[Werner's syndrome]. / Werner-Syndrom.

HISTORY AND CLINICAL FINDINGS: A 49-year-old man of German parentage with Werner's syndrome (including insulin-dependent type 2 diabetes mellitus) was treated in our department for extensive ulcers on his lower legs. GENETICS: Genetic analysis detected a novel compound heterozygous defect (1396delA and 2334delAC) of the WRN gene. TREATMENT AND FURTHER COURSE: The ulcer clearly decreased in size on local and antibiotic treatment as well as autologous fibroplast transplantation. The most severely affected right small finger required amputation with exarticulation. The severe pain caused by the ulcer was successfully treated with temporary blockage of the stellate ganglion and permanent sympathetic blockage at the level of the 2nd thoracic and lumbar vertebrae. CONCLUSION: Werner's syndrome is a rare form of progeria with an autosomal recessive mode of inheritance mimicking the symptoms of accelerated aging. The reduced life expectancy is caused by the increased incidence and early onset of atherosclerosis and malignant tumors. The detection of underlying molecular mechanisms will have an important impact in the field of anti-aging research.

A novel compound heterozygous mutation in Werner syndrome results in WRN transcript decay.

BACKGROUND: Werner syndrome (WS) is a rare autosomal recessive progeroid disorder caused by mutations of the WRN gene encoding a protein of the RecQ-type family of DNA helicases. OBJECTIVES: To develop a rapid and simple reverse transcription-polymerase chain reaction (RT-PCR) strategy for mutation analysis of the WRN gene, to identify pathogenic mutations in a German patient with WS and to determine the effects of the pathogenic mutations on WRN mRNA stability. METHODS: Allele-specific RT-PCR, semiquantitative RT-PCR, DNA sequencing. RESULTS: We describe a novel and rapid RT-PCR-based method for mutation analysis in WS and report a German patient with WS carrying a previously reported (1396delA) as well as a novel nonsense mutation (2334delAC) of the WRN gene. By semiquantitative RT-PCR analysis we demonstrate that this compound heterozygous genotype leads to WRN transcript decay. CONCLUSIONS: In previous studies WS was primarily attributed to a loss of function of stable truncated WRN gene products. Our findings indicate that mutations can also lead to markedly decreased WRN transcript stability.

[Multiple autoimmune syndrome. Reynolds-syndrome (acral scleroderma, primary biliary cirrhosis, Sjögren syndrome) associated with the lupus erythematosus/lichen planus overlap syndrome]. / Multiples Autoimmunsyndrom. Assoziation eines Reynolds-Syndroms (akrale Sklerodermie, primär biliäre Zirrhose, Sjögren-Syndrom) mit einem Lupus erythematodes/Lichen-ruber-planus-Overlap-Syndrom.

A female patient presented with acral scleroderma, Sjögren syndrome, antibodies specific for primary biliary cirrhosis and clinical as well as histological features of lichen planus and subacute lupus erythematosus. In addition an euthyroid Hashimoto thyroiditis was found. Her findings correspond to type II of the multiple autoimmune syndrome (MAS) and can be described as an association of Reynolds syndrome and the lupus erythematosus/lichen planus-overlap syndrome.

Adrenomedullin: expression and possible role in human skin and hair growth.

BACKGROUND: Adrenomedullin (AM) is a regulatory peptide that is synthesized and secreted by a wide number of cells and tissues. AM is a potent vasodilator, but also exerts other functions, such as regulating cell growth and antimicrobial defence. Two receptors, L1 and calcitonin receptor-like receptor (CRLR), which are able to bind AM, have been cloned and characterized. OBJECTIVES: To investigate expression of AM protein and its receptors in human skin and during different stages of the human hair cycle and, moreover, because of the suggested antimicrobial function of AM in skin, to investigate AM immunoreactivity (IR) in inflammatory acne lesions compared with healthy pilosebaceous follicles. METHODS: We used immunohistochemistry to determine the distribution of AM and its receptors in human skin and during different stages of the human hair cycle. AM IR in inflammatory acne lesions was investigated to evaluate the antimicrobial function of the protein, and hair follicle cultures were performed to examine the role of AM in differentiation and proliferation of hair follicle keratinocytes. RESULTS: Strong IR for AM and its receptors was present in the suprabasal epidermis, in the melanocytes of the epidermis, and in sweat and sebaceous glands. In the hair follicle, AM protein was strongly expressed in the basal and suprabasal layers of the hair bulb and the proximal outer root sheath (ORS). In the distal ORS, AM expression was increasingly suprabasal, especially in proximity to the bulge region where the basal cell layer was free of IR. IR for the CRLR revealed a similar expression pattern to that seen for AM. In contrast, L1 IR showed a suprabasal pattern of IR throughout the ORS. Similar expression of AM and its receptors was observed in catagen and early anagen follicles. AM expression was not markedly upregulated in acne lesions, suggesting a minor role for this antimicrobial peptide in acne. Despite its well-documented mitogenic effects, particularly in oral and skin keratinocytes, AM had no significant effect on hair follicle growth in vitro. CONCLUSIONS: AM and its receptors are expressed in human hair follicles, and both AM and its receptors are colocalized in the same compartments and cell types of the skin. This finding is consistent with the proposed autocrine/paracrine mechanism in the physiology of AM.

Genetic analysis of a severe case of Netherton syndrome and application for prenatal testing.

Netherton syndrome (NS) is a rare autosomal recessive disease with variable expression. It is defined by a triad of symptoms: congenital ichthyosiform erythroderma, trichorrhexis invaginata and atopy. Recently, genetic linkage has been established to the SPINK5 gene locus on chromosome 5q32 encoding the serine protease inhibitor LEKTI. In this study, we present a recurrent homozygous mononucleotide deletion (153delT) resulting in a severe case of NS exhibiting exfoliative erythroderma with lethal outcome at the age of 4 months and its application in prenatal testing in a subsequent pregnancy of the mother.

A premature stop codon mutation in the 2B helix termination peptide of keratin 5 in a German epidermolysis bullosa simplex Dowling-Meara case.

Epidermolysis bullosa simplex (EBS) is caused by defective assembly of keratin intermediate filaments in basal keratinocytes and recent studies indicated causal mutations in the keratin KRT5 and KRT14 genes. In this study, we describe a novel KRT5 mutation in a German sporadic case of EBS Dowling-Meara. Transition of G to T (nucleotide position 2334) leads to a premature stop codon (E477stop, residue 93 of the 2B helix) in the last residue of the highly conserved helix-termination peptide K/LLEGE of the 2B rod domain of keratin K5. This represents the first premature stop codon mutation identified within the K/LLEGE motif of any disorder reported so far that is caused by keratin mutations.

Novel K5 and K14 mutations in German patients with the Weber-Cockayne variant of epidermolysis bullosa simplex.

We report novel keratin 5 and 14 gene mutations in four unrelated German families with the localized subtype of the dominantly inherited blistering disease epidermolysis bullosa simplex Weber-Cockayne (MIM# 131800). The mutations are located in the keratin 14 L12 linker region (D273G), the keratin 5 L12 linker (M327K and D328H), and the H1 domain of keratin 5 (P156L). These mutations add to those previously reported and provide further evidence of phenotype-genotype correlations in epidermolysis bullosa simplex subtypes. The above mutations in mildly affected patients underline the relevance of the keratin linker regions for the epidermolysis bullosa simplex Weber-Cockayne phenotype and keratin filament integrity. In addition, they confirm that the gene segments encoding the linker regions represent hotspots for mutations.

Diagnosis and treatment of primary hyperaldosteronism.

OBJECTIVE: To characterize the clinical and laboratory features of primary aldosteronism and to evaluate which diagnostic tests can discriminate surgically curable forms of this syndrome. DESIGN: Retrospective analysis of the following data from 82 patients with primary aldosteronism: blood pressure, serum electrolytes, urinary aldosterone and electrolytes, computed tomographic scans, plasma renin and aldosterone before and during upright posture, atrial natriuretic peptide, and adrenal vein aldosterone and cortisol. Clinical outcomes assessed after treatment included blood pressure, serum electrolytes, and plasma renin activity. RESULTS: Drug therapy was discontinued before diagnostic tests were done in 56 of 82 patients (34 with adenomas and 22 with hyperplasia). Compared with patients with hyperplasia, those with adenomas had higher systolic (184 mm Hg and 161 mm Hg, respectively; P < 0.001) and diastolic blood pressures (112 mm Hg and 105 mm Hg; P = 0.03), lower serum potassium levels (3.0 mmol/L and 3.5 mmol/L; P < 0.001), and higher serum CO2 (P = 0.001), atrial natriuretic peptide (P = 0.008), and urinary 18-methyl oxygenated cortisol metabolite levels (P = 0.02). In patients with adenomas, aldosterone secretion lateralized to one adrenal gland and did not increase during the postural stimulation test; preoperative urinary aldosterone levels were correlated with diastolic pressures (r = 0.58; P = 0.001). Hypertension was "cured" postoperatively in approximately 35% of patients with adenomas and those with hyperplasia (P > 0.2) but was "improved" more frequently in those with adenomas (P = 0.002). Cured patients from both groups were younger than those not cured (mean ages, 43 years and 54 years, respectively; P = 0.002) and had lower preoperative mean plasma renin activity (0.17 ng/mL per hour and 0.50 ng/mL per hour; P < 0.001). All patients with adenomas in whom aldosterone secretion lateralized were either cured or improved. CONCLUSION: Of the 51 patients with primary aldosteronism who had adrenalectomy (43 patients with adenomas and 8 with hyperplasia), those most likely to be cured were younger and had lower plasma renin activity. In patients with adenomas who were cured or improved, aldosterone secretion was more likely to lateralize. Tests that distinguished adenomas from adrenal hyperplasia included the postural stimulation test, urinary excretion rates of 18-oxocortisol and 18-hydroxycortisol, and adrenal vein sampling.

Response to the captopril test is dependent on baseline renin profile.

OBJECTIVE: To determine prospectively the relationship between the renin-sodium profile and the renin response to captopril challenge in patients with essential hypertension. DESIGN: A standard captopril test was performed in 108 uncomplicated, untreated hypertensive subjects with normal renal function and urinary sodium excretion in the range 50-240 mmol/day. The subjects were selected from a working population with a low expected prevalence of renovascular disease. METHOD: The captopril test was considered positive if the captopril-induced rise in plasma renin activity met all three criteria established by Müller et al. Patients with a positive test and those meeting only one or two of the three criteria were further investigated for renovascular hypertension by measuring renal venous renins and by digital subtraction intravenous angiography. Renin responses were analyzed according to baseline renin-sodium profile. RESULTS: Nine of 108 subjects had a false-positive captopril test result. Among the subjects with a low or normal renin-sodium profile, 1% (one of 82) had a false-positive result. In contrast, false-positive results were seen in 31% (eight of 26) of high-renin subjects. False-positive test results were not related to urinary sodium excretion or to excessive decrease in blood pressure. The magnitude of the renin response to captopril was strongly and directly related to the baseline plasma renin activity. CONCLUSION: An exaggerated renin response to captopril challenge is common in patients with high-renin essential hypertension. Therefore, in a population with a low probability of renovascular hypertension, caution is recommended in interpreting a positive test result in patients with a high baseline renin.

Hemodynamic responses to verapamil monotherapy in patients with renal disease.

We have explored the effect of verapamil on renal hemodynamics and the renin-aldosterone system in ten patients with chronic renal disease and hypertension before and after 3 months of therapy. The mean +/- SEM glomerular filtration rates were 55 +/- 7 mL/min pre- and 55 +/- 8 mL/min posttherapy; the renal plasma flow was 231 +/- 29 mL/min pre and 244 +/- 35 mL/min posttherapy. The filtration fraction (0.24 pre; 0.23 post) and the renal vascular resistance (492 +/- 144 pre; 422 +/- 101 post) also remained stable with verapamil therapy. Blood pressure was lower after treatment (P less than .02) in 7 of 10 patients. Urinary albumin excretion was reduced only when blood pressure was lowered. Verapamil had a modest effect on the renin-aldosterone axis. While the mean increase in plasma renin activity from a pretreatment value of 1.8 +/- 0.42 ng/mL/h to 2.1 +/- 0.56 ng/mL/h failed to reach statistical significance, the increases in urinary aldosterone excretion from 8.2 +/- 2.2 mg/24 h to 11.1 +/- 2.3 mg/24 h did (P less than .001). Our results demonstrate that verapamil lowered blood pressure without renal hemodynamic compromise in hypertensive patients with chronic renal disease. The antihypertensive response was associated with a rise in urinary aldosterone excretion, with unchanged serum electrolytes. We conclude that verapamil is effective, safe, and well-tolerated in patients with renal impairment and hypertension, and may be suitable for clinical trials evaluating long-term progression of renal disease.

Suppressed aggression accelerates early development of essential hypertension.

Predictors for early development of essential hypertension were identified in a prospective study of 98 normotensive and 23 borderline hypertensive subjects of both sexes aged 18-24 years. Baseline examination included psychological tests as well as resting and stress-induced cardiovascular and neurohormonal measurements. During the 30 (+/- 4 s.d.)-month follow up, 14 out of 98 (14%) initially normotensive subjects developed borderline hypertension, while of 23 borderline hypertensive subjects, 11 (48%) remained in the borderline group (141-159/91-94 mmHg), another five (22%) increased to greater than 160/95 mmHg and seven (30%) normalized blood pressure to less than 140/90 mmHg. In the 98 normotensive subjects, the height of casual systolic blood pressure at entry was the best predictor of subsequent borderline hypertension, correctly classifying 75% of the subjects in a stepwise discriminant analysis. Stress-induced blood pressure responses, together with measures of sympathetic nervous system activity (11%) and psychological factors (6%), were relatively weak predictors of subsequent pressure classification. In the 23 borderline hypertensives, the height of systolic blood pressure induced by mental stress was the single best predictor for sustained borderline or subsequent established hypertension, classifying 74%. When all 121 subjects were taken together, the greatest increases in blood pressure were found in those subjects who had suppressed aggression, particularly those who also had normal-high or borderline blood pressure at entry. Thus, suppressed aggression emerged as a superimposed permissive factor for a steeper trajectory or acceleration of early development of hypertension.

Characterization of auscultatory gaps with wideband external pulse recording.

Three types of auscultatory gaps, called G1, G2, and G3, that occur during blood pressure measurement have been identified by using wideband external pulse recording. We have previously shown that the wideband external pulse recorded during cuff deflation can be separated into three components (K1, K2, and K3), one of which (K2) is closely related to the Korotkoff sound. G1 occurs with cuff pressure just below systolic and is characterized by the presence of K1 and K2 with intermittent disappearance of K2. G1 gaps are related to a phasic decrease of arterial (systolic) pressure and were exhibited by 13 of 60 hypertensive patients. G2 gaps are related to a phasic increase of arterial (diastolic) pressure, occur when cuff pressure is just above diastolic, and are characterized by the presence of K1, K2, and K3 with intermittent disappearance of K2. Seven of 60 hypertensive patients exhibited a G2 gap. G3 gaps occur with cuff pressure between systolic and diastolic and are characterized by an underdeveloped or blunted K2 signal. Three of 60 hypertensive patients exhibited a G3 gap. The identification of auscultatory gaps in relation to the wideband external pulse provides a qualitative measure of their existence, can be of significant value in better understanding aspects of the auscultatory blood pressure measurement technique, and provides an objective basis with which to better understand the mechanisms that cause them.

Psychosomatic factors in borderline hypertensive subjects and offspring of hypertensive parents.

Psychosomatic factors, sympathoneural and sympathoadrenal as well as cardiovascular mechanisms, were studied in 24 patients 18-24 years of age with borderline hypertension, 50 age-matched normotensive offspring of hypertensive parents, and 49 controls with no family history of hypertension. They were compared by projective and questionnaire-based psychological tests and their circulatory and neurohormonal reactivity to mental (Stroop color-word conflict test and arithmetic test) and physical stressors (orthostasis and bicycle ergometry test) were measured. Borderline hypertensive subjects externalized aggression less (p less than 0.05) but internalized it more (p less than 0.05) and were more submissive (p less than 0.05) when compared with controls. Offspring of hypertensive parents showed a similar but weaker pattern. Both risk groups reported more positive interactions with their parents (genetic risk subjects versus controls, p less than 0.05; borderline hypertensive patients versus controls, p = 0.08) and had higher state-anxiety levels (p less than 0.05). There were more subjective symptoms of beta-adrenergic receptor-mediated functions (e.g., tachycardia, tremor) in borderline hypertensive subjects and offspring of hypertensive parents, elevated heart rates (analysis of repeated measures, p less than 0.001), and enhanced plasma norepinephrine concentrations (p less than 0.05) when compared with controls. These findings in subjects at risk for the development of hypertension suggest that psychosomatic factors and sympathetic overactivity are involved in the early phase of hypertension.

Longitudinal study of the renin-angiotensin-aldosterone system in hypertensive pregnant women: deviations related to the development of superimposed preeclampsia.

A prospective longitudinal study of 25 pregnant women (30 pregnancies) with chronic hypertension, a group prone to development of preeclampsia, was conducted to explore the relationship between the renin-angiotensin-aldosterone system and the development of superimposed preeclampsia. In women with chronic hypertension in whom preeclampsia did not develop (17 pregnancies), blood pressure decreased and the renin-angiotensin-aldosterone system was stimulated, beginning in the first trimester and continuing throughout pregnancy as found previously in normotensive pregnant women (n = 58). Plasma estradiol and progesterone levels also increased progressively. In women with chronic hypertension in whom preeclampsia developed (13 pregnancies), blood pressure decreased and the renin-angiotensin-aldosterone system was stimulated in the first trimester as in the other groups. However, later in pregnancy significant differences were observed. Blood pressure began to rise in the second trimester. Initially the renin-angiotensin-aldosterone system remained stimulated, but in the early third trimester, when preeclampsia was diagnosed, plasma renin activity and urine aldosterone excretion decreased, and atrial natriuretic factor increased. These data provide information that may be useful in the recognition of superimposed preeclampsia, and in the investigation of its pathogenesis.

Effects of psychological and physical covariates on plasma catecholamines in borderline hypertensives and offspring of hypertensive parents.

The interpretation of plasma catecholamine measurements may be influenced by psychological and physical factors. Therefore, catecholamine concentrations were adjusted for between-subject differences by the following possible confounding factors, i.e. body-mass index, individual maximal physical work capacity, urinary sodium excretion rates and anxiety score. Subjects were 24 borderline essential hypertensives, aged 18-24 years, 50 age-matched normotensive offspring of hypertensive parents and 49 controls with no family history of hypertension studied at rest and during mental stressors (Stroop colour-word conflict test, mental arithmetic). Borderline hypertensives had consistently higher adjusted venous noradrenaline concentrations than control subjects (p less than 0.05). Adjusted plasma adrenaline concentrations were higher in borderline hypertensive subjects than in offspring of hypertensive parents during supine rest. Despite its limitations, venous plasma noradrenaline concentrations when adjusted for work capacity, body-mass, sodium excretion and anxiety suggest enhanced sympatho-neural activity in young borderline essential hypertensives.

Mechanisms of action and clinical use of calcium antagonists in hypertension.

Calcium antagonists are potent arterial vasodilators that do not lead to relevant chronic sympathetic reflex activation and sodium and volume retention. This favorable hemodynamic profile renders them suitable for monotherapy of hypertension in which they can reduce the calcium influx-dependent functional component of elevated vascular resistance that may be enhanced by altered vascular muscle cation handling and increased intracellular free calcium concentrations. Clinical studies have proved their efficacy, safety, and good tolerability alone or in combination with other drugs in uncomplicated hypertension in which they are particularly effective in older, low renin, and possibly, black patients. These properties and their efficacy in the treatment of severe and accelerated hypertension or hypertensive emergencies make them a valuable addition to already available drug therapy.