Studies on the mechanism of resistance to rapamycin in human cancer cells

Rapamycin is a potent cytostatic agent that arrests cells in the G1 phase of the cell cycle. The relationships between cellular sensitivity to rapamycin, drug accumulation, expression of mammalian target of rapamycin (mTOR), and inhibition of growth factor activation of ribosomal p70S6 kinase (p70(S6k)) and dephosphorylation of pH acid stable protein I (eukaryotic initiation factor 4E binding protein) were examined. We show that some cell lines derived from childhood tumors are highly sensitive to growth inhibition by rapamycin, whereas others have high intrinsic resistance (>1000-fold). Accumulation and retention of [14C]rapamycin were similar in sensitive and resistant cells, with all cells examined demonstrating a stable tight binding component. Western analysis showed levels of mTOR were similar in each cell line (<2-fold variation). The activity of p70(S6k), activated downstream of mTOR, was similar in four cell lines (range, 11.75-41. 8 pmol/2 x 10(6) cells/30 min), but activity was equally inhibited in cells that were highly resistant to rapamycin-induced growth arrest. Rapamycin equally inhibited serum-induced phosphorylation of pH acid stable protein I in Rh1 (intrinsically resistant) and sensitive Rh30 cells. In serum-fasted Rh30 and Rh1 cells, the addition of serum rapidly induced c-MYC (protein) levels. Rapamycin blocked induction in Rh30 cells but not in Rh1 cells. Serum-fasted Rh30/rapa10K cells, selected for high level acquired resistance to rapamycin, showed >/=10-fold increased c-MYC compared with Rh30. These results suggest that the ability of rapamycin to inhibit c-MYC induction correlates with intrinsic sensitivity, whereas failure of rapamycin to inhibit induction or overexpression of c-MYC correlates with intrinsic and acquired resistance, respectively.     

The choice of the optimal schedules in the vaccination procedure against influenza in elderly subjects

The paper describes a clinical case of the cerebral hyperperfusion syndrome, a rare complication of carotid endarterectomy. The syndrome appeared as the generalized convulsive syndrome in the patient in the early postoperative period. In the context of clinical observation, the results of analysis of the literature are presented and the pathogenesis, diagnosis, therapy, and prevention of the cerebral hyperperfusion syndrome considered.     

Glycated hemoglobin reference limits obtained by high performance liquid chromatography in adults and pregnant women

Pentachlorophenol (PCP) and molybdate have been shown to inhibit the sulfoconjugation of various chemicals in rats and therefore are useful to examine the role of sulfoconjugation on the toxicity of a chemical. PCP inhibits sulfation by competing with substrates for phenol-sulfotransferases, but not hydroxysteroid-sulfotransferases. In contrast, molybdate decreases sulfation by limiting sulfate availability and thereby decreasing the synthesis of 3'-phosphoadenosine 5'-phosphosulfate (PAPS), which is the obligate cosubstrate for sulfation. Therefore, it was of interest to determine whether PCP or molybdate is effective in decreasing the in vivo sulfation of dehydroepiandrosterone (DHEA), which is a substrate for hydroxysteroid-sulfotransferases. PCP (40 micromol/kg ip) or molybdate (7.5 mmol/kg po) was given 45 min and 4 h, respectively, prior to the start of DHEA infusion. The effects of these two sulfation inhibitors on DHEA sulfation were dependent on the rate of DHEA infusion in rats. PCP had different effects on the sulfation of various infusion rates of DHEA in rats. PCP had little effect on the sulfation after the two lowest infusion rates of DHEA (12.5 and 25 mg/kg) and actually increased (233%) DHEA-sulfate serum concentrations with the highest DHEA infusion rate (50 mg/kg). Although molybdate had little affect on the sulfation of the lowest DHEA infusion rate, it significantly decreased (50-85%) DHEA-sulfate serum concentrations with the two higher DHEA infusion rates. These data indicate that molybdate, unlike PCP, decreases the sulfation of DHEA and may be a useful tool to decrease the sulfation of other substrates of hydroxysteroid-sulfotransferases.     

Calcitonin and bipolar disorder: a hypothesis revisited

Many of the great discoveries and developments in the sciences and the arts were made by people who were 'mentally different'. Some such pioneers or innovators had experiences that were indistinguishable from the phenomena defined as mental illness (or madness). It has been argued that such experiences are a necessary constituent of the creative process, and that this may apply to the sciences as much as to the arts. Increasingly, scientists propose a means by which it may be possible to identify (and eliminate) the factors that influence the altered states associated with mental illness. This may be an appropriate time to review the cultural and social significance of all forms of 'madness', especially in the light of emerging models of psychiatric nursing practice.     

The characteristics of the causative agents of suppurative-inflammatory complications in hemophiliacs

Morphological-cultural and physiological-biochemical properties of 24 strains of microorganisms agents of pyo-inflammatory complications of different localization in patients with hemophilia have been studied. Microorganisms strains presented by the following species: Staphylococcus aureus, S. epidermidis, S. saprophyticus, Proteus vulgaris, P. morganii, Hafnia alvei, Serratia marcescens, have been identified. It was found out that in monoculture staphylococci prove to be the leading etiological agent (60.9%), gram-negative enterobacteria (52.2%) and bacterial associations (8.7%) occur more rarely. Special attention was paid to the study of resistance of antibiotics, circulation and pathogenicity factors that had a direct effect on the main disease severity. It was ascertained that high activity of enzymes and presence of pathogenicity factors were the peculiarities of microorganisms isolated from pyo-septic sites in patients with hemophilia. All the strains possessed multiple resistance to antibiotics.     

Alcoholism and alcohol abuse among women: report of the Council on Scientific Affairs. American Medical Association

We describe characteristics of women alcohol abusers, risk factors for alcoholism in women, barriers to treatment, and implications and strategies for physicians dealing with alcohol abuse in women patients, including risk assessments and intervention strategies. Alcohol abuse and alcoholism have a different physiologic effect on women than on men. Societal attitudes about women and alcohol and internal (self-perception) and external (environmental) factors can create barriers to the detection and treatment of female alcohol abusers. Physicians are in an excellent position to address the medical, psychologic, and social concomitants of alcoholism and alcohol abuse. The Council on Scientific Affairs recommends that physicians become more active in the prevention, diagnosis, and treatment of alcohol-related problems in women, including the diseases that may be associated with chronic alcohol abuse and the effect of alcohol on the developing fetus. Specific American Medical Association policy and recommendations for physician practice are included.     

Surgical anatomy of the infratemporal fossa: the styloid diaphragm revisited

INTRODUCTION: The infratemporal fossa (ITF) gives passage to most major cerebral vessels and cranial nerves. Dissection of the ITF is essential in many of the lateral cranial base approaches and in exposure of the high cervical internal carotid artery (ICA). We reviewed the surgical anatomy of this region. METHODS: Direct foraminal measurements were made in seven dry skulls (14 sides), and the relationship of these foramina to each other and various landmarks were determined. Ten ITF dissections were performed using a preauricular subtemporal-infratemporal approach. Preliminary dissections of the extracranial great vessels and structures larger than 1 cm were performed using standard macroscopic surgical techniques. Dissection of all structures less than 1 cm was conducted using microsurgical techniques and instruments, including the operating microscope. The anatomic relationships of the muscles, nerves, arteries, and veins were carefully recorded, with special emphasis regarding the relationship of these structures to the styloid diaphragm. The dissection was purely extradural. RESULTS: The styloid diaphragm was identified in all specimens. It divides the ITF into the prestyloid region and the retrostyloid region. The prestyloid region contains the parotid gland and associated structures, including the facial nerve and external carotid artery. The retrostyloid region contains major vascular structures (ICA, internal jugular vein) and the initial exocranial portion of the lower Cranial Nerves IX through XII. Landmarks were identified for the different cranial nerves. The bifurcation of the main trunk of the facial nerve was an average of 21 mm medial to the cartilaginous pointer and an average of 31 mm medial to the tragus of the ear. The glossopharyngeal nerve was found posterior and lateral to stylopharyngeus muscle in nine cases and medial in only one. The vagus nerve was consistently found in the angle formed posteriorly by the ICA and the internal jugular vein. The spinal accessory nerve crossed anterior to the internal jugular vein in five cases and posterior in another five cases. It could be located as it entered the medial surface of the sternocleidomastoid muscle 28 mm (mean) below the mastoid tip. The hypoglossal nerve was most consistently identified as it crossed under the sternocleidomastoid branch of the occipital artery 25 mm posterior to the angle of the mandible and 52 mm anterior and inferior to the mastoid tip. CONCLUSION: The styloid diaphragm divides the ITF into prestyloid and retrostyloid regions and covers the high cervical ICA. Using landmarks for the exocranial portion of the lower cranial nerves is useful it identifying them and avoiding injury during approaches to the high cervical ICA, the upper cervical spine, and the ITF.     

Prolonged pregnancy. Labor induction versus intensified monitoring]

This study was made in order to evaluate the effect of a policy of induction of labour at 42 weeks of gestation in post-term pregnancies. A group of 139 women with uncomplicated post-term pregnancies, who gave birth at the maternity ward at Herlev Hospital in 1993 was compared to a group of 145 women, who gave birth in 1996 at the same location. In 1993 spontaneous labour was awaited with twice weekly surveillance tests, and labour was only induced if there was evidence of foetal or maternal compromise, while in 1996 labour was induced at 42 weeks of gestation. There were at 20.1% inductions of labour in 1993 compared to 44.8% in 1996. The perinatal morbidity and birth complication rates were similar in the two groups.     

Comparison of the eye's wave-front aberration measured psychophysically and with the Shack-Hartmann wave-front sensor

The Shack-Hartmann wave-front sensor offers many theoretical advantages over other methods for measuring aberrations of the eye; therefore it is essential that its accuracy be thoroughly tested. We assessed the accuracy of a Shack-Hartmann sensor by directly comparing its measured wave-front aberration function with that obtained by the Smirnov psychophysical method for the same eyes. Wave-front profiles measured by the two methods agreed closely in terms of shape and magnitude with rms differences of approximately lambda/2 and approximately lambda/6 (5.6-mm pupil) for two eyes. Primary spherical aberration was dominant in these profiles, and, in one subject, secondary coma was opposite in sign to primary coma, thereby canceling its effect. Discovery of an unusual, subtle wave-front anomaly in one individual further demonstrated the accuracy and sensitivity of the Shack-Hartmann wave-front sensor for measuring the optical quality of the human eye.