Brian Bonanni, M.D.

• Duke University Medical Center
• Durham, NC

Due to the limited amount of publically available data suitable for modeling hypertension 8 weeks pregnant purchase innopran xl 80mg line, these studies have focused on a single machine learning classification model and the publication of three sets of structural alerts blood pressure in psi generic 40 mg innopran xl visa. Inspection of these structural alerts shows them to be mainly related to proton and electron cycling mechanisms pulse pressure heart failure purchase innopran xl 80mg on line, with there being a distinct lack of alerts relating to other mechanisms leading to mitochondrial toxicity blood pressure quick remedy discount 40mg innopran xl with amex. It is the opinion of the authors of this chapter that only a combination of targeted in vitro biology and in silico approaches is going to generate necessary data required for this challenge cuff pressure pulse pressure korotkoff sound buy innopran xl 80 mg free shipping. Chemical Toxicity Prediction: Category Formation and ReadAcross blood pressure headaches order genuine innopran xl online, Cambridge: Royal Society of Chemistry. Esposti, D, Hamelin, J, Bosselut, N, Saffroy, R, Sebagh, M, Pommier, A, Martel, C, Lemoine, A, 2012. Gille, C, Bolling, C, Hoppe, A, Bulik, S, Hoffmann, S, Hubner, K, Karlstadt, A, Ganeshan, R, Konig, M, Rother, K, Weidlich, M, Behre, J, Holzhutter, H, 2010. Koizumi, Y, Ndembi, N, Miyashita, M, Lwembe, R, Kageyama, S, Mbanya, D, Kaptue, L, Numazaki, K, Fujiyama, Y, Ichimura, H, 2006. Pessayre, D, Fromenty, B, Berson, A, Robin, M, Letteron, P, Moreau, R, Mansouri, A, 2012. Schultz, T, Amcoff, P, Berggren, E, Gautier, F, Klaric, M, Knight, D, Mahony, C, Schwarz, M, White, A, Cronin, M, 2015. Yamada, T, Tanaka, Y, Hasegawa, R, Sakuratani, Y, Yamada, J, Kamata, E, Ono, A, Hirose, A, Yamazoe, Y, Mekenyan, O, Hayashi, M, 2013. Additionally, alterations in mitochondrial dynamics (such as biogenesis, fission, fusion, mass, mitophagy, etc. Mitochondrial dynamics may change in response to physiological (exercise, starvation, hormonal changes), pathological (diabetes, infection, inflammation, cancer, neuro/cardiovascular disorders), and toxicological (drugs, carcinogens, chemicals) stress. Altered mitochondrial functions have been implicated in diseases and toxicities (Boland et al. Mitochondria also play critical roles in cell signaling and integration of signals for autophagy and apoptosis (Dorn and Kitsis, 2015; Hill et al. Consequently, in addition to physiological significance, mitochondria play an important role in toxicity, oxidative stress, and complications associated with targeted drug therapies (Gupta et al. Mitochondrial dysfunction and mitochondrial toxicity (mitotoxicity) have been reported in a number of pathophysiological conditions and drug induced inflammation and oxidative stress (Apostolova and Victor, 2015; de Castro et al. Therefore, mitochondrial function and toxicity should be considered as an important factor in any pharmacological or toxicological studies. Druginduced mitochondrial toxicity leading to a wide range of pathological conditions is seen in neuropathy, myopathy, pancreatitis, and several other disorders. The membrane extrinsic topology likely facilitates efficient interaction with soluble Adx and Adr proteins. However, some of the mitochondriaimported proteins contain noncanonical signals that are not processed after their translocation inside the mitochondria (Anandatheerthavarada et al. These signals have been characterized as a terminal amphipathic helix with diverse secondary structure and also as noncleaved internal signals (Attardi and Schatz, 1988; Bolender et al. As the protein advances into the matrix, the presequence is generally cleaved by mitochondriaspecific metalloproteases to form the mature proteins, which is then released (facilitated by local chaperons to fold into its final conformation) (Abe et al. The cryptic mitochondrial targeting signal requires activation by a cytosolic endoprotease. IngelmanSundberg, 1999, 2001; Pikuleva and Waterman, 2013; Raza and Avadhani, 1988; Robin et al. Similar signal remodeling strategies were used for developing transgenic mouse lines (Dong et al. Based on threedimensional molecular modeling, the splice variant found mostly in mitochondria retained nearly complete substrate and hemebinding domains. Mitochondrial dysfunction is also prevalent in aging, apoptosis, "offtarget" pharmacotherapy or collateral adverse effects, oxidative stress, and inflammation. Therefore, mitochondria are currently a major focus for toxicological and pharmacological studies as well as drug development. Mitochondrial biogenesis is linked to the cell cycle, as well as in response to energy demand and mitochondrial dysfunction associated with druginduced toxicities and oxidative stress (Dorn and Kitsis, 2015; Hill et al. Increased oxidative stress associated with mitochondrial dysfunction has been reported in functional defects of hepatic, cardiovascular, renal, and neural systems (Auger et al. This may be the reason for altered substrate specificities observed in some cases (see Table 4. Therefore, 42 Mitochondrial Dysfunction by Drug and Environmental Toxicants in pharmacotherapy, "offtarget/collateral" mitochondrial toxicity causing mitochondrial dysfunction may be an important factor in determining the efficacy of drugs. This emerging role of mitochondrial drug metabolism should be an important factor to consider during drug development and drug screening. In particular, mitochondrial dysfunction due to metabolic or genetic stress, as seen in diseases and toxicities, are communicated to the nucleus as an adaptive response through retrograde signaling (Amuthan et al. Retrograde signaling from mitochondria to the nucleus or cytosol controls cell growth and differentiation and hence may play a critical role in toxicity. Alterations in mitochondrial structural and functional dynamics have significant implications in retrograde signaling. Therefore, alterations in mitochondrial function and communication with other organelles are key factor in diseases and toxicities. Mitochondrial dysfunction has been implicated in many human diseases, including, but not limited to , diabetes, cancer, obesity, cardiovascular, and neurodegenerative disorders. Mitochondrial dysfunction contributes to both the etiology and progression of the diseases and toxicities. Hence, mitochondria have emerged as a potential therapeutic target against numerous human diseases. The emerging therapeutic strategies directed to mitochondria and understanding the mechanisms of drug metabolism and their effects on mitochondrial function in diseases and toxicities are being implemented by researchers in academia and pharmaceuticals companies. Therapeutic application of mitochondriatargeted antioxidants and drugs are increasingly tried experimentally and clinically. There are potential competing metabolic activation and detoxification reactions in mitochondria and extramitochondrial compartments, which lead to the differential generation/clearance of reactive metabolites and, hence, have consequences in druginduced toxicity. MitochondriaTargeted Cytochromes P450 Modulate Adverse Drug Metabolism and XenobioticInduced Toxicity 43 Acknowledgment We would like to thank the past and present members of our laboratories for their contributions in publications cited in this chapter. Manti Guha for her critical reading of this manuscript and for her help in preparing the illustrations. References Abe Y, Shodai T, Muto T, Mihara K, Torii H, Nishikawa S, Endo T, and Kohda D (2000) Structural basis of presequence recognition by the mitochondrial protein import receptor Tom20. Bolender N, Sickmann A, Wagner R, Meisinger C, and Pfanner N (2008) Multiple pathways for sorting mitochondrial precursor proteins. Dodson M, DarleyUsmar V, and Zhang J (2013) Cellular metabolic and autophagic pathways: traffic control by redox signaling. Javadov S, Jang S, and Agostini B (2014) Crosstalk between mitogenactivated protein kinases and mitochondria in cardiac diseases: therapeutic perspectives. Liu C, Sekine S, and Ito K (2016) Assessment of mitochondrial dysfunctionrelated, druginduced hepatotoxicity in primary rat hepatocytes. Purification and characterization of two distinct forms of mitochondrial cytochrome P450 from betanaphthoflavoneinduced rat liver. Wickner W and Schekman R (2005) Protein translocation across biological membranes. However, it is noteworthy that mitochondrial dysfunc tion is a generic term that includes alteration of several metabolic pathways and damage to different mitochon drial components. Thus, these mitochondrial distur bances can have a variety of deleterious consequences such as oxidative stress, energy shortage, accumulation of triglycerides (steatosis), and cell death. We then describe the main biochemical, histological, and clinical manifestations arising from the different forms of druginduced mitochondrial dysfunc tion. Finally, we provide information about different drugs for which enough clinical and experimental data indicate the potential role of mitochondrial dysfunction in the pathogenesis of liver injury. Because the inner membrane is poorly permeable to various molecules, it contains transporters allowing the entry of many endogenous compounds. Notably, a major aim of such substrate oxidation is to provide enough energy required for cell homeostasis and function. Notably, some enzymes of oxidation pathway can also produce significant amount of hydrogen peroxide within mitochondria (Kakimoto et al. This liver lesion encompasses a large spectrum of liver injury of different severity because the destruction of hepatocytes. Free fatty acids are also metabolized into acylcarnitine derivatives and dicarboxylic acids, which can be detected in plasma and urine. Free fatty acids and dicarboxylic acids can be toxic for mitochondria, thus reinforcing mitochondrial dysfunction. Low plasma levels of ketone bodies and glucose can be responsible for a profound energy deficiency in extrahepatic tissues. It has been postulated that severe inhibition of mitochondrial oxidation induces microvesicular steatosis, whereas milder inhibi tion of this metabolic pathway leads to macrovacuolar steatosis (Fromenty and Pessayre, 1995; Massart et al. The size of the fat droplets could also depend on the nature and/or the abundance of some proteins wrap ping the lipids (Bickel et al. Notably, several mitochondrial genetic diseases with hepatic dysfunction are characterized by the frequent occurrence of cholestasis in addition to steatosis and ballooning degeneration of hepatocytes (Bianchi et al. For instance, the proapoptotic proteins Bax and Bak can oligomerize into proteolipid pores within the mitochondrial outer membrane, thus promoting its permeabilization and cytochrome c release (LunaVargas and Chipuk, 2016; Pessayre et al. Such mechanisms of mitochon drial membrane permeabilization are thus insensitive to cyclosporine A (Marroquin et al. Thus, it is sometimes difficult to ascertain whether mitochondrial dysfunction is due to a direct effect of the drug on mitochondria or a secondary consequence of extramitochondrial events. Hepatic steato sis can also be observed after acetaminophen intoxica tion (Biour et al. However, when considering each drug individually, such ability to impair mitochondrial function does not necessarily mean that mitochondrial liability is a key mechanism leading to liver injury. Refer to the text for further details Amineptine was withdrawn from the market, in particular because of its hepatotoxicity. Refer to the text for further details the use of aspirin could favor the development of Reye syndrome, a severe condition characterized by microvesicular steatosis and encephalopathy. It can induce different types of liver lesions including hepatic cytolysis, steatosis, steatohepatitis, cirrhosis, phospho lipidosis, and cholestasis (Biour et al. Different investigations provided evidence that mitochondrial dysfunction is a major mechanism of amiodaroneinduced liver toxicity, in particular regard ing steatosis and steatohepatitis (Card et al. The ability of amiodarone to impair mitochondrial function is linked, at least in part, to its accumulation within the mitochondrial matrix (Fromenty and Pessayre, 1995; Fromenty et al. Interestingly, amiodarone can also accumulate inside the lysosomes where it impairs phospholipase activity and alters other key lysosomal components (Ikeda et al. These lysosomal effects explain why amiodarone can frequently cause phospholipidosis, a liver lesion that seems to have limited biochemical or clinical consequence (Fromenty and Pessayre, 1995). Amiodarone (Am) is an amphiphilic compound that harbors a protonable nitrogen within its diethylaminoethoxy moiety. In the intermembrane space of mitochondria, which is an acidic milieu, Am undergoes a protonation to generate Am+. This cationic derivative thus freely enters the mitochondrion thanks to the mitochondrial transmembrane potential. Besides steatosis, the histopathologic changes could also include marked bile ductular prolif eration and cholestasis (Kleiner et al. A possible explanation is that these animal species do not express the specific nucleoside transporter responsible for the mitochondrial entry of this drug (Lee et al. Like many other antibiotics, linezolid impairs bacterial growth by inhibiting protein synthesis. In addition, severe lactic acidosis has been observed in some of these patients and in others (Carson et al. Prolonged administration of linezolid can also induce peripheral and optic neuro pathy, skeletal myopathy, thrombocytopenia, bone mar row suppression, and renal failure (Schon and Fromenty, 2015; Song et al. Longterm treatment, high doses, and elevated linezolid blood concentrations seem to favor the occurrence of adverse effects (Song et al. Linezolid is a potent inhibitor of mitochondrial pro tein synthesis via an interaction with the mitochondrial ribosomes (Flanagan et al. Notably, these drugs are 2,3dideoxynucleoside analogues in which the hydroxyl group in the 3 position on the sugar Mitochondrial Dysfunction in DrugInduced Liver Injury 59 ring is replaced by either an hydrogen atom or another group unable to form a phosphodiester linkage. It can induce different types of chronic liver lesion including steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (Biour et al. In con trast to steatosis, tamoxifeninduced acute hepatitis and cholestasis seem to be less frequent (Biour et al. In addition to these effects, inves tigations in mice showed that chronic tamoxifen treat ment. Although all these mitochondrial effects most probably explain why tamoxifen is able to induce hepatic steatosis in a significant number of patients (Begriche et al. However, its clinical use declined because the high doses required to treat infections induced numerous adverse effects including gastrointestinal disturbances, skin reactions, blood disorders, renal dys function, and liver injury (Fromenty and Pessayre, 1995). In particular, tetracycline has been responsible for several cases of severe hepatotoxicity characterized by microvesicular steatosis and fulminant liver failure (Farrell, 1997; Fromenty and Pessayre, 1995). Synthetic tetracy clines such as doxycycline and minocycline are now preferred to tetracycline because of easier dose sched ules and faster gastrointestinal absorption when taken with food. Nevertheless, these tetracycline derivatives have been reported to induce hepatic steatosis in a few patients (Biour et al. In addition to these effects, tetracycline is able to inhibit mitochondrial protein synthesis (McKee et al. Interestingly, other tetracycline derivatives such as doxy cycline, minocycline, and rolitetracycline are able to induce mitochondrial dysfunction (CuencaLopez et al.

These are helpful in assessing the domains of sexual function as well as the impact of treatments and interventions blood pressure of 9060 buy innopran xl from india. When you had erections with No sexual sexual stimulation blood pressure chart journal cheap generic innopran xl canada, how often activity were your erections hard enough for penetration (entering your partner) During sexual intercourse blood pressure medication for anxiety buy innopran xl 40 mg lowest price, how often were you able to maintain your erection after you had penetrated (entered) your partner During sexual intercourse arteria epigastrica cranialis superficialis order innopran xl 40mg on-line, how difficult was it to maintain your erection to completion of intercourse This should include an emphasis on the neurological blood pressure medication zestoretic innopran xl 80 mg discount, cardiovascular and genital tract arrhythmia dance company purchase innopran xl with mastercard. I would also initiate lifestyle changes (including exercise and weight loss) and seek to modify any associated risk factors (stop smoking). Furthermore, tadalafil is not known to have reduced bioavailability with fatty foods. In my practice, the specific choice of which medication is given as first line is patient driven. First, it depends on whether the couple wishes to have more spontaneity in which tadalafil would be the best option. I would then explain that my patient will need to take the medication at least eight times at the maximum dose of the drug, at least 1 hour before sex 301 (Table 13. Having informed him of all these factors, the final choice is made by the patient. Tadalafil has been linked to back pain in up to 10% of cases although the side-effect profile is much better for the lower 5 mg dose. Optical neuropathies have been reported however, the actual incidence of optical neuropathy is rare. I would also ensure re-education on the effects of modifiable factors, such as dose, timing of medication, alcohol consumption, adequate sexual arousal and interaction with fatty foods. Specialist investigations include nocturnal penile tumescence studies, cavernosometry or cavernosography and Duplex ultrasound. It comprises two transducer rings which are placed around the tip and base of the penis, respectively. They are used to measure the number, duration and rigidity of nocturnal erections. If the end diastolic velocity >5 cm/s then this may indicate veno-occlusive dysfunction as the normal end diastolic velocity should be <10 cm/s. Cavernosography requires an artificial erection followed by the injection of contrast into the penis. Simultaneous imaging and blood flow parameters are measured and the flow required to maintain the erection is measured to identify any venous leaks. This particular image demonstrates a venous leak although the clinical entity of venous leak is still controversial. This consists of a reservoir which is placed in the retropubic space and is filled with saline, a pump placed in the scrotum and a pair of cylinders which are placed within the corpora of the penis. The pump in the scrotum allows fluid to flow from the reservoir to the cylinders which increase in girth and become rigid (inflation). A small release button on the pump is pressed to allow deflation of the cylinders by allowing fluid to pass back from the cylinders to the reservoir. Penile prostheses should be offered to all patients who are unwilling or unable to consider, fail to respond to , or are unable to continue with pharmacological treatment or vacuum erection devices. The long-term risks include infection (<4%), erosion (<5%) and mechanical failure (4%) which may need re-operation. A small number of patients may develop a glans droop which can be corrected at a later date by performing a glanspexy. The initial cost is high but manufacturers do offer a 10 year or lifetime guarantee for mechanical failure. The risks of surgery are higher in patients who are diabetic, have spinal cord injury or are on corticosteroids or immunosuppressives. The long-term success and satisfaction rates are reported to be over 90% for both the patient and the partner. These high success rates are due to the improved mechanical reliability of the newer prostheses and careful pre-operative counselling and patient selection [1]. The advantages of penile prosthesis surgery include long-term efficacy with a high satisfaction rate, no need for pharmacotherapy and the improved ability to lead a normal sexual life. The inability of a sexually active couple to achieve a pregnancy within 12 months following regular unprotected sexual intercourse. Approximately 20% of cases of infertility are caused entirely by a male factor, with an additional 30% of cases due to both male and female factors. In the past it was recommended not to investigate patients until 12 months of attempted conception. However, with the advancing age of infertile couples at presentation, a basic, simple, cost-effective evaluation of both the male and the female may be initiated at the time of presentation. I would ensure that his wife is also investigated and this is often best done in a joint infertility clinic, with a female fertility specialist. First, I would establish whether the period of unprotected intercourse has been regular and long enough to meet the criteria for infertility (see definition above). Once confirmed, I would try to establish the underlying cause and identify risk factors by taking a focussed urological and sexual history, performing a clinical examination and undertaking relevant investigations. Both erectile and ejaculatory function should be assessed, and the use of any vaginal lubricants during intercourse should be noted as they may affect sperm quality. The developmental history of the patient should be noted such as any history of cryptorchidism, age at puberty, and development of secondary sexual characteristics. The patient should be questioned for a history of urinary tract infections or sexually transmitted diseases as well as a history of mumps orchitis. A history of previous chemotherapy, radiation therapy or gonadotoxic treatment should also be ascertained. A history of chronic upper respiratory tract infections should be actively sought (may indicate cystic fibrosis). Anabolic steroid abuse and recreational drugs such as marijuana are also risk factors. The scrotal contents should be examined with the patient standing and lying down in a warm room to allow for relaxation of the cremasteric muscle. The testes should be carefully palpated to determine consistency and to exclude the presence of an intratesticular mass. Palpation of the epididymis should determine the presence of the head, body and tail. The possibility of epididymal obstruction is suggested by the presence of a dilated epididymal head and body. The scrotum should be examined with the patient standing up to check for the presence of a varicocele. All patients should have at least two semen analyses performed to confirm an abnormal result. An accurate semen analysis is an important investigation for the evaluation of the infertile male. To compare different semen samples from the same patient with accuracy, it is important to maintain consistency in the duration of sexual abstinence before collection of the specimen. It is recommended that specimens produced at home should be brought to the lab by placing the container in a shirt pocket next to the body to keep it warm during transit. The specimen should be examined in the laboratory within 1 to 2 hours of collection. Although interrupted coitus may be used as an alternative method for obtaining specimens, this is not recommended because the initial portion of the ejaculate may be lost and bacteria and acidic vaginal secretions may contaminate the specimen which can result in inaccurate results. The World Health Organization (2010) defines the following reference values: Volume: pH: Total sperm number: Motility: Morphology: Vitality: White blood cells: >1. His results are as follows on two occasions: Volume: pH: Total sperm number: Motility: Morphology: White blood cells: 2. Other causes include cryptorchidism, temporary insults to spermatogenesis such as heat, drugs or environmental toxins, or idiopathic causes. A heat effect may be either environmental or endogenous, such as a systemic illness resulting in fever. Differences in the venous drainage patterns of the right and left testicular veins may account for this left-sided predominance. The left testicular vein normally drains directly into the left renal vein, whereas the right testicular vein drains into the inferior vena cava. In addition, an absence of the venous valves is more commonly found on the left side than on the right. Finally, the left renal vein may be compressed between the superior mesenteric artery and the aorta. Semen samples from infertile men with varicoceles demonstrate decreased motility in 90% of patients and reduced sperm concentrations in 65% of patients. It is possible that the countercurrent exchange mechanism which normally maintains a lower intrascrotal temperature is impaired in the presence of a varicocele. Sub-fertile males with impaired semen parameters can also be offered treatment as there is likely to be an improvement in the semen parameters. Improvement in semen parameters is demonstrated in approximately 70% of patients after a varicocele repair. Improvements in motility are most common, occurring in 70% of patients, with improved sperm densities in 51% and improved morphology in 44% of patients. Semen characteristics usually improve between 3 months to 1 year following surgery or embolisation. There have been a number of studies reviewing the effects of a varicocele on fertility with conflicting results as the majority of the studies are uncontrolled with heterogenous patient and partner subgroups. The widely quoted Evers meta-analysis suggested that varicocele treatment does not improve pregnancy rates [2]. However, this meta-analysis included patients with sub-clinical varicoceles and also patients with normal semen parameters. The recommendations of the Joint Committee of the American Urological 309 Association and the American Society for Reproductive Medicine did not acknowledge the conclusions of a Cochrane meta-analysis and consider varicocele treatment to be suitable in patients with a palpable varicocele and abnormal semen parameters. I would recommend that they be seen by a urologist and also a fertility specialist. A smaller amount of tissue is removed with targeting of the best seminiferous tubules which are generally of a better calibre and colour. Gonadotropins are used to stimulate multiple oocytes during each cycle of treatment. Follicular development is then monitored ultrasonically, and the ova are harvested before ovulation with the use of ultrasound-guided needle aspiration. More than 90% of inseminated oocytes are routinely fertilized when sperm function is normal. However, fertilization rates are reduced significantly when a male factor for infertility is present. This allows for fertilization with extremely low numbers of sperm or sperm retrieved from testicular tissue. As there is a risk for the offspring patients should undergo these tests and appropriate genetic counselling before treatment. He has already been to a private laboratory and performed two semen analyses 3 months apart. The results of the latest one are below and are the same as the first one: Volume: pH: Sperm concentration: Total sperm number: Motility: Morphology: White blood cells: 2. After taking an appropriate history and a focused physical examination I would perform a baseline hormone profile. I would also consider performing genetic studies to check the karyotype and Y microdeletion. This man is likely to have non-obstructive azoospermia indicating abnormal spermatogenesis. I am looking specifically for secondary sexual characteristics, body habitus, the presence of gynaecomastia, the size and consistency of the testis and whether the vas are palpable. Patients with these microdeletions are usually phenotypically normal, with the only apparent abnormality being a defect in spermatogenesis. It is important because these gene deletions will be transmitted to male offspring. He is likely to have an obstructive cause for his azoospermia, however maturation arrest cannot be excluded without a testicular biopsy. A dilated vas or epididymis is usually indicative of obstruction which can be at the level of the ejaculatory ducts, vas or epididymis.

Orthotopic bladder substitution or neobladder formation is the favoured bladder substitution method hypertension lowering foods buy discount innopran xl online. The complications have already been outlined in the consent for cystectomy section but they can be classified in a number of ways: early or late blood pressure medication makes me dizzy 40 mg innopran xl amex, mechanical and metabolic hypertension 4011 discount innopran xl 40 mg with amex. Late complications include stomal stenosis or para-stomal herniation (24%) and uretero-ileal stenosis arrhythmia high blood pressure discount 80 mg innopran xl overnight delivery. Metabolic problems are less common with an ileal conduit than with a neobladder (as the ileal conduit does not act as storage reservoir for urine) but can include absorption of acid and chloride leading to a hyperchloraemic metabolic acidosis prehypertension risk factors order innopran xl with american express. Macrocytic anaemia can be a consequence of vitamin B12 deficiency or from a loss of iron absorption from the terminal ileum pulse pressure septic shock order innopran xl 80mg on-line. Neobladder formation is increasingly being offered to patients, particularly the young, at the time of cystectomy. The disadvantages are that it requires a larger segment of small bowel as compared to an ileal conduit, which can lead to increased risk of vitamin B12 deficiency and metabolic complications (15 cm versus 60 cm in the Studer neobladder). There is still debate as to whether neobladder affords a better quality of life then other types of urinary diversion. Traditionally, urethrectomy in females formed a routine part of radical cystectomy. It appears that the risk of urethral recurrence is lower with the use of a neobladder compared to an ileal conduit with reported decreases from 8% to 4% in the incidence of urethral recurrence if a neobladder is anastomosed to the native urethra, suggesting that urine is protective in this setting to the development of recurrent disease. If urethrectomy is not performed at the time of cystectomy then long-term follow-up of the urethra is required if no neobladder is formed. What treatment options are available for patients who present with metastatic bladder cancer What percentage of urothelial malignancies does cancer of the renal pelvis and ureter constitute Urothelial cancer of the renal pelvis and ureter is an uncommon finding accounting for 5% of urothelial malignancies and <10% of renal malignancies. A 65-year-old woman presents to your haematuria clinic with macroscopic haematuria. Although the incidence of benign histology is low in patients whether a pre-operative biopsy was performed or not, diagnosis ureteroscopy should be considered. The aetiology is similar to bladder cancer including exposure to cigarette smoking, industrial carcinogens, phenacetin and cyclophosphamide. Smoking has a long latent period of up to 20 years whereas cyclophosphamide has a much shorter latent period of around 12 years. Aristolochic acid, which is commonly used in Chinese herbal medicine, is also associated with upper tract urothelial cancer. This is essential as a high rate of ipsilateral ureteric recurrence occurs with nephrectomy alone due to the whole of the urothelium being susceptible to recurrent lesions. A second Pfannenstiel or lower midline incision can be used to facilitate excision of the bladder cuff. The entire renal unit and collecting system can be removed through a midline abdominal incision. The ureter can be dissected free either with an intravesical or extravesical technique. The intravesical approach is the most precise in terms of ureteric resection but requires an extra cystotomy. This involves the resection or cystoscopic dissection of the distal ureter to perivesical fat. Due to insufficient data on the robotic-assisted laparoscopic approaches, no recommendations have been made on its use. Do you know of any kidney-sparing treatment options for upper tract transitional cell carcinoma Where there is risk of renal insufficiency or solitary kidney, kidneysparing surgery can be considered in high-risk tumours. The ureteroscopic approach involves tissue sampling with cold cup biopsy forceps or a stone basket. The perforation rate is less than 10% in large series and can be treated with the placement of a retrograde ureteric stent. It does however allow excellent access to the renal pelvis with a 30 Fr sheath and the use of biopsy forceps, loop resection and base sampling to fully stage the lesion resected. Complications from this approach include bleeding, infection and injury to adjacent organs or pleura and potentially seeding along the tract. For both approaches, patients must be counselled for the need for long-term surveillance after treatment with imaging and direct visual inspection with repeated ureteroscopy. Using these approaches recurrence rates of 33% for pelvic tumours and 31% for ureteric tumours are reported. However, segmental resection has a role in high-risk tumours where renal preservation is paramount. This can be performed as a direct excision and spatulated tension-free uretero-ureteral anastomosis or in the lower one-third of the ureter with a Boari flap and psoas hitch. The pathologist reports that the lesion is a grade 3 transitional cell carcinoma invading into the renal parenchyma, and the nodes removed are negative for tumour spread. If high-grade upper tract malignancy is resected then the patient has a higher chance of high-grade bladder cancer at recurrence. Although synchronous bladder tumours are uncommon, 46% were found to be invasive [40]. This highlights the importance of cystoscopic, ureteroscopic and radiological surveillance of these patients following definitive treatment. Is there a role for adjuvant chemotherapy in invasive upper tract urothelial tumours A recent meta-analysis observed a beneficial effect of adjuvant chemotherapy with cisplatin-based adjuvant chemotherapy on both overall survival and disease-free survival (51% risk reduction) [41]. Flexible cystoscopy, urine cytology and radiological imaging are the main surveillance investigations. For those patients treated with kidney-sparing surgery, a more intense surveillance regime is required. Palliative care involvement will aid symptom control and support for this patient through this phase of her illness. No randomised controlled trials have reported on using chemotherapy in this setting. Asymptomatic microscopic or dipstick haematuria in adults: Which investigations for which patients: A review of the evidence. A prospective analysis of 1,930 patients with hematuria to evaluate current diagnostic practice. Diagnostic tests and algorithms used in the investigation of haematuria: Systematic reviews and economic evaluation. A prospective analysis of the diagnostic yield resulting from the attendance of 4020 patients at a protocol-driven haematuria clinic. The role of computerized tomographic urography in the initial evaluation of haematuria. A community study of bladder cancer screening by the detection of occult urinary bleeding. Early results of bladder-cancer screening in a high-risk population of heavy smokers. Photodynamic diagnosis in non-muscle invasive bladder cancer: A systematic review and cumulative analysis of prospective studies. Photodynamic diagnosis of non-muscle invasive bladder cancer with hexaminolevulinate cystoscopy: A meta-analysis of detection and recurrence based on raw data. Prognostic factors for recurrence and followup policies in the treatment of superficial bladder cancer: Report from the British Medical Research Council Subgroup on Superficial Bladder Cancer (Urological Cancer Working Party). Systematic review and individual patient data meta-analysis of randomized trials comparing a single immediate instillation of chemotherapy after transurethral resection with transurethral resection alone in patients with stage pTa-pT1 urothelial carcinoma of the bladder: Which patients benefit from the instillation A re-staging transurethral resection predicts early progression of superficial bladder cancer. Effect of routine repeat transurethral resection for superficial bladder cancer: A long-term observational study. Lymph node-positive bladder cancer treated with radical cystectomy and lymphadenectomy: Effect of the level of node positivity. The impact of extent of lymphadenectomy on oncologic outcomes in patients undergoing radical cystectomy for bladder cancer: A systematic review. The association between extent of lymphadenectomy and survival among patients with lymph node metastases undergoing radical cystectomy. Neo-adjuvant chemotherapy in invasive bladder cancer: Update of a systematic review and meta-analysis of individual patient data. Laparoscopic versus open nephroureterectomy: Perioperative and oncologic outcomes from a randomised prospective study. Prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: A 30-year experience in 252 patients. A systematic review and meta-analyses of clinicopathologic factors linked to intravesical recurrence after radical nephroureterectomy to treat upper tract urothelial carcinoma. Upper urinary tract urothelial cell carcinoma: Location as a predictive factor for concomitant bladder carcinoma. Multivariate analysis of clinical parameters of synchronous primary superficial bladder cancer and upper urinary tract tumor. A systematic review and meta-analysis of adjuvant chemotherapy and neoadjuvant chemotherapy for upper tract urothelial carcinoma. A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: A meta-analysis of published results of randomized clinical trials. There is a heterogeneous mass arising from the right kidney which is most likely to be a renal carcinoma. I would look for the presence and the morphology of the contralateral kidney; assess the primary tumour, extra-renal spread, and venous, adrenal, liver and lymph node involvement. Some symptomatic patients present with symptoms caused by metastatic disease, such as bone pain or a persistent cough. I would examine him for a palpable mass and for lymph nodes, a non-reducing varicocele (for left-sided renal tumours) and bilateral lower limb oedema, suggestive of venous involvement. Clear cell tumours have a worse outcome than chromophobe which themselves have a poorer prognosis than papillary type. Sarcomatoid features, microvascular invasion, tumour necrosis and invasion of the collecting system all confer a poorer prognosis. However, none of these markers has reliably improved the predictive accuracy of current prognostic systems and their use is not recommended in routine practice. The kidney produces 1,25-dihydroxycholecalciferol, renin, erythropoietin and various prostaglandins, all of which can precipitate symptoms. Hypercalcaemia secondary to the production of parathyroid-like peptides has been reported in 13% of cases. Hypertension secondary to renin production by the primary tumour is more common than polycythaemia due to erythropoietin production. Thrombocytopenia, neutropenia, fever, weight loss and discrete regions of hepatic necrosis are seen. His renal function is normal and he has opted for surgery after a thorough discussion with yourself. I would review the imaging prior to consent to confirm the suspected pathology and operative side. I would then describe the procedure and explain that the intended benefit was to remove the kidney which is thought to contain cancer, but explain that there is a chance that the lesion may be benign. I would describe and explain the potential complications of the procedure, including bleeding, wound infection, the potential need to convert to an open procedure, damage to adjacent organs, chest infection and the small chance of complications from the pneumoperitoneum (namely impaired venous return and gas embolism, leading to thrombosis or respiratory compromise). The patient would be told that he might have a catheter after the procedure and possibly a drain, and that the operation would take place under general anaesthetic. I would sign the consent form and ask the patient if he had any further questions. Policies on marking patients differ between departments, but it is my practice to draw a cross with indelible ink on the side for surgery. Current evidence suggests that ipsilateral adrenalectomy need only be performed in those patients in whom pre-operative imaging suggests adrenal involvement or in those in whom intra-operatively the tumour appears to involve the adrenal in contiguity. I would not routinely perform a lymph node dissection with a radical nephrectomy as there is no improved cancer-specific or overall survival benefit. However, in patients with clinically enlarged lymph nodes, I may consider a lymph node dissection for staging purposes and/or local control.

It is the most common benign solid renal tumour arteria3d urban decay city pack generic 80mg innopran xl visa, representing approximately 5% of all primary renal neoplasms with a 2:1 male-to-female predominance blood pressure reading chart order 40 mg innopran xl fast delivery. They are commonly asymptomatic and are discovered incidentally by imaging blood pressure medication leg swelling 40mg innopran xl mastercard, but up to onethird of patients have signs and/or symptoms and can present with flank/abdominal pain heart attack xi innopran xl 80mg low cost, haematuria and/or a flank mass prehypertension and chronic kidney disease buy cheap innopran xl. Describe the clinical blood pressure chart metric cheap innopran xl, radiological and pathological differences between an oncocytoma and a renal cell cancer. Clinically it is not possible to differentiate between an oncocytoma and a renal cell cancer. The age of presentation and male predominance are the same for the two conditions. Macroscopically oncocytomas are well-circumscribed, homogenous, tan-coloured lesions. Malignant features such as invasion or infiltration into the perinephric fat, collecting system or vessels are absent as is regional lymphadenopathy and metastases. Cytogenetically loss of the first and Y chromosomes, rearrangements of 11q13, loss of hetero-zygosity on chromosome 14q are seen. Absolute confirmation of the diagnosis of oncocytoma is histological, therefore nephronsparing surgery or radical nephrectomy are indicated in most cases. Once histological diagnosis is confirmed, oncocytomas do not require follow-up due to their benign nature. A renal biopsy is unreliable in accurately diagnosing an oncocytoma and this is best achieved by surgical excision. Features include fibrofolliculomas (neoplastic proliferation of the fibrous sheath of the hair follicle), pulmonary cysts, colonic lesions, oncocytomas and rarely malignant renal lesions. Familial renal oncocytomatosis is a rare condition and has been described with multicentric, bilateral tumours, with an early age of onset seen, although the genetic basis for the condition is unknown. Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: A stratification tool for prospective clinical trials. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon-alfa alone in metastatic renal-cell carcinoma: A randomised trial. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. Cytoreductive nephrectomy in patients with metastatic renal cancer: A combined analysis. Active surveillance of small renal masses: Progression patterns of early stage kidney cancer. Active treatment of localized renal tumors may not impact overall survival in patients aged 75 years or older. Survival and prognostic stratification of 670 patients with advanced renalcell carcinoma. The term does not indicate whether the condition is pathological or physiological and so when it is used it is helpful to qualify which applies. Why is it not possible to retract the prepuce in a physiological non-retractile foreskin The preputial opening is too narrow and there are adhesions between the prepuce and the glans, i. Epithelial desquamation, spontaneous erections and penile growth eventually lead to the separation of these two layers of skin. It is a chronic skin condition with some evidence suggesting an autoimmune aetiology. The process can affect the glans, foreskin, external urethral meatus and occasionally the urethra. Examination often reveals a thickened, scarred, fissured prepuce with pale white patches and with no pouting/flowering upon retraction. How is a physiological non-retractile prepuce distinguished from a pathological phimosis The more startling fact from this paper was that between 1942 and 1947 about 16 boys a year were dying as a result of complications of circumcision. Phimosis was present in 8% of 6- to 7-year-olds, 6% of 10- to 11-year-olds and 1% of 16- to 17-year-olds. Preputial adhesions were even more common affecting 63% of 6- to 7-year-olds, 48% of 10- to 11-year-olds and 3% of 16- to 17-year-olds. The message from his paper is that a non-retractile foreskin is a common observation in boys, and will usually correct itself. Physiological phimosis can safely be managed conservatively with parental reassurance and advice on bathing and maintaining proper foreskin hygiene. However, it is worth being alert to the unusual possibility of buried penis megaprepuce. When the penis is examined in a boy with buried penis megaprepuce, the outer preputial skin seems to meet directly with the abdominal wall skin dorsally, and the scrotum ventrally; the penile shaft skin is deficient. Surgical correction involves removing the inner preputial skin and excising the fibrotic tissue associated with it, and then re-applying the outer preputial skin to the shaft as a substitute for the penile shaft skin. This is an acute condition characterised by redness and swelling of the foreskin, and associated with purulent discharge from the preputial opening. Frequently Escherichia coli or Proteus vulgaris may be grown, although culture often proves sterile in up to 30%. However, if the episodes of balanoposthitis are recurrent, frequent and very bothersome, a circumcision may be warranted. Although circumcision may be justified in these last two groups, it would have to be part of a broader treatment plan to manage these conditions. This allows inspection of the urethral meatus, so that its appearance can be documented as normal. The incidence of post-operative complications following circumcision varies between 0. In patients in whom the foreskin is slow to release, a short course of topical steroid such as 0. The use of topical steroids has been shown to have no significant side effects or systemic toxicity. Preputioplasty is where a longitudinal preputial incision is closed transversely in order to widen the preputial opening. A child with hypospadias should avoid circumcision as the prepuce if often used in future surgical reconstruction. Other contraindications would include children with co-existing pathology in whom it would be unsafe to perform such an operation. Features include a ventrally situated urethral meatus, a hooded foreskin and ventral curvature, or chordee. Typically hypospadias is described in terms of the situation of the urethral meatus: a distal hypospadias would have a meatus situated on the glans or at the corona; a moderate hypospadias would have a meatus on the distal or mid-penile shaft; a proximal hypospadias would have a meatus sited on the proximal penile shaft, scrotum or perineum. This, however, provides a very limited characterisation of the abnormality and does not necessarily define which patients need which operation. The underlying problem in hypospadias is a failure of normal development of the ventral aspect of the penis. As well as a meatus that is too proximal, the urethral groove, extending from the meatus to the end of the glans may be flattened, and the urethra, glans and corpora may be hypoplastic to varying degrees. Absent or impalpable testes raise the possibility of disorders of sexual differentiation, especially where both testes are impalpable. Correction of curvature, re-siting the urethral meatus and dealing with the hooded foreskin. Thus surgical counselling ought to include no surgery/surgery at a later date/early surgical correction. In a very distal hypospadias without any chordee, a modified circumcision with careful attention to the distal urethra or a foreskin reconstruction are alternative surgical options to the hypospadias repair which aims to achieve correction of the meatal position. Correction of curvature is functionally probably the most important part of the operation; often it is because the ventral skin is short and is corrected with de-gloving and re-distribution of penile skin. Re-siting the meatus will involve creating a new urethra running from the original site to the tip of the glans. If the ventral tissues are insufficient to tubularise, then a two-stage repair is done where a free graft of preputial skin is applied to the ventral surface of the penis, and tubularised at the second operation when the graft has become fully established. The new tubularised urethra is protected with a vascular flap placed over it, usually of the dartos layer. The hooded foreskin may have been used as a source of dartos layer, or taken to be used as a free graft, or redistributed to help correct skin-level curvature. In these cases the remainder will be excised to give the penis a circumcised appearance. Some surgeons may offer to re-construct the foreskin to give the penis an un-circumcised appearance. Most surgeons would manage their hypospadias repairs with catheter drainage and a dressing. My practice is to operate at about 1 year of age, which gives a balance between the size of the patient, anaesthetic risk and how easy it will be to manage his catheter and dressing, which become more difficult between the ages of 2 and 3 years. These relate to the neo-urethra, and for a single-stage hypospadias repair, approximately 10% will need re-operation for fistula, stenosis or dehiscence of the urethral repair. You are asked to go to the neonatal ward where the staff are not able to elucidate whether a term newborn baby is a boy or a girl. Despite enormous pressure from the family there should be no rush to assigning sex, which may need to be done in a specialist unit with an appropriate multidisciplinary team. The Registry Office makes provision for this; this is one of the few situations where full registration of the child may be delayed. It is wise to advise the parents not to give their child a first name until the sex of rearing has been formally decided upon. Therefore one must immediately assess the state of hydration of the child and ensure the serum electrolytes are being checked (if in salt losing state, aggressive treatment with intravenous fluids, potassium-lowering agents, mineralocorticoid and glucocorticoid supplements will be necessary). This will include an assessment of whether gonads were palpable or present in the scrotum, the size and shape of the phallus, the appearance of the labia/scrotum and the number of openings present in the perineum. Ultimately, a child in whom there is ambiguity about the genitals will need management in a specialist centre with a full multidisciplinary team including paediatric urology, endocrinology and psychology teams. The second phase occurs between weeks 25 and 30 and is under the influence of testosterone, taking the testis from the inguinal canal down to the scrotum. Between the ages of 3 and 12 months they will give rise to adult dark spermatogonia. You see a newborn baby boy whose parents are concerned that he is missing a testis. For example, prematurity, low birth weight, neuro-muscular disorders, family history (14% of boys with undescended testis have a family history) or hypospadias. Answering these questions will distinguish between a retractile testis, an ectopic testis and an undescended testis. A large proportion of testes that are not in the scrotum at birth will continue to descend. By 3 months of age, testes that are going to descend spontaneously will have done so; those that remain high will not come down any further. One testis sits in the scrotum and the contralateral testis is not immediately visible. However, after you have calmed the child you are able to feel the other testis in the groin, and find that with gentle traction it comes down into the scrotum. A retractile testis can be brought into the fundus of the scrotum, and when released, remains there. A gliding testis will only come down under tension, and/or the traction required to pull it down causes pain. It would make sense to keep the boy under review until the testis is no longer retractile, or declares itself as an ascended testis. The next 8-month-old boy you see in the clinic by coincidence has an inguinal testis on one side and a normal testis on the other side. Although some testes that are undescended at birth will continue to descend, it is unlikely that there is going to be very much more descent after the age of 3 months. However, early orchidopexy, with more delicate vas and testicular vessels is technically challenging; anaesthesia in younger infants is a more significant undertaking. There is no randomised control trial to verify true effect on fertility of the varied ages of orchidopexy. However, there is still some degree of subfertility in unilateral cases with 11% failing to achieve paternity within 1 year compared to only 5% of controls. There is now some evidence to suggest that orchidopexy may reduce the risk of germ cell malignancy.

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