An Observational Study to Identify Drug-related Problems (DRP) in Routine Care and An Expert Panel Assessment to Rate Clinical Risk and Preventability by Unit-dose Dispensing Systems (UDDS) with Computerized Physician Order Entry (CPOE) and Clinical Decision-Support Systems (CDSS).

Background and aim: Drug-related problems (DRP) jeopardize patient safety. Unit-dose dispensing systems (UDDS) with computerized-physician-order-entry (CPOE) and clinical-decision-support-systems (CDSS) were reported as a promising concept for preventing DRP. We aimed at identifying and categorizing DRP in peroral drug administration considering their clinical risk and preventability by UDSS/CPOE/CDSS. Investigations: In surgical and internal-medicine departments, we observed routine procedures in peroral drug administration for DRP. An expert panel including pharmaceutical and nursing expertise categorized the identified 18 DRP categories into three levels: DRP that have not yet resulted in medication errors (ME) (Level-I), DRP where ME have occurred but have not yet reached the patient (Level-II), and DRP where ME have occurred and have reached the patient (Level-III). Additionally, the panel categorized DRP according to their clinical risk and whether the implementation of UDSS/CPOE/CDSS can prevent them. Results: In 77 surgical patients, 1,849 peroral drug administration procedures, and in 149 internal-medicine patients, 1,405 procedures were observed. The 18 DRP categories were identified with a frequency of 0.6%-26.7% (Level-I), 0.1%-21.5% (Level-II), and 0.0%-1.0% (Level-III). Of those, four categories were considered of high clinical risk: "Name of the medication is not readable", "Prescribed medication is not prepared for administration", "An incorrect or non-prescribed medication is prepared", and "A medication is prepared for the wrong patient (mix-up)". Twelve DRP categories were categorized as highly preventable by UDSS/CPOE/CDSS. Conclusions:Under routine conditions, we identified a substantial number of DRPs. An expert panel categorized many of those DRPs as clinically highly relevant and highly preventable by UDSS/CPOE/CDSS.

[Hyponatremia and tolvaptan : what is the situation 5 years after approval?]. / Hyponatriämie und Tolvaptan : Wo stehen wir 5 Jahre nach der Zulassung?

The diuretic tolvaptan has been approved for more than 5 years for the indications of euvolemic hyponatremia due to syndrome of inappropriate antidiuretic hormone (SIADH) secretion. In recent years many patients have been treated with tolvaptan and many physicians could gather practical experience. Other countries, such as the USA had already gained greater experience, also in the indications for hypervolemic hyponatremia. After approval was granted more than 5000 patients worldwide were included in the so-called hyponatremia register and 22 active centers in Germany with 317 patients participated. Although some details from this now concluded register have been published, the final publication of the multinational post-authorization safety study on tolvaptan in the treatment of SIADH has not yet been published. In the years 2012 and 2013 two warning letters were issued on tolvaptan. The first letter warned of the risk of a faster increase in serum sodium using tolvaptan and provided detailed information on how the risk of osmotic demeyelination can be minimized. So far only one proven case of osmotic demelination syndrome (ODS) is known; however, this occurred following incorrect use of tolvaptan in a monotherapy. The second warning letter provided information on the potential risk (reversible) of liver damage by tolvaptan, which resulted from the TEMPO 3:4 study. In this study tolvaptan was used in a higher dosage for therapy of autosomal dominant polycystic kidney disease. Although the European renal best practice (ERBP) guidelines from 2014 did not recommend tolvaptan for the indications of SIADH, other guidelines came to different conclusions. In summary, 5 years after the approval of tolvaptan there is still no consensus. At the current time many questions still remain unanswered. Initiation of therapy with tolvaptan remains reserved for experienced physicians in hospitals. Treatment must be adapted on the basis of a clinical estimation of the individual situation of each patient.

[Treatment of hyponatremia: role of vaptans]. / Behandlung der Hyponatriämie: Die Rolle der Vaptane.

Hyponatremia is encountered quite frequently in everyday clinical practice. The symptomatology mainly includes neurological manifestations. In addition, it has been noted in recent years that uncertain gait, falls, fractures, and osteoporosis are also associated with hyponatremia. Based on clinical and laboratory analyses, hyponatremia can be classified into three categories: hypovolemic (decreased volume), hypervolemic (with venous edema), and euvolemic. The severity of the neurological symptoms related to hyponatremia should serve to guide the therapeutic approach. Severe cerebral symptoms due to acute cerebral edema require a prompt and closely monitored course of action with administration of hypertonic saline solution. Milder and moderate symptoms as well as the syndrome of inappropriate ADH secretion (SIADH) can now also be managed with controlled use of the ADH antagonist tolvaptan, one of a new class of vaptans. Tolvaptan is a selective antagonist of the antidiuretic effect of vasopressin without primarily affecting blood pressure and depending on the dose leads to increased excretion of free water (aquaresis). Side effects predominantly concern thirst, polyuria, and hypernatremia. Under these conditions, vaptans represent a valuable asset to the therapeutic spectrum in SIADH. Further studies are needed to determine whether falls and fractures can also be beneficially influenced.

[Thyroid disorders and pregnancy]. / Schilddrüsenerkrankungen und Schwangerschaft.

Disorders of the thyroid in women are common during the reproductive years. Incorrect or delayed treatment during pregnancy can adversely affect the health of mother and child. Knowledge of the physiological changes during this time is essential. Thyroid disorders, in particular hypothyroidism, may compromise fertility. Autoimmune thyroiditis is associated with a higher risk of fetal loss. In women on thyroid hormone replacement therapy, the thyroxine dose has to be adjusted to meet the enhanced requirement during pregnancy. Thyroid hormone is vital to fetal brain development. During pregnancy and lactation, iodine supplementation is also recommended due to alterations in iodine metabolism. Hyperthyroidism during pregnancy can adversely affect pregnancy outcome and has to be treated accordingly. Propylthiouracil should be given using the least effective dose to keep free thyroxine levels at the upper limit of normal or slightly above. Hyperthyroidism in the fetus and the neonate can be induced by thyroid stimulating antibodies capable of passing the placenta.

[Diagnosis and treatment of interstitial cystitis (IC/PBS) : S2k guideline of the German Society of Urology]. / Diagnostik und Therapie der interstitiellen Zystitis (IC/BPS) : S2k-Leitlinie der Deutschen Gesellschaft für Urologie.

In this review article, the authors describe all relevant aspects of the new S2k guideline from the German Society of Urology (Deutschen Gesellschaft für Urologie, DGU) for the diagnosis and treatment of IC/PBS (interstitial cystitis/painful bladder syndrome). A list of necessary and optional examinations and the necessity of diagnosis of exclusion are summarized and evaluated. The treatment options listed (ranging from conservative, oral drug, and complementary medicine to interventional surgical procedures) also give the reader a good overview of the contents of the guideline and possible therapeutic approaches. Finally, the recommendations including consensus of the guideline group are also summarized in various information boxes.

Management of diabetes mellitus and hospital-related hyperglycemia in patients of a medical ICU, with the use of two "down-to-earth" protocols: a feasibility study.

OBJECTIVE: Optimal control of blood glucose in the ICU has been shown to significantly decrease mortality and morbidity of severely ill patients. The purpose of the present project was to develop and implement undemanding, "down-to-earth" protocols, enabling tight glucose control in critically ill patients, in the setting of a city hospital ICU with limited personnel and facilities. RESEARCH DESIGN AND METHODS: From January 2003 to January 2006, a total of 745 patients (3197 patient-days) were treated for hyperglycemia in our medical ICU. On July 2003 two different intensive insulin therapy protocols were implemented: A protocol of continuous intravenous insulin, including specific algorithms for calculation of initial insulin bolus, initial infusion rate and further adjustment plan, was used for patients with compromised peripheral tissue perfusion. For patients with stable circulation, a protocol of subcutaneous intensive insulin therapy, including a formula for calculation of daily insulin dosage in previously non-insulin-treated diabetics, was adopted. 134 patients were treated during the run-in phase of the project and 539 patients were treated during the main treatment phase. 72 patients treated for hyperglycemia in our ICU prior to the implementation of the two protocols (from January 2003 to July 2003) served as controls. RESULTS: After the implementation of the two protocols, a marked overall increase of normoglycemic blood glucose values (64.7% vs. 48.5%, P<0.001), a decrease of manifest hyperglycemias (6.4% vs. 17.4%, P<0.001) and an increase in hypoglycemic events (1.8% vs. 0.7%, P<0.001) was observed. Seven cases of severe hypoglycemia requiring glucose infusion were observed during the main treatment phase (0.3%). No hypoglycemia-associated deaths occurred. CONCLUSIONS: The combined implementation of the two protocols presents a simple, safe and effective way of pursuing normoglycemia in critically ill patients.

Developing effective screening strategies in multiple endocrine neoplasia type 1 (MEN 1) on the basis of clinical and sequencing data of German patients with MEN 1.

BACKGROUND: Multiple-endocrine-neoplasia-type-1 (MEN1) is an autosomal-dominant inherited disorder characterized by the combined occurrence of primary hyperparathyroidism (pHPT), gastroenteropancreatic neuroendocrine tumors (GEP), adenomas of the pituitary gland (APA), adrenal cortical tumors (ADR) and other tumors. As the tumors appear in an unpredictable schedule, uncertainty about screening programs is persisting. OBJECTIVE: To optimize screening and to analyze possible differences in sporadic versus familial cases. METHODS: We analyzed data of 419 individuals including 306 MEN-1 patients (138 isolated and168 familial cases out of 102 unrelated families). RESULTS: A total of 683 tumors occurred consisting of 273 pHPT, 138 APA, 166 GEP, 57 ADR, 24 thymic- and bronchial-carcinoids as well as 25 neoplasms of other tissues. The age-related penetrance was determined as 10%, 35%, 67%, 81% and 100% at 20, 30, 40, 50 and 65 years respectively. Although pHPT being the most frequent first manifestation (41%), also GEP (22%) or APA (21%) were found to be the first presentation. APA occurred significantly more frequent (p<0,05) in isolated (n=138) than in familial (n=168) cases, whereas GEP showed a tendency to occur more often in familial cases. Genotype/phenotype correlation in 140 clinically affected MEN-1 cases showed a tendency for truncating mutations, especially nonsense mutations to be associated to GEP and carcinoids of the lungs and thymus. CONCLUSION: In view of the morbidity and frequency in familial cases an effective screening programme should aim at an early diagnosis of GEP particularly when truncating, especially nonsense mutations are found.

Effects of incremental infusions of arginine vasopressin on adrenocorticotropin and cortisol secretion in man.

Arginine vasopressin (AVP) regulates ACTH release under certain conditions, and exogenously administered AVP is used clinically to stimulate ACTH secretion. We attempted to determine at what plasma concentration AVP can stimulate ACTH release. Six normal men were given infusions of AVP (Ferring) or vehicle between 1600 and 1700 h on five occasions: 1) saline (30 mL/h); 2) 10 ng AVP/min; 3) 30 ng AVP/min; 4) 100 ng AVP/min; and 5) 300 ng AVP/min. Plasma AVP, ACTH, and cortisol concentrations were measured every 10 min during the infusions. Basal plasma AVP levels were less than 1 ng/L (less than 0.92 pmol/L). The lowest AVP dose raised plasma AVP into the range found in fluid-deprived subjects (7-8 ng/L;6.5-7.3 pmol/L), but had no effect on plasma ACTH concentrations. AVP in a dose of 30 ng/min also had no effect. The 100 ng AVP/min dose raised plasma AVP concentrations to 51.4-65.5 ng/L (46-60 pmol/L). This increase led to a transient insignificant increase in plasma ACTH from 13.9 +/- 1.2 (+/- SEM) ng/L (3.1 +/- 0.3 pmol/L) to 20.0 +/- 1.4 ng/L (4.4 +/- 0.3 pmol/L), while plasma cortisol rose significantly from 146 +/- 10 to 209 +/- 19 nmol/L (P less than 0.01) after 60 min of infusion. The 300 ng AVP/min dose raised plasma AVP levels to about 260 ng/L (239 pmol/L); the maximal plasma ACTH and cortisol levels were 39.5 +/- 5.0 ng/L (8.7 +/- 1.1 pmol/L; P less than 0.01) and 348 nmol/L (P less than 0.01), respectively. Thus, peripheral plasma AVP levels have to be raised high above the physiological range before ACTH release is stimulated. We conclude that any AVP reaching the adenohypophysis through the peripheral circulation is of much less importance for the regulation of ACTH secretion than is AVP derived from the pituitary portal circulation.

Methodological aspects and clinical results of an assay for thyroid-stimulating antibodies: correlation with thyrotropin binding-inhibiting antibodies.

Several methodological aspects concerning the measurement of thyroid-stimulating antibodies (TSAb) were examined using a 5000-g particulate fraction from human thyroid tissue. TSH displayed maximal stimulation at 32 C. An ATP-regenerating system had no influence at ATP concentrations greater than 0.67 mM. Theophylline did not influence cAMP concentrations in the incubation medium after stimulation with increasing dosages of TSH, suggesting the absence of active phosphodiesterases in the membrane preparations. Sera dialyzed against Tris-HCl were as suitable as immunoglobulin G preparations for determination of TSAb. One hundred and nineteen patients with ophthalmic Graves' disease, 42 of whom were hyperthyroid at the time of study, were investigated for TSH binding-inhibiting antibodies ( TBIAb ) and TSAb. In 76% of these patients, concordance between the presence and absence of both activities was found independent of whether they were untreated, treated, or in remission. When gradations of potency in the two systems were compared, linear regression revealed a correlation coefficient of 0.59. The coefficient correlation increased when TBIAb and TSAb were each determined in a single assay using identical thyroid membrane preparations. In four other patients, both TSAb and TBIAb were measured repeatedly during the course of the disease. In three patients, both activities were parallel, whereas in one patient, dissociation of the two activities was found. The data suggest the presence of antibodies with varying stimulating and binding-inhibiting properties. However, in hyperthyroidism of Graves' disease, both activities usually were present in similar quantities.

Water retention after oral chlorpropamide is associated with an increase in renal papillary arginine vasopressin receptors.

Chlorpropamide (CP), a sulfonylurea used for treatment of non-insulin dependent diabetes mellitus, is known to potentiate the antidiuretic action of arginine vasopressin (AVP), predisposing to hyponatremia. It has been suggested that CP acts directly on the antidiuretic vasopressin receptor. Detailed studies on the influence of CP on the AVP receptor, however, have been hampered by lack of a suitable radioligand. Using a newly developed radioiodinated derivative of AVP with high specific activity and high affinity for the AVP V2-receptor (125I-[8-(p-(OH)-phenylpropionyl)]-LVP), we studied the role of AVP V2-receptors in CP-induced water retention. Male-Sprague-Dawley rats were treated orally with 40 mg CP/day or placebo for 7 days, after which Scatchard analysis was performed using membranes prepared from homogenized renal papilla. After oral water load, CP-treated rats but not control rats showed a significant decrease in plasma osmolality (289 +/- 2.2 to 284 +/- 0.8 mosmol/kg, p < 0.05). The Kd was 0.69 +/- 0.16 nmol/l in controls and 0.70 +/- 0.12 nmol/l after CP treatment (NS); Bmax was 129 +/- 5.3 nmol/kg protein in controls (N = 8). Chlorpropamide significantly increased receptor density (Bmax) to 167 +/- 8.4 nmol/kg protein (N = 8) (p < 0.05). Plasma AVP did not change significantly during CP treatment. These data show for the first time that CP in vivo increases the density of AVP V2 receptors without altering plasma AVP. This is associated with an impairment in water excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Absence of angiotensin II type 1 receptor gene mutations in human adrenal tumors.

Regulatory actions of angiotensin II (AngII), which is involved in the pathophysiology of hypertension and also participates in cell proliferation and cell differentiation, are mainly mediated by AngII type 1 (AT1) receptor. Recently, activating mutations of receptors causing hyperfunctioning endocrine diseases have been described in the case of the TSH and LH receptors, implicating that such mutations might occur in other G-protein-coupled receptors. Furthermore it seems to be possible that genetic variations of AT1 receptor have an influence upon the action of AngII. Therefore, we searched by sequence analysis of the coding region of AT1 receptor gene for activating mutations and genetic polymorphisms in 56 human adrenal tumors (16 aldosterone-producing adenomas, 10 cortisol-producing adenomas, 1 aldosterone-producing carcinoma, and 29 incidentalomas). We were not able to identify any activating mutation in the coding region of AT1 receptor gene. We conclude that activating mutations of the AT1 receptor are not a major cause of the development of adrenal adenomas, if at all. In addition, polymorphic subtypes of AT1 receptor do not seem to play a major role in the pathogenesis of these tumors, even though a tendency towards a higher frequency of the polymorphic base substitution at position 573 (T573-->C) in cortisol-producing tumors needs to be further evaluated.

Antigastric autoantibodies in Helicobacter pylori gastritis: prevalence, in-situ binding sites and clues for clinical relevance.

Colonization of human gastric mucosa with Helicobacter pylori leads to chronic active gastritis and induces the occurrence of an acquired mucosa-associated lymphoid tissue (MALT) in the stomach. This remodelling of the gastric mucosa together with chronic antigen persistence may induce autoimmune reactions. The aim of this study was to investigate humoral autoimmune reactions to human gastric mucosa in H. pylori gastritis and their clinical relevance. Sera from patients with dyspeptic symptoms were tested for presence of IgG immunoglobulins against H. pylori. Gastric infection with H. pylori and alterations of gastric mucosa were demonstrated by histological examination of gastric biopsy specimens. All sera were tested for reactivity against human gastric mucosa by immunohistochemistry. Two different in-situ binding sites of antigastric autoantibodies were observed. Binding to canalicular structures within parietal cells was significantly correlated with antibodies to H. pylori, elevated basal gastrin levels and atrophy of gastric corpus glands. Our data indicate that autoimmune reactions to antigens in the human gastric mucosa occur in H. pylori gastritis and that they may play a role in the pathogenesis of the disease.

Severe hyponatremia after transsphenoidal surgery for pituitary adenomas.

Severe hyponatremia has been described after elective surgery with subsequent permanent brain damage. Other authors, however, have noted that morbidity and mortality rates of severe hyponatremia have been greatly overestimated. We retrospectively examined 19 patients (8 male, 11 female) who developed severe hyponatremia (100 to 124 mmol/liter) after transsphenoidal surgery for pituitary adenomas. Eight patients had hormonally inactive adenomas, 5 ACTH-secreting adenomas, 2 GH-secreting adenomas and 4 prolactin-secreting adenomas. The mean age of the patients was 47.5 years, with a range from 16 to 71 years. The mean preoperative serum sodium level was 137.8 mmol/liter. The timing of hyponatremia showed two different patterns. Five patients developed early postoperative hyponatremia (mean 114.0 mmol/liter +/- 4.85) and 14 patients showed the lowest mean serum level one week after surgery (118.1 mmol/liter +/- 6.86). Patients with early hyponatremia had fewer and less severe symptoms than patients with delayed hyponatremia. None of the patients developed seizures or a demyelination syndrome. Despite severe degree of hyponatremia for most of our patients treatment with water restriction and oral sodium supplementation was sufficient.

Lymphocytic and granulomatous hypophysitis: experience with nine cases.

OBJECTIVE: Lymphocytic hypophysitis and granulomatous hypophysitis are rarely encountered. The aim of this study was to demonstrate their clinical peculiarities among pituitary disorders and to provide an approach for their clinical management. METHODS: In a retrospective study, we reviewed our surgical experience with nine patients harboring hypophysitis. The series included six cases of lymphocytic hypophysitis, two cases of granulomatous hypophysitis, and one case with evidence of coexisting lymphocytic and granulomatous hypophysitis. RESULTS: A striking similarity of clinical signs was found for our nine patients. Headache or aseptic meningitis, thickening of the sphenoid sinus mucosa, pituitary stalk enlargement, and tongue-shaped extension of the lesion along the basal hypothalamus were characteristic signs. Lymphocytic hypophysitis was not associated with pregnancy in any of the seven cases. No recurrence has been observed in six cases with total removal of the inflammatory tissue. CONCLUSION: Lymphocytic hypophysitis and granulomatous hypophysitis represent related inflammatory disorders. Their conspicuous clinical features frequently allow preoperative diagnosis of hypophysitis. In view of their sometimes insidious clinical course, early surgical exploration is justified.

Nonpeptide vasopressin antagonists: a new group of hormone blockers entering the scene.

After the story of success of hormone blockers for catecholamines, aldosterone and angiotensin II and their successful implementation into clinical practice another endocrine cardiovascular system has come into focus. It has long been known, that the hormone vasopressin plays an important role in peripheral vasoconstriction, hypertension and in several disease conditions with dilutional hyponatremia in edematous disorders, like congestive heart failure, liver cirrhosis, SIADH and nephrotic syndrome. A series of orally active nonpeptide antagonists against the vasopressin receptor subtypes has recently been synthesized and is now under intensive examination. Nonpeptide V1a-receptor specific antagonists, OPC 21268 and SR 49059, nonpeptide V2-receptor specific antagonists, SR 121463 A and VPA 985, and combined V1a-/V2-receptor antagonists, OPC 31260 and YM 087, have become available for clinical research. AVP-V2-receptor antagonists lead to a dose-dependent diabetes insipidus in animals and man. The term aquaretic drugs (aquaretics) has been coined for these drugs to highlight their different mechanism compared to the saluretic diuretic furosemide. V1a-receptor antagonists might offer new therapeutic advantages in the treatment of vasoconstriction and hypertension. Combined V1a-/V2-receptor antagonists might be beneficial in the treatment of congestive heart failure. Early results are promising and now need to be confirmed in large clinical studies.

Atherosclerosis, aortic stenosis and sudden onset central diabetes insipidus.

The majority of cases of central diabetes insipidus are still pathogenetically unclear (idiopathic). Atherosclerotic cholesterol emboli might be partly responsible for some of these idiopathic cases. A 54-year-old woman with known aortic valve stenosis and a history of a transitory ischemic attack presented with sudden-onset polyuria and polydipsia of up to eight l/d, which had started acutely with headaches. She had been treated with lithium for 3 years because of cyclothymic depression. Plasma sodium was in the upper normal range (142-148 mmol/l). Hypertonic saline infusion during lithium therapy revealed a normal threshold of thirst and resetting of vasopressin secretion (osmotic threshold > 300 mosmol/l), whereas vasopressin reserve was normal. Lithium withdrawal led to an even greater delay of vasopressin release upon hypertonic saline infusion (> 310 mosmol/l). Pituitary function tests revealed a normal anterior pituitary function. MR imaging of the hypothalamo-hypophyseal region showed a normal hypothalamic region and a highly intensive neurohypophyseal signal in the T1-weighted image. The patient responded well to desmopressin. We suggest that in this rare case clinical symptoms as well as biochemical findings like impairment of AVP release might be related to a minor structural hypothalamic damage by a vascular lesion, caused, for example, by an atheromatous (cholesterol) embolism in the hypothalamic region responsible for integration of osmoreceptor function and AVP-secretion. The patient's atherosclerosis and aortic stenosis might be responsible for this event.

The inhibition of low density lipoprotein oxidation by 17-alpha estradiol.

The inhibition of LDL-oxidation by 17-alpha estradiol was assessed in vitro by the determination of the duration of the lag-phase in copper ion-induced oxidation and compared to that of 17-beta estradiol, estriol, and probucol. Addition of 0.2, 0.4, and 1 micromol/l of the test substances prolonged the lag-phase of LDL-oxidation 1.3-(+/-0.09 SD), 1.7-(+/-0.14 SD), and 2.7-(+/-0.25 SD) fold for 17-alpha estradiol; 1.4-(+/-0.14 SD), 1.8-(+/-0.1 SD), and 2.6-(+/-0.16 SD) fold for 17-beta estradiol; 1.1-(+/-0.07 SD), 1.4-(+/-0.11 SD), and 1.6-(+/-0.11 SD) fold for estriol as well as 1.4-(+/-0.14 SD), 1.6-(+/-0.1 SD), and 3.0-(+/-0.21) fold for probucol, thus proving that 17-alpha estradiol is as effective as 17-beta estradiol or similar to probucol and more effective than estriol (n = 6 in all cases). These data demonstrate that 17-alpha estradiol is able to delay LDL-oxidation, hence providing a basis for clinical examination of the protective effects of 17-alpha estradiol against atherosclerosis in patients where hormonal effects of 17-beta estradiol are undesirable.

PCR-SSCP analysis of human adrenocortical adenomas: absence of K-ras gene mutations.

Little is known about the pathogenesis and etiology of benign tumors of the adrenal cortex. A variety of cellular oncogenes and tumor suppressor genes has been studied so far. The role of K-ras in this process is not yet clearly understood. Recent findings suggest a strong influence of mutated K-ras in the pathogenesis of adrenal adenomas (Lin et al., 1998). Therefore we studied 40 human adrenal tumors for mutations in the coding region of the cellular proto-oncogene K-ras by PCR-SSCP (Single-strand conformation polymorphism) analysis. We did not identify any activating mutation in the coding region of the K-ras gene. We conclude that activating mutations of the K-ras gene are not a major cause for the development of adrenal adenomas, if at all.

Ratio of serum aldosterone to plasma renin concentration in essential hypertension and primary aldosteronism.

The ratio of serum aldosterone to plasma renin activity (PRA) has been proposed as sensitive screening method in the diagnosis of primary aldosteronism under random conditions. However, the method for determination of renin activity is hampered by the necessity of ice cooling during storage and transport. The present study was therefore conducted to examine the ratio of serum aldosterone to plasma renin concentration (ARR) and its usefulness in diagnosis of primary aldosteronism under ambulatory conditions and given antihypertensive medication. 146 patients with arterial hypertension who consecutively attended the outpatient clinic were studied prospectively. Patients with secondary hypertension besides primary aldosteronism were not included in the series. 37 normotensive patients served as control. Also, 17 patients with known primary aldosteronism were retrospectively examined. Among the hypertensive group 2 patients with Conn's syndrome were newly detected (1.4%). ARR was 7.92 +/- 6.04 [pg/ml]/[pg/ml] in normotensive controls (range from 2.03 to 26.98), 14.61 +/- 18.50 [pg/ml]/[pg/ml] in patients with essential hypertension (n = 144, range from 0.41 to 115.45) and 155.92 +/- 127.84 [pg/ml]/[pg/ml] in patients with primary aldosteronism (n = 19, range from 6.75 to 515). 17 of the 19 patients with Conn's syndrome had an ARR of more than 50. Under ongoing drug treatment this represents a sensitivity of 89% and a specificity of 96%. Sensitivity decreased to 84% and specificity increased to 100% when a second criteria (aldosterone > or = 200 pg/ml) was included. In summary, ARR using renin concentration is a useful screening parameter for primary aldosteronism.

A new mutation of the arginine vasopressin-neurophysin II gene in a family with autosomal dominant neurohypophyseal diabetes insipidus.

Familial neurohypophyseal diabetes insipidus (FNDI) is an autosomally dominant inherited disorder with a typical onset at one to six years of age. The genetic locus of FNDI is the arginine vasopressin-neurophysin II (AVP-NPII) gene. The gene encoding the precursor hormone (prepro-AVP-neurophysin II) is located in the chromosomal region 20p13 and contains three exons. Mutations that cause FNDI have been found to occur within the signal peptide of the prepro-AVP-neurophysin II precursor, within the coding sequence for neurophysin II and the vasopressin-coding sequence. A family (four members with FNDI, two without FNDI) in three consecutive generations was investigated. Index case was a now 22-year old man with a history of severe polyuria (18 L/day) and polydipsia first recognized at about 4-5 months of age. The arginine vasopressin-neurophysin II gene was investigated by direct sequencing of PCR products amplified from each exon. Subsequently, a restriction analysis was performed to verify the sequencing results. The affected individuals were found to have a missense mutation in exon 2 at nucleotide position 1887 (G to C) of the AVP-NPII gene. Using both restriction enzyme digestion and sequence analysis, the mutation was found in all affected family members, but not in the unaffected members studied. This mutation (1887 G to C) represents a novel mutation of the AVP-NPII gene.