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Ci 744 (20 mg/kg, given intramuscularly (IM) produced a reliable level of surgical anesthesia in both dogs and cats. Animals anesthetized in this way did not have an increased sensitivity to cardiac fibrillation after they were given epinephrine. Epinephrine-induced ventricular arrhythmia observed in C1 744-anesthetized animals was eliminated in cats and was markedly reduced in dogs by bilateral vagotomy. Myocardial fibrillation was not produced by epinephrine (0.1 to 100 mug/kg, intravenously (IV) in dogs and cats anesthetized with C1 744 alone. Pentobarbital anesthesia, like C1 744 anesthesia, did not sensitize the heart, whereas a significant number of thiamylal-halothane-anesthetized animals died from cardiac fibrillation after they had been given epinephrine. Additional dogs were anesthetized with C1 744 or pentobarbital and given a series of pressor and depressor agents (isoproterenol, epinephrine, tyramine, 1, 1-dimethyl-4-phenylpiperazium iodide (DMPP) plus bilateral carotid occlusion) before and after vagotomy. The responses with either anesthetic were similar with the exception that the reflex bradycardia to pressor agents was more evident in C1 744- than in pentobarbital-anesthetized dogs.

Activated coagulation test (ACT) was performed in 37 adult ponies and 31 adult horses. The mean ACT time of all ponies and horses was 2 minutes 38 seconds, with a standard deviation (SD) of 29 seconds. The ACT was compared with the Lee-White clotting test in heparinized ponies. The correlation of ACT with the Lee-White test was 0.95. Anticoagulation heparinized ponies during prolonged cardiopulmonary bypass was successfully monitored with the ACT. The ACT is simple and reproducible, has a definite end point, and would seem to be an ideal screening test for hemorrhagic diathesis in equine animals.

Long-term survival data are presented for 200 patients with chronic airway obstruction of uncertain etiology who were enrolled in a prospective study approximately 14 years ago. Early death rates were closely related to the initial level of ventilatory impairment. Subjects with relatively mild impairment on entry to the study had a favorable prognosis for the first 5 to 7 years of follow-up but then began to show a higher death rate; there are few long-term survivors in the total series.

Normal children as well as those with asthma and cystic fibrosis were studied to assess the contribution of lung zones emptying at different rates to the curvilinearity of the maximal expiratory flow-volume curve. Lung volumes, maximal expiratory flow-volume curves breathing air and then breathing a helium-oxygen mixture, and single-breath nitrogen washouts were measured. Forced expiratory maneuvers from lung volumes near functional residual capacity were performed to produce transients of flow exceeding maximal flow defined by the full flow-volume curve. Normal children and those with asthma and mild cystic fibrosis had small or no transients. Those with severe cystic fibrosis had large transients as well as increased phase I on the nitrogen washout curves. These large transients were associated with increased curvilinearity of the maximal expiratory flow-volume curve and smaller than normal flow response breathing helium. In severe cystic fibrosis, the large transients suggest sequential emptying of fast and slow spaces, which influences the shape of the maximal expiratory flow-volume curve. The fast space could be due to compression of an enlarged anatomic dead space. Any time constant inequality between parenchymal units present in asthma and mild cystic fibrosis does not appear to contribute significantly tof the shape of the maximal expiratory flow-volume curve.

Tracheal mucous velocity was measured by observing the motion of teflon discs across the tracheal mucosa through a fiberoptic bronchoscope. The average rate of movement in 14 adult patients with cystic fibrosis was 2.6 mm per min plus or minus 3.3 SD, compared with 20.1 mm per min plus or minus 6.3 in 20 normal subjects of the same age (P less than 0.001). This failure of mucociliary transport may play a role in the pathogenesis of the pulmonary disease in cystic fibrosis. Administration of a beta-adrenergic agent, terbutaline, increased the average mucous velocity in the patients with cystic fibrosis (to 5.5 mm per min plus or minus 3.6 SD, P less than 0.001) but not in control subjects. This observation has potential therapeutic significance.

Fourteen subjects with reversible obstructive lung disease inhaled one per cent lidocaine mist delivered by an ultrasonic nebulizer. The effect of ultrasonic nebulization per se was evaluated by a control study utilizing normal saline. After lidocaine inhalation there was a significant decrease in expiratory flow and an increase in airway resistance compared with either baseline or post-saline values. The changes were mild and do not preclude the continued use of nebulized lidocaine as an adjunct to bronchoscopy, but caution in its use is indicated.

The various factors influencing closing volume were studied by performing the single-breath N2 test on 9 healthy nonsmokers. Time of day, day of the week, and preceding volume history had no effect on either closing volume or alveolar plateau. Slow inspiratory flow resulted in larger ratio of closing volume to vital capacity, ratio of closing capacity to total lung capacity, and change in N2 concentration than fast inspiratory flow. Voluntary regulation of the expiratory flow resulted in smaller ratios of closing volume to vital capacity and closing capacity to total lung capacity than when flow was regulated by a resistance. Prolonged breath holding of the inspired O2 led to larger ratio of closing volume to vital capacity and ratio of closing capacity to total lung capacity. To obtain uniform, comparable closing volumes, it is suggested that the subject inspire slowly, control expiratory flow (preferably voluntarily), and not pause between inspiration and expiration.

A new spirometric measurement was performed with 803 healthy, nonsmoking men and women. Using the forced vital capacity curves, the forced end-expiratory flow (FEF75-85%) had a negative correlation with age and a positive correlation with height. Prediction formulas and nomograms were constructed. Comparison with the forced mid-expiratory flow (FEF25-75%) showed generally larger correlation coefficients for physical characteristics and coefficients of variation for the FEF75-85%. Expressing both the FEF75-85% and FEF25-75% as ratios of forced vital capacity did not improve the coefficients. The mean flow rates of 75 male smokers were compared with 213 non-smokers 30 to 49 years of age. The FEF75-85% significantly distinguished between a group of smokers and a group of nonsmokers, but the FEF25-75% showed no significant difference. In 9 patients with presumed peripheral airways disease, FEF25-75% ranged from 70 to 110 per cent of predicted normal but FEF75-85% was 30 to 72 per cent of predicted. An extensively studied control group of 22 healthy, asymptomatic, nonsmoking subjects had FEF75-85% values of 80 to 163 per cent of predicted. Both small groups of 9 patients and 22 control subjects had FEF75-85% values within 1.65 standard error of estimate. In subgroups of 319 persons, use of 75 per cent of predicted mean for FEF75-85% was of greater value in attempting to screen normal from abnormal population than using 1.65 standard error of estimate. The FEF75-85% is suggested as a useful simple ventilatory test to detect early obstructive pulmonary disease.

Twenty healthy adults, 10 smokers and 10 nonsmokers, were exposed to 0.5 ppm of ozone for 6 hours in an environmental chamber. They engaged in two 15-min, medium-exercise stints on a bicycle ergometer during this period. The symptoms most commonly noted with exposure to ozone, dry cough and chest discomfort, were experienced by more nonsmokers than smokers. Subjects who experienced symptoms, in general, were those who developed objective evidence of decreased pulmonary function. Significant changes from control values for the group as a whole with exposure to ozone were observed for the following pulmonary function tests: specific airway conductance, pulmonary resistance, forced vital capacity, and 3-sec forced expiratory volume. No significant change was observed with respect to diffusing capacity for CO, static compliance, or the various tests derived from the N2 elimination rate. In addition, nonsmokers exhibited a significant decrease in dynamic compliance after exposure to ozone. When the smokers were considered as a separate group, no significant decrease in pulmonary function was observed, although some individual smokers showed adverse functional changes.

The tissue of a benign, localized, pleural mesothelioma was digested with protease, and the crude polysaccharide was fractionated by a column of Dowex-1 (Cl-form). The eluate from the column was electrophoresed and incubated with various mucopolysaccharide lysases. Based on the results of column chromatography, electrophoresis, and enzymatic digestion, it was found that hyaluronic acid was the major constituent of the glycosaminoglycans in pleural mesothelioma. The hyaluronic acid from pleural mesothelioma seemed to be identical in structure with that from human umbilical cord; however, the hyaluronic acid from mesothelioma was eluted before that from human umbilical cord when fractionated by the column of Sepharose 4B, suggesting a differnence in molecular size between the two. Also, evidence was obtained for the presence of dermatan sulfate and heparan sulfate.

Horizontal gradients in the distribution of ventilation and of regional vital capacities, as well as a reversed vertical, esophageal pressure gradient, were observed in a patient with a unilateral painful chest wall lesion. The distribution abnormalities disappeared after surgical treatment. These findings suggest that the interdependency between chest wall and lungs, and within the latter, between lobes, is an important factor determining the regional distribution of ventilation and the pleural pressure gradient in man.

This study was performed to evaluate bronchopulmonary lavage and chelation therapy as a treatment method to prevent the development of radiation pneumonitis after inhalation of a radioactive aerosol. Twelve beagle dogs were exposed to an aerosol of cerium-144 in fused clay particles resulting in initial lung burdens from 47 to 64 muCi of 144-Ce per kg of body weight. Eight of the dogs were treated with a series of 10 bronchopulmonary lavages and 10 intravenous injections of calcium diethylenetriamine pentaacetate acid during the first 56 days after exposure to remove the deposited 144-Ce; the remaing 4 exposed dogs receiged no treatment. An additional 4 dogs were exposed to stable cerium and were given the course of treatment as an additional control group. Three of the 4 untreated dogs and 2 of the 8 treated dogs died 171 to 246 days after exposure with radiation pneumonitis or pulmonary fibrosis, or both. All but one of the remaining dogs were alive and apparently in good clincial health 550 dyas after exposure; the one dog had radiographic indications of pulmonary fibrosis by 365 days after exposure. The relative distribution of 144-Ce in the lungs and other major organs was similar in the treated and untreated dogs that died.

A case is reported in which transbronchial lung biopsy using the fiberoptic bronchoscope was complicated by massive, fatal hemorrhage. This previously unreported complication occurred despite normal prothrombin and partial thromboplastin times and platelets of 93,000. Pathological examination revealed that a very small (0.5-mm) vessel was the source of the bleeding. Although severe complications are undoubtedly rare, this report suggests that the transbronchial lung biopsy is not a totally benign procedure. Suggestions are made to prevent future similar occurrences in very ill patients or in patients with coagulative abnormalities or blood dyscrasias.

A young man who had had two episodes of high-altitude pulmonary edema in the absence of any respiratroy distress was noted to have a depression of his hypoxic and hypercapnic ventilatory drives. It is postulated that because of his blunted ventilaory drives, the patient progessed to coma on exposure to low ambient oxygen tensions (i.e., high altitude) without ever increasing his ventilation. The importance of including highaltitude pulmonary edema in the differential diagnosis of any patient who is admitted with coma after a sojourn at high altitude is stressed.

When studying a group of lung cancer cases in a limited period of time to determine the relationship between age at diagnosis and smoking habits, the multiplicity of birth cohorts and the small segment of the life-span distribution of cases observed are confounding and restraining conditions. A model was constructed that suggests that small observed age shifts represent large age shifts in the life-span distributions.

Alternate-day corticosteroid therapy was compared with two daily corticosteroid regimens for the treatment of giant cell arteritis. In a prospective study 60 patients with this disease were randomly assigned to three treatment groups: group A, 15 mg of prednisone every 8 hours; group B, 45 mg of prednisone every morning; and group C, 90 mgof prednisone every other morning. After 1 month of treatment, the arteritis seemed to be completely suppressed in 18 patients in group A and 16 in group B but in only 6 in group C. In the 14 other patients in group C, the continuing symptoms were cyclic and developed during the day steroids were not given. By changing to a daily regimen, the arteritis was controlled in most patients in group C. Adverse reactions to prednisone were noted frequently in groups A and B but rarely in group C.

Automated feedback control methods were applied to a medical problem, in a computer program that used measured serum digoxin concentrations (as feedback) to predict future concentrations and to achieve desired concentrations. The system was validated by comparing its ability with the corresponding ability of physicians to regulate digoxin dosage. The prospective, randomized study included 51 patients. In the presence of varying amounts of feedback (serum digoxin concentration) information, the computer always predicted future digoxin concentrations as accurately as did physicians. For both computer and physician, the decrease in the prediction errors when two concentrations were known against that when no concentrations were known was significant: mean absolute error decreased from 0.40 to 0.25 ng/ml for the physicians and from 0.45 to 0.27 ng/ml for the computer. Thus the computer system is capable of simulating and reproducing a sophisticated aspect of physician behavior: "learning" about individual patient responses. The computer achieved desired concentrations more accurately than did physicians, especially when two or more previous digoxin concentrations were abailable (mean absolute achievement error for computer, 0.28 ng/ml; for physicians, 0.50 ng/ml).

A 15-month prospective study of the personnel and students exposed to initially unsuspected active cases of tuberculosis was undertaken to define the risk of their acquiring infection. Eight of 484 (1.65%) personnel exposed to 17 initially unsuspected tuberculosis patients and 5 of 2013 (0.25%) unexposed personnel with similar risk but no known exposures developed positive tuberculin skin tests. This greater than sixfold increase in conversion rate for the exposed group was significant (chi-2=14.83; P=0.0003). Delay in making the diagnosis in these patients was associated with failure to apply a tuberculin skin test on admission in 14 patients and radiologic misinterpretation in 15. A comprehensive surveillance method involving the Employee and Student Health Departments as well as the Public Health Department is suggested to minimize the risk of undiagnosed tuberculosis.

Since 1967, six cases of African trypanosomiasis have been diagnosed and treated in the United States. Five patients were Americans infected with Trypanosoma rhodesiense, and the other was an African student with T. gambiense. Presenting signs and symptoms for all cases were typical of the disease, but often the diagnosis was delayed. The five Americans had spent only brief periods in endemic areas. All cases responded to therapy although one relapsed. Cases of imported sleeping sickness are few, and the risk of Americans acquiring the disease while traveling to endemic areas is low. However, the early diagnosis of sleeping sickness requires that physicians be cognizant of the possibility of imported tropical diseases.

The syndrome of hereditary thrombocytopenia, deafness, and renal disease was manifest in at least eight members in three generations of a family. They had a lifelong history of bleeding, usually as epistaxis, bilateral sensorineural deafness starting in late childhood or the teenage years, and persistent proteinuria with varying degrees of renal dysfunction. Two members died at a young age, one from central nervous system hemorrhage, the other from chronic renal failure. Splenectomy and steroid therapy have been of transient benefit. There was dominant inheritance of the syndrome. Hematologic studies showed thrombocytopenia, large platelets, and megakaryocytic hyperplasia of the bone marrow. In contrast to a previous report, our studies showed that affected members had normal in-vitro platelet function and normal ultrastructural platelet morphology. At autopsy, histologic changes in the kidney of one affected family member were indistinguishable from those reported in classic hereditary nephritis with nerve deafness (Alport's syndrome).

Two patients developed severe hypomagnesemia, hypocalcemia, and hypokalemia as a result of renal wasting of magnesium and potassium shortly after being treated with large doses of gentamicin. When therapy with gentamicin was discontinued renal loss of magnesium and potassium ceased, and serum calcium, magnesium, and potassium returned toward normal. Serum immunoreactive parathyroid hormone levels were inappropriately low during the episodes of hypocalcemia. Both patients represent examples of hypomagnesemic hypocalcemia induced by inappropriate magnesuria, possibly caused by gentamicin. These observations suggest that serum calcium, magnesium, and potassium should be monitored during gentamicin therapy.

Four of six siblings, offspring of Sicillian first cousins, developed a clinical disorder in early adulthood affecting the hematopoietic and immunoglobulin-producing systems. A female sibling died at age 21 with myeloid aplasia and agranulocytosis. A male sibling, at age 17, presented with erythroid and plasma cell aplasia with hypogammaglobulinemia. Two other female siblings, ages 21 and 35, had a lymphoproliferative disorder associated with hypogammaglobulinemia. In two of the affected subjects there was complete absence of the enzyme leukocyte alkaline phosphatase. Electron microscopic studies of the peripheral leukocytes from these two subjects and from one of the two asymptomatic siblings showed curious intranuclear and intracytoplasmic linear "crystalloid" structures in the mature neutrophils. It is postulated that the family contains a genetic defect, transmitted as an autosomal recessive by the heterozygous parents, that produces a stem-cell disorder manifested by myeloid, erythroid, and plasma cell aplasias, unique electron microscopic findings, and morphologic and functional abnormalities in later generations of cells.

Invasive adrenocortical carcinoma was diagnosed in two patients, 3 1/2 and 69 years of age, respectively. Therapy with o,p'DDD was begun immediately, and the patients have survived 4 1/12 and 7 9/12 years, respectively. The prolonged survival represents possible "cure" of inoperable disease following early initiation of therapy.

Although the "health care crisis" was thought solvable by simply increasing the number of physicians, this has turned out not to be the case. The major problems in physician manpower are geographic maldistribution with a sparsity of physicians in the rural areas and the inner city and an overproduction of specialists. Certain changes in undergraduate and postgraduate medical education have contributed to this maldistribution. There is good evidence that there is an overproduction of surgeons and of medical subspecialists such as cardiologists. Much of the excess subspecialization can be laid at the foot of graduate training programs. The role of the specialty boards in affecting career choices and with them health manpower is analyzed. Some solutions to solve the geographic and specialty maldistribution problems are suggested. It is clear that more primary care physicians including general internists, family physicians, and pediatricians are needed.

Physicians and the nurse practitioners with whom they work face a number of conflicts. Conflicts develop within the individuals as they change their professional self-images. Each doctor-nurse team must develop new ways of working together and must do so against a background of long-standing professional territoriality. Comparable struggles are felt within schools and hospitals. Although governments have supported nurse practitioner programs, they have not yet enacted the fiscal and legal changes to make the role fully viable. Despite these struggles many physicians and nurses have achieved definite rewards. Research is beginning to document important successes, and educational programs are graduating significant numbers of practitioners.

Internists are well prepared to offer patients continuing and comprehensive medical care of the highest quality. Residencies must include training for the provision of primary care without compromising excellence. The teaching and practice of general internal medicine are the principal functions of Departments of Internal Medicine. Modern facilities for ambulatory care and an environment conducive to the development of internists for primary care are required. Establishment of new residency positions in general internal medicine is advocated, as is appropriate funding for education in the ambulatory patient setting. Experience with disciplines such as dermatology, office gynecology, musculoskeletal medicine, ophthalmology, otolaryngology, and psychiatry should be assured. The Board will include material relevant to primary care in its Certifying Examination.

Spontaneously occurring surface wrinkling retinopathy occurreed in 17 eyes of 16 patients and was not related to pervious surgery, retinal vascular disease, or obvious ocular inflammation. Visual symptoms were not severe and follow-up suggests that the usual course of surface wrinkling is usually benign. However, 2 eyes progressed to 20/300, so that there is a chance of considerable visual deterioration in some cases. The vitreous may or may not be detached. The ophthalmoscopic features of a wrinkled shagreen, tortuous vessels pulled toward a nidus, and intraretinal hemorrhages were seen. The leakage of fluorescein into the retina is emphasized in this series and may be fairly marked. The possible causes and mechanism of wrinkling are discussed with emphasis on mild chronic ischemia and posterior vitreous collapse.

Large penetrating transorbital foreign bodies may initially appear to be of a devastating character to the ocular tissues. However, several reports of such large foreign bodies have proved to spare the eye. A case report of a large wooden foreign body with transorbital penetration into the right frontal lobe is reported. The globe remained intact and was only displaced, with a final visual acuity of 20/40. However, complete ophthalmoplegia and ptosis persisted. A low pressure hydrocephalus ensued following intracranial debridement.

We undertook a prospective study of traumatic hyphema during the years 1970 through 1972 to compare the effects of medical management and surgical evacuation in the more severe hyphemas. A protocol for sutdy of the two regimens enabled us to compare the results of therapy. The findings indicate that medical management is preferable for the initial 4 days in major hyphemas. Surgical intervention does not offer improvement in the poor prognosis of total hyphemas during this early period. The incidence of complications and the incidence of permanent poor visual results are higher in surgically treated patients than in those managed medically. Surgical intervention should be reserved for cases showing: (1) microscopic corneal blood staining; (2)total hyphemas with intraocular pressures of 50 mm Hg or more for 5 days (to prevent optic nerve damage); (3) hyphemas that are initially total and do not resolve below 50% at 6 days with intraocular pressures of 25 mm Hg or more (to prevent corneal blood staining); and (4) hyphemas that remain unresolved for 9 days (to prevent peripheral anterior synechiae). A brief review of problems that may be encountered in the various forms of surgical management is included in an effort to prevent repeating similar pitfalls.

One hundred and twenty-seven cases of traumatic hyphema are reviewed and discussed according to a definite system of grading. Grade iii hyphemas have definitely a poorer prognosis than Grade ii and Grade i hyphemas. Rebleeding occurs more frequently when there is a delay in treatment but does not appear to affect the outcome of a traumatic hyphema. Blood staining of the cornea could be avoided by an adequate treatment started immediately after the trauma, thus decreasing the percentage of blindness following a traumatic hyphema.

One hundred cases of primary, nontraumatic, rhegmatogenous retinal separation were operated upon using 1/2 thickness 7.5 mp Silastic silicone sponge as a circumferential implant without an encircling element or suture tension. The use of this method has given 100% successful anatomical reattachment of the retina after a follow-up of 8 months to 3 1/2 years.

Eight cases of surgically repaired lower canaliculi were studied to ascertain whether the lower canaliculus is necessary for normal lacrimal drainage and whether it is advisable to probe the superior canaliculus during inferior canalicular repair. Six of 8 patients sutdied had no epiphora despite unsuccessful surgery and a normal Schirmer"1 test. Surgery was successful on 2 pateints. These results indicate that only cosmetic repair is necessary for lacerated lower canaliculi. It is suggested that the upper canalliculus alone provides sufficient lacrimal drainage to prevent epiphora.

The study was carried out to investigate the variations in blood sugar values during routine fluid therapy in surgical patients, when the rate of infusion often is very haphazardly adjusted. Surgical patients with normal sugar and fluid balance were divided into two groups. The glucose group (34 patients) was given 5% glucose solution as infusion fluid and the control group (the saline group, 26 patients) received 0.9% physiological saline solution. The preoperative mean value of blood sugar in the glucose group was 4.9 mmol/1 and in the saline group 4.6 mmol/1. Half an hour after the beginning of the operation the blood sugar in the glucose group rose to 7.2 mmol/1 (p smaller than 0.001) and in the saline group to 5.3 mmol/1 (p smaller than 0.01). At the end of the operation the blood sugar values in both groups had further increased significantly from the half-hour levels, in the glucose group to 7.8 mmol/1 and in the saline group to 6.1 mmol/1 (p smaller than 0.01). The difference between the groups, at each test after the initial test, was highly significant throughout (p smaller than 0.001). The result indicates to carefulness in using glucose solutions even during operations lasting 1-2 hours.

Our purpose was to determine whether an apparently healthy patient who died under general anaesthesia had malignant hyperpyrexia by examining her relatives and to suggest protective measures for the relatives of the deceased patient against this complication during future general anaesthetics. The family members of the deceased patient were examined systematically to determine whether or not they were prone to develop malignant hyperpyrexia. Raised serum CPK and aldolase levels, EMG changes, histopathological examination of the striated muscle, diminished muscle power during an ergometric test, and subjective symptoms revealed that other members of her family had muscular dystrophy. Our results support the theory that during general anaesthesia patients with muscular dystrophy are prone to develop malignant hyperpyrexia. Although muscular dystrophy is uncommon in Finland, affected persons should be catalogued, and preventive measures against malignant hyperpyrexia taken if they ever have to have a general anaesthetic.

This retrospective study was performed in order to evaluate the frequency and the causes for itching during pregnancy. The series consists of 129 pregnant women with generalized itching, which is 1.2% of all deliveries. The most common cause for itching was hepatosis of pregnancy (83%). The other causes were pruritus of pregnancy without any liver dysfunction (12%), dermatitis (3%) and other (2%). The average time of the onset of itching was the 30th pregnancy week in hepatosis of pregnancy and the 26.5th pregnancy week in pruritus of pregnancy. The frequency of toxaemia of pregnancy varied within 24-33% in the different itching groups and that of urinary tract infection within 21-33%. The proportion of urinary tract infection was also fairly high, 23-24%, among the previous diseases. Perinatal mortality in previous pregnancies was reported by 14 patients (9.0%), 11 of them in hepatosis group (9.6%). The corresponding frequencies of perinatal mortality in the present pregnancy were 1.6% and 1.9%. The drugs most frequently used during the present pregnancy before admission were antibiotics and other chemotherapeutic agents, sulphonamide being the most common.

A series of 107 patients with hepatosis of pregnancy and 61 controls with normal pregnancy is reported. The delivery and the condition of the infant were the main objects of investigation. The hepatosis group was also examined for liver function, glucose tolerance, and daily urinary oestrogen. The duration of the first stage of delivery was found to be slightly shortened in the hepatosis group. Two cases (1.9%) of intrauterine death occurred in the hepatosis series, and the Apgar scores at 1 and 15 minutes were somewhat lower than in the control group. Birthweight was slightly lower in the hepatosis series, corresponding to the earlier date of delivery. 11.9% of the infants weighed less than 2.5 kg at birth. The absolute and relative weights of the placenta showed no differences. The histological examination of the placenta made on part of the series revealed maturing defects in 35%. The liver function tests confirmed the cholestatic nature of hepatosis observed earlier, yielding elevated values especially for aminotransferases, alkaline phosphatase and bilirubin. The thymol turbidity test was within the normal limits, which means that hepatitis could be excluded. Neither glucose tolerance, nor daily urinary oestrogen differed significantly from the normal. The fetal survival rate has been improved considerably by intensive care of hepatosis of pregnancy.

Almost all the patients (95 women and 8 men) with interstitial cystitis, i.e. autoimmune cystitis, in this area with a population of about 970,000 were probably traced. The prevalence of the disease in the female members of this population was 18.1 cases per 100,000 women of all ages. The joint prevalence of both sexes together was 10.6 cases per 100,000. The annual incidence of new female cases was 1.2 per 100,000 women. The disease is not rare when mild and moderately severe cases are also diagnosed. Severe cases account for only a tenth of all cases. Only about a tenth of the patients are men and most of them had the mild form of the disease. It may begin at any age. The incidence has possibly been rising during the last 10 years. Interstitial cystitis does not as a rule progress continuously but reaches its final stage rapidly, then usually remains in the same category. With this prevalence and incidence every urologist in this area can expect to see at least one case a year.

A clinical series of 208 patients who had elective operations for gastroduodenal ulcer in Surgical Department II, Oslo City Hospital, has been reviewed. The study concentrates on postoperative gastric retention, comparing the frequency of this complication following antrectomy and gastroduodenal anastomosis with and without vagotomy. The patients in the nonvagotomy group had no retention problem. In the vagotomy group, 19 patients (35%) of 54 operated had troublesome postoperative retention. 7 patients (13%) had to have a further operation for this complication, all within 1 year. We no longer use the combined operation as a routine procedure for duodenal ulcer.

The proteolytic activities and trypsin inhibitors of the peritoneal exudate produced by experimental acute pancreatitis in the rat were studied by fractionation with gel filtration on Sephadex G-200 and estimation of the hydrolysis of casein and synthetic substrates. The peritoneal exudate produced by injecting formalin solution into the peritoneal cavity was used as a control. The peritoneal exudate during pancreatitis revealed distinct proteolytic and ATEE hydrolysing activities and it also hydrolysed BAPNA to a lesser extent. These activities were absent from the control exudates, or only traces of them could be demonstrated with the methods used. The trypsin inhibiting capacity (TIC) in the pancreatic exudate was about half that in the control exudate. In gel filtration on Sephadex G-200 the BAPNA hydrolysing proteolytic activity was eluted with the macroprotein fraction, suggesting that the enzyme was bound to the macroproteins. TIC differed clearly in the control exudate and the pancreatitis exudate. In both of them TIC was eluted in two peaks after the macroproteins, but in the pancreatitis group the first peak was very weak, if demonstrable at all, while in the control exudate the two peaks were clearly separated and the TIC was more pronounced. These findings suggest that pancreatic enzymes are released during pancreatitis into the peritoneal cavity, where they combine with proteinase binding factors in the exudate.

During the years 1955-1970, 260 patients were treated for acute pancreatitis in the surgical department of the Maria Hospital. 62 of them were operated on, 44 electively, and 18 as emergency cases. The main conclusions from this series are as follows: 1) if laparotomy is required, efficient debridement and drainage are of great importance, 2) random operative decompression of the biliary duct system is statistically of little benefit, 3) in most cases purely conservative treatment or conservative surgery, taking into account individual conditions, gives good results, but obviously more radical measures are necessary for a favourable outcome in the most severe cases, as reported in the current literature, 4) in elective surgery it is important to postpone the curative operation by several weeks, preferably months, when possible, to avoid exacerbation or relapse of the disease.

The reliability of the diagnosis made on the basis of symptoms of deep venous thrombosis and the development of a post-thrombotic state were studied in 53 patients. Pain in the leg was present in 93% and swelling in 82% of the series, both figures are considerably higher than those reported before. The clinical diagnosis was correct in 74% of cases. The post-thrombotic state developed with unexpected rapidity: after one to three years 87% already had symptoms and/or signs of venous insufficiency, and after eight years at the latest all patients had such symptoms and/or signs.

The distribution of genetic variants at the PGM1 and PGM2 loci in South and East Asia, the Western Pacific and Australasia has been surveyed on the basis of published and unpublished material comprising samples from some 33,000 persons. A critical comparsion of previously described and of new rare alleles at both loci has been undertaken. The present number for PGM1 is 14 and for PGM2 is 12. Many of these have restricted geographic or ethnic distribution.

Eleven independent man-mouse hybrids and 40 subclones from four to them were analysed for up to 42 enzyme markers. Nine subclones from three hybrid lines were fully karyotyped. The data presented suggest that the gene for the human enzyme MOR-M can be assigned to chromosome 7, whilst those for MPI and PK-3 are on chromosome 15. The use of a small number of well-characterized hybrids for gene assigments is discussed as well as the significance of some known human linkage relationships.

A computer-based system has been developed for the handling and retrieval of data on long-term human lymphoblastoid cell lines. It permits accurate recording of a wide range of genetic markers and other defined characteristics for the donor of each culture and for individual aliquots of any cell line. The data is recorded in relation to the in vitro age of each aliquot studied and the programme is designed to permit both the sequential examination of a single cell line and the comparison of lines of different origins. It is hoped that, by the application of this type of system, the confusion which has arisen in relation to other long-term cell lines (and which threatens to develop in relation to human lymphoblastoid cell lines) may be avoided and that the exchange of information between laboratories may be facilitated.

Inherited disorders of homocysteine metabolism produce accelerated growth and arteriosclerosis with myointimal hyperplasia. The growth of cell cultures from cystathionine synthetase deficient individuals with homocystinuria is characterized by abnormal contact inhibition and production of an aggregated proteoglycan matrix which binds excess sulfate. Homocysteic acid, a precursor of sulfate ester, increases the growth rate of normal guinea pigs. Synthesis of homocysteic acid from homocysteine thiolactone is more rapid in the livers of young animals than adults, and hypophysectomy results in a pattern of homocysteine thiolactone metabolism resembling that in liver of adult animals. Homocysteine thiolactone metabolism differs in guinea pig, an herbivorous species, and in rat, an omnivorous species. Sulfate binding by cultured human cells is slightly increased when homocysteic acid is present in the culture medium. These observations suggest a relationship between homocysteic acid and somatomedin, a serum polypeptide which mediates the action of growth hormone. The growth disorders associated with homocystinuria, including arteriosclerosis and accelerated growth, are believed to result from increased conversion of methionine to homocysteine thiolactone and homocysteic acid.

The means and standard errors of the total numbers of heterozygotes and homozygotes affected by deleterious mutant genes and the extinction time are studied by using diffusion methods. For an overdominant mutation, the effects of an increase in population size on these quantitites are much more profound than that of an increase in initial number of mutant genes whereas for a partially recessive mutation the situation is reversed. For a completely recessive mutation, the expected total number of mutant homozygotes is independent of the population size and degree of inbreeding, though the expected total number of heterozygotes and the average extinction time are dependent on these factors, particularly the population size. The effect of inbreeding on these quantitites is very similar to that of reduction in effective population size and is usally small at the prevailing level of inbreeding, except for mutations with large degrees of overdominance in large populations. The standard errors of these quantities are large. The expected total number of sickle-cell mutant homozygotes in the U.S. population has been computed.

An expression is derived for the prior probability of linkage between a random trait locus and any one of m random marker loci, and this probability is computed form=1, 10, 20, 30, 50 and 100. A similar expression is derived for two trait loci, and computed for m=1, 10, 20 and 30. When one trait locus and 30 marker loci are being studied, a priori there is over a three-quarter probability that the trait locus should be syntenic with at least one of the markers, and about a one-half probability that there should be a linkage mappable from recombination frequencies. If two traits are studied, then the prior probability that at least one should be syntenic with one of the 30 markers is 0-94, and there is a three-quarter probability that such a linkage should be mappable.

The maximum likelihood estimator of the frequency of a recessive gene in a random mating population is simply the square root of the proportion of recessive individuals in a random sample. However, its asymptotic variance, i.e. the inverse of Fisher's information, has an unexpected functional form, and its use may lead to incorrect inferences. An explanation for this is sought by deriving an expansion for the exact variance of the estimator. Further, a number of calculations reveal conditions under which the asymptotic variance provides a reasonable approximation to the exact variance. Lastly, the problem of setting confidence limits to the gene frequency is discussed, with a number of approximations being considered.

1. It is well established that p, the probability of a male birth, declines with birth order. It is suggested here that this decline occurs within individual sibships (Poisson variation). 2. Other workers have also offered good evidence that (at least in some samples) p correlates positively between adjacent births within sibships (Markov association). 3. The present paper suggests that in addition, some couples have higher values of p than others. In other words, there is Lexis variation in p between couples. It is estimated that this Lexis variation augments the variance (contingent on the Markov process above) by a value of less than 0-002. 4. Data on sex ratio by the sex composition of the pre-existing children are interpreted to support the author's hypothesis that coital rate of parents is related to the sex ratio of their children. 5. However if the decline in sex ratio with maternal age were entirely due to the concomitant decline in coital rate, the variation in p between couples seems greater than could be accounted for by the observed variation between couples in coital rate. It is concluded that sex ratio depends on other factors besides coital rate. 6. It is noted that (when sibship size and birth rank are controlled) MF birth intervals are particularly long, and FM birth intervals particularly short, MM and FF intervals being of intermediate length.

The susceptibility of 55 strains of slow-growing anaerobes to eight clinically useful or potentially useful antibiotics was determined by agar dilution and disk diffusion tests. Strains of the genera Peptococcus, Peptostreptococcus, Megasphaera, Veillonella, Eubacterium, Bifidobacterium, Clostridium, and Fusobacterium were included. All strains were susceptible to chloramphenicol, but varied in their susceptibility to penicillin, lincomycin, clindamycin, tetracyclines, and vancomycin. Correlation between minimal inhibitory concentration and inhibition zone diameters was generally good. Prediction of susceptibility based on zone diameter measurements appeared satisfactory. Although routine susceptibility testing of anaerobic bacteria is not recommended, there are circumstances where such testing is relevant to the clinical situation. For those laboratories ill-equipped to do dilution tests, a disk diffusion test would give relatively accurate preliminary information. Quantitative susceptibility tests could then be done by a reference laboratory.

A radioimmunoassay and an enzymatic assay for gentamicin have been compared. The correlation coefficient for results of gentamicin assays performed by the two methods with 45 serum specimens was 0.90. A similar standard curve for the radioimmunoassay was obtained with gentamicin complex, with gentamicin Cl, Cla, or C2, or with sisomicin as ligand, but tobramycin did not compete with [(3)H]gentamicin for binding to the antiserum.

A broth-dilution method for performing antimicrobial susceptibility tests on anaerobic bacteria has been proposed. The medium used in the test was Schaedler broth, with incubation in a glove box with an atmosphere of 5% CO(2), 10% H(2), and 85% N(2), or in the GasPak system. Minimal inhibitory concentrations for selected antibiotics were determined, under these conditions, by using a conventional twofold dilution scheme for the antibiotics and a "categorization three-tube method" in which two or three clinically significant concentrations of each antibiotic were used. Minimal inhibitory concentrations obtained by both methods were very similar. The categorization method could be used routinely to test the antimicrobial susceptibility of anaerobic bacteria.

Studies were conducted in 30 patients with neoplastic diseases. Twelve patients received sisomicin intramuscularly at doses of 20 mg/m(2) and 40 mg/m(2). The mean peak serum concentration occurred at 1 h and was 2.5 mug/ml and 4.0 mug/ml, respectively. Ten patients received intravenous sisomicin at doses of 30 mg/m(2) during 30-min infusion. Mean peak serum level determined at 30 min was 5.1 mug/ml. The levels gradually decreased and at 6 h was 0.6 mug/ml. The serum half-life was 160 min. Serum levels determined in eight patients who received sisomicin by continuous infusion at doses of 30 mg/m(2) every 6 h were greater than 1.4 mug/ml during the 6-h period. The urinary excretion of sisomicin during the 6-h period after intramuscular administration of 20 mg/m(2) and 40 mg/m(2) was 49 and 61%, respectively. The pharmacology of sisomicin is similar to gentamicin.

The comparative susceptibility of 622 recent clinical isolates of anaerobic bacteria to minocycline, doxycycline, and tetracycline was determined by an agar-dilution technique. In addition to Bacteroides fragilis, a variety of other anaerobic bacteria was resistant to achievable blood concentrations of tetracycline (55% inhibited by 6.25 mug/ml) and doxycycline (58% inhibited by 2.5 mug/ml). In contrast, minocycline was significantly more active (P < 0.05) than both doxycycline and tetracycline, and 70% of strains were inhibited by achievable blood concentrations of this antibiotic (2.5 mug/ml). The enhanced activity of minocycline was particularly striking for Peptococcus asaccharolyticus, P. magnus, P. prevotii, Peptostreptococcus anaerobius, and Bacteroides melaninogenicus. Further evaluation of the clinical efficacy of minocycline against anaerobic infections is indicated.

The in vitro antifungal activity of amphotericin B methyl ester (AME), a water-soluble derivative of amphotericin B, was compared to that of the parent compound against a variety of pathogenic and potentially pathogenic fungi. AME has a significant antifungal activity, but the activity of AME was slightly lower than that of amphotericin B. Among the yeast-like organisms, only the yeast cells of Sporothrix schenckii were more resistant than others to both antibiotics, with a minimal fungicidal concentration of 5 to 10 mug/ml. The yeast cells of other fungi were killed at concentrations of 1 mug or less of either antibiotic per ml. The filamentous forms of S. schenckii and Oidiodendron kalrai were more resistant than the filamentous forms of other dimorphic fungi to both drugs. The minimal fungicidal concentration for S. schenckii was 10 mug/ml and for O. kalrai, 50 mug/ml. The dermatophytes, phycomycetes, and dematacious and other potentially pathogenic fungi were inhibited fairly well by both drugs, but up to 50 mug/ml was required for fungicidal action. The water solubility and wide spectrum of antifungal activity of AME warrant evaluation of its chemotherapeutic activity against experimental fungal infections.

Staphylococcin 462 is a proteinaceous inhibitor produced by Staphylococcus aureus strain 462. In broth cultures, susceptible S. aureus strain 140 and 19 respond to treatment with the bacteriocin by stopping growth and cell division. Examination of macromolecular synthesis by measuring the incorporation of radioactive precursors revealed that S. aureus 140 stops synthesizing protein immediately. After exposure to staphylococcin 462, the synthesis of deoxyribonucleic acid and ribonucleic acid is quickly inhibited also, but not as completely. Treatment of S. aureus 140 with the inhibitor causes a rapid drop in cellular adenosine 5'-triphosphate level to about 60% of control levels. Of the 70 strains of gram-positive bacteria tested for susceptibility to staphylococcin 462, 24 (34%), distributed among 7 genera, were susceptible.

The mechanism of plasmid-mediated resistance to cadmium in Staphylococcus aureus was investigated. Protein synthesis in cell-free extracts from resistant or susceptible bacteria was equally susceptible to inhibition by Cd(2+), but spheroplasts from resistant bacteria retained their resistance. Resistant bacteria did not have a decreased affinity for cations in general, nor was active metabolism required for exclusion of Cd(2+). The kinetics of Cd(2+) uptake into susceptible and resistant bacteria suggested that the conformation of membrane proteins in resistant bacteria may be important in the exclusion of Cd(2+).

gamma-Thiochromanone-4-thiosemicarbazone (TCT) inhibits the growth of vaccinia virus in BSCl cells by interfering with viral maturation. A mutant of the virus (TCT(R)) which is resistant to this drug was isolated. This mutant also exhibits resistance to another thiosemicarbazone related compound, isatin beta-thiosemicarbazone (IBT). There is a good correlation between the cross-resistance of the two mutants IBT(R) and TCT(R) to TCT and IBT, respectively, and the similar antipoxvirus activity of these two thiosemicarbazone-related compounds.

The mechanism of action of enterocins E1A and E1B, bacteriocins produced by Streptococcus faecium E1, was studied. The enterocins killed susceptible cells rapidly, but cell lysis does not appear to be involved directly. Susceptible cells could be rescued from the lethal damage by trypsin treatment only within 2 to 3 min after addition of enterocin E1A. Enterocins E1A and E1B inhibited protein synthesis and drastically reduced biosynthesis of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) but did not cause degradation of DNA or RNA. Enterocin E1A strongly inhibited the accumulation of isoleucine and caused rapid exit of previously accumulated isoleucine.

The in vitro susceptibility of 155 strains of anaerobic bacteria to five cephalosporin antibiotics was tested. Cefoxitin was the most active against 33 isolates of Bacteroides fragilis; 82% of the strains were sensitive at 16 mug/ml. At 64 mug/ml cefazolin and cephaloridine were also generally effective. Cephalothin and cephalexin were relatively inactive versus B. fragilis. Cefoxitin, cephaloridine, cefazolin, and cephalothin showed comparable activity against 122 strains of anaerobes other than B. fragilis. More than 90% of the strains were sensitive to each of these antimicrobials at 16 mug/ml. Cephalexin was the least effective cephalosporin against all species tested.

Lactobacillus helveticus strain LP27 produced a bacteriocin, lactocin 27, in dialyzable and nondialyzable forms. No evidence was obtained to indicate that lactocin 27 was under the control of extrachromosomal plasmids. Lactocin 27 had a bacteriostatic effect on the indicator, Lactobacillus helveticus strain LS18. It inhibited primarily protein synthesis without affecting deoxyribonucleic acid and ribonucleic acid synthesis or adenosine 5'-triphosphate levels. Treatment of susceptible cells with the lactocin did not cause leakage of ultraviolet-absorbing material, but caused the efflux of potassium ions and the influx of sodium ions. It adsorbed non-specifically to various bacterial species irrespective of their susceptibility to lactocin 27. However, the presence of specific receptors has not been ruled out.

Parenteral clindamycin was evaluated in 41 patients with a variety of infections. The four major findings were as follows. (i) Five hours after the intravenous administration of 600 mg of clindamycin, the mean serum concentration in patients with "moderate to severe" hepatic dysfunction was 24.3 mug/ml, and in those with normal liver function it was 8.3 mug/ml (P < 0.02). This suggests that the dose of clindamycin might be modified in patients with liver disease. (ii) There was a positive association between the 5-h serum clindamycin level and the degree of elevation of the serum glutamic oxaloacetic transaminase. (iii) No significant side effects were observed. Of 24 patients with preexisting hepatic dysfunction, 5 showed deterioration and 5 showed improvement of liver function during therapy. (iv) Whereas all pre-treatment isolates of Staphylococcus epidermidis from the anterior nares were susceptible to clindamycin, 6 of 9 post-treatment isolates were resistant, most probably due to selection of resistant organisms.

The minimal inhibitory concentration of lincomycin and clindamycin for a large number of strains from multiple serogroups of streptococci was determined. The median minimal inhibitory concentration for streptococci from groups A, B, C, F, G, H, L, and M and nongroupable organisms ranged from 0.02 to 0.39 mug of lincomycin per ml and from </=0.01 to 0.09 mug of clindamycin per ml. Among the group D strains, Streptococcus faecium and Streptococcus faecalis were resistant to lincomycin and clindamycin, whereas Streptococcus bovis and four American strains of Streptococcus durans resembled nongroup D isolates in their susceptibility to these agents. Occasional strains of nongroup D streptococci were highly resistant to lincomycin and clindamycin.

Diuretics and antibiotics are frequently used concomitantly. The possibility of drug interactions led us to study the effects of several diuretics on the renal elimination of cephalothin. Five healthy volunteers received a constant infusion of 500 mg of sodium cephalothin per h for 9 h on 4 consecutive days. Each day, after the third hour of infusion, the subjects were given one of the following in varying order: (i) furosemide (1 mg/kg, intravenous), (ii) mercaptomerin (250 mg, intramuscular), (iii) mannitol (25 g, intravenous), or (iv) no diuretic (control day). Fluid losses were replaced hourly. Serum and complete urine collections were obtained each hour and assayed for creatinine and cephalothin (bioassay). Clearances (milliliter per minute) and urinary excretions (milligram per hour) of cephalothin did not differ either when the diuretic day values were compared with control day, or when pre- and postdiuretic results on the same day were compared. Creatinine clearances were not affected by diuretics except for a transient rise after furosemide.

Three aminoglycoside antibiotics and two penicillins were compared for their in vitro activity against 60 isolates of Serratia, Pseudomonas, Proteus mirabilis, and indole-positive Proteus sp. Testing was done by the agar dilution method using Mueller-Hinton broth solidified with 1.5% agar. The activity of amikacin, aminodeoxybutirosin, and gentamicin against Proteus and Pseudomonas, as related to their peak blood levels, showed no significant differences. Amikacin was the most active against Serratia marcescens. Results using Mueller-Hinton media in broth dilution tests correlated with the agar dilution method except for Pseudomonas aeruginosa. The minimal inhibitory concentration for aminoglycosides in agar was considerably greater than the minimal inhibitory concentration in Mueller-Hinton broth, and the disparity was related to the higher divalent cation concentration of agar. BL-P1654 and carbenicillin were similar except that carbenicillin was much more active against indole-positive Proteus sp. Additionally, the ratio of bactericidal to bacteriostatic concentrations of BL-P1654 was considerably greater than for carbenicillin.

The in vitro activity of cefazolin was assessed by continuous turbidimetric monitoring of cultures of gram-negative bacilli and the results were compared with those previously obtained with other beta-lactam agents using the same strains and methods. Cefazolin was found to induce rapid lysis of ampicillin-susceptible and -resistant strains of Escherichia coli at a lower concentration than any other beta-lactam agent tested; its stability to beta-lactamase, as judged by regrowth studies, was generally considerably greater than that of other antibiotics of this group. Tested against 103 ampicillin-resistant enterobacteria, cefazolin was found to be more active than cephalothin against E. coli, but no systematic increase in susceptibility to cefazolin was seen with other species. A study of cefazolin in an in vitro model which simulates the hydrokinetic features of the urinary bladder showed it to be as active as ampicillin against ampicillin-susceptible E. coli and as active as cephalothin against ampicillin-resistant E. coli.

In vitro lymphocyte blastogenic responses to the commonly employed mitogens, phytohemagglutinin, pokeweed, and concanavalin A, were evaluated when adenine arabinoside (ara-A) in a concentration of 3 mug/ml was added to the culture materials. Similarly, blastogenic and cytotoxic responses to cell cultures persistently infected with herpes simplex virus 1, herpes simplex virus 2, and varicella-zoster virus were determined in the presence of ara-A. No depression of these cellular immune responses by ara-A was demonstrated. This was in contrast to the effect of cytosine arabinoside, which at a concentration of 3 mug/ml severely inhibited these immune responses. Further studies examined lymphocyte blastogenic responses to the mitogens and blastogenic and cytotoxic responses specific for the herpes group virus infecting patients who were subsequently treated with ara-A; determinations were made before, during, and after treatment. In vitro responses during and after treatment with ara-A were unchanged or often enhanced as compared to pretreatment values. Therefore, the antiviral chemotherapeutic agent, ara-A, does not appear to depress the host's cellular immune responses, which are vital to successful elimination of invading herpes group viruses.

A sequential formation of the single components of the polyene macrolide candidin complex (heptaene) has been found. In addition to the three components occurring in the candidin complex at the end of the fermentation, two other "early" all-trans heptaene components have been characterized. They exist only during the phase of active biosynthesis of candidin. Two of the components of the polyene macrolide candihexin complex (hexaene) that have been described as lacking amino sugar were the only intracellular (mycelium-associated) components observed under conditions in which no extracellular polyene remained attached to the producing cell. The results indicate that glycosylation of the macrolide ring takes place during the secretion process.

A comparison of rifampin susceptibility test results on 407 strains of mycobacteria using conventional medium in parallel with disk medium showed good agreement. Techniques are described for utilization of drug-impregnated disks in the preparation of medium and for a quality control screening procedure for disks.

Binding of gentamicin and related deoxystreptamine-containing aminoglycoside antibiotics to proteins in human serum can vary significantly with changes in experimental conditions. The concentrations of divalent cations are important variables, and binding increases progressively as the concentrations of calcium and magnesium decrease. Maximal binding of deoxystreptamine-containing aminoglycosides to human serum is approximately 70% in the absence of divalent cations. The binding of (3)H-labeled gentamicin to Pseudomonas aeruginosa increases and its bactericidal activity against P. aeruginosa is enhanced in the absence of divalent cations. In contrast, binding of (3)H-labeled gentamicin to Escherichia coli and bactericidal activity against E. coli do not vary significantly in the presence and in the absence of divalent cations. Interference with uptake of gentamicin provides a plausible explanation for the observation that the minimal inhibitory concentration of gentamicin for P. aeruginosa increases as the concentration of calcium or magnesium in bacteriological media increases. Although significant binding of deoxystreptamine-containing aminoglycosides to plasma proteins does not occur under normal physiological conditions in man, the possibility remains that variations in protein binding of these aminoglycosides might be significant under pathological conditions.

Verdamicin is a new aminoglycoside antibiotic isolated from fermentation broths of a species of the genus Micromonospora, M. grisea. It has been differentiated from other known related antibiotics by a variety of chemical and biological methods. Its in vitro and in vivo spectrum of activity appears to be similar to those of gentamicin and sisomicin.

To reduce the incubation time requirement in the Bauer-Kirby antibiotic susceptibility test, comparisons were made of the test results at 18 to 20 h (standard) and 7 to 8 h (rapid) utilizing 100 recent clinical isolates. The zone diameters for 664 disks were monitored by using the standard classification: resistant, intermediate, or susceptible. The susceptibility determination was unchanged in 558 out of 664 instances (84.0%). An analysis of the remaining 106 sets revealed that an initial interpretation of intermediate in zone size, subsequently determined resistant or susceptible, accounted for 49 of the observed differences. The reverse changes, initial resistant or susceptible subsequently classified as intermediate, accounted for 20 of the changes. In five instances the interpretation changed from susceptible to resistant; in two cases the interpretation changed from resistant to susceptible. The remaining 30 determinations were classified as indeterminant due to (i) insufficient growth at the early (7 to 8 h) determination, and to (ii) zones which were so large that they could not be measured accurately. The data indicate that zone sizes when measured to the nearest 0.1 mm can be interpreted with reasonable accuracy and the results can be available 10 to 14 h sooner.

Two clostridocins distinguishable by their different modes of action on Clostridium pasteurianum have been isolated, namely, butyricin 7423 found in cultures of Clostridium butyricum NCIB 7423 and perfringocin 11105 produced by Clostridium perfringens type A, NCIB 11105. Both were trypsin-susceptible proteins which were soluble in concentrated aqueous ethanol and were able to bind large amounts of the nonionic detergent Triton X-100. In the presence of Triton X-100, butyricin 7423 behaved as a hydrophobic protein in being concentrated in the polyethylene glycol layer of a three-phase partition system of dextran-Ficoll-polyethylene glycol. Their capacity to bind Triton X-100 was exploited in a purification procedure applicable to both bacteriocins. After aqueous ethanol extraction of an ammonium sulfate-precipitated fraction (and, in the case of the perfringocin, a heat-treatment step), a bacteriocin-Triton X-100 adduct was purified by gel filtration through Sepharose 6B. The bacteriocin was then freed of Triton X-100 by chromatography on Sephadex LH-20. Samples of butyricin 7423 purified in this way from different sources contained variable amounts of carbohydrate. Yet sodium dodecyl sulfate-gel electrophoresis revealed the existence of a polypeptide component of 32,500 daltons (+/-10%), which displayed the biological activity of butyricin 7423 in the absence of any detectable associated carbohydrate (or lipid). Preparations of perfringocin 11105 contained no carbohydrate or lipid and migrated in sodium dodecyl sulfate-gel electrophoresis as a single protein component of 76,000 daltons (+/-10%). It was concluded that both bacteriocins behave as amphiphilic proteins, and some implications of this finding are considered.

In a rabbit model of herpes simplex corneal ulceration, 5% phosphonoacetic acid solution or ophthalmic ointment suppressed clinical disease and virus replication. The effect of 5% phosphonoacetic acid ointment was equivalent to that of 0.5% idoxuridine ointment in the treatment of this established herpetic eye infection.

Initial studies indicate that rifampin may be useful for the treatment of Staphylococcus aureus infections. Because bacterial resistance to rifampin may develop rapidly, its widespread use could result in the emergence of a resistant flora. This study evaluates the effectiveness of rifampin in reducing the nasal carriage of S. aureus and the rate at which resistant mutants emerge in a tuberculosis hospital where the drug was widely used. Anterior nares cultures were performed four times over a 13-month period. Carriage rates of S. aureus were 1.7% in 227 patients receiving rifampin, 7.8% in 190 patients receiving other antituberculous therapy, and 14.2% in 98 hospital employees (rifampin-treated versus other patients, P < 0.003; rifampin-treated versus employees, P < 0.001; employees versus other patients, P = 0.157). All four strains of S. aureus isolated from patients on rifampin therapy were rifampin resistant. All 16 strains isolated from patients not on rifampin and 15 of 16 strains isolated from hospital personnel were susceptible. One instance of apparent spread of a rifampin-resistant organism occurred in a hospital attendant who had never received rifampin.

BL-S 640 was evaluated in vitro by comparison with cephalothin, cephaloridine, cefazolin, and cephalexin. The new compound was more active than the control cephalosporins against most major gram-negative and some gram-positive species. Moreover, its antibacterial spectrum included strains of Enterobacter, Proteus morganii, P. rettgeri, and Providencia stuartii, species generally resistant to the other cephalosporins. BL-S 640 was an effective bactericidal agent for strains of various species of Enterobacteriaceae. In human plasma, the compound was 58% protein bound.

The bioavailability and therapeutic properties of BL-S 640 in rodents were compared with those of cephalothin, cephaloridine, and cefazolin after parenteral administration, and cephalexin after oral administration. When given intramuscularly in dosages of 5 to 40 mg/kg, peak concentrations of BL-S 640 in the blood of mice were proportional to dose, but when given orally, they were proportional only up to a dose of 25 mg/kg. After either route of administration, the concentration of BL-S 640 in the blood declined at a slower rate than that of the control compounds. Rats receiving BL-S 640 orally excreted an average of 39% of the drug in the urine. BL-S 640 was highly effective in the treatment of mice infected systemically with a variety of pathogenic bacteria, its therapeutic efficacy in comparison with that of other cephalosporins being frequently in excess of what would have been predicted on the basis of comparative activities in vitro.

A microdilution technique using commercially available media and materials was developed and used to determine the minimal inhibitory concentrations (MICs) of clindamycin, chloramphenicol, tetracycline, minocycline, ampicillin, carbenicillin, cephalothin, and gentamicin for 101 anaerobic isolates. Representative strains of Bacteroides, Clostridium, Fusobacterium, Peptococcus, and Peptostreptococcus were tested. The use of Schaedler broth at pH 7.2, an inoculum of 10(5) to 10(7) colony-forming units per ml, and incubation at 35 C in an anaerobic glove box with an atmosphere of 80% nitrogen, 10% hydrogen, and 10% carbon dioxide resulted in good growth and easily interpretable results. After 48 h of incubation, 97% of strains tested were inhibited by 3.1 mug or less of clindamycin per ml and 98% were inhibited by 12.5 mug or less of chloramphenicol per ml. Tetracycline and minocycline inhibited 81 and 88% of strains tested in concentrations of 1.6 mug or less per ml and 1.6 mug or less per ml, respectively. Ampicillin inhibited all strains other than B. fragilis in concentrations of 3.1 mug or less per ml. Excluding certain strains of Bacteroides and Clostridium, carbenicillin in concentrations of 12.5 mug or less per ml and cephalothin in concentrations of 6.2 mug or less per ml inhibited all strains tested. Gentamicin was inactive although some strains of anaerobic cocci and Bacteroides were inhibited by 3.1 mug or less per ml. After 18 to 24 h of incubation, eight of the 101 strains had not grown sufficiently for MICs to be determined; for the 93 strains which had grown sufficiently, 93% of 744 MICs were the same or one concentration lower than the 48-h MICs.

An investigation to study adsorption of gentamicin and other related aminoglycoside antibiotics to cellulose, diatomaceous earth (Celite), and Seitz filter sheets was carried out. Experiments with five aminoglycosides indicated that 30 to 100% of these antibiotics was adsorbed to cellulose depending on the ratio of antibiotic to adsorbent, and the total quantity could not be removed by acidification. Similarly, a study with gentamicin found adsorption to diatomaceous earth to be in the range of 33 to 98%. Neomycin and gentamicin were also readily adsorbed to Seitz filter sheets. The data indicate that large losses may occur during filtration of these antibiotics under certain conditions, and care should be taken to properly evaluate results during studies with these compounds in the presence of adsorbent materials.

The antimicrobial activity of five compounds extracted from marine algae was tested against Staphylococcus aureus, Salmonella choleraesuis, Mycobacterium smegmatis, Candida albicans, and Escherichia coli. Three of the compounds, cycloeudesmol, laurinterol, and debromolaurinterol, exhibited activity at concentrations approaching that of streptomycin. None of the compounds inhibited all of the organisms tested. There appeared to be selectivity for gram-positive microbes.

The clinical efficacy, patient tolerance, and pharmacokinetics of gentamicin and the single component gentamicin C(1) were studied after single and multiple doses in elderly male patients. Patient tolerance was extremely good at the dose levels used. There was some evidence of renal function impairment due to repeated intramuscular doses of gentamicin, but not gentamicin C(1). The antibiotics were equally effective against the organisms present in the urine of these patients. The pharmacokinetics of the two antibiotic forms were similar, although gentamicin C(1) appeared to have a larger distribution space.

Data derived from testing the bactericidal activity of combinations of penicillin with gentamicin or streptomycin and of clindamycin with gentamicin on nine isolates of Streptococcus mutans were analyzed by preparing isobolograms to determine the presence of additive, synergistic, or antagonistic effects. Synergy with penicillin-aminoglycoside combinations was found in two strains; additive effects occurred in seven instances with penicillin-gentamicin combinations; and antagonism occurred in eight instances with clindamycin-gentamicin combinations.

The inhibitory effect of lipophilic acids, antimicrobial food additives, and analgesics-antipyretics was examined at concentrations from 0.1 to 100 mM in bacteria (Bacillus subtilis and Escherichia coli) and mammalian cells (HeLa, human fibroblasts, and mouse neuroblastoma cells). Most compounds inhibit the growth of HeLa cells about as efficiently as that of B. subtilis. However, butyrate and propionate, as well as acetaminophen, antipyrene, phenacetin, and salicylamide, inhibit HeLa at millimolar concentrations whereas, at least 10 times higher concentrations are needed to inhibit B. subtilis. The concentrations needed to inhibit growth by 50% decrease with increasing octanol-water partition coefficients of the compound. Growth of E. coli is inhibited similar to that of B. subtilis by all compounds except butylbenzoate, decanoate, and linoleate which cannot penetrate the lipopolysaccharide layer. All growth inhibitors inhibit amino acid uptake into bacteria and their vesicles, and oxygen consumption in bacteria. In HeLa cells or human fibroblasts, neither amino acid uptake nor adenine 5'-triphosphate synthesis are inhibited by fatty acids at concentrations that completely inhibit growth. Short chain fatty acids (propionate, butyrate, and pentanoate) induce in HeLa the formation of cell processes. In neuroblastoma cells, grown in the presence of 10% fetal calf serum, butyrate also induces such processes which slowly continue to grow in length for at least 7 days; these processes differ in speed of formation, width, and cycloheximide susceptibility from the thin processes produced by serum deprivation alone.

To assess their potential value as early indicators of gentamicin-induced kidney damage, lysosomal hydrolases were measured in the 24-h urines of rats receiving 30 or 60 mg of gentamicin per kg per day for 15 days. Proteinuria, urine osmolality, blood urea nitrogen, and creatinine clearance were also measured. Kidney tissue was examined by both light and electron microscopy. Beta-galactosidase, beta-n-acetyl-hexosaminidase, and alpha-fucosidase were sensitive indicators and were significantly elevated above control values by day 3 at both doses (P < 0.01). Proteinuria, urine osmolality, and tests reflecting glomerular filtration rate were later indicators of nephron damage. Changes by light microscopy were detected on day 5. Necrosis was most prominent in the proximal convoluted tubules on day 10. Electron microscopy revealed numerous cytosomes with myeloid bodies within the proximal tubular epithelium on day 5. Lysosomal enzymuria appears to be an early manifestation of gentamicin nephrotoxicity and may possibly be related to the lysosomal abnormalities seen on electron microscopy.

The in vitro activity of BL-S640, a 7-(2-aryl-2-aminoacetamido)-3-(heterocyclic-thiomethyl) cephalosporin, was evaluated against 338 clinical isolates of Enterobacteriaceae in comparison with ampicillin, cephalothin, cefazolin, and cephalexin. Against Escherichia coli, BL-S640 was as active as cefazolin and more active than ampicillin, cephalothin, and cephalexin. BL-S640 was as effective as the other cephalosporins tested and far more active than ampicillin against Klebsiella and was more active than cephalexin against Proteus mirabilis and the indole-positive Proteus. The majority of Enterobacter, Serratia, and Citrobacter were resistant to ampicillin and all the cephalosporins tested. With rare exceptions, the zone of inhibition by the BL-S640 30-mug disk was either larger or the same as the zone obtained by the cephalothin 30-mug disk in the Kirby-Bauer disk susceptibility test.

A case of renal cutaneous metastases simulated Kaposi sarcoma and the condition was misdiagnosed as Kaposi sarcoma. A new technique was employed using the isotope technetium 99m as the compound sodium pertechnetate Tc 99m for the diagnosis and evaluation of the extent of Kaposi sarcoma. The failure to demonstrate a positive isotope scan in our case was a clue to the incorrect diagnosis of Kaposi sarcoma.

Contact urticaria refers to a wheal-and-flare response occurring on the application of chemicals to intact skin. Standard closed patch tests read at 48 hours after application yield misleading information; observations should be made instead using open patch tests 15 to 30 minutes after application. There are three major subdivisions of the syndrome: nonimmunologic cause (such as application of histamine), immunologic cause (immediate hypersensitivity), and uncertain cause (such as application of ammonium persulfate). Our patient had contact urticaria due to the insect repellent, diethyltoluamide. The experimental data suggest that this case was due to an immunologic response (immediate hypersensitivity) and demarcates the specificity of response. The immunologically mediated cases cover a broad spectrum of manifestations from contact urticaria only to local urticaria plus asthma and, in extreme sensitivity, includes anaphylactoid responses.

The presence of mucosal Darier disease (keratosis follicularis) was evaluated clinically and histologically in four consecutive patients with moderate to extensive cutaneous manifestations of this disease. Fiberoptic endoscopy demonstrated hypopharyngeal or laryngeal involvement or both in each patient. A dearth of corps ronds and grains in these anatomical regions was observed histologically. The routine evaluation of mucosal involvement in Darier disease should result in a higher incidence of hypopharyngeal and laryngeal lesions than is currently known. Furthermore, the recognition of hypopharyngeal and laryngeal involvement with Darier disease must be emphasized because of the clinical similarity to leukoplakia and squamous cell carcinoma.

A patient with incontinentia pigmenti archromians, who was born to consanguineous parents, is described. This is the first reported case from Iran, to our knowledge. A number of features of this disease belong more properly to classical incontinentia pigmenti.

A 68-year-old man sought dermatologic attention for a tumor of the arm. Biopsy specimen showed abnormal, essentially amelanotic, spindle-shaped cells in the cutis, greatly fibrotic stroma, and focal epidermal invasion. Desmoplastic malignant melanoma was diagnosed. The lesion was widely excised and axillary lymphadenectomy performed; one node showed metastasis. Nine months later, he died with widespread metastatic disease. To our knowledge, this is the first report of this entity since its delineation in 1971 and the only case in which diagnosis was established on initial biopsy and followed by definitive therapy. Desmoplastic melanoma has been confused with benign fibrosis, invasive fibromatosis, and fibrosarcoma, and is another example, with morpheaform basal cell carcinoma and sclerodermoid metastatic lesions from breast carcinoma, in which desmoplastic stroma may obscure the epithelial nature of cutaneous neoplasm.

A woman had a primary pedunculated malignant melanoma. This is a rare form of presentation and may result in clinical confusion with seborrheic keratosis, fibroepithelial papilloma, or granuloma pyogenicum. The aggressive nature of the lesion was indicated by the presence of erosion and bleeding. Though the tumor cells were present only in the pedunculated mass, it had metastasized to regional lymph nodes at the time of surgery.

Radon seeds, formerly used for vascular and neoplastic tumors, acne, and other dermatological disorders, are rarely, if ever, used today. Because the half-life of radon is 3.83 days, these hollow gold seeds filled with radon gas are usually left in situ permanently. A case is reported of a woman who had seeds implanted 33 years ago for a vascular lesion. The seeds were removed and found to have minute amounts of residual radiation but not sufficient to cause radiation damage. Since seeds are foreign bodies, removal is recommended if they are easily accessible.

A patient had sensory radicular neuropathy. The patient demonstrated features characteristic of this entity: (1) recurrent trophic ulcerations of the hands and feet, (2) onset in early adulthood, (3) distal, dissociated loss of pain and temperature sensation far out of proportion to the loss of other sensory perceptions, and (4) complete sparing of motor function.

Three siblings displayed an unusual form of keratoderma characterized by diffuse and striate hyperkeratosis of the palms and soles, hyperkeratotic plaques over the dorsum of the hands and toes, and linear hyperkeratotic lesions over the Achilles tendon area, ankles, elbows, and knees. The predominant location of these lesions led to the term acral keratoderma for this disorder. Histologically, besides thickening of all epidermal layers with that of the stratum corneum being most notable, various dyskeratotic changes were evident in the epidermis. Pedigree analysis of the family suggested an autosomal recessive inheritance pattern. There were similarities and differences between the type of keratoderma displayed by these three patients and that of patients described previously with the disorder known as keratoma hereditarium mutilans.

A 29-year old man had an unusual unilateral lesion of the mucous membranes of the mouth, including the lips, buccal mucosa, hard and soft palate, and uvula. The lesion was a conglomerate of tiny papillomas and had been present since birth. At the age of 8 years, a mass extending from the uvula into the pharynx was surgically excised. The histopathological findings showed acanthosis, papillomatosis, and an inflammatory infiltrate. The findings represent a rare case and perhaps a unique one, to my knowledge.

A limited investigation of respiratory and other symptom prevalence, plus before and after shift ventilatory capacity was conducted among a group of 17 meat wrappers exposed to pyrolysis products of polyvinyl chloride and a group of 21 control subjects. Exposed meat wrappers showed a higher prevalence of cough, phlegm, hay fever, and asthma than did the control group. The exposed group also demonstrated relative decreases in forced expiratory volume, one second (FEV1.0) and forced expiratory flow 50% (FEF50) after one shift of work; whereas, the controls showed an opposite tendency. These findings suggest that meat wrappers exposed to pyrolysis products of polyvinyl chloride might be adversely affected. The results, while suggestive, are not totally conclusive owing to the fact that there was not ideal matching of the exposed and control groups in regard to age, height, race, sex, and smoking status.

The incidence and characteristics of cement-asbestos pneumoconiosis were compared with those of asbestosis and cement pneumoconiosis in three homogeneous samples of cases. The clinical, functional, and radiological features of cement-asbestos pneumoconiosis are similar to those of classical asbestosis, but the observed changes are less common and occur after a longer exposure.

Lead storage in teeth was evaluated by examining the lead concentration in deciduous teeth of 32 children whose habits of pica and state of lead exposure had been studied when they were between 1 and 3 years of age. Concentratios of lead in their teeth depended on the reported amount of paint or plaster intake and the duration of exposure. The mean dental concentration of lead in exposed children was significantly higher than the mean value in 36 controls, who presumably did not have undue exposure to lead. A difference in dental lead concentration related to living area was noted. The significant difference in lead content of teeth between the two groups, even though the concentrations of lead in blood at 8 years of age were similar, emphasizes the importance of dental lead measurments for retrospective studies of lead exposure.

A multistage cryogenic trapping system was used to sample and concentrate trace organic constituents in human respiratory gas. Chemical analysis was conducted by gas chromatography and mass spectrometry. Respiratory compound identification and production rate data are given for eight human test subjects. This study reports on the use of the sampling technique to diagnose metabolic diseases and for application in the study of industrial exposure.

Ozonides of the methyl esters of oleic, linoleic, linolenic and arachidonic acids were found to produce Heinz body inclusions in human and mouse erythrocytes. No simple relationships between structure and activity were noted. Concomitant with Heinz body formation, methemoglobin and loss of cellular thiols were observed. Methyl ozonides readily oxidized glutathione and 1 mole of oxidized glutathione was formed per mole of methyl oleate ozonide. Methyl ozonides catalyzed the formation of disulfide-linked interchain polymers between hemoglobin and ovalbumin. Heinz bodies were not produced with ozone in the absence of unsaturated lipids. Heinz bodies were observed in the blood of mice exposed to ozone (0.85 ppm) for 48 hours. These observations suggest that fatty acid ozonides could serve as a toxic chemical species formed on ozone inhalation and could explain the divergent protective effects of lipid antioxidants and thiol generating systems in vivo.