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Background: Line-field confocal optical coherence tomography (LC-OCT) is a new noninvasive imaging technique that provides high-resolution skin imaging close to histopathology., Objectives: The aim of this study was to evaluate the usefulness of LC-OCT in the diagnosis of herpes virus skin infections., Methods: Patients with a clinical or anamnestic suspicion of herpes virus infection underwent LC-OCT evaluation followed by Tzanck test. The examinations were performed in a blinded manner by different dermatologists., Results: A total of 72 patients (M: 38; F: 34; age range: 13-84) were evaluated. In 57 cases, LC-OCT allowed the recognition of the typical herpetic intraepidermal vesicles containing giant, ballooning/multinucleated cells, as confirmed by Tzanck test. The final diagnosis was herpes simplex in 16 cases, herpes zoster in 31 cases, chickenpox in 8 cases, and Kaposi varicelliform eruption in 2 cases. In the remaining 15 cases, both LC-OCT and Tzanck test excluded the diagnosis of herpetic infections., Conclusions: Although the diagnosis of herpes virus skin infections is generally clinical, in minimal and/or atypical cases, LC-OCT could be a rapid and valid alternative to semi-invasive/invasive and time-consuming procedures, such as Tzanck test, viral cultures, PCR, or histopathology., (© The Author(s) 2025. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

COVID-19 pandemic led to the adoption of a different working approach: "The remote working." Evidence about the association of remote working with stress outcomes and life quality is lacking. This systematic review provides an overview of the effects of COVID-19 pandemic on remote-workers' stress and life quality. We conducted systematic literature searches in databases including Pubmed, Scopus and Web of science, from September 2020 to September 2023. Screening of titles, abstracts, and full texts were performed according to the Preferred Reporting Item for Systematic Review and Meta-analyses. The quality of the included studies was assessed using the Newcastle-Ottawa Scale. The review highlighted possible predictors (work-family conflict or a condition of social isolation) associated with improvement or worsening of quality of life and stress. The results highlighted the association between stress and family difficulties (β: -0.02, P-value <0.05), isolation during the first (β: -0.22, P-value <0.05) and second pandemic waves (β: -0.40, P-value <0.05) or due to the advancing age of workers (β:0.19, P-value <0.05) and (β: -0.05, P-value <0.05), furthermore some job categories presented greater stress such as teachers (16.94 ± 5.46). Conversely, remote working positively affected life quality, enhancing factors such as creativity (Average Variance Extracted, AVE: 0.41, R2: 0.17) and self-efficacy (AVE: 0.60, R2: 0.36). Future research should focus more on the relationship between work and family and on interventions that counteract social isolation., (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Public Health Association.)

Castleman disease is a rare and benign disorder, characterized by enlarged lymph nodes and angiofollicular lymphoid hyperplasia. We report a case of a 57-year-old male, who was admitted to our surgical department because of a retroperitoneal nodular mass measuring about 4 cm in maximum diameter, incidentally discovered on a radiologic exam performed for the onset of vague abdominal pain with posterior irradiation. The patient was subdue to laparoscopic removal of the mass and no intra- and post-operative complications were recorded. Histologic diagnosis of hyaline-vascular variant of the Castleman disease was confirmed. Only two cases have been found in the literature reporting the paraduodenal unicentric Castleman disease localization like our case. Although rare, the Castleman disease must be considered in the differential diagnosis among all the lymph nodes diseases, for avoiding improper therapies., Competing Interests: None declared., (Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2024.)

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are highly effective in improving glycaemic control either as monotherapy or in combination with other hypoglycaemic drugs, and have low incidence of side effects, such as hypoglycaemia, nausea and weight gain, thus increasing patients' adherence to therapy., Methods: In this review we report the most recent studies demonstrating the beneficial effects of GLP-1RAs on renal outcomes, and also discuss the direct and indirect mechanisms through which they confer kidney protection. Finally, we discuss the metabolic and anti-inflammatory effects of GLP-1RAs in diabetic patients with COVID-19 disease., Results: GLP-1RAs have a nephroprotective action, which is expressed through both indirect (improvement of blood pressure and glycaemic control, weight loss) and direct (restoration of normal intrarenal haemodynamics, prevention of ischaemic and oxidative damage) effects. They have shown also metabolic and anti-inflammation beneficial effects in patients with COVID-19 disease., Conclusions: GLP-1RAs prevent albuminuria and slow the decline of renal function towards end stage renal disease in patients with diabetic kidney disease. They might be an opportunity to break the typical inflammation processes of COVID-19 disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Bone marrow is the tissue contained inside the bones and can be considered one of the potential alternative tissues in forensic toxicology. This matrix could be particularly useful in those cases where the routine sample is not available due to an advanced state of decomposition or skeletonization of the corpse. The aim of this study was to develop, validate and apply an analytical method of extraction and analysis of different antidepressants and antipsychotics, commonly used in therapy, from spiked pig ribs. Pig ribs, each of 5 g and 5 cm long, were spiked at three concentration levels (100, 200 and 500 ng/g). For each concentration, 10 pig ribs were prepared. The method involves the leaching by ethanol at different pHs of nine drugs from the inside of ribs, in particular from the bone marrow, without the fragmentation of bone tissue. Following a liquid-liquid purification and extraction, analysis was performed by gas chromatography coupled with mass spectrometry in selected ion monitoring mode. For method validation was assessed linearity, sensitivity, precision and accuracy, matrix interferences and, finally, carryover. Analytical method performance was acceptable respect to acceptance criteria for validation. No matrix interferences were detected; for this reason, it is possible to affirm that this method has a good selectivity. Moreover, the method was not affected by carryover. Considering that the study conducted on pig ribs has given encouraging results, it can be assumed that this method can be used in forensic toxicological protocols (human autopsy cases) as alternative to classic procedures., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: We sought to develop and validate a novel risk assessment tool for the prediction of 30-day mortality after surgical aortic valve replacement incorporating a patient's frailty., Methods: Overall, 4718 patients from the multicentre study OBSERVANT was divided into derivation (n = 3539) and validation (n = 1179) cohorts. A stepwise logistic regression procedure and a criterion based on Akaike information criteria index were used to select variables associated with 30-day mortality. The performance of the regression model was compared with that of European System for Cardiac Operative Risk Evaluation (EuroSCORE) II., Results: At 30 days, 90 (2.54%) and 35 (2.97%) patients died in the development and validation data sets, respectively. Age, chronic obstructive pulmonary disease, concomitant coronary revascularization, frailty stratified according to the Geriatric Status Scale, urgent procedure and estimated glomerular filtration rate were independent predictors of 30-day mortality. The estimated OBS AVR score showed higher discrimination (area under curve 0.76 vs 0.70, P < 0.001) and calibration (Hosmer-Lemeshow P = 0.847 vs P = 0.130) than the EuroSCORE II. The higher performances of the OBS AVR score were confirmed by the decision curve, net reclassification index (0.46, P = 0.011) and integrated discrimination improvement (0.02, P < 0.001) analyses. Five-year mortality increased significantly along increasing deciles of the OBS AVR score (P < 0.001)., Conclusions: The OBS AVR risk score showed high discrimination and calibration abilities in predicting 30-day mortality after surgical aortic valve replacement. The addition of a simplified frailty assessment into the model seems to contribute to an improved predictive ability over the EuroSCORE II. The OBS AVR risk score showed a significant association with long-term mortality., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: To investigate mandibular morphology in adults affected by posterior unilateral crossbite (PUXB) and to evaluate the hemi mandibular volumes from the crossbite (CB) and non-CB sides of the same patients., Methods: Thirty-eight cone beam computed tomography (CBCT) images were consecutively recruited and the Digital Imaging and Communications in Medicine (DICOM)-formatted scans were volume rendered into a surface three-dimensional (3D) mesh model and volumes to obtain the 3D model of the mandibular bone. To achieve the surface point-to-point analysis of the mandibular models, a reverse engineering software was used. The same procedure was performed for an age-matched control group (19 CBCT images)., Results: Total mandibular volume showed a difference of 2.46 cm3 between patients and controls, which was not statistically significant. A mean difference of 1.53 cm3 was found comparing the hemi mandibular volumes from the CB and non-CB sides of PUXB patients, this difference was statistically significant (P ≤ 0.01). Findings for the surface-to-surface deviation analysis, demonstrated a higher percentage of mismatch in patients PUXB, over 10% at 0.5 mm tolerance level., Limitations: Limitations are related to the intrinsic surfaces matching methodology, that make difficult to evaluate discrepancies among different mandibular anatomical units., Conclusion: Adult patients affected by PUXB show a greater mandibular structural asymmetry compared to controls because of a lower matching percentage obtained from the surface-to-surface matching technique., Implications: Treatment of adult patients affected by PUXB should take into consideration the possibility of a mild mandibular asymmetry mainly localized at the condyle and gonial angle levels., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: To validate the set of clinical and biochemical criteria proposed by consensus by the Academic Research Consortium (ARC) for High Bleeding Risk (HBR) for the identification of HBR patients. These criteria were categorized into major and minor, if expected to carry in isolation, respectively, ≥4% and <4% Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding risk within 1-year after percutaneous coronary intervention (PCI). High bleeding risk patients are those meeting at least 1 major or 2 minor criteria., Methods and Results: All patients undergoing PCI at Bern University Hospital, between February 2009 and September 2018 were prospectively entered into the Bern PCI Registry (NCT02241291). Age, haemoglobin, platelet count, creatinine, and use of oral anticoagulation were prospectively collected, while the remaining HBR criteria except for planned surgery were retrospectively adjudicated. A total of 16 580 participants with complete ARC-HBR criteria were included. After assigning 1 point to each major and 0.5 point to each minor criterion, we observed for every 0.5 score increase a step-wise augmentation of BARC 3 or 5 bleeding rates at 1 year ranging from 1.90% among patients fulfilling no criterion, through 4.01%, 5.98%, 7.42%, 8.60%, 12.21%, 12.29%, and 17.64%. All major and five out of six minor criteria, conferred in isolation a risk for BARC 3 or 5 bleeding at 1 year exceeding 4% at the upper limit of the 95% confidence intervals., Conclusion: All major and the majority of minor ARC-HBR criteria identify in isolation patients at HBR., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background and Objectives: Some authors have recently postulated the possibility of a unilateral contraction of the palate in patients with crossbite. This study aimed to investigate palatal dimension size and morphology in subjects with functional posterior crossbite and to localize location of the contraction through a 3D analysis procedure., Materials and Methods: A study sample (SS) of 35 subjects (mean age 9.2 ± 0.8 years), diagnosed with functional crossbite, and a control sample (CS) of 35 subjects (mean age 9.4 ± 0.9 years) without crossbite were selected for this study. The digital models of each patient were analysed to assess palatal dimension size and symmetry by measuring linear distances between primary canines (D1) and fist molars (D2) to the median palatine plane and by performing and analysing the 3D deviation between the two specular models of the palatal vault for each patient., Results: Our findings demonstrate a significantly narrower dimension of D2 for the crossbite side than at the non-crossbite side. The 3D deviation analysis demonstrates a lower matching percentage of the palatal vault models in the SS (83.36%) compared with the CS (92.82%) and a location of that the palatal contraction is at the alveolar bone level., Conclusions: It can be assumed that there is a bilateral symmetrical contraction of the palatal vault and an asymmetric contraction of the alveolar process, but further studies are needed to corroborate this hypothesis.

Background: During rapid maxillary expansion (RME), heavy forces are transmitted to the maxilla by the anchored teeth causing buccal inclination and buccal bone loss of posterior teeth., Objective: To systematically review the literature in order to investigate whether RME causes periodontal sequelae, assessed by cone-beam computed tomography (CBCT)., Search Methods: Fifteen electronic databases and reference lists of studies were searched up to March 2017., Selection Criteria: To be included in the systematic review, articles must be human studies on growing subjects, with transversal maxillary deficiency treated with RME and with assessment of buccal bone loss by CBCT images. Only randomized and non-randomized trials were included., Data Collection and Analysis: Two authors independently performed study selection, data extraction, and risk of bias assessment. Study characteristics (study design, sample size, age, sex, skeletal maturity, type of appliance, daily activation, evaluated linear measurements, observation period, CBCT settings), and study outcomes (loss of buccal bone thickness and marginal bone) were reported according to the PRISMA statement., Results: On the basis of the applied inclusion criteria, only six articles, three randomized clinical trials and three controlled clinical trials were included. An individual analysis of the selected articles was undertaken. The risks of bias of the six trials were scored as medium to low., Limitations: The results of the present systematic review are based on a limited number of studies and only one study included a control group., Conclusions and Implications: In all considered studies, significant loss of buccal bone thickness and marginal bone level were observed in anchored teeth, following RME. Further prospective studies correlating the radiological data of bone loss to the periodontal soft tissues reaction after RME are required. A preliminary evaluation of the patient-related risk factors for RR may be advisable when considering to administering RME., Registration: This systematic review was registered in the National Institute of Health Research database with an appropriate protocol number (http://www.crd.york.ac.uk/PROSPERO Protocol: CRD42017062645)., Funding: The present study has not received any contributions from private or public funding agencies.

A previous Task Force of the European Society of Cardiology (ESC) and European Association of Percutaneous Cardiovascular Interventions (EAPCI) provided a report on recommendations for the non-clinical and clinical evaluation of coronary stents. Following dialogue with the European Commission, the Task Force was asked to prepare an additional report on the class of devices known as bioresorbable scaffolds (BRS). Five BRS have CE-mark approval for use in Europe. Only one device-the Absorb bioresorbable vascular scaffold-has published randomized clinical trial data and this data show inferior outcomes to conventional drug-eluting stents (DES) at 2-3 years. For this reason, at present BRS should not be preferred to conventional DES in clinical practice. The Task Force recommends that new BRS devices should undergo systematic non-clinical testing according to standardized criteria prior to evaluation in clinical studies. A clinical evaluation plan should include data from a medium sized, randomized trial against DES powered for a surrogate end point of clinical efficacy. Manufacturers of successful devices receive CE-mark approval for use and must have an approved plan for a large-scale randomized clinical trial with planned long-term follow-up.

Clinical differentiation between pityriasis lichenoides chronica (PLC) and guttate psoriasis (GP) may sometimes be a difficult task, which often requires histological analysis to reach a definitive diagnosis. In this study, PLC and GP lesions were examined using dermoscopy, and the significance of specific dermoscopic findings was investigated in order to facilitate their differentiation and decrease the number of cases requiring biopsy. We found that the incidence of orange-yellowish structureless areas, focal dotted vessels and nondotted vessels was statistically significant in PLC, while the incidence of diffuse dotted vessels was statistically significant in GP., (© 2015 British Association of Dermatologists.)

An efficient β-glucosidase (βG)-producing strain, Wickerhamomyces anomalus BS81, was isolated from naturally fermented olive brine and identified based on PCR/restriction fragment length polymorphism of the rDNA internal transcribed spacer and sequence analysis of the D1/D2 region of the 26S rRNA gene. The hydrolytic activity of the βG had an optimum pH of 8.5 and an optimum temperature of 35 °C. The enzyme had high substrate specificity and high catalytic efficiency (K(m) 0.99 mM, V(max) 14 U g(-1) of cells) for p-nitrophenyl-β-d-glucopyranoside. The enzyme was activated by increasing concentrations of NaCl, with maximum activity at 150 g L(-1) NaCl. Although βGs have been purified and characterized from several other sources, the W. anomalusβG is unique among βGs because its relative maximum activity occurs at alkaline pH and 35 °C. Moreover, the yeast strain has esterase activity that acts synergistically with βG to degrade oleuropein to debitter table olives and olive oil., (© 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.)

We have evaluated the effects of the carbon monoxide-releasing molecule CORM-A1 [Na(2) (BH(3) CO(2) ); ALF421] on the development of relapsing-remitting experimental allergic encephalomyelitis (EAE) in SJL mice, an established model of multiple sclerosis (MS). The data show that the prolonged prophylactic administration of CORM-A1 improves the clinical and histopathological signs of EAE, as shown by a reduced cumulative score, shorter duration and a lower cumulative incidence of the disease as well as milder inflammatory infiltrations of the spinal cords. This study suggests that the use of CORM-A1 might represent a novel therapeutic strategy for the treatment of multiple sclerosis., (© 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.)

Introduction: Peyronie's disease (PD) is a connective tissue disorder of tunica albuginea (TA), a thick fibrous sheath surrounding the corpora cavernosa of the penis. Relatively, little is known about the disease itself., Aim: To investigate whether the apoptosis cascade in degenerated and macroscopically deformed TA from men with PD is activated through the extrinsic pathway, by assessing the immunoexpression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptor, DR5., Methods: TA plaques from 15 men with PD and from four unaffected men were processed for TRAIL and DR5 immunohistochemistry and Western blot analysis., Main Outcome Measures: A greater understanding of the pathophysiology of PD through a molecular approach, to gain insights that may lead to novel forms of treatment., Results: Activation of the apoptosis mechanisms through the extrinsic pathway was demonstrated by TRAIL and DR5 overexpression in fibroblasts and myofibroblasts from affected TA., Conclusion: The finding that apoptosis activation in TA plaques occurs, at least in part, via the extrinsic pathway may help devise novel therapeutic options for these patients., (© 2010 International Society for Sexual Medicine.)

Objectives: Radiotherapy may cause severe skin changes that significantly interfere with the patient's quality of life and reduce radiotherapy effectiveness. Many skin care instructions and various topical agents are recommended to help patients in the management of radiation skin reactions, but evidence to support the value of the topical treatments of the irradiated skin is lacking. In the present study we investigated the effects of topical agents used as supportive care to minimise radiation-induced skin disease using an instrumental method., Methods: Subjects who were undergoing a planned course of radiation therapy after breast-conserving surgery were randomised to treatment (using one of two topical agents) or non-treatment (control) groups and monitored over 8 weeks. The intensity of skin erythema was evaluated once per week by non-invasive instrumental reflectance spectrophotometry in comparison with a visual scoring system., Key Findings: Examination of the erythema time course by a sensitive spectrophotometric reflectance method showed a significant increase of skin reactions in the non-treated group after the second week of treatment and maximal alterations between the fourth and sixth week., Conclusions: From the results obtained, we observed that application of topical agents used in radio-induced skin disease were able to significantly reduce the erythema extent compared to the non-treated group.

Aims: To investigate the in vitro antiviral activity of Melaleuca alternifolia essential oil (TTO) and its main components, terpinen-4-ol, alpha-terpinene, gamma-terpinene, p-cymene, terpinolene and alpha-terpineol., Methods and Results: The antiviral activity of tested compounds was evaluated against polio type 1, ECHO 9, Coxsackie B1, adeno type 2, herpes simplex (HSV) type 1 and 2 viruses by 50% plaque reduction assay. The anti-influenza virus assay was based on the inhibition of the virus-induced cytopathogenicity. Results obtained from our screening demonstrated that the TTO and some of its components (the terpinen-4-ol, the terpinolene, the alpha-terpineol) have an inhibitory effect on influenza A/PR/8 virus subtype H1N1 replication at doses below the cytotoxic dose. The ID(50) value of the TTO was found to be 0.0006% (v/v) and was much lower than its CD(50) (0.025% v/v). All the compounds were ineffective against polio 1, adeno 2, ECHO 9, Coxsackie B1, HSV-1 and HSV-2. None of the tested compounds showed virucidal activity. Only a slight virucidal effect was observed for TTO (0.125% v/v) against HSV-1 and HSV-2., Conclusions: These data show that TTO has an antiviral activity against influenza A/PR/8 virus subtype H1N1 and that antiviral activity has been principally attributed to terpinen-4-ol, the main active component., Significance and Impact of the Study: TTO should be a promising drug in the treatment of influenza virus infection.

The aim of the study was to evaluate the craniofacial morphology in Caucasian patients with sickle cell disease (SCD) by comparing them with a healthy group paired for gender and age, by means of lateral cephalometric radiographs. Thirty-six Sicilian patients with SCD (17 females and 19 males), including 14 beta(s)beta(s) (mean age 28 +/- 5.9 years), 13 beta(s)beta(0 th) (mean age 27.5 +/- 8 years), and nine beta(s)beta(+th) (mean age 32.8 +/- 9.9 years) were examined. The control group consisted of 36 subjects (mean age 28.9 +/- 8 years) without recognized haematological abnormalities. The means and standard deviations were calculated for each cephalometric variable. A two-sample t-test was used to compare the means between the study and control groups. One-way analysis of variance and Dunnet's multiple comparison test were used in order to analyse the differences between the control group and the subgroups divided according to genotype. The level of significance used was P<0.05. The cephalometric findings indicated a posterior rotation of the mandible and a tendency towards a vertical pattern (clockwise), with lower (P=0.000) and total (P=0.002) face heights increased in comparison with the control sample. These findings were more pronounced in subjects with SCD (beta(s)beta(s)). In all patients, there was a significantly greater maxillary incisor proclination than in the control group. The upper first molar position to the PTV line was significantly increased but only in patients with compound heterozygosis beta(s)beta(th). The SCD patients did not exhibit the craniofacial abnormalities noted in black American patients with SCD; the craniofacial features observed, reflecting the degree of clinical expression of SCD in Sicilian patients, were of moderate severity.

Introduction: The recent availability of noninvasive pharmacological remedies for male sexual function triggered an exponential increase in the number of men requesting help in the sexuality area., Aim: The Italian Society of Andrology explored requests for help, not included in formerly established clinical categories of sexual medicine., Methods: A central board of 67 andrologists identified new areas of requests for help, instrumental for a web-based questionnaire, forwarded to 912 members of the Italian Society of Andrology. Results were submitted to an independent consensus development panel., Main Outcome Measures: A questionnaire response rate of 30.8% was considered acceptable according to standard response rates of medical specialist samples., Results: The Central Board interaction identified two new domains of requests for help: sexual distress and unconventional requests for pro-erectile medications. Web-based questionnaire results suggested that such domains account for 29% and 9% respectively of all requests for help already presented by male patients at sexual medicine clinics. The Independent Consensus Development Panel issued a final consensus document; herewith, the statement defining male sexual distress: A non-transitory condition and/or feeling of inadequacy such as to impair "sexual health" (WHO working definition). Inadequacy can originate both from physiological modifications of male sexual functions, and from diseases, dysfunctions, dysfunctional symptoms and dysmorphisms, both of andrological and non-andrological origin, which do not relate to "erectile dysfunction" (NIH Consensus Development Panel definition), but that might also induce erectile dysfunction. Sexual Distress can lead to a request for help which needs to be acknowledged., Conclusion: The Italian Society of Andrology identified two new areas of requests for help concerning male sexual issues: sexual distress and unconventional requests for pro-erectile medications. These domains, which do not represent new diseases, nonetheless induce the sufferers to seek help and, accordingly, need to be acknowledged.

Unlabelled: We present an in silico model that simulates the immune system responses to tumor cells in naive and vaccinated mice. We have demonstrated the ability of this model to accurately reproduce the experimental results., Motivation: In vivo experiments on HER-2/neu mice have shown the effectiveness of Triplex vaccine in the protection of mice from mammary carcinoma. Full protection was conferred using chronic (prophylactic) vaccination protocol while therapeutic vaccination was less efficient. Our in silico model was able to closely reproduce the effects of various vaccination protocols. This model is the first step towards the development of in silico experiments searching for optimal vaccination protocols., Results: In silico experiments carried out on two large statistical samples of virtual mice showed very good agreements with in vivo experiments for all experimental vaccination protocols. They also show, as supported by in vivo experiments, that the humoral response is fundamental in controlling the tumor growth and therefore suggest the selection and timing of experiments for measuring the activity of T cells., Contact: francesco@dmi.unict.it, Supplementary Information: http://www.dmi.unict.it/CIG/suppdata&#95;bioinf.html.

Background: The aim of this prospective study was to evaluate the effects of the new monophasic oral contraceptives on the audiological system in premenopausal women., Methods: The auditory brainstem response (ABR) was measured in 94 women during the follicular, periovular and luteal phases of one menstrual cycle in which ovulation was confirmed using sonography and serum progesterone concentration. The latencies for waves I, III and V were determined, and the inter-peak intervals were calculated for waves I-III, I-V and III-V. All 94 women began taking oral contraceptives: 23 women used 20 microg ethinyl estradiol (EE) plus 150 microg desogestrel, 24 women used 30 microg EE plus 75 microg gestodene, and 47 women used 15 microg EE plus 60 microg gestodene. During the third month of contraceptive intake, each subject was again tested for ABR, as above., Results: The wave latencies and inter-peak intervals showed shorter values during the periovular phase with respect to the luteal phase (P < 0.05), the follicular phase for wave I and for inter-peak interval I-V (P < 0.05) of the menstrual cycle. All of the ABR results in pill users were statistically different from those of the periovular phase (P < 0.05), though similar to those of both the luteal and follicular phases (P = NS)., Conclusions: ABR seems to depend on the variations of ovarian steroids during the menstrual cycle and during oral contraceptive intake.

Background: It has been suggested that changes in immune response to infectious agents in patients on haemodialysis might be due to impaired monocyte function; uraemic and haemodialysed patients overproduce proinflammatory cytokines, such as interleukin-1 beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6)., Methods: We quantitated the cytokines released into the plasma and into the supernatants of 24-h cultured purified monocytes, under basal conditions and after stimulation by lipopolysaccharide from Escherichia coli, in 15 healthy subjects (CON), 20 uraemic patients who had not yet started dialysis (CRF) and 60 haemodialysed patients (HD), who were divided into three groups of 20 patients corresponding to short-, medium- and long-term dialysis., Results: Monocytes from HD patients spontaneously secreted significantly higher levels of cytokines than those from controls and uraemic patients who had not yet started dialysis. After stimulation with lipopolysaccharide (LPS), cytokine levels in culture supernatants of cells from HD patients were significantly lower than those from controls and uraemic patients. Moreover, levels of cytokines in monocyte supernatants and plasma from short-, medium- and long-term haemodialysed patients decreased progressively with dialytic age. Monocytes from haemodialysed patients tended to be constitutively active, but their ability to secrete proinflammatory cytokines was inversely correlated with dialytic age., Conclusions: These results indicate that prolonged treatment with dialysis can be considered a form of chronic stress that causes the progressive activation of monocytes, which ultimately leads to monocyte exhaustion and dysfunction.

In the search for novel compounds to treat disorders of smooth muscle function, efforts have focused on some 2-substituted thieno[2,3-d]pyrimidin-4-one derivatives that show interesting spasmolytic action. Our laboratories have developed a new series of quaternary salts of 2-substituted thieno[2,3-d]pyrimidin-4-one and thieno[3,2-d]pyrimidin-4-one isomers with therapeutic potential. Thesesubstances were prepared starting from simple derivatives of thiophene. Their spasmolytic activity was evaluated on transmurally stimulated guinea-pig ileum. The most active compounds (IC50 1.12-2.71 microM) 7f-7h, 12d and 12f had the terminal piperidino nucleus in the thioalkyl chain and lacked two methyl groups in the thiophene ring. Their relaxant activity on the isolated ileum was potentiated (approx. 20-25%) by phosphodiesterase inhibitors. Compounds 7f-h, 12d and 12f were less effective in inhibiting contractions of the guinea-pig ileum induced by acetylcholine (IC50 26.7-41.4 microM) or histamine (IC50 41.5-63.4 microM) and had a moderate binding activity to muscarinic receptors in membrane homogenates from the rat heart (M2 sites; pKi values between 5.55+/-0.08 and 5.14+/-0.12; n = 3) and submaxillary gland (M3 sites; pKi values between 6.15+/-0.07 and 5.76+/-0.08; n = 3). Action involving soluble guanylyl cyclase or any potential binding to guinea-pig ventricular L-type calcium channels was not considered likely. It is concluded that at least two different mechanisms of action contribute to their spasmolytic activity.

Background: We have recently shown that patients with prostato-vesiculo-epididymitis (PVE) have a greater reactive oxygen species (ROS) overproduction than patients with prostatitis or prostato-vesiculitis. Since this biochemical stress persists even after treatment with antimicrobials, it may relate to an imbalance between pro- and anti-oxidant factors at the epididymal level., Methods: To evaluate the effects of antioxidant treatment of patients with PVE, whether in the presence or absence of pro-oxidant factors, abacterial PVE infertile patients with normal (<1x10(6)/ml, group A, n = 34) or abnormal (>1x10(6)/ml, group B, n = 20) seminal white blood cell (WBC) concentrations received carnitines (L-carnitine 1 g and acetyl-carnitine 0.5 g twice/day) for 3 months followed by a wash-out period of 3 months. Semen parameters, ROS production and pregnancy outcome were evaluated before, during and following carnitine treatment., Results: Carnitines increased sperm forward motility and viability in group A patients. This was associated with a significant reduction in ROS production which persisted during wash-out. Carnitines increased only the percentage of viable spermatozoa in group B patients. Within 3 months after the discontinuation of carnitines, the rate of spontaneous pregnancy in group A patients was significantly higher than that of group B patients, being 11.7% (4/34) compared with 0%., Conclusion: These results indicate that carnitines are only an effective treatment in patients with abacterial PVE and elevated ROS production when seminal WBC concentration is normal.

A large proportion of patients with oligoasthenoteratozoospermia (OAT) have an abnormal karyotype and hence they produce aneuploid gametes. However, a normal karyotype does not exclude the chance of having germ cell aneuploidy, since an altered intra-testicular environment not only damages spermatogenesis, but may also disrupt the mechanisms controlling chromosomal segregation during meiosis. Therefore, this study was undertaken to evaluate the rate of aneuploidy in the spermatozoa of selected patients with abnormal sperm parameters. For this purpose, sperm aneuploidy rate for chromosomes 8, 12, 18, X and Y was evaluated by multicolour fluorescence in-situ hybridization (FISH) in nine patients with teratozoospermia alone and 19 OAT patients of presumably testicular origin. Thirteen normozoospermic healthy men served as controls. Patients with teratozoospermia or OAT had significantly greater disomy and diploidy rates compared with controls, whereas the rate of nullisomy was similar. XY disomy was very low in all groups, suggesting that chromosomal non-disjunction occurs mainly during the second meiotic division. Autosome 12 disomy rate was low in both patients and controls. There was a marked variability of total sperm aneuploidy rate in both groups of patients. Sperm aneuploidy rate was negatively correlated with sperm concentration and particularly with the percentage of normal forms. In conclusion, patients with teratozoospermia or OAT have an increased rate of sperm aneuploidy. This increase is similar in both groups, suggesting that teratozoospermia may be the critical sperm parameter associated with aneuploidy.

Sedum telephium L. is a medicinal plant used in antiquity to cure many types of inflammatory skin diseases. The leaves (without the external cuticle), are used to promote healing and reduce skin inflammation and pain, and contain various components. We found two major components: flavonol glycosides and polysaccharides, with molecular weight between 13,000 and 13,500 Da. We evaluated the in-vitro antioxidant and in-vivo skin photoprotective effects of three lyophilized extracts obtained from the juice of S. telephium L. leaves: a total lyophilized juice, a lyophilized flavonolic fraction, and a lyophilized polysaccharidic fraction. Two in-vitro models were used: the bleaching of the stable 2,2-diphenyl-1-picrylhydrazyl (DPPH*) radical, and the protective effect against UV-induced peroxidation on phosphatidylcholine multilamellar vesicles, as model membranes. The antioxidant/radical scavenging activity of each lyophilized extract was also assessed in-vivo by determining their ability to reduce UVB-induced skin erythema (monitored by reflectance spectrophotometry) in healthy human volunteers. The findings of the in-vitro experiments clearly demonstrated that, unlike the lyophilized polysaccharidic fraction, the lyophilized flavonolic fraction and total lyophilized juice possess strong antioxidant/free radical scavenging properties, which are likely due to phenolic compounds. Consistent with these findings, gel formulations of both the total lyophilized juice and, to a greater degree, the lyophilized flavonolic fraction appeared to possess a strong protective effect against UV-induced skin erythema in-vivo, whereas the lyophilized polysaccharidic fraction was completely ineffective. The in-vitro and in-vivo results suggest that, both the total lyophilized juice and, in particular, the lyophilized flavonolic fraction, but not the lyophilized polysaccharidic fraction of S. telephium L. leaves, have photoprotective effects against UVB-induced skin damage.

It has recently been proposed that hyperinsulinaemic insulin resistance and increased ovarian cytochrome P-450c17alpha activity, two features of the polycystic ovary syndrome (PCOS), are pathogenetically linked. The aim of the present study was to test the hypothesis of the linkage between hyperinsulinaemia and supranormal activity of cytochrome P-450c17alpha using the human chorionic gonadotrophin (HCG) challenge, which is a more direct ovarian stimulus than gonadotrophin-releasing hormone (GnRH) in detecting modifications in ovarian steroidogenesis. Eleven women with insulin resistance-related PCOS were studied. HCG (10 000 IU) was given i.m., and blood samples were obtained 0, 8, 12, 16 and 24 h thereafter. Next day, metformin was given at a dose of 500 mg three times a day for 30-32 days, at which time the pretreatment study was repeated. Two women ovulated after metformin treatment. The administration of metformin was associated with a decrease in area under the curve for insulin during a 2h, 75g oral glucose tolerance test, in plasma free testosterone concentrations and an increase in plasma sex hormone binding globulin concentration. The plasma 17-hydroxyprogesterone response to HCG was significantly lower after metformin treatment. The present study gives a direct demonstration that metformin leads to a reduction in stimulated ovarian cytochrome P-450c17alpha activity in women with polycystic ovary syndrome.

The effects on insulin secretion and on the glycaemic and androgen status before and after short-term treatment with octreotide were evaluated in 16 normal weight patients with polycystic ovarian syndrome (PCOS). Hyperinsulinaemia was determined by measuring the insulin response after oral glucose tolerance test (OGTT). Seven patients (group A) were classified as normoinsulinaemic, while nine patients (group B) were considered hyperinsulinaemic according to insulin response after OGTT. Octreotide treatment did not modify either glycaemic or insulinaemic response after OGTT, or androgen profile, in normoinsulinaemic patients. On the contrary, a significant decrease in the basal concentrations of luteinizing hormone (LH), testosterone and androstenedione, and a significant increase in serum concentrations of sex hormone-binding globulin (SHBG) were observed in the hyperinsulinaemic group of patients, in which we observed also a significant decrease of insulinaemic response and a decompensation of the glycaemic profile after OGTT. Our study is the first report showing that: (i) octreotide does not appear to significantly influence pituitary release of gonadotrophins in this group of PCOS patients; (ii) octreotide is able to reduce insulin release, LH and androgen concentrations in lean PCOS patients with hyperinsulinaemia. Due to the presence of a decompensation of glucose homeostasis during treatment, octreotide does not seem advisable for long-term therapy of hyperandrogenism in lean PCOS patients with hyperinsulinaemia.

Objective: Tight fundoplication is a well known complication of surgery for gastroesophageal reflux. We have noted, in clinical experience, that some patients operated for gastro-oesophageal reflux develop pharyngo-oesophageal dysphagia. This study was undertaken to elucidate, by comparing motility data in patients with and without tight fundoplication, the pathophysiologic characteristics of the swallowing mechanism and to clarify the cause of dysphagia in these patients., Methods: Sixteen patients with postoperative persistent dysphagia following a fundoplication have been studied, of those 10 presented a lower oesophageal sphincter resting pressure above or equal to 30 mmHg (group A). Clinical work-up included a questionnaire, oendoscopy, manometry and barium meal or video-roentgenography. Oesophageal manometry was performed using a slow pull through technique while the stationary pull through technique was used for the pharyngo-oesophageal segment. The following parameters were evaluated: (a) amplitude of pharyngeal contraction; (b) upper oesophageal sphincter resting pressure; (c) amplitude of upper oesophageal sphincter contraction; (d) amplitude of oesophageal contraction; (e) lower oesophageal sphincter resting pressure. The results were compared to those of 21 patients who had a fundoplication with normal lower oesophageal sphincter pressure (group B)., Results: in group A there were three males and seven females, with a mean age of 51 years (ranging from 28 to 60 years). Previous operations were Nissen in two and Nissen Rossetti in eight patients. Three out of 10 patients of group A presented pharyngo-oesophageal dysphagia. Mean lower oesophageal sphincter 36 versus 21 mmHg and upper oesophageal sphincter 86 versus 42 mmHg resting pressure, pharyngeal 147 versus 76 mmHg and oesophageal amplitude, upper oesophageal contraction 251 versus 103 mmHg were significantly higher in patients of group A versus group B. An increased number of repetitive contractions was also found in group A. The presence of a strong correlation was demonstrated between the pharyngeal amplitude and the closing tone of the upper oesophageal sphincter (R2 0.742 and R2 0.739) in both groups., Conclusion: Tight fundoplication is, in our experience, always associated with total fundoplication. The appearance of pharyngo-oesophageal dysphagia in the postoperative period in patients operated on to correct gastroesophageal reflux using a total fundoplication, should not be under-estimated because it suggests an obstruction of the distal oesophagus.

The potential of liposomes as an in-vivo ophthalmic drug delivery system for acyclovir was investigated. The drug-membrane interaction was evaluated by means of differential scanning calorimetry analysis. These experiments showed that acyclovir is able to interact with both positively and negatively charged membranes via electrostatic or hydrogen bonds. No interaction was observed with neutral membranes made up of dipalmitoylphosphatidylcholine. Different liposome preparation procedures were carried out to encapsulate acyclovir. The drug encapsulation mainly depends on the amount of water which the liposome system is able to entrap. In the case of multilamellar vesicles, charged systems showed the highest encapsulation efficiency. No particular difference in the encapsulation efficiency was observed for oligolamellar vesicles prepared with the reverse-phase evaporation technique. Oligolamellar liposomes showed the highest acyclovir encapsulation parameters and had release profiles similar to those of multilamellar liposomes. In-vivo experiments using male New Zealand albino rabbits were carried out to evaluate the aqueous humour concentration of acyclovir bioavailability. The most suitable ophthalmic drug delivery system was oligolamellar systems made up of dipalmitoylphosphatidylcholine-cholesterol-dimethyldioctadecyl glycerole bromide (7:4:1 molar ratio), which presented the highest encapsulation capacity and were able to deliver greater amounts of the drug into the aqueous humour than a saline acyclovir solution or a physical liposome/drug blend.

The increased incidence of tubercular diseases in industrialized countries appears to be due to several factors, including development of resistance to the most commonly used specific chemotherapeutic substances, unsuitable control programmes, HIV infection, the increased influx of immigrants, and homelessness. Different forms of cutaneous tuberculosis are caused by different species of mycobacteria (e.g., Mycobacterium tuberculosis, M. bovis, M. avium). Determining the species of mycobacteria is relevant when disease is suspected to be linked to the type of employment of the patient, mainly because the clinical features do not always indicate which species is the cause of the infection. Mycobacterium tuberculosis (MT) usually infects through the lung, but in rare cases can penetrate the skin or mucous membranes. Skin transmission can be exogenous by inoculation, or endogenous by diffusion (lymphatic or hematic) or by contiguity. The immunologic status of the patient is a crucial factor which influences the clinical variants and the course of disease itself. Here we report a case of an illegal immigrant who presented with a bilateral, symmetrical ulcer on the neck.

The clinical behavior and outcome was evaluated in 21 nonoccult differentiated thyroid carcinomas occurring in Graves' patients during the period 1982-94 and compared with that of matched tumors occurring in euthyroid controls (n = 70). At surgery, patients with Graves' disease showed distant metastases more frequently than euthyroid patients (3/21 = 14.3% vs. 1/70 = 1.4%, P = 0.0556). Graves' patients also showed a significantly higher cumulative risk of recurrent/progressive distant metastases or total adverse events (odd ratios = 3.14 and 2.07, respectively) as compared with euthyroid patients. At the last follow-up visit, persistence of distant metastases was also more frequent in the Graves' group (P = 0.007), although the cumulative individual dose of radioiodine administered was higher than in the control group (median dose = 805 mCi vs. 350 mCi). Two patients died in the Graves' group vs. none in the control group. Circulating thyroid stimulating antibodies were present in all patients but one and persisted as long as signs of disease were evident. These findings indicate that differentiated thyroid carcinomas in patients with Graves' disease are more aggressive than those occurring in matched euthyroid controls and should, therefore, be managed accordingly.

A 16S/23S ribosomal spacer from a Haemophilus parainfluenzae rrn locus was cloned and sequenced. Analysis of PCR-amplified genomic fragments showed that this region is strongly conserved among unrelated isolates; computer analysis of database homologies showed that the spacer consists of sequence blocks, arranged in a mosaic-like structure, with strong homologies with analogous blocks present in the spacer regions of Haemophilus influenzae, Haemophilus ducreyi and Actinobacillus spp. It also contains a tRNA(Glu) gene, which is highly homologous to tRNA(Glu) genes found in spacers of other species. These data strongly support the hypothesis that recombination events are involved in the organisation of the sequence of the spacer, as a result of horizontal gene transfer.

This study examined the karyotype, the fermentation performance and the optimum growth temperature (Topt) of 28 yeast strains all identified as species belonging to Saccharomyces sensu stricto. The strains were isolated from fermented musts, which had not been inoculated, at two temperature ranges: 20-40 degrees C and approximately 0-6 degrees C. The results demonstrated a correlation between the Topt and the chromosome organization. In particular, strains with Topt of less than 30 degrees C showed only two bands in the region between 365 and 225 kb, while those with a Topt greater than 30 degrees C had three bands in this size range. From a taxonomic viewpoint, the Topt is a better indicator for the Saccharomyces sp. than the ceiling temperature of 37 degrees C currently used to differentiate cryotolerant Saccharomyces bayanus and S. pastorianus from non-cryotolerant S. cerevisiae and S. paradoxus strains.

A case of solitary osteoma of the parietal skull is described in a mother and her 12-year-old son. There were no other craniofacial or dysmorphic features and there was no history of previous cranial trauma or inflammatory process and no radiographic evidence of other skeletal lesions in both patients. Family history was otherwise unremarkable. Gardner syndrome was ruled out by excluding other associated clinical abnormalities and by family history. The clinical and radiological features of the patients' osteomas were different from those of Albright hereditary osteodystrophy, fibrodysplasia ossificans progressiva, progressive osseous heteroplasia and familial ectopic ossification. To the author's knowledge this is the first case of the familial presentation of osteomas.

The first pathogenic mechanism of Porphyromonas gingivalis, which is mainly responsible for adult periodontal diseases, is the attachment of fimbriae appendages to oral epithelial cells. The ability of a subinhibitory concentration of azithromycin to inhibit the expression of fimbriae in various strains of P. gingivalis isolated was investigated. A one-eighth subinhibitory concentration of azithromycin was evaluated in vitro. The antibiotic was active in 75% of P. gingivalis strains isolated, judged by both electrophoresis and transmission electron microscopy. The results indicate that the subinhibitory concentration of azithromycin is capable of blocking the pathogenic mechanism of P. gingivalis in vitro, and, therefore, can be used in vivo as a treatment for recurrent periodontitis.

To investigate the clinical impact of Met/hepatocyte growth factor receptor (HGF-R) expression in thyroid cancer we studied 163 thyroid carcinomas (129 papillary, 21 follicular, and 13 anaplastic) from patients followed-up for 25-147 months postthyroidectomy. Forty-nine thyroid adenomas were also studied. Met/HGF-R expression was evaluated by semiquantitative immunohistochemistry, measuring both the proportion (scale of 0-5) and the intensity (scale, 0-5) of stained cells and calculating a total score (scale of 0-10). Met/HGF-R was absent in the normal thyroid tissue, absent or focally expressed in follicular and anaplastic tumors, and expressed at various levels in most papillary carcinomas, including microcarcinomas. Papillary carcinomas were thus categorized as having negative/low Met/HGF-R (n = 50; total score, < or = 5) or high Met/HGF-R expression (n = 70; total score, > 5). High Met/HGF-R was inversely associated with vascular invasion (P = 0.0308), but not with other prognostic factors. Negative/low Met/HGF-R expression was the most effective predictor by multivariate Cox analysis of distant metastases (hazard ratio = 9.71; P = 0.0036), higher than extrathyroid invasion (hazard ratio = 4.25; P = 0.0181), age (< or = 45 vs. > 45 yr; hazard ratio = 3.99; P = 0.0099), and vascular invasion (hazard ratio = 3.19; P = 0.0358). These findings suggest a role for Met/HGF-R in papillary thyroid cancer and its clinical use to select patients with a high risk of distant metastases.

It is a common clinical observation that stress is accompanied by dysfunction of the hypothalamic-pituitary-ovarian axis, and there is mounting experimental evidence that CRH, the principal regulator of ACTH release and the central coordinator of the stress response, is able to suppress gonadal function by inhibiting hypothalamic GnRH release. Recently, it has been shown that immunoreactive CRH, CRH messenger RNA, and CRH receptors are also present in the ovary. This prompted us to examine the role of CRH on ovarian function. To accomplish this, we studied the effects of this neuropeptide on estrogen production and cAMP intracellular content from rat granulosa and human granulosa-luteal cells. We also evaluated the activity of the enzyme aromatase by measuring the production of tritiated water from homogenates of cultured rat granulosa cells. CRH inhibited FSH-stimulated estrogen production from rat granulosa cells in a dose-dependent fashion. The maximal effect was achieved at a concentration of 10(-8) M, which suppressed estrogen production by about 30%. Low concentrations of CRH (10(-10) M), incapable of modulating maximal estrogen production in response to FSH, provoked a right-ward shift of the estrogen dose-response curve to FSH. CRH (10(-8) M) suppressed the production of tritiated water (equivalent to estrogen production) from homogenates of rat granulosa cells incubated with a half-maximal concentration of FSH. Basal estrogen production by human granulosa-luteal cells was also inhibited by CRH at a concentration of 10(-10) M. The maximal effect was achieved with a concentration of 10(-8) M, which lowered estrogen production by 25%. The CRH receptor antagonist alpha-helical CRH-(9-41) antagonized the inhibitory effect of CRH on estrogen production from rat granulosa and human granulosa-luteal cells, whereas alone it had no effect. CRH did not have any effect on the intracellular cAMP content of rat granulosa and human granulosa-luteal cells. In conclusion, these results suggest that CRH is able to suppress estrogen production from rat and human granulosa cells in vitro. This effect seems to be linked to inhibition of aromatase activity in the rat and is independent of cAMP generation. We speculate that CRH may also interfere with hypothalamic-pituitary-gonadal axis function by acting directly at the ovarian level.

Interleukins-1 (IL-1s) are known to inhibit the growth of cultured breast cancer cells. We examined the effects of IL-1 alpha and IL-1 beta on insulin and insulin-like growth factor I (IGF-I) stimulation of cell growth and found that both IL-1s inhibited anchorage-dependent and independent growth of MCF-7 breast cancer cells. In cells incubated with IL-1 beta (100 U/ml), insulin receptor (IR) protein and messenger RNA were increased by 100%, while IGF-I receptor protein and transcript were not significantly changed. These data were confirmed by binding studies. Incubation of MCF-7 cells with IL-1s led, however, to a significant inhibition of IR and IGF-I receptor autophosphorylation (-55%) and phosphotransferase activity (-65%). Also, in 3T3/ HIR rat fibroblasts, transfected with and overexpressing IR, IL-1s decreased insulin-stimulated cell growth in soft agar and IR tyrosine kinase activity. The present findings suggest that IL-1s antagonize the insulin and IGF-I mitogenic effects in MCF-7 cells by blocking the receptor tyrosine kinase activity that is crucial for the mitogenic effect of these factors.

Dose-dependent side effects are frequently observed with immunosuppressive drugs of potential relevance for the immunotherapy of insulin-dependent diabetes mellitus (IDDM), such as CsA and DSP. If CsA and DSP acted synergistically in vivo, their combined use would allow using each compound at lower doses than those required when each drug is given in monotherapy. Consequently, dose-dependent side effects could be reduced and the therapeutic activity maintained or even enforced. Toward this end we studied the effects of combined treatment with CsA and DSP on the course of IDDM in the diabetes-prone (DP)-BB rat. The results show that two 'low' doses of CsA (2 mg/kg) and DSP (1 mg/kg) that are clinically ineffective in suppressing IDDM development in BB rats when administered alone under a prolonged prophylactic regimen (30-105 days old), may successfully prevent, but not cure, the disease when given contemporaneously under the same experimental conditions. The combined treatment was well tolerated, and no side effects were noticed. These data suggest that the combined use of CsA and DSP may deserve consideration for its possible application in the prevention/treatment of human IDDM and other autoimmune diseases.

Experimental evidence suggests a tight relationship between cytokines and the reproductive system. Tumour necrosis factor alpha (TNF alpha), a cytokine produced by activated macrophages and mesenchymal cells, seems to participate in the control of fertility. Therefore, the present study was undertaken to evaluate the concentrations of TNF alpha in the follicular fluid of female patients with immunological infertility, as well as the possible role of this cytokine in follicular development. Concentrations of TNF alpha, 17 beta-oestradiol, progesterone, androstenedione and testosterone were measured in the follicular fluid of patients with immunological infertility and patients with a tubal factor of infertility, who served as a control group. Patients with immunological infertility had significantly higher concentrations of TNF alpha in their follicular fluid compared to the control group. In contrast, oestradiol concentrations were significantly lower in the former group. The intrafollicular concentrations of the other steroids measured did not differ significantly between the two groups. The fertilization rate of ova from follicles included in the study was significantly lower in patients with immunological infertility compared to control subjects (19.1 and 57.1% respectively). In conclusion, this study shows that patients with infertility of immunological origin have increased follicular fluid concentrations of TNF alpha and lower oestradiol concentrations. We speculate that elevated TNF alpha concentrations in the human follicle may negatively influence both ovulation-and fertilization-related events.