Robustness of a continuous direct compression line against disturbances in feeding.

The aim of the current study was to characterize the robustness of an integrated continuous direct compression (CDC) line against disturbances from feeding, i.e. impulses of API and short step disturbances. These disturbances mimicked typical variations that can be encountered during long-term manufacture. The study included a primary formulation, with API of standard particle size, which was manufactured at 5 and 10 kg/h production rates, and a modified formulation, with API of large particle size, which was manufactured at 5 kg/h production rate. Overall, the CDC line smoothened all the disturbances, fulfilling the USP uniformity of dosage units (UDU) limit for single tablets. However, runs with the modified formulation failed the pharmacopoeia UDU requirements for the entire run due to high variation between tablets. The primary formulation passed the requirements in all cases. The residence time distribution (RTD) results indicated that the primary formulation allowed better smoothening ability, and an increase in production rate led to poorer smoothening due to shorter RTD. The RTDs revealed that a substantial part of back-mixing took place after the blender. Thus, the tablet press has an important role in smoothening disturbances longer than the mean residence time of the blender, which was very short.

RTD-based material tracking in a fully-continuous dry granulation tableting line.

Continuous manufacturing (CM) offers quality and cost-effectiveness benefits over currently dominating batch processing. One challenge that needs to be addressed when implementing CM is traceability of materials through the process, which is needed for the batch/lot definition and control strategy. In this work the residence time distributions (RTD) of single unit operations (blender, roller compactor and tablet press) of a continuous dry granulation tableting line were captured with NIR based methods at selected mass flow rates to create training data. RTD models for continuous operated unit operations and the entire line were developed based on transfer functions. For semi-continuously operated bucket conveyor and pneumatic transport an assumption based the operation frequency was used. For validation of the parametrized process model, a pre-defined API step change and its propagation through the manufacturing line was computed and compared to multi-scale experimental runs conducted with the fully assembled continuous operated manufacturing line. This novel approach showed a very good prediction power at the selected mass flow rates for a complete continuous dry granulation line. Furthermore, it shows and proves the capabilities of process simulation as a tool to support development and control of pharmaceutical manufacturing processes.

Effect of work load on cutaneous vascular response to exercise.

The purpose of the present study was to examine whether intensity of exercise affects skin blood flow response to exercise. For this purpose, six healthy men cycled, in a random order on different days, for 15 min at 50, 60, 70, 80, and 90% of their maximum oxygen consumption (VO2max) at a room temperature of 25 degrees C. At the end of exercise, esophageal temperature (Tes) averaged 37.4 +/- 0.2, 37.7 +/- 0.2, 37.9 +/- 0.2, 38.6 +/- 0.3, and 38.9 +/- 0.4 degrees C (SE) at the 50, 60, 70, 80, and 90% work loads, respectively. At the two highest work loads, no steady state was observed in Tes. Skin blood flow was estimated by measuring forearm blood flow (FBF) with strain-gauge plethysmography and by laser-Doppler flowmetry on the upper back. Both techniques showed that skin blood flow response to rising Tes was markedly reduced at the 90% work load compared with other work loads. At the end of exercise, FBF averaged 7.5 +/- 1.7, 10.7 +/- 3.1, 9.6 +/- 2.1, 11.3 +/- 2.6, and 5.4 +/- 1.3 (SE) ml.min-1.100 ml-1 (P less than 0.01) at the 50, 60, 70, 80, and 90% VO2max work loads, respectively. The corresponding values for Tes threshold for cutaneous vasodilation (FBF) were 37.42 +/- 0.16, 37.48 +/- 0.13, 37.59 +/- 0.13, 37.79 +/- 0.19, and 38.20 +/- 0.22 degrees C (P less than 0.05) at 50, 60, 70, 80, and 90% VO2max, respectively. In two subjects, no cutaneous vasodilation was observed at the 90% work load.(ABSTRACT TRUNCATED AT 250 WORDS)

Thermoregulation during rest and exercise in the cold in pre- and early pubescent boys and in young men.

Eight minimally dressed pre- and early pubescent boys (age 11-12 yr) and 11 young adult men (age 19-34 yr) rested for 20 min and exercised on a cycle ergometer for 40 min at approximately 30% of their maximum oxygen consumption (VO2max) at 5 degrees C. To quantify the added increase in metabolic rate because of cold, a separate test was carried out at 21 degrees C at rest and at equal work rates as in the cold. Both groups were similar in subcutaneous fat thickness and VO2max per kilogram body weight. Rectal temperature increased slightly during the exposure to the cold, but no significant difference was observed between the boys and men. In the cold, the boys had lower skin temperatures than the adults in their extremities but not in the trunk. The boys increased their metabolic rates in the cold more than did the men. As a result, the boys maintained their core temperature as effectively as the adults. Similar age-related differences in thermoregulatory responses to cold were observed when two boys and two men with equal body sizes were compared. Our results suggest that there may be maturation-related differences in thermoregulation in the cold between children and adults.

Surgical treatment of chronic laryngeal stenosis secondary to vocal cord paralysis: pre and postoperative evaluation of ventilatory function.

Thirteen patients with chronic laryngeal stenosis were operated upon with total excision of stenotic scar tissue, enlargement of the lumen by sectioning the back and front wall of the larynx, and application of an indwelling Teflon prosthesis for 4 months. The stenosis was in many cases caused by long-standing recurrent paralysis complicated by attempted surgical correction of the stenosis. Following operation, the specific airway conductance increased in all patients (mean +/- SD pre and postoperative values 0.51 +/- 0.30 and 1.12 +/- 0.51 kPa-1.s-1, respectively). The FIV1/FVC ratio was determined in 9 patients and an increase was postoperatively noted in all of them (mean +/- SD pre and postoperative values 43 +/- 17 and 76 +/- 13%, respectively). The physiological findings confirmed the excellent clinical results of the treatment.

Complexation with tolbutamide modifies the physicochemical and tableting properties of hydroxypropyl-beta-cyclodextrin.

The physicochemical and tableting properties of hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and its tolbutamide (TBM) complex were studied. The kinetics of TBM/HP-beta-CD inclusion complex formation in solution were determined by the phase solubility method. Solid complexes were prepared by freeze-drying and spray-drying. Water sorption-desorption behaviour of the materials were studied and compacts were made using a compaction simulator. TBM and HP-beta-CD formed 1:1 inclusion complexes in aqueous solution with an apparent stability constant of 63 M(-1). HP-beta-CDs and TBM/HP-beta-CD complexes were amorphous whereas the freeze-dried and spray-dried TBMs were polymorphic forms II and I, respectively. Sorption-desorption studies showed that HP-beta-CDs were deliquescent at high relative humidities. TBM/HP-beta-CD complexes had slightly lower water contents at low relative humidities than the physical mixtures. However, at high humidities their water sorption and desorption behaviours were similar to those of corresponding physical mixtures, indicating a glass transition of the complexed materials. TBM/HP-beta-CD complexes demonstrated a worse compactability than similarly prepared HP-beta-CDs or physical mixtures. Also particle properties that resulted from these preparation methods affected the compactability of the materials. In conclusion, the physicochemical and tableting properties of HP-beta-CD were modified by complexation it with TBM.

Age and sex as determinants of the relative aerobic strain of nonmotorized mail delivery.

The relative aerobic strain (RAS) of nonmotorized mail delivery was assessed in 54 Finnish mail carriers who represented both sexes, the entire workage range and both downtown and suburban delivery districts. The mean RAS of the entire delivery time was 55% of the maximal oxygen uptake (ml/kg-min). It was higher for women than for men, and higher for suburban than for downtown delivery. The RAS tended to increase systematically with age after the age of 50. The work strain of mail carriers of over 50 years of age, especially of older women carriers in suburban areas, was concluded to be high enough to lead to possible excessive strain on the workers.

Circulatory and thermal responses of men with different training status to prolonged physical work in dry and humid heat.

Eight physically trained and eight untrained, unacclimated men walked on a treadmill at 30% of their maximum oxygen consumption up to 3.5 h in a thermoneutral [20 degrees C/40% relative humidity (RH)], a warm humid (30 degrees C/80% RH), and a hot dry (40 degrees C/20% RH) environment while wearing industrial work clothing. Their oxygen consumption, rectal and skin temperatures, sweating, cardiac output, heart rate, stroke volume, and peripheral blood pressure were measured during the tests. Thirteen of the 32 heat stress tests were prematurely stopped due to high rectal temperature, high heart rate, subjective fatigue, or heat syncope. The physiological strain, as indicated by the rectal temperature and heart rate, was not significantly different between the warm humid and hot dry environments (wet bulb globe temperature approximately 28 degrees C). The rectal temperature and heart rate responses of the physically trained and untrained subjects did not differ in any of the environments. In the heat, the heart rate was significantly higher than in the thermoneutral environment, but because of the markedly reduced stroke volume the average cardiac output was not different between the three environments. The impaired work performance in the heat seemed mainly to be related to the circulatory instability accompanying the increased cutaneous circulation.

Circadian variation of physiological functions related to physical work capacity.

The circadian variation of selected physiological functions related to physical work capacity was studied in four trained young male subjects. The twofold objective was to describe, in parametric terms, the variation of these functions and estimate the times and values of their maximum and minimum responses. Statistically significant periodic regression effects were found for the following functions: oral temperature; systolic blood pressure; heart rate at rest, during work (245 and 270 W) and after a 5-min recovery; ratings of perceived exertion; strength of hand grip; and neuromuscular coordination measured with a seesaw board balance test. The Fourier curve (sine curve) accounted for 63 % of the variation in oral temperature and from 13 to 38 % of the variation in the other significant harmonic intensities. In phase with the rhythm of oral temperature, but with larger amplitude, were systolic blood pressure, heart rate at rest and heart rate during work; roughly in phase were strength of hand grip and neuromuscular coordination. Ratings of perceived exertion and heart rate after a 5-min recovery showed a rhythm which was out of phase with the oral temperature. The number of disturbances in neuromuscular coordination was greatest at 2400 and smallest at 1200, the difference being as large as 44 %. The results suggest that the measured capacities of muscle strength and neuromuscular coordination are the lowest, that physical work is perceived as the heaviest, and recovery after work is the slowest at night. These findings appear to support the notion that performance capacity is reduced during the night.

Cold provocation tests in the evaluation of vibration-induced white finger.

Two types of cold provocation tests, a classical test with immersion of the hand in cold water and the evaluation of finger systolic blood pressure (FSBP) during local cooling, were administered to forest workers. Raynaud's phenomenon in the classical test correlated positively with the number of disabled phalanges, recovery time, and frequency of attacks. It did not correlate with the severity of paresthesia of the hands and arms. Repetition of the test enhanced the number of positive results. A significant reduction in the FSBP was observed in 22 and 25% of the subjects with inactive and active forms of vibration-induced white finger (VWF), respectively. In the same groups of subjects the classical cold provocation test yielded positive results in 7 and 25% of the subjects, respectively. A cold provocation test was found to produce a positive result even some years after the cessation of VWF attacks. The rather low severity of VWF among the examined subjects may explain the lack of positive test results. FSBP measurement was not superior to cold provocation by water immersion, but it is recommended because it is easier to standardize and more convenient for the test subject.

Transmission of vibration in the hand-arm system with special reference to changes in compression force and acceleration.

The transmission of longitudinal vibration in the hand-arm system of five subjects was investigated. Altogether 405 individual tests were made. Vibration was measured with an accelerometer (weight 0.4 g) fixed in turn to the wrist, the elbow, and the upper arm by means of a supporting device (weight 34 g). A handle with strain gauges attached was used to study the effect of compression force (10, 20 and 40 N) and constant acceleration (1, 3 and 10 g) on the transmission of vibration at frequencies from 20 to 630 Hz. In the curves recorded, sharp dips appeared which were evidently caused by resonances from the soft tissues of the hand. However in the hand-arm system no common resonance frequency was observed that would harmfully affect the health of workers. Vibration in the hand-arm system was attenuated at an average of 3 dB per octave at the frequencies between 20 and 100 Hz. Between 100 and 630 Hz the attenuation was about 6 dB per octave in the wrist and 10 dB per octave in the elbow and upper arm. At the frequency of 630 Hz the attenuation was hence about 35 dB in the wrist and about 45 DB in the elbow. The attenuation of vibration in the elbow joint was 2 to 4 dB at all frequencies. The hand-arm system appears to be linear at the acceleration range considered; the increase in handle vibration by, e.g., 10 dB also increased vibration in the hand by 10 dB. When the grip strength was increased fourfold, i.e., 12 dB, vibration increased only 3 to 5 dB in the hand-arm system. Thus changing the weight of a vibrating tool does not reduce vibration enough. Therefore attempts to reduce vibration should concentrate on the mechanical parts of the engines.

A thirteen-year follow-up of respiratory effects of acute exposure to sulfur dioxide.

OBJECTIVES: In 1977, nine men were accidentally exposed to sulfur dioxide in an explosion in a pyrite mine. The lung function of seven men was followed after the accident. A four-year follow-up has been published previously. The greatest decrease in forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1.0), and maximal midexpiratory flow (MMEF) was observed one week after the accident, after which all these parameters improved without reaching the preaccident level. Reversible bronchial obstruction was still present in three patients, and a positive reaction in the histamine challenge test was found for four. In the present paper, the lung function follow-up 13 years after the accident is reported for six men. METHODS: The patients' clinical condition, chest X-ray, spirometry, and histamine challenge test were studied 13 years after the incident. RESULTS: Spirometry was normal in one worker, two displayed obstruction, and three had a combined obstructive and restrictive, mainly obstructive, ventilatory impairment. In the histamine challenge test, four patients showed bronchial hyperreactivity, one with a nearly significant reaction. Because of bronchial obstruction one patient could not perform the challenge test. CONCLUSIONS: This 13-year follow-up showed that acute inflammatory obstruction caused by exposure to sulfur dioxide left, as sequelae, obstructive impairment of ventilatory function and permanent bronchial hyperreactivity. The clinical picture displayed by these patients was named the "reactive airways dysfunction syndrome" (RADS) in 1985. Four of the patients also showed symptoms of chronic bronchitis.

Lungco measurement of particles retained in the lungs.

Nearly all metal dusts contain iron, which is one of the most common constituents in steel. Iron has one common ferrimagnetic oxide, magnetite. Although it is considered nontoxic, magnetite can be used as a tracer for more active and pathogenic constituents of inhaled dusts. After the chest area has been magnetized, magnetite produces a weak remanent magnetic field around the body. The field is measured and the amount of dust in the lungs is calculated on the assumption that the composition of lung dust is the same as that of airborne dust. This method has been applied to shipyard and stainless steel welders, to iron and steel workers, to stainless grinders, and to foundry workers. A clear magnetic signal was found for each subject. The maximum amount of lung dust found thus far was 10 g in the lungs of a stainless steel electrode welder. Referents showed signals of 0.5 mg magnetite or less.

Vibration syndrome among Finnish forest workers, a follow-up from 1972 to 1983.

A longitudinal survey on the prevalence of vibration syndrome among professional forest workers was conducted from 1972 (118 workers) to 1983 (206 workers). The prevalence of vibration-induced white finger (VWF) was 40% among the workers in 1972; it gradually declined to 5% in 1983. Three new workers developed VWF symptoms during the follow-up period. They had only used saws equipped with antivibration handles. The prevalence of VWF has decreased mainly due to the reduction of chain-saw vibration. The prevalence of paresthesias of the hands and arms declined from 78% in 1972 to 37% in 1976, and then increased to 51% in 1983. The recent increase was thought to be due to static muscle load and the ageing of the workers. No correlation was found between the severity of VWF and peripheral nerve symptoms. No significant changes in muscle fatigue occurred during the follow-up period; it was present in about 10-15% of the workers. The forest workers subjectively assessed musculoskeletal load and strain as being more harmful than the symptoms of vibration syndrome. The preventive measures aimed at reducing chain-saw vibration, implemented since 1970, have been beneficial and explain the decreased prevalence of VWF.

Finger peripheral resistance during local cold provocation in vasospastic disease.

Finger systolic blood pressure (FSBP), finger arterial inflow (FAI), finger venous opening pressure (FVOP), and finger peripheral resistance (FPR) were evaluated in 56 workers exposed to chain-saw vibration. Twenty-one of the workers were free from vibration-induced white finger (VWF). In 17 subjects VWF had ceased; 12 of the subjects had active VWF; 6 subjects had Raynaud's disease. The subjects were examined in a supine position under thermoneutral conditions with strain-gauge plethysmography. Cold provocation of the finger caused a significant reduction in FSBP in the groups with Raynaud's disease and active VWF. The finger circulation of the subjects with active VWF and that of those with Raynaud's disease showed a significantly reduced FAI when compared with that of the symptom-free referents. Finger cooling produced a gradual reduction in the FVOP and a significantly increased FPR of the subjects with active VWF and in those with Raynaud's disease. FPR was already increased in the Raynaud's disease group at the beginning of the test, whereas it increased in the VWF group as the temperature fell. The results suggest that in Raynaud's disease the fault is in the level of activity of the sympathetic outflow and in VWF it is peripheral mechanisms controlling the vessel tone.

Changes in maximal cardiorespiratory capacity among aging municipal employees.

Before and after a four-year follow-up, maximal oxygen consumption (VO2max) was determined for 67 municipal employees (initial age about 51 years). The VO2max (ml.kg-1) decreased 6% among the women and increased 8% among the men, the greatest and smallest change occurring for employees doing mental and physical work, respectively. The men's increase was associated with an increase in leisure-time physical activity. Work content was not associated with the level of VO2max for either gender. After the four years the women's absolute VO2max was about 66% of the men's. There were marked changes in VO2max at the individual level, the most marked decreases being associated with the use of medication in some cases. After the four years the women's VO2max of 63% was insufficient according to current recommendations. Therefore physically demanding jobs are not generally recommended for older women.

Amount and distribution of welding fume lung contaminants among arc welders.

The amount and distribution of the welding fume lung contaminants was measured in 44 arc welders from two shipyards. The measurement was made from the determination of the permanent field after the subject was magnetized in a low external magnetic field, the values being used for the calculation of the amount of contaminants in the lungs. Less than 4 mg of dust was found in the lungs of nonexposed controls. In the shipyard welder's lungs, after two years of exposure, on the average 7 mg (range 4-15) of welding dust was observed. After a continuous exposure of about 18 years the amounts were 200 mg (range 30-1,500) in shipyard A and 700 mg (150-2,000) in shipyard B, respectively. On the basis of data obtained from retired welders, the clearance rate of 45% in welders from shipyard A and 18% in shipyard B were calculated, the latter figure being probably more accurate. The distribution of contaminants was 52% in the right and 48% in the left lung. The radiological findings correlated well with the amounts of welding fume contaminants measured with the magnetic method.

Respiratory status of stainless steel and mild steel welders.

Eighty-three full-time stainless steel and 29 mild steel welders from one shipyard were examined clinically, and their lung function was measured. The stainless steel welders had used both tungsten inert-gas (low-fume concentration) and manual metal-arc (MMA) (high-fume concentration) welding methods. The individual exposure of the welders was estimated based on the time spent doing MMA welding, the amount of retained contaminants in the lungs (magnetopulmography), and urinary chromium excretion. The results suggest that there is a greater prevalence of small airway disease among shipyard mild steel MMA welders than among stainless steel welders. Among the stainless steel welders the impairment of lung function parameters was associated with the MMA welding method. The type of welding, then, is important when the health hazards of welders are studied, and welders cannot be regarded as a single, homogeneous group.

Asbestosis, the nervous system and cancer.

Asbestosis patients have a high cumulative risk of cancer: four of ten asbestosis patients develop cancer. Paraneoplastic involvement of the nervous system, peripheral neuropathy in particular, is often encountered in cancer patients, even at very early stages of the disease. In order to estimate the occurrence of paraneoplastic neuropathy among asbestosis patients, we formed a small cohort (115 asbestosis patients, mean age 56 years, mean duration of exposure to asbestos 21 years) in 1979. Neurological examination revealed slight peripheral neuropathy in 44 (39%) of the patients, 24 (22%) of whom also had central nervous system signs (disturbances in gait and posture, memory and fine movements). The prevalence of peripheral neuropathy among asbestosis patients was higher than among various referent patients (fibrosing alveolitis, diagnosed solvent poisoning and gynaecological carcinoma). No significant differences were found between the patients with and without peripheral neuropathy regarding the following parameters: pulmonary function tests, tumour markers (CEA, ferritin, beta-2-microglobulin), antinuclear antibodies, C3, C4 and circulating immune complexes. Nevertheless, at group level, the asbestosis patients had increased levels of the three tumour markers. Estimates based on the data accumulated so far (10 cancer patients) show that within three years we shall probably have a sufficient number of cancer cases to draw some conclusions about the value of neuropathy in the early diagnosis of occupational cancer.