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19th century Italian theatre is chiefly related to its interpreters’ vicissitudes. Actors are professional performers, the heirs of the commedia dell’arte artists. They still conceive acting as a job handed down from father to son. Yet the roles related to masks and stock characters are abandoned, and are replaced by characters whose parts has been written in full by the playwright. The large number of acting companies that are formed and disbanded over a few seasons, fit in a wide network of personal relationships, irrespective of the audience’s support. The desire to uphold the best performances, so that they are not just ephemeral events, is often hindered by everyday life problems. This is confirmed by autobiographical books, actors’ memories, stage chronicles and anecdotes and advertisements. A useful support to theatrics comes from literature and from pictures; these challenge the idea that the fate of this art is to die away night after night, with the final curtain. Over half a century the rise and fall of ‘the great actor’ as a pivotal drama category takes place, with the contribution of prestigious writers, playwrights and critics, but only in the 1930’s the situation will dramatically change, when the function of the theatre director starts gaining new status in Italy as well.

Background: Early access of medicines occurs with an uncertainty in the evidence even higher than the one experienced when price and reimbursement status is negotiated. Our aim is discussing the role of managed entry agreements (MEA) within early access programs (EAP) in Italy., Methods: The discussion relied on a Focus Group, participated by twelve experts, including clinicians and representatives of regulatory authorities, regional and local pharmaceutical departments, pharmaceutical companies, and an association advocating for active citizenship., Results: The Focus Group emphasised that the topic under discussion should be embedded into a more general reform of EAP in Italy. The 648 List mostly includes mature products and indications that are rarely launched into the market afterwards. The 5% Fund is affected by an important administrative burden uncertainty of the timing of reimbursement., Conclusions: Starting from the discussion on MEA and EAP, the Focus Group recommended a new legislation better regulating EAP, that early access concerns specific classes of medicines selected on the grounds of the need to guarantee a rapid access and to collect real world data, that early access can be accompanied by outcome-based and population-based MEA, and that MEA are embedded into the subsequent price and reimbursement negotiation.

Some aetiopathogenetic and diagnostic considerations about the neuro-endocrine tumours, with particular attention to those pertinent of urology.Some neuroendocrine tumours (NET) occur in hereditary-familial neoplastic syndromes such as MEN (multiple endocrine neoplasias) or neuroectodermic dysplasias (neurofibromatosis-NF1, von Hippel Lindau disease, pheochromocytoma-chemodectoma familial syndrome, etc.) while others arise as solitary-isolated tumours such as those of gastrointestinal tract, pancreas, lung, skin, genitourinary system. The diagnostics of NET implies plasmatic assay of common neuroendocrine markers and specific peptide hormones, and more properly, their immuno-histochemical characterisation, together with molecular-genetic studies. Several gene alterations (MEN1, RET, NF1, VDL, SDH-B and -D) are associated with pheochromocytoma, showing that almost 25% of subjects with apparent-sporadic pheochromocytoma at the sheer clinical examination, are actually syndromic-familial pheochromocytoma patients at the genetic testing. The functional imaging provides intriguing data regarding not only the diagnostics but also the assessment of tumour response to the therapy. This paper aims to review the literature on morphological, functional as well as biological features of NET and to briefly summarize the recent advances in their diagnosis, with particular attention to those pertinent the urology.

Despite of scientific efforts over seven decades, the etiopathogenesis of Crohn's disease (CD) remains still unknown. Some conflicting hypotheses are to be settled about etiologic factors as well as on pathogenetic mechanisms. According to some authors, the disease appears to be caused by a congenital lack of patency of mesenteric lymphatic collectors giving rise to lymph-seepage in the corresponding bowel segment with following development of lymphocytic lymphangitis and transparietal phlogosis. Considering this etiopathogenetic philosophy, the surgical therapy has to be performed prompty and has to take the form of segmentary intestinal resection, depending on disease-related intestinal involvement (ileum, ileum plus right colon, ileum plus right and left colon). Other proposed pathogenetic hypotheses for CD refer, instead, to immune-mediated mechanisms, leading to identify this pathology with an abnormal immune inflammatory response in the intestinal wall to one or more undefined antigens, in genetically predisposed person (genetic background). Whereas the prevalent viewpoint is that CD lesions are induced by a dysregulated adaptive-acquired immune system, current studies lead to form the hypothesis that the disease might be initiated by a defective innate immune response. The CD acquired immune profile focuses on T-helper-l (Th1) type, with increasing production of TNF-a, IL-12, Interferon-g and other specific cytokines. In the field of diagnostic imaging, MR findings, 99mTc or 111In labelled autologous leucocyte scintigraphy or 18FDG/PET images strongly correlate with "active" phase of inflammation and contribute to differentiate this condition from established intestinal wall fibrosis, The Montreal classification of inflammatory bowel disease (2005) provides a useful framework for describing CD phenotype and for identifying different serological and genetic markers that may predict the disease course. Urological complications such as renal stones, obstructive uropathy, entero-vescical fistulas, kidney parenchymal disease, are not uncommon. According to immune-mediated pathogenesis-related theories, the basic therapy consist of medical strategies. In the last decades many inflammatory cytokines (TNF-a, IL-12, IL-1, etc.) have been targeted for therapy, particularly in patients with steroid-immunomodulator refractory or fistulizing disease, by achieving a cytokine blockade with monoclonal antibodies. Even regulatory antinflammatory cytokines, such as IL-10 and IL-11, are undergoing trials. In the clinical ground, a better assessment of etiopathogenesis of CD and of the individual case-related evolutive phase, is likely to warrant the selective drug therapies, the avoidance of untimely surgery and the prophylaxis of recurrences.

Since the late 1970s, the number of serendipitously discovered adrenal masses has progressively increased through the widespread use of great sensitivity/high resolution diagnostic imaging while abdomen scanning for extra-adrenal lesions. The majority of these masses are benign and without evidence of endocrine activity. Most adrenal incidentalomas are cortical adenomas whereas the prevalence of adrenocortical carcinomas and other adrenal masses (lipomas, myelolipomas, angio-myelo-lipomas, sarcomas, hamartomas, lymphomas) is relatively low. Computed tomography (CT), magnetic resonance (MR) and functional radioisotope imaging together with thorough biochemical-hormonal testing are carried out to define the aetiology of these lesions. An accurate management of adrenal incidentalomas requires an agreement among radiologist, endocrinologist, oncologist and surgeon. Arguments for benign incidentalomas are mainly small size (< 4 cm), low CT attenuation coefficients and/or typical features on RM imaging. Surgery is mandatory for secretory tumours (functioning cortical adenomas, pheochromocytoma) and for adrenal malignancies. Even modest hormonal activities, as sometimes exhibited from asymptomatic pheochromocytoma or in subclinical primary hypercortisolism/hyperaldosteronism, may be associated with morbidity of some importance. In accordance with international literature, the size of adrenal incidentalomas may be a discriminant criterion for their management: surgery is recommended for masses of large (> 6 cm) diameter or increasing at CT/RM follow-up reevaluation whereas the masses between 4/6 cm form an indeterminate group where the management varies from institution to institution. Laparoscopic transperitoneal as well as retro-peritoneoscopic procedures are gaining more and more attention for less invasive treatment of adrenal incidentalomas. According to 2002 USA-National Institutes of Health guidelines, further studies are necessary to better define natural history, CT and RM malignant features, functional aptitudes of adrenal incidentalomas in order to propose optimal modalities of follow-up and proper surgical strategies.

Paraneoplastic syndromes induced by inappropriate-ectopic production of hormones, cytokines and growth factors, therefore not mediated directly by local infiltration or metastatic spread, occur in approximately 10 per cent of patients with malignant disease in initial phase. Subjects with paraneoplastic syndromes often are affected by small occult tumors which may be diagnosed only at autopsy. Inappropriate secretion of peptide hormones is the commonest cause of paraneoplastic syndromes. On the basis of an up-to-date review of the literature, this article discusses pathogenetic mechanisms, diagnostic features and essential therapeutic measures concerning the syndromes of inappropriate ACTH/CRH, PTHrp, TRH/TSH, ADH and MSH secretion. Moreover, some of paraneoplastic syndromes, that are associated with production of cytokines and growth factors by either tumor- or non malignant host microenvironment -cells, are briefly outlined.

In the course of the last decades, dramatic advances in the field of molecular biology have greatly increased our knowledges regarding the chromosomal aberrations associated with both hereditary and sporadic tumours. The development of new techniques (RELF, FISH, CGH, cDNA array analysis and functional oncogenetics, etc.) has provided powerful new tools for identification of onco- and oncosuppressor predisposing-genes. The most logical consequence of genetic research is the gene-therapy by directing treatment to the site of the chromosomal defect. The implementation of gene-directed technologies (gene-replacement or augmentation, antisense, interfering small -RNAs, etc.) into clinical practice stands as a model of translational research from laboratory to bedside. Prevention and therapy may be widely influenced by the experience of these techniques. On the other hand, some chemoprevention trials are carried out in subjects with hereditary risk for prostate cancer. The paper aims to outline the advances of genetics in urogenital hereditary tumours on the basis of a review of the literature in this field.

Anatomic patterns of blood flow and specific dynamic interactions between prostate cancer cell and bone microenvironment influence the distribution of metastatic deposits. Bone components preferentially bind cancer cell and can facilitate tumor growth in bone; cancer cells, in turn, can release some factors that enhance osteoblastic activity. Recent studies, in animal models, have provided evidences of chemoattractant factors (bone homing factors) and of an enhanced adherence of prostate cancer cells to bone marrow endothelium. Additional data suggest "osteomimetic" pattern of prostate cancer cells after their arrival in bone, particularly by taking an osteoblastic behavior. The presence of the cancer cell in bone results in bone matrix increased turnover. Although prostate cancer is characterized by osteoblastic metastases, bone resorption is a regular feature of this tumor and is a necessary factor for its invasiveness in bone. Current treatment options based on radiotherapy and pharmacotherapy are essentially palliative. The bisphoshonates inhibit osteoclastic bone degradation by several mechanisms. Improved knowledges of the molecular mechanisms in the development of skeletal metastases allow to foresee biologically-based therapeutic strategies.

In order to prevent both metabolic and neoplastic complications of intestinal neobladder, various solutions have been proposed to get a truly artificial neobladder: total alloplastic prosthetic bladder in nonbiological material (silicon rubber, polyurethane, etc.), tissue-engineered bladder by autologous urothelial- and smooth muscle cells cultured on biocompatible, either synthetic or natural, substrates. Polymers of glycolic and lactic acid have been extensively used to provide cell delivery matrices. Natural-based materials such as acellular matrix and small intestinal submucosa appear to supply a useful scaffold for regeneration of the wall components in augmentation cystoplasty. Up to day, other roads are less practicable, e.g. to obtain spare bladders from human cloning or from xenogenic sources of transplantable organs.

During the last decade, the cellular pathways involved in excitation-contraction coupling have been identified and explained. The key event in the initiation of the contraction is the rise in sarcoplasmic free calcium. Inositol 1,4,5-triphosphate (IP3) and cyclic nucleotides (cAMP, cGMP) have been demonstrated to be the second messengers associated with stimulation of smooth muscle selective receptor-subtypes (cholinergic, adrenergic, non adrenergic-non cholinergic) by specific neuromodulators. Furthermore, activation of voltage-gated L type- or receptor operated calcium channels is involved in the sarcoplasmic free calcium changes. KCa and KATP-channels play an important role in smooth muscle hyperpolarization; KATP-openers excite great interest as therapeutic agents for the detrusor instability. The specificity of different receptor subtypes and their transductional pathways has increased the number of targets for drug treatment of urinary bladder disorders and erectile dysfunction. As the level of intracellular nucleotide second messengers can be modulated by tissue-specific phosphodiesterase (PDE) isoenzymes, PDEs selective inhibitors have the potential to exert organ-specific therapeutic effects. So, PDE I selective inhibitor vinpocetine has been proposed for the symptomatic treatment of detrusor instability; PDE V selective inhibitor sildenafil, enhancing the NO-cGMP pathway-mediated cavernosal smooth muscle relaxation, is an effective drug to treat erectile dysfunction.

Uroangiographic contrast media, as well as magnetic resonance or ultrasound contrast agents, are substances which are able to artificially enhance the contrast between different tissues, or between normal tissue and pathological areas. The design of ionic and nonionic, monomeric or dimeric, iodobenzene derivatives is outlined with attention given to historical developments and breakthroughs. Relationships between physicochemical properties (osmolality, viscosity, molecular structure, etc.) and pharmacological profile are described. Nonionic compounds display favourable physicochemical characteristics: high water solubility, low osmolality and viscosity and good systemic tolerability. Recent surveys on adverse reactions to uroangiographic iodinated contrast media have shown that the risk of severe reactions is about six times lower with nonionic than ionic X-ray contrast agents. The pathogenetic mechanisms of adverse reactions, generally classified as either anaphylactoid or osmotoxic and chemotoxic, are still not well understood. It has been proposed that leukotrienes, prostaglandins, kinins, etc., may be involved. Nitric oxide appears to play a crucial role in the final common pathway by which anaphylaxis-like reactions occur in response to contrast agent administration. The margin of safety (median lethal dose/diagnostic dose) for nonionic compounds is two- to three-fold greater than for ionic compounds. As a look at the future, an approach to molecules potentially useful as "blood pool X-ray contrast agents" is based on iodinated dendrimeric macromolecules, in which the core is triazacyclononane and branches are represented by trioodobenzene derivatives.

Nitric oxide has been identified as an Endothelium-Derived Relaxing Factor (EDRF). Non adrenergic-non cholinergic nerves synthesise and release nitric oxide, thus modulating the arterial tone. Nitric oxide synthase exists either as a constitutive enzyme in many cell types and as an inducible form expressed under immunological stimulation. Nitric oxide is also involved in the non adrenergic-non cholinergic neurotransmission that leads to smooth muscle relaxation in the corpus cavernosum. Similarly nitric oxide induces reduction of cytosolic free Ca++ as a result of activation of the soluble form of guanylyl cyclase. VIP and nitric oxide may function as co-transmitters. Relaxation of the corpus cavernosum is blocked by methylene blue which inhibits cyclic GMP synthesis; so, high flow priapism refractory to medical and surgical treatments can be managed successfully by intracavernous methylene blue. Moreover it is suggested that enhanced alpha 1-adrenergic mediated constrictor tone and penile flaccidity in diabetic men may respond to exogenous generators of nitric oxide. We postulate that relaxation of the corpus cavernosum, started by nitric oxide in response to non adrenergic-non cholinergic neurotransmission, could be amplified and maintained by nitric oxide production as a result of platelet trapping in the corpus cavernosum during the first phase of the penile erection.

The network of both intra- and intercellular, either physical (bioconductive connectional system) and/or chemical signals, plays a significant role in the maintenance of tissue architecture and integrity of epithelial cell layers. The basement membrane is not only a static barrier but a dynamic regulator of the urothelium. Any change in the basement membrane can lead, by the extracellular matrix-cytoskeleton-nuclear matrix interaction, to altered gene regulation of the urothelial cells. Abnormal production and deposition or proteolytic degradation of the extracellular matrix components correlate with tumour stage and progression. In some experimental models, tissue inhibitors of metalloproteinases or anti-proteinase antibodies can abrogate the proteolytic activity of those matrix metalloproteinase enzymes (collagenase IV, cathepsin, stromelysin, etc.) which promote tumour invasion. Finally, the current researches investigating the use of biologic protein (e.g., TIMP-1 e-2; agents that affect angiogenesis and spread of neoplasias) are aimed at offer new therapeutic opportunities in oncology.

Up to date etiopathogenetic knowledge of phakomatoses allows a more rational classification as compared to the known ones, based on anatomopathological and/or clinical features. Some genes have been identified, which are correlated with neurofibromatoses, tuberous sclerosis and other conditions, through general biologic mechanisms (derivatives of the embryonic neural crest; nerve growth factor and its receptor; oncogenes and antioncogenes, etc.). A prenatal predictive value from those genetic connections can also ensue. The new diagnostics, both by imaging and by laboratory techniques, may affect the therapeutic choices, as for as urological involvement is concerned.

Some recent results of both experimental and clinical researches have brought to the attention the role of new neurotransmitters and neuroreceptors involved in the process of seminal ejaculation. In the central neurochemical system (neurotransmitters and neurohormones), besides the known monoamines, several aminoacids, peptides, steroids, kinins, PGs--some of which produced by the glia--have been recently evidenced. Among the peripheral receptors, besides the muscarinic and adrenergic ones, some neuropeptidic (VIP, Neuropeptide Y, endogenous opioids, etc.) take part in the effectorial process of ejaculation. Many pharmacological agents may interfere with the ejaculation, at both central and peripheral levels.

In the field of the neuroreceptors of the lower urinary tract, knowledge is being increased by some recent experimental findings, such as muscarinic subtypes, adrenergic and serotoninergic selective receptors. Moreover, the role of peptidergic receptors (VIP, CGRP, TKs, SP, ecc.; neuropeptide release from peripheral endings of capsaicin-sensitive nerves) has been suggested and investigations are in progress.

Genetic changes on the extracellular matrix of nephron basal lamina seem to underlie the pathogenesis of renal cystic disease, as also confirmed by experimental results. The cysts behave as dynamic structures and repeat some physiological features of the nephron segment which gave origin to them. These properties reflect, for instance, on the pharmacokinetics of antibacterial drugs. New imaging techniques detect more and more asymptomatic cystic formations of very little volume. Moreover, a better definition of some complications, such as haemorrhage and infections, is afforded by the RX- and RM-CT and the use of specific radiopharmaceuticals (67Ga-citrate, 99mTc-sulfur-colloids, 111In-labeled leucocytes).

Problems of venous hemodynamics underlie several uro-andrological conditions, such as idiopathic or acquired varicocele, erective impairment from venous leakage, intercaval collateral pathways induction from venous obstructive processes (thrombosis, embolism, external caval compression). Particularly, the renal venous thrombosis seems to be ascribed to a primary membranous glomerulo-nephritis rather than to a reverse mechanism. Moreover, the caval obstruction proximal to the hepatic confluence can induce a portal system's impairment, such as in the Budd-Chiari syndrome. Some diagnostics (US, RX-CT, RM-CT) afford to day a better evidence of the underlying venous imbalances in the aforesaid conditions.

The term "unknown carcinoma" may be referred to any tumour that is not revealed by clinical examination or by routine diagnostic measures; the same term can indicate metastases whose source remains unknown until revealed by autopsy. The definition of the tumour histotype is mandatory for a correct choice of curative or a palliative treatment; therefore, a recognition of primary tumour should be cunningly aimed at. With regard to imaging diagnostics, some highly paramagnetic molecules for RM will shortly be available; with regard to nuclear medicine, some gamma-releasing immuno-specific markers reacting with tumour-associated antigens are also made available. Laboratory advances nowadays afford a better definition of biopsy samples, namely monoclonal antibodies versus cytospecific antigens and/or tumour-associated antigens; immuno-histochemical markers, such as anti-AFP and anti-HCG monoclonals, that detect the testicular source (germinal tumours) of a highly undifferentiated retroperitoneal mass; etc. It seems therefore possible the foresee a reduction in the incidence of "unknown" carcinomas.

The research on the change of antibacterial activity due to the introduction of a nitro group in the benzene nucleus linked at the heterocyclic nitrogen of N-phenylsulfanilamidopyrazoles is continued with the preparation of 1-(2'-nitrophenyl)-4-sulfanilamidopyrazole (IIa: -NO2 in 2'; R=-H), 1-(3'-nitrophenyl)-4-sulfanilamidopyrazole (IIb: -NO2 in 3'; R=-H) and 1-(4'-nitrophenyl)-4-sulfanilamidopyrazole (IIc: -NO2 in 4'; R=-H). By analogy with the results obtained for the derivatives of 4-sulfanilamidopyrazole (I) previously prepared, enhancement of the bacteriostatic activity in vitro against S. aureus and E. coli, have been observed in almost all the cases, especially with 1-(3-nitrophenyl)-4-sulfanilamidopyrazole (IIb).

On the basis of previous reports on a possible correlation between phlebographic patterns and diseases of the prostatic gland, indications of the pelvic phlebography in the staging of the prostatic cancer are discussed, in order to carry out informations according to TNM system.

A survey of functional and pathological features of adrenal tumours and of the pathogenetic pathways of related hormonal syndromes is presented. The up-to-date diagnostic means, with particular stress on nuclear techniques, are discussed.

On the basis of previous studies by means of urography, renography, cholangiocholecistography, possible analogies are sought after in the behaviour of several junctions such as upper and lower uretheral, cholecisto-choledocical, eosophago-cardial. Some significant patterns were found to be in common, or close relations, among the various syndromes.

A complete urodynamic evaluation is possible only on the basis of multichannel recordings (pressure gradients, flow rate and outflow resistance, electromiography) and X-ray. The pharmacoradiology of the urinary bladder (experimental or therapeutic employment of cholinergic and adrenergic drugs) requires the knowledge of urodynamic parameters and neurophysiology of the micturition.

A nosologic re-arrangement of medullo-adrenal neoplasms has been looked for in this article, with particular regard to their common relationship to the complex histogenic system descending from the neuroectoderma-neural crista. The morpho-biologic features of these clinical entities are also reviewed, as well as the up to date laboratory and imaging techniques, with a stress on the high sensibility and specificity levels afforded, e.g., for some of these tumours by selected radio-isotopic examinations, due to their histogenetic, thereby biologic peculiarities.

A report is given of the variations in bacteriostatic activity on introduction of a hydrophilic group, the hydroxyl group (-OH), at positions 2',3' and 4' of the phenyl group linked to the heterocyclic nitrogen os 1-phenyl-5-sulfanilamidopyrazole (I: R = -H) and of 1-phenyl-3-methyl-5-sulfanilamidopyrazole (II: R = -H). The substances prepared for this purpose: 1-(hydroxyphenyl)-5-sulfanilamidopyrazoles (Ia)(Ib))(Ic)(-OH at 2', 3',4') and 1-(hydroxyphenyl)-3-methyl-5-sulfanilamidopyrazoles (IIa)(IIb)(IIc)(-OH at 2',3'4') in vitro tests of bacteriostatic activity against strains of S. aureus and E. coli gave the following results: See journal for results.