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A literature review and health effects evaluation were conducted for n-butanol, a chemical that occurs naturally in some foods, is an intermediate in the production of butyl esters, and can be used as a gasoline additive or blend. Studies evaluating n-butyl acetate were included in the review as n-butyl acetate is rapidly converted to n-butanol following multiple routes of exposure. The primary n-butanol health effects identified were developmental and nervous system endpoints. In conducting the literature review and evaluating study findings, the following observations were made: (1) developmental findings (e.g., embryo/fetal loss, altered growth, or non-neurological structural alterations) were consistently identified; (2) neurodevelopmental findings (e.g., dilation of brain ventricles and subarachnoid space) were inconsistent; (3) evidence for nervous system effects was weak, and there were study quality issues; (4) comparing internal doses from oral and inhalation exposures using physiologically based pharmacokinetic (PBPK) models involves uncertainties due to the lack of oral pharmacokinetic data and a limited understanding of the toxicological mechanisms; and (5) a lack of mechanistic information for n-butanol resulted in the reliance on mechanistic data for ethanol, which may or may not be applicable to n-butanol. This paper presents the literature review findings on the health effects of n-butanol and proposes additional research that may help to reduce the uncertainty that exists due to database limitations.

Many patients with inflammatory bowel disease (IBD) restrict dairy products to control their symptoms. The aim of the study was to investigate the prevalence of lactose intolerance assessed with hydrogen breath test (H-BT) in IBD patients in clinical remission compared to a sex, age and BMI matched control population. We further detected the prevalence of three single nucleotide polymorphisms of the lactase (LCT) gene: the lactase non persistence LCT-13910 CC (wildtype) and the intermediate phenotype LCT-22018 CT and LCT-13910 AG, finally, we assess the correlation between genotype and H-BT. A total of 54 IBD patients and 69 control who underwent clinical evaluation, H-BT and genetic test were enrolled. H-BT was positive in 64.8% IBD patients and 62.3% control (p = 0.3). The wild-type genotype was found in 85.2% IBD patients while CT-22018, AG-13910 and CT-22018/AG-13910 polymorphisms were found in 9.3%, 1.8% and 3.7%. In the control group, the wild-type genotype, CT-22018, AG-13910 and CT-22018/AG-13910 polymorphisms were found in 87%, 5.8%, 5.8% and 1.4% of cases, respectively. Therefore, the wild-type and polymorphisms’ prevalence did not differ between IBD population and control group (85.2% vs. 87%, p = 0.1) (14.8% vs. 13%, p = 0.7). The correlation between positive H-BT and genetic analysis showed that the wild-type genotype was associated with higher rate of lactose intolerance in the total population (OR 5.31, 95%CI 1.73–16.29, p = 0.003) and in the IBD (OR 7.61, 95%CI 1.36–42.7, p = 0.02). The prevalence of lactose intolerance in IBD patients did not differ from that of control. Despite suggestive symptoms, about 1/3 of IBD patients are not lactose intolerant, thus not needing “a priori” elimination diet. This may encourage a rationale and balanced dietary management in IBD.

Background: Human exposures to bisphenol A (BPA) are widespread. The current study addresses uncertainties regarding human pharmacokinetics of BPA following dermal exposure. Objective: To examine the absorption, distribution, metabolism and excretion of BPA in humans following dermal administration. Methods: We dermally administered deuterated BPA (d6-BPA) to 10 subjects (6 men and 4 women) at a dose of 100 µg/kg over a 12-hour period and conducted blood and urine analysis from the beginning of dosing through a three- or six-day period. We present time-course serum and urine concentrations of total and unconjugated (“free”) d6-BPA and used this information to calculate terminal half-life and area under the curve. Results and Conclusions: Detectable serum levels of total d6-BPA were observed at 1.4 h after the start of dosing, and a maximum serum concentration (Cmax) of 3.26 nM was observed. Free d6-BPA was detectable in serum 2.8 h after start of dermal administration, with Cmax of 0.272 nM. Beginning at approximately seven hours and continuing to 12 h (which corresponds to cessation of exposure), the concentration of free and total serum d6-BPA plateaued. The terminal half-lives of total d6-BPA and free d6-BPA in the body were 21.4 ± 9.81 h and 17.6 ± 7.69 h, respectively. Elimination from the body was rate-limited by kinetics in the dermal compartment. Free d6-BPA was a greater percentage of the area under the curve of total serum BPA (8.81%) compared to the 0.56% observed in our previously published oral study. Recovery of total d6-BPA in urine was

Background Many patients with inflammatory bowel disease (IBD) make restriction of dairy products to control their symptoms. We aimed to investigate the prevalence of lactose intolerance assessed with hydrogen breath test (H-BT) in IBD patients in clinical remission with symptoms suggestive for lactose intolerance, compared to a sex- age- and BMI-matched control population. We further detected the prevalence of three single nucleotide polymorphisms of the lactase (LCT) gene: the lactase non persistence LCT-13910CC (genetic wildtype) and the intermediate phenotype LCT-22018AG, LCT-13910CT and we assess the correlation between genotype and H-BT Methods We performed a prospective study enrolling IBD patients in clinical remission: Crohn disease (CD) activity index CDAI Results A total of 54 IBD patients and 69 matched controls were enrolled. H-BT was positive in 35(64.8%) IBD patients and 43 (62.3%) controls (p=0.3). No significant difference in lactose intolerance rate, assessed by H-BT and symptoms,was found between CD and UC patients (p =0.8). The wild-type genotype was found in 46 (85.2%) IBD patients , CT22018, AG13910 and CT22018/AG13910 polymorphisms were found in 9.3%, 1.8% and 3.7% respectively. While in the control group, the wild-type genotype, CT22018, AG13910 and CT22018/AG13910 polymorphisms were found in 87%, 5.8%, 5.8% and 1.4% of cases, respectively. The wild type and polymorphisms’ prevalence did not differ between IBD population and control group (85.2%vs 87%, p=0.1) (14.8% vs 13%, p=0.7) [Fig.1] and between CD and UC (p>0.05) [Fig.2]. The correlation between positive H-BT and genetic analysis showed that the wild-type genotype was associated with higher rate of lactose intolerance in the total population (OR 5.31, 95%CI 1.73–16.29, p=0.003) and in the IBD population (OR 7.61, 95%CI 1.36–42.7, p=0.02), even thought not in the control group (OR 4, 95%CI 0.90–17.68, p=0.07) Fig.1 Fig.2 Conclusion The prevalence of lactose intolerance in IBD is high but not dissimilar from that of the general population. The prevalence of the wild-type genotype in patients with IBD does not differ from the general population and it correlates with higher rate of lactose intolerance assessed with H-BT. Despite suggestive symptoms, about 1/3 of IBD patients is not lactose intolerant, not needing elimination diet. These can lead to promote a rationale and balanced dietary management in IBD and thereby preventing the occurrence of calcium phosphate metabolism disorders.

Our aim was to review the literature and discuss about penile curvature in order to have an update for management after 20 years experience in the field. Penile curvature may be congenital or acquired. Congenital penile curvature is a relatively uncommon condition that may present in late adolescent or early adult life. The incidence is estimated to be 0.6 %. On the other side, acquired penile curvature has an overall prevalence of 0.5-13%. Three main factors seem to increase the risk of developing an acquired penile curvature, often related to Peyronie's disease: penile traumatism, genetic and familiar conditions and a history of diseases of the genital tract. In treating Peyronie's disease, no medical therapy is fully effective, and surgery remains the gold standard in cases of severe deformity and/or erectile disfunction. Peyronie's disease is associated with significant psychological stress for patients and their partners. Appropriate treatment should be individualized and tailored to the patient's goals and expectations. There is not the ‘best’ surgical technique and outcomes are satisfactory when proper treatment decisions are made.

Chronic oral exposure to hexavalent chromium (Cr-VI) in drinking water has been shown to induce tumors in the mouse gastrointestinal (GI) tract and rat oral cavity. The same is not true for trivalent chromium (Cr-III). Thus reduction of Cr-VI to Cr-III in gastric juices is considered a protective mechanism, and it has been suggested that the difference between the rate of reduction among mice, rats, and humans could explain or predict differences in sensitivity to Cr-VI. We evaluated previously published models of gastric reduction and believe that they do not fully describe the data on reduction as a function of Cr-VI concentration, time, and (in humans) pH. The previous models are parsimonious in assuming only a single reducing agent in rodents and describing pH-dependence using a simple function. We present a revised model that assumes three pools of reducing agents in rats and mice with pH-dependence based on known speciation chemistry. While the revised model uses more fitted parameters than the original model, they are adequately identifiable given the available data, and the fit of the revised model to the full range of data is shown to be significantly improved. Hence the revised model should provide better predictions of Cr-VI reduction when integrated into a corresponding PBPK model.

Introduction: Radical surgery is the "gold standard" for treatment of invasive penile carcinoma but very poor aesthetic, functional and psychological outcomes have been reported. Our purpose was to assess the impact of organ potency-sparing surgery in locally confined carcinoma of the penis. Materials and Methods: We evaluated retrospectively 42 patients with early penile cancer (Ta,T1,T2), treated with glandulectomy and glanduloplasty with urethral mucosa and sparing of cavernosal apexes, or glandulectomy and limited apical resection in cases of Stage T2. Sexual function, ejaculation and libido were evaluated with an IIEF-15 questionnaire before the appearance of neoplasia (about three months before the surgery) and six months after surgery. Quality of life was evaluated by the Bigelow-Young questionnaire. The scores relating to two weeks prior to the surgery have been compared to those obtained six months after surgery. The statistical analysis was conducted using t-Student for repeated measures and analysis of variance. Results: Six months after surgery 73% of patients reported spontaneous rigid erections, 60% coital activity while 76% of the group treated with urethral glanduloplasty reported normal ejaculation and orgasm, regained an average of 35 days after surgery. The average IIEF-15 scores reported in the entire series in the domains of erection, libido and coital activity of the pre-cancer period were not statistically different than those recorded six months after surgery. In the group treated with glandular reconstruction, pre-and postoperative IIEF-15 mean scores related to ejaculation and orgasm domains were not significantly different. Mean scores of Bigelow-Young questionnaires related to sexual pleasure, familial, social and professional relationships showed significant improvement after surgery. Conclusions: Potency sparing-sparing surgical treatments have a positive impact on a wide spectrum of the patient′s life including family relationships, and social and working conditions.

Physiologically based pharmacokinetic (PBPK) models are tools for interpreting toxicological data and extrapolating observations across species and route of exposure. Chloroform (CHCl(3)) is a chemical for which there are PBPK models available in different species and multiple sites of toxicity. Because chloroform induces toxic effects in the liver and kidneys via production of reactive metabolites, proper characterization of metabolism in these tissues is essential for risk assessment. Although hepatic metabolism of chloroform is adequately described by these models, there is higher uncertainty for renal metabolism due to a lack of species-specific data and direct measurements of renal metabolism. Furthermore, models typically fail to account for regional differences in metabolic capacity within the kidney. Mischaracterization of renal metabolism may have a negligible effect on systemic chloroform levels, but it is anticipated to have a significant impact on the estimated site-specific production of reactive metabolites. In this article, rate parameters for chloroform metabolism in the kidney are revised for rats, mice, and humans. New in vitro data were collected in mice and humans for this purpose and are presented here. The revised PBPK model is used to interpret data of chloroform-induced kidney toxicity in rats and mice exposed via inhalation and drinking water. Benchmark dose (BMD) modeling is used to characterize the dose-response relationship of kidney toxicity markers as a function of PBPK-derived internal kidney dose. Applying the PBPK model, it was also possible to characterize the dose response for a recent data set of rats exposed via multiple routes simultaneously. Consistent BMD modeling results were observed regardless of species or route of exposure.

BACKGROUND To analyze data from the cultural examinations of different biological fluids, obtained from urologic patients from January 2007 to April 2010, in order to describe the incidence of infections in our setting. METHODS In the period of reference a urine culture was carried out for every patient admitted, in case of suspected urinary tract infection, a blood culture in case of suspected sepsis, and a wound culture in case of wound infection. RESULTS In the period of investigation 321 patients developed some kind of infection: 589 positive isolations obtained from cultural examinations have been diagnosed in urine (63%), blood (6%), surgical wound (6%), venous central catheter (7%) and other sites (18%) (tip of ureteral and bladder catheters). The most commonly isolated pathogenic agent for all the sites of infection has been Escherichia coli (22.5%). In urine, the most frequently isolated species have been Escherichia coli (27.8%), Enterococcus (12.5%), and Candida spp (9.3%). Escherichia coli (22.9%), Pseudomonas (5.7%), and Staphylococcus aureus (3.5%) were the most frequently found pathogenic agents responsible for sepsis, compared to others. In the period of investigation we have recorded 35 episodes of sepsis. CONCLUSIONS Empiric antibiotic therapy is frequent in cases of clinical evidence of infection, before the identification of the causative microorganism is available; therefore, it is important to know which are the bacterial species mainly responsible for these specific infections. We need continuous surveillance of infections and the improvement in the use of antibiotic therapy in order to limit the antimicrobial resistance.

Introduction: Paraneoplastic syndromes (PNS) may represent the main clinical problem in cancer patients; however, the knowledge of their clinical aspect remains quite poor among urologists. Objective: To provide urologists with an overview on main clinical aspects of PNS that have been reported to be associated to urological cancers. Methods: Literature search of peer-reviewed papers published by July 2008. Results: All genitourinary tumors can cause a PNS, and renal cell carcinoma is the most frequent urological malignancy involved. Prostate cancer is the second urological tumor associated with PNS which, conversely, are uncommon in bladder cancer and rare in testicular cancer. Tumor neuroendocrine differentiation is involved in most endocrine PNS. Neurologic PNS are very uncommon but may dominate the clinical picture and need a high suspicion index to be recognized. Important advances have been made on radionuclide scan methods in order to detect the primary tumor. The most effective treatment strategy is always represented by the radical therapy of the underlying cancer, but specific therapeutic options are sometimes available. Conclusions: Endocrine PNS are frequently associated with urological cancers, especially renal and prostate carcinoma. PNS have been rarely reported in association with cancers of bladder, urethra and testicle.

Androgen ablation is thought to exert selective pressure for the development of androgen-independent forms of prostate cancer. This study was set up to investigate the effects of surgical castration on the development of prostate adenocarcinoma (ADC) from its precursor (high-grade prostate intraepithelial neoplasia (HGPIN)) and on the occurrence of androgen-independent, poorly differentiated carcinoma (PDC) in (C57Bl/6 transgenic adenocarcinoma of mouse prostate) TRAMP mice. It was found that castration cures HGPIN and ADC and prevents their further occurrence and growth, but has no effect on PDC. This indicates that in this model, PDC is not the progression of ADC favoured by androgen ablation and that its initiating cells are different from those of HGPIN and ADC.

Since its introduction in 1980, extracorporeal shockwave lithotripsy (SWL) has become the first therapeutic option in most cases of upper-tract urolithiasis, and the technique has been used for pediatric renal stones since the first report of success in 1986. Lithotripter effectiveness depends on the power expressed at the focal point. Closely correlated with the power is the pain produced by the shockwaves. By reducing the dimensions of the focus, it becomes possible to treat the patient without anesthesia or analgesia but at the cost of a higher re-treatment rate. Older children often tolerate SWL under intravenous sedation, and minimal anesthesia is applicable for most patients treated with second- and third-generation lithotripters. Ureteral stenting before SWL has been controversial. Current data suggest that preoperative stent placement should be reserved for a few specific cases. Stone-free rates in pediatric SWL exceed 70% at 3 months, with the rate reaching 100% in many series. Even the low-birth-weight infant can be treated with a stone-free as high as 100%. How can one explain the good results? Possible explanations include the lesser length of the child's ureter, which partially compensates for the narrower lumen. Moreover, the pediatric ureter is more elastic and distensible, which facilitates passage of stone fragments and prevents impaction. Another factor is shockwave reproduction in the body: there is a 10% to 20% damping of shockwave energy as it travels through 6 cm of body tissue, so the small body volume of the child allows the shockwaves to be transmitted with little loss of energy. There are several concerns regarding the possible detrimental effect of shockwaves on growing kidneys. Various renal injures have been documented with all type of lithotripters. On the other hand, several studies have not shown adverse effects. In general, SWL is considered to be the method of choice for managing the majority of urinary stones in children of all ages. Re-treatments improve the stone-free rate, often raising it to 100%. Among the predictors of success, stone size seems to be the most important. In the absence of guidelines, selecting the appropriate treatment modality for each child requires planning and depends on instrument availability and local expertise.

Peyronie's disease (PD) is characterized by the onset of a fibrous plaque within the tunica albuginea of the penile corpora cavernosa, resulting in pain and bending during the erection, which can make the intercourse difficult or impossible. Evidence from literature supports the autoimmune etiology of PD, and suggests genetic and familiar conditions, penile traumatisms and history of genital tract diseases as risk factors, even though no definitive conclusions arise about the pathogenesis of the disease. Few randomized trials demonstrated that medical therapies, such as Vitamin E, Colchicine, Potassium amminobenzoate, Tamoxifen and injection therapy with Verapamil are effective in stabilizing the acute phase of the disease. Extracorporeal shock wave therapy (ESWT) and ionophoresis cannot be considered as first line or gold standard therapies. Satisfactory results have been published about Nesbit operation in large number of cases with low-stage disease, whereas plication procedures have shown significant rates of relapse. High incidence of long-term penile retraction have been reported in high-stage disease treated with plaque incision and simple graft insertion. Malleable, soft or inflatable prostheses combined with graft implant have given the best results in terms of penile straightening and lengthening and patients’ satisfaction. In conclusion, the PD etiopathogenesis hasn't been clearly understood-yet, no medical therapy is fully effective; surgery remains therefore the gold standard in case of severe deformity and/or erectile dysfunction.

Peyronie’s disease (PD) is characterized by the onset of fibrous plaque inside the tunica albuginea of the penile corpora cavernosa that can cause pain and bending during the erection, making intercourse difficult or impossible. Evidence of the literature supports the autoimmune etiology of PD and suggests genetic and familiar conditions, penile traumatisms, and a history of genital tract diseases as risk factors, but no definitive conclusions arise about the pathogenesis of the disease. Few randomized trials demonstrated that medical therapies, such as vitamin E, colchicine, potassium aminobenzoate, tamoxifen, and injection therapy with verapamil, can stabilize the acute phase of the disease. Extracorporeal shock wave therapy and iontophoresis cannot be considered first-line or gold standard therapies. Satisfactory results have been published with the Nesbit operation in large series with low-stage disease, whereas plication procedures have shown significant relapse rates. A high incidence of long-term penile retractions has been reported in high-stage disease treated with plaque incision and simple graft insertion. Malleable, soft, or inflatable prostheses combined with graft implantation have given the best results in terms of penile straightening and lengthening and patient satisfaction. In conclusion, the etiopathogenesis of PD is not yet clearly understood, no medical therapy is fully effective, and surgery remains the gold standard in patients with severe deformity and/or erectile dysfunction.

The early nineteenth century was a time of vast cultural change for the Potawatomi of southeastern Wisconsin. Historic accounts provide significant detail on many aspects of Potawatomi culture. An abundance of archaeological sites of all types define in material terms the diversity of their activities, their cultural identity, and their widespread presence throughout the region. The waning of the fur trade, the Black Hawk War, and the encroachment of Euro-Americans impacted the Potawatomi lifeway in irreversible ways. In this article, the authors present an overview of Potawatomi life in southeastern Wisconsin around the period of their removal, as it is presently understood.

A move from fixed, statically scheduled laboratory automation systems to more dynamic and adaptive behavior introduces complexities and challenges that have not been thoroughly explored in the field of laboratory automation. Powerful tools are required for the systematic modeling, analysis, simulation, and control of such systems. In this first part of a tutorial series, we introduce and explore Petri nets as a tool that can be used to model dynamically controlled laboratory automation systems. Subsequent contributions to this series will look at formal mathematical techniques for analyzing Petri net models, and methods for simulating and controlling laboratory automation systems using Petri nets.

Background To evaluate the efficacy of tamoxifen as primary treatment in women aged over 70 years with operable breast cancer versus surgery followed by adjuvant tamoxifen. Patients and methods Patients randomly received tamoxifen alone (160 mg day 1, then 20 mg/day) for 5 years or surgery followed by tamoxifen (20 mg/day) for 5 years. Overall survival was the main study end point; secondary objectives included breast cancer survival and local control of the disease. Results Between 1987 and 1992, 239 patients were assigned to surgery plus tamoxifen and 235 to tamoxifen alone. Treatment arms were comparable for tumor size, clinical nodal status and performance status. At a median follow-up of 80 months 274 patients had died. No difference between groups had emerged in overall and breast cancer survival. There were 27 local progressions in the surgery plus tamoxifen group and 106 in the tamoxifen-alone group (P = 0.0001). In the surgery plus tamoxifen group, no difference in overall survival had emerged according to the extension of operation. Conclusions The long-term results of the study confirm the 3-year interim analysis already reported. Surgery (radical or minimal) followed by adjuvant tamoxifen does not modify overall and breast cancer survival as compared with tamoxifen alone in early breast cancer of older women. Because of the high rate of local progressions with tamoxifen alone, minimal surgery followed by tamoxifen appears to be the appropriate treatment in such patients. More extensive surgery is not useful. Tamoxifen alone is an adequate alternative treatment in very old or frail patients.

It’s known that ototoxic side effects of gentamicin are caused by an iron-gentamicin complex that produces free radicals. Antioxidants attenuate gentamicin-induced free radical formation. We have previously demonstrated hair cell regeneration in both the crista ampullaris (organ involved in dynamic balance) and the saccule (organ involved in static balance) of gentamicintreated P. sicula. We now examine the fate of papilla basilaris (organ involved in hearing) hair cells after exposure to three doses of gentamicin. We want to determine whether there is any recovery and whether this is due to repair of damaged hair cells, to regeneration or, most likely, to both. In addition, we investigate whether antioxidants can effectively inhibit gentamicin-induced hair cell loss by SEM analysis using salicylate to protect against gentamicin ototoxic effects. Moreover, using BrdU, we tested whether or not there is hair cell regeneration following somministration of gentamicin. A BrdU immuno-fluorescence protocol was followed to detect BrdU-labelled cells. It was found that Gentamicin induced damage in the hair cells. Three days after the end of gentamicin treatment the hair cells of papilla showed fused or disarrayed stereovilli and there was widespread loss of hair cell bundles from the hair cells. Subsequently, numerous hair cells were lost. Conversely, when salicylate was co-administered with gentamicin the damage was moderated. The results suggest that administration of salicylate facilitates the recovery and reduces damage to hair cells after gentamicin treatment. Finally, we found evidence of bromodeoxyuridine incorporation initially in supporting cell nuclei and then in hair cell nuclei. This indicates that a process of sensory epithelium repair and hair cell regeneration occurred and that the recovery was due to both the proliferation of supporting cells and, as seems likely, selfrepair of hair cell bundles in weakly damaged sensory cells.

Although there is little information from primary or secondary prevention trials on cholesterol- lowering medication in diabetic patients, the reduction of elevated cholesterol is widely recommended for this group. The American Diabetes Association (ADA) recommends drug therapy in diabetic patients if low density lipoprotein (LDL)-cholesterol remains at > 130 mg/dl, or > 100 mg/dl in patients with macroangiopathy, after dietary intervention. When cholesterol- lowering medication is indicated, the choice of the drug must take into account the other lipid abnormalities that are often present and the need to maintain optimal glycaemic control. In the present study we compared the ef®cacy and safety of the novel HMG-CoA reductase inhibitor atorvastatin at the dose of 10 mg/day with simvastatin , lovastatin and pravastatin at doses of 10, 20 and 20 mg/day, respectively, and placebo, in type 2 diabetic patients with moderate elevation of LDL-cholesterol with or without elevation of triglycerides. All the quoted agents are enzyme inhibitors effective in lowering LDL-cholesterol in humans. The ef®cacy endpoints were the mean per cent changes in plasma LDL-cholesterol (primary), total cholesterol, triglycerides, and high-density lipoprotein (HDL)-cholesterol concentrations from baseline to the end of treatment (24 weeks). Atorvastatin at a dose of 10 mg/day produced: (1) a signi®cant reduction in LDL-cholesterol (± 37%) in comparison with equivalent doses of simvastatin (± 26%), pravastatin (± 23%), lovastatin (± 21%), and placebo (± 1%); (2) HDL-cholesterol increases (7.4%) comparable to or greater than those obtained with simvastatin (7.1%), pravastatin (3.2%), lovastatin (7.21%), and placebo (± 0.5%); (3) a signi®cantly greater reduction in total cholesterol (± 29%) than that obtained with simvastatin (± 21%), pravastain (± 16%), lovastatin (± 18%), and placebo (1%); and (4) a signi®cantly greater reduction in triglycerides than that obtained with all the other drugs and placebo. In all treatment groups no signi®cant variation in ®brinogen concentration was observed. All reductase inhibitors studied had similar levels of tolerance. There were no incidents of persistent elevations of serum aminotransferases or myositis.

Recent literature suggests the hypothesis of an immune etiology of Peyronie's disease. In this controlled study, the immune response pattern of the disease is investigated.Sixty-six patients with Peyronie's disease and 20 age-matched controls were studied. In all patients, skin test (multitest), in vitro lymphocyte transformation test (LTT), serum immunoglobulin (Ig) A, G, and M, anti-DNA, antinuclear and anti-smooth muscle cell antibodies, C3 and C4 complement fractions, antistreptolysin, and C-reactive protein titers were evaluated.A fair percentage (75.8%) of the patients with Peyronie's disease exhibited at least one abnormal immunologic test, in comparison to only 10% among controls (chi-square = 27.8, df = 1; P0.0001). Alterations of cell-mediated immunity (multitest, LTT) were observed in 48.5% of patients, alterations of humoral immunity (Ig) in 31.8%, and alterations of markers of autoimmune disorders (autoantibodies, complement activation) in 37.9% of the cases.Our results support the hypothesis that there is some involvement of the immune system in the pathogenesis of Peyronie's disease, although the available data still appear to be insufficient to formulate a definite pathogenetic hypothesis.

While most of the theater ballistic missiles (TBM) in threat countries' inventories are of the shorter range SCUD varieties, mid- to long-range versions are currently in development in a number of third world countries. Threat potential exists in the following three battle spaces: endo-atmosphere (0-30 km), high endo-atmosphere (30-70 km) and exo-atmosphere (greater than 70 km). The inherent short range and low speed of endo-atmospheric threats match well with capabilities of SM-2 Block IVA, which equips the Navy with an area defense capability. The exo-atmospheric TBMs are longer range and can threaten more targets which may be widely dispersed. Their higher velocities reduce response times dramatically. Therefore, exo-atmospheric TBMs create the need for Standard Missile-3 (SM-3), which provides the Navy with theater wide defense capability. Defining its area and theater wide systems as clearly endo-atmospheric and exo-atmospheric systems allows the Navy to use derivatives of the Standard Missile Block IV to take full advantage of the conditions associated with each of these operating zones. Use of an existing missile and ship system baseline also allows use of the existing interface structure to minimize cost. To counter the endo-atmospheric TBMs, the SM-2 BLK IVA upgrades include an advanced imaging infrared (IIR) seeker, an improved fast-reaction auto pilot and a forward looking RE all in the same volume as the existing missile. The highly responsive SM-2 Block IVA missile, complemented with Aegis weapons systems modifications, provides capability against enemy aircraft and cruise missiles, as well as TBMs. Standard Missile-3 (SM-3) replaces the SM-2 Block IV warhead, radar and guidance section with a boosted third stage and an advanced kinetic warhead (KW). Operation in the exo-atmospheric region permits a KW design with autonomous guidance control and divert thrusters for high maneuverability and has the capability of achieving very high interceptor velocities.

BACKGROUND Both thiopurines and anti-tumor necrosis factor (TNF) α agents are effective for treating Crohn's disease (CD) as they can induce clinical remission (CR) and mucosal healing (MH) in most patients. Nevertheless, data on transmural healing (TH) induced by thiopurines and anti-TNF-α agents are still lacking. This study aimed to explore the rate of TH evaluated by bowel sonography in patients with CD treated with biologics and immunosuppressors and its correlation with CR and MH. METHODS We performed an observational longitudinal study evaluating TH, CR, and MH in all patients with CD attending our clinic who would complete 2 years of maintenance treatment with biologics or thiopurines. CR and MH were assessed in accordance with current literature, whereas TH was recorded using bowel sonography. All patients underwent endoscopy and bowel sonography before starting treatment and 2 years later. RESULTS The study included 66 patients with CD treated with biologics and 67 patients receiving thiopurines. Finally, TH was present in 17 patients on biologics and only 3 patients treated with thiopurines (25% versus 4%; P < 0.01; odds ratio = 6.2). CR was achieved in 37 patients on biologics and in 34 patients on thiopurines (59.7% versus 53%; P = not significant), whereas MH was more frequent in patients treated with anti-TNF-α agents even though without statistical significance (38% versus 25%; P = not significant). CONCLUSIONS TH can be achieved in approximately 25% of patients with CD treated with anti-TNF-α agents and significantly correlates with MH. Further studies are needed to define the potential role of TH as long-term prognostic factor.

We have studied cavernous electrical activity in 42 subjects, healthy volunteer controls and groups of impotent patients using a nonspecific electromyographic device (PICO-MENFIS) and a specific one, the SPACE-recorder 7500 designed to achieve electric recordings from the corpora cavernosa. In all of the patients, we detected under basal conditions a mean amplitude of 583 +/- 323 microV, a mean duration of 4.9 +/- 7 s, a mean polyphasicity of 3.5 +/- 1.4. It should be emphasized that a significant reduction of potential amplitudes was recorded after pharmacological stimulation in both the controls and the impotent patients. The healthy controls showed amplitudes significantly higher than the impotent patients after radical cystectomy (715 +/- 141 microV versus 381 +/- 227 microV, p0.01). The patients after a "nerve-sparing" radical cystectomy with a mean amplitude similar to the controls (500-700 microV) reacted well to the intracavernous drugs in a high percentage of cases. In our experience, CC-EMG seems to be a reliable method which can pinpoint directly lesions to the cavernous smooth muscle and penile autonomic nerves. It has also been able to assess the effects of stress, anxiety and pain on the erectile mechanisms.

Purpose: Due to the lack of a gold standard for performing cavernosometry, we selected 30 patients with veno-occlusive dysfunction to evaluate the internal relationships of cavernosometric parameters and their reliability for therapeutic decisions.Materials and Methods: Cavernosometry was performed after injection of 20 to 40 microgram of prostaglandin E1. Maintenance flow rates, intracavernous pressure decay following cessation of flow and intracavernous pressure changes after compression maneuvers were the main parameters considered.Results: Cavernosometric results were standardized as grade 1--7 patients with maintenance flow rate less than 20 ml. per minute (mean 18 plus/minus 2.5) and intravernous pressure decay 27.5 plus/minus 15 percent, grade 2--11 with maintenance flow rates significantly lower (p less than 0.001) than grade 1 (mean 37 plus/minus 11 ml. per minute) and intracavernous pressure decay 33 plus/minus 20 percent, and grade 3--12 with only recorded induction flows greater than 7...

OBJECTIVES To assess the effects of autonomic nerve damage on the basis of cavernous electrical changes. METHODS A study was carried out on the cavernous electrical activity in healthy volunteers (controls) and impotent patients after radical cystoprostatectomy using a specific electromyographical device, the 'SPACE-recorder 7500'. RESULTS A significant reduction in the amplitude of potentials was recorded after pharmacological stimulation in both the controls and impotent patients. The healthy controls showed amplitude values which were significantly higher than the impotent patients after radical cystectomy (715 +/- 141 vs. 381 +/- 227 microV, p < 0.01). After 'nerve-sparing' radical cystectomy with a mean amplitude similar to controls (500-700 microV), the patients showed rigid erections after injection of intracavernous drugs in a high percentage of cases. CONCLUSION In our experience, corpora cavernosa electromyography seems a reliable method which can directly point out damage in the cavernous smooth muscle and the penile autonomic nerves.

A lipid-based physiologically based toxicokinetic (PBTK) model has been developed for a mixture of six polychlorinated biphenyls (PCBs) in rats. The aim of this study was to apply population Bayesian analysis to a lipid PBTK model, while incorporating an internal exposure-response model linking enzyme induction and metabolic rate. Lipid-based physiologically based toxicokinetic models are a subset of PBTK models that can simulate concentrations of highly lipophilic compounds in tissue lipids, without the need for partition coefficients. A hierarchical treatment of population metabolic parameters and a CYP450 induction model were incorporated into the lipid-based PBTK framework, and Markov-Chain Monte Carlo was applied toin vivodata. A mass balance of CYP1A and CYP2B in the liver was necessary to model PCB metabolism at high doses. The linked PBTK/induction model remained on a lipid basis and was capable of modeling PCB concentrations in multiple tissues for all dose levels and dose profiles.

Objectives To evaluate the usefulness of the ileocecal sphincter in preventingureteral refluxes in ileocecal orthotopic neobladder, thus avoiding the use of antireflux technique for ureteroileal anastomosis. Methods. From 1980 to 1992, 95 patients underwent orthotopic bladder substitution. In 30 our detubularized ileal reservoir was used and in 65 first only an integral ileocecal segment was used and subsequently multiple transverse teniamyotomies on the cecal portion to increase the capacity and reduce the pressure. The upper urinary tract was indirectly protected in the ileal reservoir technique by leaving an integral 8 to 10 cm long afferent segment folded behind the reservoir and in the ileocecal technique by the ileocecal sphincter, thus keeping the anastomosis between ureters and ileum simple and direct. Results. The mean follow-up of the 65 patients with ileocecourethrostomy is 37 ± 33months (range, 2 to 141 months); in 13.8% of the patients (9/65) monolateral refluxes appeared, but without any evident clinical consequences. The appearance of monolateral stenosis on the ureterointestinal anastomosis requiring treatment occurred in 4 patients (6%): 3 underwent an endoscopic treatment and 1 a surgical one. Modifications of renal function with respect to the preoperative status were not verified in any of the patients. Conclusions. The ileocecal sphincter is an effective antireflux mechanism for an orthotopicneobladder in which multiple transverse teniamyotomies (5 to 7) increase the capacity of the neobladder itself, reduce its internal pressure, and confer a nearly spherical configuration. Moreover, a correct anastomosis between the cecum and membranous urethra decisively reduces the resistance to emptying of the neobladder, thus avoiding too strong pressures against the ileocecal sphincter. The integrity of the circular muscular layer maintains a healthy tonic wall: this fact, combined with the low peripheral resistances, ensures good emptying and a stable capacity. The procedure is easy to perform and not time-consuming; these considerations lead us to consider the ileocecal unit an excellent structure for bladder substitution.

High-dose chemotherapy (HDC) followed by autologous stem cell rescue (ASCR) is the only curative treatment for metastatic retinoblastoma, but its feasibility in developing countries is unknown. We report 11 consecutive children (six unilateral) treated in three South-American middle-income countries with HDC-ASCR. One patient had metastatic retinoblastoma at diagnosis and the remaining ones had a metastatic relapse. Metastatic sites included BM=6, bone=4, orbit=5 and central nervous system (CNS)=4. All patients received induction with conventional chemotherapy achieving CR at a median of 5.7 months from the diagnosis of metastasis. Conditioning regimens included carboplatin and etoposide with thiotepa in six or with CY in four or melphalan in one patient. All patients engrafted after G-CSF-mobilized peripheral blood ASCR and no toxic deaths occurred. Two children received post-ASCR CNS radiotherapy. Seven children have disease-free survival (median follow-up 39 months). CNS relapse, isolated (n=3) or with systemic relapse (n=1), occurring at a median of 7 months after ASCT was the most common event. In the same period, five children with metastatic retinoblastoma did not qualify for HDC-ASCR and died. We conclude that HDC-ASCR is a feasible and effective treatment for children with metastatic retinoblastoma in middle-income countries.

Peyronie's disease (PD) is characterized by the onset of a fibrous plaque within the tunica albuginea of the penile corpora cavernosa, resulting in pain and bending during the erection, which can make the intercourse difficult or impossible. Evidence from literature supports the autoimmune etiology of PD, and suggests genetic and familiar conditions, penile traumatisms and history of genital tract diseases as risk factors, even though no definitive conclusions arise about the pathogenesis of the disease. Few randomized trials demonstrated that medical therapies, such as Vitamin E, Colchicine, Potassium amminobenzoate, Tamoxifen and injection therapy with Verapamil are effective in stabilizing the acute phase of the disease. Extracorporeal shock wave therapy (ESWT) and ionophoresis cannot be considered as first line or gold standard therapies. Satisfactory results have been published about Nesbit operation in large number of cases with low-stage disease, whereas plication procedures have shown significant rates of relapse. High incidence of long-term penile retraction have been reported in high-stage disease treated with plaque incision and simple graft insertion. Malleable, soft or inflatable prostheses combined with graft implant have given the best results in terms of penile straightening and lengthening and patients' satisfaction. In conclusion, the PD etiopathogenesis hasn't been clearly understood-yet, no medical therapy is fully effective; surgery remains therefore the gold standard in case of severe deformity and/or erectile dysfunction.

Background Humans are routinely and concurrently exposed to multiple toxic chemicals, including various metals and organics, often at levels that can cause adverse and potentially synergistic effects. However, toxicokinetic modeling studies of exposures to these chemicals are typically performed on a single chemical basis. Furthermore, the attributes of available models for individual chemicals are commonly estimated specifically for the compound studied. As a result, the available models usually have parameters and even structures that are not consistent or compatible across the range of chemicals of concern. This fact precludes the systematic consideration of synergistic effects, and may also lead to inconsistencies in calculations of co-occurring exposures and corresponding risks. There is a need, therefore, for a consistent modeling framework that would allow the systematic study of cumulative risks from complex mixtures of contaminants. Methods A Generalized Toxicokinetic Modeling system for Mixtures (GTMM) was developed and evaluated with case studies. The GTMM is physiologically-based and uses a consistent, chemical-independent physiological description for integrating widely varying toxicokinetic models. It is modular and can be directly "mapped" to individual toxicokinetic models, while maintaining physiological consistency across different chemicals. Interaction effects of complex mixtures can be directly incorporated into the GTMM. Conclusions The application of GTMM to different individual metals and metal compounds showed that it explains available observational data as well as replicates the results from models that have been optimized for individual chemicals. The GTMM also made it feasible to model toxicokinetics of complex, interacting mixtures of multiple metals and nonmetals in humans, based on available literature information. The GTMM provides a central component in the development of a "source-to-dose-to-effect" framework for modeling population health risks from environmental contaminants. As new data become available on interactions of multiple chemicals, the GTMM can be iteratively parameterized to improve mechanistic understanding of human health risks from exposures to complex mixtures of chemicals.

In the last decades a growing interest has been dedicated to prevention, diagnosis and therapy of male genital pathologies, such as varicocele, infertility and erectile dysfunction in the population involved in sport activities. High incidence (up to 30%) of varicocele has been reported in a population of athletes and up to 60-80% in the subgroup of body-builders. The incidence of varicocele specifically increases with hours of training, in a linear model. Controversial data come from literature about the effects of physical activity on fertility, with prevalence of trials demonstrating worsening of seminal parameters. Furthermore, it has been demonstrated that physical stress in healthy male athletes can interfere with LH levels. Bicycling is one of the major risk factors for erectile dysfunction, with incidence of 13-24%. This is due to the prolonged compression of perineal arteries leading to reduced chronic penile perfusion. Bioengineering studies have been the basis for industry to produce specifically shaped saddles that significantly reduce and minimize compressive effects. Finally, high frequency of lower urinary tract symptoms (LUTS) in cyclists has been related to increased incidence of erectile dysfunction in comparison with normal population.

Purpose: We evaluated short and long-term results of simple and complex venous surgery in patients with veno-occlusive dysfunction unresponsive to maximum recommended doses of intracavernous alprostadil, who were selected with newly developed diagnostic indicators.Materials and Methods: A total of 23 impotent men with a mean age of 41 years (range 20 to 50) underwent complex penile venous surgery. Only patients fulfilling at least 3 criteria were included in study. The criteria were mild cavernous leak assessed by cavernosometry (grades 1 and 2), more than 30% cavernous smooth muscle tissue (histomorphometric analysis), normal analogical corpus cavernosum electromyography recordings according to international standards, cavernosal oxygen tension greater than 65 mm. Hg at erection and age younger than 50 years.Results: Of 23 patients 17 (74%) had normal erections within a year after surgery, and 5 of them (29%) complained of recurrent erectile dysfunction. At long-term followup 6 of 12 patients had...

A conceptual/computational framework for exposure reconstruction from biomarker data combined with auxiliary exposure-related data is presented, evaluated with example applications, and examined in the context of future needs and opportunities. This framework employs physiologically based toxicokinetic (PBTK) modeling in conjunction with numerical “inversion” techniques. To quantify the value of different types of exposure data “accompanying” biomarker data, a study was conducted focusing on reconstructing exposures to chlorpyrifos, from measurements of its metabolite levels in urine. The study employed biomarker data as well as supporting exposure-related information from the National Human Exposure Assessment Survey (NHEXAS), Maryland, while the MENTOR-3P system (Modeling ENvironment for TOtal Risk with Physiologically based Pharmacokinetic modeling for Populations) was used for PBTK modeling. Recently proposed, simple numerical reconstruction methods were applied in this study, in conjunction with PBTK models. Two types of reconstructions were studied using (a) just the available biomarker and supporting exposure data and (b) synthetic data developed via augmenting available observations. Reconstruction using only available data resulted in a wide range of variation in estimated exposures. Reconstruction using synthetic data facilitated evaluation of numerical inversion methods and characterization of the value of additional information, such as study-specific data that can be collected in conjunction with the biomarker data. Although the NHEXAS data set provides a significant amount of supporting exposure-related information, especially when compared to national studies such as the National Health and Nutrition Examination Survey (NHANES), this information is still not adequate for detailed reconstruction of exposures under several conditions, as demonstrated here. The analysis presented here provides a starting point for introducing improved designs for future biomonitoring studies, from the perspective of exposure reconstruction; identifies specific limitations in existing exposure reconstruction methods that can be applied to population biomarker data; and suggests potential approaches for addressing exposure reconstruction from such data.

This study reports our experience in 6 cases of acute idiopathic scrotal oedema. Although children were the primary targets, this pathologic condition was also encountered in adults. Specific diagnosis of acute idiopathic scrotal oedema, opposed to other causes of scrotal swelling, is based on history, an objective examination, velocimetric Doppler exam and echography. Correct diagnosis is important in order to avoid unnecessary surgery. We are inclined to consider acute idiopathic scrotal oedema as an allergic disorder and recommend a follow-up within two days.

No satisfactory techniques are available to replace the anatomy and function of the penile glans after radical surgery for penile carcinoma. We report a new technique of glans reconstruction using distal urethra. We evaluated anatomical, physiological and esthetic features as well as short-term and long-term clinical outcomes.A total of 14 patients with a mean age of 54 who had squamous penile carcinoma underwent glans reconstruction after simple glansectomy in 8 and after amputation of the distal third of the shaft in 6. Glans sensibility, erectile function, ejaculation, orgasm, penile length, local recurrence, patient and partner satisfaction, and quality of life were evaluated before and after the operation. Mean followup was 13 months.All patients noticed subjective and objective thermal and tactile epicritic sensibility in the area of the neoglans. Ten of 14 patients (71%) noticed spontaneous and/or induced rigid erections. Interestingly International Index of Erectile Function scores in the ejaculation and orgasm domains did not significantly change in the period before and after surgery. No local disease recurrence or penile retraction were reported at long-term followup.Reconstructive glanuloplasty with distal urethra in penile tumor surgery is an innovative, easy and rapid surgical technique with appreciable functional and esthetic results.

Dear Sir, Diarrhea can cause crucial electrolyte disorders such as hypokalemia.1 More rarely hypokalemia can effect muscular complications in the form of myopathy and rhabdomyolysis.2 Some reports of hypokalemic myopathy (HM) have been described in infective and malabsorbitive diseases3 while no case is documented in inflammatory bowel diseases (IBD). Here we report two cases of HM in IBD. On September 2007, a 39 year old male with a known Crohn's disease (CD) was admitted to our department because of longstanding diarrhea, severe fatigue and muscle weakness. …

Treatment satisfaction, subanalysed by demographic variables, was evaluated in patients switching from successful intracavernosal prostaglandin E(1) (PGE(1)) therapy to oral sildenafil citrate. The validated Erectile Dysfunction Inventory of Treatment Satisfaction questionnaire was administered at the end of PGE(1) therapy and after 12 weeks of sildenafil treatment in a multicentre, open-label study. Men with erectile dysfunction (n=176) who were switched from stable PGE(1) therapy to sildenafil (25-100 mg) were equally satisfied with onset of action, duration of action, and confidence in ability to engage in sexual activity, but expressed greater overall treatment satisfaction with sildenafil (P0.01), better ease of use (P0.001), naturalness of erectile process (P0.001), and intention to continue treatment (P0.001). Partners (n=32) were overall more satisfied with sildenafil (P0.05), and their responses correlated with patient satisfaction (r=0.68). Compared with PGE(1) injection, these data suggest that patients may be less likely to discontinue taking sildenafil treatment for their erectile dysfunction.

Depth of invasion and stage of the disease are well known prognostic indicators in cutaneous melanoma (CM). However, the role of other parameters, such as the variations in cytomorphology of melanocyte tumours, mitotic activity and angiogenesis is still open to question. The aim of this study was to analyse proliferation by mitotic activity index (MAI) and immunostaining of proliferating cell nuclear antigen (PCNA), and the intensity of neovascularization (microvessel density; MVD) in CM clinical stage I in relation to epithelioid, spindle and nevoid cell type, histological type (superficial spreading melanoma and nodular melanoma), Clark's level and Breslow thickness. Finally, the role of all parameters in the prognosis of CM was evaluated. Statistical analysis demonstrated that cytological characteristics of CM correlate only with Clark's level, while histological types correlate with MAI, PCNA and MVD. MAI and PCNA also showed correlation between groups according to Clark's level and Breslow thickness. Finally, tumour cell PCNA was found to correlate with MVD. Survival of patients with CM correlated significantly with MAI. These results suggest that cytological variation, histological type, PCNA and MVD alone are not independent prognostic parameters, whereas MAI is a potentially important prognostic marker in CM.

We evaluated corpora cavernosa metabolism in flaccidity and in erection, analyzing some blood gas analytical parameters and comparing them by histomorphometric examination to find a direct relation between biochemical-metabolic parameters and histological data.We selected 33 patients with erectile dysfunction and divided them into 2 groups, including 1-those with congenital penile deviation who were responders to prostaglandin E1, and 2-those with severe organic erectile dysfunction who were not responders to prostaglandin E1. We evaluated O(2) and CO(2) pressure, pH and O(2) saturation in blood samples. We then made a histomorphometric study of cavernous tissue. We obtained specimens by cavernous biopsies and calculated O(2) and CO(2) exchange, the Haldane effect and the respiratory quotient into the corpora cavernosa. All data were evaluated by statistical analysis.Mean O(2) arterial pressure and saturation +/- SD were lower in group 2 than in group 1 (74.85 +/- 8.78 versus 96.43 +/- 14.87 and 94.98 +/- 1.4 versus 97.35 +/- 0.83, respectively). Mean CO(2) arterial pressure was 35.59 +/- 4.78 group 1 versus 38.8 +/- 2.71 in group 2 with borderline statistical significance. The Haldane effect was superior in flaccidity than in erection because of the influence of arterial-venous O(2) difference and the respiratory quotient, which was also an inverse ratio. Cavernous histomorphometry showed that in group 1 smooth muscle was a mean of 38.8 +/- 8.94% of cavernous tissue versus 24.9% in group 2.Our study shows that starting with blood gas analytical data we can completely study the metabolism of the corpora cavernosa and its relationships to erectile dysfunction. Cavernous histomorphometry can suggest the presence of smooth muscle into cavernous tissue, whereas our mathematical elaboration allowed us to evaluate all data in a more complete manner.