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Biomedical subjects

C Kramers

Publications and source records attributed to C Kramers.

At least 19 recordsLinked to original sources

[A patient who refused treatment after self-poisoning with paracetamol].

Two patients, a 20-year-old man and a 33-year-old woman, were admitted with paracetamol poisoning. Both patients refused treatment initially but eventually complied. The man had a paracetamol concentration of 47.5 mg/l 2.5-5.0 h after ingestion, so antidote treatment was not considered necessary. The woman had a paracetamol concentration of 1.37 mg/l 32 h after ingestion and elevated liver enzymes and was treated with N-acetylcysteine intravenously. Both patients recovered. When a patient refuses treatment, the physician must judge whether the patient is capable of making that decision by himself or herself. In the acute setting of attempted suicide, the patient is either incapable of deciding or there is not enough time to make a proper judgement. This means that consent for treatment should be sought from a legal representative of the patient. If this is impossible and treatment is necessary to prevent serious harm, the physician must judge whether the advantages of treatment outweigh the disadvantages of enforced treatment. If this is the case, as in serious paracetamol poisoning, the patient must be treated against their will, even if it requires sedation.

Acetaminophen↗

Enhanced extracorporeal elimination of valproic acid in overdose.

The treatment of the poisoned patient has been based on three main approaches: use of supportive nonspecific therapy, if available administration of antidotes and removal of the offending drug from the body. Gastric lavage and binding of nonabsorbed drug by activated charcoal are often used in an attempt to eliminate the intoxicating agent from the body. In addition, elimination of already absorbed drug can sometimes be enhanced by the induction of brisk diuresis coupled to manipulation of urine pH (e.g. alkalinise for salicylates) or applying extracorporeal techniques such as haemodialysis, haemofiltration or haemoperfusion. In this issue of the journal Meek et al. describe the application of haemodialysis in a patient with severe valproic acid (VPA) overdose and demonstrate an increased elimination after the start of haemodialysis.

Drug Overdose↗

[Increased serum activity of angiotensin-converting enzyme (ACE): indication of sarcoidosis? A 'Bayesian' approach].

Two patients, a man aged 23 and a woman aged 42 years, complained of fatigue and arthralgia respectively. A particularly high serum activity of angiotensin-converting enzyme (ACE) was established during the diagnostic work-up, although sarcoidosis was considered to be unlikely. This led to a series of diagnostic procedures, some invasive, to confirm the diagnosis of sarcoidosis. The diagnosis was not made in either of these patients. The fatigue appeared to be self-limiting and the arthralgia was due to arthrosis. Eventually it was discovered that these patients had a familial elevation of serum ACE activity. The elevation of ACE levels has limited specificity for sarcoidosis (85%) and is therefore of no value in the diagnostic workup, if the a priori probability for sarcoidosis is low.

Adult↗

[Familial hyperactivity of angiotensin-converting enzyme (ACE)].

An extremely high level of serum angiotensin-converting enzyme (ACE) activity was found in eight individuals, women aged 31, 60, 42 and 67 years, and men aged 50, 47, 23 and 50 years. They had consulted a specialist due to a wide range of non-specific complaints or abnormalities (fatigue, dyspnoea, arthralgia, kidney stones with high urinary calcium, neurological symptoms and an elevated blood alkaline phosphatase activity level). As each of these complaints could be a symptom of sarcoidosis, the ACE activity was measured. However, sarcoidosis was not diagnosed in any of these patients. A subsequent analysis revealed that all eight individuals had family members with a similar elevation of ACE. Therefore, the increase in ACE activity was familial. Patients with this disorder have serum ACE levels of between 3 and 7 times the upper limit of normal, whereas in the case of sarcoidosis, serum ACE levels rarely exceed three times this limit. Familial ACE hyperactivity is not accompanied by clinical symptoms. It is caused by a point mutation in the ACE gene, which results in the cell-bound ACE being more readily loosened from the cell surface into the circulatory system.

Adult↗

Predicting the need for hospital admission in patients with intentional drug overdose.

BACKGROUND: Self-poisoned patients are often admitted to a medical unit. However, often no treatment is given. We have developed a model to predict those patients who will not be treated and how long patients should be observed before this prediction can be safely made. METHODS: In this retrospective study a model to predict treatment was developed based on cases of self-poisoning in 1996 and validated on cases between 1997 and 1999. In a teaching hospital in The Netherlands 299 adults performing 353 episodes of self-poisoning were studied. The main outcome measures were predicted versus initiated medical treatment, time to prediction and time to initiation of treatment. RESULTS: The model predicted that in 51% (156/307) of all autointoxications no treatment would be given. In 2% (6/307) of all cases, treatment was incorrectly not predicted. All but one of these were preventive treatments based on the ingested compound. 4.5 hours after admission no additional patients fulfilled the criteria for prediction of treatment and all treatments were started within 4.5 hours. CONCLUSIONS: In 51% of patients that present with an autointoxication the model accurately predicts that no treatment will be initiated. This decision can be made in the first 4.5 hours after presentation. This model can be used for a first screening of patients. It can also be used as a basis for a further prospective study to establish rational guidelines in the management of these patients.

Adult↗

Point mutation in the stalk of angiotensin-converting enzyme causes a dramatic increase in serum angiotensin-converting enzyme but no cardiovascular disease.

BACKGROUND: Angiotensin-converting enzyme (ACE) metabolizes many small peptides and plays a key role in blood pressure regulation. Elevated serum ACE is claimed to be associated with an increased risk for cardiovascular disease. Previously, two families with dramatically increased serum ACE were described, but no systematic survey of affected individuals was performed, and the molecular background of this trait is unknown. METHODS AND RESULTS: Eight families were identified with autosomal dominant inheritance of a dramatic (5-fold) increase of serum ACE activity. Strikingly, no clinical abnormalities were apparent in the affected subjects. Isolated blood cells were used for genetic and biochemical analysis. The level of ACE expression on the blood leukocytes and dendritic cells and total cell-associated ACE of the affected individuals was similar to that in nonaffected relatives; however membrane-bound mutant ACE was much more efficiently clipped from the cell surface compared with its wild-type counterpart. A point mutation causing Pro1199Leu in the stalk region of the ACE molecule cosegregates with the increase in serum ACE (LOD score, 6.63). CONCLUSIONS: A point mutation in the stalk region of the ACE protein causes increased shedding, leading to increased serum ACE, whereas cell-bound ACE is unaltered, and affected individuals exhibit no clinical abnormalities. These findings qualify the importance of serum ACE and establish a new determinant of ACE solubilization.

Adult↗

Increased shedding of angiotensin-converting enzyme by a mutation identified in the stalk region.

Angiotensin-converting enzyme (ACE), an enzyme that plays a major role in vasoactive peptide metabolism, is a type 1 ectoprotein, which is released from the plasma membrane by a proteolytic cleavage occurring in the stalk sequence adjacent to the membrane anchor. In this study, we have discovered the molecular mechanism underlying the marked increase of plasma ACE levels observed in three unrelated individuals. We have identified a Pro(1199) --> Leu mutation in the juxtamembrane stalk region. In vitro analysis revealed that the shedding of [Leu(1199)]ACE was enhanced compared with wild-type ACE. The solubilization process of [Leu(1199)]ACE was stimulated by phorbol esters and inhibited by compound 3, an inhibitor of ACE-secretase. The results of Western blot analysis were consistent with a cleavage at the major described site (Arg(1203)/Ser(1204)). Two-dimensional structural analysis of ACE showed that the mutated residue was critical for the positioning of a specific loop containing the cleavage site. We therefore propose that a local conformational modification caused by the Pro(1199) --> Leu mutation leads to more accessibility at the stalk region for ACE secretase and is responsible for the enhancement of the cleavage-secretion process. Our results show that different molecular mechanisms are responsible for the common genetic variation of plasma ACE and for its more rare familial elevation.

Amino Acid Sequence↗

[Lavage almost never indicated after an autointoxication].

In many Dutch hospitals gastric lavage leaving charcoal and a laxative is the treatment of choice after autointoxication. Gastric lavage is not without risks. No difference has been demonstrated in efficacy and safety of gastric lavage combined with administration of activated charcoal on the one hand and just administration of activated charcoal on the other. In theory, gastric lavage might be useful in patients presenting shortly after the selfpoisoning (up to 2 hours) and in the case of delayed gastric emptying up to 4 hours. Gastric lavage is indicated without doubt in patients presenting shortly after ingestion of toxic substances which are poorly adsorbed by charcoal (for instance lithium). In case of a mild intoxication (for example with benzodiazepines), the risks of drug toxicity do not outweigh those of lavage, regardless of the time elapsed after ingestion. If gastric lavage is applied, it should be performed properly, i.e. with warm water (38 degrees C), with a 36-40 Fr. tube, using aliquots of 200-300 ml. In a minority of the intoxications whole bowel lavage should be employed.

Charcoal↗

Verapamil causes decreased diaphragm endurance but no decrease of nocturnal O(2) saturation in patients with chronic obstructive pulmonary disease.

OBJECTIVE: In animal studies, it has been shown that verapamil reduces strength and endurance of the diaphragm and inhibits the beneficial effects of theophylline. We examined whether the use of verapamil in patients with severe chronic obstructive pulmonary disease (COPD) who use theophylline leads to a deterioration of diaphragmatic function resulting in a decrease of nocturnal O(2) saturation. METHODS: A double-blind, placebo-controlled crossover study was designed in eight stabile severe COPD patients [forced expiratory volume in 1 s (FEV(1)) 0.9 +/- 0.1 l] taking theophylline. The doses of theophylline ranged from 600 mg daily to 1200 mg daily (7.0 mg/kg daily to 16.9 mg/kg daily). Nocturnal recordings, maximal respiratory muscle strength and endurance tests, lung function, blood pressure, electrocardiogram and arterial blood gas analysis were performed after 6 days of verapamil and after placebo. RESULTS: A significant decrease of the endurance time from 7.7 min to 6.4 min was found in the threshold loading test. However, the mean nocturnal saturation values did not change significantly: 89.8% and 89.6%, respectively. Results of pulmonary function tests, arterial blood gas analysis and routine blood samples also did not change. CONCLUSION: The decrease of the respiratory muscle endurance after the use of verapamil is in line with experiments in animal diaphragms. However, the nocturnal saturation did not change. This finding suggests that the effect found on diaphragm endurance is of no clinical significance and that verapamil can be given to COPD patients without risk of worsening nocturnal saturation. However, this must be confirmed by future larger scale studies.

Aged↗

Sulphonylurea drugs reduce hypoxic damage in the isolated perfused rat kidney.

Sulphonylurea drugs have been shown to protect against hypoxic damage in isolated proximal tubules of the kidney. In the present study we investigated whether these drugs can protect against hypoxic damage in a whole kidney preparation. Tolbutamide (200 microM) and glibenclamide (10 microM) were applied to the isolated perfused rat kidney prior to changing the gassing from oxygen to nitrogen for 30 min. Hypoxic perfusions resulted in an increased fractional excretion of glucose (FE % glucose 14.3+/-1.5 for hypoxic perfusions vs 4.9+/-1.6 for normoxic perfusions, mean +/- s.e. mean, P<0.05), which could be completely restored by 200 microM tolbutamide (5.7+/-0.4 for tolbutamide vs 14.3+/-1.5 for untreated hypoxic kidneys, P<0.01). Furthermore, tolbutamide reduced the total amount of LDH excreted in the urine (220+/-100 mU for tolbutamide vs. 1220+/-160 mU for untreated hypoxic kidneys, P<0.01). Comparable results were obtained with glibenclamide (10 microM). In agreement with the effect on functional parameters, ultrastructural analysis of proximal tubules showed increased brush border preservation in tolbutamide treated kidneys compared to untreated hypoxic kidneys. We conclude that glibenclamide and tolbutamide are both able to reduce hypoxic damage to proximal tubules in the isolated perfused rat kidney when applied in the appropriate concentrations.

ATP-Binding Cassette Transporters↗

Nucleosomes and histones are present in glomerular deposits in human lupus nephritis.

BACKGROUND: Recently we showed that antinuclear autoantibodies complexed to nucleosomes can bind to heparan sulphate (HS) in the glomerular basement membrane (GBM) via the histone part of the nucleosome. Histones have been identified in glomerular deposits in human and murine lupus nephritis. In addition, a decreased HS staining in the GBM was found, most probably due to masking by deposition of antibodies complexed to nucleosomes. METHODS: In this study we first investigated whether histones or nucleosomes could be identified in glomerular deposits in human lupus nephritis, and secondly whether the presence of these nuclear components was correlated with absence of HS staining. Kidney biopsies of SLE patients (11 with diffuse proliferative glomerulonephritis (DPGN) and six with membranous glomerulonephritis (MGN)) and non-SLE glomerular diseases were stained for histones. DNA, nucleosomes, IgG and HS. RESULTS: Using a polyclonal anti-H3 1 21 antiserum, histones were detected in all patients with DPGN and in two of six patients with SLE-MGN (P < 0.01). Using a monoclonal antihistone antibody, histones were stained in three patients with DPGN, but in none of the biopsies with MGN. Using nucleosome specific monoclonal antibodies, nucleosomes were detected in five patients with DPGN, in two patients with MGN, but in none of the biopsies with non-SLE glomerulonephritis. HS staining was nearly absent in DPGN, whereas staining was only moderately reduced in patients with MGN and controls (P = 0.001). CONCLUSION: Using polyclonal and monoclonal antihistone antisera, histones were identified in all patients with DPGN and their presence was associated with a decrease of HS staining. Nucleosomes were identified in five of 11 patients with DPGN and in two of six patients with MGN. This is the first demonstration of nucleosomes in glomerular deposits in SLE nephritis.

Adolescent↗

Significance of anti-nuclear and anti-extracellular matrix autoantibodies for albuminuria in murine lupus nephritis; a longitudinal study on plasma and glomerular eluates in MRL/l mice.

The relationship between autoantibody reactivities and nephritis in systemic lupus erythematosus (SLE) is unclear. We studied MRL/l mice which developed a considerable albuminuria (either mice with short ( < 1 week) or heavy and prolonged (3 weeks) albuminuria) and compared them with non-albuminuric age-matched controls, with young (12 weeks old) non-albuminuric mice and with mice which were followed for 36 weeks and did not develop albuminuria. In a longitudinal prospective study on plasma samples we correlated a variety of anti-nuclear reactivities and reactivities against extracellular matrix (ECM) components, with the onset of albuminuria. We found that at the onset of albuminuria, anti-DNA was higher while anti-nucleosome and anti-H2A/H2B-DNA subnucleosome reactivities were lower compared with age-matched non-albuminuric mice. We also studied glomerular eluates of these mice in ELISA and in indirect immunofluorescence (IF). In the eluates we found with IF that anti-glomerular basement membrane (GBM)-tubular basement membrane (TBM) antibodies were already present in 12-week-old non-albuminuric mice. These eluates showed no anti-nuclear antibodies. In eluates of albuminuric mice more immunoglobulin was deposited, and anti-ECM, anti-DNA and anti-nucleosome reactivities were higher than in eluates of age-matched non-albuminuric mice. The deposition of anti-nucleosome antibodies preceded the deposition of anti-DNA antibodies since they were deposited to a greater extent in mice with a short albuminuria. We conclude that anti-GBM-TBM antibodies are the first autoantibodies that deposit in glomeruli of MRL/l mice at an early age. The onset of albuminuria is associated with additional deposition of both anti-ECM and anti-nuclear (anti-nucleosome and anti-DNA) antibodies, but the difference with non-albuminuric mice seems to be more quantitative than qualitative.

Albuminuria↗

Autoimmunity against nucleosomes and lupus nephritis.

It is generally assumed that anti-dsDNA antibodies play an important role in the pathogenesis of lupus nephritis. This is mainly based on the facts that an increase in anti-dsDNA titer often precedes onset of renal disease, that immune deposits are present in glomeruli and that eluates of glomeruli are enriched for anti-dsDNA. This led to the classical concept that deposition of DNA-anti-DNA complexes incites the glomerular inflammation. However, important pieces of evidence are lacking to support this hypothesis. Free, naked, DNA is not present in the circulation. The existence of DNA/anti-DNA complexes is highly questionable and injection of these complexes hardly leads to glomerular localization. As an alternative concept cross-reactivity of anti-dsDNA with glomerular constituents like heparan sulfate (HS) and laminin has been proposed. However, subsequent research has indicated that this cross-reactivity is due to nucleosomal antigens (histones and DNA) complexed to the auto-antibodies. The cationic histone part of the complex is responsible for the binding to the anionic HS. This binding also occurs in vivo since renal perfusion of nucleosome complexed antibodies leads to abundant binding of auto-antibodies to the GBM, while enzymatic removal of HS from the GBM, decreases this binding considerably. Non-complexed antibodies did not bind at all. This mechanism of binding is also consistent with the decrease of HS staining in the GBM in human and murine lupus due to masking of HS with nucleosome-complexed auto-antibodies. Furthermore the presence of histones and nucleosomes in glomerular deposits in lupus nephritis was recently shown. Elution of auto-antibodies from glomeruli not only showed anti-dsDNA but also anti-nucleosome specificities. Nucleosomes are not only important for the induction of glomerular lesions, but there is now also increasing evidence that the nucleosome is the auto-antigen that drives the auto-immune response in SLE. There is ample evidence that this response is antigen-driven and T cell dependent. However immunization with DNA in general fails to induce pathogenic anti-dsDNA antibodies. Recently, in SLE T helper cells were identified specific for nucleosomes. These nucleosome specific T helper cells were not only able to induce anti-nucleosome antibodies but also anti-dsDNA and anti-histone antibodies. This is in line with the finding that in SLE nucleosome specific antibodies are formed. These antibodies react exclusively with nucleosomes and not with its constituents DNA or histones. The formation of these nucleosome specific antibodies precedes the development of anti-dsDNA or anti-histone suggesting that the loss of tolerance for nucleosomes is a primary event. The systemic release of nucleosomes is due to an aberrant apoptosis. There is now growing evidence that apoptosis is disturbed both in certain murine lupus models as well as in human lupus. In conclusion, nucleosomes seem to play a central role in the induction and the effector phase of SLE.

Antibodies, Antinuclear↗

No evidence for an independent role of anti-heparan sulphate reactivity apart from anti-DNA in lupus nephritis.

The presence of anti-heparan sulphate (HS) reactivity in serum is closely related to the occurrence of nephritis in patients with systemic lupus erythematosus (SLE). Since patients with lupus nephritis in general also have high titres of anti-DNA antibodies, we wanted to clarify the relationship between anti-HS and anti-DNA reactivity in serum. Therefore, we studied longitudinally six patients with lupus nephritis who experienced 12 exacerbations of their disease, and five SLE patients without nephritis experiencing 10 periods of non-renal disease exacerbations. In addition, we tested single serum samples of another 24 patients obtained during a renal disease exacerbation and 22 sera of patients without nephritis. The sera of all patients were tested for anti-DNA (Farr assay) and anti-HS reactivity (ELISA). We confirmed that SLE patients during renal exacerbations have a significantly higher anti-HS reactivity than patients without nephritis (P < 0.003). In addition, patients with nephritis also had higher titres of anti-DNA antibodies during renal exacerbations than during non-renal exacerbations (P < 0.01). A correlation between anti-DNA and anti-HS reactivity was observed (r = 0.40, P < 0.02), which in itself explains the correlation between nephritis and anti-HS reactivity. Comparing sera from nephritis and non-nephritis patients matched for anti-DNA titre, we found no difference in anti-HS reactivity, and therefore must conclude that the anti-HS reactivity is a direct reflection of anti-DNA reactivity.

Antibodies, Antinuclear↗

A new ELISA for the detection of anti-heparan sulfate reactivity, using photobiotinylated antigen.

Autoantibodies reacting with a great variety of autoantigens are characteristic for the autoimmune disease systemic lupus erythematosus (SLE). Although reactivity with heparan sulfate (HS) in sera of patients with SLE is found in association with the occurrence of nephritis, the aetiological significance of this association is not clear. The assay which is generally used to measure anti-HS reactivity is subject to false-positive results, as a consequence of the binding of negatively charged moieties within immune complexes to the precoat employed (protamine sulfate). Therefore, we have developed a new ELISA in which photobiotinylated HS is efficiently and reproducibly bound to streptavidin-coated wells. We compared the new ELISA with the classical anti-HS ELISA by testing culture supernatants of 20 murine monoclonal antibodies (mAb) to DNA (containing free anti-DNA and anti-DNA/nucleosome immune complexes) and preparations of these mAb (containing only free anti-DNA), purified under dissociating conditions. In the classical anti-HS ELISA, 14 out of 20 of the culture supernatants reacted positively with HS; after purification no reactivity remained. The discrepancy must be due to anti-DNA/nucleosome immune complexes present in the culture supernatants. In the new ELISA only four out of 20 culture supernatants and one of the purified preparations reacted with HS. This latter reactivity is probably not specific, since this mAb also reacted with streptavidin alone. To find out whether there is a correlation between the occurrence of nephritis and anti-HS reactivity, measured in this new anti-HS ELISA, we tested sera of patients with a renal- or non-renal exacerbation of SLE in the newly developed anti-HS ELISA. We observed a correlation between anti-HS reactivity and nephritis.

Animals↗