[Therapy of tuberculosis in the adult].
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AIDS-Related Opportunistic Infections↗
Biomedical subjects
K Wassermann
Publications and source records attributed to K Wassermann.
Lung function changes and exercise-induced ventilatory responses to external resistive loads in normal subjects.
AIM: The aim of this study was (1) to assess the value of common lung function variables in the follow-up of patients with obstructive lesions of the larynx and trachea and (2) to study the respiratory response to progressive upper airway stenosis at rest and during exercise. METHODS: Lung function tests, including vital capacity (VC), residual volume (RV), total body plethysmographic resistance (RT), specific body plethysmographic resistance (Rs), total body plethysmographic resistance at low inspiratory/expiratory flows (Rlo), forced expiratory volume in 1 s (FEV1), peak expiratory flow rate (PEF), peak inspiratory flow rate (PIF), maximum expiratory flow at 50% VC(MEF50) and maximum inspiratory flow at 50% VC(MIF50) were performed in 14 normal subjects with added external resistive loads (inner diameter of circular orifice: 15, 10, 8, 6 mm; equivalent to surface areas of 177, 79, 50 and 28 mm2, respectively), applied in random order. The relative sensitivity of each variable to detect a stepwise decrease in orifice size by evoking 'relevant' obstructive responses was calculated. In addition, ventilatory and gaz exchange responses to loaded breathing (10-, 8- and 6-mm orifices, randomly inserted) during steady-state bicycle exercise (80 and 160 W) were assessed in a subgroup of 10 subjects. RESULTS: The gradual increase of external load did not influence static lung volumes (VC, RV). MEF50/MIF50 (1.63 +/- 1.03 at baseline) remained essentially unchanged, consistent with the rigid nature of the obstructive device. PEF was superior in reproducing the transition from unloaded over mild (15 mm) and moderate (10 mm) to high grade (8 mm) central obstruction. Except for mild loads, PIF was equal in sensitivity to PEF. At high grade (8 mm) and severe loads (6 mm), no difference in sensitivity could be established between RT, Rs, FEV1, PIF and PEF. However, they were all superior to Rlo. Compared to unloaded breathing, ventilation across the 10- and 8-mm orifices at both rest and exercise produced a continuous significant increase in oxygen uptake (VO2). Respiratory rate (RR) fell, and a simultaneous enlargement of tidal volume (VT) was observed to maintain or even enhance minute ventilation (VE). However, ventilation across the 6 mm orifice was associated with a substantial decline in VO2, VCO2 and VE relative to the preceding load (8 mm) CONCLUSIONS: It is suggested that the experimental use of inspiratory and expiratory extrinsic loads can mimic rigid obstructive lesions of the larynx and trachea. Among all conventional lung function values, PEF and, to a certain degree, PIF, seem to be the best suitable follow-up parameters to assess airway mechanics before and after surgical/endoscopic procedures. Upper airway stenosis involving surface areas of no more than 50 mm2 can be overcome using adequate respiratory compensation. But any additional narrowing below this limit will result in hypoventilation, inappropriate oxygen uptake and retention of CO2. Thus, experimental evidence indicates that laryngotracheal obstruction within a critical range below 50 mm2 surface area (diameter of circular orifice < 8 mm) compromises respiratory efforts enough to be of clinical importance.
Adult↗
[Peak flow measurement in patients with laryngeal and tracheal stenoses. A simple and valuable spirometric method].
Body plethysmographic and spirometric indices can be used for routine examinations of obstructive lesions of the larynx and upper trachea. Total resistance, forced expiratory volume in 1 sec (FEV1) and the S-shaped flow-pressure loop can show clinically significant extrathoracic stenoses. We have now also measured peak inspiratory flow (PIF) and peak expiratory flow (PEF) with a peak flow meter. Easy handling was compared with good reliability of the measurements and possible detection of laryngeal lesions. Extrathoracic stenoses caused turbulent flow, with a flow-dependent increase in total resistance (Rtot). This resistance increased only with severe stenoses, while mild stenoses were often not detected. Peak expiratory flow reacted earlier than did peak inspiratory flow and seemed to be the most reliable parameter for detecting an extrathoracic stenosis. Testing was easy to perform and was usually reproducible. Patients with additional peripheral obstructive stenoses required a more specific examination.
Airway Obstruction↗
Ongoing activity of RNA polymerase II confers preferential repair of nitrogen mustard-induced N-alkylpurines in the hamster dihydrofolate reductase gene.
Recently, it has been demonstrated that nitrogen mustard-induced N-alkylpurines are excised rapidly from actively transcribing genes, while they persist longer in noncoding regions and in the genome overall. It was suggested that transcriptional activity is implicated as a regulatory element in the efficient removal of lesions. By treating cells or not with the transcription inhibitor alpha-amanitin, we have explored whether ongoing activity of RNA polymerase II was coordinately related to proficient repair of nitrogen mustard-induced alkylation products in the actively transcribed dihydrofolate reductase gene in the Chinese hamster ovary B11 cells. Nuclear run-off transcription analysis verified that alpha-amanitin completely and selectively inhibited transcription by RNA polymerase II. At the drug exposure examined, nitrogen mustard induced DNA damage capable of a complete transcription termination in the RNA polymerase II-transcribed dihydrofolate reductase gene and reduced 28S rDNA transcription by a factor of 7.9. The transcription activity did partially recover following reincubation in drug-free medium; this recovery was about 34 and 76% of ribosomal 28S gene transcripts and dihydrofolate reductase gene transcripts, respectively, after 6 h of repair incubation. alpha-Amanitin significantly inhibited the removal of nitrogen mustard-induced N-alkylpurines in the 5'-half of the essential, constitutively active dihydrofolate reductase gene, while no effect of alpha-amanitin was observed on the lesion removal from a noncoding region 3'-flanking to the gene and from the genome overall. In the actively transcribed gene region, about 77% of N-alkylpurines were removed 21 h following drug exposure of cells not treated with alpha-amanitin and about 47% in 21 h in alpha-amanitin treated cells. The global semiconservative replication seemed unaffected by the alpha-amanitin treatment. From these results we suggest that gene-specific repair of nitrogen mustard-induced N-alkylpurines is dependent on ongoing activity of the transcribing RNA polymerase II. The findings are discussed in terms of the current ideas about the mechanism of preferential DNA repair.
Amanitins↗
Complete nucleotide sequence of the Bacillus thuringiensis subsp. israelensis plasmid pTX14-3 and its correlation with biological properties.
The complete nucleotide sequence of the plasmid pTX14-3 from Bacillus thuringiensis subsp. israelensis has been determined. The circular DNA molecule was 7649 bp and had a G + C content of 35.1%. Twenty-two open reading frames larger than 50 codons were identified. Ten of these open reading frames are suggested to be protein coding regions. The existence of the polypeptides encoded by the mob14-3 and rep14-3 genes were verified by maxi-cells analysis in Escherichia coli. Even though the rep14-3 gene was expressed in E. coli the plasmid pTX14-3 was unable to replicate in this bacterium. The minimal region of the plasmid pTX14-3 required for replication in B. thuringiensis was identified. Potential secondary structures upstream of the rep14-3 gene indicated regulation by antisense RNA and transcription attenuation. Extensive sequence homology with the B. thuringiensis subsp. thuringiensis plasmid pGI2 was found in the last part of the mob14-3 gene, downstream of the rep14-3 gene, and in the region containing the single-strand origin of replication (i.e., the minus origin) of pTX14-3. A sequence of 700 bp containing multiple direct repeats was found in an ORF encoding a glycine and proline rich protein of 35.9 kDa. 1.2 kbp upstream and 0.1 kbp downstream of this ORF was found a large direct repeat of 230 bp (87% identity). The region between this direct repeat was often spontaneously deleted from plasmid derivatives containing the entire pTX14-3.
Amino Acid Sequence↗
Cellular resistance to cancer chemotherapy.
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Alkylation↗
Transcription-independent repair of nitrogen mustard-induced N-alkylpurines in the c-myc gene in Burkitt's lymphoma CA46 cells.
Recently, it has been demonstrated that N-alkylpurines produced by nitrogen mustard are excised more rapidly from actively transcribing genes compared to non-coding regions of the overall genome. Such studies have suggested that transcriptional activity is a determinant of the rate of removal of these DNA lesions. We have examined the removal of nitrogen mustard-induced N-alkylpurines in the actively transcribed/translocated and transcriptionally repressed native alleles of the c-myc gene in Burkitt's lymphoma, CA46 cells. Burkitt's lymphoma cells, exhibiting a c-myc translocation that can be distinguished from the native allele by Southern blotting, provide a useful model system in which to explore regulatory elements that govern DNA repair in transcriptionally active genes. Northern analysis verified the selective allelic expression of the translocated c-myc gene in CA46 cells. At the drug exposure examined, nitrogen mustard produced a similar level of N-alkylpurines in the two alleles of c-myc. Also, the kinetics of lesion repair from both c-myc alleles over a 24 h repair incubation period was of the same order of magnitude: approximately 34% and approximately 25% of nitrogen mustard-induced N-alkylpurines were removed by 8 h; approximately 72% and approximately 66% of nitrogen mustard lesions were removed by 24 h from the untranslocated and translocated alleles respectively. The untranslocated allele did not become transcriptionally activated upon drug treatment and nitrogen mustard produced a suppression of c-myc message levels from the translocated allele. Therefore, our results suggest that the rate of repair of nitrogen mustard-induced N-alkylpurines is independent of transcriptional activity of the c-myc gene in Burkitt's lymphoma. These findings are discussed in terms of the current views about the mechanisms of gene-specific repair.
Alkylation↗
Impairment of exercise capacity in various groups of HIV-infected patients.
It is known that pulmonary function is impaired during the course of HIV infection even in early stages. In order to estimate the resulting reduction of exercise capacity, different groups of HIV patients were investigated. Group 1 consisted of 20 patients without a history of respiratory disease and without actual lung disease, group 2 of 18 patients with a former episode of Pneumocystis carinii pneumonia (PCP) without actual lung disease, and group III of 37 patients with different broncho-pulmonary complications including PCP. 20 normal subjects served as controls. Spirometry, diffusing capacity (DLCO) and exercise tests including arterial blood gas analysis (BGA) were performed in patients and controls. Compared to the controls group 1 patients revealed a decreased DLCO (TCO: 83 +/- 15 vs. 67 +/- 15% pred.norm.) while spirometric data were normal. VO2 and O2 pulse at the anaerobic threshold (17.7 +/- 5.1 vs. 14.3 +/- 2.6 ml/kg.min and 10.8 +/- 4.0 vs. 8.6 +/- 1.9 ml/beat, respectively) and maximum exercise (33.9 +/- 9.7 vs. 22.1 +/- 3.4 ml/kg.min and 15.0 +/- 5.0 vs. 11.3 +/- 2.5, respectively) were decreased, whereas AaDO2, VD/VT, and the HR/VO2 slope were normal. The reserves of heart rate and ventilation were high. Except for a reduced maximum work rate in group 1, no significant difference was found between groups 1 and 2. Group 3 patients differed most from groups 1 and 2 with respect to spirometry, DLCO and AaDO2, rather than VO2.(ABSTRACT TRUNCATED AT 250 WORDS)
AIDS-Related Opportunistic Infections↗
Cordectomy versus arytenoidectomy in the management of bilateral vocal cord paralysis.
Our objective was to assess the effectiveness of transoral laser cordectomy and laser arytenoidectomy and to compare the results with a view to respiratory and phonatory function and deglutition. Twenty-eight patients with bilateral vocal cord paralysis were included in a prospective study. Eighteen patients had cordectomy, and 10, arytenoidectomy. Lung function tests and voice analysis were performed preoperatively and postoperatively. Subclinical aspiration was determined by endoscopic evaluation of the larynx during deglutition. The results were compared to determine the relative effectiveness of both surgical methods. Flow volume spirograms documented equally improved flow rates in both groups. The final voice evaluation revealed that maximum phonation time, peak sound pressure levels, and frequency range were reduced in all 28 patients, but the phonatory results varied considerably in each group. Subclinical aspiration was noticed in 5 of 10 patients after arytenoidectomy, but in none of 18 patients after cordectomy. Four of 6 previously tracheostomized patients were decannulated within 2 weeks after surgery, while the other 22 patients had no perioperative tracheostomies. We conclude that transoral laser cordectomy and arytenoidectomy are equally effective and reliable in the management of the restricted airway. Phonatory outcome is not predictable with either surgical procedure. Cordectomy is easier and faster to perform, and subclinical aspiration is not encountered with this procedure.
Adult↗
Intragenomic heterogeneity of DNA damage formation and repair: a review of cellular responses to covalent drug DNA interaction.
Chemical DNA interaction and its processing can now be studied at the level of specific genomic regions. Such investigations have revealed important new information about the molecular biology of the cellular responses to genomic insult and especially of the repair processes. They also have demonstrated that both the formation and repair of DNA damage display patterns of intragenomic heterogeneity. Therefore, mechanistic studies should involve examination of DNA damage formation and repair in specific genomic sequences besides in the overall genome to provide clues to the way in which specific modifications of DNA or chromatin could have specific biological effects. This review primarily focuses on studies done to elucidate the nature of DNA damage induction and intragenomic processing provoked by covalent drug-DNA modification in mammalian cells. The involvement of DNA damage formation and cellular processing as critical factors for genomic injury is exemplified by studies of the novel alkylating morpholinyl anthracyclines and the bifunctional alkylating agent nitrogen mustard as a prototype agent for covalent drug DNA interaction.
Alkylating Agents↗
Air trapping and cardiopulmonary exercise testing in patients with mild to moderate bronchial obstruction: clinical role of trapped gas measurements.
UNLABELLED: In 14 patients with obstructive airways disease (7 atopic asthmatics, 7 COPD pts with stable disease, FEV1 < 65% pred., 11 m, 3 f, age 50.9 +/- 17.2 y) the effect of a beta mimetic agent on physical performance was studied. PROTOCOL: Inhalation of 2.5 ml normal saline (P) or salbutamol 0.1% (S) in double-blind random order on 2 successive days. Spirometry, body-plethysmography, single-breath helium dilution at rest. Spiroergometry with incremental workload to tolerance. The volume of trapped gas (D) was derived from: TLC Body-TLC Helium Single Breath. RESULTS: Base line values revealed mild to moderate airways obstruction (FEV1 2.04 +/- 0.81 L, FEV1/VC 60.2 +/- 8.5%). Subsequent to inhaling S FEV1 increased significant by 20% to 2.38 +/- 0.87 L. There was a concomitant substantial improvement of VC (3.37 +/- 1.09 L to 3.60 +/- 0.93 L). Rs declined sign. (2.37 +/- 1.43 to 1.69 +/- 0.8 kPa*s), and so did D (1.15 +/- 0.73 L to 0.55 +/- 0.89 L = -20% from base line). Despite clear-cut bronchodilation exercise performance did not improve in response to S (114.6 +/- 49.3 vs 112.5 +/- 50.0 Watt max, ns). Base line max. VO2 (19.78 +/- 6.36 ml/min/kg) and VO2 at anaerobic threshold (13.29 +/- 3.21 ml/min/kg) suggested only minimal impairment of physical performance. S induced a small but significant decrease in max. VO2 (19.78 +/- 6.36 to 18.43 +/- 6.27 ml/min/kg, p < 0.025). Gas exchange (derived from AaDO2) was impaired at rest (30.18 +/- 10.4 mmHg) and during exercise (28.07 +/- 13.03 mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
[Predictive value of ergospirometry in preoperative assessment of risk factors before lung resections].
Surgical resection for lung cancer provides the only real chance for cure. However, there is a high risk of postoperative complications including death for patients with pulmonary dysfunction. Therefore preoperative identification of patients at risk is necessary. Apart from history and physical examination three tests are currently used: 1. resting lung function (RFL), 2. invasive measurement of pulmonary vascular resistance (PVR) and 3. exercise testing with measurement of oxygen consumption (VO2). Main studies in the literature report the probability of abnormal tests for prediction of pulmonary complications (positive predictive value) and the probability of normal tests for prediction of uneventful outcome (negative predictive value) as follows: [table: see text] In conclusion, the "ideal" test predictive for morbidity and mortality after lung resection has not been found. The positive predictive values of RLF and PVR are disappointing, while the negative predictive values are acceptable. Measurement of VO2 is simple, noninvasive and might predict survivable morbidity, as suggested in the literature. Obviously, additional studies are necessary.
Exercise Test↗
[Non-invasive measurement of stroke volume in steady-state and unsteady-state workload with CO2 rebreathing].
During steady-state exercise the noninvasive measurement of cardiac output using CO2-rebreathing has been found to be reliable and reproducible. In contrast, reliability of cardiac output measurement during unsteady state exercise is unclear. The ability to determine cardiac output (CO) noninvasively during steady state and unsteady state exercise was assessed in nine healthy students aged 25.7 +/- 7.4 years. Two cycle ergometer exercise tests were performed, one maximal unsteady state test with 25 watts increment of workload per minute, and also one steady state test at 25, 50, and 75 percent of max. VO2. CO was measured using the equilibrium CO2-rebreathing technique during unloaded cycling in both tests, at 75 and 150 watts in the unsteady state test and at all workloads during steady state exercise. Mean max. VO2 was 31.4 +/- 5.9 ml/kg/min and mean VO2 at the anaerobic threshold 24.5 +/- 7.2 ml/kg/min, respectively. During unsteady state exercise the CO2/workload slope was linear (r = 0.973), as with steady state exercise (r = 0.976). There was no difference concerning the slopes of both curves, but the elevation of VO2 with unsteady state exercise was lower, compared to steady state (p < 0.005). The relationships of CO/VO2 during unsteady and steady state exercise were best expressed by linear equations: CO = 7.49 x VO2 + 2.35 (r = 0.866) and CO = 8.24 x VO2 + 1.4 (r = 0.852), respectively. Similar to VO2/workload, both regressions did not have different slopes, but did have different elevations (p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
[Ergospirometric studies of normal probands for an unsteady-state increment test program].
One-hundred-sixteen healthy subjects (60 female and 56 male) with normal height (L) and weight (w) were selected to provide an even distribution of age (A, 20-70 years). All underwent an unsteady state cycle ergometer test with work increments of 20 watts each minute to exhaustion. A commercially available exercise testing system (EOS SPRINT, Jäger Corp., FRG) with gas analysis from a mixing chamber was used to study oxygen uptake (VO2), carbon dioxide output (VCO2), heart rate (HR), tidal volume (VT), breathing frequency (BR) and arterial oxygen tension (PO2) with special regard to the ventilatory anaerobic threshold (VAT) and maximum power output. For all parameters multiple regression equations were determined. Furthermore, heart rate reserve (HR-reserve), breathing reserve (VE-reserve), O2-pulse (VO2/HR), the dead space/tidal volume ratio (VD/VT) and the alveolar-arterial PO2-difference (AaDO2) were calculated. Day-to-day reproducibility was proven in 21 subjects. VO2max in females was 1584 +/- 300 ml/min (VO2max = -17 A + 10 L + 10 G + 58, r = 0.75, p < 0.0001), VO2AT 957 +/- 159 ml/min (VO2AT = 0.35 VO2max + 0.40 l/min, r = 0.77, p < 0.0001). The ratio VO2AT/VO2max was 50 +/- 7%. In male, VO2max was 2452 +/- 529 ml/min (VO2max = -23 A + 23 L + 9.5 G - 1395, r = 0.78, p < 0.0001), VO2AT 1209 +/- 213 ml/min (VO2AT = 0.29 VO2max + 0.51 l/min, r = 0.71, p < 0.0001), and VO2AT/VO2max 62 +/- 9%.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
[Stress studies in pneumology].
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Blood Gas Analysis↗
Repair of individual DNA strands in the hamster dihydrofolate reductase gene after treatment with ultraviolet light, alkylating agents, and cisplatin.
We have analyzed gene-specific and strand-specific DNA damage and repair in the dihydrofolate reductase gene in hamster cells. Cells were UV-irradiated or treated with two types of chemotherapeutics, alkylating agents or cisplatin. UV-induced pyrimidine dimers were detected using a previously published technique in which the T4 endonuclease V enzyme is used to create nicks at the lesion sites. 6-4 photoproducts were detected in a similar assay using ABC excinuclease after prior reversal of the pyrimidine dimers with photolyase. Adducts formed by the alkylating agents nitrogen mustard and dimethyl sulfate were quantitated by generating strand breaks at basic sites after neutral depurination. Cisplatin-induced intrastrand adducts were detected with ABC excinuclease, and cisplatin interstrand cross-links were detected using a denaturation-reannealing reaction before electrophoresis. In accord with previous reports by other investigators, we find distinct strand specificity of the repair of pyrimidine dimers after UV; the transcribed strand was much more efficiently repaired than the nontranscribed strand. In contrast, there was little or no strand bias in the repair of the 6-4 photoproducts. For alkylating agents, a slight bias toward repair in the transcribed strand was found after treatment with nitrogen mustard, but there appeared to be no bias in the repair after treatment with dimethyl sulfate. Cisplatin interstrand cross-links are repaired with equal efficiency from the two strands, but the more common cisplatin-induced lesion, the intrastrand adduct, is preferentially repaired from the transcribed strand. In conclusion, there is strand bias in the repair of pyrimidine dimers and cisplatin intrastrand adducts, but the strand specificity of repair may not be a general feature for all DNA lesions, as we found little or no strand bias in the repair of other lesions studied.
Alkylating Agents↗
Cancer risk related to genetic polymorphisms in carcinogen metabolism and DNA repair.
Chemical carcinogenesis involves metabolism in the body of the carcinogen to the ultimate carcinogen and its interaction with DNA. There is considerable interindividual variation in the metabolic ability to activate as well as detoxify the carcinogens and in the ability to repair the carcinogen-DNA adducts. In many cases such differences occur as genetic polymorphisms and form the basis for variation in susceptibility to carcinogens and thereby to cancer risk. The activation mechanism is particularly related to the cytochromes P-450 (CYPs), and four of these are known to activate carcinogens: CYP1A1, CYP1A2, CYP2E1, and CYP3A4. Increased cancer risk has been related to polymorphisms in the CYPs and other activating enzymes. The DNA repair mechanisms show considerable complexity, and deficient repair mechanisms in certain human disorders are clearly related to increased cancer risk. Yet, there is no unambiguous epidemiological evidence available for cancer risk among individuals in general. In vivo methods have to be refined and developed for use in epidemiological studies.
Animals↗
Mobilization of small plasmids in Bacillus thuringiensis subsp. israelensis is accompanied by specific aggregation.
Mobilizations of pBC16 and pAND006, containing the replicon of the Bacillus thuringiensis subsp. israelensis plasmid pTX14-3, between strains of B. thuringiensis subsp. israelensis were examined. Transconjugants appeared after a few minutes and reached a maximum frequency after approximately 2 h. Plasmid pBC16 was mobilized at a frequency approximately 200 times that of pAND006. However, pAND006 was consistently transferred, suggesting that the replicon of pTX14-3 is sufficient to sustain mobilization in B. thuringiensis subsp. israelensis. A specific protease-sensitive coaggregation between strains of B. thuringiensis subsp. israelensis was found to be unambiguously correlated with plasmid transfer. Two aggregation phenotypes, Agr+ and Agr-, were identified in this subspecies. Aggregation disappeared when the optical density of the mating mixture at 600 nm exceeded approximately 1, and it did not reappear upon dilution. Aggregation was shown to involve interactions of cells with opposite aggregation phenotypes, and evidence of a proteinaceous molecule on the surface of the Agr- that is cells involved in aggregation formation is presented. Matings and selection for the presence of two antibiotic resistance plasmids followed by identification of the host cell revealed that mobilization was unidirectional, from the Agr+ cell to the Agr- cell. The aggregation phenotype was found to be transferred with high frequency (approximately 100%) in broth matings, and the appearance of Agr- isolates from Agr+ strains suggested that the loci involved in aggregation formation are located on a plasmid. No excreted aggregation-inducing signals were detected in the supernatant or culture filtrate of either the donor, the recipient, or the mating mixture.
Bacillus thuringiensis↗