A novel approach to nonlinear variable-order fractional viscoelasticity.

This paper addresses nonlinear viscoelastic behaviour of fractional systems with variable time-dependent fractional order. In this case, the main challenge is that the Boltzmann linear superposition principle, i.e. the theoretical basis on which linear viscoelastic fractional operators are formulated, does not apply in standard form because the fractional order is not constant with time. Moving from this consideration, the paper proposes a novel approach where the system response is derived by a consistent application of the Boltzmann principle to an equivalent system, built at every time instant based on the fractional order at that instant and the response at all the previous ones. The approach is readily implementable in numerical form, to calculate either stress or strain responses of any fractional system where fractional order may change with time. This article is part of the theme issue 'Advanced materials modelling via fractional calculus: challenges and perspectives'.

Paracrine activity of heparin-binding EGF-like growth factor in atherogenesis: an immunohistochemical study.

AIM: Cells involved in atherogenesis produce growth factors crucial for the progression of the atherosclerotic lesions. One of them is the heparin-binding EGF-like growth factor (HB-EGF), a member of the epidermal growth factor (EGF) family, synthesized as a transmembrane precursor (proHB-EGF). This anchored insoluble juxtacrine growth factor can be converted into a soluble molecule with paracrine activity and mature HB-EGF is released in the extracellular matrix from the cell surface. HB-EGF is a potent stimulator of cell proliferation, migration and cell motility and several studies show that HB-EGF is associated with pathologies of hyperplasia of smooth muscle cells including atherosclerosis. METHODS: We localized HB-EGF by immunohistochemistry within the atherosclerotic lesions collected from right or left internal carotid artery of 20 patients with evident clinical symptoms. RESULTS: In the 20 samples we tested, the proportion of positive samples was significant. Considering the only positive samples the proportion difference related to the gender of patients was highly significant. CONCLUSION: The aim of our investigation was to better understand if this growth factor exerts its role through a juxtacrine or paracrine mechanism, or both in the process of atherogenesis. According to the results, the paracrine role of HB-EGF was clear.

The Sapienza University of Rome network of automated external defibrillators: a prototype webMap developed to speed access to community defibrillators and increase survival from out-of-hospital cardiac arrest.

OBJECTIVE: In Italy, only around 10% of people who experience out-of-hospital cardiac arrest (OHCA) survive. A large portion of OHCA events in public settings are characterized by an initial shockable rhythm, which requires prompt defibrillation. We aimed to create a system to quickly locate nearby public access automated external defibrillators (AEDs) on the campus of Sapienza University of Rome, the largest public university in Europe. MATERIALS AND METHODS: We developed the AED webMap through a 6-step process involving the: 1) collection of information and geographical coordinates for each AED from the university management system; 2) development of a new geolocation database; 3) integration of information contained in the new database with data provided by university departments; 4) geolocation of AEDs in the Google MyMaps environment; 5) graphic representation of all AEDs on digital map templates using specific symbols, with pop-ups containing additional information for each AED; and 6) publication of the webMap on the university website. RESULTS: The AED webMap was published on the university website (https://www.uniroma1.it/it/pagina/defibrillatori-sapienza-in-rete) and facilitates prompt identification of nearby AEDs by providing: 1) detailed AED geolocalization with interactive pop-up information for each AED, including whether the AED is located internally or externally; 2) the option to use different base maps (e.g., digital street map); 3) calculation and display of the route to reach the chosen AED; and 4) the possibility to migrate towards multiple platforms. CONCLUSIONS: The webMap can help bystanders quickly identify, locate, and reach nearby AEDs present on the campus of the largest public university in Europe, a measure that could help speed defibrillation and maximize the life-saving potential of AEDs in the event of OHCA.

Neurological manifestations in individuals with pure cutaneous or syndromic (Ruggieri-Happle syndrome) phenotypes with "cutis tricolor": a study of 14 cases.

BACKGROUND: The term cutis tricolor describes the combination of congenital hyper- and hypo-pigmented skin lesions in close proximity to each other in a background of normal complexion. This phenomenon has been reported so far: (i) as pure cutaneous trait, (ii) as a part of a complex malformation syndrome (Ruggieri-Happle syndrome--RHS), (iii) as a distinct type (cutis tricolor parvimaculata); (iv) in association with other (e. g., vascular) skin disturbances. AIM: The aim of this study was to define the spectrum of neurological abnormalities in cutis tricolor. METHODS: A retrospective and prospective 14-year study of clinical, electroencephalographic (EEG), neuroradiological (MRI), cytogenetic and ZFHX1B gene studies of 14 individuals (8 M, 6 F; aged 2-28 years) with cutis tricolor (4 pure cutaneous; 10 syndromic) was undertaken. RESULTS: Neurological involvement was recorded in 71.4% (10/14) of the patients [100% (10/10) in RHS and null (0/4) in cases with isolated skin manifestations] and included psychomotor delay (n=8), seizures (n=9), EEG abnormalities (n=6), a behavioural phenotype (n=4), non-specific brain abnormalities (n=6). Genetic analyses excluded ZFHX1B mutations and revealed a 19qter deletion (n=1). CONCLUSIONS: Even though we could not exclude the ascertainment and referral biases, we concluded that cutis tricolor may be a marker of underlying neurological involvement particularly in subjects with a syndromic (RHS) phenotype.

Proteases and chronic leg ulcers.

AIM: The aim of this study was to compare the effect of cadexomer on reducing wound surface area of leg ulcers compared to that obtained in a group patients whose ulcers were treated by compression therapy. METHODS: For each ulcer group, wound surface area was calculated at day 0 and after 28 days of treatment: this allowed to calculate the average wound surface area reduction, the percent reduction in wound size, as well as the weekly wound size reduction index. RESULTS: In the cadexomer-treated ulcers the total wound area reduction was 9.67 cm(2)/week, with a weekly wound size reduction index per patient of 0.96 cm(2); in the controls (compression therapy-treated patients) the total wound area reduction was 6.11 cm(2)/week, with a weekly reduction index per patient of 0.61 cm(2). At the end of treatment, in the group of patients whose ulcers were treated with cadexomer ointment the average wound size reduction was 43%, whereas in the control-treated patient group the average wound size reduction was 28%. CONCLUSION: These data suggest that cadexomer can play an important role in the healing of chronic leg ulcers.

Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer.

PURPOSE: To evaluate whether two commonly used newer platinum-based regimens offer any advantage over vinorelbine-cisplatin (reference regimen) in response rate for patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naive patients were randomized to receive gemcitabine 1,250 mg/m(2) days 1 and 8 plus cisplatin 75 mg/m(2) day 2 every 21 days (GC arm), or paclitaxel 225 mg/m(2) (3-hour infusion) then carboplatin (area under the concentration-time curve of 6 mg/mL x min), both on day 1 every 21 days (PCb arm), or vinorelbine 25 mg/m(2)/wk for 12 weeks then every other week plus cisplatin 100 mg/m(2) day 1 every 28 days (VC arm). RESULTS: Six hundred twelve patients were randomized to treatment (205 GC, 204 PCb, and 203 VC). Overall response rates for the GC (30%) and PCb (32%) arms were not significantly different from that of the VC arm (30%). There were no differences in overall survival, time to disease progression, or time to treatment failure. Median survival for the GC, PCb, and VC groups was 9.8, 9.9, and 9.5 months, respectively. Neutropenia was significantly higher on the VC arm (GC 17% or PCb 35% v VC 43% of cycles, P <.001), as was thrombocytopenia on the GC arm (GC 16% v VC 0.1% of cycles, P <.001). Alopecia and peripheral neurotoxicity were most common on the PCb arm, as was nausea/vomiting on the VC arm (P <.05). CONCLUSION: Efficacy end points were not significantly different between experimental and reference arms, although toxicities showed differences. These findings suggest that chemotherapy in NSCLC has reached a therapeutic plateau.

Prevalence of epilepsy in rural Bolivia: a door-to-door survey.

OBJECTIVE: To carry out a door-to-door survey in rural areas of the Cordillera Province, Santa Cruz Department, Bolivia, to determine the prevalence of neurologic diseases (epilepsy, stroke, parkinsonism, and peripheral neuropathy) in a sample of approximately 10,000 inhabitants. METHODS: A team of nondoctor health workers administered a standard screening instrument for neurologic diseases-a slightly modified version of the World Health Organization protocol. All subjects found positive during the screening underwent a neurologic examination. RESULTS: On screening, the authors found 1,130 positive subjects, of whom 1,027 were then investigated by neurologists. On the basis of the definition proposed by the International League Against Epilepsy, we detected 124 epileptic patients (prevalence, 12.3/1,000), 112 of whom had active epilepsy (prevalence, 11.1/1,000) on the prevalence day (November 1, 1994). Peak age-specific prevalence occurred in the 15 to 24-year age group (20.4/1,000). Sex-specific prevalence was higher in women (13.1/1,000) than men (11.4/1,000). Eighty-nine patients (71.8%) underwent a standard EEG recording. Considering both EEG and clinical data, partial seizures were the most common type (53.2%) based on the classification of the International League Against Epilepsy. The mean age at onset was 20.7 years for partial seizures and 13.6 years for generalized seizures. Only 10.5% of patients had received specific treatment for more than 2 months of their life. CONCLUSION: This report on epilepsy prevalence in Bolivia confirms that epilepsy is a major health problem in rural areas of developing countries.

Disorders of micturition in neurological patients. A clinical study of 786 patients.

Our aim was to evaluate the utility and effectiveness of a study protocol for neurological involvement in neurological disorders. We studied a sample of 786 patients with neurological disorders followed by the Neurological Department of Catania University and applied to them a four-step diagnostic protocol. Fifty-six per cent of the sample showed urological functional abnormalities; only 78 patients (9.9%) presented with an organic urological disease. Among the vesicosphincteric dysfunctions, bladder hyperreflexia was the most common pattern with remarkable differences between diseases. The present study demonstrated the utility of a standardized urological protocol in the screening and detection of neurological involvement in neurological diseases. Our protocol showed good specificity and reasonable low costs.

Neuropsychological, neuroradiological and clinical findings in multiple sclerosis. A 3 year follow-up study.

Cognitive impairment is a frequent feature in multiple sclerosis patients. To assess its evolution in comparison with clinical and neuroradiological evolution, we followed up 57 multiple sclerosis patients over a 3-year period. During this time EDSS deteriorated significantly but not the MRI lesional load nor the cognitive test performance; nevertheless both at the beginning and at the end of the follow-up neuropsychological results showed a significant correlation with both EDSS and lesional load. No clinical or paraclinical features could reliably predict neuropsychological evolution.Copyright Lippincott-Raven Publishers

A short-term infusion regimen of Cisplatin, 5-Fluorouracil and L-folinic Acid in advanced head and neck-carcinoma.

Treatment of advanced head and neck cancer is still a matter of controversy. Although current chemotherapy regimens are able to induce high response rates, they have not shown improved survival. We employed a combination of cisplatin (CDDP), 5-fluorouracil (5FU) and 1-folinic acid (1-FA) in a 6-hour infusion schedule easy to administer on an outpatient basis. 49 patients have been included to date. The treatment plan consists of 5-FU (375 mg/m(2)) plus 1-FA (100 mg/m(2)) in a 4-hour i.v. infusion followed by a 2-hour i.v. administration of CDDP (20 mg/m(2)). This therapy was repeated for five consecutive days and recycled every 3-4 weeks. Out of 46 evaluable patients there were 6 complete responses (CR) and 23 partial responses (PR) for an overall response rate of 63%. Overall survival was 10.2 months (mean). Untreated patients had a higher probability of response as well as patients with naso-oropharyngeal primary tumor. Toxicity was generally mild with leukopenia, anemia and vomiting being the most frequent side effects. In conclusion, this combination appears well tolerated and active in the palliation of advanced head and neck cancer. However we think that increasing dose intensity of standard regimens and experimental new therapeutic approaches are needed to improve the clinical outcome of this disease.

Prolonged 5-fluorouracil infusion in patients with metastatic colon cancer pretreated with bolus schedule of the same agent.

5-Fluorouracil (5FU) is the most important drug in the treatment or gastrointestinal cancer. 5FU can be administered by bolus or continuous infusion. It seems that continuous infusion is capable of producing responses in patients pretreated with bolus of the same drug. To overcome drug resistance in metastatic colon cancer patients, we have administered (via programmable pump) 5FU by prolonged infusion with doses of 250 mg/m2/die for six weeks with a one week rest period. Twenty-one patients with disease progression following bolus 5FU leucovorin were enrolled. The treatment was well tolerated with mucositis (grade I-II) in five patients and hand-foot syndrome in four; these side effects were managed with brief interruption of the infusion. Four partial responses and six stable disease were obtained. Two patients are alive after 14 months. The data of this study suggest that it is possible to overcome acquired 5FU bolus resistance by use of different schedules of the same drug.

Phase I study of FUDR continuous infusion with circadian variability in advanced cancer patients.

A phase I study of floxuridine circadian infusion was performed in 14 patients with advanced solid tumors (9 colonic, 1 gastric, 4 renal). The starting dose was 0.15 mg/kg/day for 14 days followed by a 14-day therapy-free interval. Sixty-eight percent of the daily dose was infused between 3pm and 9pm. The dose was increased by 0.025 mg/kg/day for each successive course. Eighty-one cycles of therapy were given for a total of 1134 days of treatment. The mean dose intensity was 0.868 mg/kg/day for the entire group. The highest dose achieved (maximum tolerated dose) was 0.325 mg/kg/day. The most frequent toxicity was diarrhea (4.9% of all courses) and nausea-vomiting (3.7% of all courses). These side effects were of a low grade and all were resolved without hospitalization. Our results suggest the circadian modulation of floxuridine infusion.

Fludarabine phosphate as an active and well tolerated salvage therapy in an elderly heavily pretreated Hodgkin's disease patient: a case report.

Up to two thirds of all patients affected by advanced Hodgkin's disease will be cured by chemotherapy alone or by combined chemoradiation modalities. High-dose chemotherapy with autologous stem cell rescue may be potentially curative for patients progressing under frontline chemotherapy or developing early relapse of disease. In spite of this, an unacceptably high percentage of these high-risk patients will relapse after salvage treatments and die of their disease. Fludarabine phosphate is an adenosine nucleoside analog highly active in chronic lymphocytic leukemia and low-grade non-Hodgkin's lymphomas. There are only few data in the literature concerning its use in the management of Hodgkin's disease. We report the case of an elderly, heavily pretreated Hodgkin's disease patient in progression under third-line chemotherapy who experienced good palliation of her B symptoms and a major clinical response of her refractory bone lesions with the administration of fludarabine as monotherapy. The treatment was well tolerated, without grade 4 hematological toxicity or opportunistic infections. The duration of clinical remission and systemic symptom palliation was 9 and 11 months, respectively. Further evaluation of fludarabine phosphate as salvage therapy in relapsed/refractory elderly Hodgkin's disease patients is needed.

[Clinical significance of the determination of serum phosphohexose isomerase in malignant neoplasms]. / Significato clinico del dosaggio della fosfoesosoisomerasi serica nelle neoplasie maligne.

The results of a preliminary study on the serous level of PHI in patients undergoing treatment at the Catania Oncology Institute are reported. Of 53 subjects with ongoing cancer, higher than normal values were encountered in 70% of cases. This percentage rose to 82.3% in cancer patients with metastasis affecting the skeleton. Of 12 subjects who underwent mastectomy with no clinical signs of recurrence only three showed abnormal values while in no case of fibrocystic mastopathy were levels higher than normal observed. A constant correlation was identified between effectiveness of surgical, radiotherapeutical or medical treatment and reduction in serous level of PHI. The usefulness of this investigation in oncology is thus confirmed.

[Evaluation of acute cardiotoxicity from the combination cyclophosphamide-mitoxantrone-5-fluorouracil (CMF) with Holter ECG]. / Valutazione della cardiotossicità in acuto dell'associazione ciclofosfamide-novantrone-5-fluorouracile (CNF) mediante ecg di Holter.

By making use of a twenty-four hour Holter monitoring, it as been possible to compute the acute cardiotoxicity of the cyclophosphamide + mitoxantrone + 5-fluorouracil (CNF) association in twenty oncologic patients (pts) each of whom being immune from organic cardiopathy emerging clinically and at their first cycle of chemotherapy. The following parameters have been computed: meaningful changes in the heart frequency; premature atrial and ventricular depolarizations, both as a first appearance and as a clear growth in the number; the ST dislocation entity; malignant ventricular arrhythmias. The administration of CNF at the doses of: 600 mg/m2 of cyclophosphamide, 12 mg/m2 of mitoxantrone and 600 mg/m2 of 5-fluorouracil , has caused a meaningful increase in the heart frequency on 6 pts (30%), an increase of premature atrial depolarization on 4 pts (20%) with an appearance ex novo on 2 pts (10%), an increase of premature ventricular depolarization, without any passing to superior Lown classes, on 2 pts (10%) with an appearance ex novo on 3 pts (15%). Although the results in the study point out a frequency percentage of simple hyperkinetic arrhythmias equal to the 55%, the lack of more serious hyperkinetic arrhythmias and of intense disorders of ventricular repolarization testified to a synergic effect as a determining factor on the acute cardiotoxicity of the previously discussed association, in our opinion.

[Critical ischemia of the diabetic patient]. / L'ischemia critica nel paziente diabetico.

BACKGROUND: Critical ischemia of the lower limbs is the final result of diabetic arteriopathy. The surgeon is more and more forced to choose between amputation d emblée and the attempt to revascularization in very old patients and in deficient general conditions. Shall we point out some principle to address our strategy? METHODS: To answer this question we reviewed retrospectively our surgical choices and the results obtained during two years, from January 1997 to December 1998 (medium follow-up 11.3 months), at the Emergency Division of the Cannizzaro Hospital of Catania. In this period 143 diabetic patients were selected by our ambulatory. Of these, nineteen had a critical lower limb ischemia and therefore were submitted to a revascularization and/or amputation. All the revascularized patients were controlled by Doppler-sonography immediately after operation and then daily, till their discharge. Controls were done at the first, third, sixth month and after one year, except for patients who complained a new objective or subjective ischemic symptomatology. RESULTS: The primary patency rate was 84.2% and the secondary patency rate was 89.4%. The amputation rate due to the procedure failure was 5%. The complications were three: two graft infections (10.5%) and one early thrombosis of a femoro-popliteal bypass graft, due to technical defect (5.2%). Perioperative mortality rate was 15.7%. CONCLUSIONS: These results, if related with those reported in the letterature about amputations, are in favour of the attempt to revascularization.

[The use of endobronchial aztreonam in the treatment of bronchiectatic suppuration]. / Impiego dell'aztreonam per via endobronchiale nel trattamento delle suppurazioni bronchiectasiche.

The authors submitted 8 patients with bronchiectasis to endobronchial therapy with Aztreonam 2 gr twice a week for 4 weeks after endobronchial lavage with sodium chloride solution. They observed a definite clinical and radiological improvement and a stabilized condition of the disease was observed. No hepatic or renal toxicity was detected.

[Medullary carcinoma of the thyroid: diagnosis and therapy]. / Il carcinoma midollare della tiroide: diagnosi e terapia.

Medullary thyroid carcinoma (MTC) originates in the thyroid C cells, or parafollicular cells, secreting calcitonin. It may be either sporadic or familial. Familial form can be isolated or expression of a multiple endocrine neoplasia type II. Mutations of the RET proto-oncogene have been identified in the germline DNA of patients with familial MTC syndromes. Genetic testing can identify patients affected by multiple endocrine neoplasia and familial MTC, allowing early diagnosis and possible cure. The initial treatment is surgical and the adequate surgery consists of total thyroidectomy. The treatment of occult or minimal disease can be curative. Plasma calcitonin measurements are excellent markers for post-operative follow-up. Imaging study can help to discover recurrent or metastatic disease. Adjunctive therapy includes radiotherapy and chemotherapy. Radiotherapy is reserved for bone metastases or for non resectable neck recurrences. Chemotherapy is reserved for patients with progressive MTC. Many chemotherapeutic regimens have been tried, results are controversial.

[Anaplastic carcinoma of the thyroid: diagnosis and treatment]. / Il carcinoma anaplastico della tiroide: inquadramento diagnostico e attuali possibilità terapeutiche.

Anaplastic thyroid carcinoma (ATC), accounting for 5% to 15% of primary malignant thyroid neoplasm, is one of the most aggressive solid tumors in humans. It is rapidly fatal, with a mean survival of 6 months after diagnosis. Multimodality treatment with surgery and/or external beam radiotherapy and chemotherapy are of fundamental importance for local control of disease and to enhance survival. Molecular biology studies have shown that ATC is associated with a p 53 mutation. ATC usually does not concentrate radioiodine or express thyroglobulin. It is essential to verify the diagnosis histologically because insular thyroid cancer, lymphomas, and medullary thyroid cancer are occasionally confused with undifferentiated neoplasms. Immunohistochemical study is helpful in establishing the diagnosis. Multimodal therapy and development of effective systemic chemotherapy agents would provide to result in improvements in survival although no single agent has yet been identified. Aggressive multimodality treatment regimens show promise in improving local control in patients with ATC. Survival rates however remain low. Despite intense applications of such integrated therapy, no standardized successful treatment protocol has yet been established.

[A case of breast metastasis in bladder urothelioma]. / Su di un caso di metastasi mammaria da urotelioma vescicale.

A case of isolated mammary metastasis from surgically untreated urothelial vesical carcinoma is discussed. An integrated chemo-radiotherapeutical treatment had been planned, due to bad general condition; after this, an optimal subjective benefit and good objective response (reduction in lesion diameter < 50%, MR) were obtained. An isolated breast lesion appeared ten months after; its metastatic nature was only indirectly suspected by mammographic and echographic features. Only immunohistochemical study, realized on percutaneous needle biopsy specimen, definitively confirmed the urothelial metastatic origin. In present work, biological and prognostic significance of mammary metastases and the needing of distinguishing them from primary breast neoplasm are analysed, basing on the literature review.