[Pregnancy-associated osteoporosis. Differential diagnosis of "common" musculoskeletal pain during pregnancy and lactation]. / Schwangerschaftsassoziierte Osteoporose. Differentialdiagnose des "banalen" muskuloskelettalen Schmerzes in Schwangerschaft und Stillzeit.

Musculoskeletal pain during pregnancy and lactation is a common finding. Differential diagnoses range from"normal" findings to disturbances in bone metabolism and pregnancy-associated osteoporosis (PAO). Imaging options are limited due to pregnancy, and laboratory diagnostics are time-consuming. Treatment of PAO with physiotherapy, pain killers and substitution of vitamin D and calcium leads to a rapid recovery from symptoms.

Long-term oral bronchodilator therapy of asthma with pirbuterol.

We studied the effects of an oral beta2 selective bronchodilator, pirbuterol, in 12 male asthmatic patients over periods ranging from 6 to 23 months (mean, 13.8). Each patient was evaluated initially by physical examination, urinalysis, blood analysis, and pulmonary function tests. Patients were examined at regular intervals thereafter. Patients remained off all bronchodilator therapy for 12 hr before each visit. Blood analysis, urinalysis, and pulmonary function tests were performed and the pulmonary function tests were repeated approximately 2 hr after an oral dose of pirbuterol. We found no significant changes in the baseline resistance or in the bronchodilator response to pirbuterol during the course of the study, but there was a significant decrease in the functional residual capacity (FRC). The reduction in FRC could be due to the prolonged reduction in airways resistance with continuous therapy. We found no increase in the bronchodilator response to pirbuterol during oral prednisone therapy. There were no significant changes in serum potassium. Side effects attributable to pirbuterol, nervousness and tremor, occurred in only 2 patients and were easily controlled.

Malignancies in families of women with medullary, tubular and invasive ductal breast cancer.

Breast cancer seems to represent a heterogeneous group of neoplasia originating from the parenchymal epithelium of the mammary gland. Family studies combined with genetic epidemiological analyses and histological evaluations were used to gain an insight into this nosological entity. Special emphasis was given to the type and frequency of neoplasia in close relatives. This study represents pedigrees of 36 histologically defined pure tubular and 22 pure medullary breast cancer patients as well as 171 with the invasive ductal form. The incidence of cancer in the first degree relatives of all three groups is compared to that of the local population. The first degree relatives did not have a higher risk (RR) for the neoplastic diseases. However, breast cancer occurs more frequently in the female relatives of all three groups. Other cancers have different relative risks.

The effects of the combination of inhaled ipratropium and oral theophylline in asthma.

BACKGROUND: In comparison to beta-agonist drugs, which are the primary bronchodilator drugs in current use in asthma, both oral theophylline and inhaled ipratropium have a weaker bronchodilating action in asthma. Although a number of studies have shown an additive effect of ipratropium in combination with beta-agonist bronchodilator drugs in asthmatics, to our knowledge, the effects of combined treatment with ipratropium and theophylline have not been assessed. STUDY OBJECTIVE: To assess whether the combination of oral theophylline and inhaled ipratropium has an additive bronchodilator effect in asthmatics. DESIGN: Double-blind, placebo-controlled, crossover study. SUBJECTS: Nineteen patients (8 male, 11 female) with mild-to-moderate stable asthma. METHODS: Initially the optimal single oral dose of theophylline required to achieve therapeutic blood levels (10 to 20 microg/mL) was established in each patient. They then returned at varying intervals on 4 subsequent days. On each day, they received, in a random, placebo-controlled, double-blind, crossover design, one of four different therapies: oral and inhaled placebo; oral theophylline at the established optimal dose (range, 300 to 700 mg) plus inhaled placebo; oral placebo plus inhaled (40 microg) ipratropium; and the combination of theophylline and ipratropium. Spirometry was performed at baseline and at 15 min, 30 min, and hourly intervals for 6 h after therapy. RESULTS: Each drug regimen resulted in a significant (p<0.05) increase in FEV1, but the combined regimen resulted in a significantly greater bronchodilation (p<0.05) over either ipratropium or theophylline alone (FEV1=3.00+/-0.75 L vs 2.48+/-0.77 L vs 2.61+/-0.72 L, respectively, at 3 h postdrug). CONCLUSIONS: There was a significant, early, sustained additive bronchodilator effect of the combination therapy; there were no untoward side effects. These findings indicate that the addition of inhaled ipratropium to oral theophylline provides greater bronchodilation than either drug alone and may be a useful therapeutic modality in asthma.

Resting ventilatory pattern, mouth occlusion pressure, and the effects of aminophylline in asthma and chronic airways obstruction.

Patients with obstruction of the airways can maintain normocapnia either by increasing the central inspiratory neuromuscular output or by altering the central timing of each breath. This point and the effects of administration of aminophylline on ventilatory regulation were studied in six normal subjects, seven asthmatic patients, and eight patients with unresponsive chronic obstruction of the airways. Spirometric and body plethysmographic values, the ventilatory pattern, and the mouth occlusion pressure did not differ between the two groups of patients. The results indicate that in these patients, normocapnia is maintained at rest by increased central inspiratory neuromuscular output; central respiratory timing is not altered. Intravenous administration of aminophylline (5.6 mg/kg of body weight) increased alveolar ventilation in all three groups, without increasing the uptake of oxygen. In normal subjects, there was no significant effect on ventilatory regulation or drive. In asthmatic patients the central timing of each breath was altered, with no significant effect on central inspiratory output. In unresponsive obstruction of the airways, the central inspiratory output increased transiently, with no effect on central timing.

Breathlessness and mouth occlusion pressure in patients with chronic obstruction of the airways.

In order to evaluate the hypothesis that the sensation of dyspnea is due to an "inappropriate relationship between length and tension" in the respiratory musculature, studies were performed in 24 patients with chronic obstruction of the airways. They were divided into two groups solely on the basis of subjective and objective presence or absence of breathlessness and dyspnea at rest. Spirometric tests and body plethysmography were performed in each patient. The ventilatory pattern at rest was recorded and repeated measurements of mouth occlusion pressure were made. It is concluded that breathlessness in patients with airways obstruction is not associated with major differences in arterial blood gases or in VO2, VE, f or the pattern of individual breaths; there is a greater degree of airway obstruction and increased inspiratory neuromuscular drive. The minute ventilation achieved for a given inspiratory neuromuscular output, which may be considered analogous to the length-tension relationship of the respiratory musculature, is significantly decreased. These results are in accordance with the theory of mechanical inappropriateness as a cause of dyspnea.

Ventilatory effects of doxapram in conscious human subjects.

The ventilatory effects of a bolus intravenous dose of doxapram (0.37 to 0.47 mg/kg) were studied in ten healthy normal subjects. An immediate significant (p less than 0.001) increase in minute ventilation (VE) was due, in equal part, to significant increases in tidal volume (VT) and frequency (f). The inspiratory (TI) and expiratory time (TE) per breath decreased significantly. Mouth occlusion pressure increased significantly, in association with the increase in VT; there was no change in the ratio of VE to mouth occlusion pressure, indicating that respiratory mechanics did not alter. These results indicate that doxapram increases ventilation in conscious, normal man by an increase in inspiratory neuromuscular drive and a change in central breath timing. The ventilatory and mouth occlusion pressure responses to progressive isocapnic hypoxia and progressive hyperoxic hypercapnia were significantly altered by an intravenous infusion of doxapram (1 mg/min) only in the elevations (Y-intercepts) of the slopes of VE and mouth occlusion pressure; the regression coefficients did not change significantly. These results indicate that in conscious normal subjects, doxapram acts on both the peripheral and central respiratory receptors.

Alterations in ventilatory pattern and ratio of dead-space to tidal volume.

The effects of alterations in ventilatory pattern on the simultaneously measured physiologic and anatomic dead-spaces (VDphys and VDan, respectively) and the dead-space to tidal volume ratio (VD-VT) were studied in 17 healthy normal subjects (13 men, four women, ages 21 to 36 years). There were no significant changes in VDan with increases in respiratory frequency (f) or tidal volume (VT). The VDphys increased (mean change +0.153 L, p less than 0.05) with increase in VT (mean increase +0.84 L, p less than 0.01), but did not alter significantly with a twofold increase in f, at control VT. Increase in VT significantly reduced VD/VT (mean change -10.4 percent, p less than 0.05), but increase in f, at control VT, did not significantly alter VD/VT. These results indicate that in normal subjects, increase in VT alters ventilation/perfusion matching in the lungs, whereas an increase in f, at constant VT, has no effect on ventilation/perfusion matching. Increases in VD/VT cannot, therefore, be ascribed to alterations in ventilatory pattern where either VT, or f, or both are increased.

The relationship of resting ventilation to mouth occlusion pressure. An index of resting respiratory function.

In order to examine the relationship of mouth occlusion pressure (MOP), an index of central inspiratory neuromuscular drive, to age and sex and to resting ventilation (VE), measurements were made in the seated posture in 84 healthy, normal subjects (38 men, 46 women; ages 18-72 years, mean +/- SD = 39.8 +/- 14.5 years) and in 79 patients with either airways obstruction (n = 63) or restrictive lung disease (n = 16). In the normal subjects, there was no significant relationship between age or sex and MOP (expressed as P0.1), which is the mouth pressure developed against a complete occlusion at 0.1 s after the beginning of inspiration, and dP/dtmax, the maximal rate of rise of this pressure; mean +/- SD for P0.1 = 0.75 +/- 0.32 cmH2O, and dP/dtmax = 19.41 +/- 10.10 cmH2O/s. Similarly, there was no significant relationship between age or sex and VE/P0.1 or VE/dP/dtmax. In 99 percent of normal subjects (83 of 84), VE/P0.1 was greater than 8.0 L/min/cmH2O, whereas in only 1 of the 79 patients was the value greater than 7.9 L/min/cmH2O. While the mean values of P0.1 and dP/dtmax were significantly different between normal subjects and patients, there was considerable overlap, whereas the ratio VE/P0.1 or VE/dP/dtmax provided excellent differentiation between normal subjects and patients with lung disease. This index, which is easily measured and requires minimal patient cooperation, provides valuable information in the clinical assessment of ventilatory drive and lung mechanics.

Maximal expiratory flow patterns after single-lung transplantation in patients with and without chronic airways obstruction.

BACKGROUND: A biphasic-plateau pattern in the maximal expiratory flow-volume (MEFV) curve has been described after single-lung transplantation (SLT) in patients with chronic airways obstruction (CAO). It has been theorized that this pattern is either related to stenosis at the anastomotic or subanastomotic site, or the sum of the airflow contribution from the native lung with airways obstruction and transplanted lung. SUBJECTS AND METHODS: We analyzed data in 16 patients with CAO who had undergone transplantations (5 men, 11 women; mean age [+/- SD], 53.8 +/- 4.9 years), and 9 patients with pulmonary vascular disease (PVD) without airways obstruction who had undergone transplantations (2 men, 7 women; mean age, 35.4 +/- 11.4 years). RESULTS: In the patients with PVD, there were no significant changes in static or dynamic lung volumes or in the MEFV curve after SLT. In the patients with CAO, indexes of airways obstruction improved significantly after SLT, and the typical biphasic-plateau pattern developed in the MEFV curve. In one patient with CAO who required pneumonectomy of the native lung after SLT, the biphasic pattern was absent. CONCLUSIONS: These results support the view that this MEFV pattern is a result of airflow from the native and transplanted lungs in patients with CAO. In addition, the results show that in patients with no prior airways obstruction, SLT does not alter static or dynamic lung volumes or maximal expiratory flow rate.

Fiberoptic bronchoscopy. Comparison of procedures used in the diagnosis of lung cancer.

We have compared the relative value of various techniques used in association with fiberoptic bronchoscopy for the diagnosis of lung cancer. We analyzed the results in 114 patients who underwent diagnostic fiberoptic bronchoscopy and in whom a definite histologic diagnosis of lung cancer was made. A comparison of the diagnostic yield from cytologic examination of prebronchoscopy and postbronchoscopy sputum and of fiberoptic bronchial biopsy, brushing, and washing was made. Over-all, bronchial washings gave the highest diagnostic yield (75.4%) and forceps biopsy the next higher (65.8%). The combination of bronchial washings and forceps biopsy gave the highest diagnostic yield (95.8%). In six patients, postbronchoscopy sputum was the only source of positive diagnostis; in 20 patients only one procedure was positive. Our results suggest that although fiberoptic bronchoscopy washings and forceps biopsy have the highest diagnostic yield, brushings and postbronchoscopic sputum examination are also important diagnostic maneuvers and should be routinely performed.

Pulmonary gas exchange during histamine-induced bronchoconstriction in asthmatic subjects.

Bronchial provocation for testing airway hyperreactivity is now well-established. However, the effects of histamine-induced bronchoconstriction on pulmonary gas exchange in man have not been systematically studied. We empirically noted marked decreases in PaO2 in some asthmatic subjects following induced bronchoconstriction. Nine subjects with mild, stable asthma were studied, each on two separate days. The first determined the dose of inhaled histamine necessary to decrease FEV1 by 20 percent and the relationship to lung volume and to pulmonary resistance by the interrupter technique (Rint). On the second day arterial blood gases, ventilation, Rint, and the anatomic (VDan) and physiologic (VDphys) dead spaces were measured simultaneously. There was a significant (p less than 0.05), profound fall in PaO2 (mean, -21.8 mm Hg) and in P(A-a)O2 (mean +14.7 mm Hg) within 5 min after bronchoconstriction, associated with a significant (p less than 0.05) increase in respiratory frequency (mean +5.1 min-1); and decrease in tidal volume (mean, -0.3 L). The ratio VDphys/VT increased significantly (p less than 0.05; mean change, +0.08) even though VDan and VDphys did not. Bronchoconstriction induced the broadening of ventilation (V)/perfusion (Q) ratios, with, most likely, an increase in areas of high V/Q. Histamine-induced bronchoconstriction in mild asthma results in a marked fall in PaO2 due to induced V/Q inequality. Therefore, histamine airway challenge should be used with caution in patients with any preexisting hypoxemia.

The effects of acetazolamide on the ventilatory response to high altitude hypoxia.

Acetazolamide treatment ameliorates the symptoms of AMS; however, the mechanism by which this occurs is unclear. To examine the effects of acetazolamide on oxygenation, CO2 responsiveness and ventilatory pattern during acute exposure to HA, we studied two groups of subjects at SL and following rapid (less than 8 h) transport to HA. Acetazolamide or placebo tablets were given to groups 1 and 2, respectively, in a double-blind manner after baseline SL measurements; treatment was continued during HA exposure. There was no difference in the ventilatory pattern at HA, between the two groups. While the Ve achieved in response to CO2 at HA vs SL was much greater in each group the percent change from baseline at HA versus that at SL was not significantly different. The beneficial effects of acetazolamide in AMS are associated with a higher level of ventilation at HA and better oxygenation: CO2 chemosensitivity is not affected by acetazolamide at HA.

Airways responsiveness determined by consecutive histamine challenges in asymptomatic asthmatics.

The effect of two consecutive histamine inhalation challenges on airways responsiveness was assessed in a group of eight nonsmoking nonmedicated asthmatics aged 19-27 yr. All subjects had a base-line forced expiratory volume in 1 s (FEV1) of greater than 80% of their predicted normal value before the initial challenge and were allowed to recover to greater than 95% of the initial base-line FEV1 value before the second challenge was initiated. The average airways recovery time after the first challenge was 44 min but ranged between 30 and 90 min. The mean +/- SD values of cumulative histamine dose units provoking a 20% decrease of the FEV1 from the buffer control value (PD20FEV1) were 10.79 +/- 5.95 determined with the first and 30.50 +/- 46.36 with the second challenge (P greater than 0.05). We conclude that sequential histamine challenges performed in mild asthmatics with closely controlled prechallenge airways function are well tolerated. Although some variance does exist in intersubject airways recovery time and in intra-subject histamine airways responsiveness determined by sequential challenges, our data do not support recent observations (J. Appl. Physiol. 63: 1572-1577, 1987) that histamine tolerance is a characteristic finding associated with bronchial asthma.

Role of tachykinins in sulfur dioxide-induced bronchoconstriction in anesthetized guinea pigs.

To investigate the role of tachykinin release in mediating the bronchoconstrictive effect of sulfur dioxide (SO2) inhalation, measurements of dynamic lung compliance (Cdyn), total pulmonary resistance (RL), and arterial blood pressure (ABP) were made in anesthetized guinea pigs. Brief exposure (six tidal breaths) to SO2 at concentrations between 500 and 2,000 parts/million resulted in a concentration-dependent increase in RL, decrease in Cdyn, and systemic hypotension. For example, SO2 at 2,000 parts/million induced reversible and reproducible changes in RL, Cdyn, and ABP of 1,041 +/- 234, -60 +/- 6, and -25.8 +/- 4.3% of the baseline values, respectively. Pretreatment with two selective neurokinin- (NK) receptor (NK1 and NK2) antagonists, CP-99994 and SR-48968, resulted in almost complete inhibition of the increase in RL and of the decrease in Cdyn while preserving the decrease in ABP. Antagonism of the NK2 receptor alone resulted in inhibition of the majority of the SO2-induced bronchoconstriction, whereas that of the NK1 and muscarinic receptors did not have a significant effect. We conclude that the release of tachykinins from sensory endings plays a central role in SO2-induced bronchoconstriction in anesthetized guinea pigs, primarily via the activation of the NK2 receptor.

Nicotine is responsible for airway irritation evoked by cigarette smoke inhalation in men.

To determine whether nicotine is involved in evoking the irritant effects of cigarette smoke in airways, we studied the responses to inhalation of a single puff (30 ml) of three types of smoke (high nicotine, low nicotine, and gas phase) in healthy male nonsmokers. After the upper airways were locally anesthetized, the subjects, breathing through a mouthpiece, were instructed to signal the detection and the intensity of airway irritation with a push-button device. Inhalation of high-nicotine smoke consistently triggered an intense airway irritation in the lower neck and upper chest region; the total number of push-button signals generated in the first 5 s was 6.61 +/- 0.87 (mean +/- SE, n = 12), with a detection latency of 0.93 +/- 0.11 s. By contrast, inhalation of low-nicotine and gas phase smoke either was not detected or caused only very mild irritation (0.89 +/- 0.4 and 0.36 +/- 0.22, respectively). In addition, the intensity of smoke-induced airway irritation was markedly reduced after premedication with aerosolized hexamethonium, a nicotinic receptor antagonist (P < 0.01, n = 8). Furthermore, inhalation of nicotine aerosol also immediately evoked intense airway irritation and coughs (n = 5). Thus we conclude that the airway irritation evoked by inhaling cigarette smoke results from an activation of sensory endings located in the central airways and nicotine is the primary agent responsible for this action.

Pulmonary function in the elderly: response to theophylline bronchodilation.

This clinical investigation was designed to characterize the pharmacologic response to theophylline in elderly individuals. Incremental theophylline plasma concentrations (0, 5, 10, 15, and 20 mcg/mL), achieved through dose escalation of intravenous aminophylline, were correlated with pulmonary airway responses in ten young and ten elderly male asthmatic volunteers. The older group had lower baseline pulmonary function values, suggestive of a greater degree of baseline airways obstruction. Despite wide intersubject variability, the elderly subjects demonstrated a lower absolute change in bronchodilator response to equal concentrations of theophylline than did their younger counterparts (P less than .05). A progressive increase in heart rate was noted with increasing theophylline concentrations, but no significant difference in heart rate change between groups was detected (P greater than .05). Whether the difference in theophylline induced bronchodilator response observed in the young and elderly groups is due to a difference in age or in severity of airway obstruction is yet unknown.

Measurements of ventilatory regulation.

The ventilatory control system, although not yet fully understood, is a complex interaction of volitional and reflex mechanisms extending from the cerebral cortex to receptors in the lungs and chest wall. Measurements of ventilatory control mechanisms can be made at rest, during exercise, during sleep, and during hypercapnic or hypoxic stimuli. Measurements of ventilation, ventilatory pattern, and mouth occlusion pressure at rest provide valuable information on ventilatory control mechanisms; these measurements can be extended by measurements of diaphragmatic EMG (indicating central neural output) and measurements of ventilation and mouth occlusion pressure during CO2 or hypoxic stimulation. Clinical assessment of ventilatory control abnormalities requires an understanding of the basic features of the control system and a logical application of the available tests.

Hypercalcemic-type of small cell carcinoma of the ovary: characterization of a new tumor line.

BACKGROUND: The aim of this study was to develop and characterize a mouse xenograft model for the hypercalcemic-type of small cell carcinoma of the ovary (HTSCCO). PATIENTS AND METHODS: Tumor fragments were removed from a patient and cultured in six subsequent generations of nude mice. Histology, comparative genomic hybridization (CGH), electron microscopy and serum calcium levels were investigated. RESULTS: Morphology remained the same from the primary tumor of the patient through the 6th passage in the mouse. Serum calcium levels were significantly higher in the tumor-bearing mice compared to controls. CGH of the HTSCCO did not show evidence of a close relationship to either a germ cell tumor or an epithelial ovarian cancer. CONCLUSION: Some evidence was provided that the HTSCCO is an inhomogeneous tumor that is neither related to a germ cell tumor nor to an epithelial ovarian cancer, but is a distinct tumor entity.

[Familial cancer. Initial results of an inquiry into its occurrence in Basel]. / Familiäre Tumorkrankheiten. Erste Ergebnisse einer Erhebung über ihr Vorkommen in Basel.

The initial results of a systematic study conducted in Basel on the existence of relatives with cancer in the families of more than 600 tumour patients indicate that neoplasm of all organs have forms in whose etiology genetic predisposition is an important factor. This is illustrated by the examples of mammary carcinoma, colorectal carcinoma, gastric carcinoma and lymphoproliferative diseases. Research into genetic predisposition to cancer is of practical value in order to protect persons at risk from the serious consequences of malignant tumors, and also of scientific interest because the characterisation of certain tumours can provide a fundamental insight into the pathogenesis of these diseases.