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1.
J Mass Spectrom ; 48(6): 718-31, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23722963

ABSTRACT

The p38 mitogen-activated protein kinase α (p38α) is an important drug target widely investigated for therapy of chronic inflammatory diseases. Its inhibitors are rather lipophilic and as such not very favourable lead compounds in drug discovery. Therefore, we explored various approaches to access new chemical space, create diversity, and generate lead libraries with improved solubility and reduced lipophilicity, based on known p38α inhibitors, e.g., BIRB796 and TAK-715. Compound modification strategies include incubation with human liver microsomes and bacterial cytochrome P450 mutants from Bacillus megaterium and treatment by electrochemical oxidation, H2O2, and intense light irradiation. The MS/MS fragmentation pathways of p38α inhibitors and their conversion products have been studied in an ion-trap-time-of-flight MS(n) instrument. Interpretation of accurate mass MS(n) data for four sets of related compounds revealed unexpected and peculiar fragmentation pathways that are discussed in detail. Emphasis is put on the usefulness of HRMS(n)-based structure elucidation in a screening setting and on peculiarities of the fragmentation with regard to the analytes and the MS instrument. In one example, an intramolecular rearrangement reaction accompanied by the loss of a bulky group is observed. For BIRB796, the double-charge precursor ion is used in MS(2), providing a wider range of fragment ions in our instrument. For TAK-715, a number of related compounds could be produced in a large-scale incubation with a Bacillus megaterium mutant, thus enabling comparison of the structure elucidation by (1)H NMR and MS(n). A surprisingly large number of homolytic cleavages are observed. Competition between two fragmentation pathways involving either the loss of CH3(•) or OH(•) radicals was observed for SB203580 and its conversion products.


Subject(s)
Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Tandem Mass Spectrometry/methods , Humans , Ions/analysis , Ions/chemistry , Models, Molecular , Protein Kinase Inhibitors/analysis , Recombinant Proteins/analysis , Recombinant Proteins/chemistry
2.
Biochemistry ; 51(3): 750-60, 2012 Jan 24.
Article in English | MEDLINE | ID: mdl-22208729

ABSTRACT

Cytochrome P450 BM3 from Bacillus megaterium is a monooxygenase with great potential for biotechnological applications. In this paper, we present engineered drug-metabolizing P450 BM3 mutants as a novel tool for regioselective hydroxylation of steroids at position 16ß. In particular, we show that by replacing alanine at position 82 with a tryptophan in P450 BM3 mutants M01 and M11, the selectivity toward 16ß-hydroxylation for both testosterone and norethisterone was strongly increased. The A82W mutation led to a ≤42-fold increase in V(max) for 16ß-hydroxylation of these steroids. Moreover, this mutation improves the coupling efficiency of the enzyme, which might be explained by a more efficient exclusion of water from the active site. The substrate affinity for testosterone increased at least 9-fold in M11 with tryptophan at position 82. A change in the orientation of testosterone in the M11 A82W mutant as compared to the orientation in M11 was observed by T(1) paramagnetic relaxation nuclear magnetic resonance. Testosterone is oriented in M11 with both the A- and D-ring protons closest to the heme iron. Substituting alanine at position 82 with tryptophan results in increased A-ring proton-iron distances, consistent with the relative decrease in the level of A-ring hydroxylation at position 2ß.


Subject(s)
Amino Acid Substitution/genetics , Bacillus megaterium/enzymology , Bacillus megaterium/genetics , Bacterial Proteins/chemistry , Bacterial Proteins/genetics , Cytochrome P-450 Enzyme System/chemistry , Cytochrome P-450 Enzyme System/genetics , NADPH-Ferrihemoprotein Reductase/chemistry , NADPH-Ferrihemoprotein Reductase/genetics , Norethindrone/metabolism , Testosterone/metabolism , Alanine/genetics , Bacillus megaterium/metabolism , Bacterial Proteins/metabolism , Biotransformation/genetics , Catalytic Domain/genetics , Cytochrome P-450 Enzyme System/metabolism , Hydroxylation/genetics , Mutagenesis, Site-Directed , NADPH-Ferrihemoprotein Reductase/metabolism , Nuclear Magnetic Resonance, Biomolecular , Oxidation-Reduction , Spectrophotometry, Ultraviolet , Tryptophan/genetics
3.
Neth J Med ; 67(7): 296-300, 2009.
Article in English | MEDLINE | ID: mdl-19687528

ABSTRACT

BACKGROUND: Delirium in the ICU can compromise the recovery process, prolong ICU and hospital stay and increase mortality. Therefore, recognition of delirium is of utmost importance. METHODS: To ascertain current attitude pertaining to delirium in critically ill patients a simple questionnaire was sent to all intensive care units (ICUs) throughout the Netherlands. RESULTS: Seventy-five questionnaires were sent and 44 returned. A delirium protocol was present in the majority of cases (n=35, 80%), although implementation had occurred in only 22 ICUs (50%). The reported general incidence of delirium varied widely (25% of ventilated patients (n=33, 75%) and in patients older than 70 (n=38, 86%). Most participating centres reported that they could certainly (n=9, 20%) or most certainly (n=22, 50%) identify delirium. A geriatrician or a psychiatrist predominantly diagnosed delirium (n=30, 68%), while a diagnostic instrument such as the CAM -ICU was used in a minority of cases (n=11, 25%). A geriatrician or a psychiatrist was consulted when patients were agitated (n=40, 90%), or when routine pharmacological treatment had failed (n=40, 91%). CONCLUSION: In the Netherlands, delirium is considered an important problem in the ICU, although its incidence is estimated to be low by the ICU team. The diagnosis of delirium is most frequently established by a geriatrician or psychiatrist after consultation, while diagnostic instruments are infrequently used. Efforts should be undertaken to implement delirium protocols and a routinely applied diagnostic instrument in the ICU.


Subject(s)
Critical Care/standards , Delirium/diagnosis , Health Knowledge, Attitudes, Practice , Intensive Care Units/standards , Attitude of Health Personnel , Clinical Protocols , Critical Care/methods , Delirium/epidemiology , Delirium/etiology , Health Care Surveys , Humans , Intensive Care Units/statistics & numerical data , Netherlands , Nursing Staff, Hospital , Respiration, Artificial/adverse effects , Respiration, Artificial/statistics & numerical data
4.
Resuscitation ; 80(11): 1318-20, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19699573

ABSTRACT

A patient with Prinzmetal's variant angina (PVA) developed a cardiac arrest due to coronary vasospasm and subsequent myocardial infarction. After resuscitation postanoxic brain injury was diagnosed. After an initial improvement of consciousness he deteriorated rapidly on the seventh day after admission due to severe brain ischaemia apparently caused by cerebral vasospasm, until ultimately brain death was diagnosed. To our knowledge, the association between PVA and cerebral vasospasm has never been described. The combination suggests that this patient had a generalized vasospastic disorder.


Subject(s)
Angina Pectoris, Variant/etiology , Vasospasm, Intracranial/complications , Angina Pectoris, Variant/diagnosis , Cerebral Angiography , Diagnosis, Differential , Electrocardiography , Fatal Outcome , Humans , Male , Middle Aged , Tomography, X-Ray Computed , Vasospasm, Intracranial/diagnosis
5.
Ned Tijdschr Geneeskd ; 149(35): 1947-53, 2005 Aug 27.
Article in Dutch | MEDLINE | ID: mdl-16159035

ABSTRACT

In 4 patients with temporal arteritis or polymyalgia rheumatica, women aged 60, 57, 83 and 73 years respectively, signs of aortic involvement were established. The first patient presented with signs of systemic inflammation without signs of temporal arteritis or aortitis. In the second, an acute symptomatic thoracoabdominal aneurysm developed. In the third, temporal arteritis was associated with chronic progressive dilatation ofthe thoracic aorta. The fourth developed signs of intermittent claudication of the extremities. The clinical manifestations in all patients were attributed to chronic inflammation of the aorta caused by giant cell arteritis. Aortic giant cell arteritis frequently accompanies temporal arteritis, but is rarely diagnosed. Up to 75% of patients with temporal arteritis may have some degree of aortic involvement. Thoracic aneurysms, complicated by rupture or dissection, are the most serious complications. Aortic disease associated with signs of systemic inflammation should trigger the suspicion of giant cell arteritis. Corticosteroids are the most important part of treatment. Three patients recovered following treatment; the first two received an endoprosthesis; in the woman aged 83 years, this was not technically possible; she died after 1.5 years.


Subject(s)
Aortic Aneurysm, Abdominal/complications , Aortic Aneurysm, Thoracic/complications , Giant Cell Arteritis/complications , Intermittent Claudication/etiology , Polymyalgia Rheumatica/complications , Adrenal Cortex Hormones/therapeutic use , Aged , Aged, 80 and over , Aortic Aneurysm, Abdominal/drug therapy , Aortic Aneurysm, Abdominal/surgery , Aortic Aneurysm, Thoracic/drug therapy , Aortic Aneurysm, Thoracic/surgery , Blood Vessel Prosthesis , Fatal Outcome , Female , Giant Cell Arteritis/drug therapy , Giant Cell Arteritis/surgery , Humans , Intermittent Claudication/drug therapy , Middle Aged , Polymyalgia Rheumatica/drug therapy , Polymyalgia Rheumatica/surgery , Risk Factors , Treatment Outcome
6.
Hypertension ; 37(4): 1179-83, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11304521

ABSTRACT

Animal studies have demonstrated that CNP causes endothelium-independent vasodilation, which is limited by neutral endopeptidase (NEP) activity. However, the vasodilating mechanism of CNP in humans is still unknown. Therefore, we investigated the vasodilator actions of CNP in human forearm resistance vessels before and after inhibition of nitric oxide (NO) and then prostacyclin production and after inhibition of Ca(2+)-dependent potassium channel activation and NEP activity. Three separate studies were performed. In each study, forearm blood flow was recorded by venous occlusion plethysmography in 8 healthy nonsmoking subjects. Brachial artery infusion of CNP (70, 140, 280, and 560 ng per 100 mL forearm volume per minute) caused significant forearm vasodilation in all studies (forearm blood flow from 3.94 to 8.50 mL per 100 mL forearm volume per minute). Inhibition of the endogenous generation of NO by L-N(G)-monomethyl arginine (by use of the NO-clamp technique) did not block the maximal vasodilating effects of CNP (forearm blood flow from 3.69 to 6.93). In addition, when the cyclooxygenase system was inhibited by 600 mg of acetylsalicylic acid (aspirin) administered orally 30 minutes before start of measurements, the rise in forearm blood flow remained intact (forearm blood flow from 3.31 to 8.27 mL per 100 mL forearm volume per minute). However, inhibition of Ca(2+)-dependent potassium channels with tetraethylammonium chloride (0.1 mg per 100 mL forearm volume per minute) significantly attenuated vasodilation caused by CNP (forearm blood flow from 2.28 to 3.06 mL per 100 mL forearm volume per minute), which suggests that CNP opens vascular potassium channels. Vasodilation to all doses of CNP was significantly increased when activity of NEP was blocked with thiorphan (30 nmol/min), which suggests that NEP activity limits vasodilation of CNP. CNP is a dilator of human resistance vessels that mediates its effects through hyperpolarization of the vessel wall independent of the NO and prostaglandin system. Inhibition of local NEP activity increases CNP bioavailability. This may be of relevance to cardiovascular disease, given that vascular tone is well balanced between NO and an endothelium-derived hyperpolarizing factor, which suggests that in pathological situations, impaired NO activity can be compensated for by enhanced endothelium-derived hyperpolarizing factor release to maintain vascular homeostasis.


Subject(s)
Natriuretic Peptide, C-Type/physiology , Vascular Resistance/physiology , Vasodilation/physiology , Adolescent , Adult , Analysis of Variance , Biological Availability , Cyclooxygenase Inhibitors/pharmacology , Epoprostenol/antagonists & inhibitors , Epoprostenol/physiology , Forearm/blood supply , Humans , Neprilysin/antagonists & inhibitors , Neprilysin/metabolism , Nitric Oxide/physiology , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase/physiology , Potassium Channel Blockers , Potassium Channels/metabolism , Prostaglandin-Endoperoxide Synthases/physiology , Vasodilation/drug effects
7.
Br J Clin Pharmacol ; 49(6): 562-73, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10848720

ABSTRACT

AIMS: Endothelins (ETs) may play a role in the pathogenesis of a variety of cardiovascular diseases. The present study was designed to investigate the pharmacokinetic and pharmacodynamic effects of the orally active ETA selective receptor antagonist ABT-627 in healthy humans. METHODS: Healthy volunteers were included in two studies with cross-over design. Subjects received single or multiple dose (an 8 day period) administration of oralABT-627 or matched placebo, in a dose range of 0.2-40 mg. The pharmacokinetics of ABT-627 were described and its effects on systemic haemodynamics under resting conditions and on forearm vasoconstriction in response to ET-1 were assessed. RESULTS: ABT-627 was generally well tolerated in both studies, with transient headache being the most reported adverse event (in 62% vs 4% during placebo, P < 0.05, for Study 1 and in 42% vs 60%, P = 0.2, for Study 2). ABT-627 was rapidly absorbed, reaching maximum plasma levels at approximately 1 h post dose. Single dose ABT-627, at a dose of 20 and 40 mg, inhibited ET-1 induced forearm vasoconstriction at 8 h post dose. Eight days ABT-627 treatment, at a dose level of 5 mg and above, also effectively blocked forearm vasoconstriction to ET-1. ABT-627 caused a significant reduction in peripheral resistance as compared with placebo (16 +/- 1 vs 19 +/- 1, 18 +/- 2 vs 23 +/- 3, 15 +/- 1 vs 17 +/- 1 AU at 1, 5, 20 mg in Study 2) with only a mild decrease in blood pressure (79 +/- 2 vs 84 +/- 3, 80 +/- 4 vs 90 +/- 5, 75 +/- 3 vs 79 +/- 1 at 1, 5, 20 mg in Study 2). ABT-627 caused a moderate dose-dependent increase in circulating immunoreactive ET levels (a maximal increase of 50% over baseline at the 20 mg dose level). CONCLUSIONS: The oral ETA receptor blocker ABT-627 is well tolerated, rapidly absorbed, effectively blocks ET-1 induced vasoconstriction and causes a decrease in total peripheral resistance and mean arterial pressure. Our data suggest that ABT-627 may be a valuable tool in treatment of cardiovascular disease.


Subject(s)
Endothelin Receptor Antagonists , Pyrrolidines/pharmacology , Pyrrolidines/pharmacokinetics , Adult , Aged , Area Under Curve , Atrasentan , Biological Availability , Endothelins/antagonists & inhibitors , Endothelins/metabolism , Forearm/blood supply , Half-Life , Hemodynamics/drug effects , Hemodynamics/physiology , Humans , Male , Middle Aged , Receptor, Endothelin A , Regional Blood Flow/physiology , Vasoconstriction/drug effects
8.
Hypertension ; 35(6): 1314-8, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10856283

ABSTRACT

Bradykinin (BK) stimulates endothelial cells to release a number of relaxing factors, such as NO, prostanoids (PGs), and an endothelium-derived hyperpolarizing factor (EDHF). However, the contributions of NO, PG, and EDHF in the vascular relaxation to BK vary with species and anatomic origin of blood vessels used. Therefore, the present study was designed to investigate the contributions of NO, PG, and EDHF in vasodilation caused by BK in human forearm resistance vessels. Forearm blood flow (FBF) was recorded with venous occlusion plethysmography in healthy nonsmoking subjects. At first, studies were performed to validate the NO clamp technique for its ability to inhibit endogenous NO generation. Brachial artery infusion of serotonin (0.6, 1.8, and 6 ng. 100 mL forearm volume [FAV](-1). min(-1)) caused significant forearm vasodilation (2.6 to 4.6 mL. 100 mL FAV(-1). min(-1)), which is known to be NO mediated. Indeed, during the NO clamp, cumulative doses of serotonin caused no vasodilation (2.4 to 2.6 mL. 100 mL FAV(-1). min(-1)), indicating that the generation of endogenous NO was completely blocked. Thereafter, the vasodilative actions of BK were investigated. Brachial artery infusion of BK (50, 100, and 200 ng. 100 mL FAV(-1). min(-1)) caused significant forearm vasodilation in all studies (from 3.1 to 20.4 mL. 100 mL FAV(-1). min(-1)). After the inhibition of cyclooxygenase and NO synthase activity through the use of aspirin and the NO-clamp technique, BK increased FBF in a similar manner (3.9 to 18.9 mL. 100 mL FAV(-1). min(-1)), indicating that the vasodilative actions of BK are independent of NO and PG generation. However, vasodilation caused by the 2 lower doses of BK were significantly attenuated after K(Ca) channel activity was blocked with tetraethylammonium chloride (0.1 mg. 100 mL FAV(-1). min(-1)), suggesting that in the lower dose range, BK mediates vasodilation through the opening of vascular potassium channels. In conclusion, BK is a potent vasodilator peptide in human forearm resistance vessels, causing vasodilation through hyperpolarization of the vascular wall independent of NO and PG production. In addition, the NO-clamp technique is a valid instrument to investigate the contribution of NO in the vasodilative response to different agents.


Subject(s)
Brachial Artery/drug effects , Bradykinin/pharmacology , Endothelium, Vascular/physiology , Forearm/blood supply , Vascular Resistance , Vasodilation , Adolescent , Adult , Brachial Artery/physiology , Cyclooxygenase Inhibitors/pharmacology , Electrophysiology , Enzyme Inhibitors/pharmacology , Humans , Middle Aged , Nitric Oxide/antagonists & inhibitors , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase Type III , Nitroprusside/pharmacology , Potassium Channel Blockers , Serotonin/pharmacology , Tetraethylammonium/pharmacology , omega-N-Methylarginine/pharmacology
9.
Cardiovasc Res ; 42(3): 752-60, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10533616

ABSTRACT

OBJECTIVE: Dihydropyridine calcium antagonists have been shown to retard atherogenesis in animal models and to prevent the development of early angiographic lesions in human coronary arteries. Endothelial dysfunction is an early event in the pathogenesis of cardiovascular disease. We investigated whether nifedipine could improve endothelial function in hypercholesterolemia, independently of changes in blood pressure or plasma lipids. METHODS: First, we compared in vivo forearm vascular responses to the endothelium-dependent and independent vasodilators serotonin (5-HT) and sodium nitroprusside (SNP) in 11 patients with familial hypercholesterolemia before and after 6-weeks treatment with nifedipine GITS (60 mg, OD) and in 12 matched controls. In a subgroup of six control subjects forearm vascular function was also assessed before and after 6-weeks nifedipine GITS treatment. In vitro, we subsequently explored possible mechanisms underlying the effect of nifedipine on endothelial function. We investigated the effects of nifedipine on both NO production by recombinant endothelial NO synthase (eNOS) and endothelial cells, using 3H-arginine conversion, as well as on superoxide generation by endothelial cell lysates, using lucigenin enhanced chemiluminescence. RESULTS: In hypercholesterolemia 5-HT-induced vasodilation was impaired (47 +/- 9% increase in forearm bloodflow vs. 99 +/- 8% in controls). Treatment with nifedipine completely restored 5-HT-induced vasodilation (113 +/- 13%), whereas it did not influence basal forearm vasomotion or SNP-induced vasodilation. Nifedipine did not alter forearm vascular responses in control subjects and did not alter blood pressure or plasma lipids. In vitro, we found no direct effect of nifedipine on NO production by recombinant eNOS or endothelial cells. However, we did observe a reduction in endothelial superoxide generation. CONCLUSIONS: Our data show that nifedipine improves endothelial function in hypercholesterolemia. It is suggested from our in vitro experiments that this effect is due to reduced NO degradation.


Subject(s)
Calcium Channel Blockers/therapeutic use , Endothelium, Vascular/drug effects , Hyperlipoproteinemia Type II/drug therapy , Nifedipine/therapeutic use , Adult , Case-Control Studies , Cells, Cultured , Endothelium, Vascular/metabolism , Female , Humans , Hyperlipoproteinemia Type II/metabolism , Male , Middle Aged , Nitric Oxide/metabolism , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type III , Nitroprusside/pharmacology , Recombinant Proteins/metabolism , Regional Blood Flow/drug effects , Serotonin/pharmacology , Time Factors , Vasodilator Agents/pharmacology
10.
Diabetes Metab Rev ; 14(3): 241-9, 1998 Sep.
Article in English | MEDLINE | ID: mdl-9816472

ABSTRACT

Diabetes mellitus is associated with early development of cardiovascular complications. Under physiological conditions the endothelium protects against the development of atherosclerosis. Endothelial cells produce, e.g., nitric oxide (NO), a substance which is capable of keeping vascular tone, coagulation and inflammation well balanced. However, in pathological conditions, such as in diabetes mellitus, impaired NO activity may be present. Decreased NO activity can be caused by impaired production of NO, due to uncoupling of receptor-mediated signal transduction, a deficiency of the NO synthase (NOS) substrate L-arginine, or a decreased availability of one or more cofactors essential for optimal functioning of NOS. However, hyperglycaemia also stimulates the production of advanced glycosylated end products, enhances the polyol pathway and activates protein kinase C. These conditions may lead to increased oxidative stress. Reactive oxygen species rapidly inactivate NO leading to the formation of peroxynitrite. Peroxynitrite is a toxic oxidant capable of damaging many biological molecules. Reduced NO availability may not only be of relevance to the development of atherosclerotic complications in diabetes but may also interfere with insulin-mediated postprandial glucose disposal and possibly contribute to the development of insulin resistance. Understanding of the complex metabolic disturbances interacting with the NO system may provide us with further therapeutic options to decrease cardiovascular morbidity and mortality in diabetes mellitus.


Subject(s)
Diabetes Mellitus/metabolism , Nitric Oxide/metabolism , Animals , Diabetes Mellitus/therapy , Humans , Insulin Resistance , Nitric Oxide/biosynthesis
11.
Neth J Med ; 52(2): 75-8, 1998 Feb.
Article in English | MEDLINE | ID: mdl-9557530

ABSTRACT

A 71-year-old woman presented with a rapidly growing goitre which was diagnosed as chronic autoimmune thyroiditis. Despite treatment with levothyroxine, she developed progressive airway obstruction. Biopsy revealed a primary thyroid lymphoma which was successfully treated with radiotherapy.


Subject(s)
Lymphoma, B-Cell, Marginal Zone/pathology , Thyroid Neoplasms/pathology , Aged , Airway Obstruction/etiology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biopsy, Needle , Chronic Disease , Fatal Outcome , Female , Follow-Up Studies , Humans , Lymphoma, B-Cell, Marginal Zone/complications , Lymphoma, B-Cell, Marginal Zone/radiotherapy , Neoplasm Recurrence, Local , Thyroid Neoplasms/complications , Thyroid Neoplasms/radiotherapy , Thyroiditis, Autoimmune/complications , Tomography, X-Ray Computed
12.
J Hand Surg Br ; 21(2): 271-5, 1996 Apr.
Article in English | MEDLINE | ID: mdl-8732418

ABSTRACT

A dysfunctional posture of the hand could be due to an anatomical disorder or a conversion reaction. A conversion reaction implies that an unconscious intrapsychic conflict is expressed in a physical dysfunction. Treatment of dysfunctional postures due to conversion reactions is often difficult, and case reports are used to outline management. The need for a multidisciplinary approach is stressed.


Subject(s)
Contracture/psychology , Conversion Disorder , Hand , Adult , Aged , Child , Contracture/therapy , Female , Fingers , Humans , Middle Aged , Physical Therapy Modalities
13.
Ned Tijdschr Geneeskd ; 139(14): 723-7, 1995 Apr 08.
Article in Dutch | MEDLINE | ID: mdl-7731468

ABSTRACT

OBJECTIVE: To analyse the impact of the introduction of laparoscopic cholecystectomy on overall morbidity and mortality of gall bladder surgery. DESIGN: Retrospective study. SETTING: Medisch Centrum Alkmaar, Alkmaar. METHODS: All cholecystectomies performed in our final 'prelaparoscopic' year 1990 were compared with all cholecystectomies performed in 1992, the year in which laparoscopic cholecystectomy has become a standard procedure, thus eliminating selection bias. The analysis included morbidity and mortality related to all procedures. RESULTS: In 1990, 173 open cholecystectomies were performed, in 1992 40, and 146 laparoscopic ones; the conversion rate was 4%. The number of patients undergoing investigation for common bile duct stones did not change, but there was a shift from intraoperative cholangiography to preoperative ERCP. In 1992 more endoscopic sphincterotomies were performed (13.5%, versus 5.4% in 1990; p = 0.02). One patient died from complications due to diagnostic ERCP. There was no difference in mortality rate of all procedures taken together, between the two years (3/186 in 1992 (1.6%); 2/173 in 1990 (1.2%)). The morbidity rate of all procedures in 1992 was slightly less than in 1990 (chi 2 = 1.91; p = 0.2). There were no common bile duct injuries caused by laparoscopy. In 1992, the mean operation time was longer than in 1990 (82 versus 46 min; p < 0.001) and the median postoperative hospital stay was significantly shorter than in 1990 (2 versus 6 days; p < 0.001). CONCLUSION: Introduction of laparoscopic cholecystectomy was responsible for shorter hospital stays and longer operation times. When common bile duct stones were predicted, endoscopic sphincterotomy was performed more frequently. These changes did not negatively influence morbidity and mortality rates for gall bladder surgery in general.


Subject(s)
Cholecystectomy, Laparoscopic , Cholecystectomy/methods , Adolescent , Adult , Aged , Aged, 80 and over , Cholangiography , Cholangiopancreatography, Endoscopic Retrograde , Cholecystectomy/mortality , Cholecystectomy, Laparoscopic/mortality , Female , Humans , Length of Stay , Male , Middle Aged , Netherlands , Postoperative Complications/etiology , Retrospective Studies , Time Factors
14.
Surg Radiol Anat ; 17(4): 339-41, 1995.
Article in English | MEDLINE | ID: mdl-8896155

ABSTRACT

An anomalous, digastric flexor digitorum superficialis in addition to a normal flexor digitorum superficialis to the index finger, is reported. To our knowledge, this is an anatomic variation never described before. The anomalous muscle belly presented as a progressive pseudotumor of the palm and needed exploration to provide the final diagnosis.


Subject(s)
Fingers , Muscle, Skeletal/abnormalities , Adult , Diagnosis, Differential , Edema/etiology , Female , Fingers/pathology , Fingers/surgery , Humans , Magnetic Resonance Imaging , Muscle, Skeletal/pathology , Muscle, Skeletal/surgery , Pain/etiology , Tenosynovitis/diagnosis
15.
J Am Soc Mass Spectrom ; 6(8): 656-67, 1995 Aug.
Article in English | MEDLINE | ID: mdl-24214392

ABSTRACT

Sixteen carbamate pesticides that belong to four chemical classes (oxime-N-methylcarbamates, aryl N-methylcarbamates, N-phenylcarbamates, and methyl esters of substituted carbamic acids) were investigated via three different commercially available thermospray interfaces and ion sources that exhibit wide differences in source geometry. Comparisons were made between the three interfaces with respect to ion formation and sensitivity of detection. Experimental parameters were standardized to obtain comparable experimental conditions. Very similar mass spectra for most carbamates were obtained that illustrate independence from the geometry of the ionization and desolvation chambers of the interfaces. These findings are in sharp contrast to several literature reports. However, thermally labile carbamates gave unsatisfactory results with regard to spectral compatibility between the interfaces. Such differences were due to thermally assisted hydrolysis reactions that occur in the vaporizer probe prior to ionization and reflect differences in the vaporizer designs. The study proves conclusively that comparable spectra can be obtained under thermospray with different interfaces and mass spectrometers.

16.
J Am Soc Mass Spectrom ; 5(10): 913-27, 1994 Oct.
Article in English | MEDLINE | ID: mdl-24226238

ABSTRACT

The effects of three additives-ammonium acetate, ammonium formate, and nicotinic acid-to the liquid chromatographic (LC) eluent and of the vaporizer temperature on the ion formation of N-methyl carbamate pesticides in thermospray (TSP) mass spectrometry was investigated by using filament- or discharge-assisted ionization. Nineteen carbamates and 12 of their known environmental degradation products were used as model compounds. The additives cause a strong reduction in the abundance of the characteristic fragment ions [M + H - CH3NCO](+) and [M - H - CH3NCO](-) for some of the carbamates. The addition of nicotinic acid reduces the quasimolecular ion intensity and, in most cases, produces nicotinic acid adduct ions. The addition of ammonium acetate or ammonium formate increases the intensity of the quasimolecular ion and in most cases produces a base peak for the ammonium adduct ion. The combination of a suppression of fragmentation and an enhancement of quasimolecular ion formation produces an overall gain in sensitivity. As to more specific effects, the addition of the ammonium salts reduces the intensity of M(-•) with the chlorinated carbamate barban and suppresses the formation of "odd" adduct ions in the TSP mass spectra of most other carbamates. Monitoring the intensity of the fragment and the quasimolecular ion signal as a function of the probe stem temperature, and the related probe tip temperature, proved to be an easy method to study the thermal degradation of the carbamates. This monitoring procedure showed that methiocarb and its sulfone already suffer from thermal degradation at a stem temperature of 90°C and that these compounds will therefore present problems in quantitation with LC/TSP mass spectrometry.

17.
Biol Mass Spectrom ; 22(11): 621-32, 1993 Nov.
Article in English | MEDLINE | ID: mdl-8251549

ABSTRACT

Liquid chromatography/thermospray mass spectrometry (LC/TSP MS) has been used for the determination of vitamin D3 and some of its metabolites, i.e. 1 alpha(OH) vitamin D3, 25(OH) vitamin D3, 1 alpha,25(OH)2 vitamin D3 and 24,25(OH)2 vitamin D3, using positive and negative ion detection. Using these two modes positional isomers can be identified. Detection in the negative ion mode was preferred because of the slightly higher sensitivity. The limits of detection, using multiple ion detection, are 50-100 nM (6-12 pmol injected). On-line post-column derivatization based on [4 + 2] cyclo-addition (Diels-Alder reaction) proceeds within 1 min at room temperature. If this step is included in LC/TSP MS, the detection limits of the analytes can be improved 7-70-fold depending on the analyte tested. The best results (detection limits down to 1 nM, i.e. 0.12 pmol injected) are obtained with discharge ionization in the negative ion mode.


Subject(s)
Cholecalciferol/analysis , Chromatography, Liquid , Mass Spectrometry/methods
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