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.

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.

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.

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.

[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.

The multi-face expression of familial Mediterranean fever in the child.

Familial Mediterranean fever (FMF) is characterized by recurrent self-limiting flares of fever in the absence of pathogens, autoantibodies or antigen specific T cells and is inherited as an autosomal recessive trait probably deriving from common ancestors of Armenian, Jew, Turk and Arab origin. The underlying pathogenetic mechanisms of FMF have not been fully interpreted, but mutations in the gene MEFV encoding pyrin, a natural repressor of proinflammatory molecules, result in uncontrolled relapsing systemic inflammation, increased leukocyte migration to serosal membranes or joints and inappropriate response to inflammatory stimuli. FMF heterogeneous phenotypic expression could originate both from allelic heterogeneity or from the existence of modulating genes. Proper diagnosis of FMF is needed to begin both specific clinical management and treatment based on continuous prophylactic administration of colchicine, preventing flares or at least the onset of amyloidosis.

The pharmacologic basis of treatment with colchicine in children with familial Mediterranean fever.

Familial Mediterranean fever (FMF) is the prototype of auto-inflammatory disorders and is ethnically restricted to people living in the Mediterranean basin and Middle-East. Pyrin, the protein product of the FMF gene, expressed in myeloid cells and fibroblasts, interacts with the cytoskeletal machinery and may modulate leukocyte effector functions. At present colchicine, an alkaloid with antimitotic activity interfering with microtubule formation, which has been used to alleviate acute gout, is the only available drug for patients with FMF to prevent both acute attacks and long-term complications such as amyloidosis. The anti-inflammatory effect of colchicine may be mediated not only through direct interaction with microtubules, but also through changes at the transcriptional level influencing cell cycle regulation and leukocyte migration. Gastrointestinal side effects may occur early and are the most frequent manifestations of colchicine toxicity in children, whilst multiple organ failure is very rarely reported as overdosage expression.

The clinical spectrum and treatment options of macrophage activation syndrome in the pediatric age.

Macrophage activation syndrome is a rare and potentially fatal complication of many childhood pathological settings, most frequently reported in systemic onset-juvenile idiopathic arthritis. The disruption of the macrophage-lymphocyte interaction leads to uncontrolled proliferation of highly activated macrophages and T lymphocytes. The syndrome comprises a heterogeneous group of disorders featuring sepsis-like characteristics typically combined with impaired function of natural killer cells and cytotoxic T-cells, haemophagocytosis and hypercytokinemia, often resulting in fatal multiple organ failure. The clinical picture shows high grade fever, hepatosplenomegaly, pancytopenia, lymphoadenopathy, central nervous system involvement and consumptive coagulopathy. Macrophage activation syndrome is associated with high mortality: even though diagnostic criteria have been proposed, definite diagnosis can be a challenge for clinicians, especially in early phases. There is no standardized therapeutic protocol for macrophage activation syndrome, but it is widely recognized that aggressive treatment strategies might strongly influence prognosis. First line-therapy is usually represented by parenteral administration of high dose-corticosteroids, whilst cyclosporine is added in the steroid-resistant cases. In this paper we provide clinical clues and summarize the most recent studies about pathophysiology and management suggestions for macrophage activation syndrome.

Diagnostic clues in the idiopathic pulmonary fibrosis of children.

Idiopathic pulmonary fibrosis (IPF) in children is a heterogeneous group of progressive disorders characterized by variable extents of inflammation and interstitial deposition of collagen fibers with numerous putative triggers. Children affected with this condition show breathlessness, non-productive cough and bibasilar/inspiratory dry rales. Diagnosis can be obtained by the exclusion of all known causes of fibrosing alveolitis such as neoplasms, toxic treatments, collagen vascular diseases, occupational exposure or granulomatous diseases.

[Risk factors conditioning the incidence and severity of cyclosporine A-induced gingival overgrowth and methods of prevention]. / Fattori condizionanti l'incidenza e la severità dell'ipertrofia gengivale indotta da ciclosporina A e possibilità di prevenzione.

Cyclosporin A (CsA) induced gingival overgrowth is one of the major side-effects conditioning the quality of life of the patient under immunosuppressive therapy. This adverse effect has been first reported in 1983 and affects almost 30% of treated patients. Several papers have been published concerning the cellular/molecular mechanisms by which CsA may induce, at the same time, an immunosuppressive and proliferative action. In this review various factors concerning the patient and his milieu that account for the different prevalence of the severity of gingival overgrowth in clinical studies are analyzed and briefly discussed. In particular, age, sex, pharmacokinetic properties, pharmaceutical preparation, genetic predisposition, association with other drugs and the parodontal conditions before transplantation are considered. In addition, a unique approach to the patients with gingival overgrowth as well as effective methods of prevention and therapy are suggested.

Etanercept induces improvement of arthropathy in chronic infantile neurological cutaneous articular (CINCA) syndrome.

Chronic infantile neurological cutaneous articular (CINCA) syndrome is a rare disorder of unknown aetiology with neonatal onset, characterized by severe arthropathy, persistent skin rash and central nervous system disease. Joint involvement may vary from minimal swelling to destructive arthritis, with inability to stand or walk. The most striking findings of CINCA syndrome are cartilage anomalies with epiphyseal modifications and abnormal ossification, for which a pathogenetic role of tumour necrosis factor-alpha (TNF-alpha) is postulated. We describe a 4-year-old child affected with CINCA syndrome and presenting progressive joint disease, in whom non-steroidal anti-inflammatory drugs (NSAID) and systemic corticosteroidal therapy had been ineffective. Etanercept, anti-TNF-alpha therapy, was administered over a 6-month-period resulting in a dramatic improvement of the arthropathy. This good response to anti-cytokine treatment supports our hypothesis that TNF-alpha might play an important role in the pathogenesis of CINCA syndrome, which needs to be evaluated and confirmed in further studies.

Systemic thrombin generation in cancer patients is correlated with extrinsic pathway activation.

Since the first report by Trousseau in 1865, several experimental and clinical studies have established that activation of coagulation is common in cancer. However, the biochemical basis of the activation of coagulation in cancer patients is still not completely understood. The current most accepted opinion is that initiation of coagulation in malignancy is driven primarily by activation of the extrinsic (tissue factor-dependent) pathway. In order to further prove that such a pathogenetic mechanism is actually involved in cancer patients, we correlated the plasma levels of activated factor VIIa (FVIIa), which represent a very small fraction of plasma FVII, with some well-established markers of systemic thrombin generation. Circulating FVIIa was measured using a prothrombin time-based assay that employs a truncated form of human recombinant tissue factor, while plasma levels of the thrombin-antithrombin complex, the prothrombin fragments 1 + 2 and D-dimer were determined by commercially available ELISA kits. The study was carried out in 37 patients with different types of cancer and 20 healthy controls. Plasma levels of FVIIa were significantly increased while those of FVII antigen (FVIIag) were decreased in cancer patients compared with controls. Furthermore, the FVIIa/ VIIag ratio was more than two-fold higher in cancer patients than in controls. In addition, an excess of thrombin generation was observed in cancer patients. Interestingly, a positive correlation between the FVIIa/VIIag ratio and the plasma levels of either D-dimer (Spearman's r = 0.325; P = 0.027) or prothrombin fragments 1 + 2 (r = 0.309; P = 0.034) was observed in cancer patients. In conclusion, our study further supports the hypothesis that the tissue factor/VIIa complex is the main determinant of coagulation activation in cancer patients. Large clinical studies will be necessary to determine whether FVIIa and the FVIIa/VIIag ratio are useful prognostic factors of thromboembolic events in cancer patients.