Interferon ß-1a reduces increased interleukin-16 levels in multiple sclerosis patients.

OBJECTIVES: There is convergent evidence for an important role of interleukin-16 (IL-16) in the pathogenesis of multiple sclerosis (MS). IL-16 serves as a chemoattractant for different immune cells that are involved in developing lesions. Here, we compared IL-16 levels of MS patients and controls and addressed the long-term effect of IFN-ß, the most common immunomodulatory MS therapy, on IL-16 serum levels in MS patients over 2 years. Beyond this, we analysed the expression of IL-16 in two CD4(+) T-cell subsets, Th1 and Th17 cells, which are important autoimmune mediators and affected by IFN-ß treatment, derived from myelin-specific T-cell transgenic mice. MATERIALS AND METHODS: IL-16 serum levels of 17 controls and of 16 MS patients before therapy and at months 1, 2, 3, 6, 9, 12 and 24 during IFN-ß1a therapy were determined by ELISA. MRI was performed before therapy, at months 12 and 24. IL-16 expression of in vitro differentiated murine myelin oligodendrocyte glycoprotein (MOG)-specific Th1 and Th17 cells was quantified by real-time PCR. RESULTS: Before therapy, MS patients showed significantly elevated IL-16 levels compared with controls irrespective of disease activity determined by MRI. Therapy with IFN-ß1a led to a significant linear decrease in IL-16 serum levels beginning after 2 months. MOG-specific Th17 cells expressed more IL-16 than Th1 cells. CONCLUSIONS: Reduction in increased IL-16 levels may be of relevance for the therapeutic effect of IFN-ß1a in MS. Easily accessible IL-16 serum levels hold a potential as biomarker of treatment efficacy in MS.

Suboccipital neuropathy after bone conduction device placement.

OBJECTIVE: To describe the clinical characteristics of a 70-year-old female with occipital neuropathy following bone conduction device surgery. DESCRIPTION: A 65-year-old woman underwent bone conduction device placement surgery on the left temporal bone. Postoperatively she progressively developed chronic pain at the implantation site. The pain led to minimal neck movement, which resulted in complaints of the shoulder and arm on the left side. She was treated by an orthopaedic surgeon for a frozen shoulder. Pain medication and occipital nerve blocking had no sustained effect on the pain. DISCUSSION: Occipital neuropathy is a syndrome with continuous aching involving the occipital and parietal scalp caused by trauma or peripheral compression of the occipital nerves. The most common causes of occipital neuropathy are probably direct trauma to the nerve and hypertrophic fibrosis of subcutaneous tissue surrounding the nerve. Scar formation after surgery may therefore cause entrapment of the nerve. CONCLUSION: We describe a case of occipital neuropathy as a complication of BAHA surgery.

[Career prospects for ophthalmologists under 49 years old : A survey in Germany from 2022]. / Berufliche Zukunftsperspektive von Augenärzten unter 49 Jahren : Eine Umfrage in Deutschland aus dem Jahr 2022.

OBJECTIVE: The need for care in ophthalmology is constantly increasing due to demographic changes. The study analyzed the current professional situation and future prospects of ophthalmologists under 49 years old. METHODS: The survey of members of the German Association of Ophthalmologists (Berufsverband der Augenärzte Deutschlands) and the German Ophthalmologic Society (Deutsche Ophthalmologische Gesellschaft) was conducted in 2022. All members under the age of 49 years received an online questionnaire on the current professional situation as well as future perspectives (desired working hours, form of organization). The results of the survey were additionally compared with the 2016 survey of the German Association of Ophthalmologists. A similar questionnaire was used at that time. RESULTS: A total of 1014 people participated in the survey (62.7% women, mean age 39.3 ± 8 years, 75.6% specialists). The response rate to the survey was 25%. Specialist practice from 0 to 5 years showed a higher number of employed ophthalmologists (21% self-employed vs. 32% employed); over time the number of self-employed ophthalmologists increased (6-10 years: 40%, > 10 years: 59.3%). Overall, 46% of women were employed in a practice compared with 33% of men. Of the self-employed specialists, 95.9% said they planned to work in the same type of employment in 10 years as currently. Regarding ophthalmologists' career future, the other employment types showed a desire to move to independent practice. Compared to the 2016 survey, gender differences related to the current type of employment were evident. The number of self-employed women decreased from 43% to 26% and self-employed men decreased from 63% to 39%. The number of ophthalmologists in ambulatory healthcare centers was doubled compared to 2016. Ophthalmologists reported similar future perspectives at both survey times. CONCLUSION: The results of the survey of ophthalmologists under 49 years in Germany showed similar perceptions as in 2016. It became clear that the desire to be self-employed in 10 years is very high; however, ophthalmologists expected large practices or medical care centers to prevail in the market. The number of self-employed doctors is decreasing and the desire for self-employment is difficult to realize.

Dynamic prediction of mortality in COVID-19 patients in the intensive care unit: A retrospective multi-center cohort study.

Background: The COVID-19 pandemic continues to overwhelm intensive care units (ICUs) worldwide, and improved prediction of mortality among COVID-19 patients could assist decision making in the ICU setting. In this work, we report on the development and validation of a dynamic mortality model specifically for critically ill COVID-19 patients and discuss its potential utility in the ICU. Methods: We collected electronic medical record (EMR) data from 3222 ICU admissions with a COVID-19 infection from 25 different ICUs in the Netherlands. We extracted daily observations of each patient and fitted both a linear (logistic regression) and non-linear (random forest) model to predict mortality within 24 h from the moment of prediction. Isotonic regression was used to re-calibrate the predictions of the fitted models. We evaluated the models in a leave-one-ICU-out (LOIO) cross-validation procedure. Results: The logistic regression and random forest model yielded an area under the receiver operating characteristic curve of 0.87 [0.85; 0.88] and 0.86 [0.84; 0.88], respectively. The recalibrated model predictions showed a calibration intercept of -0.04 [-0.12; 0.04] and slope of 0.90 [0.85; 0.95] for logistic regression model and a calibration intercept of -0.19 [-0.27; -0.10] and slope of 0.89 [0.84; 0.94] for the random forest model. Discussion: We presented a model for dynamic mortality prediction, specifically for critically ill COVID-19 patients, which predicts near-term mortality rather than in-ICU mortality. The potential clinical utility of dynamic mortality models such as benchmarking, improving resource allocation and informing family members, as well as the development of models with more causal structure, should be topics for future research.

Structure of the regulatory complex of Escherichia coli IIIGlc with glycerol kinase.

The phosphocarrier protein IIIGlc is an integral component of the bacterial phosphotransferase (PTS) system. Unphosphorylated IIIGlc inhibits non-PTS carbohydrate transport systems by binding to diverse target proteins. The crystal structure at 2.6 A resolution of one of the targets, glycerol kinase (GK), in complex with unphosphorylated IIIGlc, glycerol, and adenosine diphosphate was determined. GK contains a region that is topologically identical to the adenosine triphosphate binding domains of hexokinase, the 70-kD heat shock cognate, and actin. IIIGlc binds far from the catalytic site of GK, indicating that long-range conformational changes mediate the inhibition of GK by IIIGlc. GK and IIIGlc are bound by hydrophobic and electrostatic interactions, with only one hydrogen bond involving an uncharged group. The phosphorylation site of IIIGlc, His90, is buried in a hydrophobic environment formed by the active site region of IIIGlc and a 3(10) helix of GK, suggesting that phosphorylation prevents IIIGlc binding to GK by directly disrupting protein-protein interactions.

Cloning human fetal gamma globin and mouse alpha-type globin DNA: preparation and screening of shotgun collections.

Shotgun collections of Charon 3A bacteriophages containing Eco RI fragments of human and mouse DNA were constructed with the use of in vitro packaging. Plaques were screened by hybridization, and globin-specific clones were isolated from both human (Charon 3AHs51.1) and mouse (Charon 3AMm30.5). The fragments cloned were detected in unfractionated genomic DNA by the Southern method of hybridization.

Charon phages: safer derivatives of bacteriophage lambda for DNA cloning.

The Charon lambda bacteriophages have been developed as vectors for cloning. Their construction incorporates mutations that make them simple to use and also greatly increases their safety for the biological containment of cloned recombinant DNA. Three of the Charon vector phages, 3A, 4A, and 16A, have been certified for use as EK2 vector-host systems, when propagated in bulk in a special bacterial host, DP50SupF. We present here some of the data on which the safety of these systems was evaluated. DNA fragments ranging in size from 0 to 2.2 X 10(4) base pairs can be cloned in these EK2 Charon phages.

Interferon-beta increases BAFF levels in multiple sclerosis: implications for B cell autoimmunity.

B cells are increasingly recognized as major players in multiple sclerosis pathogenesis. The BAFF/APRIL system is crucial for B cell homoeostasis and may drive B cell-dependent autoimmunity. We asked whether this system is affected by Interferon (IFN)-beta therapy. We analysed transcription of the ligands (BAFF, APRIL, TWE-PRIL) and the corresponding receptors (BAFF-R, TACI and BCMA) by TaqMan-PCR ex vivo in whole blood and in immune cell subsets purified from IFN-beta-treated multiple sclerosis patients. Serum BAFF concentrations were determined by ELISA. This cross-sectional study involved 107 donors. IFN-beta therapy strongly induced BAFF transcription proportionally to the IFN-beta biomarker MxA in monocytes and granulocytes in vivo. BAFF serum concentrations were elevated in IFN-beta-treated multiple sclerosis patients to a similar level as observed in SLE patients. In cultured PBMC, neutrophils, fibroblasts and astrocytes, BAFF was induced by IFN-beta concentrations similar to those reached in vivo in treated multiple sclerosis patients. BAFF turned out to be the main regulated element of the BAFF/APRIL system. In untreated multiple sclerosis patients, there was no BAFF increase as compared to healthy controls. Our study reveals a complex situation. We show that IFN-beta therapy induces a potent B cell survival factor, BAFF. However, B cell depletion would be desirable at least in some multiple sclerosis patients. The systemic induction of BAFF by IFN-beta therapy may facilitate the production of various autoantibodies and of IFN-neutralizing antibodies. Individual MS/NMO patients who have major B cell involvement may benefit less than others from IFN-beta therapy, thus explaining interindividual differences of the therapeutic response.

1.8 A crystal structure of the C-terminal domain of rabbit serum haemopexin.

BACKGROUND: Haemopexin is a serum glycoprotein that binds haem reversibly and delivers it to the liver where it is taken up by receptor-mediated endocytosis. Haemopexin has two homologous domains, each having a characteristic fourfold internal sequence repeat. Haemopexin-type domains are also found in other proteins, including the serum adhesion protein vitronectin and various collagenases, in which they mediate protein-protein interactions. RESULTS: We have determined the crystal structure of the C-terminal domain of haemopexin at 1.8 A resolution. The domain is folded into four beta-leaflet modules, arranged in succession around a central pseudo-fourfold axis. A funnel-shaped tunnel through the centre of this disc-shaped domain serves as an ion-binding site. CONCLUSIONS: A model for haem binding by haemopexin is proposed, utilizing an anion-binding site at the wider end of the central tunnel, together with an associated cleft. This parallels the active-site location in other beta-propeller structures. The capacity to bind both cations and anions, together with the disc shape of the domain, suggests that such domains may be used widely for macromolecular recognition.

Glycerol kinase from Escherichia coli and an Ala65-->Thr mutant: the crystal structures reveal conformational changes with implications for allosteric regulation.

BACKGROUND: Glycerol kinase (GK) from Escherichia coli is a velocity-modulated (V system) enzyme that has three allosteric effectors with independent mechanisms: fructose-1,6-bisphosphate (FBP); the phosphocarrier protein IIAGlc; and adenosine nucleotides. The enzyme exists in solution as functional dimers that associate reversibly to form tetramers. GK is a member of a superfamily of ATPases that share a common ATPase domain and are thought to undergo a large conformational change as an intrinsic step in their catalytic cycle. Members of this family include actin, hexokinase and the heat shock protein hsc70. RESULTS: We report here the crystal structures of GK and a mutant of GK (Ala65-->Thr) in complex with glycerol and ADP. Crystals of both enzymes contain the same 222 symmetric tetramer. The functional dimer is identical to that described previously for the IIAGlc-GK complex structure. The tetramer interface is significantly different, however, with a relative 22.3 degrees rotation and 6.34 A translation of one functional dimer. The overall monomer structure is unchanged except for two regions: the IIAGlc-binding site undergoes a structural rearrangement and residues 230-236 become ordered and bind orthophosphate at the tetramer interface. We also report the structure of a second mutant of GK (IIe474-->Asp) in complex with IIAGlc; this complex crystallized isomorphously to the wild type IIAGlc-GK complex. Site-directed mutants of GK with substitutions at the IIAGlc-binding site show significantly altered kinetic and regulatory properties, suggesting that the conformation of the binding site is linked to the regulation of activity. CONCLUSIONS: We conclude that the new tetramer structure presented here is an inactive form of the physiologically relevant tetramer. The structure and location of the orthophosphate-binding site is consistent with it being part of the FBP-binding site. Mutational analysis and the structure of the IIAGlc-GK(IIe474-->Asp) complex suggest the conformational transition of the IIAGlc-binding site to be an essential aspect of IIAGlc regulation.

Crystallization and preliminary X-ray studies of Escherichia coli glycerol kinase.

Escherichia coli glycerol kinase, a major regulatory enzyme which catalyzes the reversible MgATP-dependent phosphorylation of glycerol has been crystallized by the hanging drop vapor diffusion method at room temperature. Three different crystal forms have been obtained in the presence of glycerol and appear to be suitable for X-ray crystallographic studies. Vapor diffusion against 55% ammonium sulfate and 1% beta-octyl glucoside (pH 7.0) yields rhombohedral crystals with space group R32, a = b = 277.1 A, c = 78.7 A (hexagonal indexing) containing a dimer of Mr 112,000 in the asymmetric unit (Vm = 2.64 A3/dalton). Vapor diffusion against sodium chloride in the presence of 10% (w/v) polyethylene glycol (pH 6.5 to 7.0) yields two different crystal forms, both with space group P2(1). The first form has a = 88.1 A, b = 99.3 A, c = 114.6 A, beta = 119 degrees, the second form has a = 92.5 A, b = 117.6 A, c = 108.3 A, beta = 93.64 degrees. Addition of ADP enhances growth of the monoclinic forms. These forms appear to contain an entire tetramer of Mr 224,000 in the asymmetric unit and have Vm values of 2.28 and 2.65 A3/dalton, respectively. All forms diffract to better than 3.0 A resolution while the second monoclinic form diffracts to approximately 1.8 A.

Altered domain closure and iron binding in transferrins: the crystal structure of the Asp60Ser mutant of the amino-terminal half-molecule of human lactoferrin.

The crystal structure of a site-specific mutant of the N-terminal half-molecule of human lactoferrin, Lf(N), in which the iron ligand Asp60 has been mutated to Ser, has been determined at 2.05 A resolution in order to determine the effects of the mutation on iron binding and domain closure. Yellow monoclinic crystals of the D60S mutant, in its iron-bound form, were prepared, and have unit cell dimensions a = 110.2 A, b = 57.0 A, c = 55.2 A, beta = 97.6 degrees, space group C2, with one molecule of 333 residues in the asymmetric unit. The structure was determined by molecular replacement, using the wild-type Lf(N) as search model, and was refined by restrained least-squares methods. The final model, comprising 2451 protein atoms (from residues 2 to 315) one Fe3+ and one CO2-(3), and 107 water molecules, gives an R-factor of 0.175 for all data in the resolution range 20.0 to 2.05 A. The model conforms well with standard geometry, having root-mean-square deviations of 0.014 A and 1.2 degrees from standard bond lengths and angles. The structure of the D60S mutant deviates in two important respects from the parent Lf(N) molecule. At the mutation site the Ser side-chain neither binds to the iron atom nor makes any interdomain contact as the substituted Asp does; instead a water molecule fills the iron coordination site and participates in interdomain hydrogen bonding. The domain closure is also changed, with the D60S mutant having a more closed conformation. Consideration of crystal packing suggests that the altered domain closure is a genuine molecular property but both the iron coordination and interdomain contacts are consistent with weakened iron binding in the mutant. The implications for iron binding in transferrins generally are discussed.

Structure of a stabilizing disulfide bridge mutant that closes the active-site cleft of T4 lysozyme.

The engineered disulfide bridge between residues 21 and 142 of phage T4 lysozyme spans the active-site cleft and can be used as a switch to control the activity of the enzyme (Matsumura, M. & Matthews, B.W., 1989, Science 243, 792-794). In the oxidized form the disulfide increases the melting temperature of the protein by 11 degrees C at pH 2. The crystal structure of this mutant lysozyme has been determined in both the reduced and oxidized forms. In the reduced form, the crystal structure of the mutant is shown to be extremely similar to that of wild type. In the oxidized form, however, the formation of the disulfide bridge causes the alpha-carbons of Cys 21 and Cys 142, on opposite sides of the active-site cleft, to move toward each other by 2.5 A. In association with this movement, the amino-terminal domain of the protein undergoes a rigid-body rotation of 5.1 degrees relative to the carboxy-terminal domain. This rotation occurs about an axis passing through the junction of the amino-terminal and carboxy-terminal domains and is also close to the axis that best fits the apparent thermal motion of the amino-terminal domain seen previously in crystals of wild-type lysozyme. Even though the engineered Cys 21-Cys 142 disulfide links together the amino-terminal and carboxy-terminal domains of T4 lysozyme, it does not reduce the apparent mobility of the one domain relative to the other. The pronounced "hinge-bending" mobility of the amino-terminal domain that is suggested by the crystallographic thermal parameters of wild-type lysozyme persists in the oxidized (and reduced) mutant structures. In the immediate vicinity of the introduced disulfide bridge the mutant structure is more mobile (or disordered) than wild type, so much so that the exact conformation of Cys 21 remains obscure. As with the previously described disulfide bridge between residues 9 and 164 of T4 lysozyme (Pjura, P.E., Matsumura, M., Wozniak, J.A., & Matthews, B.W., 1990, Biochemistry 29, 2592-2598), the engineered cross-link substantially enhances the stability of the protein without making the folded structure more rigid.

Alendronate treatment of established primary osteoporosis in men: results of a 2-year prospective study.

Men with osteoporosis have been neglected in the past, and only a few therapeutic trials have been performed in men. The bisphosphonate, alendronate, has been widely used for the treatment of postmenopausal osteoporosis. This prospective, open label, active controlled, randomized clinical study compared the effects of oral alendronate (10 mg daily) and alfacalcidol (1 microg daily) on bone mineral density (BMD), safety, and tolerability in 134 males with primary established osteoporosis. All men received supplemental calcium (500 mg daily). After 2 yr, alfacalcidol-treated patients showed a mean 2.8% increase in lumbar spine BMD (P < 0.01) compared with a mean increase of 10.1% in men receiving alendronate (P < 0.001). The corresponding changes in femoral neck BMD were +2.2% and +5.2% for the alfacalcidol and alendronate groups, respectively (P = 0.009). The incidence rates of patients with new vertebral fractures were 18.2% and 7.4% for the alfacalcidol and alendronate groups, respectively (P = 0.071). Both therapies were well tolerated. Thus, alendronate produced favorable effects on BMD consistent with the results from another study in male osteoporosis. The average increase rates were higher than with alfacalcidol. Alendronate may be superior to alfacalcidol in the treatment of men with established primary osteoporosis.

Rate of increase in the plasma concentration of nifedipine as a major determinant of its hemodynamic effects in humans.

The relevance of the rate of increase in the plasma concentration of nifedipine for the drug's hemodynamic effect was investigated in healthy volunteers. Nifedipine was given intravenously according to two regimens, each designed to produce the same steady-state concentration, but attained gradually (within 5 to 7 hours) with one regimen and rapidly (within 3 minutes) with the other. The mean steady-state concentrations obtained were 31.7 +/- 5.2 (SD) ng/ml and 29.4 +/- 9.8 ng/ml, respectively (not significant). With the gradual regimen, heart rate was unchanged and diastolic blood pressure was lowered gradually by approximately 10 mm Hg. With the rapid regimen, heart rate increased immediately and remained elevated for the duration of the infusion, whereas diastolic blood pressure did not change significantly. At the end of the gradual-rise regimen, the infusion rate was increased tenfold for 10 minutes, promptly resulting in tachycardia and a paradoxical rise in diastolic blood pressure. These divergent hemodynamic responses of the gradual- and rapid-rise regimens could well be related to differences in baroreceptor activation. It is concluded that the hemodynamic response to nifedipine is influenced by the rate of increase of its concentration in plasma.

Cloning of Epstein-Barr virus (EBV) DNA fragments in pBR32 and Charon3A.

Restriction fragments of Epstein-Barr virus (EBV; B95-8) DNA were cloned in the Tc gene of pBR322 (HindIII-F, -G, -I, -J, -K, -L, and -M) and in Charon3A (EcoRI-GI and -G2). Altogether these cloned fragments covered 39% of the entire viral genome. The cloned EcoRI-G2 fragment of EBV (B95-8) DNA was shown to contain, in addition to HindIII-J, two more HindIII-fragments : HindIII-M, which had not been located on the linkage map of the viral genome (Given and Kieff, 1978) and HindIII-N, which had been unrecognized up to now. The utility of this cloning method is discussed in regard to the detailed mapping of a viral genome and large-scale production of the viral DNA.

Influence of haemodialysis on the pharmacokinetics and haemodynamic effects of nifedipine during continuous intravenous infusion.

The pharmacokinetics and haemodynamic effects of nifedipine were studied in 5 patients on long term haemodialysis. In addition, clearance of the drug on 2 different types of artificial kidneys were measured in vitro. Nifedipine was administered intravenously (1.3 mg/h) from 6 hours before starting haemodialysis to the end of haemodialysis, performed according to the standard protocol of each patient. Before and during haemodialysis, blood samples were taken for determination of free and total plasma nifedipine concentrations. Recovery was determined by measuring nifedipine concentrations in the dialysate. Heart rate and systolic and diastolic blood pressures were determined serially. The haemodynamic changes during nifedipine were compared with those of 3 previous dialysis sessions. Haemodialysis was accompanied by a slight decrease in steady-state nifedipine concentrations. The recovery in dialysate varied between 0.6 and 0.9% of the amount infused during the period of dialysis. Artificial kidney clearance of nifedipine varied between 2.8 and 8.3 ml/min, which was in agreement with in vitro data. Changes in steady-state nifedipine concentrations were most likely due to changes in systemic clearance caused by haemodialysis itself. Systolic and diastolic blood pressure dropped by approximately 15% and 25%, respectively, in comparison with dialysis without nifedipine, but changes in heart rate were not different. It is concluded that nifedipine is poorly dialysable. During haemodialysis, blood pressure is markedly reduced but dose schedules need not to be changed.

Structural Aspects of Plant Ferredoxin : NADP(+) Oxidoreductases.

Ferredoxin reductase (FNR) is ubiquitous among photosynthetic organisms as the enzyme directly responsible for the generation of NADPH. Structural studies over the last 15 years have generated over 30 crystal structures of wild-type and mutant FNRs that have yielded a great deal of insight into its structure-function relations. These insights are summarized and combined to propose a structurally informed cycle for FNR catalysis in vivo.

Fournier's gangrene as first presentation of promyelocytic leukemia.

A 50-year-old male is described who presented with Fournier's gangrene as what is probably the first manifestation of a newly diagnosed acute myelogenous leukemia (AML), promyelocytic type or variant type M3 according to the FAB classification. Despite aggressive fluid resuscitation, tuned infusion of vasoactive drugs, appropriate antibiotics and extensive surgical debridement, the patient died within 24 h as a result of irreversible septic shock.

ACE inhibitors and the kidney. A risk-benefit assessment.

ACE inhibitors effectively reduce systemic vascular resistance in patients with hypertension, heart failure or chronic renal disease. This antihypertensive efficacy probably accounts for an important part of their long term renoprotective effects in patients with diabetic and non-diabetic renal disease. The renal mechanisms underlying the renal adverse effects of ACE inhibitors--intrarenal efferent vasodilation with a consequent fall in filtration pressure--are held to be involved in their renoprotective effects as well. The fall in filtration pressure presumably contributes to the antiproteinuric effect as well as to long term renoprotection. The former is suggested by the positive correlation between the fall in filtration fraction and the reduction in proteinuria found during ACE inhibition. The latter is suggested by the correlation between the (slight) reduction in glomerular filtration rate at onset of therapy and a more favourable course of renal function in the long term. Such a fall in filtration rate at the onset of ACE inhibitor treatment is reversible after withdrawal, and can be considered the trade-off for long term renal protection in patients with diabetic and nondiabetic chronic renal disease. In conditions in which glomerular filtration is critically dependent on angiotensin II-mediated efferent vascular tone (such as a post-stenotic kidney, or patients with heart failure and severe depletion of circulating volume), ACE inhibition can induce acute renal failure, which is reversible after withdrawal of the drug. Systemic and renal haemodynamic effects of ACE inhibition, both beneficial and adverse, are potentiated by sodium depletion. Consequently, sodium repletion contributes to the restoration of renal function in patients with ACE inhibitor-induced acute renal failure. Our the other hand, co-treatment with diuretics and sodium restriction can improve therapeutic efficacy in patients in whom the therapeutic response of blood pressure or proteinuria is insufficient. Patients at the greatest risk for renal adverse effects (those with heart failure, diabetes mellitus and/or chronic renal failure) also can expect the greatest benefit. Therefore, ACE inhibitors should not be withheld in these patients, but dosages should be carefully titrated, with monitoring of renal function and serum potassium levels.