Inhibition and superactivation of the calcium-stimulated isoforms of adenylyl cyclase

It was shown previously that chronic exposure to opiate agonists increases adenylyl cyclase (AC) activity, a phenomenon termed AC superactivation (or supersensitization). More recently, we showed that acute G_i/o-coupled receptor activation inhibits the activity of several AC isozymes, including Ca²⁺/calmodulin-stimulated AC-I and -VIII, whereas chronic receptor activation induces their superactivation. Here, we report that both acute μ-opioid receptor-induced inhibition and chronic induced superactivation of AC-I and -VIII are pertussis toxin sensitive. In addition, we show that proteins that interfere with the activity of {ie195-2} subunits ({ie195-3} scavengers) strongly attenuate the acute inhibition of AC-I and -VIII and the superactivation of AC-I, and abolish the superactivation of AC-VIII. Based on these results, we suggest that {ie195-4} is involved in the acute inhibition and chronic agonist-induced superactivation of AC types I and VIII.     

Competing functions encoded in the allergy-associated F(c)epsilonRIbeta gene

Allergic reactions are triggered via crosslinking of the high-affinity receptor for immunoglobulin E, F(c)epsilonRI. In humans, F(c)epsilonRI is expressed as a tetramer (alphabetagamma(2)) and a trimer (alphagamma(2)). The beta subunit is an amplifier of F(c)epsilonRI surface expression and signaling. Here, we show that as a consequence of alternative splicing, the F(c)epsilonRIbeta gene encodes two proteins with opposing and competing functions. One isoform is the full-length classical beta, the other a novel truncated form, beta(T). In contrast to beta, beta(T) prevents F(c)epsilonRI surface expression by inhibiting alpha chain maturation. Moreover, beta(T) competes with beta to control F(c)epsilonRI surface expression in vitro. We propose that the relative abundance of the products of the beta gene may control the level of F(c)epsilonRI surface expression and thereby influence susceptibility to allergic diseases.     

Substantial pain burden in frequency,intensity, interference and chronicity among children and adults with neurofibromatosis Type 1

Tumor growths, migraine headaches, and other health‐related complications reported in patients with neurofibromatosis type 1 (NF1) are often associated with pain. Thus, this study sought to describe and quantify the pain experience in children and young adults with NF1. Surveys were administered to 49 participants (28 children and 21 adults), ages 8 through 40 years. The survey included the Numeric Rating Scale 11 (NRS11) to assess pain intensity and the Patient Reported Outcomes Measurement Information System (PROMIS) to assess pain interference. A supplemental survey was created to measure pain frequency, chronicity, quality, and location. Results suggest pain is not only present in 55% of the cohort, but that it can begin at early ages. Pain was chronic in 35% of participants, with 41% reporting the use of medication to manage pain symptoms. Common sources of pain included migraine headaches and NF‐related tumors. Pain was described as having neuropathic features (i.e., burning, tingling, numbness, or itching), and was localized to the head, back, and extremities. Further, subsets of participants reported moderate‐to‐severe pain intensity, high frequency of pain, and interference of pain in daily activities. Continued investigation of the pain experience in a multisystem disorder, such as NF1, remains essential to providing guidance in the setting of complex pain management.     

The effect of caffeine ingestion on physical performance after prolonged exercise

Summary The purpose of this study was to determine the effect of caffeine ingestion on physical performance after prolonged endurance exercise. Twenty three trained male volunteers participated in a 40-km march and were divided into two groups, matched for caffeine clearance rate and aerobic capacity. The experimental group ingested, prior to the march, a caffeinated drink at a dose of 5 mg·kg⁻¹ body mass and at the 3rd and 5th h of marching an additional drink at a dose of 2.5 mg·kg⁻¹ body mass. The control group ingested a drink of equal volume at the same times. Upon termination of the march each subject performed a cycle ergometer test at an intensity of 90% maximal oxygen consumption. Time to exhaustion and rate of perceived exertion (RPE) were recorded. Blood samples were drawn predrink, at the 3rd and 5th h of marching and immediately after the cycle ergometer test, and were analysed for caffeine, free fatty acids (FFA), lactate and glucose levels. Plasma FFA levels increased during the march (p<0.05), with no significant difference between groups. Lactate levels increased in the experimental group (p<0.05), with no significant change in the control group. Glucose levels did not change significantly in either group. After the cycle ergometer test, lactate levels were significantly higher in the experimental, as compared to the control group (3.77±0.33 vs 2.52±0.35 mmol·l⁻¹, respectively). There was no significant difference between treatments in the time to exhaustion on the cycle ergometer, but RPE was different (p<0.05). Under the conditions of this study, the results do not indicate caffeine ingestion as an ergogenic aid which will postpone exhaustion following prolonged endurance exercise. This work was presented, in part, at the Canadian Association of Sports Sciences Annual Meeting, October 1987, Lake Louise, Alberta, Canada     

A comparative immunogenicity-reactogenicity dose-response study of influenza vaccine

This study examined the immunogenic and reactogenic responses of influenza vaccine in 29 healthy nonallergic adults at three vaccine dosages: 0.5 mL, 0.1 mL, and 0.05 mL. After immunization a 7-day assessment of adverse reactions was made and serial serum hemagglutination-inhibition (HAI) antibody responses were measured during a 28-day period. The incidence of adverse reactions was significantly decreased in the group receiving 0.1 mL and 0.05 mL compared with the group receiving 0.5 mL of vaccine. After immunization with 0.1 mL or 0.05 mL vaccine increases in serum HAI antibody to A/Leningrad, A/Taiwan, and B/Ann Arbor influenza antigens were seen comparable to those observed after 0.5 mL. However the magnitude of these rises were lower and were directly correlated with the dose of vaccine. Since immunization of egg-sensitive allergic patients with influenza vaccine poses a risk of localized and systemic reactions, a common clinical practice is to prevent such reactions by vaccine dilution. Although the results of the present study suggest that vaccine dilution results in a decrease in adverse reactions, there is also the risk of decrease protective immunity with this procedure and therefore the practice should not be condoned.     

Intracerebral mass lesions in patients affected by AIDS

Summary Toxoplasma gondii cerebral abscess is a common opportunistic infection in patients affected by AIDS. Making a reliable diagnosis of acute cerebral toxoplasmosis is difficult in AIDS patients because of the lack of specificity of serological data and neuroradiological findings. Brain biopsy is the only procedure which enables a reliable diagnosis to be made a trial of specific medical therapy for toxoplasmosis in patients affected by AIDS and intracranial mass lesion can be advisable before performing brain biopsy. The authors report the cases of three patients affected by AIDS and cerebral toxoplasmosis.Tissue diagnosis was made in the first patient from autopsy material while a presumptive diagnosis was made in the other two cases since specific medical therapy resulted in a dramatic improvement of the neurological status.Despite the good possibilities in the treatment of this complication AIDS, however, carries a poor prognosis.     

Growth and growth hormone in children during and after therapy for acute lymphoblastic leukaemia

Growth impairment and growth hormone (GH) deficiency have been reported in children treated for acute lymphoblastic leukaemia (ALL). We have studied growth and GH secretion in a group of 50 patients, affected by ALL, during a 2- to 5-year period after diagnosis, and in 12 long-term-survivors. We observed a significant decrease in growth velocity during the 1st year (in particular during the first 6 months) of therapy and a catch-up growth after the end of therapy. Longterm survivors did not exhibit a significant reduction of height standard deviation score (SDS), as compared to height SDS at diagnosis. None of the patients showed GH deficiency. Our data indicate that chemotherapy significantly affects growth of patients treated for ALL, whereas radiotherapy-at the doses used in this study-does not induce GH deficiency, at least not within 9 years after diagnosis.     

Quercetin inhibits the growth of a multidrug-resistant estrogen-receptor-negative MCF-7 human breast-cancer cell line expressing type II estrogen-binding sites

Summary It has been demonstrated that the flavonoid quercetin (3,3,4,5,7-pentahydroxyflavone; Q) inhibits the growth of several cancer cell lines. There is evidence suggesting that the antiproliferative activity of this substance is mediated by the so-called type II estrogen-binding, site (type II EBS). We looked for the presence of type II EBS and the effect of Q on the proliferation of an Adriamycinresistant estrogen-receptor-negative human breast-cancer cell line (MCF-7 ADRr). By whole-cell assay using estradiol labelled with 6,7-tritium ([³H]-E2) as a tracer, we demonstrated that MCF-7 ADRr cells contain type II EBSs. Competition analysis revealed that diethylstilbestrol (DES) and Q competed with similar potency for [³H]-Es binding to type II EBSs. The antiestrogen tamoxifen (TAM) competed for type II EBSs, albeit to a lesser extent than either DES or Q. Growth experiments demonstrated that Q and DES exerted a dose-dependent inhibition of cell proliferation in the range of concentrations between 10 nM and 10 m, whereas TAM was less effective. Q could also inhibit colony formation in a clonogenic assay. Our results indicate that multidrug-resistant estrogen-receptor-negative MCF-7 cells express, type II EBSs and are sensitive to the inhibitory effect of Q. This substance could be the parent compound of a novel class of anticancer agents.     

Reproductive outcome after ovarian surgery: suturing versus nonsuturing of the ovarian cortex

The purpose of this study was to ascertain if microsurgical approximation of the ovarian edges after ovarian surgery alters postoperative results, as determined by both adhesion formation and reproductive outcome. Sixteen female white New Zealand rabbits were anesthetized, and the ovaries were exposed. Each ovary was longitudinally bivalved with a scalpel, but only one ovary was reconstructed microsurgically, whereas the contralateral ovary was left open. Four weeks after surgery, the rabbits were mated, and two weeks later, a laparotomy was performed to evaluate postoperative adhesions, the number of corpora lutea in each ovary, and the number of embryos in each uterine horn. The nidation index was calculated. No significant differences were found between the microsurgically sutured and the nonsutured ovaries for all the parameters evaluated. Our data suggest that not closing the ovarian incision does not alter either postoperative adhesion formation or reproductive outcome.