Plasma pentraxin 3 in idiopathic inflammatory myopathies: a possible new biomarker of disease activity.

Pentraxin-3 (PTX3) is a component of humoral innate immunity with essential functions both in promotion and resolution of inflammation. We aimed to study the PTX3 in the plasma and in the muscle of patients with idiopathic inflammatory myopathies (IIM) and whether PTX3 may correlate with disease activity. Plasma PTX3 levels were assessed in 20 patients with IIMs, 10 dermatomyositis (DM), and 10 polymyositis (PM), compared to 10 patients with rheumatoid arthritis (RA) and 10 healthy donors (HDs) aged, sex, and body mass index matched. Disease activity in IIMs was assessed by Myositis Disease Activity Assessment Visual Analog Scale (MYOACT), while disease activity score on 28 joints (DAS28) was used for RA patients. Muscle histopathology and immunohistochemical (IHC) analyses were also performed. Mean plasma PTX3 levels were significantly higher in IIM patients than HDs (518 ± 260 pg/ml vs. 275 ± 114 pg/ml, P = 0.009). Linear regression analysis adjusted for age, sex, and disease duration showed a direct correlation between PTX3 and CPK levels (ß: 0.590), MYOACT (ß: 0.759), and physician global assessment of disease activity (ß: 0.832) in IIMs. No association between PTX3 levels and DAS28 was found in RA. Global PTX3 pixel fraction was higher in IIM than HDs muscle, but a lower PTX3 expression was found in perifascicular areas of DM and in myofibers with sarcolemmal staining for membrane attack complement. PTX3 plasma levels were increased in IIMs and correlated with disease activity suggesting a possible role as biomarker of disease activity. PTX3 showed a different distribution in DM or PM muscle.

Occult HBV infection may negatively impact on drug survival in patients with rheumatoid arthritis on treatment with a first biologic drug. An appraisal from the Biologic Apulian Registry (BIOPURE).

We performed a retrospective analysis to evaluate the survival on first line biologic drug of rheumatoid arthritis (RA) patients with potential occult HBV infection (pOBI). We analysed longitudinal data of 486 consecutive RA patients starting a first biological drug in a time frame from 1st January 2008 to 31st December 2014. Demographic and disease related characteristics were collected at baseline and at the last observation visit. Baseline serological markers of HBV infection and causes of treatment discontinuation were also recorded. Primary endpoint was the influence of pOBI on drug survival, estimated by Kaplan-Meier life table analysis. Estimates hazard ratios (HRs) of drug discontinuation, adjusted for disease characteristics, biological drug class and HBcAb status were computed by Cox-regression models. The retention rate was significantly lower in pOBI positive patients (58.2%) when compared to pOBI negative ones (67.8%) and this data was confirmed also when only discontinuation due to ineffectiveness was considered (pOBI positive 66.4% vs pOBI negative 75.3%, long rank 7.93, p=0.005). Cox regression models showed a significant association between HBcAb-neg (HR 0.58, 0.41-0.84), higher ESR-DAS28 at baseline (HR 1.07, 1.03-1.11) or RF/ACPA-neg (HR 1.46, 1.04-2.06) and drug discontinuation. Occult HBV infection seems to influence negatively the effectiveness of biological therapies in RA patients.

Depression and pain: primary data and meta-analysis among 237 952 people across 47 low- and middle-income countries.

BACKGROUND: Depression and pain are leading causes of global disability. However, there is a paucity of multinational population data assessing the association between depression and pain, particularly among low- and middle-income countries (LMICs) where both are common. Therefore, we investigated this association across 47 LMICs. METHODS: Community-based data on 273 952 individuals from 47 LMICs were analysed. Multivariable logistic and linear regression analyses were performed to assess the association between the International Classification of Diseases, 10th Revision depression/depression subtypes (over the past 12 months) and pain in the previous 30 days based on self-reported data. Country-wide meta-analysis adjusting for age and sex was also conducted. RESULTS: The prevalence of severe pain was 8.0, 28.2, 20.2, and 34.0% for no depression, subsyndromal depression, brief depressive episode, and depressive episode, respectively. Logistic regression adjusted for socio-demographic variables, anxiety and chronic medical conditions (arthritis, diabetes, angina, asthma) demonstrated that compared with no depression, subsyndromal depression, brief depressive episode, and depressive episode were associated with a 2.16 [95% confidence interval (CI) 1.83-2.55], 1.45 (95% CI 1.22-1.73), and 2.11 (95% CI 1.87-2.39) increase in odds of severe pain, respectively. Similar results were obtained when a continuous pain scale was used as the outcome. Depression was significantly associated with severe pain in 44/47 countries with a pooled odds ratio of 3.93 (95% CI 3.54-4.37). CONCLUSION: Depression and severe pain are highly comorbid across LMICs, independent of anxiety and chronic medical conditions. Whether depression treatment or pain management in patients with comorbid pain and depression leads to better clinical outcome is an area for future research.

Does the "Silver Bullet" Lose its Shine Over the Time? Assessment of Loss of Lithium Response in a Preliminary Sample of Bipolar Disorder Outpatients.

BACKGROUND: Though often perceived as a "silver bullet" treatment for bipolar disorder (BD), lithium has seldom reported to lose its efficacy over the time. OBJECTIVE: The aim of the present study was to assess cases of refractoriness toward restarted lithium in BD patients who failed to preserve maintenance. METHOD: Treatment trajectories associated with re-instituted lithium following loss of achieved lithium-based maintenance in BD were retrospectively reviewed for 37 BD-I patients (median age 52 years; F:M=17:20 or 46% of the total) over an 8.1-month period on average. RESULTS: In our sample only 4 cases (roughly 11% of the total, of whom F:M=2:2) developed refractoriness towards lithium after its discontinuation. Thirty-three controls (F:M=15:18) maintained lithium response at the time of re-institution. No statistically significant difference between cases and controls was observed with respect to a number of demographic and clinical features but for time spent before first trial ever with lithium in life (8.5 vs. 3 years; U=24.5, Z=-2.048, p=.041) and length of lithium discontinuation until new therapeutic attempt (5.5 vs. 2 years; U=8, Z=-2.927, p=.003) between cases vs. controls respectively. Tapering off of lithium was significantly faster among cases vs. controls (1 vs. 7 days; U=22, Z=-2.187), though both subgroups had worrisome high rates of poor adherence overall. CONCLUSION: Although intrinsic limitations of the present preliminary assessment hamper the validity and generalizability of overall results, stating the clinical relevance of the topic further prospective research is warranted. The eventual occurrence of lithium refractoriness may indeed be associated with peculiar course trajectories and therapeutic outcomes ultimately urging the prescribing clinicians to put efforts in preserving maintenance of BD in the absence of any conclusive research insight on the matter.

Matrix metalloproteinase (MMP)-2 and MMP-9 as inflammation markers of Trichinella spiralis and Trichinella pseudospiralis infections in mice.

Trichinella spiralis and Trichinella pseudospiralis exhibit differences in the host-parasite relationship such as the inflammatory response in parasitized muscles. Several studies indicate that matrix metalloproteinases (MMPs) represent a marker of inflammation since they regulate inflammation and immunity. The aim of this study was to evaluate the serum levels of gelatinases (MMP-9 and MMP-2) in mice experimentally infected with T. spiralis or T. pseudospiralis, to elucidate the involvement of these molecules during the inflammatory response to these parasites. Gelatin zymography on SDS polyacrilamide gels was used to assess the serum levels and in situ zymography on muscle histological sections to show the gelatinase-positive cells. In T. spiralis infected mice, the total MMP-9 serum level increased 6 days post-infection whereas, the total MMP-2 serum level increased onward. A similar trend was observed in T. pseudospiralis infected mice but the MMP-9 level was lower than that detected in T. spiralis infected mice. Significant differences were also observed in MMP-2 levels between the two experimental groups. The number of gelatinase positive cells was higher in T. spiralis than in T. pseudospiralis infected muscles. We conclude that MMP-9 and MMP-2 are markers of the inflammatory response for both T. spiralis and T. pseudospiralis infections.

Alexithymia and its relationships with acute phase proteins and cytokine release: an updated review.

The alexithymia construct is multidimensional and comprises several features: (a) difficulty in identifying and describing feelings, (b) difficulty in distinguishing feelings from the bodily sensations, (c) diminution of fantasy, and (d) concrete and poorly introspective thinking. Altered immune responses have been seen in some psychiatric disorders and several data suggest that analogous changes could also be observable in alexithymia. Hence, the aim of this review is to investigate the relationships between alexithymia and acute phase proteins and cytokines in psychiatric, psychosomatic and medical diseases. Several studies have reported an association between alexithymia and higher circulating levels of acute phase proteins, especially C-Reactive Protein. Moreover, in alexithymic subjects the pro-inflammatory and anti-inflammatory cytokine balance may be tuned toward a pro-inflammatory imbalance with a concomitant altered cell-mediated immunity. These findings may be consistent with the "“stress-alexithymia hypothesis"”. Therefore, the screening of alexithymic traits and the administration of appropriate psychological and psychotherapeutical interventions should be integral parts of disease management programs. Supplying such interventions will probably help with prevention of the development of the disease and/or its exacerbation by improving the quality of life of alexithymic individuals.

Is there a role for agomelatine in the treatment of anxiety disorders?A review of published data.

Anxiety disorders (Ads) are the most common type of psychiatric disorders, Pharmacologic options studied for treating ADs may include benzodiazepines, tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRIs), noradrenergic and specific serotonergic antidepressants (NaSSA) and serotonin and noradrenaline reuptake inhibitors (SNRIs). Agomelatine, a new melatonergic antidepressant, has been shown effective in various types of mood disorders. Moreover, some evidence points towards a possible efficacy of such a drug in the treatment of ADs. Therefore, the aim of this review was to elucidate current (facts and views) data on the role of agomelatine in the treatment of ADs. The trials evaluating agomelatine in the treatment of generalized anxiety disorder are few but, overall, encouraging in regards to its efficacy. However, further randomized, placebo-controlled studies on larger samples use are needed. Apart from some interesting case reports, no large studies are, to date, present in literature regarding agomelatine in the treatment of other ADs, such as panic disorder, social anxiety disorder, obsessive-compulsive disorder and post-traumatic stress disorder. Therefore, the clinical efficacy and the relative good tolerability of agomelatine in generalized anxiety (GAD) warrants further investigation in ADs.

Antidepressant discontinuation syndrome: A state-of-the-art clinical review.

Antidepressant drugs are prescribed to patients with depressive, anxiety disorders, and other conditions. Evidence about antidepressant discontinuation syndrome (ADS) and related outcomes is sparse, although potentially burdensome in some patients. The present state-of-the-art review aims to appraise the most current evidence about ADS critically. ADS has been documented for most antidepressant drugs, although most literature focuses on selective serotonin reuptake inhibitors prescribed for depression. While down-titration cannot exclude the chance of ADS, it is nonetheless warranted in the clinical setting, especially for short half-life and sedative compounds such as paroxetine. Integrative management with concurrent pharmacotherapy and psychotherapy may minimize the eventual unpleasant effects arising within the discontinuation process. In addition, patient-tailored interventions and education should be part of the discontinuation strategy. Future research must rely on broadly accepted definitions for ADS and related phenomena such as antidepressant withdrawal and shed further light on the underpinning neurobiology. Discriminating between ADS-related phenomena and relapse of depression is likewise warranted, along with a neuroscience-based nomenclature instead of a class one.

Selective immunoglobulin A deficiency and celiac disease: let's give serology a chance.

Patients with selective immunoglobulin (Ig) A deficiency have a 10- to 20-fold increased risk of celiac disease. In these patients, serological diagnosis of celiac disease can be difficult, since specific IgA-based assays are usually negative and IgG-specific antibody tests are insufficiently reliable. We describe a girl with selective IgA deficiency who had a troublesome diagnosis of celiac disease that was established only after an unexpected positive test result for antitransglutaminase IgA and antiendomysium IgA. Our observation indicates that IgA-based serology should not be forgotten in patients with selective IgA deficiency, since positive results for antitransglutaminase IgA, antiendomysium IgA, or both can be observed at any time during diagnostic investigations.

High disease relapse after bDMARD spacing in psoriatic arthritis compared to rheumatoid arthritis and axial spondyloarthritis patients: real-life data from BIOPURE registry.

The objective is to evaluate the effectiveness of a spacing strategy of bDMARDs in a cohort of selected patients in disease remission or low-disease activity (LDA) without glucocorticoids affected with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). This was a single-centre study carried out on patients prospectively enrolled in the biologic Apulian registry. Patients whose disease was in remission or LDA without taking glucocorticoids during the previous 6 months and who had agreed to increase the time interval between bDMARD doses were included in this study. Demographic and clinical characteristics were recorded at baseline and at 3, 6 and 12 months of follow-up. Endpoint of the study was the survival of spacing doses in the time lag of the study. Failure of spacing was defined as the first flare of disease. Thirty-seven RA, 28 PsA and 20 axSpA patients underwent bDMARD spacing according to a local strategy. During the follow-up, 5 RA, 6 PsA and 4 axSpA patients had a joint flare, but further 5 PsA patients manifested a skin relapse. Global persistence was 86.5% for RA (MST = 41 (95% CI: 37-45) months) and 80% for axSpA patients (MST = 36 (95% CI: 31-42) months). PsA patients showed a lower persistence, being of 60.7% (MST = 30 (95% CI: 23-36) months) (log-rank test, p = 0.03). Dose reduction by spacing bDMARD doses may be a feasible approach in patients with persistent remission/LDA activity. However, PsA patients might have greater odds of spacing failure because of skin psoriasis relapse. Key Points • Spacing of bDMARDs may be a feasible strategy for some patients with rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis who achieve the target and withdrawn glucocorticoids. • Psoriatic arthritis patients showed lower persistence because of both articular and skin relapses.

Clinical features associated with early drop-out among outpatients with unipolar and bipolar depression.

Drop-out from follow-up visits carries significant burden for people diagnosed with depression. The present study assesses multiple clinical moderators of drop-out among depressed outpatients. We retrospectively followed-up 131 outpatients over 6 months: 78 major depressive disorder (MDD), and 53 bipolar disorder (BD-I = 24; BD-II = 29) patients diagnosed according to the Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition. Participants were assessed with standard rating scales administered by experienced psychiatrists. Upon descriptive and Cox regression analyses, 17/53 BDs (32%) dropped-out; the overall survival time until drop-out was 57.94 ± 17.79 days. BD drop-outs were younger, had an earlier age at onset, shorter illness duration, lower rates of lifetime obsessive-compulsive disorder/suicidal behavior, higher rates of substance use disorder (SUD), anxious and mixed features of depression compared to BDs attending up to six months. Among MDD patients, 10/78 cases (13%) dropped-out by month-6 with an average survival of 42.40 ± 16.45 days. Earlier age of onset, younger age, positive family history for mood disorders, lower rates of lifetime generalized anxiety disorder were significantly more frequent among drop-outs than completers, as opposite to SUD, and lifetime recurrent depression. Older age predicted lower drop-out among BDs and MDDs, although with almost null hazard ratio (HR) = 0.928, p < 0.01 vs. HR = 0.941, p < 0.01, respectively. Higher rates of lifetime SUD predicted higher drop-out rates by month-6 among MDDs (HR = 5.477, p = 0.02). Limitations of the study: retrospective design, small sample size, lack of objective measures of treatment-adherence/mood rating during follow-up. Drop-out is common in the real-world setting, warranting specific interventions since the beginning of the treatment.

Suicide associated with COVID-19 infection: an immunological point of view.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is a pandemic and leading cause of death. Beyond the deaths directly caused by the virus and the suicides related to the psychological response to the dramatic changes as socioeconomic related to the pandemic, there might also be suicides related to the inflammatory responses of the infection. Infection induces inflammation as a cytokine storm, and there is an increasing number of studies that report a relationship between infection and suicide. MATERIALS AND METHODS: We searched the World Health Organization status report and the PubMed database for keywords (COVID-19, suicide, infection, inflammation, cytokines), and reviewed five cytokine pathways between suicide and inflammation using two meta-analyses and two observational studies starting from November 31, 2020, focusing on the relationship between suicide and inflammation by infection. First, we discussed existing evidence explaining the relationship between suicidal behaviors and inflammation. Second, we summarized the inflammatory features found in COVID-19 patients. Finally, we highlight the potential for these factors to affect the risk of suicide in COVID-19 patients. RESULTS: Patients infected with COVID-19 have high amounts of IL-1ß, IFN-γ, IP10, and MCP1, which may lead to Th1 cell response activation. Also, Th2 cytokines (e.g., IL-4 and IL-10) were increased in COVID-19 infection. In COVID-19 patients, neurological conditions, like headache, dizziness, ataxia, seizures, and others have been observed. CONCLUSIONS: COVID-19 pandemic can serve as a significant environmental factor contributing directly to increased suicide risk; the role of inflammation by an infection should not be overlooked.

Inhibition of cell cycle progression by the alternatively spliced integrin beta 1C.

Integrins regulate cell growth, differentiation, and behavior in many systems. Integrin beta 1C (beta 1S) is an alternatively spliced variant of integrin beta 1 with a specific cytoplasmic domain and is expressed in several human tissues. Human beta 1c transiently expressed in mouse 10T1/2 fibroblasts showed a diffuse pattern of cell surface staining, whereas beta1 localized to focal adhesions. Moderate concentrations of beta 1C had no effect on actin stress fibers or focal adhesions, but markedly inhibited DNA synthesis. Inhibition by beta 1C mapped to the late G1 phase of the cell cycle, near the G1-S boundary. Thus, alternative splicing of beta1 results in transmission of distinct signals that may regulate growth in vivo.

Neuronal intermediate filament expression in rat dorsal root ganglia sensory neurons: an in vivo and in vitro study.

Qualitative and quantitative examination was performed to evaluate the expression of peripherin and 200 kDa neurofilament in the sensory compartment of the peripheral nervous system of the rat both in vivo and in a new in vitro model. Under physiological conditions, these two neuronal intermediate filaments show different expression patterns in sensory neurons. To have a more complete comprehension of the role of these intermediate filaments and to fill in the blanks left in previously reported literature, we demonstrate in vivo using a morphological approach that peripherin and 200 kDa neurofilament define two distinct subpopulations within the dorsal root ganglia sensory neurons. Moreover, peripherin is specifically expressed in unmyelinated fibers while 200 kDa neurofilament is expressed in myelinated fibers. Additionally, in vitro analysis of RNA taken from dorsal root ganglia explants suggested that 200 kDa neurofilament is downregulated and peripherin is transiently expressed throughout sensory fiber regrowth. In particular, both neuronal intermediate filaments are downregulated immediately after sensory fiber axotomy thus suggesting that neither peripherin nor 200 kDa neurofilament has a role in the first steps of fiber regrowth. However, the upregulation of peripherin a few days after the beginning of fiber regrowth in vitro suggests that low levels of peripherin may be require to carry on the sequence of events involved in the correct regeneration and direction of sensory fibers.

Use of hybrid chitosan membranes and N1E-115 cells for promoting nerve regeneration in an axonotmesis rat model.

Many studies have been dedicated to the development of scaffolds for improving post-traumatic nerve regeneration. The goal of this study was to develop and test hybrid chitosan membranes to use in peripheral nerve reconstruction, either alone or enriched with N1E-115 neural cells. Hybrid chitosan membranes were tested in vitro, to assess their ability in supporting N1E-115 cell survival and differentiation, and in vivo to assess biocompatibility as well as to evaluate their effects on nerve fiber regeneration and functional recovery after a standardized rat sciatic nerve crush injury. Functional recovery was evaluated using the sciatic functional index (SFI), the static sciatic index (SSI), the extensor postural thrust (EPT), the withdrawal reflex latency (WRL) and ankle kinematics. Nerve fiber regeneration was assessed by quantitative stereological analysis and electron microscopy. All chitosan membranes showed good biocompatibility and proved to be a suitable substrate for plating the N1E-115 cellular system. By contrast, in vivo nerve regeneration assessment after crush injury showed that the freeze-dried chitosan type III, without N1E-115 cell addition, was the only type of membrane that significantly improved posttraumatic axonal regrowth and functional recovery. It can be thus suggested that local enwrapping with this type of chitosan membrane may represent an effective approach for the improvement of the clinical outcome in patients receiving peripheral nerve surgery.

Employment of the mouse median nerve model for the experimental assessment of peripheral nerve regeneration.

The experimental investigation of nerve regeneration after microsurgical repair is usually carried out in rats, rather than mice, because of the larger sized peripheral nerves. Today however, the availability of genetically modified mice makes the use of this laboratory animal very intriguing for investigating nerve regeneration at a molecular level. In this study we aimed to provide a standardization of the experimental model based on microsurgical direct repair, by 12/0 suture, of the left median nerve in adult male mice. Postoperative recovery was regularly assessed by the grasping test. At day-75 postoperative, regenerated median nerve fibers were analyzed by design-based quantitative morphology and electron microscopy. Yet, sections were immuno-labelled using two axonal antibodies commonly employed for rat nerve fibers. Results indicated that functional recovery begun at day-15 and progressively increased reaching values not significantly different from normal by day-50. Quantitative morphology showed that, at day-75, the number of regenerated nerve fibers was not significantly different in comparison to controls. In contrast, differences were detected in fiber density, mean axon and fiber diameter and myelin thickness which were all significantly lower than controls. Immunohistochemistry showed that axonal markers commonly used for rat nerves studies are effective also for mouse nerves. Similar to the rat, the mouse median nerve model is superior to sciatic nerve model for the minimal impact on animal well-being and the effectiveness of the grasping test for motor function evaluation. The main limitation is the small nerve size which requires advanced microsurgical skills for performing 12/0 epineurial suturing.

Predictors of hospitalization length of stay among re-admitted treatment-resistant Bipolar Disorder inpatients.

BACKGROUND: Hospitalization accounts for significant health care resource utilization for treatment-resistant Bipolar Disorder (BD), especially among frequent users of acute inpatient psychiatric units. Appraisal of the clinical features and predictive role of selected variables is therefore crucial in such population, representing the aim of the present research. METHODS: A hundred and nineteen BD inpatients with an established history of pharmacological treatment resistance for either mania or bipolar depression were classified as long hospitalization cases (LOS+) and their controls and compared against each other for a number of demographic, clinical, and psychopathological features. RESULTS: Overall, female sex, current second-generation atypical antipsychotic (SGA)/mood stabilizer other than lithium as well as antidepressant treatment at the admission occurred statistically more frequently among LOS+ cases, concordant with higher scores at the Hamilton scales for depression and anxiety. Lithium utilization at the time of hospitalization did not differ between cases and controls (LOS-, n = 81/119), as predominant affective temperament and other psychopathological rating did not. Overall, the time of admission, use of SGA, anticonvulsant (other than lithium), antidepressant, lifetime alcohol dependence, and BD Type (-I or -II), but not current mood polarity at the time of hospitalization, correctly predicted LOS+ grouping 68.2% of the times: Exp(B) = 3.151, p042. LIMITATIONS: Post-hoc, cross-sectional study, relatively small sample size, recall and selection bias on some diagnoses. CONCLUSIONS: Overall, LOS+ treatment-resistant BD inpatients characterize for higher severity and greater pharmaco-utilization use, which warrants replication studies to include additional predictors to shed further light on the matter.

p27(kip1) acts as a downstream effector of and is coexpressed with the beta1C integrin in prostatic adenocarcinoma.

Integrins are a large family of transmembrane receptors that, in addition to mediating cell adhesion, modulate cell proliferation. The beta1C integrin is an alternatively spliced variant of the beta1 subfamily that contains a unique 48-amino acid sequence in its cytoplasmic domain. We have shown previously that in vitro beta1C inhibits cell proliferation and that in vivo beta1C is expressed in nonproliferative, differentiated epithelium and is selectively downregulated in prostatic adenocarcinoma. Here we show, by immunohistochemistry and immunoblotting analysis, that beta1C is coexpressed in human prostate epithelial cells with the cell-cycle inhibitor p27(kip1), the loss of which correlates with poor prognosis in prostate cancer. In the 37 specimens analyzed, beta1C and p27(kip1) are concurrently expressed in 93% of benign and 84%-91% of tumor prostate cells. Forced expression of beta1C in vitro is accompanied by an increase in p27(kip1) levels, by inhibition of cyclin A-dependent kinase activity, and by increased association of p27(kip1) with cyclin A. beta1C inhibitory effect on cell proliferation is completely prevented by p27(kip1) antisense, but not mismatch oligonucleotides. beta1C expression does not affect either cyclin A or E levels, or cyclin E-associated kinase activity, nor the mitogen-activated protein (MAP) kinase pathway. These findings show a unique mechanism of cell growth inhibition by integrins and point to beta1C as an upstream regulator of p27(kip1) expression and, therefore, a potential target for tumor suppression in prostate cancer.

Lack of topographic specificity in nerve fiber regeneration of rat forelimb mixed nerves.

Multiple nerve repair by means of a Y-shaped nerve guide represents a good model for studying the specificity of peripheral nerve fiber regeneration. Here we have used it for investigating the specificity of axonal regeneration in mixed nerves of the rat forelimb model. The left median and ulnar nerves, in adult female rats, were transected and repaired with a 14-mm Y-shaped conduit. The proximal end of the Y-shaped conduit was sutured to the proximal stump of either the median nerve or the ulnar nerve. Ten months after surgery, rats were tested for functional recovery of each median and ulnar nerve. Quantitative morphology of regenerated myelinated nerve fibers was then carried out by the two-dimensional disector technique. Results showed that partial recovery of both median and ulnar nerve motor function was regained in all experimental groups. Performance in the grasping test was significantly lower when the ulnar nerve was used as the proximal stump. Ulnar test assessment showed no significant difference between the two Y-shaped repair groups. The number of regenerated nerve fibers was significantly higher in the median nerve irrespectively of the donor nerve, maintaining the same proportion of myelinated fibers between the two nerves (about 60% median and 40% ulnar). On the other hand, nerve fiber size and myelin thickness were significantly larger in both distal nerves when the median nerve was used as the proximal donor nerve stump. G-ratio and myelin thickness/axon diameter ratio returned to normal values in all experimental groups. These results demonstrate that combined Y-shaped-tubulization repair of median and ulnar nerves permits the functional recovery of both nerves, independently from the proximal donor nerve employed, and that tissue, and not topographic, specificity guides nerve fiber regeneration in major forelimb mixed nerves of rats.

Functional, morphological and biomolecular assessment of posttraumatic neuro-muscular recovery in the rat forelimb model.

Over the last five years, we have used the rat forelimb model for investigating neuromuscular recovery after microsurgical nerve reconstruction of median and ulnar nerves by end-to-side neurorrhaphy and muscle-vein-combined tubulization (using both straight and Y-shaped guides). The outcome of nerve repair at different postoperative times was assessed by functional, morphological and biomolecular analysis. Results showed that both end-to-side and tubulization repair of rat median and ulnar nerves led to successful axonal regeneration along the severed nerve trunk as well as to a partial recovery of the lost function as assessed by grasping test. Biomolecular analysis by means of reverse transcription polymerase chain reaction (RT-PCR) demonstrated early overexpression during nerve regeneration of the gliotrophic factor NRG1 and two of its receptors: erbB2 and erbB3. Finally, our experience also suggests that the rat forelimb experimental model is particularly appropriate for the study of microsurgical reconstruction of major mixed nerve trunks. Furthermore, since the forelimb model is less compromising for the animal, it should be preferred to the hindlimb model for many research purposes.