Influence of antihypertensive therapy with cilazapril and hydrochlorothiazide on the stiffness of the aorta.

The purpose of this study was to examine the effects of the angiotensin-converting enzyme (ACE) inhibitor cilazapril on the elastic properties of the aorta. A standard diuretic antihypertensive drug, hydrochlorothiazide, served for comparisons. Increased aortic stiffness leads to a reduction of the buffering windkessel function and is a major component in the pathophysiology of systolic hypertension, inducing an increase in left ventricular afterload and arterial pulsatile stress as well as a decrease in the subendocardial blood supply. Stiffness of arteries increases with age and blood pressure, and depends on the functional elastic structures of the aortic wall. ACE inhibitors have been shown to directly influence elastic properties of peripheral arteries. Seventeen patients with mild to moderate essential hypertension (age 45-67 years) were treated for 3 months double-blind randomized with either cilazapril (C) 5 mg daily (n = 9) or hydrochlorothiazide (HCTZ) 25 mg daily (n = 8). Aortic elastic properties were noninvasively assessed by measurement of pulse wave velocity along the aorta at rest and during isometric handgrip stress. Accelerated pulse wave velocity indicates elevated arterial stiffness and vice versa. A pressure standardized index of aortic cross-sectional distensibility (2 m) was calculated from arterial mean pressure and pulse wave velocity. Compared with pretreatment values, both therapies significantly reduced blood pressure and pulse wave velocity at rest (C: 9.4 +/- 0.9 vs. 7.7 +/- 0.7 m/sec; HcTZ: 8.9 +/- 0.3 vs. 7.8 +/- 0.4 m/sec; means +/- SEM p < 0.05). During isometric stress only C showed a significant decrease in pulse wave velocity (C: 11.3 +/- 0.8 vs. 9.1 +/- 0.8 m/sec; HCTZ: 9.9 +/- 0.5 vs. 9.0 +/- 0.5 m/sec; means +/- SEM p < 0.05). The index 2m at rest and during handgrip increased significantly (p < 0.05) after C but not after HCTZ. With cilazapril we obtained steeper slopes for the treatment-induced reductions in blood pressure and pulse wave velocity for both rest and handgrip stress values. Correlation of the data at rest and during stress revealed a direct relationship between blood pressure and pulse wave velocity. HCTZ linearly extended the relation observed before treatment toward lower values of blood pressure and corresponding pulse wave velocity without changing the relation per se. Cilazapril, in contrast, moved the relation between these variables and decelerated the pulse wave velocities to a greater extent than would have been expected from the corresponding blood pressure reduction (delta approximately 1 m/sec). These results in patients with mild to moderate essential hypertension support the idea that ACE inhibitors, in addition to reducing blood pressure, may exert an additional hemodynamic effect in improving the elastic properties of the aorta.

Non-invasive assessments of compliance of the aortic wind-kessel in man derived from pulse pressure/storage volume ratio and from pulse wave velocity.

Two noninvasive methods for assessment of the compliance (1/E') of the aortic windkessel in man are presented and were tested for their ability to detect increases in stiffness of the aorta induced by atropine (0.012 and 0.024 mg/kg sequentially) in the presence and absence of a beta-blockade with propranolol 240 mg (n = 9). Method A, based on the calculation of the relation between pulse pressure and systolic storage volume of the aorta, requires measurement of blood pressure, systolic and diastolic time intervals and stroke volume. Method B, based on measurement of pulse wave velocity along the aorta also requires several anthropometric data (body surface area, age). Both methods were able to detect a dose-dependent increase in E' following atropine injections; method A has greater relative changes than method B. The average maximal increases were 90 and 40 percent of the baseline before atropine. The daily baselines of E' averaged 0.6 Torr x cm-3 for method A and 0.9 Torr x cm-3 for method B. Propranolol itself did not influence E' but dampened the atropine effects. The results from method A and B were correlated with r = 0.70 and 0.60 resp. (p < 0.01). The results suggest the use of these relatively simple techniques for evaluation of aortic compliance under influence of varying pathophysiological conditions or/and pharmacological interventions.

[Correlations of homeostatic disorders of tubule function, type of clinical course of chronic glomerulonephritis and histologic changes in the diagnosis of tubulo-interstitial lesions]. / Zusammenhänge zwische den homöostatischen Tubulusfunktionsstörungen, dem klinischen Verlaufstyp der chronischen Glomerulonephritis und den histologischen Veränderungen für die Diagnostik tubulointerstitieller Läsionen (tiK).

In 366 patients with bioptical verified and functional compensated chronic glomerulonephritis the relations between the clinical course types of glomerulonephritis according to Ratner, the histological changes and the tubular homoeostatic parameters of renal function, respectively, were investigated. A reliable connection was found between the clinical course type and special tubular functional parameters. With reference to histological changes the occurrence of a tubulo-interstitial lesion (tiK) is the cause of an excessive disturbance of the renal tubular function. Independently of this, however, the clinical course type of chronic glomerulonephritis may be responsible for the pathological reactive failure of tubular functional parameters. In the case of renal tubular dysfunction in the active nephritic type (ANT) and the nephrotic type with hypertension (NHT), respectively, the occurrence of a tik is much likely. By the lack of reno-tubular dysfunction in ANT and NHT a tik be cannot excluded. In contrast to this, in the inactive nephrotic type (INT) and the nephrotic type without hypertension (NHT), respectively, a tik be can excluded by lack of tubular dysfunction. On the other side, a tubular dysfunction in these groups is not a certain proof of a tik.

[Recommendations for a clinical classification of chronic glomerulonephritis]. / Vorschlag zur klinischen Klassifizierung der chronischen Glomerulonephritis.

As a result of the long-term treatment of 360 patients with histologically ascertained glomerulonephritis including 41 dead patients who had suffered from uraemia a clinical classification of the chronic glomerulonephritis (Ratner, M.) is presented. In detail 5 types of clinical course are characterized: Nephritic types of course: maximally active nephritic type of course, active nephritic type of course, inactive nephritic type of course. Nephrotic types of course: nephrotic type of course without hypertension, nephrotic type of course with hypertension. The elaborated clinical classification allows conclusions to underlying renal histology, tendency of the progression of the disease and prognosis, including survival time.

[New results concerning the effectiveness of therapy of chronic glomerulonephritis. Results of cytostatics-anticoagulants-aggregation inhibitors, cystostatics-anticoagulants-aggregation inhibitors-prednisone and cystostatics-prednisone therapy, derived from a retrospective study]. / Neue Ergebnisse zur Effektivität der Therapie der chronischen Glomerulonephritis. Resultate der Zytostatika-Antikoagulantien-Aggregationshemmer (ZAA)-, Zytostatika-Antikoagulantien-Aggregationshemmer-Prednison (ZAAP)- und Zytostatika-Prednison (ZP)-Therapie im Ergebnis einer retrospektiven Studie.

The indication and effectiveness of the immunosuppressive therapy of chronic glomerulonephritis is now as ever controversial. As a result of a retrospective therapy study in an at least one-year therapy with cytostatics, thrombocyte aggregation inhibitors and anticoagulants (CAA-therapy, n = 27), additional prednisone therapy (CAAP-therapy, n = 95) and cytostatic-prednisone therapy (CP-therapy, n = 33) we find favourable results for the CAA/CAAP-therapy in the nephrotic syndrome and glomerulonephritides with distinct clinical exacerbation also in sclerosations in histology. Clinically inactive nephritides with exclusive urinary findings and sclerosations cannot be influenced therapeutically.

[Treatment of hip joint dislocation with the Hanausek apparatus]. / Die Behandlung der Hüftgelenksluxation mit dem Hanausek-Apparat.

The Hanausek apparatus has been used for reposition and retention of luxation of the hip joint in the Orthopädische Klinik Hessisch Lichtenau in 37 cases aged up to 2 years, if there was no hindrance of reposition in arthrography. It is a functional method which avoids the extreme Lorenz position that is claimed to endanger the caput femoris respecting necrosis. In a retrospective roentgenological observation it became evident, that the method of Hanausek leads generally to a good development of the acetabulum. The rate of necrosis in our patients was high (17%). Our patients started treatment later (38% aged more than one year). 2/3 of the patients had a high luxation of the hip joint.

[Diagnosis and therapy of chronic glomerulonephritis in long-term follow-up]. / Diagnostik und Therapie der chronischen Glomerulonephritis (GN) im Langzeitverlauf.

Patients with bioptically ascertained glomerulonephritis of the years 1969-1981 were examined. At the time of the kidney biopsy etiology, onset of the disease and data of the findings were evaluated. Moreover, in 160 out of 300 patients after-examinations were performed. Especially also the examination of patients with erythrocyturia was carried out with the help of the phase contrast microscopy. In a second part of the examinations which we report on 2 therapy studies were performed. In the first therapy study the effectiveness of the therapy with prednisolone (n = 33), prednisolone + cytostatic drug (n = 43) as well as the indomethacin treatment (n = 52) in patients with and without nephrotic syndrome was examined. We found that an initial prednisolone dose of more than 50 mg/die for at least over 1 month is more successful than a low prednisolone dose. Indomethacin has no clinically provable therapeutic effect in the nephrotic syndrome. In normal renal function the duration of the disease has no ascertained influence on the results of the therapy. In the second therapy study the effectiveness of the CAA- (n = 27) and the CAAP-therapy, respectively, (n = 98) (cytostatic drugs, anticoagulant drugs, thrombocyte aggregation inhibitors and prednisolone) was investigated. The results of the therapy depending upon the clinical course and the morphological findings revealed that there is an indication to the CAA-CAAP-therapy in nephrotic syndromes in glomerulonephritis with and without sclerosation as well as in glomerulonephritis with relapsing exacerbations with and without sclerosations. No indication for this therapy is given in chronic courses of glomerulonephritis with slight proteinuria and in nephrotic syndromes with hypertension.

Tubular function disturbances in chronic glomerulonephritis and their significance for identifying tubulointerstitial lesions.

The tubular and tubulointerstitial renal functions of 237 patients with chronic glomerulonephritis and functional compensation corresponding to their plasma creatinine levels were investigated and the results were compared with the light microscopic findings obtained by examination of kidney interstices obtained by biopsy. Pronounced structural interstitial lesions (TiC) were found in 30% of the cases. Investigation of the predictive values of tubular function data in respect of the presence or exclusion of TiC showed that, although individual parameters of the renal function permit the exclusion of TiC disturbances with a high degree of certainty, the diagnostic value can be enhanced by considering pairs of such parameters. Five parameter combinations were found to have the highest predictive value regarding the diagnosis of TiC. These were disturbed concentration capacity accompanied by reduced ammonia excretion or total acid excretion, reduced water diuresis accompanied by disturbed ammonia excretion or total acid elimination; and, finally, the total acid excretion and maximum dilution capacity. The highest predictive values for the exclusion of TiC are shown by inconspicuous concentration capacity accompanied by normal ammonia excretion, total acid excretion, water diuresis, free water clearance or urine dilution capacity.

[Results of immunosuppressive therapy of chronic glomerulonephritis in 400 patients]. / Ergebnisse der immunsuppressiven Therapie der chronischen Glomerulonephritis bei 400 Patienten.

For the judgment of the success of the immunosuppressive therapy of chronic glomerulonephritis 400 patients (242 males and 158 females) at an average age of 31.2 years were examined after an average duration of treatment of 31.9 months. Apart from the renal function (serum creatinine), the histological and immunohistological form of the glomerulonephritis for the valuation further clinico-paraclinical data were taken into consideration: proteinuria, nephrotic syndrome, arterial hypertension and the combination of nephrotic syndrome and arterial hypertension. At the beginning of the treatment 293 of 400 patients (73.2%) had a normal renal function, 107 of 400 patients (26.8%) were initially renal-insufficient. 16 of 400 patients (4.0%) had additionally a pyelonephritis and 12 of 400 patients (3.0%) had a lupus nephritis. 27 of 400 patients (6.9%) developed a terminal renal insufficiency after an average duration of observation of 40.5 months. Complications caused by therapy were registered in 104 of 400 patients (26.0%). Recommendations for the present therapy of chronic glomerulonephritis are formulated.

[Correspondence of functional and structural findings in tubulo-interstitial disorders in chronic glomerulonephritis]. / Zur Ubereinstimmung funktioneller und struktureller Befunde der tubulo-interstitiellen Störung bei chronischer Glomerulonephritis.

In 237 patients with chronic glomerulonephritis and according to the serum creatinine level of functional compensation tubular and tubulointerstitial renal functions, respectively, were investigated and compared with the light-microscopic findings of the renal interstice. A distinct structural tubulointerstitial lesion (tiK) was found in 30%. The diagnostic predictivity for the recognition and the exclusion of the tiK was tested for single or paired data of the renal function. As a result it is possible with a suitable combination of parameters in on an average more than 80% of the cases to establish or to exclude function-diagnostically a tubulointerstitial structural lesion even in still inconspicuous creatinine values. From the clinical point of view thus the information value of functional diagnostic investigations of the renal water treatment is confirmed (concentration power, dilution ability, water diuresis), in which case the differentiated test of the renal acidification may supplement the informations about the tiK-situation.

[Methodologic references for clinical function diagnosis of glomerular permeability selectivity by molecular wight related protein analysis and additional para-aminohippuric acid load]. / Methodologische Hinweise zur klinischen Funktionsdiagnostik der glomerulären Permselektivität durch molekulargewichtsbezogene Proteinanalyse und zusätzlicher Paraamonohippursäure-Belastung.

Glomerular perm selectivity can be approximately estimated from the apparent glomerular protein clearance in terms of molecular weight since the relative protein clearance is approximately identical with the corresponding screen coefficient relation. Systematic relativization of individual protein clearances by reference to albumin (or transferrin) clearance requires the application of special calculations to find out the regression coefficients relevant to functional diagnosis. A PAH load influences tubular protein reabsorption so that the clearance of higher-molecular proteins (IgA alpha 2-macroglobuli, IgM) rises. Taking the changes in protein clearance under renotubular PAH load into account allows a more precise estimation of glomerular permeability to be made, in comparison with protein analyses not using PAH load.

[Complications in the treatment of chronic glomerulonephritis]. / Komplikationen bei der Therapie der chronischen Glomerulonephritis (GN).

In a retrospective study involving 97 patients with histologically confirmed glomerulonephritis the complications which led to the breaking off or changing of an immunosuppressive therapy [Prednison monotherapy (n = 39), Prednison cyclophospohamide therapy (n = 13), Prednison azathioprin therapy (n = 49), Indometazin therapy (n = 25)] were examined. Of 97 patients treated repeatedly over long periods, 22 suffered complications which caused the therapy to be broken off or changed. Because of the risk involved, immunosuppressive therapy of glomerulonephritis should only be practised by institutions specializing in nephrology.

Morphologic and functional tubular changes in chronic glomerulonephritis.

In 135 patients with different glomerular diseases but normal glomerular filtration rates (CCr and In = 103 +/- 2ml/min) correlations between morphological tubular lesions (tic) and changes in tubular function were investigated. Between the extent of tubular lesions and the impairment of specific tubular functions (formula; see text) exists a highly significant correlation. The combined diminution in Uosmmax and UNH4 + V reflects in 72 per cent the appearance of a severe tubular lesion and should be used for its clinical recognition.

[New aspects of steroid therapy of glomerulonephritis]. / Neue Aspekte der Steroidtherapie der Glomerulonephritis.

The results of a 6-month Prednisone therapy (initial 60 mg/d with later reduction of dose) are given as the immediate results of therapy (after 6 months in 128 patients) and as a late result (after 11 years in 107 patients). The course is evaluated on the basis of clinical symptoms. The early effect proved to be an improvement in 2/3 of all cases, whereby 22% were total remissions. In the late results patients with primary total remission showed the best functional results. This therapy is justified in nephrotic, proteinuric-hypertonic, purely proteinuric and proteinuric-haematuric forms of mesangioproliferative glomerulonephritis.

Stimulation of heparan sulphate synthesis in cultured rat hepatocytes by (+)-catechin.

The secretion of heparan sulphate by cultured rat hepatocytes was increased in the presence of (+)-catechin. The increase was due to a new species of heparan sulphate that lacked the carbohydrate-protein linkage between xylose and serine in normal heparan sulphate proteoglycan. The mean molecular weight of this heparan sulphate varied between 6300 and 9500, was not affected by treatment with alkali or Pronase and was 2-3-fold lower than that of chains released from heparan sulphate proteoglycan. After digestion with Pronase, only a minor fraction of chains contained serine, and after treatment with alkali and NaB3H4 reduction less than 5% of the chains exposed [3H]xylitol at the reducing terminals. These results suggested that (+)-catechin or metabolites of it acted as acceptors of heparan sulphate synthesis. In cultures treated wih cycloheximide, synthesis of heparan sulphate decreased to less than 5%. (+)-Catechin could restore the heparan sulphate synthesis to almost normal values. The (+)-catechin-induced heparan sulphate was secreted. Only a small fraction was incorporated into the plasma membrane or other cellular compartments. This may indicate that the protein core is essential for association of heparan sulphate with cellular compartments.

[DNCB-skin specimens for immunodiagnosis]. / DNCB-Hautproben zur Immundiagnostik.

By epicutaneous skin test by means of 1-monochlorine-2,4-dinitrobenzene (DNCB) the primary cell-conditioned immunity is induced and is provable by the allergic skin reaction of late type. The examination of 125 clinically healthy persons of either sex at the age of 17-57 years confirms the suitability of self-produced, welded into foil skin test plasters layered with DNCB in various stages of concentration for clinical use. A 48-hour skin contact with 0.049 molar DNCB-solution (1,000 microgram DNCB: 100 microliter Ol. oliv.) leads to a late reaction in 84% of the cases, in the repeated case in 98% of the cases. The valuation of the eczema-typical symptoms is suitable for the characterization and quantification. There were no differences in age and sex. Ultrastrong reactions were not registered.

Initiation of altered heparan sulphate on beta-D-xyloside in rat hepatocytes.

Inhibition of protein synthesis by cycloheximide 10(-3)M reduced the incorporation of [35S]sulphate into heparan sulphate to about 5% of untreated hepatocytes. Addition of rho-nitrophenyl beta-D-xyloside could partially revert this inhibitory effect. The sulphated material isolated from the cell layer or secretions of hepatocytes grown in presence of cycloheximide and rho-nitrophenyl beta-D-xyloside were shown to be mostly free heparan sulphate chains not bound to core protein. Covalent association of beta-xylosides to the heparan sulphates was demonstrated for heparan sulphate synthetized in the presence of [35S]sulphate, cycloheximide and the fluorogenic 4-methylumbelliferyl beta-D-xyloside. Beta-Xylosides served as an initiator of heparan sulphate chain synthesis in rat hepatocytes only in the absence of protein synthesis. Heparan sulphates primed on artificial beta-xylosides are slightly smaller in molecular size and are more sulphated than chains linked to core protein.

[Relationship between lead concentration in the air and blood lead levels of people living and working in the centre of a city (Frankfurt blood lead study). II. Correlations and conclusions (author's transl)]. / Uber den Zusammenhang von Luftbleikonzentration und Bleigehalt des Blutes von Anwohnern und Berufstätigen im Berngebiet einer Grossstadt (Blutbleistudie Frankfurt). II. Korrelationen und Konklusionen.

The correlation analysis of the relationship between blood lead levels and lead-in-air concentrations measured in three winter periods showed a highly significant association despite a generally loose dependence of the variables. The regression equations clearly show that there would be a finite residual blood lead value even with completely lead-free air. In the case of the populations exposed to motor traffic in this study, this residual blood lead value is 80--90% of the initial value prior to the decrease in immission. The regression equations, statistically yield results which compare convincingly with ones obtained from model calculations based on studies of metabolism and respiratory physiology. The correlation between the observed changes in blood lead and the initial absolute values of blood lead concentration demonstrates with high statistical certainty that the higher the initial level, the greater was the observed change. This type of association also implies that there is a lower limit value of blood lead below which the decrease in blood lead changes to an increase despite reduction of lead-in-air.

Regulation of heparan sulphate metabolism by adenosine 3':5'-cyclic monophosphate in hepatocytes in culture.

Freshly isolated rat hepatocytes maintained as monolayers in a serum-free medium synthesize sulphated glycosaminoglycans, most of which behave as heparan sulphate and are mainly distributed into intracellular compartments. Cyclic AMP, dibutyryl cyclic AMP, glucagon, noradrenaline, prostaglandin E(1), and theophylline, all drugs and hormones known to increase intracellular cyclic AMP concentrations, decreased the incorporation of (35)SO(4) (2-) into heparan sulphate of intra-, extra- and peri-cellular pools. The inhibition mediated by dibutyryl cyclic AMP was dose-dependent and observed as early as 2h after exposure to the drug. In the presence of 1mm-dibutyryl cyclic AMP, incorporation of (35)SO(4) (2-) or [(14)C]glucosamine into heparan sulphate was decreased to 40-50%, suggesting that dibutyryl cyclic AMP interfered with the synthesis of heparan sulphate. This was further supported by pulse-chase experiments, where dibutyryl cyclic AMP had no effect on the degradation of sulphated glycosaminoglycans. Heparan sulphates synthesized and secreted into the extracellular pool in the presence of dibutyryl cyclic AMP were smaller in size, whereas the degree of sulphation and molecular size of the heparan sulphate chains released by beta-elimination from these proteoglycans were not different from control values. In the presence of 1mm-cycloheximide, (35)SO(4) (2-) incorporation was decreased to 5%. Addition of p-nitrophenyl beta-d-xyloside, an artificial acceptor of glycosaminoglycan chain synthesis, enhanced this incorporation to 18%. Dibutyryl cyclic AMP did not have any inhibitory effect on the synthesis of chains initiated on p-nitrophenyl beta-d-xylosides. Incorporation of [(3)H]serine into heparan sulphate was not affected by dibutyryl cyclic AMP, whereas the degree of substitution of serine residues with heparan sulphate chains was less in heparan sulphate synthesized in the presence of dibutyryl cyclic AMP, suggesting that cyclic AMP exerts its effect on the metabolism of sulphated glycosaminoglycans by affecting the transfer of xylose on to the protein core.