Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus.

LL37 exerts a dual pathogenic role in psoriasis. Bound to self-DNA/RNA, LL37 licenses autoreactivity by stimulating plasmacytoid dendritic cells-(pDCs)-Type I interferon (IFN-I) and acts as autoantigen for pathogenic Th17-cells. In systemic lupus erythematosus (SLE), LL37 also triggers IFN-I in pDCs and is target of pathogenic autoantibodies. However, whether LL37 activates T-cells in SLE and how the latter differ from psoriasis LL37-specific T-cells is unknown. Here we found that 45% SLE patients had circulating T-cells strongly responding to LL37, which correlate with anti-LL37 antibodies/disease activity. In contrast to psoriatic Th17-cells, these LL37-specific SLE T-cells displayed a T-follicular helper-(TFH)-like phenotype, with CXCR5/Bcl-6 and IL-21 expression, implicating a role in stimulation of pathogenic autoantibodies. Accordingly, SLE LL37-specific T-cells promoted B-cell secretion of pathogenic anti-LL37 antibodies in vitro. Importantly, we identified abundant citrullinated LL37 (cit-LL37) in SLE tissues (skin and kidney) and observed very pronounced reactivity of LL37-specific SLE T-cells to cit-LL37, compared to native-LL37, which was much more occasional in psoriasis. Thus, in SLE, we identified LL37-specific T-cells with a distinct functional specialization and antigenic specificity. This suggests that autoantigenic specificity is independent from the nature of the autoantigen, but rather relies on the disease-specific milieu driving T-cell subset polarization and autoantigen modifications.

Understanding Complex Tribofilms by Means of H3BO3-B2O3 Model Glasses.

The discovery of the spontaneous reaction of boric oxides with moisture in the air to form lubricious H3BO3 films has led to great interest in the tribology of boron compounds in general. Despite this, a study of the growth kinetics of H3BO3 on a B2O3 substrate under controlled relative humidity (RH) has not yet been reported in the literature. Here, we describe the tribological properties of H3BO3-B2O3 glass systems after aging under controlled RH over different lengths of time. A series of tribological tests has been performed applying a normal load of 15 N, at both room temperature and 100 °C in YUBASE 4 oil. In addition, the cause of H3BO3 film failure under high-pressure and high-temperature conditions has been studied to find out whether the temperature, the tribostress, or both influence the removal of the lubricious film from the contact points. The following techniques were exploited: confocal Raman spectroscopy to characterize the structure and chemical nature of the glass systems, environmental scanning electron microscopy to examine the morphology of the H3BO3 films developed, atomic force microscopy to monitor changes in roughness as a consequence of the air exposure, focused-ion-beam scanning electron microscopy to measure the average thickness of the H3BO3 films grown over various times on B2O3 glass substrates and to reveal the morphology of the sample in the vertical section, tribological tests to shed light on the system's lubricating properties, and finally small-area X-ray photoelectron spectroscopy to investigate the composition of the transfer film formed on the steel ball while tribotesting.

Endothelin A receptor drives invadopodia function and cell motility through the ß-arrestin/PDZ-RhoGEF pathway in ovarian carcinoma.

The endothelin-1 (ET-1)/ET A receptor (ETAR) signalling pathway is a well-established driver of epithelial ovarian cancer (EOC) progression. One key process promoted by ET-1 is tumor cell invasion, which requires the scaffolding functions of ß-arrestin-1 (ß-arr1) downstream of the receptor; however, the potential role of ET-1 in inducing invadopodia, which are crucial for cellular invasion and tumor metastasis, is completely unknown. We describe here that ET-1/ETAR, through ß-arr1, activates RhoA and RhoC GTPase and downstream ROCK (Rho-associated coiled coil-forming kinase) kinase activity, promoting actin-based dynamic remodelling and enhanced cell invasion. This is accomplished by the direct interaction of ß-arr1 with PDZ-RhoGEF (postsynaptic density protein 95/disc-large/zonula occludens-RhoGEF). Interestingly, ETAR-mediated invasive properties are related to the regulation of invadopodia, as evaluated by colocalization of actin with cortactin, as well as with TKS5 and MT1-MMP (membrane type 1-matrix metalloproteinase) with areas of matrix degradation, and activation of cofilin pathway, which is crucial for regulating invadopodia activity. Depletion of PDZ-RhoGEF, or ß-arr1, or RhoC, as well as the treatment with the dual ET-1 receptor antagonist macitentan, significantly impairs invadopodia function, MMP activity and invasion, demonstrating that ß-arr1/PDZ-RhoGEF interaction mediates ETAR-driven ROCK-LIMK-cofilin pathway through the control of RhoC activity. In vivo, macitentan is able to inhibit metastatic dissemination and cofilin phosphorylation. Collectively, our data unveil a noncanonical activation of the RhoC/ROCK pathway through the ß-arr1/PDZ-RhoGEF complex as a regulator of ETAR-induced motility and metastasis, establishing ET-1 axis as a novel regulator of invadopodia protrusions through the RhoC/ROCK/LIMK/cofilin pathway during the initial steps of EOC invasion.

ß-arrestin-1 is a nuclear transcriptional regulator of endothelin-1-induced ß-catenin signaling.

Despite the fundamental pathophysiological importance of ß-catenin in tumor progression, the mechanism underlying its final transcriptional output has been partially elucidated. Here, we report that ß-arrestin-1 (ß-arr1) is an epigenetic regulator of endothelin (ET)-1-induced ß-catenin signaling in epithelial ovarian cancer (EOC). In response to ET A receptor (ETAR) activation by ET-1, ß-arr1 increases its nuclear translocation and direct binding to ß-catenin. This in turn enhanced ß-catenin nuclear accumulation and transcriptional activity, which was prevented by expressing a mutant ß-arr1 incapable of nuclear distribution. ß-arr1-ß-catenin interaction controls ß-catenin target gene expressions, such as ET-1, Axin 2, Matrix metalloproteinase 2, and Cyclin D1, by promoting histone deacetylase 1 (HDAC1) dissociation and the recruitment of p300 acetyltransferase on these promoter genes, resulting in enhanced H3 and H4 histone acetylation, and gene transcription, required for cell migration, invasion and epithelial-to-mesenchymal transition. These effects are abrogated by ß-arr1 silencing or by mutant ß-arr1, as well as by ß-catenin or p300 silencing, confirming that nuclear ß-arr1 forms a functional complex capable of regulating epigenetic changes in ß-catenin-driven invasive behavior. In a murine orthotopic model of metastatic human EOC, silencing of ß-arr1 or mutant ß-arr1 expression, as well as ETAR blockade, inhibits metastasis. In human EOC tissues, ß-arr1-ß-catenin nuclear complexes are selectively enriched at ß-catenin target gene promoters, correlating with tumor grade, confirming a direct in vivo ß-arr1-ß-catenin association at specific set of genes involved in EOC progression. Collectively, our study provides insights into how a ß-arr1-mediated epigenetic mechanism controls ß-catenin activity, unraveling new components required for its nuclear function in promoting metastasis.

Systemic lupus erythematosus developing immediately after necrotizing fasciitis.

Necrotizing fasciitis (NF) is a medical-surgical emergency characterized by severe bacterial infection that affects the subcutaneous tissue and spreads to the underlying fascia; usually it is caused by penetrating trauma, sometimes by surgical therapy, very rarely by minor insults such as insect bites. Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease involving virtually all the key components of the immune system. Although cases of post-infection autoimmunity were already described, a literature search using Pub Med and Medline revealed that SLE was never reported to occur in patients affected, immediately before, with NF. We observed and herein report, however, a case of a woman showing an insect-bite-induced NF, which was immediately followed by the development of a SLE. In conclusion, this case of postinfection autoimmunity provides early evidence of a patient developing SLE immediately after NF, and suggests that caution in the follow-up of NF is necessary, because NF might favor the development of a severe autoimmunity.

Insulin-like growth factor-II is a useful marker to detect hepatocellular carcinoma?

BACKGROUND: Hepatocellular carcinoma (HCC) is a typical hypervascular tumor. The utility of serum alpha-fetoprotein (α-FP) in its detection is questionable. Over-expression and high circulating levels of insulin-like growth factor-II (IGF-II) were reported in tissue and in serum of patients with HCC. We investigated the diagnostic application of IGF-II in the diagnosis of HCC. METHODS: Serum IGF-II and α-FP levels were measured in 178 patients (82 with HCC and 96 with liver cirrhosis) and in 30 healthy controls. Spearman test, non parametric combination test and confidence interval analysis were used for statistical evaluation of data. RESULTS: The best cut-off values selected by ROC curves were 796 ng/ml for IGF-II and 132 ng/ml for α-FP. IGF-II mean values were higher in patients with HCC than in those with liver cirrhosis (LC) (p=0.0001) but lower in LC than in controls (p=0.0001). Serum IGF-II levels above cut-off were found in 22% of patients with HCC, in 9.3% of those with cirrhosis and in 20% of controls. α-FP serum levels >132 ng/ml were observed in 48% of HCC, in 3.1% of LC and in none of control group. By correlation study, serum IGF-II levels were significantly correlated with serum α-FP levels (r=0.427, p=0.0001) and with nodules' diameter (r=0.252, p=0.0130) but not with nodules' number (p>0.050). Finally, IGF-II showed lower sensitivity, specificity and predictive values than α-FP. CONCLUSION: Circulating IGF-II is not a useful marker for HCC. Further researches are however needed to evaluate its diagnostic accuracy before and after nutritional adjustment.

The effect of Na(2)CO(3), NaF and NH(4)OH on the stability and release behavior of sol-gel derived silica xerogels embedded with bioactive compounds.

Stability, defined as the reproducible behavior of a device upon its storage, is an important issue in pharmaceutical formulation. Silica xerogels obtained through the sol-gel route are relatively new as matrices for the controlled release of drugs. In some cases, it was observed that their behavior changes upon storage, so that they cannot always be defined as "stable". This occurs especially when gel processing is performed at mild temperatures, a procedure that may have to be used to prevent degradation of the embedded drug. This work investigated the use of inorganic catalysts as potential xerogel stability inducers when gel curing by heating is not applicable. Three compounds known to accelerate sol-gel polymerization, namely ammonia, sodium fluoride and sodium carbonate, were introduced during the polymerization of low-temperature processed inorganic and organically modified gels, and the effect of each compound on xerogel stability and drug release was monitored. The use of carbonate leads to formulations with good retention properties, as opposed to ammonia and NaF, which lead to poorly retentive xerogels in accordance with their known ability to increase porosity. Ammonia was shown to be a poor stability promoter independently of gel composition, as opposed to fluoride and carbonate, which both displayed stabilizing properties in a dose-dependent manner. No correlation was found between xerogel stability and drug release properties. An attempt was also made to correlate stability data with polymerization rates and wet gel syneresis time evolution with the purpose of identifying one or more synthesis parameters that could act as stability predictors for pre-formulation studies. No correlation was found between stability and syneresis data. A similar trend in the curve of gel time vs. catalyst concentration was observed for the two stabilizing catalysts, which was different for the non-stabilizing ammonia. It was concluded that the trend of this curve could potentially provide an indicator of catalyst stabilizing efficacy.

Increased expression of heat shock proteins in rat brain during aging: relationship with mitochondrial function and glutathione redox state.

It is generally recognized that lipid peroxides play an important role in the pathogenesis of several diseases and that sulfhydryl groups are critically involved in cellular defense against endogenous or exogenous oxidants. Recent evidence indicates that lipid peroxides directly participate in induction of cytoprotective proteins, such as heat shock proteins (Hsps), which play a central role in the cellular mechanisms of stress tolerance. Oxidative damage plays a crucial role in the brain aging process and induction of Hsps is critically utilized by brain cells in the repair process following various pathogenic insults. In the present study, we investigated, in rats 6, 12, and 28 months old, the role of heat shock expression on aging-induced changes in mitochondrial and antioxidant redox status. In the brain expression of Hsp72 and Hsc70 increased with age up to 28 months; at this age the maximum induction was observed in the hippocampus and substantia nigra followed by cerebellum, cortex, septum and striatum. Hsps induction was associated with significant changes in glutathione (GSH) redox state and HNE levels. Interestingly, a significant positive correlation between decrease in GSH and increase in Hsp72 was observed in all brain regions examined during aging. Analysis of mitochondrial complexes showed a progressive decrease of Complex I activity and mRNA expression in the hippocampus and a significant decrease of Complex I and IV activities in the substantia nigra and septum. Our results sustain a role for GSH redox state in Hsp expression. Increase of Hsp expression promotes the functional recovery of oxidatively damaged proteins and protects cells from progressive age-related cell damage. Conceivably, heat shock signal pathway by increasing cellular stress resistance may represent a crucial mechanism of defence against free radical-induced damage occurring in aging brain and in neurodegenerative disorders.

Cellular localization and functional role of phosphatidylcholine-specific phospholipase C in NK cells.

Although several classes of phospholipases have been implicated in NK cell-mediated cytotoxicity, no evidence has been reported to date on involvement of phosphatidylcholine-specific phospholipase C (PC-PLC) in NK activation by lymphokines and/or in lytic granule exocytosis. This study demonstrated the expression of two PC-PLC isoforms (M(r) 40 and 66 kDa) and their IL-2-dependent distribution between cytoplasm and ectoplasmic membrane surface in human NK cells. Following cell activation by IL-2, cytoplasmic PC-PLC translocated from the microtubule-organizing center toward cell periphery, essentially by kinesin-supported transport along microtubules, while PC-PLC exposed on the outer cell surface increased 2-fold. Preincubation of NK cells with a PC-PLC inhibitor, tricyclodecan-9-yl-xanthogenate, strongly reduced NK-mediated cytotoxicity. In IL-2-activated cells, this loss of cytotoxicity was associated with a decrease of PC-PLC exposed on the cell surface, and accumulation of cytoplasmic PC-PLC in the Golgi region. Massive colocalization of PC-PLC-rich particles with perforin-containing granules was found in the cytoplasm of NK-activated (but not NK-resting) cells; both organelles clustered at the intercellular contact region of effector-target cell conjugates. These newly detected mechanisms of PC-PLC translocation and function support an essential role of this enzyme in regulated granule exocytosis and NK-mediated cytotoxicity.

Nitric oxide synthase induction in astroglial cell cultures: effect on heat shock protein 70 synthesis and oxidant/antioxidant balance.

Glial cells in the nervous system can produce nitric oxide in response to cytokines. This production is mediated by the inducible isoform of nitric oxide synthase. Radical oxygen species (ROS) and nitric oxide (NO) derivatives have been claimed to play a crucial role in many different processes, both physiological such as neuromodulation, synaptic plasticity, response to glutamate, and pathological such as ischemia and various neurodegenerative disorders. In the present study we investigated the effects of NO synthase (iNOS) induction in astrocyte cultures on the synthesis of heat shock proteins, the activity of respiratory chain complexes and the oxidant/antioxidant balance. Treatment of astrocyte cultures for 18 hr with LPS and INFgamma produced a dose dependent increase of iNOS associated with an increased synthesis of hsp70 stress proteins. This effect was abolished by the NO synthase inhibitor L-NMMA and significantly decreased by addition of SOD/CAT in the medium. Time course experiments showed that iNOS induced protein expression increased significantly by 2 hr after treatment with LPS and INFgamma and reached a plateau at 18 hr; hsp70 protein synthesis peaked around 18 and 36 hr after the same treatment. Addition to astrocytes of the NO donor sodium nitroprusside resulted in a dose dependent increase in hsp70 protein that was comparable to that found after a mild heat shock. Additionally, a decrease in cytochrome oxidase activity, a marked decrease in ATP and protein sulfhydryl contents, an increase in the activity of the antioxidant enzymes mt-SOD and catalase were found which were abolished by L-NMMA. These findings suggest the importance of mitochondrial energy impairment as a critical determinant of the susceptibility of astrocytes to neurotoxic processes and point to a possible pivotal role of hsp70 in the signalling pathways of stress tolerance.

Increased cerebrospinal fluid and plasma levels of ultraweak chemiluminescence are associated with changes in the thiol pool and lipid-soluble fluorescence in multiple sclerosis: the pathogenic role of oxidative stress.

The pathogenesis of multiple sclerosis (MS), the major neurological disease of young adults in the western world, is still poorly understood and no effective therapy to block MS is yet available. It is generally accepted that reactive oxygen species have a major role in the mediation of cell damage and that free sulfhydryl groups are vital in cellular defense against endogenous or exogenous oxidants. Modification of the cellular oxidant/antioxidant balance has been involved in the neuropathogenesis of several diseases, e.g., stroke, Parkinson's disease, Alzheimer's disease and physiological aging. An increasingly important area of antioxidant defense is based on sulfhydryl chemistry, owing to the role of sulfhydryl groups in the function of macromolecular structures such as enzymes and cellular membranes. The chemical composition of human cerebrospinal fluid (CSF) is considered to reflect brain metabolism and in the present study we provided experimental evidence of a decrease in sulfhydryl groups and increased content of products of lipid peroxidation, such as ultraweak chemiluminescence and liposoluble fluorescence, which we found higher in the CSF and plasma of MS patients than in controls, pointing out the role of oxidative stress in the pathogenesis of MS.

[Adrenal gland morphological alterations in the acquired immunodeficiency syndrome]. / Alterações morfológicas da glândula supra-renal na síndrome da imunodeficiência adquirida.

In the acquired immunodeficiency syndrome (AIDS), the adrenal glands are subject to opportunistic infections, neoplasm or direct cytopathic effect by HIV. It is know that the incidence and type of adrenal involvement vary according to the patient's place of origin. In this paper we evaluate adrenal involvement in fourteen patients that died from AIDS in the University Hospital of Uberaba, Brazil. The group studied was comprised of thirteen males and thirteen whites. The age was 29.9 +/- 7.8 years, and the body mass index was 19.0 +/- 4.1 kg/m2. Adrenal specimens obtained from autopsies were analyzed by light microscopy. Inflammation was found in 100% of the cases and the etiologic agent(s) was (were) identified in eight (58.1%) patients. Cytomegalovirus was identified in seven cases, Cryptococcus sp and Herpes simplex in two and Histoplasma sp in one case, these pathologic findings were similar to literature. We also found parenchymal calcification and adrenal central vein phlebitis in one case each. Injury was found in some cases without identified infections agent. This fact could be due to the direct cytopathic effect by HIV, or due to toxicity of drug therapy used during treatment of AIDS and opportunistic infections.

Long-term ethanol administration enhances urinary ultraweak luminescence and age-dependent modulation of redox in central and peripheral organs of the rat.

Numerous experimental evidence sustains a pathogenic role for oxidative stress in aging. Acute and chronic ethanol metabolism is also known to be associated with oxidative perturbation of cellular oxidant/antioxidant balance. In the present work we investigated the effects of 25 months of ethanol consumption on the antioxidant defense system in different organs of rats, in comparison with normal and aged animals. We show that aged rats underwent a significant perturbation of the antioxidant defense system, as indicated by depletion of reduced glutathione content, increases in oxidized glutathione and free radical-induced urinary luminescence associated with a decrease of glutathione reductase and increase of glutathione transferase activities. These modifications, observed particularly in the liver and brain, were enhanced by long-term alcohol exposure. Our results indicate that increased glutathione transferase activity and decreased glutathione reductase activity, followed by thiol depletion, are important factors sustaining a pathogenic role for oxidative stress in aging and in all situations where age-correlated changes occur. They also reinforce the oxidative potential of toxic compounds, such as ethanol intoxication.

Alteraçoes morfológicas da glândula supra-renal na síndrome da imunodeficiência adquirida / Adrenal gland morphological alterations in the acquired immunodeficiency syndrome

Na síndrome da imunodeficiência adquirida (AIDS) pode-se verificar o acometimento da supra-renal por efeito citopático direto pelo HIV, por infecções oportunistas ou neoplasias. Estes achados poderiam variar de acordo com a procedência do paciente, devido às doenças peculiares à região. Neste trabalho avaliou-se o comprometimento da supra-renal em quatorze pacientes que morreram de AIDS no Hospital Escola, em Uberaba. Treze eram do sexo masculino e treze brancos. A idade foi de 29,9 ± 7,8 anos e o índice de massa corporal foi de 19 ± 4,1kg/m2. Os fragmentos de supra-renal obtidos nas necropsias foram analisados em microscópio de luz. Encontramos inflamação em 100% dos casos, identificando-se o agente etiológico em oito (58,1%) casos. O Citomegalovírus foi identificado em sete casos, o Cryptococcus sp e o Herpes simplex em dois e o Histoplasma sp em um caso, estes achados são semelhantes aos da literatura. Em um caso, encontramos calcificação do parênquima e em outro, flebite da veia central. Em alguns casos que apresentavam lesão não foi possível identificar o agente etiológico, talvez em decorrência do efeito citopático direto pelo HIV ou devido a toxicidade das drogas utilizadas no tratamento da AIDS e das infecções oportunistas.

In the acquired immunodeficiency syndrome (AIDS), the adrenal glands are subject to opportunistic infections, neoplasm or direct cytopathic effect by HIV. It is know that the incidence and type of adrenal involvement vary according to the patient's place of origin. In this paper we evaluate adrenal involvement in fourteen patients that died from AIDS in the University Hospital of Uberaba, Brazil. The group studied was comprised of thirteen males and thirteen whites. The age was 29.9 +/- 7.8 years, and the body mass index was 19.0 +/- 4.1 kg/m2. Adrenal specimens obtained from autopsies were analyzed by light microscopy. Inflammation was found in 100% of the cases and the etiologic agent(s) was (were) identified in eight (58.1%) patients. Cytomegalovirus was identified in seven cases, Cryptococcus sp and Herpes simplex in two and Histoplasma sp in one case, these pathologic findings were similar to literature. We also found parenchymal calcification and adrenal central vein phlebitis in one case each. Injury was found in some cases without identified infections agent. This fact could be due to the direct cytopathic effect by HIV, or due to toxicity of drug therapy used during treatment of AIDS and opportunistic infections.

Effect of nitric oxide synthase induction on the expression of mitochondrial respiratory chain enzyme subunits in mixed cortical and astroglial cell cultures.

In the present study we evaluated the effects of NO synthase (NOS) induction on the regulation of cytochrome c oxidase (CO) and F0F1-ATPase subunit expression in astroglial and mixed cortical cell cultures. In mixed cortical cell cultures, 18 h of treatment with lipopolysaccharide (LPS, 0.1 microgram/mL) plus interferon-gamma (INF-gamma, 10 U/mL) caused an increase of mRNAs for CO-I, F0F1-ATPase 6 and also for iNOS at 20 DIV. The induction of both CO-I and F0F1-ATPase 6 was abolished by the NOS inhibitor N-monomethyl-L-arginine (NMMA) or by the enzymatic scavenger superoxide dismutase/catalase (SOD/CAT). In primary astroglial cell cultures, treatment for 18 h with increasing concentrations of LPS and INF gamma, produced an increase in the amount of mitochondrial encoded CO-I and -II subunits, with no significant modifications of nuclear encoded subunit IV. An increase was also observed at level of transcription for CO-I and -II, and F0F1-ATPase 6 mRNAs. These effects were abolished by addition of NMMA or SOD/CAT. mRNA induction of CO-I was higher in mixed cortical than in astroglial cell cultures while that of F0F1-ATPase 6 was similar in both cell types. These results suggest that the expression of mitochondrial encoded subunits (CO-I, CO-II and F0F1-ATPase 6) is up-regulated in response to oxygen and NO reactive species. The activity of cytochrome c oxidase decreased after LPS/INF gamma treatment in both astroglial and mixed cortical cultures. The activity of ATP synthase was unmodified, while ATP content drastically decreased after LPS/INF gamma treatment, in both astroglial and mixed cortical cultures. The enzymatic activities of catalase and Mn-SOD (mitochondrial) showed a significant increase after LPS/INF gamma treatment, which was abolished by NMMA.

[HPV infections in the lower genital tract in the female. Results of beta-interferon treatment]. / Lesioni da HPV del tratto genitale inferiore femminile. Risultati del trattamento con beta-interferone.

The Authors have analyzed the results obtained by treating 60 patients affected by HPV lesions of the lower female genital tract (flat vulvar, vaginal and cervical condylomatosis) with beta-interferon. At vulvovaginal level, the action of the drug is independent from the colposcopic aspect of the lesion but is closely correlated to its extension. The drug proved to be more efficacious at cervical level in case of condylomatous cervicitis rather than ANTZ with a reduction in the size of the lesion and disappearance, if present, of the dysplasia. The positive action of the beta-interferon has never occurred before 2-6 months from the end of the farmacologic treatment. The best results have been obtained in case of condylomatous cervicitis with complete remission in 58% of the cases, and in vaginal condylomatosis (CR at 6 months: 45%). On the basis of these results we may conclude that in these HPV lesions priority should be given to medical treatment whereas in vulvar condylomatosis (especially if extended greater than 1/3) where results are not very satisfactory (not more than 20% of CR) physical therapy is advisable.

Protective action of phosphatidylserine on stress-induced behavioral and autonomic changes in aged rats.

Phosphatidylserine (PS) was administered in aged rats subjected to various stressor stimuli in order to evaluate its effect on grooming behavior, core temperature and gastric ulcers. Novelty-induced grooming appeared to be increased in aged rats as compared to young controls. The subchronic intraperitoneal treatment with PS (20 mg/kg/day for 20 days) decreased grooming activity in aged rats, whereas it did not affect that of young animals. Restraint stress induced hyperthermia in both aged and young rats. However, 90 min after the beginning of restraint, PS-treated old rats showed a normalization of core temperature. Furthermore, restraint-plus-cold stress induced gastric ulcers in both aged and young rats. The treatment with PS was followed by a decreased incidence of gastric lesions in aged, but not in young rats. The mechanism of PS protective action against stress-induced behavioral and autonomic changes is unknown, but it may involve the brain level as this drug exerts a noteworthy influence on behavior and autonomic functions.

Intracerebroventricular administration of interleukin-1 to mice alters investigation of stimuli in a novel environment.

The behavior of mice administered recombinant interleukin-1 (IL-1) was observed in a novel multicompartment chamber. Doses of human IL-1 alpha (4 pg to 40 ng) injected intracerebroventricularly (ICV) 20 min before testing significantly reduced the mean time mice spent in contact with novel stimuli. No other behavior scored (locomotor activity, grooming, scratching) was significantly affected. Similar results were obtained with murine IL-1 alpha (770 pg or 77 ng) and hIL-1 beta (1 pg to 10 ng). This behavioral change resembled that induced following restraint or ICV injection of corticotropin-releasing factor (CRF). The behavioral effect of ICV IL-1 was lost after it was heated for 10 min at 100 degrees C. Neither the CRF antagonist, alpha-helical CRF9-41 (10 or 20 micrograms ICV) nor the prostaglandin synthesis inhibitor indomethacin (50 mg/kg IP) significantly altered the hIL-1 alpha-induced behavioral changes, but naloxone (0.7 mg/kg SC) or sulpiride (5 mg/kg IP) completely prevented them. Our results suggest that intracerebral administration of IL-1 reduces the exploratory behavior of mice. This effect does not apparently involve CRF or prostaglandins, but may involve opioid and dopaminergic systems. This behavioral response to IL-1 administration is consistent with the behavioral effects of IL-1 reported previously, and strengthens the hypothesis that IL-1 secretion may be responsible for behavioral changes associated with immune activation.

Acetylcarnitine reduces the immobility of rats in a despair test (constrained swim).

Male rats forced to swim in a cylinder adopted an immobile posture. Immobility was reduced by acetylcarnitine (5, 10, and 20 mg/kg) and by antidepressant drugs, such as desipramine and iproniazid, injected 24, 5, and, again, 1 h prior to behavioral testing. Acetylcarnitine also potentiated the anti-immobility effect of antidepressant drugs in the despair test. Chronic (10 days) treatment with acetylcarnitine mimicked the effect found after acute administration. It is possible that the action of the acetylcarnitine on the despair test is indicative of an antidepressant activity of this drug that is dependent on a change in the sensitivity of monoamine receptors in the brain.