[Serious complications during treatment with methotrexate: also in chronic low-dosage use]. / Ernstige complicaties tijdens methotrexaatbehandeling.

Methotrexate is a frequently prescribed drug and is considered to be safe at a low dosage. However, serious complications may occur during treatment. In this article we describe a 78-year-old male who used low-dose methotrexate for psoriatic arthritis. He died of multi-organ failure caused by sepsis and methotrexate intoxication as a result of deteriorating renal function. The second patient was a 56-year-old male who used low-dose methotrexate for rheumatoid arthritis. This patient developed pancytopenia and methotrexate pneumonitis during treatment with methotrexate. We recommend the frequent monitoring of blood count and renal and liver function tests to detect early deterioration. Furthermore, doctors should be aware of conditions and factors predisposing to methotrexate intoxication, such as impaired kidney function and co-medication. If methotrexate intoxication is suspected, intravenous folinic acid should be administered immediately.

In-one-continuity rectal excision and anal mucosectomy of a giant villous adenoma: an alternative surgical approach.

BACKGROUND: The authors present a woman suffering from McKittrick-Wheelock syndrome (MKWS) with a giant rectal villous adenoma. MKWS is a rare disorder caused by fluid and electrolyte hypersecretion from a rectal tumor. The most frequently reported tumors are villous adenomas. Symptoms of dehydration with severe hyponatremia, hypokalemia, metabolic acidosis and acute renal failure are typical in MKWS. Several options for operation have been reported, such as a transsacral approach (according to Kraske), transanal endoscopic microsurgery (TEM) or total mesorectal excision (TME). In this case we report an alternative surgical approach: in-one-continuity transanal mucosectomy and transabdominal TME with a handsewn colonic-anal anastomosis. CASE: A 54-year-old woman had a history of hospital admissions because of repeated bouts of dehydration with electrolyte disorders since 2004. At admission she presented with prerenal azotemia, hyponatremia and severe hypokalemia in combination with watery stools. At colonoscopy an 8-cm villous adenoma was seen in the rectum. Dehydration and electrolyte disturbances were treated by appropriate intravenous fluid administration. An in-one-continuity anal mucosectomy and complete rectal excision were performed and restored by a handmade colonic-anal anastomosis. Postoperative recovery was uneventful. CONCLUSION: MKWS can be a difficult problem to assess in both gastroenterological and nephrological ways. Patients may develop severe complications which require surgical intervention in some cases. In-one-continuity transanal mucosectomy and rectum excision with a handmade colonic-anal anastomosis seemed to be a new and solid surgical therapeutic option in this case.

[Fatigue, loss of appetite and anuria due to retroperitoneal fibrosis]. / Vermoeidheid, verminderde eetlust en diurese door retroperitoneale fibrose.

Two men aged 58 and 76, respectively, presented with fatigue and loss of appetite followed by anuria. Laboratory tests showed anaemia, elevated ESR and renal failure. CT of the abdomen revealed obstruction of the ureters by retroperitoneal fibrosis. The first patient had retroperitoneal fibrosis in combination with an aneurysm of the aorta; in the second patient, the image was suggestive of pancreatic carcinoma with secondary fibrosis, but eventually the retroperitoneal fibrosis proved to be idiopathic. Both patients were successfully treated with prednisone and temporary placement ofnephrostomy catheters. Retroperitoneal fibrosis is an often idiopathic disease that can cause compression of retroperitoneal structures such as the ureters. The clinical picture is aspecific so that the diagnosis is often delayed. Treatment with prednisone is preferable, followed by immunosuppressive therapy or tamoxifen in case of resistance to steroids. Relief of the obstruction by means of temporary nephrostomy catheters often makes surgery unnecessary. Retroperitoneal fibrosis is an uncommon disease that deserves more attention in view ofthe favourable therapeutic options following timely diagnosis.

BCG immunotherapy: be cautious of granulomas. Disseminated BCG infection and mycotic aneurysm as late complications of intravesical BCG instillations.

We describe a 65-year-old man with a granulomatous hepatitis and a progressive mycotic aneurysm of the abdominal aorta. One year before he received intravesical bacillus Calmette--Guérin (BCG) for carcinoma of the bladder without any complaints. Only post-mortem investigations could confirm that he suffered from a systemic BCG infection. Literature is reviewed for this rare complication.

Are angiotensin converting enzyme inhibitors superior to beta blockers in retarding progressive renal function decline?

We questioned the superiority of angiotensin converting enzyme (ACE) inhibitors to beta blocking drugs with regard to renal function outcome in patients with mild to moderate renal insufficiency and normal to moderately elevated blood pressure (BP). We therefore studied 89 patients in a prospective double-blind randomized trial comparing the effect of enalapril and atenolol on the slope of glomerular filtration rate (GFR). Mean baseline GFR was 53 +/- 20 ml/min, untreated BP 152 +/- 20 mm Hg systolic and 90 +/- 11 mm Hg diastolic and median proteinuria 0.6 g/24 hr (interquartile range 0.0 to 2.5). After a run-in period without antihypertensives, the test drug was titrated to lower diastolic BP to a predefined goal of 10 mm Hg below baseline and/or below 95 mm Hg. The median follow up was 3.9 years. Antihypertensive therapy resulted in a comparable decrease of BP in both study groups. Filtration fraction and proteinuria decreased in both groups. The slope of GFR over time was not different between both groups (-1.39 +/- 2.82 and -1.97 +/- 3.38 ml/min/year on atenolol and enalapril, respectively). In multiple regression analysis a higher baseline GFR, a greater decrease in GFR and in proteinuria during titration and a lower proteinuria during follow up were independently related to a better GFR slope. We conclude that the use of ACE inhibitors is not imperative in all patients with non-diabetic nephropathy.

Association between angiotensin-converting-enzyme gene polymorphism and failure of renoprotective therapy.

BACKGROUND: Polymorphism in the gene for angiotensin-converting enzyme (ACE), especially the DD genotype, is associated with risk for cardiovascular disease. Glomerulosclerosis has similarities to atherosclerosis, and we looked at ACE gene polymorphism in patients with kidney disease who were in a trial of long-term therapy with an ACE inhibitor or a beta-blocker. METHODS: 81 patients with non-diabetic renal disease had been entered into a randomised comparison of oral atenolol or enalapril to prevent progressive decline in renal function. The dose was titrated to a goal diastolic blood pressure of 10 mm Hg below baseline and/or below 95 mm Hg. The mean (SE) age was 50 (1) years, and the group included 49 men. Their renal function had been monitored over 3-4 years. We have looked at their ACE genotype, which we assessed with PCR. FINDINGS: 27 patients had the II genotype, 37 were ID, and 17 were DD. 11 patients were lost to follow-up over 1-3 years. The decline of glomerular filtration rate over the years was significantly steeper in the DD group than in the ID and the II groups (p = 0.02; means -3.79, -1.37, and -1.12 mL/min per year, respectively). The DD patients treated with enalapril fared as equally a bad course as the DD patients treated with atenolol. Neither drug lowered the degree of proteinuria in the DD group. INTERPRETATION: Our data show that patients with the DD genotype are resistant to commonly advocated renoprotective therapy.

Concurrent presentation of hemolytic uremic syndrome in two adult siblings: effects of plasma therapy on hemolysis and renal function.

We describe 2 sisters who presented with the hemolytic uremic syndrome (HUS) almost simultaneously. In both patients an upper airway infection with Haemophilus influenzae immediately preceding HUS may have been the environmental trigger. Fresh plasma infusion had only minor therapeutic effects but plasma exchange was followed by hematological remissions. One patient stayed dialysis dependent, the other had slow recovery of renal function on prolonged plasma exchange. These case histories suggest that in genetically predisposed patients HUS can be triggered by an infection with H. influenzae. Furthermore, when there is a poor response to plasma infusion recovery may be accelerated by plasma exchange.

Effects of ibopamine on postural hypotension in pure autonomic failure.

We wished to determine whether ibopamine, a dopaminergic prodrug with weak agonist activity on alpha- and beta-adrenoceptors, improves orthostatic tolerance in autonomic insufficiency. Three subjects with severe orthostatic hypotension resulting from pure autonomic failure (PAF) were studied. Direct arterial blood pressure (ABP) and heart rate (HR) were recorded continuously. Orthostatic tolerance was evaluated by 60 degrees passive head-up tilting. Tilting was performed before and after a single oral 100-mg dose of ibopamine. Blood samples for measurement of plasma catecholamines, free epinine (the active metabolite of ibopamine), and conjugated epinine were taken at regular intervals. In all 3 subjects, orthostatic tolerance was greatly improved by ibopamine. This improvement occurred as soon as 10-30 min after administration of ibopamine and lasted 20-50 min. alpha-Adrenoceptor blockade with phentolamine abolished the effect of ibopamine. The interindividual pharmacokinetics of ibopamine varied considerably: Peak plasma concentrations of ibopamine in the three subjects were 2.8, 4.5, and 35.4 ng/ml, respectively. The high level of epinine in one patient was associated with severe hypertension and tachycardia. Ibopamine may be a valuable new pharmacologic treatment for orthostatic hypotension in PAF, but in light of the highly variable interindividual pharmacokinetics further studies must be performed before use of the compound can be advocated in this disorder.

Anisotropic conduction and reentry in perfused epicardium of rabbit left ventricle.

An experimental model of anisotropy was developed, consisting of a thin layer (1 mm) of perfused ventricular epicardium created by cryodestruction of the interventricular septum and the inner four-fifths of the free wall of the left ventricle. The electrophysiological properties of the 1-mm-thick surviving layer were the same as before freezing. Epicardial conduction was mapped with a 192-fold mapping electrode (spatial resolution 1 mm). In the intact ventricle transverse conduction was interrupted near the site of stimulation by epicardial breakthrough of faster intramural wavefronts, whereas in the thin epicardial layer transverse conduction proceeded over a much longer distance, resulting in enlargement of the area of effective anisotropy. Induction of premature beats or incremental pacing resulted in the development of lines of transverse conduction block. The occurrence of transverse conduction block, however, only rarely led to reentry, because fast longitudinal activation of the tissue distal to the line of block provided insufficient delay for the fibers proximal to the line of block to restore their excitability. Initiation of reentry was associated with the development of longitudinal arcs of conduction block during which the area distal to the line of block was activated by a slowly propagating transverse wavefront providing a longer delay for the proximal fibers to restore their excitability. In conclusion, thin layers of myocardium may provide a substrate for reentry because of enlargement of the effective area of anisotropy.

Hypopituitarism following complicated child birth (Sheehan's syndrome).

We describe two patients with hypopituitarism and a history of severe bleeding or hypotensive shock at the time of child birth. Both patients had a decrease of all or some endocrine functions of the anterior pituitary. Although the frequency of Sheehan's syndrome is low in developed countries, it should still be considered in the differential diagnosis of hypopituitarism. An interval of many years between delivery and time of diagnosis does not exclude the diagnosis.

Length of excitation wave and susceptibility to reentrant atrial arrhythmias in normal conscious dogs.

We calculated the wavelength of the atrial impulse in chronically instrumented conscious dogs by measuring both conduction velocity and refractory period: wavelength = refractory period X conduction velocity. Implantation of multiple stimulating and recording electrodes allowed wavelength determination at four different areas: the right and left parts of Bachmann's bundle and the free walls of the right and left atria. During programmed electrical stimulation, three types of arrhythmias were observed: rapid repetitive responses, atrial flutter, and atrial fibrillation. During normal rhythm, the wavelength of the atrial impulse varied between 14 and 18 cm. Premature beats had a shorter wavelength, depending on the degree of prematurity. Premature beats that evoked rapid repetitive responses showed a critical shortening of the wavelength below 12.3 cm. Episodes of atrial flutter were induced at a wavelength below 9.7 cm, while fibrillation occurred at wavelengths shorter than 7.8 cm. We correlated the induction of these arrhythmias with the values of refractory period, conduction velocity, and wavelength during control and during administration of several drugs. Intravenous administration of acetylcholine shortened the wavelength by 30-40%, mainly because of refractory period shortening. Both propafenone and lidocaine had strong but opposite effects on refractoriness and conduction and, consequently, little effect on the wavelength. Quinidine markedly prolonged the refractory period, but prolongation of wavelength was less because of a simultaneous decrease in conduction velocity. d-Sotalol also increased refractory period, but because it had no appreciable effect on conduction velocity, this drug was the most effective in prolongation of wavelength. Linear discriminant analysis of the data showed that the refractory period and the conduction velocity each were poor parameters to predict the occurrence of the different arrhythmias (predictive value 48% and 38%, respectively). The combination of both properties, however, as expressed in the wavelength, was a more reliable index that predicted the induction of the different arrhythmias correctly in 75% of the cases. We conclude that the wavelength is a useful parameter for evaluating antiarrhythmic drugs.