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Biomedical subjects

G Lazarus

Publications and source records attributed to G Lazarus.

At least 19 recordsLinked to original sources
PubMed1999

Increased formation of thromboxane in vivo in humans with mastocytosis.

Clinical manifestations of mastocytosis are mediated, at least in part, by release of the mast cell mediators histamine and prostaglandin D2. It has been previously reported that in addition to prostaglandin D2, mast cells produce other eicosanoids, including thromboxane. Nonetheless, little information exists regarding the formation of other prostanoids in vivo. The most accurate method to examine the systemic production of eicosanoids in vivo is the quantitation of urinary metabolites. We previously developed a highly accurate assay employing mass spectrometry to measure a major urinary metabolite of thromboxane, 11-dehydro-thromboxane B2, in humans. We utilized this assay to quantitate thromboxane production in 17 patients with histologically proven mastocytosis. We report that thromboxane formation was significantly increased (>2 SD above the mean) in at least one urine sample from 65% of patients studied. Of these, 91% of patients with documented systemic involvement had elevated thromboxane generation. In addition, endogenous formation of thromboxane was highly correlated with the urinary excretion of the major urinary metabolite of prostaglandin D2 (r = 0.98) and Ntau-methylhistamine (r = 0.91), suggesting that the cellular source of increased thromboxane in vivo could be the mastocyte. Enhanced thromboxane formation in patients with this disorder is unlikely to be of platelet origin as other markers of platelet activation, platelet factor 4 and beta-thromboglobulin, were not increased in three patients with marked overproduction of thromboxane. Furthermore, the recovery of 11-dehydro-thromboxane B2 excretion in two patients after the administration of aspirin occurred significantly more rapidly than the recovery of platelet thromboxane generation. These studies, therefore, report that thromboxane production is significantly increased in the majority of patients with mastocytosis that we examined and provide the basis to elucidate the role of this eicosanoid in disorders of mast cell activation.

6-Ketoprostaglandin F1 alpha↗
PubMed1996

Topical calcipotriene has no short-term effect on calcium and bone metabolism of patients with psoriasis.

BACKGROUND: The biologically active form of vitamin D3, calcitriol, is effective in the treatment of psoriasis but can alter calcium metabolism. Calcipotriene is an analog of calcitriol that has low calcemic activity and aids in clearing psoriasis. OBJECTIVE: The purpose of this study was to determine the safety of topical therapy with calcipotriene particularly in relation to calcium and bone metabolism. METHODS: In a double-blind, randomized, parallel, vehicle-controlled trial, 78 adults with plaque psoriasis were treated twice daily with topical calcipotriene ointment (50 microgram/gm, maximum usage, 120 gm per week) or vehicle for 8 weeks. After a screening visit, patients were admitted to the hospital at weeks 0 (baseline), 1,2,4, and 8. Blood and urine chemistry analysis included parathyroid hormone, serum calcium, bone-specific alkaline phosphatase, urinary hydroxyproline, and 24 hour urinary calcium excretion. Bone densitometry measures were performed at baseline and week 8. RESULTS: No incidences of calcipotriene treatment-related hypercalcemia, calcium mobilization from bone, or clinically significant changes in bone density wer noted during this study. CONCLUSION: Topical application of up to 120 gm per week of calcipotriene ointment for 8 weeks is safe and effective for plaque psoriasis. There were no adverse effects on calcium and bone metabolism during this 8 week study.

Administration, Cutaneous↗
PubMed1995

Improved diagnosis of mastocytosis by measurement of the major urinary metabolite of prostaglandin D2.

Symptoms of mastocytosis have been attributed to the overproduction of both histamine and prostaglandin (PG) D2. Recently, we developed an assay for the major urinary metabolite of PGD2 (PGD-M), 9 alpha,11 beta-dihydroxy-15-oxo-2,3,18,19-tetranorprost-5-ene-1,20-dioic acid, and demonstrated that urinary excretion of this compound is markedly increased in patients with mastocytosis. It had been shown previously that measurement of the urinary excretion of histamine metabolites provides a more sensitive biochemical diagnostic indicator of systemic mastocytosis than does measurement of unmetabolized histamine. Therefore, we examined the correlation between the urinary excretion of the histamine metabolite, NT-methylhistamine, and PGD-M in urine samples from patients with mastocytosis. Urinary excretion of NT-methylhistamine and PGD-M was measured in 46 urine samples from 17 patients with histologically documented mastocytosis. Both compounds were quantified by mass spectrometry. In all urine collections showing an increase above normal (2 SD above the mean) in the excretion of NT-methylhistamine, the fold increase above normal in the urinary excretion of PGD-M was substantially greater. Further, in some urine samples from four patients whose excretion of NT-methylhistamine was consistently normal, the excretion of PGD-M was increased above normal by as much as 300%. These data indicate that quantification of the urinary excretion of PGD-M is a more sensitive biochemical diagnostic indicator of mastocytosis than is the quantification of NT-methylhistamine.

Adult↗
PubMed1994

Expression of plasminogen activator inhibitor type 2 in normal and psoriatic epidermis.

The plasminogen activator (PA) proteolytic cascade has been implicated in the regulation of cell activities, including proliferation and differentiation, both of which occur continuously in normal human epidermis and are aberrant in psoriatic epidermis. To elucidate further the mechanisms by which PA is regulated in epidermis, we evaluated the levels of PA inhibitors type 1 (PAI-1) and type 2 (PAI-2) in normal and psoriatic epidermis. PAI-2, but not PAI-1, was detectable by mRNA, antigen, and activity assays, indicating that PAI-2 is the predominant epidermal PA inhibitor. In situ hybridization revealed that PAI-2 mRNA occurred throughout normal epidermis, although the signal was most intense in the granular layers. Similarly, PAI-2 antigen was most prominent in the granular layers; its distribution in these differential layers was along the cell periphery. Diffuse, fainter staining for PAI-2 was also detected in the basal cells and in some spinous layers of normal epidermis. Extracts of normal epidermis contained PA inhibitory activity identified as PAI-2 by immunoprecipitation with specific antibody. In psoriatic epidermis, PAI-2 mRNA and antigen were most prominent in the more superficial layers beneath the cornified cells. As with normal epidermis, PAI-2 assumed a pericellular distribution in the psoriatic cells. These data demonstrate that PAI-2 is constitutively expressed in vivo by keratinocytes in human epidermis and indicate that this protein is the predominant inhibitor of PA activity in normal and psoriatic human epidermis.

Antigens↗
PubMed1992

[The reliability of proximal and distal gas samples in the capnometry of infants].

UNLABELLED: To compare the accuracy of end-tidal pCO2 measurement derived from the connector (petCO2 proximal) and from the tip of the endotracheal tube (petCO2 distal), we measured paCO2, petCO2-proximal and distal in 42 infants (weight: 2500-9500 g) manually ventilated with an Ayre's t-piece breathing circuit (Kuhn modification). For distal gas sampling we used a commercially available "uncuffed tracheal tube with monitoring lumen" Mallinckrodt, Hennef, with a separate monitoring lumen leading to the distal tip of the endotracheal tube. Compared with paCO2 (26.2 +/- 5.3 mmHg), proximal gas sampling resulted in a significantly lower petCO2 (17.3 +/- 6.0; P less than 0.001) and a large arterial-end-tidal pCO2 difference (pa-etCO2 9.0 +/- 6.8 mmHg). The correlation between paCO2 and petCO2 was poor (r = 0.29; n.s.). In infants weighing less than 5000 g the arterial-end-tidal pCO2 difference was found to be especially high (12.1 +/- 5.1 mmHg); it was slightly smaller in infants with more than 5000 g (5.6 +/- 7.0 mmHg). Distal petCO2 values approximated arterial pCO2 much better (petCO2 26.0 +/- 5.8 mmHg; diff pa-etCO2 0.4 +/- 3.0 mmHg, r = 0.86) even in very small children. In 12 children (weight: 2500-8000 g) ventilated with a circuit (Dräger-Kreissystem) accurate petCO2 measurements were obtained from both the proximal and the distal sampling site. CONCLUSIONS: When an Ayre's t-piece is used for ventilation of children weighing less than 10 kg, distal gas sampling for petCO2 measurement should be preferred. Proximal gas sampling does not allow correct capnometry except in a circuit with one-way valves.

Carbon Dioxide↗
PubMed1991

Rapid and specific conversion of precursor interleukin 1 beta (IL-1 beta) to an active IL-1 species by human mast cell chymase.

Secretory granules of human dermal mast cells contain a chymotrypsin-like serine proteinase called chymase. In this study, we demonstrate that the inactive cytokine, 31 kD interleukin 1 beta (IL-1 beta), can be converted rapidly to an 18 kD biologically active species by human mast cell chymase. The product formed is three amino acids longer at the amino terminus than the mature IL-1 beta produced by peripheral blood mononuclear cells and has comparable biological activity. Because chymase is a secretory granule constituent, it is likely to be released into the surrounding tissue when mast cells degranulate. It is also known that non-bone marrow derived cells resident in skin (keratinocytes, fibroblasts) produce but do not process 31 kD IL-1 beta. In this context, chymase may be a potent activator of locally produced 31 kD IL-1 beta. Mast cells lie in close apposition to blood vessels in dermis; therefore, chymase mediated conversion of 31 kD IL-1 beta might be expected to have a critical role in the initiation of the inflammatory response in skin.

Amino Acid Sequence↗
PubMed1991

Urticaria pigmentosa. Systemic evaluation and successful treatment with topical steroids.

Nine patients with adult-onset urticaria pigmentosa were studied for the incidence of extracutaneous mast cell involvement and the efficacy of potent topical corticosteroid therapy for cutaneous lesions. Seven of the nine patients had increased mast cells in the marrow biopsy specimens, and five patients had focal aggregates of mast cells. The bone scan was abnormal in one patient. Liver-spleen scans revealed a shift of colloid uptake from liver to spleen in four patients. No abnormal gastrointestinal tract roentgenograms were obtained. Urinary histamine metabolites correlated with nodular bone marrow involvement, but not with other parameters. Results of the psychoneurologic testing revealed significant deviation from the norm with a verbal memory deficit in all nine patients and abnormalities on the Minnesota Multiphasic Personality Inventory in four patients. All nine patients were treated with 0.05% betamethasone dipropionate ointment under occlusion over half of the body nightly for 6 weeks. Seven of nine patients treated responded with almost complete resolution of their lesions. Hypothalamic pituitary adrenal axis suppression was evaluated with intramuscular cosyntropin stimulation and metyrapone administration during treatment. Only two patients, both of whom used the medication improperly, developed transient abnormalities. Slow return of lesions was noted 6 months after completion of therapy. Remissions could be lengthened with single weekly applications of topical steroids. Systemic involvement is frequent in patients with cutaneous mast cell disease and it is best demonstrated by bone marrow biopsy. Mast cell lesions can be safely and effectively treated with topical steroids in motivated patients.

Administration, Topical↗
PubMed1991

Treatment of psoriasis with piritrexim, a lipid-soluble folate antagonist.

Methotrexate is an effective and convenient treatment for severe psoriasis whose use is limited by the development of hepatic fibrosis and cirrhosis in a small number of patients. The mechanism of hepatotoxicity is unknown, but it is believed to be the result of intracellular polyglutamation and prolonged retention of methotrexate within the cell. Piritrexim isethionate is a lipid-soluble antifolate that has a mechanism of action similar to that of methotrexate. Since it is not polyglutamated, piritrexim could be effective in the treatment of psoriasis without the associated long-term hepatotoxicity. A 12-week phase I/II clinical trial of severe chronic plaque psoriasis assessed the safety and efficacy of oral piritrexim therapy. Based on experience gained from oncologic trials, each patient received a twice-daily dosage for 5 consecutive days every 2 weeks. Dosages ranged from 25 to 100 mg twice a day. Improvement in both lesion scores and percentage of body involvement was significant at a dose of 50 mg or more twice daily. Fifteen of 19 patients who completed 12 weeks of therapy demonstrated greater than 50% improvement in lesion scores. Improvement was limited by recrudescence of lesions over the 9-day rest period. Adverse experiences were minimal and dose related. Piritrexim is efficacious in the treatment of psoriasis.

Adult↗
PubMed1989

[Pulmonary segmental artery angiography in intensive care patients].

The indication for wedge angiograms in intensive-care patients within the scope of X-ray chest examination is outlined. The obligatory wedge angiogram in patients with Swan-Ganz catheter is redundant. 4 indications for this special examination are specified. As a new possibility for differentiating between the ventral or dorsal course of pulmonary vessels, an inverse ratio of arborization angles is outlined for the first time.

Catheterization, Swan-Ganz↗
PubMed1987

[Antagonism of an intubation dose of vecuronium].

To study the problem of rapid antagonization of an intubation dose of vecuronium (0.08 mg/kg), 36 surgical patients undergoing barbiturate/halothane anesthesia were given edrophonium 0.5, 0.75, and 1.0 mg/kg or neostigmine 0.04, 0.06, and 0.08 mg/kg precisely 5 min following injection of the muscle relaxant. T1 twitch (T1/Tc) and train-of-four (TOF) ratios (T4/T1) of the hypothenar muscle were monitored every 20 s with the aid of a commercially available EMG monitor (Datex-Relaxograph). As documented by T1 and T4/T1 follow-up curves (Figs. 1 and 2) and derived parameters of relaxation as well (Dur25, Dur50, Dur75, recovery index, and reversal time; Table 4), both edrophonium and neostigmine resulted in a significantly shorter duration of vecuronium blockade (P less than 0.001). The mean time for recovery of TOF ratio to above 0.7 was between 10.8 +/- 6.0 (neostigmine 0.08 mg/kg) and 21.2 +/- 7.8 (neostigmine 0.06 mg/kg) min (mean +/- SD) following injection of the antagonist as compared to 58 +/- 18.4 min in the control group (P less than 0.001). Recurarization did not occur. Differences between drugs and dose-dependent effects were minimal; edrophonium did not prove superior to neostigmine with the exception of less pronounced muscarinic side effects, hence less bradycardia and a minimum heart rate of 57 +/- 8.2 bpm 20 min after the injection of neostigmine as opposed to 72 +/- 8.2 bpm following edrophonium (P less than 0.05; Fig. 4). As to the restitution of a ventilatory force sufficient to allow spontaneous breathing, no definite conclusions can be made.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1986

[Hemodynamic side effects of high-frequency jet ventilation as a function of lung volume. Impedance spirometric studies].

In five patients with acute respiratory insufficiency the changes in tracheal pressure (P), lung volume (V) and transthoracic electric impedance TEI (Z) were measured during delayed expiration all over the inspiratory capacity (IC) from TLC to FRC. The quasi-static V/Z- and Z/P-curves were two-dimensionally displayed, and the Z/P-curve was volume-calibrated on the Y-axis (Z) using the linear V/Z-relationship. During high-frequency jet ventilation (HFJV, 200/min), the Z- and P-excursions were displayed on the "frozen" Z/P-curve as flat discs. By well-aimed increase in driving pressure and I/E-ratio the unknown FRC was enhanced in 4 stages (I-IV) by 0.33 IC, 0.5 IC, 0.66 IC and 0.75 IC, to measure haemodynamic reactions 10 minutes later (Swan-Ganz catheter). The pulmonary vascular resistance remained unchanged between stage I and II. It changed moderately in stage III (+14%) and was found to be markedly increased in stage IV (+45%). The increase in PVR was well parabolically correlated (r = 0.88) to the fraction of IC by which FRC was expanded. In a previous study a very similar function could be documented by us for the end-inspiratory lung volume during conventional PEEP ventilation. Concomitant to the increase in PVR the CI fell linearilly (r = 0.95). We conclude from our results: 1. TEI may be of value in monitoring HFJV. It offers the possibility to measure the increase in lung volume ("PEEP effect") and to titrate it deliberately within the usable volume range IC. 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiography, Impedance↗
PubMed1985

[PEEP ventilation without hyperinflation of the lungs. A primary ventilatory pattern of controlled respiration based on expiratory volume curves].

When starting controlled ventilation with PEEP, a ventilation within the mid-third of the inspiratory capacity (IC) with a tidal volume (VT) of IC/3 ("primary VT") is recommended, to increase functional residual capacity (FRC) effectively and to avoid adverse haemodynamic effects related to hyperinflation of the lung. The quasi-static expiratory pressure-volume curves (VPE) of 28 patients with acute respiratory failure were graphically analyzed to evaluate the PEEP which could be expected to increase FRC by 1/3 of the IC ("primary PEEP"). the volume by which VT must be reduced, to keep the endinspiratory lung volume constant, if a higher PEEP would be desired. The "primary PEEP" was found to be 12,2 +/- 2,5 cmH2O, thus confirming the clinical practice to use preferentially 10 cmH2O. In 3 patients with progressive pulmonary failure and severely reduced IC as well as in 3 grossly obese patients the "primary PEEP" was markedly higher (15-18 cmH2O). The volume-pressure relation in the steep linear mid-third of the VPE correlated closely with the IC (r = 0.92). This means that the increase in FRC per 1 cmH2O PEEP in this range can be expressed as a nearly constant fraction of the IC (delta FRC/ delta PEEP = IC/32). Hence, to avoid endinspiratory hyperinflation of the lung, it is recommended to reduce the "primary VT" by IC/32 or, which means the same, by VT/10 per 1 cmH2O PEEP exceeding 10. If, however, a ventilatory pattern has to be chosen with respect to gas exchange, where hyperinflation cannot be excluded, this should be done under close haemodynamic control using a Swan-Ganz catheter.

Adolescent↗
PubMed1983

[End inspiratory lung volumes as the limiting factor in PEEP ventilation].

In 17 patients requiring artificial ventilation expiratory pressure-volume curves (VPE) were plotted all over the inspiratory capacity (IC) between total lung capacity (TLC) and functional residual capacity (FRC). Then patients were ventilated with PEEP of 0, 5, 10 and 15 cmH2O for 30 min. The volume excursions with known PEEP were displayed graphically into the VPE to determine the position of end-inspiratory volume within the IC. The steep, quasi-linear part of each VPE was flattening exponentially against TLC in the upper part of the curve. This "overdistension range" was found to be identical with the upper 40% of IC. Heavy side-effects of PEEP ventilation were never seen before the inspiratory volume excursion had reached this upper 40% of IC. If this was the case, the following observations were made: 1. Static compliance (Cst) decreased by more than 10% in all cases. 2. Pulmonary vascular resistance (PVR) increased by more than 20% in 12 cases. 3. Cardiac index (CI) decreased by more than 15% in 12 cases. 4. The alterations observed in Cst, PVR and CI increased rapidly, when the lungs were further distended, and were well correlated parabolically to the position of end-inspiratory volume within IC. --5 patients failed to show important circulatory alterations. It is concluded that overdistension-related side-effects of PEEP on respiratory mechanics and circulation do not occur before the linear part of the pressure-volume curve has been exceeded by hyperinflation. For the first adjustment of controlled ventilation at least the upper third of IC should be avoided.

Adolescent↗
PubMed1982

[Pulmonary fibrosis following ARDS. Case report of successful intensive therapy (author's transl)].

The course of the illness of a 56 year old female patient is reported, who is still surviving one and a half years after developing advanced, presumably progressive, so called "shock-lung syndrome". Following two episodes of hemorrhagic shock due to intestinal hemorrhage and post-operative secondary hemorrhage, interstitial lung edema developed, which was resistant to therapy. During the following weeks this was followed by bronchopneumonia with symptoms of sepsis persisting over several weeks. Between the third and seventh week of artificial ventilation X-ray of the lungs showed significant progressive changes of the interstitial tissues. This correlated with a progressive deterioration in gas exchange for O2 and CO2, which reached its peak in the seventh week with a paO2 of 71 mm Hg at a FIO2 = 1 and a paCO2 of 68 mm Hg at a minute volume of 15,51. The compliance of lung and thorax was severely reduced at 19 m1/cm H2O. At this apparently unfavourable time the patient was weaned off the respirator, and subsequently, over a period of three weeks, from oxygen insufflation. After eleven weeks of therapy, transfer to the medical ward was possible, with discharge from the hospital following three weeks later. The lung function tests at the time of discharge revealed a high grade reduction of all lung volumes and capacities without a significant obstructive component. The findings have shown a definite improvement during the following one and a half years. In retrospect the polypragmatic intensive therapy measures do not allow valid generalised therapeutic guidelines to be derived. We conclude, however, from this single observation, that therapeutic nihilism is not justified even in a progressive shock-lung syndrome which appears clinically and radiologically to be at an "irreversible" end stage.

Anesthesia↗
PubMed1981

Hexobarbitone disposition at different stages of intensive care treatment.

The pharmacokinetics of hexobarbitone were investigated in 22 patients in an intensive care unit. The results were compared with those obtained in a healthy group for three time periods: 3rd or 4th day (I), 5-8th days (II) and 13-29th days (III) of treatment. Hexobarbitone 7.32 mg per kg of body weight was administered by i.v. infusion in 60 min. At the end of the infusion, the mean plasma concentration of group I was 71% greater than control group; groups II and III were near to control. In all patients the post-infusion concentration-time course of hexobarbitone could be described by two-compartment kinetics. The biphasic decrease in plasma concentration of hexobarbitone was more rapid in groups II and III, than in either the control group or in group I. At the beginning of treatment patients generally showed an unchanged hexobarbitone half-life, a slightly decreased plasma clearance, a reduction of approximately 50% of the initial distribution volume. (V1) and a reduction of 44% of the distribution volume at steady state. In groups II and III the mean of these values were comparable to control. However, plasma clearance had increased by about 87% in group II compared with control, and after 2-3 weeks (group III) by about 143%. Correspondingly, half-life was reduced by 45% and 58% respectively. The pharmacokinetics were not related to change in liver function. The presence of clinical and bacteriological signs of septicaemia was closely associated with an enhanced hexobarbitone clearance.

Adult↗