Pattern recognition receptors and their involvement in the pathogenesis of arthritis

PURPOSE OF REVIEW: Pattern recognition receptors are germ-line encoded receptors that recognize specific pathogen-associated molecules, thereby allowing the innate immune system to distinguish self from nonself structures. Pattern recognition receptors mediate activation of different signaling pathways, resulting in the production of proinflammatory cytokines and the expression of antimicrobial genes. Additionally, pattern recognition receptors play a central role in the activation and direction of the adaptive immune response. This review summarizes recent advances in research trying to elucidate the link between different pattern recognition receptors and inflammatory autoimmune disorders. RECENT FINDINGS: The best known pattern recognition receptors, the toll-like receptors, are involved in the regulation of inflammation during infectious diseases. They affect apoptotic pathways and dendritic cell maturation, and interact with B-cell receptors in priming T-cell responses to host-derived DNA. This brought toll-like receptors and other pattern recognition receptors into focus as potential players in the induction of autoimmune diseases. Indeed, several inflammatory autoimmune diseases have been linked during the past few years to defects or polymorphisms of genes encoding pattern recognition receptors. SUMMARY: The discovery of toll-like receptors and other groups of pattern recognition receptors, such as the caspase recruitment domains or the triggering receptors expressed by myeloid cells, allowed one to draw an increasingly complex picture of immune responses to pathogens. The growing evidence for an involvement of pattern recognition receptors in the pathogenesis of autoimmune disorders warrants further investigation of the expression and function of pattern recognition receptors to develop novel therapeutics for diseases such as rheumatoid arthritis.     

Predictors of CD4+ cell count response and of adverse outcome among HIV-infected patients receiving highly active antiretroviral therapy in a public hospital in Peru.

OBJECTIVES: Our aim was to investigate CD4+ cell recovery and adverse outcome after highly active antiretroviral therapy (HAART) under the Peruvian National Program for HIV. METHODS: A prospective, observational study was conducted between May 2004 and September 2005. Data were collected from records of patients receiving HAART at a public hospital under the Peruvian National Program for HIV. Predictors of CD4+ cell count recovery and adverse outcome were analyzed by multiple regression. RESULTS: Three hundred and twenty-six patients were included in the study. The mean increase in CD4+ cell count at six months was 114 cells/microl (95% confidence interval: 103-126). Patients with a lower CD4+ cell count at baseline and those starting HAART with a didanosine-based regimen had a higher increase in CD4+ cell count at six months. Patients starting HAART with a stavudine-based regimen had a lower increase in CD4+ cell count at six months. World Health Organization clinical stage IV at diagnosis of HIV infection, a low body weight at baseline, and starting HAART with a stavudine-based regimen were independently associated with an adverse outcome. CONCLUSIONS: The CD4+ cell response to HAART under Peruvian National Program for HIV was comparable with reports from other countries. However, the fact that advanced clinical disease predicted adverse outcome emphasizes the need for earlier access to HAART.     

Association of klotho, bone morphogenic protein 6, and annexin A2 polymorphisms with sickle cell osteonecrosis

In patients with sickle cell disease, clinical complications including osteonecrosis can vary in frequency and severity, presumably due to the effects of genes that modify the pathophysiology initiated by the sickle mutation. Here, we examined the association of single nucleotide polymorphisms (SNPs) in candidate genes (cytokines, inflammation, oxidant stress, bone metabolism) with osteonecrosis in patients with sickle cell disease. Genotype distributions were compared between cases and controls using multiple logistic regression techniques. An initial screen and follow-up studies showed that individual SNPs and haplotypes composed of several SNPs in bone morphogenic protein 6, annexin A2, and klotho were associated with sickle cell osteonecrosis. These genes are important in bone morphology, metabolism, and vascular disease. Our results may provide insight into the pathogenesis of osteonecrosis in sickle cell disease, help identify individuals who are at high risk for osteonecrosis, and thus allow earlier and more effective therapeutic intervention.     

Valsalva maneuver in chagasic patients with documented past medical history of acute chagasic myocarditis

BACKGROUND: We studied the heart rate responses to the Valsalva maneuver in eight patients with documented past medical history of acute Chagas' disease. METHODS: Four patients were studied 8-21 months after the acute episode and four, 58-68 months thereafter (age 25+/-8.65 years M+/-S.D.). Seventeen healthy subjects of similar age were included as controls (age 27+/-7.5 years, P=NS). RESULTS: Baseline heart rate was higher in chagasic patients (88+/-15 beats/min) compared to controls (69.8+/-9.8, P=0.001). Maximum heart rate at phase II of the maneuver was also higher (114+/-16.3 vs. 101.5+/-9.9, P=0.02). Minimum heart rate at phase IV was, however, not different (57.4+/-10.4 vs. 63.3+/-7.3 P=NS). The magnitude of the absolute negative change at phase IV was larger in the chagasic patients, although, not different (-50.8+/-13.8 vs. -44+/-13.8, P=NS). The Valsalva index was 1.81+/-0.26 in the chagasic patients and 1.82+/-0.42 in the controls (P=NS). Minimum heart rate at phase IV correlated neither with the baseline heart rate (r=-0.28, P=NS) nor with the Valsalva index (r=-0.40, P=NS). The magnitude of the absolute negative change during phase IV correlated with, both, the baseline heart rate (r=-0.80, P<0.01) and the Valsalva index (r=-0.95, P<0.0001). The higher baseline high rate influenced the magnitude of the negative heart rate change, but not the minimum heart rate reached at phase IV. CONCLUSIONS: Chagasic patients with proven past medical history of acute Chagas' disease had unimpaired heart responses to the Valsalva maneuver.     

The global cardiovascular risk chart]

BACKGROUND: Risk charts, built through risk functions deriving from longitudinal studies, are used in order to identify individuals at high risk for cardiovascular disease. For this reason the function has been identified and the global cardiovascular risk chart of the CUORE Project has been prepared, using Italian data coming from different cohorts enrolled between the '80s and the '90s, whose risk factors had been collected by standardized procedures. METHODS: The following risk factors have been used: age (10-year period, 40-49, 50-59, 60-69 years), gender (men and women), systolic blood pressure (< or = 129, 130-149, 150-169, > or = 170 mmHg), serum cholesterol (< or = 173, 174-212, 213-251, 252-290, > or = 291 mg/dl), smoking habit (yes, no) and presence of diabetes (yes, no); the first coronary or cerebrovascular event in people aged 40-69 years with no other previous cardiovascular events was considered as endpoint; survival has been assessed up to December 1998. RESULTS: Out of 18,028 people aged 40-69 years with no previous cardiovascular events, 647 first major cardiovascular events have been identified and validated, 449 coronary and 198 cerebrovascular. Charts are divided according to men and women and to diabetics and non-diabetics respectively; the different colors represent the percent level of risk and go from light green (< 5% in 10 years for men, < 1% in 5 years for women), dark green (between 5 and 10% for men, between 1 and 3% for women), yellow (between 10 and 15% for men, between 3 and 5% for women), orange (between 15 and 20% for men, between 5 and 7% for women), red (between 20 and 30% for men, between 7 and 10% for women), violet (> 30% for men, > 10% for women). CONCLUSIONS: The risk charts were built with data collected in recent years on men and women with a median follow-up of 10 years for men and 5 years for women, considering the first major fatal or non-fatal cardiovascular event as endpoint. Such a tool is easy to be applied by general practitioners and cardiologists in order to achieve a fast and objective evaluation of global cardiovascular risk.     

Introduction of iodized salt to severely iodine-deficient children does not provoke thyroid autoimmunity: a one-year prospective trial in northern Morocco.

To determine if introduction of iodized salt induces thyroid autoimmunity in goitrous children, we conducted a prospective trial in iodine-deficient Moroccan schoolchildren (n = 323). Local salt was iodized at 25 microg iodine per gram of salt and distributed to households. Before introduction of iodized salt and at 10, 20, 40, and 52 weeks, we measured antithyroid peroxidase antibodies (TPO-Ab), antithyroglobulin antibodies (Tg-Ab), urinary iodine (UI), and thyroid hormones, and examined the thyroid using ultrasound. At baseline, median UI was 17 microg/L and the prevalence of goiter and hypothyroidism was 72% and 18%, respectively. Provision of iodized salt maintained median UI at 150-200 microg/L for the year (p < 0.0001). There was a significant increase in mean total thyroxine (T(4)) and a significant reduction in the prevalence of hypothyroidism (p < 0.001). There was a transient increase in the prevalence of detectable antibodies after introduction of iodized salt (p < 0.0001) with levels returning to baseline at 1 year. Only congruent with 1% of children had elevated TPO-Ab and none had elevated Tg-Ab over the course of the study, and no child with elevated TPO-Ab had abnormal thyrotropin (TSH) or T(4) concentrations. None developed clinical or ultrasonographic evidence of thyroid autoimmune disease and/or iodine-induced hypothyroidism or hyperthyroidism. Rapid introduction of iodized salt does not provoke significant thyroid autoimmunity in severely iodine-deficient children followed for 1 year.     

Human ejaculated spermatozoa contain active P450 aromatase

The generation of cytochrome P450 aromatase (P450arom) and estrogen receptor (ER) knockout mice has raised new interest in the physiological role of estrogens in male reproduction. Testicular expression of P450arom, the enzyme that converts androgens into estrogens, has been shown in both somatic and germ cell types in several species, whereas in humans, testicular expression is confined to the somatic cells. The aim of this study was to determine whether P450arom is present in human ejaculated spermatozoa. Using RT-PCR and specific primers, we amplified the highly conserved helical, aromatic, and heme-binding sequences of the conventional human P450arom from RNA isolated from human spermatozoa. Employing a rabbit polyclonal antiserum directed against human placental P450arom, immunoblotting analysis demonstrated aromatase protein expression, which was localized primarily to the tail and midpiece of spermatozoa. Measurement of enzymatic activity using a sensitive (3)H(2)O aromatase assay revealed that activity was enhanced by the 2'-O-dibutyryl cAMP and completely inhibited in the presence of the specific aromatase inhibitor, letrozole. These results represent the first demonstration that human spermatozoa are a potential site of estrogen biosynthesis. The physiological relevance of estrogen synthesis in spermatozoa remains to be elucidated and opens a new area of investigation in male fertility.     

Preoperative selective portal vein embolization (PSPVE) before major hepatic resection. Effectiveness of Doppler estimation of hepatic blood flow to predict the hypertrophy rate of non-embolized liver segments

Hepatocellular carcinoma may be unresectable for volumetric reasons. The future remaining liver after hepatectomy might be too small to ensure survival. Preoperative selective portal vein embolization of the tumorous lobe can induce hypertrophy of the future remaining liver and enable safer surgery. A 76-year-old patient with hepatocellular carcinoma needed right lobectomy however, the future remaining liver was judged insufficient to ensure an uneventful postoperative course. The left lobe to whole liver volumetric ratio was to small (29.7%) and a preoperative selective portal vein embolization of the right portal branch via a percutaneous, transhepatic, contralateral approach was performed without side effects. A Doppler estimation of left branch portal blood flow and velocity was carried out before and after preoperative selective portal vein embolization. After 21 days the left lobe volume increased by about 44.2% with a safe left lobe/whole liver ratio of 40.8%. The portal blood flow and portal blood flow velocity showed an increase of 253% and 122%, respectively. A right lobectomy was performed without complications. Three months later, computed tomography scan showed no hepatocellular carcinoma recurrence. Preoperative selective portal vein embolization is a safe technique which can enable major hepatectomy to be performed in situations otherwise judged unresectable for a life-threatening volumetric insufficiency. The portal blood flow and portal blood flow velocity evaluations can easily predict the hypertrophy rate of non-embolized liver segments.     

Comparable functions of plasmacytoid and monocyte-derived dendritic cells in chronic hepatitis C patients and healthy donors

BACKGROUND/AIMS: Dendritic cells (DCs) play a key role in immune responses through antigen presentation and cytokine secretion. Hepatitis C virus (HCV) is able to escape elimination by the immune system and often establishes a chronic infection. To investigate whether DC dysfunction is involved in this process, we have studied monoycte-derived DCs (Mo-DCs) and plasmacytoid DCs (pDCs), which produce large amounts of IFN-alpha, from chronic HCV patients and healthy donors. METHODS: We have assessed TNF-alpha and IFN-alpha production by pDCs using intracellular staining after total PBMCs stimulation with unmethylated CG dinucleotides (CpGs). The induction of allogeneic T cell proliferation by immature Mo-DCs was measured using the MLR assay. The up-regulation of maturation markers and the production of TNF-alpha in response to LPS were analyzed using flow cytometry and ELISA, respectively. RESULTS: We have detected comparable frequencies of pDCs producing TNF-alpha and IFN-alpha in both chronic HCV patients and healthy donors and we have found that immature Mo-DCs from both patients and donors similarly induce allogeneic T cell proliferation and mature and secrete TNF-alpha in response to LPS. CONCLUSIONS: Our results demonstrate that both pDC and Mo-DCs are not impaired in HCV infected patients.     

Diabetes in Italy: a public health problem]

BACKGROUND: Type 2 diabetes is the most frequent form of diabetes in the adult population and is associated with an increasing risk of cardiovascular diseases. The objective of this study was to describe the prevalence and the state of control in an Italian population sample examined within the Osservatorio Epidemiologico Cardiovascolare study. METHODS: The sample of this study consisted in 8972 subjects, men and women aged 35-74 years. A fasting capillary blood glucose > or = 126 mg/dl or being on antidiabetic treatment were the criteria used to define diabetes, while a fasting capillary blood glucose < 140 mg/dl was considered to represent effective treatment (controlled diabetes) in treated patients. RESULTS: Diabetes was present in 8.4% of men and 6% in women. The prevalence of glucose intolerance was 8.2% in men and 4.3% in women. Only 50.7% of diabetic men and 56.5% of diabetic women knew about their disease; among these people, 21% was on treatment with oral antidiabetics and/or insulin. Such a therapy was effective in 39.5% of the treated cases. CONCLUSIONS: The prevalence of diabetes as well as glucose intolerance was greater in men and in the regions of the Center and South of Italy. The state of control of diabetes cannot be considered satisfactory; women and older age groups, when prevention strategies are less important, appear to be under better care.