The impact of mpMRI-targeted vs systematic biopsy on the risk of prostate cancer downgrading at final pathology.

PURPOSE: Although targeted biopsies (TBx) are associated with improved disease assessment, concerns have been raised regarding the risk of prostate cancer (PCa) overgrading due to more accurate biopsy core deployment in the index lesion. METHODS: We identified 1672 patients treated with radical prostatectomy (RP) with a positive mpMRI and ISUP ≥ 2 PCa detected via systematic biopsy (SBx) plus TBx. We compared downgrading rates at RP (ISUP 4-5, 3, and 2 at biopsy, to a lower ISUP) for PCa detected via SBx only (group 1), via TBx only (group 2), and eventually for PCa detected with the same ISUP 2-5 at both SBx and TBx (group 3), using multivariable logistic regression models (MVA). RESULTS: Overall, 12 vs 14 vs 6% (n = 176 vs 227 vs 96) downgrading rates were recorded in group 1 vs group 2 vs group 3, respectively (p < 0.001). At MVA, group 2 was more likely to be downgraded (OR 1.26, p = 0.04), as compared to group 1. Conversely, group 3 was less likely to be downgraded at RP (OR 0.42, p < 0.001). CONCLUSIONS: Downgrading rates are highest when PCa is present in TBx only and, especially when the highest grade PCa is diagnosed by TBx cores only. Conversely, downgrading rates are lowest when PCa is identified with the same ISUP through both SBx and TBx. The presence of clinically significant disease at SBx + TBx may indicate a more reliable assessment of the disease at the time of biopsy potentially reducing the risk of downgrading at final pathology.

Is it possible to identify the inguinal nerves during hernioplasty? A systematic review of the literature and meta-analysis of cadaveric and surgical studies.

PURPOSE: Patients who undergo inguinal hernioplasty may suffer from persistent postoperative pain due to inguinal nerve injuries. The aim of this systematic review and meta-analysis was to provide comprehensive data on the prevalence (identification rates), anatomical characteristics, and ethnic variations of the ilioinguinal (IIN), the iliohypogastric (IHN) and the genital branch of the genitofemoral (GNF) nerves. METHODS: The systematic literature search was conducted using the PubMed, Scopus and Web of Science databases. RESULTS: A total of 26 articles (5265 half-body examinations) were included in this study. The identification rate of the IIN was 94.4% (95% CI 89.5-97.9) using a random-effects model. Unweighted multiple regression analysis showed that study sample size (ß = - 0.74, p = .036) was the only statistically significant predictor of lower prevalence. The identification rates of the IHN and GNF was 86.7% (95% CI 78.3%-93.3%) and 69.1% (95% CI 53.1%-83.0%) using a random-effects model, respectively. For those outcomes, a visual analysis of funnel and Doi plots indicated irregularity and provided evidence that larger studies tended to have lower identification rates. In terms of the synthesis of anatomical reference points, there was a large and statistically significant amount of heterogeneity for most outcomes. CONCLUSIONS: The identification rates of the inguinal nerves in our study were lower than reported in literature. The lowest was found for GNF, suggesting that this nerve was the most difficult to identify. Knowledge regarding the anatomy of the inguinal nerves can facilitate their proper identification and reduce the risk of iatrogenic injury and postoperative pain.

Long term effects of cigarette smoke extract or nicotine on nerve growth factor and its receptors in a bronchial epithelial cell line.

Long-term exposure to cigarette smoke induces severe injuries to respiratory system through several mechanisms, some of them are well defined, but many others are not yet elucidated. Beside its classical role in nervous system, we have previously shown that Nerve Growth Factor (NGF) and its receptors have a crucial role in airway inflammatory diseases, such as Chronic Obstructive Pulmonary Disease. To expand our knowledge about the relevance of NGF and its receptors in airway diseases induced by cigarette smoking, we exposed for 16 weeks the bronchial epithelial cell line BEAS-2B to sub-toxic concentrations of whole cigarette smoke extract or pure nicotine. Viability, cell cycle gene expression, cell morphology and migration ability were tested and compared to NGF release and gene expression. Modulation of its receptors TrKA and p75NTR was also analyzed. The present study shows that long term exposure of BEAS-2B cells to cigarette smoke extract or nicotine induces: (A) differences: in cell viability, in the expression of cell cycle-related genes, in NGF release and in gene expression of NGF and its receptors; (B) similarities: in morphology and migration ability. Taken together, our data provide new insights about the biological role of NGF and its receptors in airway diseases induced by long-term cigarette smoking and, finally, our data evidence the opportunity not to use nicotine lozenges or e-cigarettes as anti smoking replacement therapy in patients with a previous airway disease according to the ability of nicotine to increase the amount of the pro-inflammatory cytokine NGF into the bronchial environment.

Insemination extender supplementation with bestatin and EDTA has no effect on rabbit reproductive performance.

The addition of aminopeptidase inhibitors (AMIs) to rabbit semen extenders could be a solution to decrease the hormone degradation (GnRH) by the aminopeptidases existing in the seminal plasma. Therefore, the quantity of GnRH needed to induce ovulation in doe would be comparable with the amount administered intramuscularly (i.m.). This study was conducted to evaluate the effects of two AMIs (bestatin and EDTA) on rabbit semen quality parameters, ß nerve growth factor (ß-NGF) degradation and reproductive performance after artificial insemination. Results showed that seminal quality was not affected by the incubation with AMIs; the values of motility, acrosome integrity and sperm viability were not significantly different between the AMIs and the control groups (positive i.m. and negative intravaginally without AMIs). In addition, the aminopeptidase activity of seminal plasma was inhibited in a 55.5% by the AMIs as well as ß-NGF degradation. On the other hand, regarding the effect of AMIs on reproductive performance, our results showed that the presence of bestatin and EDTA did neither affect fertility (85.3 vs. 88.6%), nor the prolificacy rate (10.12 vs. 10.51 kits per delivery), comparing AMIs group to positive control group, respectively. We conclude that the addition of specific AMIs in the rabbit semen extender has no effect on reproductive performance. Therefore, due to the fact that AMIs inhibit part of the aminopeptidase activity that degrades the GnRH analogue and ß-NGF, they could be used to develop new extenders with less hormone concentration.

Long-term penile morphometric alterations in patients treated with robot-assisted versus open radical prostatectomy.

Neglected side effects after radical prostatectomy have been previously reported. In this context, the prevalence of penile morphometric alterations has never been assessed in robot-assisted radical prostatectomy series. We aimed to assess prevalence of and predictors of penile morphometric alterations (i.e. penile shortening or penile morphometric deformation) at long-term follow-up in patients submitted to either robot-assisted (robot-assisted radical prostatectomy) or open radical prostatectomy. Sexually active patients after either robot-assisted radical prostatectomy or open radical prostatectomy prospectively completed a 28-item questionnaire, with sensitive issues regarding sexual function, namely orgasmic functioning, climacturia and changes in morphometric characteristics of the penis. Only patients with a post-operative follow-up ≥ 24 months were included. Patients submitted to either adjuvant or salvage therapies or those who refused to comprehensively complete the questionnaire were excluded from the analyses. A propensity-score matching analysis was implemented to control for baseline differences between groups. Logistic regression models tested potential predictors of penile morphometric alterations at long-term post-operative follow-up. Overall, 67 (50%) and 67 (50%) patients were included after open radical prostatectomy or robot-assisted radical prostatectomy, respectively. Self-rated post-operative penile shortening and penile morphometric deformation were reported by 75 (56%) and 29 (22.8%) patients, respectively. Rates of penile shortening and penile morphometric deformation were not different after open radical prostatectomy and robot-assisted radical prostatectomy [all p > 0.5]. At univariable analysis, self-reported penile morphometric alterations (either penile shortening or penile morphometric deformation) were significantly associated with baseline international index of erectile function-erectile function scores, body mass index, post-operative erectile function recovery, year of surgery and type of surgery (all p < 0.05). At multivariable analysis, robot-assisted radical prostatectomy was independently associated with a lower risk of post-operative penile morphometric alterations (OR: 0.38; 95% CI: 0.16-0.93). Self-perceived penile morphometric alterations were reported in one of two patients after radical prostatectomy at long-term follow-up, with open surgery associated with a potential higher risk of this self-perception.

Glycaemic variability in patients with severe sepsis or septic shock admitted to an Intensive Care Unit.

BACKGROUND: Sepsis is associated with morbidity and mortality, which implies high costs to the global health system. Metabolic alterations that increase glycaemia and glycaemic variability occur during sepsis. OBJECTIVE: To verify mean body glucose levels and glycaemic variability in Intensive Care Unit (ICU) patients with severe sepsis or septic shock. METHOD: Retrospective and exploratory study that involved collection of patients' sociodemographic and clinical data and calculation of severity scores. Glycaemia measurements helped to determine glycaemic variability through standard deviation and mean amplitude of glycaemic excursions. RESULTS: Analysis of 116 medical charts and 6730 glycaemia measurements revealed that the majority of patients were male and aged over 60 years. Surgical treatment was the main reason for ICU admission. High blood pressure and diabetes mellitus were the most usual comorbidities. Patients that died during the ICU stay presented the highest SOFA scores and mean glycaemia; they also experienced more hypoglycaemia events. Patients with diabetes had higher mean glycaemia, evaluated through standard deviation and mean amplitude of glycaemia excursions. CONCLUSION: Organic impairment at ICU admission may underlie glycaemic variability and lead to a less favourable outcome. High glycaemic variability in patients with diabetes indicates that monitoring of these individuals is crucial to ensure better outcomes.

Differential Role of Neurohypophysial Hormones in Hypotension and Nitric Oxide Production During Endotoxaemia.

Besides their well-established endocrine roles, vasopressin and oxytocin are also important regulators of immune function, participating in a complex neuroendocrine-immune network. In the present study, we investigated whether and how vasopressin and oxytocin could modulate lipopolysaccharide (LPS)-induced nitric oxide (NO) production in a well-established model of experimental endotoxaemia. Male Wistar rats were previously treated i.v. with vasopressin V1 or oxytocin receptor antagonists and then received either an i.v. LPS injection to induce endotoxaemia or a saline imjection as a control. The animals were divided into two groups: in the first group, blood was collected at 2, 4 and 6 h after LPS injection; in the second group, mean arterial blood pressure (MABP) and heart rate (HR) were recorded over 6 h. Plasma vasopressin and oxytocin values were higher in LPS- compared to saline-injected animals at 2 and 4 h but returned to basal levels at 6 h. NO levels exhibited an opposite pattern, showing a progressive increase over the entire period. The previous administration of a vasopressin V1 receptor antagonist significantly reduced NO plasma concentrations at 2 and 4 h but not at 6 h. By contrast, oxytocin receptor agonist pre-treatment had no effect on the NO plasma concentration. In relation to MABP, previous treatment with vasopressin V1 receptor antagonist reversed the LPS-induced hypotension at 4 h, although this was not the case for oxytocin antagonist-treated animals. None of the antagonists affected HR. Our findings indicate that vasopressin (but not oxytocin) has effects on NO production during endotoxaemia in rats, although they do not lend support to the proposed anti-inflammatory actions of vasopressin during endotoxaemia.

Gene Expression and Localization of NGF and Its Cognate Receptors NTRK1 and NGFR in the Sex Organs of Male Rabbits.

Experiments were devised to characterize the expression of nerve growth factor, beta polypeptide (NGF), and its cognate receptors neurotrophic tyrosine kinase receptor type 1 (NTRK1) and nerve growth factor receptor (NGFR) in rabbit male sex organs, as well as the concentrations of NGF in both seminal and blood plasma of sexually mature male rabbits. Immunoreactivity and gene expression for NGF and cognate receptors were detected in testis, prostate gland and seminal vesicle. The highest levels of NGF and NTRK1 transcripts were found in the prostate, while intermediate expressions were found in the testis. NGFR transcripts were expressed at the same levels in both testis and prostate and were more abundant than in seminal vesicles. The widespread distribution of NGF in all prostate glandular cells, together with its relative high mRNA abundance, confirms that the prostate of rabbits is the main source of this neurotrophin. In conclusion, the present data suggest that the NGF system is involved in the testicular development and spermatogenesis of rabbits and that NGF may act as a potential ovulation-inducing factor being abundantly present in the seminal plasma.

Primary PCI for the treatment of ectatic infarct-related coronary artery.

AIM: There is lack of information on the outcome of patients treated with primary angioplasty for lesions located in an ectatic coronary artery segment in the setting of acute myocardial infarction. The aim of this study was to analyse the 2-year follow-up of this specific patient population. METHODS: By means of a systematic review of the databases and cine-films of 5912 primary angioplasties performed in eight Italian cardiac centers we identified 101 patients with infarct-related coronary artery ectasia. Ectasia was defined as a dilatation exceeding the 1.5-fold of normal adjacent segment and was classified according to its severity. The primary end point was the composite rate of cardiac death, recurrence of acute myocardial infarction and a new revascularisation at 2-year. RESULTS: The procedure was successful in 70.3% of cases, unsuccessful or complicated in 29.7%. The primary endpoint was met in 6.9% of cases during hospitalization (95% CI: 2.0-11.8), in 17.8% (95% CI: 10.3-25.3) at 1 year, and in 38.5% (95% CI: 29.0-48.0) at 2 years. Nine patients had a stent thrombosis: 3 acute and 6 sub-acute. A statistically significant correlation between the dimensions of the stent and stent thrombosis was observed (P=0.005). CONCLUSION: In subjects undergoing primary angioplasty for acute myocardial infarction the rate of patients treated on lesions located in an ectatic coronary artery segment is very small (1.7%). The procedural success was low, whereas the rate of events at follow-up was quit high reflecting the complexity of this disease.

Celecoxib treatment does not alter recruitment and activation of osteoclasts in the initial phase of experimental tooth movement.

In a previous study, we reported that the short-term treatment with celecoxib, a non-steroidal anti-inflammatory drug (NSAID) attenuates the activation of brain structures related to nociception and does not interfere with orthodontic incisor separation in rats. The conclusion was that celecoxib could possibly be prescribed for pain in orthodontic patients. However, we did not analyze the effects of this drug in periodontium. The aim of this follow-up study was to analyze effects of celecoxib treatment on recruitment and activation of osteoclasts and alveolar bone resorption after inserting an activated orthodontic appliance between the incisors in our rat model. Twenty rats (400-420 g) were pretreated through oral gavage with celecoxib (50 mg/kg) or vehicle (carboxymethylcellulose 0.4%). After 30 min, they received an activated (30 g) orthodontic appliance, set not to cause any palate disjunction. In sham animals, the appliance was immediately removed after introduction. All animals received ground food and, every 12 h, celecoxib or vehicle. After 48 h, they were anesthetized and transcardiacally perfused through the aorta with 4% formaldehyde. Subsequently, maxillae were removed, post-fixed and processed for histomorphometry or immunohistochemical analyses. As expected, incisor distalization induced an inflammatory response with certain histological changes, including an increase in the number of active osteoclasts at the compression side in group treated with vehicle (appliance: 32.2 ± 2.49 vs sham: 4.8 ± 1.79, P<0.05) and celecoxib (appliance: 31.0 ± 1.45 vs sham: 4.6 ± 1.82, P<0.05). The treatment with celecoxib did not modify substantially the histological alterations and the number of active osteoclasts after activation of orthodontic appliance. Moreover, we did not see any difference between the groups with respect to percentage of bone resorption area. Taken together with our previous results we conclude that short-term treatment with celecoxib can indeed be a therapeutic alternative for pain relieve during orthodontic procedures.

Moxonidine improves cardiac structure and performance in SHR through inhibition of cytokines, p38 MAPK and Akt.

BACKGROUND AND PURPOSE: Regression of left ventricular hypertrophy by moxonidine, a centrally acting sympatholytic imidazoline compound, results from a sustained reduction of DNA synthesis and transient stimulation of DNA fragmentation. Because apoptosis of cardiomyocytes may lead to contractile dysfunction, we investigated in spontaneously hypertensive rats (SHR), time- and dose-dependent effects of in vivo moxonidine treatment on cardiac structure and function as well as on the inflammatory process and signalling proteins involved in cardiac cell survival/death. EXPERIMENTAL APPROACH: 12 week old SHR received moxonidine at 0, 100 and 400 µg·kg(-1)·h(-1) , s.c., for 1 and 4 weeks. Cardiac function was evaluated by echocardiography; plasma cytokines were measured by elisa and hearts were collected for histological assessment of fibrosis and measurement of cardiac proteins by Western blotting. Direct effects of moxonidine on cardiac cell death and underlying mechanisms were investigated in vitro by flow cytometry and Western blotting. KEY RESULTS: After 4 weeks, the sub-hypotensive dose of moxonidine (100 µg) reduced heart rate and improved global cardiac performance, reduced collagen deposition, regressed left ventricular hypertrophy, inhibited Akt and p38 MAPK phosphorylation, and attenuated circulating and cardiac cytokines. The 400 µg dose resulted in similar effects but of a greater magnitude, associated with blood pressure reduction. In vitro, moxonidine inhibited norepinephrine-induced neonatal cardiomyocyte mortality but increased fibroblast mortality, through I(1)-receptor activation and differential effects on downstream Akt and p38 MAPK. CONCLUSIONS AND IMPLICATIONS: While the antihypertensive action of centrally acting imidazoline compounds is appreciated, new cardiac-selective I(1)-receptor agonists may confer additional benefit.

Tuberculin skin testing in HIV-infected patients in Campo Grande, Mato Grosso do Sul State, Brazil

A cross-sectional study on HIV/AIDS was carried out in 108 outpatients from the university hospital of the Federal University of Mato Grosso do Sul, Campo Grande, Brazil, from July to December 2008, to investigate latent tuberculosis infection using the tuberculin skin test (TST). The prevalence of positive results was 13.9 percent. The CD4+ T cell count (p = 0.091) and the diagnosis time (p = 0.010) were statistically significant when compared with TST positivity. In the cohort of HIV/AIDS patients who had latent tuberculosis infection, the median diagnosis time was eight years. Undetectable viral load presented significant association (p = 0.046) with tuberculosis infection. The fact that numerous individuals with HIV/AIDS infection presented a negative reaction to the tuberculin skin test is probably related to alterations in the cellular immune response induced by HIV infection. The tuberculin test is a useful tool for the detection of latent tuberculosis infection and should be performed in all HIV/AIDS individuals at the time of the diagnosis and on a yearly basis, if negative. Both the early identification of the tuberculosis infection by the tuberculin skin test at the moment of immunological restoration and chemoprophylaxis in infected individuals are mechanisms to control HIV/AIDS and tuberculosis coinfection.

Effects of short-term acetaminophen and celecoxib treatment on orthodontic tooth movement and neuronal activation in rat.

Non-steroidal anti-inflammatory drugs (NSAIDs) have been used for pain relief in orthodontics, but clinical studies reported that they may reduce tooth movement (TM). By other side, TM seems to activate brain structures related to nociception, but the effects of NSAIDs in this activation have not been studied yet. We analyzed the effect of short-term treatment with acetaminophen or celecoxib in the separation of rat upper incisors, as well as in neuronal activation of the spinal trigeminal nucleus, following tooth movement. Thirty rats (400-420 g) were pretreated through oral gavage (1 ml/dose) with acetaminophen (200mg/kg), celecoxib (50mg/kg) or vehicle (carboxymethylcellulose 0.4%). After 30 min, they received an activated (30 g) orthodontic appliance for TM. In controls, this appliance was immediately removed after its introduction. Rats received ground food, and every 12h, one of the drugs or vehicle. After 48 h, they were anesthetized, maxilla was radiographed, and were perfused with 4% paraformaldehyde. Brains were further processed for Fos immunohistochemistry. TM induced incisor distalization (p<0.05) and neuronal activation of the spinal trigeminal nucleus. Treatment with both drugs did not affect tooth movement, but reduced c-fos expression in the caudalis subnucleus. No changes in c-fos expression were seen in the oralis and interpolaris subnuclei. We conclude that neither celecoxib nor acetaminophen seems to affect tooth movement, when used for 2 days, but both drugs are able to reduce the activation of brain structures related to nociception. Short-term treatment with celecoxib, thus, may be a therapeutic alternative to acetaminophen when the latter is contraindicated.

Rapid maxillary expansion causes neuronal activation in brain structures of rats.

A correlation between pain sensation and neuronal c-fos expression has been analyzed following experimental rapid maxillar expansion (RME). Adult male Wistar rats were anaesthetized and divided into three groups: animals that received an orthodontic apparatus, which was immediately removed after the insertion (control), animals that received an inactivated orthodontic apparatus (without force), and animals that received an orthodontic apparatus previously activated (140 g force). After 6, 24, 48, or 72 h, the animals were re-anaesthetized, and perfused with 4% paraformaldehyde. The brains were removed, fixed, and sections containing brain structures related to nociception were processed for Fos protein immunohistochemistry (IHC). The insertion of the orthodontic apparatus with 140 g was able to cause RME that could be seen by radiography. The IHC results showed that the number of activated neurons in the different nuclei changed according to the duration of appliance insertion and followed a temporal pattern similar to that of sensations described in clinics. The animals that received the orthodontic apparatus without force did not show RME but a smaller c-fos expression in the same brain structures. In conclusion, we demonstrate that orthodontic force used for palate disjunction activates brain structures that are related to nociception, and that this activation is related to the pain sensation described during orthodontic treatment.

Anti-phospholipid syndrome: clinical spectrum and therapeutical/prophylactic strategies in the pediatric population.

Anti-phospholipid syndrome (APS) is a potentially life-threatening autoimmune condition characterized by the presence of anti-phospholipid antibodies (aPL) giving rise to increased hypercoagulability, which induces venous or arterial thrombotic events at whatever age and recurrent fetal loss in the fertile age. Antigens that are targeted by aPL include cardiolipin and beta2-glycoprotein I. Primary APS is defined in the absence of an underlying disease, while secondary APS is observed in the context of another established pathological condition. APS has a wide variety of clinical signs and serological characteristics. This paper describes the current approaches towards diagnosis, therapeutic modalities and secondary prevention applied to children.

Role of dexamethasone on vasopressin release during endotoxemic shock.

The present study was designed to assess the hypothesis that dexamethasone (DEX) through the control of nitric oxide (NO) synthesis could regulate the release of vasopressin (AVP), which plays an important role in the regulation of arterial pressure and plasma osmolality. Endotoxemic shock was induced by intravenous (i.v.) injection of 1.5 mg/kg lipopolisaccharide (LPS) in male Wistar rats weighing 250-300 g. After LPS administration, a group of animals were treated with DEX (1.0 mg/kg of body weight), whereas saline-injected rats served as controls. The LPS administration induced a significant decrease in mean arterial pressure (MAP) with a concomitant increase in heart rate (HR) (Delta VMAP: -16.1+/-4.2 mm Hg; Delta VHR: 47.3+/-8.1 bpm). An increase in plasma AVP concentration occurred and was present for 2 h after LPS administration (11.1+/-0.9 pg/mL) returning close to basal levels thereafter and remaining unchanged until the end of the experiment. When LPS was combined with i.v. administration of a low dose of DEX, we observed an attenuation in the drop of MAP (Delta VMAP: -2.2+/-1.9 mm Hg) and a decrease in NO plasma concentration [NO] after LPS administration (1098.1+/-68.1 microM) compared to [NO] after DEX administration (523.4+/-75.2 microM). However, this attenuation in the drop of MAP was accompanied by a decrease in AVP plasma concentration (3.7+/-0.4 pg/mL). These data suggest that AVP does not participate in the recovery of MAP when DEX is administered in this endotoxemic shock model.

[Identification of candidate genes and expression profiles, as doping biomarkers]. / Individuazione di geni candidati e profili d'espressione, come indicatori molecolari di assunzione di sostanze dopanti.

Administration of prohibited substances to enhance athletic performance represents an emerging medical, social, ethical and legal issue. Traditional controls are based on direct detection of substances or their catabolites. However out-of-competition doping may not be easily revealed by standard analytical methods. Alternative indirect control strategies are based on the evaluation of mid- and long-term effects of doping in tissues. Drug-induced long-lasting changes of gene expression may be taken as effective indicators of doping exposure. To validate this approach, we used real-time PCR to monitor the expression pattern of selected genes in human haematopoietic cells exposed to nandrolone, insulin-like growth factor I (IGF-I) or growth hormone (GH). Some candidate genes were found significantly and consistently modulated by treatments. Nandrolone up-regulated AR, ESR2 and PGR in K562 cells, and SRD5A1, PPARA and JAK2 in Jurkat cells; IGF-I up-regulated EPOR and PGR in HL60 cells, and SRD5A1 in Jurkat; GH up-regulated SRD5A1 and GHR in K562. GATA1 expression was down-regulated in IGF-1-treated HL60, ESR2 was down-regulated in nandrolone-treated Jurkat, and AR and PGR were down-regulated in GH-treated Jurkat. This pilot study shows the potential of molecular biology-based strategies in anti-doping controls.

Serum macrophage migration inhibitory factor (MIF) in the intercritical phase of hereditary periodic fevers and its relationship with the MIF-173G/C polymorphism.

OBJECTIVES: To examine the association of the -173 single-nucleotide G/C polymorphism of the macrophage migration inhibitory factor gene (MIF) and serum macrophage migration inhibitory factor (MIF) concentrations in a group of Italian patients with hereditary periodic fevers (HPF), tested during a symptom-free phase of their disease. METHODS: Genomic DNA for MIF and serum MIF were evaluated in 22 patients with HPF and compared with healthy controls of the same ethnic group. The MIF-173G/C polymorphism was genotyped using polymerase chain reaction (PCR) and visualized by ethidium bromide staining. Serum MIF levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: MIF-173*C allele frequency and MIF serum concentrations were significantly higher in patients with HPF than in controls, with no statistically significant difference between familial Mediterranean fever (FMF) and hyperimmunoglobulinaemia D/periodic fever syndrome (HIDS) and no correlation with specific MIF genotypes. CONCLUSIONS: The MIF-173*C allele was found more frequently in patients with HPF than in controls and MIF serum concentrations were considerably elevated in attack-free phases, suggesting a persistent state of subclinical cytokine activation with MIF involvement in the autoinflammatory cascade.