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Observations were made of the chronic administration of norethindron e orally to 2 male baboons (Papio anubis), 1 mg/day daily for 1 month and then 5 mg/day for 5 months. A third animal was given the biscuits used for administration but without the drug. Liver biopsies were made 1 week prior to treatment, each month during treatment, and for 2 months following termination of treatment. Under electron microscopic magnification of 3000-12000 diameters, ultrastructural observations revealed dilatation and vesiculation of the endoplasmic reticulum as well as of the Golgi complexes. Cells with depleted glycogen granules w ere frequent and usually seen next to cells with glycogen. Accumulation of increased numbers and sizes of electron-dense microbodies was observed as treatment continued. Cells with large vacuolated inclusion bodies were always associated with anomalous bile canaliculi. Endothelial sinusoids included both macrophages and numerous electron-dense microbodies, especially in the later stages of treatment. A collagen substance appeared to have infiltrated the sinusoids of some of the parenchymal cells. When therapy was terminated the ultrastructure of the biopsy material showed progressive regeneration toward normal morphology. At the end of 2 months this structure was similar to control materials. Hepatic changes observed in this study are similar to those reported by others as occurring in women using oral contraceptives. The hepatocellurlar changes were temporary and reversible.

A group of investigators interested in the standardization of inhalation challenge techniques was selected by the program directors of the Asthma and Allergic Disease Centers (AADC). This effort has been assisted by the National Institute of Allergic and Infectious Diseases of the National Institutes of Health. At the last meeting of the panel on February 15, 19’75, criteria for procedures and materials used were suggested in order to standardize bronchial inhalation challenges as they pertain to allergic disease.

Repeated electrical stimulation of the brain stem including the hypothalamus, pons and medulla in monkeys produced an increase in arterial blood pressure, cardiac arrhythmias, various degrees of S-T segment or T wave changes and structural damage to the myocardium. The following ultrastructural changes in the myocardium occurred: distension of sarcoplasmic reticulum, swelling of mitochondria, disarrangement of filamentous arrays, formation of contraction bands, dissociation of intercalated discs and focal necrosis. These changes are similar to those found in ischemic myocardial tissue and myocardial necrosis induced by catecholamines. The myocardial lesions are probably related to activation of the sympathetic mechanism in the brain stem.

SUMMARY The influence of an altered thyroidal function on induced superovulation in B6AF1 mice has been investigated. The hypothyroid condition induced by feeding propylthiouracil (PTU) produced a significant increase in average numbers of ova from 20·3 to 28·7 (0·01 < P < 0·05). There was also an increase in ovarian weight from 42·7 to 86·5 mg./100 g. body weight (P < 0·001). Six groups fed PTU were also injected with l-thyroxine daily for 6 days to produce hyperthyroidism. This resulted in a decrease in average numbers of ova from 28·7 to 17·0 (0·01 < P < 0·05). The level of thyroxine has a highly significant effect on ova count, but the data are not sufficiently precise to determine the form of the dose-response relation.

Summary An eight-year review of the five common cosmetic surgical operations done in our clinic shows that there is a difference in the types of operations for Orientals. Because of the facial characteristics of these people, plastic construction of the superior palpebral fold is a very common operation. Next comes augmentation rhinoplasty. Cases for reduction rhinoplasty are seldom seen. Similarly, augmentation and not reduction mammaplasty frequently engages our attention out here in the Orient. Another interesting finding is that our cases for rhytidectomy are on the whole much younger in age than those seen in the West. The mean age for this operation is 37·1 years. The various operation techniques carried out in our clinic are briefly described. Lastly, we found that even among the various overseas Chinese communities living in Singapore there is a significant difference in their response to cosmetic surgery.

Thyroidal iodine metabolism was studied in four inbred strains of mice and two groups of F1 hybrids by use of radioiodine. Significant strain differences were found in both the 48-hour thyroidal retention of I131 and its output rate constant. Three closely related groups studied were C57BL/6, C57BR/cd and BBF1, their F1 hybrid. The other three groups included A/Jax, BALB/c and CAF1, their F1 hybrid. C57BL/6 mice had a significantly faster output rate and lower 48-hour I131 retention than any other group. The first three groups listed had a more rapid output rate and lower 48-hour retention than the last three. In intergroup comparisons and inverse relationship between I131 output rate and 48-hour retention was clearly shown. The results indicate that in mice pituitary TSH output, as indicated by thyroidal I131 output rate and thyroidal iodine pool size, is controlled by separate genetic factors.

Adenylate kinase activity was measured in rat tissues by a spectrophotometric procedure in which ADP formation from ATP and AMP was coupled with pyruvate kinase, phosphoenolpyruvate, and lactate dehydrogenase to oxidation of NADH. Activity, at 135 µmoles per min per g of tissue, was extremely high in the supernatant fraction from rat liver obtained by centrifugation of 0.25 m sucrose homogenate at 100,000 x g and was much lower in the mitochondria, at 13 units per g. No activity was found in the microsomes or nuclei. Both supernatant and mitochondrial fractions were nearly as active with other nucleoside monophosphates as cosubstrates as with AMP, but were much less active with other nucleoside triphosphates than with ATP. Apparent Km values for both supernatant and mitochondrial enzymes were 0.3 mm for MgATP and 0.03 mm for AMP. A 48-hour fast increased the liver supernatant enzyme activity to 374 units per g, and this was lowered strikingly in 24 hours, to about 40 units per g, by feeding a high glucose diet. The high fasting level was lowered only slightly by feeding a high fat or a high protein diet. In fed alloxandiabetic rats, activity was about as high as in fasted normal rats, and it was lowered by insulin treatment to levels found in normal fed rats. Activities were somewhat lower in adrenalectomized rats, and the effects of fasting and glucose feeding were not as pronounced as they were in normal rats. The mitochondrial enzyme activity remained essentially unaffected by dietary and hormonal alterations.

✓ A new isotopic method for the detection of cerebral tumors using labeled bleomycin is described. In a series of 104 patients, bleomycin was found superior to technetium-99m for the diagnosis of intracranial metastatic lesions; in 50% of the cases, bleomycin revealed metastases undetected by the Tc-99m, particularly in the posterior fossa. This method also provides valuable data for the differentiation of gliomas from metastases.

A former heroin addict treated with methadone maintenance throughout pregnancy, with rapid dose reduction from 110 mg to 9 mg during the last five weeks pre-partum, was evaluated in late pregnancy, at time of labor and delivery, and post-partum; her child was also evaluated. Using gas and thin-layer chromatography and mass spectroscopy, methadone levels were measured, and other drugs looked for in (1) plasma during late pregnancy, (2) mixed cord blood, (3) amniotic fluid at delivery, (4) maternal plasma and milk post-partum (on 50 mg methadone), (5) neonatal plasma and urine. Low levels of methadone were present in amniotic fluid and neonatal urine but not in mixed cord blood or neonatal plasma. Levels of methadone present in breast milk during moderate dose maintenance were also low. Unexpectedly, pentobarbital was identified in amniotic fluid. Neonatal infection was also diagnosed. Multiple factors may have contributed to symtoms observed in the neonate.

Compliances of the lungs and thorax are normal in chronic obstructive lung disease. However, despite its normal compliance, the overinflated thorax may contribute in a major way to ventilatory failure by being an ineffective inspiratory pump. This effect of the overinflated thorax is predicted by the respiratory pressure-volume diagram of Rahn and associates. The thorax does not become less compliant at lung volumes at or even considerably above the normal total lung capacity. Thus, in emphysema, when lung retractive force is impaired, overinflation is not seriously limited by the elastic recoil of the thorax.

Observations of variability of body size at different periods of postnatal growth of mice from different inbred and crossbred populations have been presented. The variability following body growth was shown to decrease in both inbred and F1 hybrid groups of mice but to increase in the backcross and F2 generations. Inferences concerning developmental homeostasis and time of gene action have been made.

Within the total therapeutic spectrum for asthma, some patients (currently 46 percent of the resident population of patients at CARIH) require prolonged maintenance therapy with corticosteroids. After a daily minimal effective dose of a selected "short acting" cortisone analogue has been established, patients can generally control their asthma with prednisone or methylprednisolone taken every 48 hours in the early morning at doses slightly more than twice the amount previously taken daily. Such an alternate day regimen has been found to be associated with fewer clinical side effects and also with minimal adrenal cortical suppression. Pulmonary function of the patients on alternate-day treatment could be maintained at a satisfactory level throughout the 48 hour cycle, showing the physiologic circadian variations observed in healthy individuals. Ordinary stress, such as an acute febrile illness, was tolerated by patients on alternate-day therapy uneventfully. Severe stress—not noted among the patients studied—may still require additional corticosteroid therapy immediately. Acute exacerbations of asthma necessitated interruption of alternate-day therapy and the administration of additional steroids initially and repeatedly at intervals of 4 to 6 hours, in conjunction with all other appropriate therapy, for at least 24 to 48 hours or a few days. Patients adequately controlled on an alternate-day schedule should be and are being observed continuously in order to assess the ultimate benefits—or untoward effects—of alternate-day steroid therapy.

SummaryImplantation into a 4-day worker larva of corpora allata from a queen larva 3 or 4 days old was followed by a reduction in the extent of ovary regression in the prepupal and pupal stages. The average number of ovarioles in adults developing from treated larvae was increased by several times, but no oocytes developed. Corpora allata from a worker larva had no effect on ovary regression. Injection of farnesol or farnesyl methyl ether did not affect the number of ovarioles but did result in the development of oocytes. The prepupal period was lengthened both by supernumerary corpora allata from queen larvae and by farnesol compounds. Results were consistent with a hypothesis of endocrine control of retrogressive changes in the worker reproductive system.

Summary The technique for the injection of a poly-linked silicone gel into a well prepared pocket in the retro-mammary space for breast augmentation is described. This silicone compound is supplied in the gel state ready for use without any preliminary addition of a catalyst. It retains its chemical and physical properties in situ. The complications encountered with this method in a fairly large series of cases seen over several years are described. Based on our experience, we would like to emphasise that the injection method should be used with extreme care and in selected multiparous women only.

Thyroid secretion rate was determined in four strains of inbred mice and two groups of F1 hybrids. In all genotypes the thyroid secretion rate was consistently but not significantly greater in males than in females. The average thyroid secretion rates, expressed as micrograms l-thyroxine/ 100 gm body weight with the standard errors for the males and females, were: A/Jax 2.13 ± 0.12 and 1.84 ± 0.10; BALB/c 2.44 ± 0.21 and 1.84 ± 0.12; C57BR/cd 3.35 ± 0.34 and 2.45 ± 0.11; C57BL/6 4.19 ± 0.64 µg. and 3.33 ± 0.34. The secretion rate for hybrids CAF1 and BBF1 males and females, respectively, were: 2.34 ± 0.185 and 1.84 ± 0.106; 3.79 ± 0.644 and 2.74 ± 0.268 µg/100 gm. C57BL strain and BBF1 hybrid had significantly higher secretion rates than all other groups. The results are consistent with the output rate values reported earlier by the same authors, and clearly indicate that thyroid activity is under genetic control.

To the Editor .—Drs. Chai and Newcomb have presented an excellent discussion of the pharmacological management of chronic asthma in childhood (125:757, 1973). Recent advertising for the newest pharmacological agent available for asthma, cromolyn sodium, emphasizes its supposedly unique role as a potential prophylactic drug for chronic asthma. I think that the most important contribution of Drs. Chai and Newcomb is their emphasis on using even the more traditional therapeutic drugs as prophylactic agents, aiming for sufficient continuous suppression of symptoms so that the patient can function acceptably. I submit this letter in an attempt to clarify recent work, 1,2 to which Drs. Chai and Newcomb referred, that may allow bronchodilators to be used orally with both greater effectiveness and safety in the management of chronic asthma. As the authors state, bronchodilators should form the backbone of office management of asthma. Such agents, however, have commonly been prescribed in fixed-dose combinations

Fifty-three vagotomized cats under chloralose were studied for cardiac augmentation, cardioacceleration, and vasomotor reaction on direct stimulation of the medulla oblongata and via reflex activations. Cardiac augmentation as well as other cardiovascular responses could be induced on stimulation of the dorsal medulla or the central cut end of the sciatic nerves, or on occlusion of the carotid arteries. The augmentation and other responses remained essentially unchanged regardless of the presence or absence of the rostral neural structures, including the hypothalamus. The results confirm and support the concept that a central control mechanism for vasomotor reaction and cardioacceleration as well as augmentation resides in the dorsal region of the lower brain stem.

SUMMARY Mice were selectively bred for high and low thyroidal 131I release rates. Two lines with sharp contrast in the selection criterion were produced, and an estimate of heritability was made. There were correlated differences in thyroid histology, protein-bound 131I, cholesterol level, haematocrit, adrenal and testicular weights, and some behavioural characteristics. It was concluded that multiple genetic factors affect the rate of thyroidal iodine release, and that the high release strain had greater thyroid activity than the low release strain. Some genetic aspects of thyroid function are discussed.

The serum proteins of three neurological mutations, tremulous, quivering, and waddler, were studied. The albumin level rose while the globulin level, especially the level of alpha fraction, fell in tremulous mice, but the trend was reversed in quivering mice. In waddler mice the changes were observed only in females.

SummaryExperiments were performed on mice with a hereditary neurological disorder characterized by spasm. Simple tests which were used to assess response to drugs included measurement of righting time after being placed on the back, and evaluation of degree of tremor and extent of flexibility and alertness. When single doses of Dilantin, trimethadione, or aminooxyacetic acid were administered intraperitoneally to the spastic mice, only the latter substance was found to be effective in decreasing the symptoms. Subcutaneously injected aminooxyacetic acid in doses of 5 to 15 μg/g produced marked improvement which was sustained for 12-24 hours or more. In some animals which received repeated injections of the drug there was a depression of motor activity, decreased alertness, and loss in weight. Two-dimensional paper chromatograms of extracts of brains of the spastic mice showed no significant alteration of distribution of ninhydrin-reactive constituents by comparison with normal controls.

One hundred fourteen mice castrated at weaning were given different dosages of testosterone propionate by daily subcutaneous injection for 20 days. The seminal vesicle weight was chosen as the quantitative indicator of growth response in secondary sex organ. Thirty-four noncastrates were used for comparison. The growth of the seminal vesicles in response to the different dosages of hormone stimulation was shown, as are population growths, to be well fitted with the logistic curve. It was found also that the point of inflection of the dose-response curve was at a seminal vesicle weight which was close to the seminal vesicle weight of the untreated controls.

Ten children with chronic intractable asthma whose airway sensitivity had been established by means of inhalation challenges to specific antigens were hyposensitized over a period of 5 to 12 months. Five additional asthmatic children acted as “controls.” Various aqueous antigens were used both for immunotherapy and for inhalational challenges. Therapy was given uninterruptedly. The total dose varied from 1,000 to 8,000 protein nitrogen units (PNU) in the controls and from 30,000 to 230,000 PNU in the subjects. Repeat challenges in the low-dose “control” group showed no changes in bronchial sensitivity. Ten children who received high total dosage all showed decreased bronchial sensitivity to specific antigens. Three children who were under study for 12 months could be evaluated clinically as well as physiologically since all four seasons were covered. There was no evidence of clinical, physiologic, or medication improvement in any of them, despite significant decreases in bronchial sensitivity. High-dose therapy appeared to decrease bronchial sensitivity significantly in all except two subjects. The effect was not related to the antigen dose but appeared to be an individual response of the subject.

Two doses of potassium iodide (KI) and an idcntical placebo tablet were given three times daily by mouth to 52 children with intractable asthma, ranging from 8 to 16 years of age. Each patient received in random order 12 week courses of KI, 900 and 300 mg. daily, and placebo given in coded form, according to a double-blind design. During each treatment period several indicators of the severity of asthma were recorded weekly and scored by methods described. Serum iodide levels and several aspects of thyroid function were assayed regularly. Evidences of side effects, including thyroid enlargement and acne, were also monitored. Examination of the results of individual responses, and the use of "improvement" and "condition" scores indicated that in the population as a whole asthmatic symptoms were improved by KI, particularly at the high dose level. There was, however, considerable variability in the responses observed in individual children. It is estimated that asthma improved significantly in 18 per cent, and moderately in another 46 per cent. The remaining 36 per cent did not seem to be influenced by KI with respect to symptoms of asthma. Moderate or marked thyroid enlargement occurred in 4 per cent of the children during treatment with KI, and barely palpable goiters in another 14 per cent, within three to six weeks after therapy was initiated. The enlargements were not clearly related to dose level, but no goiters occurred during placebo therapy. Acneform skin lesions were produced or aggravated primarily among the adolescents. While the mechanisms of action of KI in asthma remain unclear, the evidence presented here indicates that 300 mg. three times a day is a tolerable and effective dose for many children in the age ranges and population described. The efficacy is great enough to warrant further studies of the optimal uses of this drug.

Five areas commonly used in the measurement of asthma were examined. These are the clinical examination, history, pulmonary physiology, medication requirements, and school activity levels. Correlations between these measurements were possible by using two investigations in order to provide the necessary data. The value and shortcomings of each of these measures are discussed. The need for frequent observations has been shown in order to improve the low order of correlations obtained, even with those that are statistically significant. All five measurements are a requirement if research in this field is contemplated.