EPI Update, September 1, 2006

Weekly newsletter for Center For Acute Disease Epidemiology of Iowa Department of Public Health.

EPI Update, December 1, 2006

Weekly newsletter for Center For Acute Disease Epidemiology of Iowa Department of Public Health.

Role of T-cell-mediated inflammation in psoriasis: pathogenesis and targeted therapy

Psoriasis is one of the most common chronic, inflammatory, T-cell-mediated autoimmune diseases. Over the past decade, increased knowledge of disease pathogenesis has fundamentally changed psoriasis treatment, with the introduction of biologics, and this has led to a multitude of improved selective targets providing potential therapeutic options. Indeed, numerous pathogenesis-based treatments are currently in development, as psoriasis has also become increasingly relevant for proof-of-concept studies. The purpose of this review was to summarize current knowledge of psoriasis immunopathogenesis, focusing on the T-cell-mediated immune response and its initiation. The authors describe recent advances in psoriasis treatment and discuss pathogenesis-based therapies that are currently in development or which could be envisioned for the future. Although current biologics are well tolerated, several issues such as long-term efficacy, long-term safety, and high costs keep driving the search for new and better therapies. With further advances in understanding disease pathogenesis, more genomic data from psoriasis patients becoming available, and potentially the identification of autoantigens in psoriasis, current research should lead to the development of a growing arsenal of improved targeted treatments and to further breakthrough immunotherapies.

Assessing the vulnerability of women to sexually transmitted diseases STDS/ HIV: construction and validation of markers

Objective To construct and validate markers of vulnerability of women to STDs/HIV, taking into consideration the importance of STDs/HIV. Method Methodological study carried out in three stages: 1) systematic review and identification of elements of vulnerability in the scientific production; 2) selection of elements of vulnerability, and development of markers; 3) establishment of the expert group and validation of the markers (content validity). Results Five markers were validated: no openness in the relationship to discuss aspects related to prevention of STDs/HIV; no perception of vulnerability to STDs/HIV; disregard of vulnerability to STDs/ HIV; not recognizing herself as the subject of sexual and reproductive rights; actions of health professionals that limit womenR17;s access to prevention of STDs/HIV. Each marker contains three to eleven components. Conclusion The construction of such markers constituted an instrument, presented in another publication, which can contribute to support the identification of vulnerabilities of women in relation to STDs/HIV in the context of primary health care services. The markers constitute an important tool for the operationalization of the concept of vulnerability in primary health care and to promote inter/multidisciplinary and inter/multi-sectoral work processes.


Interferon-gamma impacts at multiple points during the progression of autoimmune diabetes.

The role of interferon-gamma in autoimmune diabetes was assessed by breeding a null mutation of the interferon-gamma receptor alpha chain into the nonobese diabetic mouse strain, as well as into a simplified T cell receptor transgenic model of diabetes. In contrast to a previous report on abrogation of the interferon-gamma gene, mutation of the gene encoding its receptor led to drastic effects on disease in both mouse lines. Nonobese diabetic mice showed a marked inhibition of insulitis-both the kinetics and penetrance-and no signs of diabetes; the transgenic model exhibited near-normal insulitis, but this never evolved into diabetes, either spontaneously or after experimental provocation. This failure could not be explained by perturbations in the ratio of T helper cell phenotypes; rather, it reflected a defect in antigen-presenting cells or in the islet beta cell targets.

EPI Update, June 1, 2007

Weekly newsletter for Center For Acute Disease Epidemiology of Iowa Department of Public Health.

Characterization of NALP2 and NALP3 IL-1β processing inflammasomes

Résumé II y a cinq ans, la découverte d'un nouveau domaine, le PYD domaine, lié aux domaines de la mort, a permis la description de la nouvelle famille des NALP protéines. L'analyse structurelle de cette famille de protéines révéla la présence de deux autres domaines, impliqués dans l'oligomerisation, NACHT, et la détection des ligands, Leucine rich repeats ou LRR. Cette architecture protéique est homologue à celle qui est décrite pour les NODs, les Tol1 récepteurs et tes protéines de résistance chez les plantes. Cette homologie suggère une possible implication des NALPs dans la régulation de l'immunité innée. Premièrement, nous avons décrit les composants minimaux qui permettent à l'inflammasomeNALP3 d'activer la caspase pro-inflammatoire, caspase-1. En comparaison à NALP1, NALP3 ne contient pas de FIIND domaine, ni de CARD domaine en C-terminus et n'interagit pas avec caspase-5. Nous avons découvert une protéine très homologue au C-terminus de NALP1, Cardinal, qui se lie au NACHT domaine de NALP2 et NALP3 par l'intermédiaire de son FIIND domaine. Cardinal possède la capacité d'interagir avec caspase-l, mais seul ASC semble être nécessaire à la maturation de la prointerleukine-1β suite à la stimulation de NALP3. Deuxièmement, notre étude s'est concentrée sur la nature du stimulus capable d'induire la formation et l'activation de l'inflammasome-NALP3. Nous avons démontré que l'ajout de muramyl dipeptide (MDP), produit à partir de la digestion enzymatique de peptidoglycaris bactériens, induit à la fois l'expression de la proIL-1β par la voie NOD2 et sa maturation en IL-1β active par la voie NALP3. Bien que le MDP active l'inflammasome-NALP3, il est incapable d'induire la sécrétion de l'IL-1β mature dans la lignée cellulaire THP1, comparé aux monocytes primaires humains. Cette différence pourrait être liée à l'absence, dans les THP1, de la protéine Filamin, qui est proposée d'interagir avec Cardinal. L'implication de NALP3 dans la maturation de l'IL-lb est confirmée suite à la découverte de mutations sur le gène CIAS1/NALP3/cryopyrin associées à trois maladies auto-inflammatoires : le syndrome de Muckle-Wells (MWS), l'urticaire familial au froid (FCU) et le syndrome CINCA/NOMID. Une élévation constitutive de la maturation et de la sécrétion de la proIL-1β en absence de stimulation MDP est détectée dans les macrophages des patients Muckle-Wells. En conclusion, nos études ont démontré que l'inflammasome-NALP3 doit être finement régulé pour éviter une activité incontrôlée qui représente la base moléculaire des symptômes associés aux syndromes auto-inflammatoires liés à NALP3. Summary Five years ago, the description of the NALP family originated from the discovery of a new death-domain fold family, the PYD domain. NALP contains aprotein-protein interaction domain (PYD), an oligomerization domain (NACHT) and a ligand-sensing domain, leucine rich repeats or LRR. This protein architecture shares similarity with receptors involved in immunity, such as NODS, Toll receptors (TLRs) and related plant resistance proteins, and points to an important role of NALPs in defense mechanisms. We first described the minimal complex involved in the pro-inflammatory Interleukin-1beta (IL-1β) cytokine maturation, called the inflammasome, which contains NALP3. In contrast to NALP1, NALP3, like other members of the NALP family, is devoid of C-terminal FIIND and CARD domains and does not interact with the pro-inflammatory caspase-5. Interestingly, a homolog of the C-terminal portion of NALP1 was found in the human genome and was named Cardinal. We found that NALP2 and NALP3 interact with the CARD-containing proteins Cardinal. Cardinal is able to bind to caspase-1 but is not required for IL-1β maturation through NALP3 activation, as demonstrated for the adaptor ASC. Secondly, our study focused on the stimuli involved in the activation of the NALP3 inflammasome. MDP was shown to induce the expression of proIL1β through NOD2 and then the maturation into active IL-1β by activation of the NALP3 inflammasome. However, in the monocytic THP1 cell line, secretion of IL-1β upon MDP stimulation seems to be independent of the inflammasome activation compared to human primary monocytes. This difference might be linked to a Cardinal-interacting protein, filamin. Until now, the role of Cardinal and filamin is still unknown and remains to be elucidated. Finally, mutations in the NALP3/cryopyrin/CIAS1 gene are associated with three autoinflammatory diseases: Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and CINCA. Constitutive, elevated IL-1β maturation and secretion, even in the absence of MDP stimulation, was observed in macrophages from Muckle-Wells patients and confirmed a key role for the NALP3 inflammasome in innate immunity In conclusion, our studies describes the formation of the NALP3 inflammasome and suggests that this complex has to be tightly regulated to avoid an increased deregulated inflammasome activity that is the molecular basis for the symptoms associated with NALP3-dependent autoinflammatory disorders.

Continuous electroencephalography in the medical intensive care unit.

OBJECTIVES: To examine predictors and the prognostic value of electrographic seizures (ESZs) and periodic epileptiform discharges (PEDs) in medical intensive care unit (MICU) patients without a primary acute neurologic condition. DESIGN: Retrospective study. SETTING: MICU in a university hospital. PATIENTS: A total of 201 consecutive patients admitted to the MICU between July 2004 and January 2007 without known acute neurologic injury and who underwent continuous electroencephalography monitoring (cEEG) for investigation of possible seizures or changes in mental status. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Median time from intensive care unit (ICU) admission to cEEG was 1 day (interquartile range 1-4). The majority of patients (60%) had sepsis as the primary admission diagnosis and 48% were comatose at the time of cEEG. Ten percent (n = 21) of patients had ESZs, 17% (n = 34) had PEDs, 5% (n = 10) had both, and 22% (n = 45) had either ESZs or PEDs. Seizures during cEEG were purely electrographic (no detectable clinical correlate) in the majority (67%) of patients. Patients with sepsis had a higher rate of ESZs or PEDs than those without sepsis (32% vs. 9%, p < 0.001). On multivariable analysis, sepsis at ICU admission was the only significant predictor of ESZs or PEDs (odds ratio 4.6, 95% confidence interval 1.9-12.7, p = 0.002). After controlling for age, coma, and organ dysfunction, the presence of ESZs or PEDs was associated with death or severe disability at hospital discharge (89% with ESZs or PEDs, vs. 39% if not; odds ratio 19.1, 95% confidence interval 6.3-74.6, p < 0.001). CONCLUSION: In this retrospective study of MICU patients monitored with cEEG, ESZs and PEDs were frequent, predominantly in patients with sepsis. Seizures were mainly nonconvulsive. Both seizures and periodic discharges were associated with poor outcome. Prospective studies are warranted to determine more precisely the frequency and clinical impact of nonconvulsive seizures and periodic discharges, particularly in septic patients.

Alterations of bone microarchitecture in young patients with inflammatory bowel diseases are associated with fracture risk during growth

Aims: Inflammatory bowel diseases (IBD) appearing during childhood and adolescence compromise peak bone mass acquisition and increase fracture risk. The structural determinants of bone fragility in IBD however remain unknown. Methods: We investigated volumetric bone mineral density (vBMD), trabecular and cortical bone microstructure at distal radius and tibia by high-resolution pQCT (XtremeCT, Scanco, Switzerland), aBMD at distal radius, hip and spine and vertebral fracture assessment (VFA) by DXA in 107 young patients (mean age 22.8 yrs, range 12.2-33.7 yrs; 62 females and 45 males) with Crohn's disease (n=75), ulcerative colitis (n=25), undetermined colitis (n=2), and no definitive diagnosis (n=5), and in 389 healthy young individuals. Results: Mean disease duration was 6.1 yrs, 89/107 IBD patients received corticosteroids, 83 other immunomodulators, and 59 vitamin D. Clinical fractures were reported by 38 patients (mean age at 1st fracture, 12.6 yrs), the vast majority of the forearm, arm or hand; 5 had vertebral crush fractures (Grade 1 or 2) and 11 had multiple fractures. As compared to healthy controls (matched 2:1 for age, sex, height and fracture history), the 102 patients with established IBD had similar weight but significantly lower aBMD at all sites, lower trabecular (Tb) BV/TV and number, and greater Tb separation and inhomogeneous Tb distribution (1/SD TbN) at both distal radius and tibia, lower tibia cortical thickness (CTh), but no differences in cortical vBMD nor bone perimeter. Among IBD's, aBMD was not associated with fractures (by logistic regression adjusted for age, age square, sex, height, weight and protein intake). However, radius and tibia Tb BV/TV, thickness and SD 1/TbN, as well as radius Tb separation and perimeter, were significantly associated with fracture risk (fully adjusted as above), whereas cortical vBMD and CTh were not. After adjustment for aBMD at radius, respectively at femur neck, radius SD 1/TbN and tibia BV/TV, TbTh and perimeter remained independently associated with fracture risk. Conclusions: Young subjects with IBD have low bone mass and poor bone microarchitecture compared to healthy controls. Alterations of bone microarchitecture, particularly in the trabecular bone compartment, are specifically associated with increased fracture risk during growth.

ZNRD1 (zinc ribbon domain-containing 1) is a host cellular factor that influences HIV-1 replication and disease progression.

BACKGROUND: Human immunodeficiency virus (HIV) takes advantage of multiple host proteins to support its own replication. The gene ZNRD1 (zinc ribbon domain-containing 1) has been identified as encoding a potential host factor that influenced disease progression in HIV-positive individuals in a genomewide association study and also significantly affected HIV replication in a large-scale in vitro short interfering RNA (siRNA) screen. Genes and polymorphisms identified by large-scale analysis need to be followed up by means of functional assays and resequencing efforts to more precisely map causal genes. METHODS: Genotyping and ZNRD1 gene resequencing for 208 HIV-positive subjects (119 who experienced long-term nonprogression [LTNP] and 89 who experienced normal disease progression) was done by either TaqMan genotyping assays or direct sequencing. Genetic association analysis was performed with the SNPassoc package and Haploview software. siRNA and short hairpin RNA (shRNA) specifically targeting ZNRD1 were used to transiently or stably down-regulate ZNRD1 expression in both lymphoid and nonlymphoid cells. Cells were infected with X4 and R5 HIV strains, and efficiency of infection was assessed by reporter gene assay or p24 assay. RESULTS: Genetic association analysis found a strong statistically significant correlation with the LTNP phenotype (single-nucleotide polymorphism rs1048412; [Formula: see text]), independently of HLA-A10 influence. siRNA-based functional analysis showed that ZNRD1 down-regulation by siRNA or shRNA impaired HIV-1 replication at the transcription level in both lymphoid and nonlymphoid cells. CONCLUSION: Genetic association analysis unequivocally identified ZNRD1 as an independent marker of LTNP to AIDS. Moreover, in vitro experiments pointed to viral transcription as the inhibited step. Thus, our data strongly suggest that ZNRD1 is a host cellular factor that influences HIV-1 replication and disease progression in HIV-positive individuals.

Influence of the timing of cardiac surgery on the outcome of patients with infective endocarditis and stroke.

BACKGROUND: The timing of cardiac surgery after stroke in infective endocarditis (IE) remains controversial. We examined the relationship between the timing of surgery after stroke and the incidence of in-hospital and 1-year mortalities. METHODS: Data were obtained from the International Collaboration on Endocarditis-Prospective Cohort Study of 4794 patients with definite IE who were admitted to 64 centers from June 2000 through December 2006. Multivariate logistic regression and Cox regression analyses were performed to estimate the impact of early surgery on hospital and 1-year mortality after adjustments for other significant covariates. RESULTS: Of the 857 patients with IE complicated by ischemic stroke syndromes, 198 who underwent valve replacement surgery poststroke were available for analysis. Overall, 58 (29.3%) patients underwent early surgical treatment vs 140 (70.7%) patients who underwent late surgical treatment. After adjustment for other risk factors, early surgery was not significantly associated with increased in-hospital mortality rates (odds ratio, 2.308; 95% confidence interval [CI], .942-5.652). Overall, probability of death after 1-year follow-up did not differ between 2 treatment groups (27.1% in early surgery and 19.2% in late surgery group, P = .328; adjusted hazard ratio, 1.138; 95% CI, .802-1.650). CONCLUSIONS: There is no apparent survival benefit in delaying surgery when indicated in IE patients after ischemic stroke. Further observational analyses that include detailed pre- and postoperative clinical neurologic findings and advanced imaging data (eg, ischemic stroke size), may allow for more refined recommendations on the optimal timing of valvular surgery in patients with IE and recent stroke syndromes.

EPI Update, February 1, 2008

Weekly newsletter for Center For Acute Disease Epidemiology of Iowa Department of Public Health.

Value of sTREM-1, procalcitonin and CRP as laboratory parameters for postmortem diagnosis of sepsis.

OBJECTIVES: Triggering receptor expressed on myeloid cells-1 (TREM-1) was reported to be up-regulated in various inflammatory diseases as well as in bacterial sepsis. Increased cell-surface TREM-1 expression was also shown to result in marked plasma elevation of the soluble form of this molecule (sTREM-1) in patients with bacterial infections. In this study, we investigated sTREM-1, procalcitonin and C-reactive protein in postmortem serum in a series of sepsis-related fatalities and control individuals who underwent medico-legal investigations. sTREM-1 was also measured in pericardial fluid and urine. METHODS: Two study groups were prospectively formed, a sepsis-related fatalities group and a control group. The sepsis-related fatalities group consisted of sixteen forensic autopsy cases. Eight of these had a documented clinical diagnosis of sepsis in vivo. The control group consisted of sixteen forensic autopsy cases with various causes of death. RESULTS: Postmortem serum sTREM-1 concentrations were higher in the sepsis group with a mean value of 173.6 pg/ml in septic cases and 79.2 pg/ml in control individuals. The cutoff value of 90 pg/ml provided the best sensitivity and specificity. Pericardial fluid sTREM-1 values were higher in the septic group, with a mean value of 296.7 pg/ml in septic cases and 100.9 pg/ml in control individuals. The cutoff value of 135 pg/ml provided the best sensitivity and specificity. Mean urine sTREM-1 concentration was 102.9 pg/ml in septic cases and 89.3 pg/ml in control individuals. CONCLUSIONS: Postmortem serum sTREM-1, individually considered, did not provide better sensitivity and specificity than procalcitonin in detecting sepsis. However, simultaneous assessment of procalcitonin and sTREM-1 in postmortem serum can be of help in clarifying contradictory postmortem findings. sTREM-1 determination in pericardial fluid can be an alternative to postmortem serum in those situations in which biochemical analyses are required and blood collected during autopsy proves insufficient.