Synthesis of heteroaromatic potential beta-adrenergic antagonists by the glycidol route.

The synthesis of several 3-alkylamino-2-hydroxypropyl heteroaryl ethers (13-15, 17, and 18) is described. These compounds were prepared by the alkylamination of the corresponding glycidyl ethers (6-8, 10, and 11), which in turn were obtained from the requisite heteroaryl halides and the sodium salt of glycidol. The above basic ethers exhibited beta-blocking activity, but the potency of the tested compounds was considerably less than that of propanolol. Only 3-tert-butylamino-2-hydroxyl-1-(1,2,4-thiadiazol-5-yl) propyl ether (13) showed some selective myocardial beta-blocking activity.

Synthesis and antiinflammatory and analgesic activity of 5-aroyl-6-(methylthio)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-ca rboxyl ic acids and 1-methyl-4-(methylthio)-5-aroylpyrrole-2-acetic acids.

5-Aroyl-6-(methylthio)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carb oxylic acids and 1-methyl-4-(methylthio)-5-aroylpyrrole-2-acetic acids were synthesized and assayed as antiinflammatory and analgesic agents. The majority of these compounds exhibit a surprisingly low level of antiinflammatory activity (rat carrageenan paw) but have considerable potency as analgesics (mouse phenylquinone writing). For example, the p-tolyl-substituted bicyclic and monocyclic compounds 44 and 58 are 301 and 66 times more potent than aspirin (mouse writhing) but only 3.4 and 1.5 times more potent than phenylbutazone in the antiinflammatory screen (rat paw).

Semantic standards for the representation of medical records.

Physicians developed their sublanguage (a system to represent medical concepts and their relations) to store and transmit general medical knowledge and patient-related information. Adequate formalisms are needed to obtain a standard representation of semantics of medical expressions for computer use. Comparison of the semantic contents of two expressions is possible only if a unique canonical form is defined; the transmission of medical facts or patient-related information is really meaningful only by defining a set of primitives (semantic categories and links) and the domains of values (concepts). These primitives must be harmonized to yield a "common core subset" of semantic categories and links. This subset provides a common basis; a procedure to register extension sets of primitives must also be defined, to comply with specific representation needs of specialties and classes of application software.

Standards to support development of terminological systems for healthcare telematics.

The Technical Committee on "Medical Informatics" of the European Committee for Standardization (CEN/TC251) is supporting developers of terminological systems in healthcare by a series of standards. The dream of "universal" coding system was abandoned in favor of a coherent family of terminologies, diversified according to tasks; two ideas were introduced: (1) the "categorical structure", i.e. a model of semantic categories and their relations within a subject field and (2) the "cross-thesaurus", i.e. a system of descriptors to build a systematic representation (called here "dissection") for each terminological phrase, coherent across diverse terminologies on a given subject field. The goal is to assure coexistence and interoperability (and reciprocal support for development and maintenance) to three generations of systems: (1) traditional paper-based systems (first generation); (2) compositional systems built according to a categorical structure and a cross-thesaurus (second generation) and (3) formal models (third generation). Various scenarios are presented, on the exploitation of computer-based terminological systems. The idea of "operational meaning" of terminological phrases within administrative and organizational contexts and the idea of "task-oriented details" are also introduced, to justify and exploit design constraints on terminological systems.

Immunological investigations on tonsillar and peripheral blood lymphocytes after adeno-tonsillectomy. Possible suggestions for phenotypical and functional differences.

The phenotypical and functional aspects of tonsillar (TMNC) and peripheral blood mononuclear cells (PBMNC) obtained from 40 patients who had undergone adeno-tonsillectomy for different tonsillar diseases were investigated. TMNC and PBMC were separately tested at the time of surgery; then a further investigation on the peripheral blood lymphocytes was performed three months after surgery. The most interesting findings are presented and discussed with particular attention to their clinical implications.

Interleukin 2 receptors on squamous cell carcinomas of the head and neck. Characterization and functional role.

IL2Rs, in the presence of IL2, mediate activation and proliferation of human normal lymphocytes and modulate functional changes of some human leukocytic malignancies. IL2Rs have been demonstrated also on human neoplastic and fetal non-hematologic cells in vitro, although their functional role has not been described. We describe the presence of high affinity IL2Rs on squamous cell carcinoma of the head and neck (SCCHN) lines in vitro. Expression of 200 binding sites for IL2 with an affinity of 17 x 10(-12) was demonstrated by radiobinding experiments. When cytocentrifuged SCCHN cells were studied by immunoperoxidase staining, strong positive staining was repeatedly obtained using a monoclonal antibody to the p70 subunit of the IL2Rs. Experiments in vitro and in vivo, in a nude mouse model, showed a functional role for these receptors. In fact, low doses (8-500 U/ml) of IL2 were able to inhibit growth of 11 of the 16 SCCHN lines tested. Our observations may have broad implications for the immunotherapy of cancer in general, showing the complementary immunomodulatory and direct effects of IL2.

The effect of preoperative local interleukin-2 (IL-2) injections in patients with head and neck squamous cell carcinoma. An immunological study.

Clinical, immunological, immunophenotypical, pathological and molecular biological studies were performed on tumor infiltrating lymphocytes (TIL) and lymph node lymphocytes (LN-ly) of 8 patients with squamous cell carcinoma of the oral cavity and oropharynx treated with 10 daily locoregional injections of low doses of IL-2 before surgery. No complications were seen during or after surgery. In 3 cases the LN-ly showed a moderate LAK activity, higher in the LN-ly omolateral to the tumor and near the IL-2 injection site; in 2 of these 3 patients a good LAK activity was induced after 6-day culture with IL-2. The LN-ly derived from nodes next to the tumor showed a decreased NK activity and proliferative ability both in basal conditions and after in vitro lymphokine challenging. LN-ly of 2 IL-2 treated patients showed high levels of mRNA encoding for IL-2-R, while it was absent in 2 untreated cases. Immunophenotypical studies on TIL showed statistically improved levels of CD25+ and LAK1+ cells in treated cases. Clusters of CD11c+ (macrophages) cells were seen close to the neoplastic sheets.

Development of a cross-thesaurus with Internet-based refinement supported by UMLS.

Combinatorial terminological systems are appearing, to solve the issues related to flexibility and precision of representation requested by modern healthcare information systems and in particular by messaging standards. The development of a robust system of descriptors ('cross-thesaurus') is a crucial activity in the production of combinatorial terminological systems. We developed a tool (I-BROWSE) to produce a cross-thesaurus by analysing existing terminological corpora. To facilitate the work of experts and to produce re-usable results, our application interacts via the Internet with the UMLS Knowledge Sources Server. We applied our tool on 6372 dissections on surgical procedures produced in the project GALEN-IN-USE, as a part of the internal Quality Assurance Program. Support from UMLS seems mostly promising about descriptors on , , and . Additional assistance can be given to domain experts on less frequent descriptors on pervasive modifiers. We plan to apply our tool also to production of terminological standards in CEN, as a part of a world-wide process of gradual convergence and transformation of coding systems into second-generation systems and terminological services.

[Clinical usefulness of the blood gastrin curve after protein meal in duodenal ulcer]. / Utilità clinica della curva gastrinemica dopo pasto proteico nella malattia ulcerosa duodenale.

Conflicting data are present in the literature on pathophysiological role of serum gastrin and peptic ulcer disease. The aim of this study was to evaluate, in duodenal ulcer patients, the possible correlation between post-prandial serum gastrin concentrations and some epidemiological (sex, family history, onset of the disease, blood group status, smoking habit, alcohol consumption) and clinical (effectiveness of therapy, bleeding episodes) factors. The gastrin levels were expressed in absolute values and as per cent increase of fasting serum gastrin concentrations. As regards sex, the per cent increase of fasting serum gastrin concentration was significantly higher in females (No. 16) than in males (No. 60) at 30 and 60 minutes (192.25% vs 116.52% and 105.42% vs 40.96% respectively; p less than 0.05 and p less than 0.005). Post-prandial serum gastrin concentrations, expressed as per cent increase, were higher in heavy drinkers (No. 14) and statistically significant at 120 minutes (40.57% vs 9.58%, p less than 0.025); as well as in smoker patients (No. 31), at 15, 30 and 60 minutes (227.59% vs 123.52%, 177.23% vs 101.62%, 0.025 and p less than 0.05). Post-prandial gastrin was unrelated to blood group status, onset of the disease, family history, effectiveness of medical treatment and bleeding episodes.

[Spontaneous limited dissection of the external iliac artery. Case report after 14 year follow-up]. / Spontane limitierte Dissektion der A. iliaca externa. Fallbeschreibung nach 14 Jahren Beobachtungszeit.

The case of a limited dissection of the external iliac artery in a 31-year-old woman is described. The clinical symptomatology was that of an acute ischemia of the right lower extremity. Histology revealed the existence of a cystic Medionecrosis. With reference to the literature, the clinical and surgical aspects are discussed.

[Evaluation of anti-thrombophilic properties of heparan sulfate in venous vascular pathology. A controlled clinical study versus active reference]. / Valutazione delle proprietà antitrombofiliche dell'eparansolfato in patologia vascolare venosa. Studio clinico controllato verso reference attivo.

Forty adult patients (31 females and 9 males), mean age 48.41 years with chronic venous insufficiency of the lower limbs due to a variety of etiopathogenesis, were randomly divided into two groups of twenty subjects and treated with heparan sulphate and sulodexide. The experimental clinical protocol was formulated using a single blind model. The following dosages were used: a tablet of heparan sulphate in the morning and evening (200 mg/die), and one capsule of sulodexide in the morning and evening (500 ULS/die); treatment lasted 60 days. The aim of the study was to compare the two compounds in terms of efficacy and tolerability. The clinical effect of the two drugs was substantially similar: in particular the symptoms of itch, edema, spontaneous pain and nocturnal cramp responded significantly to (p less than 0.01) to both forms of treatment. The response of fibrin degradation products to heparan sulphate treatment was more positive and differed significantly from that obtained using sulodexide (p less than 0.001). Other parameters, namely erythrocytic filtration and blood viscosity, responded significantly to heparan sulphate treatment in comparison to sulodexide (p less than 0.001). Other blood coagulation and hemorheological parameters and Doppler response showed no change using either drug. With regard to side effects, five cases of digestive intolerance were observed using heparan sulphate and two with sulodexide. Two patients failed to complete heparan sulphate treatment, and one sulodexide treatment. In conclusion, heparan sulphate showed a marked pro-fibrinolytic and prohemorheological effect compared to the reference drug.

Building cross-thesauri with the support of UMLS.

The absence of a robust system of descriptors (cross-thesaurus) hampers the development of combinatorial terminological systems. We developed a tool (I-BROWSE) to produce a cross-thesaurus by analyzing terminological corpora. To facilitate the work of experts and to produce re-usable results, our application interacts via the Internet with the UMLS Knowledge Sources Server. We applied our tool on 2999 dissections on surgical procedures produced in the project GALEN-IN-USE, as a part of the internal Quality Assurance program. Support from UMLS seems mostly promising about descriptors on , , and . Additional assistance can be given to domain experts on less frequent descriptors on pervasive modifiers. We plan to apply our tool also to production of terminological standards in CEN, as a part of a worldwide process of gradual convergence and transformation of coding systems into second-generation systems and terminological services.

A cooperative methodology to build conceptual models in medicine.

We designed a methodology to perform distribute activities on conceptual modelling among cooperating centers. Our methodology assigns responsibilities and tasks and regulates interactions preserving coherence; it passes through the construction of unambiguous paraphrases to make explicit the context within the original sources, and through their compositional representation in an intermediate language. The process is intrinsically iterative, with continuous feedbacks and refinements, alternating analytic view on details and synthetic view on regularities and structures. Our methodology is based on requirements and experience made in the first GALEN project, and was applied in the GALEN-IN-USE project to coordinate modelling activities of three teams of surgeons in Rome with activities of other partners, during the production of an extensive model of surgical procedures.

A second generation of terminological systems is coming.

Diverse achievements by recent computer-based terminological systems are outlining a new generation of systems (i.e. a "second generation"). We collected the relevant features of various advanced terminological systems and we systematized these features into four components of a unique framework. We review a set of systems according to our framework, and we discuss how standardization activities can support the evolution of computer-based terminological systems towards a complete set of new performances.

[Loco-regional treatment with low and high doses of interleukin-2 of head and neck squamous cell carcinoma recurrences]. / Trattamento loco-regionale con basse ed alte dosi di interleuchina-2 di recidive di carcinomi squamosi della testa e del collo.

The present study reports the effects of repeated administration of two different doses of recombinant (r) Interleukin-2 (IL-2) around tumor-draining lymph nodes in 22 patients with recurrent squamous cell carcinoma of the head and neck (HNSCC). Each patient was randomly assigned a dose of 500 or 500,000 IU/r-IL-2/day. Inoculation was made at a depth of 15 mm in the anterior margin of the sternocleidomastoid muscle at 15 mm from its insertion into the mastoid. The injections were made on the same side as the recurrent tumor when draining lymph nodes were still present and contralaterally when only contralateral lymph nodes were present. The 10 daily injection were followed by an interval without treatment until day 40. A further three courses of 10 injections were made at thirty-day intervals in the absence of a CR. There was no toxicity. One complete response (CR) and 2 partial responses (PR) were observed in the 11 patients who received 500 U of IL-2, whereas the higher dose was not effective. The CR was recorded in the 4 patients with an oropharyngeal recurrence. One PR was obtained in the 4 patients with hypopharyngeal recurrences and one in 3 with oral cavity recurrences. Clinical responses were nearly always preceded by improvement of the functional impairment caused by tumour infiltrations of the upper respiratory-digestive organs. The responses lasted 3-5 months and additional courses of 10 injections of IL-2 had no further effects.

[Local immunity following treatment with S-carboxymethylcysteine-lysine in tracheotomy patients]. / Immunità locale in seguito a trattamento con S-carbossimetilcisteina sale di lisina nei soggetti tracheotomizzati.

Pathological modification in secretory IgA values as well as in circadian rhythms were found in tracheotomized patients in both nasal and tracheo-bronchial secretions. The protective role of the mucosal immune system in addition to the frequency of severe infectious respiratory diseases in laryngectomized patients justifies the efforts of clinicians to prevent and treat such modifications. Mucoregulatory drugs have a peculiar role in these therapeutical attempts. Forty tracheotomized subjects with neoplastic disease were studied. Twenty received SCMC-Lys as a mucoregulatory drug. IgA 7S, 11S and albumin values in nasal and tracheo-bronchial secretions, were evaluated at surgery, 15 and then 40 days later. In accordance with clinical data, an improvement in local antibody production, damaged by tracheostomy, was found in the treated group. The influence of SCMS-Lys on SIgA production, whose evaluation was made by means of an original, highly selective and sensitive Immuno-IsoElectroFocusing procedure, seems to encourage the use of mucoregulatory drugs in laryngectomized patients.

[Antitumor activity of adherent LAK cells (A-LAK) in a model of squamous carcinoma of the head and neck]. / L'attività antitumorale di cellule LAK aderenti (A-LAK) in un modello di carcinoma squamoso della testa e del collo.

Local adoptive immunotherapy employed on a selected population using IL2-activated immune cells (A-LAK cells) and IL2 resulted in complete growth inhibition of a human squamous cell carcinoma of the head and neck implanted three to seven days previously and growing in nude mice. Although the in vitro cytotoxicity of A-LAK cells against the carcinoma cells was not higher than that of the whole population (LAK cells), the in vivo antitumor efficacy was from 4 to 9 times higher for A-LAK cells, as confirmed by the total number of injected cells needed for a complete growth inhibition. In addition, local A-LAK cell administration was characterized by early peritumoral erythema and swelling, not observed during LAK-cell therapy, which disappeared at the end of therapy. Histology of the tumors, during and at the end of therapy, showed an initial granulocytic and plasma cellular infiltration followed by mononuclear infiltration of the stroma of the tumor. The tumors showed a terminal-like differentiation with an increase of the keratinic layer and decrease of basal epithelial cells. These effects were proportional to the number of A-LAK cells injected. With the highest number of A-LAK cells, a complete epithelial disorganization was observed and 4 weeks from therapy termination the tumors were reduced to keratinic areas surrounded by connective tissue. These observations suggest the possibility of a A-LAK cell-dependent process of accelerated tumor differentiation and keratinization leading to tumor regression in nude mice.

[Determination of 11S IgA in nasal secretions in the monitoring of local immunomodulating therapy]. / Il dosaggio delle IgA 11S nel secreto nasale nel monitoraggio delle terapie immunomodulanti locali.

Twenty pediatric patients with recurrent infectious diseases of the upper respiratory tract (tonsillitis, adenotonsillitis with or without involvement of the ear and/or lower respiratory tract) were studied. An immunological assay of the nasal secretum was performed at time of diagnosis and following treatment with a local immunomodulator drug, administered by spray. The 7S, 11S IgA and albumin rates were evaluated. The authors emphasize the importance of SIgA in mucose defense mechanisms as well as the need for a selective method for determining the 11S IgA level. An original method for immuno-isoelectrofocusing (IIEF) determination was employed in the present study. After treatment a significant increase in 11S IgA level was observed, especially in those patients with a significant basal SIGA deficit. The authors describe details of the technique for determination and discuss the results.

[Perilymphatic injection of interleukin-2 (IL-2) in recurrent squamous cell carcinoma of the head and neck]. / Iniezione perilinfatica di interleuchina-2 (IL-2) in recidive di carcinomi a cellule squamose della testa e del collo.

Twenty patients with recurrent squamous cell carcinoma of the head and neck received daily injections of interleukin-2 (IL-2) from the Jurkat T-cell line, purified by high pressure liquid chromatography for 10 days. Two hundred (ten patients), one thousand (five patients) and five thousand (five patients) units of IL-2 in 0.5 ml were injected 1.5 cm from the point where the sternocleidomastoid muscle inserts itself on the mastoid. Whenever possible, the treatment cycles were repeated at 45 day intervals. In 13 patients with contralateral or bilateral cervical lymph nodes, complete or partial disappearance of the tumor was observed. There were non systemic disturbances after injection and only moderate local swelling and pain.