the in vivo data cast doubt on the consequences of this finding. In a mouse model of collagen-induced arthritis, the inhibitors are efficacious both prophylactically and therapeutically. The efficacy seen is equivalent to strategies that neutralise TNFalpha. In many studies greater efficacy is observed with the TACE inhibitors, presumably owing to greater penetration to the site of TNFalpha production.

Mixed lens opacities and subsequent mortality.

BACKGROUND: Previous studies have found an association between cataract or lens opacity and increased risk of mortality. Further work on determining explanatory factors for this association is needed. OBJECTIVES: To determine, in a population-based cohort of older persons, the 2-year risk of death associated with different types of lens opacities; whether an association of mortality and lens opacity is explained by confounding risk factors such as smoking, diabetes, age, race, and sex, which are known to be related to opacity and mortality; whether lens opacity is a marker for health status; and whether there are differences in cause-specific mortality for persons with and without lens opacity. MAIN OUTCOME MEASURE: Two-year mortality rate. METHODS: The Salisbury Eye Evaluation Project consists of a random sample of 2520 residents of Salisbury, Md, aged 65 to 84 years. At baseline, lens photographs were taken to document nuclear, cortical, posterior subcapsular cataract, and mixed opacities. Data on education, smoking, alcohol use, hypertension, diabetes and other comorbid conditions, handgrip strength, and body mass index were also collected. Two-year follow-up was conducted for mortality and cause of death. RESULTS: Nuclear opacity, particularly severe nuclear opacity, and mixed opacities with nuclear were significant predictors of mortality independent of body mass index, comorbid conditions, smoking, age, race, and sex (mixed nuclear: odds ratio, 2.23; 95% confidence interval, 1.26-3.95). CONCLUSION: Lens opacity status is an independent predictor of 2-year mortality, an association that could not be explained by potential confounders.

Proliferative response of mantle cell lymphoma cells stimulated by CD40 ligation and IL-4.

Mantle cell lymphoma (MCL) is a tumor of intermediate-size, IgM+, IgD+ B cells derived from the mantle zone of the germinal center. Little is known about its specific immunologic features or responsiveness to T cell-derived signals. In this work, we evaluated the proliferation and cell cycle properties of freshly isolated MCL cells after CD40 ligation, in the absence and presence of interleukin 4 (IL-4). In each MCL case examined, there was a marked growth-enhancing effect of these two stimuli characterized by improved viability, augmented expression of Ki-67, and induction of the proliferating cell nuclear antigen (PCNA). Cyclin D1 was expressed throughout the cell cycle in MCL cells induced to enter S phase. From these investigations, we conclude that the biology of MCL B lymphocytes is affected by CD154 (CD40 ligand) and IL-4, two signals usually provided by CD4+ T cells. The capacity to manipulate the activation and cell cycle state of MCL cells by these specific immunological stimuli may be exploited to confer susceptibility to chemotherapy agents and develop novel therapies in this disease.

Bone growth in nonorganic nutritional dwarfing rats

Since no data are available to characterize mandibular growth in nonorganic nutritional dwarfing (ND), the purpose of the present study was to describe the effects of a diet on mandible and femur growth in a nutritional dwarfish animal model. Male Wistar rats were divided into two groups of 10 animals each: Control (C) and Experimental (E80: diet-restricted group). C rats were fed a standard diet ad libitum. E80 rats received 80

of the amount of standard diet eaten by group C. Food intake and body weight (Wt) and length (Lt) were recorded periodically. Growth data (Wt and Lt) were expressed as a Z-score of weight-for-length (WLZ) ratio, an index of body size. Five animals of each group were selected at random at 4 and 8 weeks and sacrificed. Additionally at t = 0, 5 animals were sacrificed for baseline measurements. Mandibular growth was estimated directly on the right mandible by measuring ten dimensions. Femur growth was estimated from Wt and Lt measurements of the bone. Mandibular weight, area, length and height were negatively affected by dietary restriction during the first 4 weeks of the experimental period. Mandibular growth ceased after this point. Dimensions corresponding to the alveolar unit did not change with time. However, all other dimensions were negatively influenced but not to the same extent. Femur rather than mandibular weight was severely affected. Therefore, the negative effects of the nutritional stress that occurs after weaning would be stronger for the femur, than for the mandible. Femur length was also negatively affected by suboptimal nutrition. In summary, the results of the present study showed that mandible and femur growth respond differently to mild chronic food restriction. These observations could be explained in terms of the different critical bone growth periods and of the time at which nutritional stress was imposed.

Optic nerve avulsion secondary to a basketball injury.

Optic nerve avulsion secondary to a basketball injury is a rare complication. The patient underwent a vitrectomy for a non-clearing vitreous hemorrhage. The nerve was partially avulsed with multiple choroidal ruptures in the fovea. It was concluded that optic nerve disorders rarely occur after basketball injuries. Patients with a dense vitreous hemorrhage may benefit from a vitrectomy although the vision will be limited by the optic nerve disorder.

CD40 ligation impedes lymphoblastoid B cell proliferation and S-phase entry.

The CD40 cell surface antigen and member of the tumor necrosis factor (TNF) receptor superfamily is expressed in many cell types, including normal and neoplastic B cells. Signaling through CD40 induces B cell proliferation, differentiation and, in some circumstances, protects the B cell from apoptosis. Lymphoblastoid cells (LCLs) resemble the malignant B cells that comprise the Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorders, in that the cells bear a highly activated phenotype and, unlike most other EBV positive tumor cells, express the majority of latent EBV genes. In this study, we use assays of cell viability, proliferation, cell cycle and apoptosis to demonstrate that ligation of the CD40 receptor in EBV-transformed LCLs inhibits their growth. The process does not involve apoptosis, but is characterized by reduced S-phase entry from G0/G1. A better understanding of the negative effects of CD40 ligation in these cells may offer clues for the development of novel therapies in EBV-related B cell disorders.

Chronic lymphocytic leukemia B cells can express CD40 ligand and demonstrate T-cell type costimulatory capacity.

Chronic lymphocytic leukemia (CLL) is characterized by a clonal expansion of CD5(+) B cells in the peripheral blood. Associated immune aberrations include abnormal Th-cell function and pathogenic autoantibodies. Under most circumstances, CLL B cells do not proliferate in culture and express a limited repertoire of surface antigens, including CD19, CD20, CD23, CD27, CD40, and CD70. In this report, we demonstrate that freshly isolated B cells from a subset of CLL cases constitutively express CD40 ligand (CD40L, CD154), a member of the tumor necrosis factor family which is normally expressed by activated CD4(+) T cells and mediates T-cell-dependent B-cell proliferation and antibody production. The degree of CD40L expression varied considerably among the CLL cases examined. CD40L was detected in purified CLL B cells by immunofluorescence flow cytometry, by RT-PCR, and by immunoprecipitation. To demonstrate that CD40L in the CLL B cells is functional, we used irradiated CLL cells to stimulate IgG production by target, nonmalignant B cells in coculture. The CLL B cells induced IgG production by normal B cells to a similar degree as did purified T cells in a process which was partially inhibited by monoclonal antibody to CD40L. This is one of the first reports of CD40L expression in a B-cell tumor. The data suggest that CD40L in the tumor cells may be a factor in the generation of pathologic antibodies by normal B cells in some patients with CLL.

Fas ligand expression and function in systemic lupus erythematosus.

Mutations in the Fas receptor or its ligand (FasL) lead to lupus-like systemic autoimmune diseases in mice and in some humans. To determine whether a significant number of patients with systemic lupus erythematosus (SLE) have impaired FasL function, we compared T cell effector function by superantigen-activated CD4+ T cell lines or by anti-CD3- and IL-2-generated cytotoxic T cells. No differences were observed between SLE and normal control superantigen-derived CD4+ T cells in either the ability of these cells to up-regulate Fas expression or to induce apoptosis of the Fas-sensitive target B cells. When anti-CD3/IL-2-activated T cells were examined, SLE T cells had a modest reduction (-8%) in T cell cytotoxicity compared with normal controls, but the reduction was similar to the rheumatoid arthritis disease controls. A modest reduction in cytotoxicity was evident in both the Fas and perforin/granzyme pathways as determined by testing Fas-positive and -negative targets as well as by selective blockade of the perforin/granzyme pathway with concanamycin. These results indicate that no specific defects in FasL function are evident in the majority of SLE patients under the in vitro conditions tested. The proportional reduction in FasL and perforin/granzyme function in SLE and rheumatoid arthritis patients following anti-CD3/IL-2 stimulation most likely reflects subtle differences in activation in patient-derived vs normal control T cells.

Positive vitreous cultures from eyes without signs of infectious endophthalmitis.

BACKGROUND AND OBJECTIVE: There is little information on the rate of false-positive vitreous cultures, because cultures from presumably sterile vitreous are not routinely taken in clinical practice. The objective of this study was to determine the rate of positive vitreous cultures from patients who have no signs of endophthalmitis. PATIENTS AND METHODS: Aerobic cultures from vitreous biopsies were taken from 36 consecutive eyes in which there was no clinical evidence of endophthalmitis. Effluent collected in cassettes during pars plana vitrectomies was processed and cultured in a standard manner. Balanced salt solution was processed intraoperatively through the vitrector and cultured as a negative control. RESULTS: Positive cultures were obtained in 8 of 36 eyes (22.2%). Coagulase-negative Staphylococcus and Corynebacteria accounted for 7 of the 9 identified organisms. No organism was grown in more than one medium. None of the patients were treated for endophthalmitis after surgery, and none had signs of intraocular infection. CONCLUSIONS: A substantial number of vitrectomy cultures from effluent specimens grow low-virulence organisms in the absence of clinical signs of endophthalmitis. The absence of inflammation at the time of surgery suggests that these positive cultures are contaminants.

CD4+ T-cell induction of Fas-mediated apoptosis in Burkitt's lymphoma B cells.

Cytotoxic function of CD4+ Th1 cells is mediated by Fas (CD95, APO-1) and its ligand (Fas ligand). Recent studies using nontransformed B cells and the Ramos Burkitt's lymphoma (BL) B-cell line cells show that CD40 ligation at the B-cell surface by activated, CD40 ligand (CD40L)-bearing, CD4+ T cells upregulates Fas expression on B cells and primes B cells for Fas-mediated death signals. In this work, we examine whether this CD4+ T-cell-dependent molecular pathway for Fas upregulation and B-cell apoptosis reflects a peculiarity of the Ramos B-cell line or is applicable to other Burkitt's tumors as well. In 5 of the 6 Epstein-Barr virus-negative BL cell lines examined, the cells constitutively express undetectable or low levels of Fas and are resistant to Fas-mediated signals induced by monoclonal anti-Fas antibody. All 6 of the BL cell line B cells upregulate Fas in response to CD40 ligation, and in 4 of the cases they become sensitive to Fas-mediated death signals. In one BL cell line, the cells are constitutively sensitive to Fas-mediated cytolysis and are unaffected by CD40 signals. Next, we applied these immunologic manipulations to cells from a refractory clinical sample and observed that the tumor cells could be induced to express Fas and undergo apoptosis in our system. These results establish CD4+ T cells and the Fas-Fas ligand system as important immune regulators of Burkitt's lymphoma B cells and indicate that the susceptibility of tumor cells to Fas-mediated death signals can be modulated by specific activation events at the cell surface.