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To quantify valve area in mitral stenosis, a modified continuity equation method using continuous wave Doppler and thermodilution measurements was applied. In 14 patients with mitral stenosis and sinus rhythm (age: 49 +/- 11 years), transmitral flow velocity was recorded by continuous wave Doppler during right and left heart catheterization. Mitral valve area was calculated by three different methods: 1. According to the continuity equation, stroke volume (thermodilution technique) was divided by the registered time velocity integral of the mitral stenotic jet (continuous wave Doppler). 2. Mitral valve area was calculated by the pressure half-time method. 3. Simultaneous pulmonary capillary wedge and left ventricular pressure measurements were used for determination of mitral valve area according to the Gorlin formula. The mitral valve area determined by application of the continuity equation (y) showed a close correlation to the valve area calculated by the Gorlin equation (x): y = 0.73x + 0.12, SEE = 0.11 cm2, r = 0.88, P less than 0.001. In contrast, the correlation between mitral valve area determined by pressure half-time (y) and the Gorlin formula (x) was not as good: y = 0.77x + 0.11, SEE = 0.26 cm2, r = 0.65, P less than 0.05. Thus, the continuity equation method using combined continuous wave Doppler and thermodilution technique allows a valid determination of mitral valve area. In patients with mitral stenosis and sinus rhythm, this technique is superior to the noninvasive determination of mitral valve area by the conventional pressure half-time method.

There is increasing evidence that lipids, especially those in low density lipoprotein, may be oxidised during the development of atherosclerotic lesions. The lipid-laden "foam cells" of atherosclerosis are macrophages, which are known to produce oxygen radicals in their microbicidal role. The same process could result in oxidation of lipid or lipoprotein in atherosclerosis. In human atherosclerotic lesions, many of the macrophage foam cells also contain ceroid, an insoluble polymer formed by oxidation of mixtures of lipid and protein. Using in vitro systems, we have studied the possibility that macrophages may be responsible for the oxidation of lipid and/or lipoprotein. Experiments are described in which mouse peritoneal macrophages and human monocyte-derived macrophages have been shown to oxidise cholesteryl linoleate, added to the cultures in the form of an artificial lipoprotein, with the production of soluble oxidised lipids, including oxidised sterols, and, in the case of mouse peritoneal macrophages, abundant ceroid. The oxidation was inhibited by radical scavengers. Oxidised sterols are cytotoxic. It is thus conceivable that oxidised sterols produced by monocyte-macrophages may lead to necrosis and progression of the lesion. Possibilities for prevention of this oxidation are discussed.

We examined the molecular basis of adenine phosphoribosyltransferase (APRT) deficiency in homozygous-deficient, identical twin brothers who were born to non-consanguineous German parents. DNA was isolated from blood, and the APRT gene was amplified by PCR, subcloned into M13, and sequenced completely. A single T insertion between bases 1831–1832 or 1832–1833 was identified. This alters the consensus sequence at the exon 4 — intron 4 splice donor site and leads to aberrant splicing. The same mutation has been described previously in two affected brothers from Belgium, and the Indianapolis group has also identified it in two other, unrelated Caucasian patients. Thus, this mutation may be a common cause of APRT deficiency in the Caucasian population.

In the last decade it has become quite clear that oxygen free radicals are involved in a vast amount of diseases such as cataract, atherosclerosis, rheumatism, arthritis, Parkinson's disease, reperfusion injuries and many others. The induction of defence systems against certain stresses (heat shock, inflammation) is also mediated by activated oxygen species. Oxygen-activation and -desactivation has to be regulated and well attenuated in aerobic cells and tissues. The biochemical basis of the biological efficacy of oxidants is thus based on a sophisticated balance between catalysis of production and reactivity of oxygen radicals by certain cofactors and transition metals on the one hand and on a reliable detoxification by antioxidants or metabolic chains on the other hand. In this communication, different oxygen activating principles are compared and the biochemical basis for the induction of repair processes by a synthetic heme oxidant, (Tetrachlorodecaoxide, TCDO) is presented.

The present work reviews the evidence for an involvement of free radicals in the pathophysiology of chronic pancreatitis and the potential of treatment with antioxidant and scavenger substances. Preliminary results indicate that exposure of isolated pancreatic acinar cells to a reaction mixture containing hypoxanthine, xanthine oxidase, and chelated iron causes cell damage and death probably due to generation of superoxide anion and hydrogen peroxide. It still needs to be analyzed which scavengers and antioxidants are able to ameliorate the damage due to oxidant stress in cell models. Such knowledge from cellular studies might help to plan therapeutical trials to evaluate potentially effective antioxidants and scavengers in the experimental animal and in patients with pancreatitis. As yet there are no published studies about the role of free radicals in animal models of chronic pancreatitis. This fact is probably due to the shortcomings of the animal models available. Recent studies presented evidence that activation of oxygen-derived free radicals occurs in patients with chronic pancreatitis. There is also some evidence that the dietary intake of antioxidants may be reduced in patients with chronic pancreatitis. It was suggested that such reduction of antioxidant defenses in the face of an increased demand due to heightened induction of P450 activities may facilitate lipid peroxidation. However, as yet, there is no direct evidence that a reduction of dietary antioxidants with a simultaneous increase in P450 activity is the primary mechanism which initiates chronic pancreatitis without contribution of other factors. Many of the findings in patients with chronic pancreatitis (increase in P450 activity, increase in hepatic lipid peroxidation, decrease in dietary intake of antioxidants) may be the sequelae and not the cause of chronic pancreatitis. Only controlled clinical trials will determine whether supplements of antioxidants can alter the clinical course of chronic pancreatitis.

There is considerable evidence to implicate aggressive species of oxygen in the pathogenesis of organ dysfunction consequent to sepsis and septic shock. The inflammatory process appears to participate ubiquitously in this setting. A characteristic of inflammation is the involvement of activated neutrophils and their generation of aggressive oxygen species. Such species may both directly injure cells proximal to the oxidant generating cells, and may inactivate any proteolytic mechanisms normally protective against proteolytic injury caused by neutrophil elastase and other proteolytic enzymes released during inflammation. The offending agent in sepsis is most commonly envisioned as bacterial lipopolysaccharide, or endotoxin. Infusion of endotoxin into animals can reproduce much of the pathophysiology of sepsis and septic shock. In addition, administration of endotoxin to cultured cells, particularly endothelial cells, can cause responses consistent with a sequence of events that occurs in intact animals and humans. In both experimental models, it appears that aggressive oxygen species are important actors in the scenario eventuating in cell or organ injury. Of importance, the toxic consequences of these free radicals probably occurs in relatively protected spaces, including microenvironments created by close adherence between inflammatory cells and endothelial cells and the cell interior. For those reasons, the potential for antioxidants as therapy should include consideration of the volume of distribution of such substances. It is probably important that antioxidants access excluded spaces including cell interiors in order to have their maximum effect in this setting. We have studied in a preliminary way the effects of n-acetyl-cysteine, a highly permeable free radical scavenger and antioxidant, in patients with established ARDS. The preliminary data suggest that this antioxidant may indeed be beneficial and a larger prospective study is underway. Novel, new therapies are on the horizon. The explosion of knowledge concerning the manipulation of DNA and the technologies for delivering functioning foreign genes to intact organisms promise completely new categories of therapies which may be applicable in sepsis and septic shock as well as the acute and subacute clinical situations. Eventual realization of the potential of such therapy must await additional basic and clinical investigation.

Summary. In the current study we evaluated effluent blood from extremities of human patients undergoing reconstructive surgical treatment which is routinely accompanied by upper extremity exsanguination and application of a tourniquet. Following tourniquet release (reperfusion), there were immediate increases in the plasma levels of xanthine oxidase activity, uric acid, and histamine. Xanthine dehydrogenase activity was not detectable. Plasma also contained products consistent with the formation of oxygen-derived free radicals, namely hemoglobin and fluorescent compounds. Our data indicate in humans that ischemia-reperfusion events are associated with the appearance of xanthine oxidase activity and it's products in the plasma effluent.

Oxidation of LDL is proposed to accelerate atherogenesis by the following sequence of events. LDL accumulates in atherosclerotic plaques, presumably due to interaction with intimal proteoglycans. The LDL then undergoes oxidation, and aldehydic products of lipid peroxidation such as HNE or other aldehyde products derived from lipid peroxidation, induce blocking of lysine residues on apo B. This results in its recognition by the scavenger receptor on tissue macrophages at sites in which LDL concentrations are low. At sites in which the LDL concentration is high, modification with such products induces intermolecular cross-linking and particle aggregation. The aggregated, oxidized LDL particles are then phagocytosed by tissue macrophages to induce lipid loading of these cells and the formation of foam cells, a characteristic of the earliest atherosclerotic lesion. By these mechanisms oxidation of LDL accelerates atherogenesis.

The case of a 50-year-old patient with hypertrophic obstructive cardiomyopathy is reported. The patient demonstrated somatic signs of the Turner phenotype, but a cytogenetically normal karyotype was shown. These findings were compatible with the diagnosis of Noonan syndrome. The most commonly diagnosed cardiac disease in this syndrome is pulmonary stenosis, followed by hypertrophic cardiomyopathy. The patient's prognosis is limited by the natural history or the typical complications of the underlying cardiac lesion.

This work studies some of the advances that have participated in the development of the liver transplantation-reperfusion injury. This lesion is a rather complex one that probably is not only associated with the production of free radicals, but also of other vasoactive substances such as, prostanoids, altered calcium related compounds, abnormal coagulation factors, as well as other important potentially harmful substances. Our interest since 1975, has resided in compounds that modify the xanthine oxidase pathway, such as allopurinol, that might either protect from the formation of free radicals or might act through other mechanisms such as, purine salvage and production of high energy compounds, among few of them. The pharmacological manipulation of the reperfusion injury, will require in this way, the use of various substances in the protection of the transplanted liver.

During the past decade, remarkable progress has been made in our understanding of cancer-causing agents, mechanisms of cancer formation and the behavior of cancer cells. Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, and lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites (metastasis). It has been estimated that about 75–80% of all human cancers are environmentally induced, 30–40% of them by diet. Only a small minority, possibly no more than 2% of all cases, result purely from inherent genetic changes. Several lines of evidence confirm that the fundamental molecular event or events that cause a cell to become malignant occur at the level of the DNA and a variety of studies indicate that the critical molecular event inchemical carcinogenesis is the interaction of the chemical agent with DNA. The demonstration that DNA isolated from tumor cells can transfect normal cells and render them neoplastic provides direct proof that an alteration of the DNA is responsible for cancer. The transforming genes, or oncogenes, have been identified by restriction endonuclease mapping. One of the characteristics of tumor cells generated by transformation with viruses, chemicals, or radiation is their reduced requirement for serum growth factors. A critical significance of electrophilic metabolites of carcinogenes inchemical carcinogenesis has been demonstrated. A number of “proximate” and “ultimate” metabolites, especially those of aromatic amines, were described. The “ultimate” forms of carcinogens actually interact with cellular constituents to cause neoplastic transformation and are the final metabolic products in most pathways. Recent evidence indicates that free radical derivatives of chemical carcinogens may be produced both metabolically and nonenzymatically during their metabolism. Free radicals carry no charge but do possess a single unpaired electron, making the radical extremely reactive. That such forms may be important in the introduction of neoplastic transformation by chemicals comes from two lines of evidence. (1) Various molecules that inhibit the formation of free radicals, many of which are termed antioxidants, can inhibit the carcinogenic action of a variety of chemical carcinogens. (2) There are relatively specific metabolic reactions of certain chemical carcinogens, particularly of polycyclic hydrocarbons, for which it has been shown to proceed through free radical intermediates. In conclusion, free radical processes withdirect effects on DNA can be proposed for a variety of human and animal carcinogens. As already mentioned, part of the indirect evidence supporting a role for free radicals and active species of oxygen in carcinogenesis is the inhibitory effects of antioxidants in a number of encouraging but yet inconclusive, epidemiological studies and ongoing prospective trials of antioxidant treatment in humans (chemoprevention). Cancer chemoprevention research takes leads from epidemiologic and laboratory research and develops them through in vitro and in vivo preclinical research and initial human studies into randomized controlled clinical trials. The most commonly used chemopreventive agents are retinoids,β-carotene, and vitamins. Some of the most exciting developments in the control of cancer over the next decade will very likely result from this chemopreventive approach, with application not only to prevention of the first or primary malignancy, especially in high risk populations, but also to clinical situations traditionally considered to be in the domain of chemotherapeutic strategies, such as adjuvant treatment after definitive therapy of a primary cancer.

Liver transplantation has evolved into a relatively safe clinical procedure for end stage liver disease but the success is absolutely dependent on the quality of the donor organs. Graft malfunction is an important source of morbidity and mortality after liver transplantation so further improvement of organ quality is mandatory. Experimental data seem to justify application of antioxidant therapy in clinical liver transplantation. According to the mode of action antioxidant therapy treatment should be considered for donor and recipient of the graft.

Ulcerative colitis and Crohn's disease are chronic inflammatory bowel diseases. The most widely prescribed drug for treatment of these diseases, sulfasalazine, has been shown to inhibit the activity of free radicals, as the active moiety of sulfasalazine, 5-aminosalicylic acid, is a radical scavenger. This effect of 5-aminosalicylic acid may be of clinical relevance, as a recent study has shown that 5-aminosalicylic acid reacts with oxygen-derived free radicals formed in the intestine in this disease. Reaction with free radicals does not, however, occur in patients with rheumatoid arthritis treated with the same agent. Furthermore, a significant correlation exists between the activity in the intestine of free radicals, as measured by the rate of lipid peroxidation, and the disease activity.

Osteocalcin (bone Gla protein) is a promising marker of bone turnover useful in the diagnosis and follow-up of high turnover osteoporosis. Conflicting results have been reported about its physiological variations according to sex, age, and menopause. Several, but not all, authors have found increased levels in males, with aging, and after menopause. We measured serum osteocalcin in 126 healthy subjects, 57 males and 69 females, aged between 45 and 88 years. Osteocalcin was higher (P less than 0.01) in males (6.24 +/- 0.36) than in females (4.32 +/- 0.34). This sexual difference was significant, too, in subjects younger and older than 60 years. Osteocalcin increased with age, linearly in males (P less than 0.05), and exponentially in females (P less than 0.05). Although there was a difference in age (P less than 0.05), no difference in osteocalcin levels between premenopausal women and women in their first two postmenopausal years was detected, while osteocalcin was significantly increased in women more than two years into menopause. We conclude that osteocalcin in healthy subjects is higher in males than in females and increases with age after 45 years in both sexes. Osteocalcin levels increase in women more than two years beyond menopause, but not only as an effect on aging.

Cardiac surgical complications may be caused by a plethora of events. Oxygen free radicals may participate in the pathophysiology of cardiopulmonary bypass and myocardial ischaemia-reperfusion injury. The evidence of free radical production during bypass is limited, and studies of the effect of free radical scavengers even more limited. Experimental work points towards a role of oxygen free radicals in reperfusion damage of the ischaemic myocardium, but clinical data are lacking. Hitherto the clinical availability of free radical scavengers/antioxidants has been scarse. At present more such drugs are becoming clinically applicable, and trials on their effect are highly warranted, in particular as an adjuvant in myocardial protection.

We present a case report on a 35-year-old patient in whom a malignant sympathetic paraganglioma of the organ of Zuckerkandl was the cause of severe hypertension with excessive perspiration at night. Since curative surgery was not possible medical treatment was initiated. Interferon alfa 2b (Intron A, Essex Pharma) and the somatostatin-analogue SMS 201–995 (Sandostatin, Sandoz) had no effect on catecholamine production and progression of the tumor. Treatment with alpha-methyl-para-tyrosin (MPT, [Metyrosin], Demser, MSD) turned out to be an effective and well tolerable therapy in this patient with peritoneal carcinosis. Clinical and hormonal progression of the paraganglioma resumed only after two years of therapy, which constitutes the longest documented period of time of successful MPT treatment. The superior efficacy of MPT in our patient should encourage postoperative medical treatment with MPT in malignant pheochromocytoma or malignant paraganglioma, particularly when the tumor turns out to be resistent to alpha blocking drugs.

The purpose of this study was to assess the involvement of oxygen radicals in acute edematous and hemorrhagic panreatitis. Acute pancreatitis was induced in rats by the CCK-analogue cerulein (5 μg/kg/h) and by retrograde injection of 5% sodium taurocholate for 30 min, 3.5 h, and 12 h. At the end of the infusion and observation time, serum enzymes, conjugated dienes, and malondialdehyde in the tissue were measured. Moreover, the tissue samples underwent light microscopical examination. In cerulein pancreatitis, an interstitial edema and intravascular margination of granulocytes in the pancreatic gland were observed after 3.5 h. After 12 h, the histological evaluation revealed a pronounced zymogen degranulation, extensive tissue necrosis and migration of granulocytes into the tissue. Parallelly, amylase and lipase increased by 15 and 35 times, respectively. In contrast, conjugated dienes and malondialdehyde increased in cerulein pancreatitis and reached their highest level after 3.5 h and decreased to normal levels after 12 h. The development of the histological damages and serum enzyme levels with sodium taurocholate pancreatitis was similar as compared to the cerulein pancreatitis, however, the development was faster and more traumatic. Already after 3.5 h an extensive zymogen degranulation and cell necrosis was observed. Concomitantly, the amylase and lipase levels increased by 90 and 30 times, respectively. Treatment with superoxide dismutase (100000 U/kg/h) and catalase (400 000 U/kg/h) prevented lipid peroxidation and reduced zymogen degranulation and tissue necrosis. Tissue edema and inflammatory response were not affected in both models of acute pancreatitis. Moreover, scavenger treatment improved the survival rate in sodium taurocholate pancreatitis. It is therefore concluded that oxygen free radicals seem to be instrumental for the development of the disease. Scavenger treatment can mitigate the pancreatic tissue damages and the extrapancreatic complications.

To determine whether blood-borne factors in hypertension accompanying early-stage kidney disease might be responsible for altered cellular calcium homeostasis, we measured changes in cytosolic calcium before and after incubating platelets in plasma ultrafiltrates from normotensive and hypertensive renal patients. With the use of the chelating agent quin 2, we found the free-calcium concentrations in platelets to be higher in the hypertensive than in the normotensive group. When both groups of participants were combined, a direct correlation was found between arterial pressure and cytosolic calcium. The cytosolic calcium concentration in platelets of normotensive renal patients increased after incubation with plasma from patients with untreated renal hypertension, but it was unchanged after incubation with plasma from normotensive subjects. These data indicate that the total cell burden of calcium is increased in platelets of hypertensive patients with early-stage renal disease, and that plasma from these patients contains a substance that is capable of increasing the cytosolic calcium concentration in platelets. If the plasma factor (or factors) acts not only on platelets, but also on vascular smooth muscle cells, it may contribute to the increased peripheral vascular resistance associated with hypertension of renal origin.

There is controversy over the role of oxygen free radical-induced damage in preserved organs following reperfusion. Furthermore, there has been no definitive study that shows a dramatic improvement in organ functions, delayed graft functions, or improved longevity in organ transplants with oxygen free radical scavenger therapy. However, the presence of glutathione in a new organ preservation solution (University of Wisconsin, UW, solution) yields improved preservation of the liver and heart. The beneficial effect of glutathione may involve in scavenging of cytotoxic products of oxygen metabolism. The results discussed here show that glutathione improves liver preservation. Also, it is shown that glycine, and amino acid component of glutathione, can also give cytoprotection to the rabbit and dog liver tested by either isolated perfusion or orthotopic transplantation. Thus, there may be an involvement of oxygen free radicals in damage to organs hypothermically preserved and transplanted. The injury may occur within the cells or may be due to oxygen within the cells or may be due to oxygen free radicals generated in the extracellular environment.

Oxygen metabolites have been reported to produce vasoconstriction and/or vasodilation in a variety of in vitro or in vivo vascular preparations. Certain basic mechanisms appear to contribute to these responses. Hydrogen peroxide can produce either vasodilation or constriction via stimulation of prostaglandins. The soluble form of guanylate cyclase in vascular smooth muscle, an enzyme which produces the intracellular mediator of relaxation cyclic GMP, is also a site of action of vasoactive O2 metabolites. Guanylate cyclase is directly activated by nanomolar concentrations of nitric oxide (produced by endothelial cells or nitrovasodilator drugs) or H2O2 (via its metabolism by catalase). These cyclic GMP-mediated mechanisms of relaxation are inhibited by superoxide anion, produced from endogenous sources after inhibition of superoxide dismutase or produced by pharmacological agents that undergo redox cycling. In addition, O2 metabolites may modulate vascular tone via the chemical destruction of physiological contractile agents (e.g. norepinephrine) and relaxant agents (e.g. nitric oxide), and via injury to cells important for the regulation of vascular tone (e.g. endothelium). We have found in a variety of preparations that reexposure to O2 after a brief period of severe hypoxia produces vascular responses that appear to be mediated by intracellular H2O2 generation. Thus, active O2 species may contribute to vascular responses in pathophysiological situations associated with their formation (e.g. inflammation, ischemia/reperfusion, etc.) and to the physiological regulation of vascular tone produced by changes in O2 tension (e.g. reactive hyperemia, hypoxic vasoconstriction, etc).

The influence of transforming growth factor-beta (TGF-beta) on hematopoiesis has been evaluated by adding blocking antibodies against TGF-beta to colony forming assays (CFU-c). When optimum concentrations of recombinant growth factors, granulocyte-macrophage colony stimulating factor (GM-CSF), and interleukin-3 (IL-3) were added to stem cells from the peripheral blood of healthy individuals and certain patients with tumors or HIV infection, the anti-TGF-beta capable of blocking 5 ng/ml of active TGF-beta had no significant influence on erythroid or myeloid colony formation. However, in certain immunosuppressed individuals, anti-TGF-beta resulted in a significant decrease of erythroid colony formation and slight suppression of myeloid colony formation. The significant inhibition of hematopoiesis by plasma of HIV patients could be due to the presence of active forms of TGF-beta. The results of the blocking experiments are consistent with the concept that TGF-beta in low concentrations is essential for erythropoiesis and myelopoiesis but that higher levels of TGF-beta primarily inhibit erythropoiesis in vitro. TGF-beta serves as a coordinating factor when efficient recruitment of granulocytes and monocytes is more essential than erythropoiesis and stem cell growth.

Calculation of a dialysis index (Teehan; Perit Dial Bull 1985, 3∶152–156) and estimations of the protein catabolic rate (PCR) (reflecting protein intake under steady state conditions) were performed in 20 CAPD patients instructed to eat 1.2–1.5 g/kg BW protein per day and treated with 8–10 l dialysate exchange per day. Dialysis indices were 1.20+-0.44, >1.0 reflecting adequate treatment. PCR was based on nitrogen loss by dialysis and urine as well as by losses assumed to be constant in stools and through skin; dialysis loss was obtained eighther by collection of the 24 h dialysate volume or by estimating the equilibration ratio between blood and dialysate for calculation of nitrogen removal from serum urea nitrogen and 24 h dialysate volume. Values obtained were 0.90±0.23 and 0.89±0.23 g/kg BW, respectively (r=0.97,p=0.0001). These low PCR values were found to correlate with data from dietary surveys (r=0.77). Total serum protein, albumin content and transferrin concentration were all within the normal range and there was no correlation between these parameters and protein intake. It is concluded that protein intake and dialysis adequacy must be monitored individually. Whereas generally recommended CAPD schedules provide effective treatment, a mean protein intake > 0.9 g/kg BW seems to be adequate.

The prevalence of underweight, short stature, and abnormal laboratory tests was assessed in a retrospective study of 335 patients with biopsy-verified childhood celiac disease (CCD). Of the patients younger than 2 years old, 67.4% were underweight (body weight: less than - 2SD) and 33.9% were short (height: less than - 2SD). In children older than 2 years, underweight was present in 36.0% of patients; the prevalence of short stature was 50.0%. Therefore, diagnostic procedures related to CCD appear justified in all children with short stature of unknown etiology. However, because 50% of patients were neither short nor underweight, normal height and weight should not preclude workup of a patient with symptoms suggestive of CCD. Of the laboratory tests evaluated, antigliadin antibodies were the most sensitive for CCD. Insulin-like growth factor (IGF-I) serum levels were prospectively studied in 62 patients (32 CCD patients, 30 controls) referred for jejunal biopsy. IGF-I levels were significantly lower in female CCD patients than in control patients. There was a significant negative association between the duration of gluten exposure and IGF-I levels. Results indicate that significant reduction in IGF-I levels in CCD patients occurs only after prolonged gluten exposure but before growth failure. Reevaluation of IGF-I levels on a glutenfree diet showed rapid reversal of reduced IGF-I values.

We examined the effects of 60 minα-hANP infusion (24 ng/min/kg) on glomerular filtration rate (GFR), renal blood flow (RBF), cardiac index (CI) and blood pressure (BP) in 8 patients with chronic renal failure (CRF) with GFR ranging from 18 to 80 ml/min/1.73 m2 and in 8 control (C) subjects with normal renal function. Basal plasma levels of ANP and cGMP were elevated in CRF (ANP: 60.6±9.1 vs 13.6±1.9 pmol/l,p

Sodium dodecylsulphate-polyacrylamide gel electrophoresis (SDS-PAGE) of urinary proteins is becoming increasingly significant in monitoring renal allograft recipients. After conventional Coomassie Blue staining, changes in renal proteinuric patterns during acute renal transplant rejection could not be seen in many cases. Discrimination between rejection and nephrotoxic side effects of cyclosporine overdosage was also not possible. We therefore examined the possible advantages of a highly sensitive silver staining technique in this study. A total of 734 urine samples obtained from 38 patients after allogenic kidney transplantation were examined by SDS-PAGE with consecutive Coomassie Blue and silver staining. Twenty-two histologically proven rejections and 20 cyclosporine overdosage episodes were diagnosed in these patients within a time period of up to 524 days after transplantation. No changes in proteinuric patterns were seen in 9 of 22 patients after Coomassie stain during rejection, and only 12 cases showed a rise of glomerular protein bands, whereas silver stain revealed an increase in 19 of 22 cases. Discrimination between cyclosporine overdosage and rejection was possible with a probability of p less than 0.001 after silver stain when using the changes in the number of glomerular protein bands as a criterion. These findings suggest that application of a highly sensitive silver stain instead of the conventional Coomassie stain after SDS-PAGE reflects considerable progress in monitoring renal allograft recipients.

Diarrhea represents the most frequent health problem of Western tourists visiting subtropical and tropical areas. Antibiotic prophylaxis has been suggested by some authors but may not be generally advisable because of adverse drug effects. In the present study we investigated the prophylaxis of traveler's diarrhea using a combination of tannalbuminate and ethacridin-lactate. During a 16-day cruise in Egypt, 77 tourists were assigned to either placebo or prophylactic doses of tannalbuminate (500 mg) and ethacridin-lactate (50 mg), 1 tbl. b.i.d., in a randomized double-blind fashion. The number of bowel movements, consistency of stools, and clinical symptoms like nausea, abdominal cramps, vomiting, and fever were monitored daily. In the placebo group (n = 43) 35 tourists developed diarrhea (81.4%), whereas in the verum group (n = 34) only 18 tourists (52.9%) had diarrhea (p less than 0.0125). In the travelers receiving verum and developing diarrhea the clinical symptoms were less pronounced than in the placebo group. These results demonstrate that the events of traveler's diarrhea may be reduced; moreover, symptoms are attenuated by medical prophylaxis with tannalbuminate and ethacridin-lactate.

Due to its paramount adsorption capacity, activated charcoal is supposed to be the remedy of choice for binding a variety of drugs in the gastrointestinal tract. Hence it is surprising — at least according to the advice of German textbooks — that activated charcoal is only recommended for administration after time-consuming treatments like induced emesis and gastric lavage. Particularly with infants at home, a ready-for-use suspension of activated charcoal would allow the early management of acute poisoning. In such cases, inactivation of the poison by adsorption could be particularly helpful, since the period after ingestion is usually short. The charcoal-sorbitol-suspension (30 g activated charcoal in 150 ml of 70% sorbitol) is a creamy preparation which is easy to drink, because density and viscosity prevent sedimentation. The prescription-free drugs can be dispensed by each pharmacist. The present study was undertaken to investigate the influence of sorbitol on the adsorption capacity of activated charcoal. To this end, adsorption isotherms were established in vitro and compared with results in volunteers to whom NAPAP, diphenhydramine or codeine was administered separately. These drugs are gaining increasing importance in medicinal toxicology since they are constituents of various analgesics and cold remedies. To determine absorption, the cumulative urinary excretion was estimated of the parent drugs and their main metabolites. Without charcoal the volunteers were dosed with 500 mg NAPAP, 50 mg diphenhydramine-HCl, and 50 mg codeine phosphate, respectively. When the charcoal-sorbitol-suspension was swallowed two min after ingestion of the tablett-slurry, the five-fold dose of each drug was administered. The charcoal-sorbitol-suspension significantly (p

Summary Reduced glutathione (GSH) is the main intracellular low molecular weight thiol. GSH acts as a nucleophilic scavenger and as an enzyme-catalyzed antioxidant in the event of electrophilic/oxidative tissue injury. Therefore, GSH has a major role as a protector of biological structures and functions. GSH depletion has been recognized as a hazardous condition during paracetamol intoxication. Conversely, GSH rescue, meaning recovery of the protective potential of GSH by early administration of N-acetylcysteine (NAC), has been found to be life-saving. Lack of GSH and electrophilic/oxidative injury have been identified among the causes of the adult respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), and the acquired immunodeficiency syndrome (AIDS). Experimental and early clinical data (in ARDS) point to the role of NAC in the treatment of these conditions. Recently, orally given NAC has been shown to enhance the levels of GSH in the liver, in plasma, and notably in the bronchoalveolar lavage fluid. Rescue of GSH through NAC needs to be appreciated as an independent treatment modality for an array of different diseases, all of which have one feature in common: pathogenetically relevant loss of GSH.

Quantitative finger nailfold capillary microscopy was performed in 25 patients with type I diabetes and in 27 healthy control subjects. In the last consecutive 6 patients and 7 controls of these populations, finger nailfold biopsies were taken. Measurements of loop width as an in vivo parameter for deformities of the capillary loops showed significantly higher values in diabetic patients than in controls. Histopathological examination showed markedly and significantly increased deposition of collagen in nailfold dermal papillae of the diabetic patients. The deposition of collagen was positively correlated with the number of capillary endothelial cells in the nailfold dermal papillae and with the size of the papillae in diabetic patients. It is concluded that, in addition to deformity of nailfold capillaries, collagen deposition may also be a sign of metabolic disturbance and perhaps of proliferation of capillary endothelial cells in diabetic microangiopathy.

Long-term administration of ciclosporin has been complicated by side-effects, the predominant being nephrotoxicity. We performed renal function studies on 20 patients treated with ciclosporin (group 1) and on 12 patients serving as controls (group 2). Only patients with serum creatinine less than 1.3 mg/dl entered the study. The renal function studies consisted of: Inulin clearance, PAH clearance, sodium sulphate loading, sodium bicarbonate loading. Plasma renin activity (PRA), inactive renin (IR) and aldosterone (ALDO) were measured basally and after stimulation with 40 mg furosemide i.v. Serum creatinine was not significantly impaired under ciclosporin with 1.1±0.1 mg/dl vs 0.9±0.1 mg/dl in the control group (ns). Glomerular filtration rates as measured by creatinine and inulin clearance were significantly impaired in group 1 as compared to group 2. Inulin clearance was impaired by ciclosporin with 93.5±4.4 ml/min/1.73m2 as compared to 121±6.6 ml/min/1.73 m2 (p

Summary A 40-year-old, HIV-infected female patient received antibiotic treatment for a urinary tract infection. After the initial success of therapy and a symptom-free period, she developed pneumonia with septic shock and adult respiratory distress syndrome (ARDS). In spite of intensive care and respirator therapy with positive end-expiratory pressure (PEEP), she died of infectious toxic shock. Autopsy findings showed relapsing, gramnegative, bacterial pneumonia (morphologically compatible with Klebsiella pneumonia) and secondary, invasive aspergillosis. The pathogenesis and epidemiology of these unusual complications of AIDS are discussed.

We report the case of 43-year-old homosexual patient with HIV infection and a history of travel to the Far East in whom visceral leishmaniasis was the first infectious complication. Symptoms were fever, malaise, weight loss, hepatosplenomegaly, generalized lymphadenopathy, and oral thrush. Laboratory abnormalities included a slight elevation of liver enzymes, impairment of liver function tests, leukocytopenia, anemia, hypergammaglobulinemia, and markedly depressed CD4(+)-cell counts. Despite initially successful treatment with pentavalent antimony, a relapse of leishmaniasis occurred after 7 months. Eradication of the infection was not achieved. Treatment was continued as a palliative chronic suppressive treatment with fortnightly pentamidine infusions. The clinical course was complicated by legionella pneumonia and the development of rapidly progressing Kaposi's sarcoma. The case is presented in detail, and the influence of HIV infection on the course of leishmaniasis is discussed.

The rapid expansion of computer-based systems for problem solving or decision making in medicine, the so-called medical expert systems, emphasize the need for reappraisal of their indication and value. Where specialist knowledge is required, in particular where medical decisions are susceptible to error these systems will probably serve as a valuable support. In the near future computer-based systems should be able to aid the interpretation of findings of technical investigations and the control of treatment, especially where rapid reactions are necessary despite the need of complex analysis of investigated parameters. In the distant future complete support of diagnostic procedures from the history to final diagnosis is possible. It promises to be particularly attractive for the diagnosis of seldom diseases, for difficult differential diagnoses, and in the decision making in the case of expensive, risky or new diagnostic or therapeutic methods. The physician needs to be aware of certain dangers, ranging from misleading information up to abuse. Patient information depends often on subjective reports and error-prone observations. Although basing on problematic knowledge computer-born decisions may have an imperative effect on medical decision making. Also it must be born in mind that medical decisions should always combine the rational with a consideration of human motives.

Intestinal permeability has been assessed as a parameter of the small intestinal barrier function in 33 patients with AIDS (WR 6), in 25 healthy volunteers, 32 patients with Crohn's disease, 18 patients with ulcerative colitis and in 12 patients with untreated coeliac disease. Permeability was measured by means of the 5 hour urinary excretion of lactulose and rhamnose after administration of these sugars (1 g rhamnose, 10 g lactulose) which allowed to calculate the urinary lactulose/rhamnose--ratio (L/R-r) as an index of intestinal permeability. Compared to the controls (L/R-r = 0.014 +/- 0.010) patients with AIDS had significantly increased lactulose/rhamnose--ratios (0.189 +/- 0.164; p less than 0.01) indicating abnormal permeation both of lactulose and rhamnose. This alteration of intestinal permeability was more pronounced than the significant increase of the L/R-r in the patients with either Crohn's disease or coeliac disease. However, intestinal permeability was not altered in the patients with ulcerative colitis. Among the patients with AIDS, the most abnormal permeability ratios were observed in two subjects with intestinal cryptosporidiosis. This investigation demonstrates by means of the "double sugar ratio", that intestinal permeability in patients with AIDS is highly abnormal, the impairment being even more abnormal than in patients with other small intestinal disease.

Leukotriene B4 (LTB4) plays an important role in acute and chronic inflammatory and hypersensitive reactions. We studied the time course of LTB4 biosynthesis in whole blood in 18 patients with end-stage renal failure maintained on regular hemodialysis with two different membranes, cuprophane and polyacrylonitrile (AN 69). The basal levels of LTB4 from dialysis patients did not differ significantly from a normal control group. Compared to predialytic values, the cuprophane membrane caused a maximal release of LTB4 by a factor of about 4.5 (p less than 0.01) within the first 10 to 20 minutes. Thereafter the level fell and returned to baseline range at the end of the hemodialysis session. With the use of the AN 69 membrane no significant increase of LTB4 could be demonstrated. The changes in LTB4 concentration showed a close temporal correlation to the alterations in white blood cell count. We conclude that (1) LTB4 is a biologically important mediator of neutrophil activation during hemodialysis, and (2) LTB4 may be a sensitive marker of biocompatibility in vivo.

During a six-year period five patients with Campylobacter fetus subspecies fetus infections were seen at the Mayo Clinic in Rochester, Minnesota. Bacteremia was observed in two patients, one presenting with aortic valve endocarditis and the other with abdominal atherosclerotic aortic aneurysm. C. fetus subsp. fetus was isolated from tibial tissue of a patient with osteomyelitis. Diarrhea was the main complaint of two further patients, and was also mentioned by the patient with the aortic aneurysm. Despite the use of incubation conditions and selective media geared to detect only Campylobacter jejuni, C. fetus subsp. fetus was isolated from stool specimens of the two patients with gastrointestinal symptoms. The fact that three of five C. fetus subsp. fetus infections observed in this study were associated with intestinal symptoms further supports the importance of the gastrointestinal tract in the pathogenesis of C. fetus subsp. fetus infections.

In a random HIV-seropositive population, malignant lymphomas were diagnosed in 31 patients, of whom 24 (77%) had non-Hodgkin lymphoma (NHL) and 7 (23%) Hodgkin lymphoma (HL). The prevalence of NHL among AIDS patients was 8% (23/279 cases), with a prevalence of 17% among autopsied patients (16/96 cases). No patient with HL had AIDS at the time of diagnosis. In 7 of 23 AIDS patients with NHL (30%) the diagnosis was made only post mortem; among these were all 5 patients with primary CNS NHL. Median survival from the time of diagnosis was 1 month for patients with NHL and 3 months for those with HL. In individual patients, survival for several years may be possible with chemotherapy. Certain patients with NHL appear to benefit from intensive chemotherapy with a combination of methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOPB protocol). Appropriate, therapeutic strategies taking into account the patients' individual conditions, including the overall prognosis, urgently requires development. Metastatic CNS involvement, which was the primary cause of death in 5 of 11 patients with NHL (45%) receiving chemotherapy, represents a serious limitation to successful treatment.

Distribution and number of ischemic cerebrovascular events were studied in 57 patients who suffered from heart disorders with proven or highly probable source of cardiac embolism and compared to 39 patients with ulcerations of the craniocervical vessels. Patients with coexisting lesions were excluded from the present study. Out of the 57 patients with cardiac disorders, a single episode of cerebral embolism occurred in 33 patients. Of the 24 patients with recurrent ischemic episodes, different vascular territories were involved in only six cases. There was no evidence of a distinct distribution of vascular territories involved in cerebral embolism. The left middle cerebral artery was affected in 42.9%, the right middle cerebral artery in 23.8%, the vertebrobasilar territory in 19%, and the ophthalmic arteries in 14.2%. Statistical analysis revealed no significant differences in lesion localization between the group with a cardiac source of embolism and the group with ulcerations of the craniocervical vessels. There was a high frequency of patients with recurrent cardiogenic emboli in the ophthalmic (6 of 9 patients) as well as in the vertebrobasilar (6 of 12 patients) circulation who experienced a delayed initiation of cardiac assessment. The possibility of cardiac embolism should be considered in any patient with cerebral ischemia, independently of the vascular territory affected.

Despite all its limitations, the spontaneous reporting system still forms the basis for drug safety assessments in the Federal Republic of Germany. Although there have been some promising attempts to standardise the methodology of detecting, analysing and evaluating adverse drug events (ADEs) in certain clinico-pharmacological institutes and psychiatric departments, the approaches have not been integrated and are used only locally. The only exception is the Freiburg Documentation Centre for Severe Skin Diseases, which is attempting comprehensive, country-wide documentation of toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome. We show that surveillance of 40% of all hospital beds would allow the acquisition of reliable data even on rare and serious AEs which could then be extrapolated in a statistically meaningful way. The medical societies in Germany have traditionally taken a leading role in establishing standards for the preclinical and clinical investigation of new drug compounds. We suggest that they also make it their task to define the framework for an intensified adverse events monitoring system, since it is the patient who ultimately benefits from a quantification of drug therapy risks.

In an open, randomized study, we investigated the effect of oral potassium chloride (KCl) and of potassium citrate/bicarbonate (K-cit/bic) in 42 patients with hypokalemia (≤3.5 mmol/l). In both groups 80 mmol K+ were administered daily. The parameters examined were serum potassium concentration, acid-base status, and urinary electrolyte excretion. Parameters were evaluated on days 0, 2, 4, and 6. With KCl, [K+] increased from 3.2± 0.2 (mean± SD) on day 0 to 3.8± 0.4 mmol/l on day 2 (p

Nine patients on maintenance hemodialysis and transfusion-demanding renal anemia (group A) were treated with rHuEPO 120 IU/kg i.v. three times per week. Hemoglobin-content was raised from 7.2 +/- 0.9 to 10.4 +/- 0.8 g/dl. In all patients blood pressure rose, three patients developed arterial hypertension. Mean diastoloic blood pressure was 66 +/- 12 and 78 +/- 16 mmHg (p less than 0.001) before and after rHuEPO. Rise in blood pressure was accompanied by a significant fall in plasma-noradrenaline-levels (from 498 +/- 100 to 383 +/- 75 pg/ml; p less than 0.05) and alpha 2-adrenoceptor-density (from 574 +/- 76 to 384 +/- 49; p less than 0.05). Compared to nine patients on maintenance hemodialysis and hematocrit over 30% (group B), patients with severe renal anemia (group A before treatment) had higher densities of alpha 2-adrenoceptors (574 +/- 76 vs. 218 +/- 32; p less than 0.001) despite higher plasma-noradrenaline-levels (498 +/- 100 vs. 399 +/- 63; n.s.). We suppose a anemia-related disturbance of alpha 2-receptor-function with the result of abolished receptor down-regulation and impaired vascular reagibility to vasoconstricting stimuli. With the correction of anemia receptor-function improves, receptor down-regulation as well as vascular reagibility is re-established resulting in augmented vascular resistance and higher blood pressure.

The spontaneous course of 58 patients with compensated autonomous adenoma of the thyroid was followed. Scintigraphic appearance (compensated (CAA) or decompensated (DAA)) was documented and the serum levels of thyroxine (T4), trijodthyronine (T3) and thyroid-stimulating hormone after TSH-stimulating hormone were measured at the beginning of observation and 3,8 years (median) later. During follow-up period, 13 patients (22%) with CAA developed DAA. 9/ 13 patients (15%) had overt hyperthyreoidism with elevated T4 and/or T3 levels, 4/13 patients (7%) had normal thyroid hormone levels. Life table analysis showed a risk for developing hyperthyreoidism of 19% at five years. The size of all adenomata measured scintigraphically was increasing during follow-up, and there was no discrimination of CAA from DAA using this technique. Eight CAA patients received iodinated contrast medium but none develope DAA. In conclusion from these results as well as from the literature, there is no indication for surgery or radioiodine therapy of patients with a CAA, even if there are plans to administer iodinated contrast medium.

In a retrospective study of 632 patients with pituitary disease we diagnosed pituitary insufficiency without hypersecretion of any pituitary hormone in 122 patients. Patients were substituted with sex hormones (76%), hydrocortisone (74%) and/or L-thyroxine (77%). 76% had additional growth hormone deficiency, as shown by an increase of growth hormone of less than 5 ng/ml after i.v. administration of L-arginine. In 17% of all patients the diagnosis of osteoporosis was proven or suspected radiologically. 57% had low bone mass of lumbar spine (dualphotonabsorptiometry) and 73% had low bone mass of the proximal forearm (singlephotonabsorptiometry). BMD values of pituitary insufficient patients were in the same range as those of patients with established osteoporosis. More than half of all patients (53%) complained of tiredness, exhaustion and muscle weakness. 40% suffered from adipositas. 77% had hyperlipidemia (68% hypertriglyceridemia and 42% hypercholesterinemia), 18% had hypertension. 14% of the patients had arteriosclerotic events in their history (myocardial infarction or stroke). These figures are higher than incidences shown in the German PROCAM-study. These data show an increased prevalence of osteoporosis and vascular diseases. This is in contrast to the general opinion, that patients with pituitary insufficiency are adequately treated by substitution with adrenal, thyroid and sex hormones. Whether other factors such as the additional growth hormone deficiency are responsible for these diseases has to be examined in prospective studies.

22 patients on chronic hemodialysis underwent low-molecular-weight-heparine (LMWH) (Fragmin, Kabi Chemie Corp., Munchen) instead of conventional heparine (CH) for anticoagulation during dialysis. Blood evaluations before start, 2, 4 and 6 months under LWMH treatment and 3 and 6 months after switching back to CH were performed. During LWMH-treatment whole cholesterol decreased significantly, LDL-cholesterol being the main part accounting for this. HDL-cholesterol and the subfractions of HDL-cholesterol remained nearly unchanged. The apolipoproteins A1 and B decreased significantly, too. Apolipoprotein B decreased during the 6 months LMWH-period continuously, while Apolipoprotein A1 rapidly decreased during the first two months and then stabilized at a lower level. The triglycerides, starting from a normal range level, increased during the first 2 months significantly, then decreased reaching, the starting values again at the end of the LMWH-period. Platelet aggregation induced with collagen showed a significant improvement during the use of LMWH. After switching back to CH the parameters returned to the starting values again.

Out of a random population of 4208 non-diabetic pupils without a family history of Type I diabetes 44 (1.05%) individuals had islet cell antibody (ICA) levels greater or equal to 5 Juvenile Diabetes Foundation (JDF) units. 39 of these ICA-positives could be repeatedly tested for circulating insulin autoantibodies (CIAA) using a competitive radiobinding assay. The results were compared with the insulin responses in the intravenous glucose tolerance tests (IVGTT) and with HLA types. Six pupils were positive for CIAA. All of them had complement-fixing ICA, and 5 of them were HLA-DR4 positive. Three of the 6 showed a first-phase insulin response below the first percentile of normal controls. Our data indicate that in population-based studies CIAA can be considered as a high risk marker for impaired beta-cell function in non-diabetic ICA-positive individuals.

After a 48-hour rehydration period 28 of 31 patients with cancer-associated hypercalcemia (serum calcium ≥2.8 mmol/1) were treated intravenously with the bisphosphonate pamidronate. In three patients fluid repletion with 0.9% saline solution had already normalized serum calcium levels. Pamidronate was given in a single infusion on day 0, the dose of pamidronate adapted to the severity of hypercalcemia. If the serum calcium concentration was ≥2.8 mmol/1 on day 3, application of pamidronate was repeated. In all patients normocalcemia was restored; mean serum calcium decreased from 3.2±0.35 on day 0 to 2.15±0.32 on day 12. Hypercalcemia recurred in 11 patients, seven of these underwent pamidronate treatment according to the same therapeutical regimen. Normal calcium levels were attained in five cases. Side effects were of minor gravity:brief hyperthermia occurred in four patients and transient, asymptomatic hypocalcemia was noticed in nine cases.

The antigenic specificity and clinical distribution of the antineutrophil cytoplasmic antibodies (ANCA) in kidney diseases have recently been extensively studied. In patients with systemic vasculitis, the great predominance of two major ANCA antigens, proteinase 3 (PR3) and myeloperoxidase (MPO), is now established. PR3 and MPO are colocalized in the azurophilic granules of neutrophils and translocated to the cell surface during activation, and thus are able to interact with autoantibodies after neutrophil preactivation. Furthermore, by comparison of amino acid and DNA sequences, it has been shown that PR3 is identical to myeloblastin, which has been described independently and is involved in the control of growth and differentiation of leukemic cells. Aside from the two major ANCA antigens, a number of neutrophil cytoplasmic antigens recognized by ANCA have been identified, including human leukocyte elastase, lactoferrin, CAP57, and cathepsin G. These rare ANCA specificities occur in a limited number of patients. The variety of ANCA antigen specificities contrasts, however, with the fact that the vast majority of ANCA-positive sera are monospecific for one single ANCA antigen. With regard to clinical distribution, ANCA have major diagnostic significance in the four conditions in which they are frequently detected: Wegener's granulomatosis (WG), Churg and Strauss Syndrome (CSS), microscopic periarteritis (MPA), and necrotic and crescentic glomerulonephritis (NCGN). However, the initial dichotomy between MPO-associated vasculitis (NCGN, MPA) and that associated with anti-PR3 antibodies (WG) appears far from absolute.

We studied retrospectively patients with hyperparathyroidism after successful renal allotransplantation. Since 1972, 1119 transplantations have been performed in our department, and 534 patients survive with functioning grafts. Hyperparathyroidism requiring parathyroidectomy developed in 32 (5.9%). The frequency of interventions increased markedly after introduction of cyclosporine A treatment in our unit. The time between transplantation and parathyroidectomy was 22.5 months (SD 16.5, range 1-82 months). The age of the patients was 49.0 years (SD 10.5, range 17-63 years); the group consisted of 16 female and 16 male patients. All patients but two (no measurement performed) repeatedly exhibited high serum parathormone and calcium levels and therefore underwent surgery. In comparison to a control group, matched for time of transplantation, age, sex, and cause of renal failure, the patients with hyperparathyroidism had longer dialysis treatment (54.2 months, range 9-132 vs 26.9 months, range 1-72) and exhibited lower phosphate concentrations in the early posttransplantation period. Before surgery, serum chemistry was different for hyperparathyroid and control subjects: serum calcium 2.80 +/- 0.23 mmol/l vs 2.48 +/- 0.13 mmol/l and alkaline phosphatase 157.4 +/- 92.0 U/l vs 85.2 +/- 51.5, respectively. We did not see any influence of oral phosphate binders, calcium supplementation, or vitamin D treatment on the development of parathyroid gland hyperactivity during dialysis treatment. Serum creatinine concentration did not change after parathyroidectomy. In four patients, long-term calcium supplementation after surgery was necessary.

The diagnosis of classical cystic fibrosis (CF) is easily made by clinical assessment alone, but may be missed or delayed in cases with an atypical clinical course. In a recent major study the age at diagnosis varied between 2 months and 47 years. For diagnostic purposes we have investigated the cystic fibrosis transmembrane regulator (CFTR) gene in 10 adult patients (age 18 to 45 years) with chronic obstructive pulmonary disease since childhood or adolescence and bronchiectases disseminated through both lungs. Only one subject (a 29-year-old male) had exocrine pancreatic insufficiency (PI); all others were pancreatic-sufficient (PS). The first nucleotide (ATP)-binding fold of the CFTR was analyzed by direct sequencing of polymerase chain reaction (PCR)-amplified genomic DNA in these cases. Two patients with different phenotypes (one PI, one PS) were found to be homozygous for the common ΔF508 mutation of the CFTR gene, which proved the diagnosis of cystic fibrosis in their cases and allowed genetic counselling. The PS patient had normal sweat tests and had not previously been recognized as having CF. Four other patients were heterozygous for ΔF508, with no other mutation in exons 10 or 11 of the gene, and four patients had normal sequences of these exons. Because only about 70% of all CF chromosomes carry ΔF508, the unexpectedly high frequency (4/8=50%) of heterozygosity for ΔF508 among the non-ΔF508/ΔF508 patients with bronchiectases suggests that some of these might also have unrecognized CF with rare genotypes and mutations in any of the 22 exons not sequenced. About 90 different mutations have already been detected in coding regions of the CFTR gene and a very broad and so far not fully recognized spectrum of clinical phenotypes may be caused by mutations of this gene. Screening for the most frequent CFTR gene mutations, which is practicable using recent technology, may provide significant new diagnostic information in patients with CF-like pulmonary phenotypes, especially if they have normal or borderline sweat tests and no pancreatic insufficiency.