Eine 78-jährige, seit 2,5 Jahren dialysepflichtige Patientin wurde zur weiteren Abklärung einer zunehmenden Verschlechterung des Allgemeinzustands mit Appetitverlust und multiplen Ulzera im Bereich der Ohren, Gaumen und Unterschenkel stationär aufgenommen. Die Endoskopie des unteren Gastrointestinaltraktes zeigte ebenfalls Ulzera der Kolonmukosa. Die Biopsie des Ulkus der linken Ferse zeigte eosinophilenreiche Granulome, sodass in Kombination mit deutlich erhöhten c-ANCA-Konzentrationen die Diagnose einer aktiven Wegener-Granulomatose gestellt werden konnte.

The regulation of renin secretion is not understood in detail. There is evidence that amiloride (CAS 17440-83-4) has a stimulatory effect on the renin secretion but it is still in question whether this is volume and/or sodium independent. The purpose of this study was to investigate whether a single dose of amiloride has a direct stimulatory effect on the renin secretion in humans independent of its diuretic effect. Blood pressure, plasma renin activities and plasma aldosterone concentrations as well as serum electrolytes and serum creatinine were assessed in 11 healthy male humans over a period of 6 hours after a single dose of 20 mg of amiloride (Midamor), or placebo. Furthermore every hour urine was collected for analysis of urinary creatinine and electrolytes. To avoid a possible effect on the renin secretion via augmented diuresis induced by amiloride the urinary volume loss was replaced by 0.9% NaCl solution. There was a decrease in plasma renin activities and plasma aldosterone concentrations after amiloride and placebo administration, but the plasma renin activity after amiloride was significantly higher compared with placebo. Also the plasma aldosterone concentration was higher after amiloride compared with placebo, but the difference did not reach statistical significance. Serum and urinary concentrations of sodium and potassium clearly confirmed the known potassium-saving and natriuretic effect of amiloride. Serum creatinine concentrations decreased and urinary sodium chloride concentrations increased due to the administered volume load using physiologic sodium chloride solution. The present study provides evidence that amiloride induces renin secretion by direct mechanisms in man, which might go along with augmented aldosterone secretion.

We report on the case of an ABO-incompatible renal re-transplant recipient maintained on an intensified immunosuppressive regimen for recurrent cellular rejection episodes and transplant glomerulopathy who presented with rapidly growing hepatic tumors, radiologically suggestive of hemangiosarcoma. Upon resection and pathological work-up, the lesions revealed alveolar echinococcosis, a rare but potentially life-threatening parasitosis. Usually infection with Echinococcus multilocularis remains asymptomatic for extended periods of time and can go unrecognized for years. In the case presented, we observed an atypically rapid growth pattern of E. multilocularis that might have been due to the extent of the immunosuppressive regimen, which included repetitive anti-CD20 treatments. Retrospectively performed serological studies with enzyme-linked immunosorbent assays known to provide high sensitivity and specificity for the detection of echinococcosis in the general population, yielded ambiguous results in our immunocompromised host, which could be, in part, explained by B-cell depletion and its effects on antibody production and indirect actions on cellular immunity. In conclusion, this is the first report to our knowledge of hepatic alveolar echinococcosis in a renal transplant recipient. This case documents an altered clinical course of the parasitosis and the challenge of serological diagnostic tools under an intensified regimen of immunosuppressive agents, including rituximab.

History and admission findings: A 29-years-old Brazilian woman was admitted to hospital because of progressive dyspnoea, shivering and fever. She reported a noticeable swelling at the right mandible and an ulcerative tumor at the side of the nose.Investigations: Laboratory tests showed normocytic, normochromic anemia with an elevation of the inflammatory parameters. Radiology showed an enlargement of the upper mediastinum. Computed tomography revealed extensive, confluent lymphoma. There were groups of cervical lymph nodes, especially in the area of the right jaw. Bronchoscopy showed extensive space-occupying lesions with severe inflammation of the trachea.Diagnosis: Bronchial biopsy revealed necrotizing, granulomatous inflammation with dense infiltration of lymphatic cells. Small and spheroidal pathogens were seen within giant cells. Grocott-silver stain was positive, indicating histoplasmosis. Histological work-up of the ulcerating tumor at the side of the nose also showed Histoplasma capsulatum.Treatment and course: 8 weeks after starting specific treatment with oral itraconazole the inflammatory parameters had fallen to normal and computed tomography showed regression of the mediastinal bulge.Conclusion: Large mediastinal and cervical lymphatic masses with space-occupying bronchial lesions suggest should, in the dfferential diagnosis, consider not only malignant tumor but also infections. If the patient had been abroad (in this case in Brazil), pathogens like Histoplasma capsulatum, which is not present in Europe, have to be considered. In this immunocompetent patient the severe progression and dissemination of the disease, involving mediastinum, throat and skin, is most unusual.

BACKGROUND:Patients with diabetes type 2 receiving dialysis therapy have a poor survival prognosis, mainly due to cardiovascular events. Increased C-reactive protein (CRP) levels, important in atherosclerosis, are associated with an increased risk for cardiovascular events. However, to date no study has shown the predictive value of CRP in relation to peripheral arterial disease stage.METHODS:We enrolled all 445 prevalent patients with diabetic nephropathy receiving maintenance hemodialysis in 30 centers in Southern Germany from August 1999 to January 2000 for prospective study until December 2003. At inclusion, CRP and a complete clinical phenotype, including peripheral arterial disease Fontaine Stage were determined. The primary end point was all-cause mortality.RESULTS:A total of 305 (68.5%) patients died. An increased log CRP at study inclusion was significantly associated with an increase in hazard ratio (HR) by multivariate Cox regression for all-cause (HR = 1.5, P= 0.002) and cardiac death (HR = 1.76, P= 0.02) in the entire collective. This result was applicable only to patients with peripheral arterial disease Fontaine stage IV (N= 190, multivariate HR = 1.75 for all-cause mortality, P= 0.006). Possibly due to inadequate power, we observed only an insignificant trend for CRP as predictor of all-cause death in patients without peripheral arterial disease or with less severe forms of peripheral arterial disease (HR = 1.36, P= 0.08).CONCLUSION:In contrast to patients with peripheral arterial disease stage IV, patients with less severe atherosclerosis and elevated CRP are, if any, at less risk for cardiovascular mortality, possibly due to the difference in extent of affected vasculature and thus activated platelets and coagulation. Before judging the predictive value of CRP for mortality, peripheral vessel status should be determined.

INTRODUCTION:Patients with type 2 diabetes (DM2) and end stage renal disease (ESRD) have a dismal survival prognosis, mainly due to cardiovascular events. There is sparse data on genetic predictors. Chemokines and their receptors are important in regulating leukocyte influx and activation in atherosclerosis, and functional polymorphisms in the respective genes are associated with cardiovascular disease risk. METHODS:We enrolled 225 prevalent Caucasian DM2 patients receiving maintenance hemodialysis in 30 centres in Southern Germany (time from dialysis initiation <2.0 years) from August 1999 to January 2000 for prospective study until December 2003. The CX3CR1 T280M, and MCP-1 -2518 and RANTES -403 and -28 promoter and intronic In1.1T/C polymorphisms were assessed by real-time PCR. Primary end point was all-cause mortality (ACM). RESULTS:Patients carrying the RANTES -403A or In1.1C allele had a significantly higher ACM risk (multivariate hazard ratio for -403A, dominant model=1.81 [95% CI: 1.22-2.67], p=0.003), mainly due to cardiac events. Similar data were obtained by haplotype analysis. The other SNPs showed no effect on survival. DISCUSSION:In DM2 patients with ESRD, ACM due to cardiac events is associated with RANTES gene variants that are known to alter the expression of this chemokine important in atherosclerosis. Further study of the role of chemokine and chemokine receptor gene variation in determining vascular end points is needed.

SUMMARY: The purpose of this study was to investigate the effect of high fluid intake for the prevention of march‐induced proteinuria and haematuria. Thirty‐six male soldiers participated in two 25 km marches in a comfortable environment (outside temperature 13°C, cloudy weather), achieving a moderate average marching time of 3.5 h. Fluid intake during march 1 was not restricted (= habitual intake), whereas during march 2, the participants were asked to achieve a fluid intake of 1 L before and 2 L during the march. Urinary excretion of protein and albumin, haematuria, and various serum parameters were assessed before, during and after both marches. Unexpectedly, urinary albumin and protein excretion was higher during march 2 (with a high fluid intake), whereas haematuria was unaffected. the haemoconcentration, as judged from haemoglobin levels, was more intense in group 1 (with usual fluid intake) in accordance with the higher decrease of bodyweight during the march, and probably accounted for most of the serum creatinine concentration increases observed. A standardized (high) fluid intake of 2.5 L before and during a moderate exercise failed to confer any prevention against mild exercise‐induced renal abnormalities.

Zusammenfassung Bei der vorgestellten Patientin bestand eine dekompensierte globale Herzinsuffizienz mit rezidivierenden und anhaltenden Tachykardien. Sowohl eine ischämische als auch eine hypertensive Herzerkrankung konnten ausgeschlossen werden.Aufgrund von Anamnese, Verlauf und laborchemischen Befunden konnten die wichtigsten Differenzialdiagnosen der Herzinsuffizienz mit inflammatorischer, toxischer, infiltrativer, genetischer oder idiopathischer Genese weitgehend ausgeschlossen werden.Somit ergab sich die Hauptdiagnose einer tachykardieinduzierten Herzinsuffizienz, bei der durch die elektrophysiologische Untersuchung verschiedene Ursprünge der beobachteten Reentrytachykardien verifiziert und mittels Katheterablation behoben werden konnten. Die besondere Bedeutung des hier vorgestellten Fallberichts zur interventionellen Herzinsuffizienztherapie beim Erwachsenen besteht darin, erneut auf das Krankheitsbild der tachykardieinduzierten Herzinsuffizienz hinzuweisen und die Möglichkeit einer kausalen und kurativen Therapieoption durch Hochfrequenzablation aufzuzeigen.

Naftidrofuryl, a 5-hydroxytryptamine 2 (5-HT 2 ) serotonergic receptor antagonist with vasodilator effects, has successfully been used for intermittent claudication, some forms of dementia, and glaucoma. Recently, an additional mode of action of naftidrofuryl (i.e., mixed endothelin receptor antagonism) has been suggested. However, in the current study naftidrofuryl was unable to block endothelin-3-induced free intracellular calcium increases, in contrast to a mixed endothelin receptor antagonist, bosentan. The inhibition of forskolin-induced renin secretion by endothelin-3 in primary cultures of mouse juxtaglomerular cells and by endothelin-1 in the isolated perfused rat kidney could not be blocked by naftidrofuryl. Naftidrofuryl was unable to block marked endothelin-1-induced renal vasoconstriction in isolated perfused rat kidney. In contrast, naftidrofuryl markedly attenuated serotonin-induced renal vasoconstriction and nearly completely blocked serotonin's renin inhibitory properties in isolated perfused rat kidney. The present results suggest that naftidrofuryl is a potent antagonist of serotonin's renal effects, but has no endothelin receptor-blocking properties.

The aim of this study was to examine the effects of highly selective inhibition of cyclooxygenase 2 (COX‐2) with rofecoxib on the renin system during long‐term stimulation and after short‐term stimulation. Six healthy male volunteers received, in a randomized crossover design, a low‐sodium diet for days 1 through 9 with or without 25 mg rofecoxib twice daily on days 5 through 9 and, in addition, 20 mg of furosemide intravenously on day 8. Plasma renin activity increased 2 to 3 times over baseline with a low‐sodium diet and 5 times over baseline 30 minutes after intravenous furosemide; it was still elevated nearly 5 times on day 9. These effects were completely blocked by rofecoxib. Plasma aldosterone and urinary aldosterone concentrations basically reflected the findings with plasma renin activity. Urinary sodium excretion decreased during a low‐sodium diet and increased after intravenous furosemide without being significantly affected by rofecoxib. We have concluded that low‐sodium and furosemide‐stimulated renin and aldosterone secretion is completely blocked in healthy volunteers during COX‐2 inhibition with rofecoxib, suggesting that intact COX‐2 is of major importance for stimulation of the renin system under these conditions in man.Clinical Pharmacology & Therapeutics (2001) 70, 468–474; doi: 10.1016/S0009‐9236(01)49789‐X

Though Cushing's syndrome is a well-known clinical problem in terms of side effects of steroid therapy, endogenous Cushing's syndrome is a relatively rare diagnosis. We treated a 27-year-old patient who presented with severe hypertension and massive osteoporosis. We could diagnose a central Cushing syndrome by endocrinological function tests which, in retrospect, existed undiagnosed for more than 5 years. However, magnetic resonance imaging did not display an adenoma neither of the hypophysis nor of the adrenal glands. During explorative surgery, a cylindric microadenoma of the pituary gland was found and excised. After surgery, the blood pressure returned to normal, making further antihypertensive treatment unnecessary.

Paul Emery and colleagues (Dec 18/25, p 2106)1Emery P Zeidler H Kvian TK et al.Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison.Lancet. 1999; 354: 2106-2111Summary Full Text Full Text PDF PubMed Scopus (530) Google Scholar showed that treatment with celecoxib caused fewer gastrointestinal side-effects than diclofenac. However, potential side-effects of cyclo-oxygenase (COX-2)-selective inhibitors may include impairment of renal function. In a study by Swan and colleagues,2Swan SK Lasseter KC Ryan CF et al.Renal effects of multiple-dose rofecoxib (R), a COX-2 inhibitor in elderly subjects.J Am Soc Nephrol. 1999; 10 (abstr): 641AGoogle Scholar rofecoxib reduced glomerular filtration rate (GFR) by about 12% in elderly patients with mild renal impairment (baseline creatinine clearance 30–80 mL/min; 10% reduction of GFR with indomethacin). Brooks and colleagues3Brooks DP Adams J De Palma PD Webb EF Griswold DE Palmer R Induction of sodium retention by a COX-2 inhibitor in volume depleted dogs: comparison with other COX inhibitors.J Am Soc Nephrol. 1999; 10 (abstr): 629AGoogle Scholar found that in volume-depleted dogs, intravenous celecoxib reduced urine flow by 57%, sodium excretion by 70%, renal plasma flow by 65%, and GFR by 58% (reduction of 57%, 33%, 33%, 27%, respectively, for indomethacin). And Whelton and colleagues4Whelton A Schulman G Verburg KM Drower EJ Geis GS Effects of celecoxib and naproxen on renal funtion in the elderly.J Am Soc Nephrol. 1999; 10 (abstr): 471AGoogle Scholar found that celecoxib caused significant reductions of urinary sodium excretion on the first 2 days of treatment in healthy elderly patients, but did not significantly affect GFR (reduction of -1·1 mL/min). They also found that urinary prostaglandin E2 and 6-keto prostaglandin F1 α were decreased to the same extent by celecoxib and naproxen. In the study by Emery and colleagues, a small increase in serum creatinine concentration from 93·3 μmol/L at baseline to 95·5 μmol/L at the final visit, and of serum urea concentration from 6·0 mmol/L to 6·4 mmol/L was reported (serum creatinine 93·2 vs 97·2 μmol/L, serum urea 6·0 vs 6·7 mmol/L with diclofenac). With regard to changes in renal function during COX-2 inhibition, it would be of interest to know serum creatinine and urea concentrations measured at 4-weekly intervals, and the results of urine analyses. However, one has to keep in mind that in the study by Emery and colleagues, only patients with normal renal function were studied. In a larger study of 1149 patients, celecoxib versus naproxen was studied.5Simon LS Weaver AL Graham DY et al.Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial.JAMA. 1999; 282: 1921-1928Crossref PubMed Scopus (817) Google Scholar Baseline serum creatinine concentrations were as low as 66 μmol/L. Not surprisingly serum creatinine concentrations were unaffected by celecoxib or naproxen treatment in this study. Why there are such large differences in baseline serum creatinine concentrations between these two studies is not clear; the patients with rheumatoid arthritis studied were of nearly identical age and sex distribution.Evidence suggests that COX-2 inhibitors impair renal function and cause sodium retention in patients with mild pre-existing renal failure and presumably also in some elderly patients with, for example, volume depletion. The published randomised trials have regularly excluded these patients. We feel that it is important for unpublished data from these trials to be made available to allow a better estimation of the renal risk conferred by COX-2 inhibitors. Furthermore, randomised trials that assess renal sideeffects of COX-2 inhibition in patients with pre-existing renal failure are eagerly awaited. Paul Emery and colleagues (Dec 18/25, p 2106)1Emery P Zeidler H Kvian TK et al.Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison.Lancet. 1999; 354: 2106-2111Summary Full Text Full Text PDF PubMed Scopus (530) Google Scholar showed that treatment with celecoxib caused fewer gastrointestinal side-effects than diclofenac. However, potential side-effects of cyclo-oxygenase (COX-2)-selective inhibitors may include impairment of renal function. In a study by Swan and colleagues,2Swan SK Lasseter KC Ryan CF et al.Renal effects of multiple-dose rofecoxib (R), a COX-2 inhibitor in elderly subjects.J Am Soc Nephrol. 1999; 10 (abstr): 641AGoogle Scholar rofecoxib reduced glomerular filtration rate (GFR) by about 12% in elderly patients with mild renal impairment (baseline creatinine clearance 30–80 mL/min; 10% reduction of GFR with indomethacin). Brooks and colleagues3Brooks DP Adams J De Palma PD Webb EF Griswold DE Palmer R Induction of sodium retention by a COX-2 inhibitor in volume depleted dogs: comparison with other COX inhibitors.J Am Soc Nephrol. 1999; 10 (abstr): 629AGoogle Scholar found that in volume-depleted dogs, intravenous celecoxib reduced urine flow by 57%, sodium excretion by 70%, renal plasma flow by 65%, and GFR by 58% (reduction of 57%, 33%, 33%, 27%, respectively, for indomethacin). And Whelton and colleagues4Whelton A Schulman G Verburg KM Drower EJ Geis GS Effects of celecoxib and naproxen on renal funtion in the elderly.J Am Soc Nephrol. 1999; 10 (abstr): 471AGoogle Scholar found that celecoxib caused significant reductions of urinary sodium excretion on the first 2 days of treatment in healthy elderly patients, but did not significantly affect GFR (reduction of -1·1 mL/min). They also found that urinary prostaglandin E2 and 6-keto prostaglandin F1 α were decreased to the same extent by celecoxib and naproxen. In the study by Emery and colleagues, a small increase in serum creatinine concentration from 93·3 μmol/L at baseline to 95·5 μmol/L at the final visit, and of serum urea concentration from 6·0 mmol/L to 6·4 mmol/L was reported (serum creatinine 93·2 vs 97·2 μmol/L, serum urea 6·0 vs 6·7 mmol/L with diclofenac). With regard to changes in renal function during COX-2 inhibition, it would be of interest to know serum creatinine and urea concentrations measured at 4-weekly intervals, and the results of urine analyses. However, one has to keep in mind that in the study by Emery and colleagues, only patients with normal renal function were studied. In a larger study of 1149 patients, celecoxib versus naproxen was studied.5Simon LS Weaver AL Graham DY et al.Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial.JAMA. 1999; 282: 1921-1928Crossref PubMed Scopus (817) Google Scholar Baseline serum creatinine concentrations were as low as 66 μmol/L. Not surprisingly serum creatinine concentrations were unaffected by celecoxib or naproxen treatment in this study. Why there are such large differences in baseline serum creatinine concentrations between these two studies is not clear; the patients with rheumatoid arthritis studied were of nearly identical age and sex distribution. Evidence suggests that COX-2 inhibitors impair renal function and cause sodium retention in patients with mild pre-existing renal failure and presumably also in some elderly patients with, for example, volume depletion. The published randomised trials have regularly excluded these patients. We feel that it is important for unpublished data from these trials to be made available to allow a better estimation of the renal risk conferred by COX-2 inhibitors. Furthermore, randomised trials that assess renal sideeffects of COX-2 inhibition in patients with pre-existing renal failure are eagerly awaited.

Authors' replySir—The HOPE Study was designed to find out if the addition of the angiotensin-converting enzyme (ACE) inhibitor ramipril to the medical regimen of patients at high risk of having cardiovascular events, reduces the risk of such events. For those with diabetes, we ensured that the results would be relevant to individuals at high risk for cardiovascular events by specifying that included individuals had to have at least one other cardiovascular risk factor. We did not design the study to find out whether the intervention was more effective in subgroups of participants with diabetes and certain risk factors, including those with microalbuminuria, a previous history of cardiovascular disease, or other baseline risk factors (eg, hypertension, dyslipidaemia, or smoking). It is important to avoid over-interpreting the results of any subgroup analysis they are only presented to illustrate the fact that the results were consistent across subgroups. Indeed, when a study shows a clear overall benefit, the results are applicable to most types of participants studied, unless a significant statistical interaction is shown. No study is designed to provide independent significance in every subgroup of interest. In the HOPE study we showed a clear overall benefit for patients with diabetes who were taking ramipril, this benefit was consistent in those with and without previous cardiovascular disease or microalbuminuria. There was no evidence of statistical heterogeneity for any subgroup. We therefore disagree with Tonny Jensen's comment: the results are relevant for a broad range of individuals who are at high risk of having cardiovascular events.Jensen is indeed correct to point out that ramipril reduced the risk of the overt nephropathy (a pre-specified outcome of the analysis). This finding therefore extends the results of previous work done in younger, normotensive, microalbuminuric people with type-2 diabetes1Ravid M Lang R Rachmani R Lishner M Long-term renoprotective effect of angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus: a 7 year follow-up study.Arch Intern Med. 1996; 156: 4286-4289Crossref Google Scholar to a broader group of older, high cardiovascular risk, normotensive, and hypertensive individuals with diabetes with and without microalbuminuria. We combined nephropathy with laser therapy or renal failure (both considered to be signs of microvascular disease) and showed consistent results.We welcome Mark Webster's comments and would like to emphasise the difficulties inherent in comparing the HOPE study results in the treated hypertensive (56%) and nonhypertensive (44%) subgroups (with a mean blood pressure at entry of 142/80 mm Hg), to the UKPDS study's results in hypertensive individuals (with a mean blood pressure at entry of 159/94 mm Hg) randomly assigned atenolol or captopril.2UK Prospective Diabetes Study (UKPDS) GroupEfficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39.BMJ. 1998; 317: 713-720Crossref PubMed Google Scholar The HOPE study was not a trial of antihypertensive therapy, and no attempt was made to treat blood pressure to any predetermined target. It therefore provides no information on the relative efficacy of one active agent versus another. Instead, it shows that in addition to current care (which may include β-blockers, diuretics, or calciumchannel blockers), ramipril effectively reduced the risk of cardiovascular events and nephropathy.Finally, we agree with V Lewis and colleagues, and Gerry Fegan and colleagues that many people with diabetes may expect to benefit from the addition of an ACE inhibitor. We also agree with Mike Stubanus and colleagues that the metabolic effects of ramipril and other modulators of the renin-angiotensin system require further study. Authors' reply Sir—The HOPE Study was designed to find out if the addition of the angiotensin-converting enzyme (ACE) inhibitor ramipril to the medical regimen of patients at high risk of having cardiovascular events, reduces the risk of such events. For those with diabetes, we ensured that the results would be relevant to individuals at high risk for cardiovascular events by specifying that included individuals had to have at least one other cardiovascular risk factor. We did not design the study to find out whether the intervention was more effective in subgroups of participants with diabetes and certain risk factors, including those with microalbuminuria, a previous history of cardiovascular disease, or other baseline risk factors (eg, hypertension, dyslipidaemia, or smoking). It is important to avoid over-interpreting the results of any subgroup analysis they are only presented to illustrate the fact that the results were consistent across subgroups. Indeed, when a study shows a clear overall benefit, the results are applicable to most types of participants studied, unless a significant statistical interaction is shown. No study is designed to provide independent significance in every subgroup of interest. In the HOPE study we showed a clear overall benefit for patients with diabetes who were taking ramipril, this benefit was consistent in those with and without previous cardiovascular disease or microalbuminuria. There was no evidence of statistical heterogeneity for any subgroup. We therefore disagree with Tonny Jensen's comment: the results are relevant for a broad range of individuals who are at high risk of having cardiovascular events. Jensen is indeed correct to point out that ramipril reduced the risk of the overt nephropathy (a pre-specified outcome of the analysis). This finding therefore extends the results of previous work done in younger, normotensive, microalbuminuric people with type-2 diabetes1Ravid M Lang R Rachmani R Lishner M Long-term renoprotective effect of angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus: a 7 year follow-up study.Arch Intern Med. 1996; 156: 4286-4289Crossref Google Scholar to a broader group of older, high cardiovascular risk, normotensive, and hypertensive individuals with diabetes with and without microalbuminuria. We combined nephropathy with laser therapy or renal failure (both considered to be signs of microvascular disease) and showed consistent results. We welcome Mark Webster's comments and would like to emphasise the difficulties inherent in comparing the HOPE study results in the treated hypertensive (56%) and nonhypertensive (44%) subgroups (with a mean blood pressure at entry of 142/80 mm Hg), to the UKPDS study's results in hypertensive individuals (with a mean blood pressure at entry of 159/94 mm Hg) randomly assigned atenolol or captopril.2UK Prospective Diabetes Study (UKPDS) GroupEfficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39.BMJ. 1998; 317: 713-720Crossref PubMed Google Scholar The HOPE study was not a trial of antihypertensive therapy, and no attempt was made to treat blood pressure to any predetermined target. It therefore provides no information on the relative efficacy of one active agent versus another. Instead, it shows that in addition to current care (which may include β-blockers, diuretics, or calciumchannel blockers), ramipril effectively reduced the risk of cardiovascular events and nephropathy. Finally, we agree with V Lewis and colleagues, and Gerry Fegan and colleagues that many people with diabetes may expect to benefit from the addition of an ACE inhibitor. We also agree with Mike Stubanus and colleagues that the metabolic effects of ramipril and other modulators of the renin-angiotensin system require further study. The HOPE study and diabetesThe Heart Outcomes Prevention Evaluation (HOPE) Study Investigators (Jan 22, p 253)1 report that ramipril given to people with diabetes mellitus lowered the risk of major cardiovascular outcomes by 25–30%. They claim that the effect was apparent irrespective of whether participants had a history of cardiovascular events, hypertension, or microalbuminuria, were taking insulin or oral hypoglycaemic agents, or had type-1 or type-2 diabetes mellitus. The investigators also state that ramipril lowered the risk of overt nephropathy, renal failure, or laser therapy, and that it had no long-term effect on glycaemic control. Full-Text PDF The HOPE study and diabetesThe Heart Outcomes Prevention Evaluation (HOPE) Study Investigators1 found that patients treated with the angiotensin-converting-enzyme (ACE) inhibitor ramipril as well as other antihypertensive medications had fewer cardiovascular events, despite a modest further lowering of blood pressure. How do these findings fit with other trials assessing drugs with antihypertensive and other cardiovascular effects in similar diabetic populations? Consistent results were reported in the Captopril Prevention Project (CAPPP) trial,2 in which cardiovascular events were found to be reduced in patients with diabetes assigned antihypertensive treatment with captopril, compared with patients assigned conventional therapy with diuretics, β-blockers, or both. Full-Text PDF The HOPE study and diabetesTo assess the possible impact of the Heart Outcomes Prevention Evaluation (HOPE) study1 in clinical practice, we examined data on 109 consecutive patients over the age of 55 years seen in a single diabetes clinic within a medium-sized district general hospital in the UK. Eight of these patients would have been excluded from the HOPE study because of established proteinuria or renal failure. Of the remaining 101 patients, only 12 did not have at least one additional risk factor for ischaemic heart disease as defined in the HOPE trial (total cholesterol >5·2 mmol/L, hypertension, smoking, previous cardiovascular event, or microalbuminuria; table). Full-Text PDF The HOPE study and diabetesThe HOPE study1 has major implications for the care of patients with type-2 diabetes. Although the investigators chose to study patients at increased cardiovascular risk by confining recruitment to patients with diabetes and an additional risk factor, we believe this represents most patients with type-2 diabetes. Full-Text PDF The HOPE study and diabetesIn the study by the Heart Outcomes Prevention Evaluation (HOPE) Study Investigators1 ramipril lowered the risk of overt nephropathy by 24% and lowered the albumin/ creatinine ratio in the affected patients. Furthermore, ramipril treatment prevented a new diagnosis of diabetes in non-diabetic patients by 34%.2 This is in accordance with data from the Captopril Prevention Project (CAPPP) study3 in which the number of patients newly diagnosed as having diabetes decreased by 11% during captopril treatment. Full-Text PDF

The giant 358-kDa protein Ran binding protein 2 (RanBP2/Nup358) is localized at the cytoplasmic side of the nuclear pore complex and likely constitutes the Ran-GTP binding site at the cytoplasmic face of the complex. RanBP2/Nup358 furthermore acts as a chaperone for red/green opsin molecules. Here, we report on the physical mapping of human RanBP2 between markers D2S340 and D2S1893. A duplication of the 5'-end sequence of RanBP2 occurs within 3 Mb distal to RanBP2. Detailed sequence analysis resulted in primers specific for this distal duplication. Polymerase chain reaction-based screening of cDNA libraries indicates that this transcript, called RanBP2alpha (HGMW-approved symbol RANBP2L1), is expressed in several tissues. Screening of a fetal brain cDNA library yielded a 4057-bp partial cDNA clone for RanBP2alpha. Its 5'-end is almost identical to RanBP2, whereas its 3'-part is distinct from RanBP2. Northern blot analysis using a probe of the 3'-untranslated sequence of RanBP2alpha detected in several tissues an 8-kb transcript representing the full length of the transcript. In pancreas and placenta, an additional transcript of 14 kb was detected. PAC clones containing the bona fide RanBP2 sequences were localized to 2q11-q12 by FISH analysis, and a region of high similarity was detected on 2p11-p12. In summary, we have identified a RanBP2 gene cluster on 2q11-q12 together with a novel gene termed RanBP2alpha, with high sequence similarity to RanBP2.