Ligand-induced autoregulation of IL-2 receptor {alpha} chain expression in murine T cell lines

The IL-2 receptor (IL-2R) is composed of three chains a, ßand . In mice, contrary to the human system, we have previouslydemonstrated that the IL-2Rß complex does not bindIL-2. Therefore, mouse IL-2 response is completely dependenton the expression of the IL-2R gene product. T cell clones expressingmouse IL-2Rß and the human IL-2R transgene have beenstudied. When cells are grown in IL-4, mouse IL-2R is not expressed.However, exposure to IL-2 leads to the expression of the endogenousmurine IL-2R subunit. The T cell line expressing mouse IL-2Rand human IL-2Rß can grow in IL-2 but does not expressendogenous murine IL-2 R. Transfection of these cells with thehuman IL-2R gene restores the capacity to induce murine IL-2R.This result demonstrates that IL-2-IL-2R interactions are requiredfor induction of IL-2R. The kinetics of induction and deinductionof murine IL-2R have been studied using clone 18.III. From negativecells, expression of murine IL-2R is a very slow phenomenon.From cells fully expressing IL-2R, deinduction is a two-stepprocess: after a rapid decrease of IL-2R the cells continueto express, for a long period of time, basal levels of murineIL-2R. When cells expressing basal levels of IL-2R are exposedto IL-2, induction of IL-2R is a very rapid phenomenon. Theautoregulatory loop formed by IL-2-IL-2R therefore displaysdifferent levels of functioning.     

A Novel Locus for Ectodermal Dysplasia of Hairs, Nails and Teeth Type Maps to Chromosome 18q22.1–22.3

Ectodermal dysplasias (EDs) are developmental disorders affecting tissues of ectodermal origin including hair, nails, teeth and sweat glands. Ectodermal dysplasia of hair, nails and teeth is a rare type of congenital disorder characterized by sparse and thin hair, dystrophic finger-and toenails and missing and abnormal teeth. In an effort to understand the molecular basis of this form of ED a family of Pakistani origin with an autosomal recessive pattern of inheritance was ascertained from a remote region in Pakistan. The clinical features of the affected individuals included thin and fine hair on the scalp, dystrophic and flat nails, absent or sparse eyebrows and eyelashes, missing and abnormal teeth, and thin body hair. A human genome scan carried out using microsatellite markers mapped the disease locus in this family to chromosome 18q22.1–18q22.3. A maximum two-point LOD score of 2.73 (θ= 0.0) was obtained at marker D18S541. Multipoint linkage analysis resulted in a maximum LOD score of 3.42 obtained with several markers, including D18S1125, ATA82B02, D18S848, D18S488, D18S1091, and D18S485, which supported the linkage. The linkage interval is flanked by markers D18S857 and D18S815, which corresponds to a region of 17.32 cM according to Rutgers combined linkage and physical map (build 36). This region covers 8.63 Mb according to the sequence-based physical map. Three candidate genes, CDH7, CDH19 and ZNF407 , from the linkage interval were sequenced and found to be negative for functional sequence variants. This study is the first step towards the identification of a gene involved in hair, nails and teeth type ED.     

Do Eye Hospitals Have a Role in Our Future?

Eye hospitals, originally founded to care for the poor, have developed into academic centers and tertiary "hospitals of last resort." Inexorable economic pressures, especially price competition, are likely to close many of them, particularly those which are marginal in quality or management. Survival of the remainder may further depend on their ability to adapt to a rapidly changing environment and to fulfill, better than anyone else, the special mission of basic and clinical research and training. Society must be convinced that some of these complex, highly differentiated, relatively expensive eye hospitals are significant national resources, serve the public welfare, and are worth preserving.     

Influence of food on the intravenous and oral dose kinetics of propranolol in the dog

The intravenous and oral dose kinetics of propranolol were studied in the dog both in a fasted state and immediately after a meal consisting of 100 g of cooked beef liver. Fifty Ci of³H-propranolol was administered intravenously simultaneously with a 40-mg oral dose of unlabeled propranolol. Plasma³H-propranolol was measured by specific extraction and liquid scintillation spectrometry, and unlabeled plasma propranolol was determined by gas chromatography-mass spectrometry. Feeding significantly reduced (25%) the elimination half-life and increased (52%) the systemic clearance of intravenous propranolol. The increase in the systemic clearance of propranolol after feeding was mostly due to an increase (60%) in apparent hepatic blood flow, which appeared to remain elevated for 5–7 hr. The meal had no influence on the apparent volume of distribution or plasma binding. Feeding did not affect the area under the concentration-time curve of oral propranolol, but significantly delayed the rate of oral propranolol absorption, shifting the time to reach peak plasma levels from 60 to 158 min. The results of this study suggest that feeding alters the disposition of propranolol in the dog by producing a sustained increase in hepatic blood flow.This work was supported by National Institute of Health grants GM 07534, GM 20387, and HL 29566.     

Pretherapeutic flow cytometric DNA investigations in radiotherapy patients with maxillo-facial carcinomas

In order to analyze the possible meaning of cellular DNA content and cell cycle phases for the radiosensitivity and the prognosis of human malignant tumors, flow cytometric measurements have been performed in biopsies of 131 patients with histologically proven squamous cell carcinomas of the maxillo-facial region. In two-thirds of the patients (88/131; 67%), aneuploid tumor cell lines have been found, only 33% (43/131) had a diploid DNA distribution pattern. The average DNA index (DI) of the aneuploid carcinomas was 3.4 +/- 0.6 (normal nonmalignant tissue DI = 2.0). The frequency of S-phase cells, which represents the "proliferative activity", was between 4.8 and 63.2%, regardless of the ploidy stages. The aneuploid carcinomas had about twice as many S-phase cells (mean 23.7 +/- 11.8%) than diploid tumors (mean 12.7 +/- 4.8%). Mean survival for patients with diploid carcinoma and aneuploid carcinoma was 12 and 9.5 months, respectively. Concerning the relationship of S-phase frequency and survival times in our material there was a high negative statistical correlation (Spearman-Rank test) in patients with diploid carcinomas. A high S-phase fraction resulted in short survival times. No correlation was found in the aneuploid carcinomas: patients with tumors in high S-phase values in their biopsies showed no difference in prognosis in comparison to tumors with lower S-phase fractions.     

Chronopharmacokinetics of beta-receptor blocking drugs of different lipophilicity (propranolol,metoprolol, sotalol,atenolol) in plasma and tissues after single and multiple dosing in the rat

Summary Comparative pharmacokinetic studies with the -receptor blocking drugs propranolol, metoprolol, sotalol and atenolol, differing greatly in lipophilicity, and their main route of elimination were performed in light-dark-synchronized rats after equimolar single (6 moles/kg) or multiple (6x6 moles/kg) drug application. Drug concentrations were determined in plasma and various target organs of the drugs, e.g. heart, muscle, lung and brain, after drug application in the light period (L) and dark period (D), respectively. After single drug administration pharmacokinetic parameters of all drugs depended on the L and D conditions. Elimination half-lives in plasma and organs were shorter during D than during L. No L-D-differences were found in initial drug concentrations of the hydrophilic drugs sotalol and atenolol. In contrast, C₀-values of the lipophilic propranolol in highly perfused organs (muscle, lung, brain) and of metoprolol in muscle tissue were significantly higher in D than in L. No obvious temporal dependency was found in other pharmacokinetic parameters (AUC, plasma clearance,V _d) with the exception inV _d of propranolol. Due to the different physico-chemical properties of the compounds inter-drug-differences in pharmacokinetic parameters including drug accumulation into lung and brain tissue were observed. Multiple drug dosing abolished the circadian-phase-dependency in the elimination half-lives of the drugs due to an increase in D. Only for the highly lipophilic propranolol half-lives in highly perfused organs were still shorter in D than in L. It is concluded that L-D-differences in drug half-lives after single dose application are mainly due to circadian variations in drug elimination with a higher hepatic (propranolol, metoprolol) or renal (sotalol, atenolol) elimination in the activity period of rats during D. Additional studies with propranolol on heart rate of conscious rats revealed that a maximum in -receptor blockade was achieved at 10 moles/kg in L but not in D. Thus, it is assumed that abolition of circadian-phase-dependency in half-lives after 6x6 moles/kg of the drugs may be due to the longer lasting and more pronounced -receptor blockade after multiple drug dosing over a period of several hours in D. Thereby, liver-flow-dependent elimination of propranolol and metoprolol and renal elimination of sotalol and atenolol is reduced to base-line levels found in L.Parts of this work were presented at the 22nd Spring Meeting (Lemmer 1981) and at the Joint Meeting (Lemmer et al. 1983a) of the German Pharmacological Society     

Substance P antagonists and mucociliary activity in rabbit

Summary Substance P (SP) is known to accelerate mucociliary (m.c.) activity in the rabbit maxillary sinus in vivo. The physiological significance of this finding was investigated by testing three putative SP antagonists. [Arg⁵, d-Trp^{7, 9}, Nle¹¹]SP_5–11 could not be used as an antagonist because it stimulated m.c. activity. [d-Arg¹, d-Trp^{7, 9}, Leu¹¹]SP had no effect on the m.c. activity changes induced by SP. [d-Pro², d-Trp^{7, 9}]SP was found to be an effective antagonist, 1 mg/kg of this drug reversibly inhibiting both the effects of 0.1 g/kg SP and the stimulating effect of 1.0 g/kg bradykinin and 30.0g/kg capsaicin; the stimulating effect of 0.5 g/kg methacholine was not inhibited. It is suggested that bradykinin and capsaicin stimulate m.c. activity at least partly by releasing SP.The results of this investigation also support the view that the accelerating effect of SP on m.c. activity reflects physiological SP-mediated protective mechanisms in the airways. It is concluded that [d-Pro², d-Trp^{7, 9}]SP is a useful pharmacological tool for studying the role of SP in the control of m.c. actvity in rabbits.     

The effect of cost containment on the practice of cardiology: predictions

When health care cost containment is tied to unit pricing, the system may become price-driven rather than care-driven. Although the incentives engendered by unit pricing may not necessarily result in practices detrimental to the young or the patient with relatively pure disease, the potential for adverse effects on the elderly, the poor and the chronically ill is real. Hospitals will soon emphasize quick turnover, efficiency and intensive care. Diagnostic evaluations and chronic disease care will be moved out of hospitals into physician owned-and-operated facilities and out-of-hospital settings, respectively. The health care system will fractionate, and quality control will require restructuring to achieve the present level of quality assurance. Cardiologists, as well as other physicians, will need to alter their teaching style and teaching locations. Better methods for predicting outcomes will need to be developed; we will no longer have the safety net of following a patient closely and altering management plans according to the patient's response. Cost containment may occur under diagnosis related groups, preferred provider organizations, health maintenance organizations and other prepaid or "capped" systems. There are, however, many issues relative to cost versus quality that need to be resolved if severe detrimental effects on care are to be avoided.     

Plasticity of the central nervous system—a neurosurgeon's experience of cerebral compensation and decompensation

Summary Cerebral plasticity constitutes one of the most decisive factors in recovery and readaptation after cerebral lesions. In contrast to the considerable progress in current studies on normal neuronal plasticity including the idea of l'homme neuronal, the concept of plasticity postulated by Albrecht Bethe in 1929 received little attention. The author, as a neurosurgeon, has tried to describe cranial morphological plasticity, morphological and functional plasticity in infantile encephalopathies and especially in hemiatrophic lesions. It is supposed that a true morphological substrate exists due to compensatory hyperplasia of the uninvolved hemisphere.Modern neurosurgical techniques have demonstrated that the functional plastic capacity is much larger than has been supposed, even in the elderly. Some aspects of the mechanisms of compensation and decompensation of cortical and subcortical structures as well as of the central regulation systems are discussed. The full extent of the amazing recovery and functional reorganization is reached by plastic capacity, personal motivation, adequate training and sufficient time.The contribution ends with an exposition of a personal philosophy concerning psycho-somatic dualism, the body-mind problem, the future of the human brain and the ethical outlook, based on the progressive biological evolution of the basal neocortex and the immanent functional development (H. Spatz).In grateful memory of my paternal friends, the great German brain researchers Julius Hallervorden (1882–1965) and Hugo Spatz (1888–1969).     

Konsekutive Serie von 100 Colonresektionen mit einer modifizierten fortlaufenden Nahttechnik

Zusammenfassung Es wird anhand einer konsekutiven Serie über eine modifizierte fortlaufende Nahttechnik am Colon berichtet, die gerade bei älteren Patienten eine sichere und rasche Methode der Anastomosierung darstellt. Die klinisch relevante Insuffizienzrate sowie auch die Letalitätsrate betrugen in dieser Serie je 2%, wobei die Ursachen für die Letalität aber keine Folge der Insuffizienz waren. Die Komplikationsrate betrug 11%, die urologischen Komplikationen mit 6% standen hierbei im Vordergrund.

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A consecutive series of 100 resections of the colon using a modified technique of continuous (running away) suture

Summary Based on a consecutive series it is reported about a modified type of continuous suture on the colon, used especially in elderly patients for being a secure and prompt method of anastomosing. The rate of insufficiency and mortality, as far as the clinical relevance is concerned, turns out to be 2% each and there was no relation between mortality and insufficient anastomosis. The complication rate was 11%, whereby the urological complications predominated with 6% of the total.