Biomedical subjects
Publications and source records attributed to N Weger.
Spontaneous renal artery dissection (SRAD) is rare. Clinical manifestations vary from minimal symptoms to life-threatening hypertension. We analysed three cases from our institution and conducted a literature review in order to design diagnostic and treatment algorithms for SRAD.
The ubiquitous species Pseudomonas stutzeri has type IV pili, and these are essential for the natural transformation of the cells. An absolute transformation-deficient mutant obtained after transposon mutagenesis had an insertion in a gene which was termed pilT. The deduced amino acid sequence has identity with PilT of Pseudomonas aeruginosa (94%), Neisseria gonorrhoeae (67%), and other gram-negative species and it contains a nucleotide-binding motif. The mutant was hyperpiliated but defective for further pilus-associated properties, such as twitching motility and plating of pilus-specific phage PO4. [(3)H]thymidine-labeled DNA was bound by the mutant but not taken up. Downstream of pilT a gene, termed pilU, coding for a putative protein with 88% amino acid identity with PilU of P. aeruginosa was identified. Insertional inactivation did not affect piliation, twitching motility, or PO4 infection but reduced transformation to about 10%. The defect was fully complemented by PilU of nontransformable P. aeruginosa. When the pilAI gene (coding for the type IV pilus prepilin) was manipulated to code for a protein in which the six C-terminal amino acids were replaced by six histidine residues and then expressed from a plasmid, it gave a nonpiliated and twitching motility-defective phenotype in pilAI::Gm(r) cells but allowed transformability. Moreover, the mutant allele suppressed the absolute transformation deficiency caused by the pilT mutation. Considering the hypothesized role of pilT(+) in pilus retraction and the presumed requirement of retraction for DNA uptake, it is proposed that the pilT-independent transformation is promoted by PilA mutant protein either as single molecules or as minimal pilin assembly structures in the periplasm which may resemble depolymerized pili and that these cause the outer membrane pores to open for DNA entry.
In ragweed (RW)-sensitized beagle dogs, we tested the hypothesis that reactivity of the pulmonary vasculature was enhanced with aerosolized histamine (Hist) and RW. Seven dogs were neonatally sensitized with repeated intraperitoneal RW injections, and 12 dogs were controls (Con). The dogs were anesthetized with intravenous chloralose, mechanically ventilated, and instrumented with femoral arterial and pulmonary artery catheters. Specific lung compliance (CLsp), specific lung conductance (Gsp), systemic vascular resistance index, and pulmonary vascular resistance index (PVRI) were measured before and after bronchoprovocation with Hist and RW. After Hist inhalation (5 breaths of 30 mg/ml), both Con and RW dogs had significant (P < 0.05) decreases in CLsp (-51 +/- 4 and -53 +/- 5%, respectively) and Gsp (-65 +/- 5 and -69 +/- 3%, respectively), but only RW-sensitized dogs had a significant increase in PVRI (38 +/- 10%). After RW inhalation (60 breaths of 0.8 mg/ml), only RW-sensitized dogs had significant increases (62 +/- 20%) in PVRI and decreases in Gsp (-77 +/- 4%) and CLsp (-65 +/- 7%). We conclude that, compared with Con, RW-sensitized beagle dogs have increased pulmonary vasoconstrictive responses with Hist or RW inhalation.
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The effects of monofluoroacetate (FAC) on suspensions of isolated rat kidney tubules were investigated. FAC inhibited gluconeogenesis from lactate, pyruvate, fructose, dihydroxyacetone, alpha-ketoglutarate, and succinate. The gluconeogenesis from pyruvate, ketoglutarate, and lactate was less sensitive to FAC than that from other substrates. FAC also caused a decrease in oxygen consumption, hydroxybutyrate to acetoacetate ratio, alpha-ketoglutarate, ATP, and total adenine nucleotide content; the citrate content was increased. Addition of alpha-ketoglutarate, 5 mmol/l, caused a reversal of gluconeogenesis inhibition, an increase in ATP content, and a delay in citrate accumulation in isolated rat kidney tubules incubated with FAC.
The cyanide antidote 4-dimethylaminophenol . HCl (DMAP) was administered orally, i.v., or i.m. to man and dog. Ferrihemoglobin formation and changes of several parameters in human blood were investigated to obtain information on damage to liver, kidney, muscle, and red blood cells; in addition, the metabolism of DMAP was studied. In dogs, the initial rate of ferrihemoglobin production (DMAP, 3.25 mg/kg i.v. or i.m., 15 mg/kg orally) amounted to 28%, 3.5%, and 2% of the total hemoglobin per min; the corresponding values for man were 9%, 2%, and 2% per min. The dogs behaved normally while CPK increased after i.m. injection. In man, only i.m. injection of DMAP (3.25 mg/kg) was followed by increases in LDH, GOT, and CPK of 110, 260, and 490%, resp.; while total bilirubin, conjugated bilirubin, and iron concentration rose by 270, 120, and 50%, respectively. Bilirubin and iron concentration increased also after DMAP i.v. (3.25 mg/kg) or when it was taken orally (600 or 900 mg). The lactate concentration was not influenced while the pyruvate concentration increased by 50%. DMAP produced hemolysis in vitro. Generally, the values determined in vivo approached the starting level within 1 week. Intramuscular injection of DMAP induced reversible subjective and objective symptoms, e.g., local pain, swollen buttock, fever reaction. The urine showed no pathological changes. About 54% of DMAP taken orally was excreted as metabolites in the urine, 41% as glucuronide, 7% as sulfate, and 6% as thioethers. After i.v. administration the total of metabolites was somewhat higher, and the thioether proportion was 15%. The results indicate that DMAP is readily absorbed after oral administration but undergoes significant first pass effect in the liver. Therefore, the 4-fold i.v. dose must be administered orally to achieve the same ferrihemoglobin formation.
The effects of the cyanide antidotes DMAP, Co2EDTA, and NaNO2 on cerebral blood flow (CBF) and cerebral blood gases were investigated in connection with acute poisoning of dogs by cyanide. The substances were injected intravenously. Local CBF as measured with thermocouples in the cingulum increased by 100-200% after a non-lethal dose of KCN (1 mg/kg) and by 50% after injection of NaNO2 (15 mg/kg), that oxidized some 20% of the total hemoglobin to ferrihemoglobin. Co2EDTA (10 mg/kg) induced a decrease in local CBF of 30% and in brain temperature of 0.5 degree C. The temperature diminished also after poisoning by KCN, but it rose by 0.15 degree C after the administration of NaNO2. Local CBF and sinus sagittalis blood flow increased by 60-160% for about 15 min, and the brain temperature decreased by 0.4-0.5 degree C when DMAP (3.25 mg/kg) or Co2EDTA (15 mg/kg) was injected 1 min after poisoning by cyanide (4 mg/kg), a dose that always caused respiratory arrest. Immediately after injection of DMAP the brain temperature rose transiently by 0.1-0.2 degree C. Co2EDTA did not exert such an effect. In the sinus sagittalis blood of artificially ventilated animals pCO2 decreased rapidly by 10-20 mmHg after poisoning and approached the initial level after treatment with DMAP or Co2EDTA. The highest value of pO2 was about 80 mmHg and 50 mmHg after injection of DMAP and Co2EDTA, respectively; thereafter pO2 declined to 20 mmHg or 40 mmHg at 20 min. The lactate concentration increased by 60-70% without tendency to return to normal.
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The effects of 4-dimethylaminophenol . HCl (DMAP) and 100% oxygen on cerebral blood flow (CBF) and peripheral circulation, arterial and venous blood gases, and other parameters have been investigated in dogs in the course of slow cyanide infusion. The i.v. infusion of KCN increased the respiratory minute volume, accompanied by a rise in arterial pO2 and pH and a decrease in arterial pCO2 while the venous lactate concentration increased by about 500% and the hemoglobin content and hematocrit by about 30%. Heart rate and carotid artery blood flow decreased. Local CBF in the cingulum as measured with thermocouples rose steadily, and the brain and oesophagus temperature were lowered. The breathing of 100% oxygen raised the local CBF, the temperature, and the arterial pCO2. During the infusion of KCN into the femoral artery of artificially ventilated dogs the femoral venous pO2 increased continuously by some 40 mm Hg, attended with a decrease in pCO2 of 15 mm Hg. The femoral blood flow, however, rose sharply within 3 min. 100% oxygen induced a rise in pCO2 and a diminution of pH in the femoral vein and in the sinus sagittalis, and the femoral flow rose rapidly. After DMAP i.v. the values of most of the parameters returned to normal or finally stabilized below or above the initial level. The rise in the hemoglobin content, hematocrit, and lactate concentration was stopped, but the arterial and venous pH remained or were lowered. DMAP elicited a rapid, strong decrease in the pO2 of the femoral vein and the sinus sagittalis with a concomitant marked increase in pCO2.
Uptake of the water soluble 1,2-dimercaptopropanol (BAL) derivative 2,3-dimercapto-1-sulfonate (DMPS) into human red blood cells was found in vitro and the mode of penetration studied in detail. The compound entered erythrocytes in a concentration dependent manner. In contrast to sealed ghosts where inside and outside concentrations reached the same value, DMPS accumulated in intact erythrocytes. Since no binding of DMPS could be detected, the reason for accumulation was assumed to be a conversion of DMPS into chelates or metabolites which penetrated the membrane in a slower rate. A facilitated transport of DMPS mediated by the anion carrier protein was concluded on the basis of the following similarities with the anion transport: inhibition of [14C]DMPS-uptake by N-ethylmaleimide (NEM), tetrathionate (90%), sulfate (50%), 5,5'-dithio bis(2-nitrobenzoic acid) (DTNB) (25%); inhibition of uptake and efflux by 4,4'-diisothiocyano-2,2'-stilbene disulfonate (DIDS) (80%), dipyridamole (55%); temperature dependency (activation energy 24 Kcal/mol); pH-dependency (pH optimum about 6.9); counter-transport; activation of uptake by preincubation with DMPS (transmembrane effect).
The implications of the carrier mediated uptake of 2,3-dimercaptopropane-1-sulfonate (DMPS) (D.B. Wildenauer et al., Chem.-Biol. Interact., 42 (1982) 165) on cytoplasmic components of human red blood cells have been investigated in vitro. The water-soluble chelating agent caused a mobilization of metals (zinc and copper) from metalloproteins which resulted in a permeation of the membrane. Furthermore, a cytoplasmic protein was found to be attached to the membrane after DMPS treatment of red blood cells. The protein was isolated and identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), amino acid analysis and finger-printing as carbonic anhydrase. The enzyme could be solubilized from the membrane by addition of beta-mercaptoethanol, suggesting an involvement of sulfhydryl-groups. In a reconstitution experiment, DMPS-treated human carbonic anhydrase could be attached to inside-out vesicles which were prepared from human erythrocytes. In contrast, bovine carbonic anhydrase, which is known to lack sulfhydryl-groups, failed to bind to the same vesicles. Moreover, attachment of carbonic anhydrase to the membrane did not occur when intact bovine erythrocytes were treated with DMPS. It is suggested that zinc-depletion of carbonic anhydrase causes the liberation of a sulfhydryl-group of the enzyme. This is followed by a disulfide formation with a component of the membrane which results in the observed membrane attachment.
Postganglionic compound action potential (AP) and intracellular NAD(P)H-fluorescence were recorded simultaneously in the perifused superior cervical ganglion of the rat (SCG) to study the effects of the bispyridinium oximes HGG12, HGG42 and obidoxime. HGG12 and HGG42 inhibit the compound action potential (AP) (ID50: 70 microM) and the reductive part of NAD(P)H changes (ID50: 75 microM) recorded upon stimulation of the SCG, while obidoxime has no ganglion blocking effects in concentrations up to 1 mM. The effects of inhibitors of cholinergic transmission were also studied in order to understand the mechanisms of action of the oximes. Hexamethonium (C6) and atropine, competitive inhibitors of receptors of nicotinic and muscarinic cholinergic transmission respectively, were found to block synaptic transmission (C6 ID50:150 microM, atropine ID50: 70 microM) and the reductive part of the NAD(P)H response (C6 ID50: 70 microM, atropine ID50: 50 microM) in a quantitatively similar way. Comparison of the ganglionic action of HGG12 and HGG42 with that of the inhibitory agents characterises them as inhibitors of receptors of nicotinic ganglionic transmission. Furthermore at concentrations of about 10 microM, HGG12 behaves like atropine and leads to an increase in AP and reductive fluorescence response. It is therefore probable that HGG12 has in addition an affinity for ganglionic muscarinic receptors which HGG42 does not have.
The effects of i.v. injected 4-dimethylaminophenol HCl, a ferri-hemoglobin-forming substance, on cerebral blood flow, brain temperature, blood gases, and lactate concentration in the sinus sagittalis blood were measured on male beagle dogs anesthetized with chloralose. An increase in cerebral blood flow became measurable when 5% or more of the hemoglobin was oxidized to ferrihemoglobin. The local cerebral blood flow of the cingulum region and the flow in the sinus sagittalis increased, while the sinus pO2 decreased. An increase in the ferrihemoglobin content of some 20% of the total hemoglobin at a constant arterial pO2 and pCO2 was attended with a decrease in the sinus pO2 of about 10 mm Hg when less than 40% of the heme iron was oxidized. The sinus pO2 approached a threshold value of some 8 mm Hg when the ferrihemoglobin content was increased above 40%. The lactate concentration began to rise very rapidly when 40-50% of the hemoglobin was oxidized. At the same time pCO2 increased and pH decreased in the sinus blood. The brain temperature remained unchanged. The behavior of conscious dogs with a ferrihemoglobin content of 40% of the total hemoglobin showed no abnormalities.
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The effect of tris-(2-chloroethyl)-amine (HN-3) on RNA and DNA was investigated spectrophotometrically. The shift in the absorbance spectrum caused by the addition of HN-3 was used to test a variety of compounds for their ability to inhibit RNA alkylation. The effect of HN-3 on the activity of several enzymes was also investigated. The activities of ribonuclease A, desoxyribonuclease I, acetylcholinesterase, diaphorase, glutathione reductase, adenosine desaminase, glyoxalase I, 3-hydroxyacyl-CoA-dehydrogenase, xanthine oxidase, glucose-6-phosphate dehydrogenase, hexokinase and the microsomal N-oxygenation of aniline were not changed by HN-3, whereas the activity of cytochrome-c-reductase exhibited a dose dependent diminution in the presence HN-3. Of 105 compounds tested only 14, namely, sodium thiosulfate, dithioxanthine, thiosalicylic acid, 1,2,4-triazole-5-thiol, 2-thiocytosine, 2-thiohistadine, 2,3-dithiosuccinic acid, thioglycolic acid, 3-mercapto-D-valine,6-amino-2-thiouracil, thionicotine amide, dithiothreitol, sodium sulfite, and ergothioneine prevented the alkylation of RNA. All of them also reacted with HN-3 in absence of RNA. No correlation was found between the reaction constant of the reaction compound:HN-3 in the absence of RNA and the concentration of the compound which inhibited RNA alkylation by 50%. The compounds which were effective in vitro were also tested in mice for their ability to reduce HN-3 toxicity in vivo. Only sodium thiosulfate, d-penicillamine, and dithiosuccinic acid were effective. A 3.9fold increase in the LD50 of HN-3 was achieved in mice treated with sodium thiosulfate 3330 mg/kg i.p., a 1.7fold with 2125 mg dithiosuccinic acid/kg, and a 2fold increase with 2500 mg/kg d-penicillamine. The compound tested was injected i.p. 0.5 to 1 min after the s.c. injection of HN-3.
Concerning the often discussed carcinogenic risk of psoriasis treatment with 0.005% S-mustard-vaseline (so-called Russian Ointment) -- especially by inhalation -- 19 patients were treated with a radioactive labeled S-mustard-ointment and examined. The patients' whole bodies were inuncted for 1--2 days with about 50 g of radioactive S-mustard vaseline (U14C, 3 muCi/g). Afterwards the radioactivity was determined in the patients' expired air, blood, urine, and in their surrounding air. In three patients punch biopsy material from normal and psoriatic skin was assayed for radioactivity after combustion. In the skin, radioactivity distinctly decreased from the epidermis (13.1 pCi/mg) to the subcutis (0.77 pCi/mg) without significant differences between normal skin and psoriatic lesions as confirmed by autoradiography. In all samples of air, body fluids and tissue, definitive amounts of radioactivity were found, which, however, were far below the US-American MAK-values. Between skin surface and shirt, the values varied from 1.5 to 13.7 nCi/20 l air, at a distance of 2 meters by 0.3 nCi/100 l air, in the breath by 0.5 nCi/20 l. The radioactivity decreased to 1/10 of the maximum values after 1--2 hours. In blood the activity was at the limit of detection and was parallelled by the activity of the urine. Generally, 1--7% of the radioactivity applied to the skin was eliminated with the urine within one week. Thus, the carcinogenic risk may be very low in the external S-mustard therapy of psoriasis and other skin diseases.
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