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The bottom two panels illustrate the interaction between alcoholism and volume loss with age buy eulexin 250mg with mastercard prostate cancer 78 years old. Top figures: The relationship between corticalgray matter rate of change and theamount of alcohol consumed during the follow-up period (left) (Spearman rho 0 generic 250mg eulexin with amex prostate cancer 7 out of 10. One alcoholic patient who reported 950 kg of alcohol consumption is omitted from the left panel so as not to distort scaling discount 250 mg eulexin free shipping prostate ultrasound video. The darker circle represents two patients with overlapping values. A controlled study of cortical gray matter and ventricular changes in alcoholic men over a 5-year interval. Data from individual ethanol-dependent pa- tients are expressed as age-corrected Z-scores plotted as a function of age. Brain gray and white matter volume loss accelerates with aging in chronic alcoholics: a quantitative MRI study. Alcohol Clin Exp Res 1992;16:1078–1089, with permission. There is a limited understanding of the extent populations. Thus, atrophy may not be detectable in young to which these studies also reflect genetic or alcohol-related healthy ethanol-dependent populations (220). Studies of ethanol intoxication ethanol-dependent adolescents show hippocampal volumet- suggest that it reduces cortical metabolism in humans (233). The study in adolescents raises the possibility that or following medications for detoxification, predominately adolescents show disruptive effects on brain development or describe reductions in regional cerebral perfusion or glucose an increased sensitivity to the neurotoxic effects of ethanol. More Over the initial years of sobriety, there is recovery in the pronounced deficits were observed in patients with evidence volumes of gray and white matter and reductions in sulcal of cortical atrophy based on structural neuroimaging (236), and ventricular volume (222). There are differences in the years of ethanol use, age (237), and multiple ethanol detoxi- rate of particular brain regions and particular tissue types fications (238). Cerebral perfusion and metabolic deficits with regard to the rate of recovery (222,223). The relatively may attenuate over the initial months of sobriety (237), rapid recovery of white matter volume with sobriety does and improvement may continue over several years (239). Ethanol with- cal perfusion and metabolic rate is associated with reduced drawal seizures have been linked to neurotoxicity in these performance on cognitive tests that engage the frontal cortex patients (225). Similarly, cerebellar metabolic deficits are associated white matter loss was particularly associated with ethanol with behavioral evidence of cerebellar dysfunction (236). Although cortical atrophy has been described in ethanol-dependent patients with good nutritional status (227), the Wernicke-Korsakoff syndrome Behavioral Studies and hepatic cirrhosis are generally associated with more prominent MRI volumetric deficits in cortical and limbic The most profound cognitive deficits associated with alco- structures than ethanol-dependent patients who are other- holism are the memory impairments arising from nutri- wise healthy (228). Although the factors that might predispose individuals to develop alcohol- most severe consequences of alcoholism for cognition may ism. One risk factor, antisocial personality disorder, appears not reflect the direct toxic effects of ethanol on the brain, to be independently associated with reductions in frontal many patients exhibit cognitive deficits independent of cortex gray matter volume (229). Thus, the observation that these factors that reflect the combined impact of age, famil- frontal gray matter volume loss is present in young ethanol- ial vulnerability for alcoholism, adaptations to ethanol dependent patients could reflect a combination of the vul- effects on the brain, perhaps degree of liver injury (244), nerability to alcoholism and atrophic effects of ethanol de- presence of comorbid depression, and ethanol-related neu- pendence (214). Cognitive function is further compromised in those patients who continue to drink, due to the direct effects of ethanol on cognition (246). The familial vulnerability to alcoholism and traits associ- Magnetic Resonance Spectroscopy ated with that vulnerability are associated cognitive deficits Magnetic resonance spectroscopy (MRS) has been applied and educational achievement (247). Although reductions to the evaluation of structural deficits in alcoholic patients in attention, planning, visual-spatial learning, and impulse in a limited fashion. Proton-MRS ([1H]MRS) enables the control have been described in children of alcoholics (248), measurement of N-acetyl-aspartate (NAA), a constituent of these findings are not universal (249). One study found reductions in the NAA/ be largely accounted for by comorbid traits such as antisocial creatine ratio in the frontal cortex and cerebellum of personality, similar to both MRI and event-related potential ethanol-dependent patients (230,231). A phosphorus-MRS (ERP) findings in alcohol dependent patients (250,251). Familial his- these effects contribute to its complex array of behavioral tory of alcoholism appears to compound the negative conse- effects in animals and humans. Direct effects of ethanol on quences of social drinking on cognitive function (253). Further, the cellular consequences of exposure to a familial alcoholism history (254). Thus it is possible that ethanol are modulated by ethanol-sensitive regulatory en- cognitive responses to ethanol may also contribute to the zymes, such as PKA and PKC. In this regard, there is growing evidence that the in patients (255). Ethanol-dependent patients show many interplay of the prefrontal cortex (PFC) and limbic struc- impairments in cognitive function. Deficits in the level of tures including the nucleus accumbens (NAc) and amygdala performance and efficiency of verbal skills, learning and generally plays an important role in reward (266,267). Cognitive deficits the output of the NAc including NMDA receptor antago- may reflect in part the degree of neurotoxicity related to nism, GABA facilitation, and enhancement in 5-HT and alcoholism. For example, young ethanol-dependent patients dopamine release (267). Drugs that antagonize the inhibi- may show normal brain volumes on MRI and normal cogni- tory effects of ethanol in the NAc, such as naltrexone (268), tive function (257,258). With repeated episodes of ethanol may play an important role in the treatment of alcoholism withdrawal and advancing age, cognitive deficits become even if opiate receptors are not a major site of action for more pronounced (259). Cognitive function improves over the initial year of so- Abnormalities in PFC development may be an important briety; however, the domains of cognitive function do not factor influencing the vulnerability to alcoholism, in part recover at the same rate and recovery may be partial (260, by altering the interplay of PFC and NAc that underlies 261). Poor cognitive function at the time that treatment is reward. As noted above, the vulnerability to alcoholism, initiated appears to predict improved alcohol-related treat- particularly in the case of individuals with antisocial person- ment outcomes (262). However, progress in treatment may ality disorder or impulsive traits, appears to be associated be reflected in improved cognitive function (263). Consis- with behavioral, physiologic, and structural evidence of PFC tent with the view that treatment may modulate cognitive dysfunction. An important and unanswered question is, recovery, some cognitive deficits in recovering patients ap- How does PFC dysfunction contribute to the vulnerability pear to respond to cognitive rehabilitation (264). Hypotheses have been presented that suggest In summary, the behavioral studies describe the display that alcoholism is just one of several forms of impulsive of deficits in cognitive functions that may have implications behavior that these individuals fail to inhibit due to a general for circuitry dysfunction in alcoholism: executive function deficiency in behavioral inhibition or as a consequence of deficits associated with the prefrontal cortex, visual-spatial the failure to anticipate the negative consequences of alco- deficits associated with the parietal cortex, and learning/ holism (269,270). Overall, these studies reward dysfunction hypothesis resting on a consideration of are consistent with the findings related to reduced tissue the impact of PFC dysfunction on mechanisms underlying volume on MRI, reductions in cortical metabolism with reward. The PFC input into limbic structures responsible fluorodeoxyglucose (FDG)-PET (242), and information for reward is critical to the experience, anticipation, and processing deficits in ERP studies (265). The activation of PFC outputs plies a connection between alterations in brain structure, to limbic structure causes a release of glutamate that may function, and behavior related to alcoholism. From this perspective, PFC activation serves THE INTERPLAY OF THE NEURAL as a 'brake' on reward mechanisms.

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Applications for commercial reproduction should be addressed to: NIHR Journals Library eulexin 250 mg amex prostate cancer dogs, National Institute for Health Research discount 250 mg eulexin fast delivery prostate cancer levels, Evaluation order eulexin 250mg without prescription prostate cancer hormone treatment, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. STAKEHOLDER VIEWS: THE PREDICTIVE RISK STRATIFICATION MODEL IMPLEMENTATION AND USE Using the NPT framework to interpret interview data enabled us to fully consider the stages and actions associated with implementing an intervention in a health-care setting to increase our understanding of the ways they responded in this study. Limitations Interviews with policy and health board staff about the story of PRISM took place some years after PRISM was developed, potentially affecting their memory of events because of the time period and role changes. In most cases, we talked to only one respondent from participating general practices. This was usually the GP responsible for leading use of PRISM, and their knowledge and use of PRISM was not always shared by other staff. In a minority of practices, the PRISM lead GP changed between the three data collection points, because they retired or moved practice. We were unable to gather the views of community health staff after the tool was implemented, as most staff declined to attend a follow-up focus group because their roles had changed. Only one health services manager agreed to be interviewed at the end of the study. General practitioners taking part in the PRISMATIC trial volunteered for the study. In interviews, several identified themselves as interested in, or supportive of, research and wanted to contribute to knowledge generation by participating. They were therefore likely to be atypical of many GPs and their response to PRISM may not be that of other members of their profession. A summary of service user involvement can be found in Table 42. TABLE 42 Summary of service user involvement in the PRISMATIC trial Type of involvement activity Role Process Comments Supporting Service users were actively Information, guidance, honoraria, Named individual (BAE) supported service user involved across all activities expenses and briefing sessions the trial manager (MRK) to ensure involvement associated with delivering were provided to facilitate active active involvement. In addition, the PRISMATIC trial involvement provided single contact for service users Service users recruited through the SUCCESS group: membership of this group gave access to mutual support and a wider service user perspective Mid-study meeting held to review involvement and further support needed Long time scales enabled strong relationships across all research partners RMG Two service users were 24 meetings scheduled (2010–16) One individual remained involved meetings invited to be members of throughout the study; the second the RMG, and contributed Two service users were at almost place was taken by four different to all decisions about all meetings; just one meeting individuals managing and undertaking took place without a service user the study member present Individuals received induction before starting role and were offered pre-meeting briefings Service user perspectives were sought at all stages, especially when developing patient consent process, preparing patient information and questionnaires, holding a prize draw for questionnaire respondents, interpreting final results TSC meetings Two service users were Five meetings held (2013–15) Service users received training before invited to be members of joining the TSC which covered the the six-person TSC, and Three out of the five meetings role of a TSC and provided provided independent attended by at least one service background about the PRISMATIC study scrutiny and user trial oversight Opportunity provided for briefing before each TSC meeting Qualitative One service user was Two meetings held (2013–14) analysis and invited to the qualitative write-up of subcommittee to develop Both meetings were attended by results coding framework and one service user and three review drafts of qualitative researchers. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 103 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. SERVICE USER INVOLVEMENT TABLE 42 Summary of service user involvement in the PRISMATIC trial (continued) Type of involvement activity Role Process Comments Writing events To contribute service user Six meetings held (2012–15) Workshop sessions held at two perspective to all meetings to consider potential study discussions about Two service users were invited to outputs for service user audience communications and each meeting: at least one dissemination attended each meeting Discussions held about how to describe the PRISMATIC trial service user involvement in final report Service users contributed to all discussions as equal team members and agreed publications plan Publicity and Service users contributed to Service users reviewed and One service user contributed to dissemination publicity and dissemination contributed to seven PRISMATIC edition 6, writing about her materials about PRISMATIC newsletters, aimed at participating experience of being involved in GP practices and health services research managers One service user contributed to edition 7, explaining how risk prediction tools can help patients, especially those with early-stage chronic illness who can expect their condition to deteriorate Two newsletters contained articles by GP champions linked to the research team The SUCCESS group members advised on, and reviewed, the patient information pages of the PRISMATIC trial website Service users involved in Service users suggested production publicising PRISMATIC to patients and distribution of a poster about the PRISMATIC trial, for display in GP practices, to inform patients about the study One service user and one GP champion were interviewed by a TV crew about the study. The package was screened on the BBC Wales evening news Service users were co-authors on Service users co-authored conference all study outputs presentations Service users co-authored journal publication reporting baseline qualitative findings (Porter et al. As people changed, five individuals were involved over 5 years. All were diagnosed with chronic conditions and some also cared for family members. One of these individuals was actively involved throughout the whole period of the PRISMATIC trial. Poor health meant three other individuals had to give up their role. To reduce the burden on individuals, we recruited a reserve service user so there were potentially three to attend meetings and less need for anyone with family responsibilities or feeling unwell. Despite receiving briefings and project information, the reserve person reported that it was difficult to retain continuity when not regularly involved and there were long periods between meetings. When his health limited his ability to drive, the study team agreed not to recruit another person and resumed working with two service users. Halfway through the trial (December 2013), we held a meeting for service users and core research staff (BAE, MRK and HH) to review their experience and identify ways to enable them to sustain and increase their involvement. Study meetings At least one, often two, service users attended almost all RMG meetings (23/24). We recruited two different service users to the TSC; they attended three of five meetings. We also involved service users in task-related meetings such as writing days, meetings to undertake qualitative analysis and research development groups discussing further research linked to the topic of risk prediction. Research activities Throughout the period of the PRISMATIC trial, service users were involved in a range of research activities including: l RMG meetings – all aspects in an equal role with other RMG members l reviewing research information ¢ format of patient questionnaires ¢ patient letters and information sheets ¢ interview schedules ¢ abstracts and posters presented at conferences l qualitative data analysis l commenting on strategies to increase questionnaire response rates (prize draw) l deciding to have a patient page on the PRISMATIC trial website (RMG decision) l developing and reviewing the patient page of the PRISMATIC trial website (at SUCCESS group meetings) l commenting on consent issues relating to the use of anonymised data l publicity (British Broadcasting Corporation, newsletters); focus of British Broadcasting Corporation publicity was on one of the service users l TSC – two members l developing and piloting service user terms of reference (at SUCCESS group meetings and RMG) l informal dissemination about the PRISMATIC trial to patient networks l co-applicant on further research bids, including a systematic review of risk prediction models and developing an intervention to communicate risk scores with patients. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 105 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. SERVICE USER INVOLVEMENT Reflections from one service user member of the PRISMATIC study I considered the PRISMATIC research to be advantageous to service users and I was pleased to be part of its development. I was able to pose questions and ask for explanations as part of the PRISMATIC team but felt there were some aspects of the research which could have taken a wider view. As a service user with chronic conditions I am aware of the problems with access to health services especially primary services, for example, GP surgeries. The research did not address the initial presentation at a GP surgery. GP receptionists were not able to identify the patients on the top of the PRISM pyramid (this was a problem when these patients were requesting an appointment). The remit for PRISMATIC did not include this and was considered to be the responsibility of the surgeries and I accept this. I do not have any issues to raise about involving service users as it has got to be beneficial in a research study. Service users, to be an asset to research and researchers, need to have some training and understanding of working within this environment. They must also understand the remit but never be afraid to put forward issues that they consider will benefit patients. That should be why we are taking part in research and we must not lose sight of this. What could be done better is explaining the remit more. There have been times when I could not see how a particular research project can work without some other basic changes made to make the research work in practice. When I have posed these questions I can tell the information is not compatible with the research criteria. Being part of a research project like PRISMATIC works for me. But what really worked for me was when I asked [name] to explain in plain English where we were at a particular time and the newsletter he produced after the event. Primary outcome l The rate, and proportion, of people with emergency admissions increased overall in the intervention phase of the trial, effects that were consistent across predicted risk levels. Secondary outcomes l Attendances at the ED were higher in the intervention phase than in the control phase; GP event-days were slightly lower; there were no clear effects on outpatient visits; bed-days overall were higher; mental health quality-of-life scores were similar between phases, but physical health scores were higher in the intervention phase; satisfaction scores were slightly lower in the intervention phase. Evidence of underprediction of risk was apparent at higher-risk levels, balanced by overprediction of risk at the lowest risk level. Costs l The implementation cost of PRISM in the first year was estimated to be £822 per practice, £0.

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Gene defect Genetic studies have identified mutations in Pathophysiology the genes encoding the bumetanide-sensitive Defective NaCl ↓ Voltage-driven sodium-potassium-2chloride cotransporter transport in TAL paracellular (N KCC2) safe 250 mg eulexin androgen hormone migraine, lum inal ATP–regulated potas- reabsorption of Ca2+ and M g2+ sium channel (ROM K) 250 mg eulexin mastercard mens health 10k glasgow 2013, and kidney-specific Volume ↑ NaCl delivery to chloride channel (ClC-K2) discount eulexin 250 mg free shipping prostate 8k springfield. In the proposed model ↑ Angiotensin II (AII) the potential interrelationships of the com- plex set of pathophysiologic phenomena are Hypercalciuria illustrated. The resulting clinical manifesta- ↑ Kallikrein ↑ Aldosterone ↑ H+ and K+ tions are highlighted in boxes. Ca2+— Hypermagnesuria secretion calcium ion; H+— hydrogen ion; K+— potas- sium ion; M g2+— magnesium ion; PGE2— Normotension prostaglandin E2. Blunted vascular response to AII and M etabolic alkalosis Impaired norepinephrine Hypokalemia vasopressin- stimulated urinary ↑ PGE2 concentration Fever Hyposthenuria ↑ Urinary ↑ Bone prostaglandins reabsorption Renal Tubular Disorders 12. H ow- ever, it is im portant to caution that evidence for N CCT m utations in sporadic cases has not yet been established. Ca2+— calci- um ion; Cl-— chloride ion; H+— hydrogen ion; K+— potassium ion; M g2+— m agnesium ion; N a+— sodium ion. Pseudohypoparathyroidism CLINICAL SUBTYPES OF PSEUDOHYPOPARATHYROIDISM Disorder Pathophysiology Skeletal anomalies Associated endocrinopathies Pseudohypoparathyroidism type Ia Defect in guanine nucleotide— binding protein Yes Yes Pseudohypoparathyroidism type Ib Resistance to parathyroid hormone, normal guanine No No nucleotide— binding protein activity? Affected patients are hypocalcemic and hyperphos- and resistance to m ultiple adenylate cyclase–coupled horm ones, phatem ic, despite elevated plasm a PTH levels. H ypocalcem ia and m ost notably thyrotropin and gonadotropin. The m olecular hyperphophatemia result from the combined effects of defective PTH- defect in a guanine nucleotide–binding protein (Gs) blocks the mediated calcium reabsorption in the distal convoluted tubule and coupling of PTH and other hormone receptors to adenylate cyclase. The latter leads to The m olecular defect has not been identified in type Ib, although defects in renal phosphate excretion, calcium mobilization from bone, specific resistance to PTH suggests a defect in the PTH receptor. Differences in clinical fea- O ral supplem entation with 1,25 dihydroxy-vitam in D3 and, if tures and urinary cyclic adenosine monophosphate response to infused necessary, oral calcium , is used to correct the hypocalcem ia and PTH provide the basis for distinguishing three distinct subtypes of m inim ize PTH -induced bone disease. Pseudohypoparathroid- pseudohypoparathyroidism (type Ia, type Ib, and type II). Sodium m oves from the lum en into the cell and down its electrochemical gradient, thus generating a lumen-negative Aldosterone synthetase 11-OHase transepithelial voltage that drives potassium secretion from the principal cells and hydrogen secretion from the intercalated cells. Unequal crossover The type I m ineralocorticoid receptor (M R) is nonspecific and can bind both aldosterone and cortisol, but not cortisone. The selective receptor specificity for aldosterone is mediated by the kidney isoform of the enzym e, 11- -hydroxysteroid dehydrogenase, which oxidizes Aldosterone synthetase Chimeric gene 11-OHase intracellular cortisol to its m etabolite cortisone. The m olecular defect in GRA derives + from an unequal crossover event between two adjacent genes K encoding 11- -hydroxylase and aldosterone synthase (A). The resulting chim eric gene duplication fuses the regulatory elem ents Aldosterone M R of 11- -hydroxylase and the coding sequence of aldosterone synthase. Deficiency of the kidney type 2 isozyme (C) AM E of 11- -hydroxysteroid dehydrogenase (C) can render type I M R responsive to cortisol and produce the syndrome of apparent mineral- ocorticoid excess. Inhibitors of this enzyme (eg, licorice) also can FIGURE 12-18 produce an acquired form of apparent m ineralocorticoid excess. Aldosterone-regulated transport in the cortical collecting duct and M edical m anagem ent of these disorders focuses on dietary sodium defects causing low-renin hypertension. The mineralocorticoid aldos- restriction, blocking the sodium channel with the potassium-sparing terone regulates electrolyte excretion and intravascular volum e by diuretics triam terene and am iloride, downregulating the ectopic way of its action in the principal cells of the cortical collecting duct. K+— potassium ion; PE— physical exam ina- tion; TH 18oxoF/TH AD— ratio of urinary Abnormal PE Normal PE 18-oxotetrahydrocortisol (TH 18oxoF) to Serum K+ urinary tetrahydroaldosterone (norm al: 0–0. The diagnosis is sup- CLINICAL SUBTYPES OF PSEUDOHYPOALDOSTERONISM ported by elevated plasma renin and plasma aldosterone concentrations. Life-saving inter- ventions include aggressive sodium chloride supplementation and treatment with ion-bind- Disorder Clinical features Treatment ing resins or dialysis to reduce the hyper- Pseudohypoaldosteronism type I kalemia. This autosomal recessive form of Autosomal recessive Dehydration, severe neonatal salt wasting, Sodium chloride PHA1 results from inactivating mutations in hyperkalemia, metabolic acidosis supplementation the or subunits of the epithelial sodium Elevated plasma renin activity Ion-binding resin; dialysis channel. A milder form of PHA1 with Severity of electrolyte abnormalities may autosomal dominant inheritance also has diminish after infancy been described; however, the molecular defect Autosomal dominant Mild salt wasting remains unexplained. Pseudohypoaldo- sensitive cotransporter (NCCT) has been steronism type I (PH A1) is characterized by severe neonatal salt wasting, hyperkalem ia, excluded as a candidate gene. N ephrogenic diabetes insipidus (N DI) is charac- 1200 Pituitary diabetes insipidus terized by renal tubular unresponsiveness to the antidiuretic hor- m one AVP or its antidiuretic analogue 1-desam ino-8-D-arginine 1000 vasopressin (DDAVP). In both the congenital and acquired form s of this disorder the clinical picture is dom inated by polyuria, poly- 800 dipsia, and hyposthenuria despite often elevated AVP levels. As shown, the binding of Physiologic Pathophysiologic arginine vasopressin (AVP) to the vaso- pressin V2 receptor (V2R) stim ulates a AQP3 AQP2 X-linked AQP3 AQP2 series of cyclic adenosine m onophosphate– –ADH H O NDI H O (cAM P) m ediated events that results in the 2 2 fusion of cytoplasm ic vesicles carrying V2R V2R water channel proteins (aquaporin-2 [AQ P2]), with the apical m em brane, thereby increasing the water perm eability AQP4 AQP4 of this m em brane. W ater exits the cell through the basolateral water channels AQ P3 and AQ P4. In the absence of AVP, water channels are retrieved into cytoplasmic AQP2 Autosomal AQP2 vesicles and the water perm eability of the recessive apical m em brane returns to its baseline +ADH AQP3 AQP3 NDI low rate. H2O ATP ATP Genetic studies have identified m utations V2R H2O V2R in two proteins involved in this water trans- cAM P cAM P port process, the V2 receptor and AQ P2 water channels. M ost patients (>90% ) AQP4 AQP4 inherit N DI as an X-linked recessive trait. In these patients, defects in the V2 receptor Interstitium Lumen Interstitium Lumen have been identified. In the rem aining patients, the disease is transm itted as either an autosom al recessive or autosom al dom i- FIGURE 12-22 nant trait involving m utations in the AQ P2 Pathogenic m odel for nephrogenic diabetes insipidus (N DI). ADH — antidiuretic horm one; m edullary collecting duct is the site where fine tuning of the final urinary com position and ATP— adenosine triphosphate. Cystinuria is the leading single gene cause of INHERITED CAUSES OF UROLITHIASES inheritable urolithiasis in both children and adults [41,42]. The X-linked recessive nephrolithiasis Calcium-containing High fluid intake, urinary alkalization com m on m olecular basis for these three X-linked recessive hypophos- Calcium-containing High fluid intake, urinary alkalization inherited kidney stone diseases has led to phatemic rickets speculation that ClC-5 also may be involved Hereditary renal hypouricemia Uric acid, calcium oxalate High fluid intake, urinary alkalization in other renal tubular disorders associated Allopurinol with kidney stones. Hereditary renal hypour- Hypoxanthine-guanine phospho- Uric acid High fluid intake, urinary alkalization icem ia is an inborn error of renal tubular ribosyltransferase deficiency Allopurinol transport that appears to involve urate reab- Xanthinuria Xanthine High fluid intake, dietary purine restriction sorption in the proximal tubule. Primary hyperoxaluria Calcium oxalate High fluid intake, dietary oxalate restriction In addition to renal transport deficiencies, Magnesium oxide, inorganic phosphates defects in m etabolic enzym es also can cause urolithiases. Inherited defects in the purine salvage enzymes hypoxanthine-guanine phos- phoribosyltransferase (H PRT) and adenine FIGURE 12-23 phosphoribosyltransferase (APRT) or in the Urolithiases are a common urinary tract abnormality, afflicting 12% of men and 5% of women catabolic enzym e xanthine dehydrogenase in North America and Europe. Renal stone formation is most commonly associated with (XDH ) all can lead to stone form ation. Perhaps in as many as 45% of these patients, there seems to be a familial Finally, defective enzym es in the oxalate predisposition. In com parison, a group of relatively rare disorders exists, each of which is m etabolic pathway result in hyperoxaluria, transmitted as a M endelian trait and causes a variety of different crystal nephropathies. The oxalate stone form ation, and consequent most common of these disorders is cystinuria, which involves defective cystine and dibasic loss of renal function.

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A higher value suggests renal potassium losses buy eulexin 250 mg overnight delivery mens health zumba, as through hyperaldostero- Potassium-sparing diuretics Increased distal nephron potassium nism purchase 250mg eulexin visa prostate yellow sperm. The expected TTKG during hyperkalemia is greater than 10 cheap eulexin 250mg on line prostate 06. Amiloride reabsorption An inappropriately low TTKG in a hyperkalemic patient suggests Pseudohypoaldosteronism type II hypoaldosteronism or a renal tubule defect. Administration of the Triamterene Urinary tract obstruction mineralocorticoid 9 -fludrocortisone (0. Circumstances are Tubular resistance to aldosterone listed in which the TTKG would not increase after mineralocorticoid Interstitial nephritis challenge, because of tubular resistance to aldosterone. Sickle cell disease Urinary tract obstruction Pseudohypoaldosteronism type I Drugs Trimethoprim Pentamidine Diseases of Potassium M etabolism 3. H eparin im pairs aldosterone synthesis by inhibiting the enzym e 18-hydroxylase. Despite its frequent use, heparin is rarely associated with overt hyperkalem ia; this suggests that other m echanism s (eg, reduced renal potassium secretion) m ust be present sim ultaneously for hyperkalem ia to m ani- fest itself. Both angiotensin-converting enzym e inhibitors and the angiotensin type 1 receptor blockers (AT1) receptor blockers interfere with adrenal aldosterone synthesis. FIGURE 3-29 Approach to hyperkalem ia: pseudohypoaldosteronism. The m echa- nism of decreased potassium excretion is caused either by failure to secrete potassium in the cortical collecting tubule or enhanced reabsorption of potassium in the m edullary or papillary collecting tubules. Decreased secretion of potassium in the cortical and m edullary collecting duct results from decreases in either apical sodium or potassium channel function or dim inished basolateral N a+-K+-ATPase activity. Alternatively, potassium m ay be secreted norm ally but hyperkalem ia can develop because potassium reab- sorption is enhanced in the intercalated cells of the m edullary col- lecting duct (see Fig. The transtubule potassium gradient (TTKG) in both situations is inappropriately low and fails to nor- m alize in response to m ineralocorticoid replacem ent. This rare autosom ally transm itted disease is characterized by neonatal dehydration, failure to thrive, hyponatrem ia, hyper- kalem ia, and m etabolic acidosis. Kidney and adrenal function are norm al, and patients do not respond to exogenous m ineralocorti- coids. Genetic m utations responsible for PH A I occur in the and subunits of the am iloride-sensitive sodium channel of the collecting tubule. Fram eshift or prem ature stop codon m utations in the cyto- plasm ic am ino term inal or extracellular loop of either subunit dis- rupt the integrity of the sodium channel and result in loss of chan- nel activity. Failure to reabsorb sodium results in volum e depletion and activation of the renin-aldosterone axis. Furtherm ore, since sodium reabsorption is indirectly coupled to potassium and hydro- gen ion secretion, hyperkalem ia and m etabolic acidosis ensue. Hyperkalemia: Clinical M anifestations FIGURE 3-31 CLINICAL M ANIFESTATIONS OF HYPERKALEM IA Clinical m anifestations of hyperkalem ia. Cardiac Renal electrolyte Abnormal electrocardiogram Decreased renal NH4+ production Atrial/ventricular arrhythmias Natriuresis Pacemaker dysfunction Endocrine Neuromuscular Increased aldosterone secretion Paresthesias Increased insulin secretion Weakness Paralysis Diseases of Potassium M etabolism 3. B, Peaked, narrow-based T waves are the earliest sign of hyperkalem ia. C, The P wave broadens and the Q RS com plex widens when the plam sa potassium level is above 7 m Eq/L. D, W ith higher elevations in potassium , the P wave becom es difficult to identify. E, Eventually, an undulating sinu- soidal pattern is evident. Although the ECG changes are depicted here as correlating to the severity of hyperkalem ia, patients with even m ild ECG changes m ay abruptly progress to term inal rhythm disturbances. Thus, hyperkalem ia with any ECG changes should be treated as an em ergency. Hyperkalemia: Treatment FIGURE 3-33 Treatm ent of hyperkalem ia. Bia M J, DeFronzo RA: Extrarenal potassium hom eostasis. Arch Int M ed 1985, gene locus on chrom osom e 16q13 in a large kindred. Funder JW : Corticosteroid receptors and renal 11 -hydroxysteroid 7. M arriott H JL: M iscellaneous conditions: H ypokalem ia. Riem anschneider TH , Bohle A: M orphologic aspects of low-potassi- crossovers between CYP11B1 and CYP11B2. Proc N atl Acad Sci USA um and low-sodium nephropathy. Tolins JP, H ostetter M K, H ostetter TH : H ypokalem ic nephropathy in 9. In A Prim er on the rat: Role of am m onia in chronic tubular injury. DeFronzo RA: Regulation of extrarenal potassium hom eostasis by 19. In Current Topics in M em branes and the control of the plasm a potassium concentration. Kam el KS, Q uaggin S, Scheich A, H alperin M L: Disorders of potassi- 11. Giebisch G, W ang W : Potassium transport: from clearance to channels um hom eostasis: an approach based on pathophysiology. N ora N A, Berns AS: H ypokalem ic, hypophosphatem ic thyrotoxic concentration gradient in patients with hypokalem ia and hyper- periodic paralysis. Department of Health and Human Services 540 Gaither Road Rockville, MD 20850 www. The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U. 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