miR-19b-3p and miR-20a-5p are associated with the levels of antiphospholipid antibodies in patients with antiphospholipid syndrome.

Monocytes play a key role in pathophysiology of antiphospholipid syndrome (APS), nevertheless it is unclear if microRNA expression is associated with particular APS features. Identify whether miR-19b-3p and miR-20a-5p expression in monocytes are associated with hallmarks of the APS. Fifty-seven APS patients and 18 healthy controls were studied. Expression of miR-19b-3p and miR-20a-5p was measured in monocytes by RT-qPCR. Both miR-19b-3p (AUC = 0.835, 95% CI 0.733-0.938; P < 0.001) and miR-20a-5p (AUC = 0.857, 0.757-0.957; P < 0.001) discriminated APS patients from healthy individuals. A cut-off point of 1.98 for miR-19-3p and 2.18 for miR-20a-5p showed that APS patients with low microRNA expression had higher levels of IgM and IgG anticardiolipin antibodies than patients with high microRNA expression. In addition, APS patients with low microRNA expression had higher IgG anti-ß2 glycoprotein I antibody levels than their counterparts with high microRNA expression. Finally, miR-19b-3p and miR-20a-5p expression levels were significantly higher in APS patients using oral anticoagulants. Monocyte expression of miR-19b-3p and miR-20a-5p is low in APS, and patients with the lowest microRNA expression presented the highest levels of antiphospholipid antibodies.

Transition voltage spectroscopy and the nature of vacuum tunneling.

Transition voltage spectroscopy (TVS) has been proposed as a tool to analyze charge transport through molecular junctions. We extend TVS to Au-vacuum-Au junctions and study the distance dependence of the transition voltage V(t)(d) for clean electrodes in cryogenic vacuum. On the one hand, this allows us to provide an important reference for V(t)(d) measurements on molecular junctions. On the other hand, we show that TVS forms a simple and powerful test for vacuum tunneling models.

Modulation of mammary gland development in pre-pubertal mice as affected by soya and milk protein supplements.

The objective of the present study was to determine the effects of soya and whey milk protein, α-lactalbumin (α-LA), on mammary gland morphology and the structural support of the gland, in pre-pubertal mice after 7 d of treatment. In Expt 1, weaned (day 21) CD1 mice were given one of the four treatments, three included dietary supplements: (1) control diet, casein, (2) soya, (3) α-LA and (4) subcutaneous injection of 2·5 µg oestradiol benzoate in 20 µl maize oil and fed the control diet. All diets were isoenergetic with equal protein concentrations. All groups that were not treated with oestradiol received the vehicle. Whole-mount analyses were performed to determine longitudinal ductal growth and terminal end bud development. DNA was extracted from the gland and assessed by spectrophotometry (260/280 nm). Tissue extracts for extracellular matrix (ECM) proteins, matrix metalloproteinase-2 (MMP(2)), tissue inhibitor of MMP(2) (TIMP(2)), and serum oestradiol and mammary tissue epidermal growth factors (EGF) were measured by immunoassays. Expt 2 utilised the Her2/neu transgenic strain, with the same protocols. Statistical significance was determined by one-way ANOVA. From Expt 1 and 2, soya and α-LA significantly increased ductal elongation when compared with the oestrogen and control groups. These results were corroborated by data on total DNA and the ratio of MMP(2):TIMP(2). The ratio of MMP(2):TIMP(2) was affected by α-LA. Serum oestradiol was decreased only in the oestradiol-treated groups in both experiments. Soya is known to be oestrogenic and can act on epithelia directly. The mechanism by which α-LA affects glandular development is by modulating the ECM or by promoting the synthesis/activity of EGF.

Interleukin 3-dependent and -independent mast cells stimulated with IgE and antigen express multiple cytokines.

In response to IgE and specific multivalent antigen, mast cell lines (both growth factor-dependent and -independent) induce the transcription and/or secretion of a number of cytokines having a wide spectrum of activities. We have identified IL-1, IL-3, IL-5, IL-6, IFN-gamma, GM-CSF, JE, MIP1 alpha, MIP1 beta, and TCA3 RNA in at least two of four mast cell clones. The production of these products (except JE) is activation-associated and can be induced by IgE plus antigen. In selected instances cytokine expression can also be induced by activation with Con A or phorbol ester plus ionophore, albeit to levels less than those observed with IgE plus antigen. In addition, long-term mast cell clones and primary cultures of bone marrow-derived mast cells specifically release IL-1, IL-4, and/or IL-6 bioactivity after activation. These findings suggest that in addition to their inflammatory effector function mast cells may serve as a source of growth and regulatory factors. The relationship of mast cells to cells of the T lymphocyte lineage is discussed.

Assessment of a conduction-repolarisation metric to predict Arrhythmogenesis in right ventricular disorders.

BACKGROUND: The re-entry vulnerability index (RVI) is a recently proposed activation-repolarization metric designed to quantify tissue susceptibility to re-entry. This study aimed to test feasibility of an RVI-based algorithm to predict the earliest endocardial activation site of ventricular tachycardia (VT) during electrophysiological studies and occurrence of haemodynamically significant ventricular arrhythmias in follow-up. METHODS: Patients with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) (n = 11), Brugada Syndrome (BrS) (n = 13) and focal RV outflow tract VT (n = 9) underwent programmed stimulation with unipolar electrograms recorded from a non-contact array in the RV. RESULTS: Lowest values of RVI co-localised with VT earliest activation site in ARVC/BrS but not in focal VT. The distance between region of lowest RVI and site of VT earliest site (Dmin) was lower in ARVC/BrS than in focal VT (6.8 ±â€¯6.7 mm vs 26.9 ±â€¯13.3 mm, p = 0.005). ARVC/BrS patients with inducible VT had lower Global-RVI (RVIG) than those who were non-inducible (-54.9 ±â€¯13.0 ms vs -35.9 ±â€¯8.6 ms, p = 0.005) or those with focal VT (-30.6 ±â€¯11.5 ms, p = 0.001). Patients were followed up for 112 ±â€¯19 months. Those with clinical VT events had lower Global-RVI than both ARVC and BrS patients without VT (-54.5 ±â€¯13.5 ms vs -36.2 ±â€¯8.8 ms, p = 0.007) and focal VT patients (-30.6 ±â€¯11.5 ms, p = 0.002). CONCLUSIONS: RVI reliably identifies the earliest RV endocardial activation site of VT in BrS and ARVC but not focal ventricular arrhythmias and predicts the incidence of haemodynamically significant arrhythmias. Therefore, RVI may be of value in predicting VT exit sites and hence targeting of re-entrant arrhythmias.

Kiss and tell: what do we know about pre- and early adolescent females who report dating? A pilot study.

STUDY OBJECTIVE: To evaluate the implications of dating in pre- and early adolescent females. DESIGN: Cross-sectional survey. SETTING: Child psychiatry clinic; pediatric clinic; family clinic. PARTICIPANTS: Pre- and early adolescent females (n = 80) aged 11-14 and their parents. INTERVENTION: Pre- and early adolescent females aged 11-14 and a parent were recruited during a regular clinic visit. Pre- and early adolescent females completed a survey that included measures of dating; sensation seeking; lifetime individual and peer drug use; Attention Deficit Hyperactive Disorder, Oppositional Defiant Disorder and Conduct Disorder symptoms; and onset of menses. Parents were asked similar questions about their child's dating behaviors and peer relationships. MAIN OUTCOME MEASURE: Association of early dating with individual and peer drug use, sensation seeking, aggressive behavior, and onset of menses. RESULTS: In pre- and early adolescent females, dating regularly is associated with nicotine and alcohol use, sensation seeking, and aggressive behavior. Dating regularly is also associated with onset of menses and a younger age of onset of menses in those who had started menstruating. Parents under-report their child's dating practices and associated high-risk behaviors. CONCLUSION: Early dating is associated with nicotine and alcohol use, sensation seeking, aggressive behavior, and early onset of menses in adolescent females. Questions about early dating are a simple and efficient way to open inquiry of both parents and children about high-risk behaviors in the clinic setting.

Treating psychiatric problems in medical students.

The medical school educational experience is very stressful for many students, prompting some to seek formal psychiatric care. The authors describe the Medical Student Support Services program of the University of Kentucky College of Medicine. From July 1983 to June 1985, this program served 66 patients, representing 417 visits. On the basis of retrospective chart review with the examining clinicians, the authors present DSM-III diagnoses, types of problems seen, descriptive profiles of the patients, duration of treatment, types of therapy used, and data on marital issues. They discuss the intricacies of providing psychiatric services to medical students and make recommendations for program development for such patients.

Effects of two beta 3-adrenoceptor agonists, SR 58611A and BRL 37344, and of salbutamol on cholinergic and NANC neural contraction in guinea-pig main bronchi in vitro.

1. The aim of the present study was to investigate the type of adrenoceptor which modulates constriction of the guinea-pig isolated main bronchus in response to electrical field stimulation (EFS). Drugs used were salbutamol and two agonists reportedly selective for the putative beta 3-adrenoceptor: BRL 37344 and SR 58611A. 2. At basal tone, all three drugs induced relaxation, however, SR 58611A and BRL 37344 (10(-9) to 10(-6) M) relaxed guinea-pig isolated main bronchus more weakly than salbutamol (10(-9) to 10(-6) M). The effects observed at 10(-6) M were 43% +/- 9%, 63% +/- 4% and 98% +/- 1% of the maximal effect induced by theophylline (3 x 10(-3) M) for SR 58611A, BRL 37344 and salbutamol, respectively. 3. SR 58611A and BRL 37344 (10(-8) to 10(-6) M) did not significantly modify the cholinergic component of the response to EFS, but caused a concentration-dependent reduction of the nonadrenergic non-cholinergic (NANC) excitatory component (41.8% +/- 10.1% and 56.8% +/- 7.4% respectively at 10(-6) M, n = 6-7). Salbutamol (10(-9) to 10(-7) M) strongly inhibited both components, with 91.1% +/- 4.2% of inhibition for the NANC contraction and 62.0% +/- 5.2% of inhibition for the cholinergic contraction (10(-7) M, n = 7). 4. Whereas the inhibitory effects of salbutamol were strongly inhibited by both propranolol (10(-6) M) and ICI 118,551 (10(-6) M), those of BRL 37344 were only slightly, albeit significantly reduced by both propranolol and ICI 118,551, and those of SR 58611A were unaffected by treatment with either beta-adrenoceptor antagonist. An alpha2-adrenoceptor antagonist, yohimbine, did not influence the inhibitory effects of any of the beta-adrenoceptor agonists tested.5. Concentration-response curves to acetylcholine (10-8 to 10-3 M), [Nle10]NKA(4-10) (10-10 to10-6 M) and substance P (10- to 3 x 10-6 M) were also significantly shifted to the right by salbutamol(10-6 M), whereas SR58611A and BRL37344 (10-6 M) had no effect.6. These results suggest that the stimulation of putative beta 3-adrenoceptors exerts a specific prejunctional inhibitory action on NANC excitatory response induced by EFS of the isolated main bronchus of the guinea-pig. They also suggest that a beta2-adrenoceptor agonistic component may be involved in the effects of BRL 37344.

Regulation of epidermal growth factor receptor activity by crotoxin, a snake venom phospholipase A2 toxin. A novel growth inhibitory mechanism.

Crotoxin (CT), a phospholipase A2 (PLA2) derived from the venom of Crotalus durissus terrificus, is a heterodimeric protein composed of subunit B with enzymatic activity and a binding regulatory subunit (A) without enzyme activity. Although the PLA2 activity of CT may be important in its anti-proliferative activity, its cytostatic mechanism is unknown. In this study, we examined the cytostatic effect of PLA2-associated CT activity on squamous carcinoma cells expressing distinct levels of epidermal growth factor receptor (EGFr). CT was most effective in suppressing growth on cells expressing high intrinsic levels of EGFr. Cardiotoxin, another membrane active toxin with no intrinsic PLA2 activity, had no differential anti-proliferative activity on cells expressing high EGFr levels, suggesting a correlation between EGFr expression and CT-directed anti-proliferative activity. Both chemically modified CT (MCT) devoid of PLA2 activity and covalently cross-linked CT (CCT), which is functionally unable to utilize cellular membranes as PLA2 substrate, were also without growth inhibitory activity. No evidence for direct binding of CT to EGFr was found, although pretreatment with EGF was able to partially suppress the anti-proliferative activity of CT. Tyrosine phosphorylation of EGFr, however, was stimulated by CT in intact A431 cells. Tyrosine phosphorylation of EGFr was concentration-dependently stimulated (3- to 8-fold) in cellular membranes of A431 cells treated in vitro with CT but not with anti-proliferatively inactive MCT or CCT. The data provide evidence for transmembrane receptors involved in growth signaling (namely EGFr) as cellular targets and potential effectors of PLA2-mediated anti-proliferative activity of snake venom.

Enhanced expression of c-fos is not obligatory for retinoic acid-induced F9 cell differentiation.

c-fos was studied in F9 cells to determine whether changes in its expression are an early and/or obligatory event in retinoic acid-induced F9 cell differentiation. Induction of c-fos transcripts was not observed at times early or late during retinoic acid-promoted differentiation, but a decrease in c-myc mRNA was noted as early as 1 h after retinoic acid dosing. Induction of a rapid and transient change in c-fos expression in F9 cells was observed only in response to serum stimulation. Therefore, although expression of c-fos may be involved in the cellular growth and proliferation of F9 cells, as indicated by the response to serum, an increase in c-fos is not required for retinoic acid-induced differentiation.

The human chorionic gonadotrophin alpha subunit gene in gestational trophoblastic disease. 1. Restriction fragment length polymorphisms in hydatidiform moles.

The distribution of EcoR1 and HindIII restriction fragment length polymorphisms in the region of the gene coding for the alpha subunit of human chorionic gonadotrophin have been examined in 71 normal controls, six families, and 65 cases of hydatidiform mole, all of European origin. In control samples the genotypes generated by the presence or absence of the restriction sites, fitted a Hardy Weinberg distribution while in family studies the two polymorphisms showed Mendelian inheritance. The distribution of the genotypes in hydatidiform moles differed from that in control samples. However, the frequency of the alternative alleles R+, R- and H+, H- was not significantly different in the two populations and differences in the distribution of genotypes could be explained in terms of the unique origin of hydatidiform moles. The frequency of the rare homozygous genotype R-R-,H+H+, which has previously been suggested to be associated with the development of choriocarcinoma, was similar in those complete moles which resolved spontaneously (35 per cent) and those which progressed to trophoblastic tumours (27 per cent). No association was found between the genotype of the hydatidiform mole and the subsequent clinical outcome of the patient. Thus the pattern of restriction fragment length polymorphisms associated with the human chorionic gonadotrophin alpha subunit gene would not appear to be an appropriate marker of clinical outcome in patients with hydatidiform moles.

Diethylpropion-induced psychosis reprecipitated by an MAO inhibitor: case report.

A case of diethylpropion-induced psychosis in a 26-year-old woman is reported. The patient's psychosis recurred while she was receiving phenelzine. It is postulated that chronic stimulant use leads to increased sensitivity to the psychosis-inducing effects of monoamine oxidase inhibitors.

Hyperthyroidism in a cocaine-dependent patient.

Although clinical manifestations of cocaine use are similar to the signs and symptoms of hyperthyroidism and research suggests that cocaine may affect the thyroid, no occurrences of cocaine-associated thyroid toxicity have been reported. The authors report a case of Graves' disease in a cocaine-dependent patient and propose that the patient's cocaine use may have precipitated thyroid toxicity.

CHD in Australia and New Zealand.

Death rates from coronary heart disease (CHD) have been declining in Australia and New Zealand for 20 years. Data from the three MONICA Project Centres in Newcastle (Australia), Perth (Australia), and Auckland (New Zealand) show similar trends for fatal CHD but differing trends for non-fatal myocardial infarction (MI). In Auckland, there has been a consistent decline in out-of-hospital death rates but no decline in non-fatal MI rates. In Perth, the greater contribution to the overall decline has been from out-of-hospital deaths, but in-hospital death rates and non-fatal MI rates have also declined. There is also some evidence of an increase in survival following MI in Perth. In Newcastle, both death rates and non-fatal MI rates have declined. The limited data available suggest that at least one-half of the decline in mortality can be attributed to improvements in population risk-factor levels. Improvements in medical management of both risk factors and established disease are also making contributions to the decline.

Excimer laser instrumentation and technique for human corneal surgery.

The design and development of the instrumentation utilized during the clinical and histopathologic evaluations of the first human eyes treated by argon fluoride excimer laser radiation are described. The laser, optical, alignment, measurement, and control subsystems required for this research were constructed to create a laser beam that has an axially symmetric energy distribution, can be calibrated and measured, can be aligned with the target tissue, and can be manipulated to excise surface tissue. The use of this excimer laser system has demonstrated that a nonuniform superficial lamellar keratectomy can be produced to excise areas of opacified, scarred, or abnormal cornea or to create a new anterior corneal curvature in attempts to correct refractive errors.

Neurotensin modulates cholinergic and noncholinergic neurotransmission in guinea-pig main bronchi in vitro.

Guinea-pig main bronchi were stimulated transmurally in vitro by electrical field stimulation in the presence of indomethacin 10(-6) M, propranolol 10(-6) M and phosphoramidon 10(-5) M. Two contractile neurogenic responses were successively observed. The second noncholinergic contraction was concentration dependently inhibited or abolished by neurotensin whereas the first cholinergic contraction was only partially inhibited. SR 48692, a novel antagonist of neurotensin receptors, reduced the inhibition induced by neurotensin (pKB = 9.75) whereas levocabastine, an antagonist of low-affinity neurotensin receptors, did not significantly modify the inhibitory effects of neurotensin on both neurally-mediated contractions. These results demonstrate that neurotensin exerts an inhibitory effect on neurotransmission in guinea-pig airways. Furthermore, the present study shows that the newly developed neurotensin receptors antagonist, SR 48692, is a potent inhibitor of the neurotensin inhibitory effects on cholinergic and noncholinergic contractions induced by electrical field stimulation of the guinea-pig isolated main bronchus.

The development of the woman child psychiatry researcher--a review.

Greater efforts should be made to recruit women into child psychiatry research. Women's tendencies to minimize their creativity and to avoid competition and criticism and women's underrepresentation and isolation in research and academia should be addressed. Nontraditional lateral tracks should be developed for women during phases of intense professional and personal demands. Mentorships, stimulating collegial relationships, and open forums at local and national levels to address these issues may encourage women's growth as child psychiatry researchers. In addition, changes for improving hiring, promoting, and facilitating career development for women are mandated.

Imipramine treatment of ADHD in a fragile X child.

Fragile X syndrome, an X-linked genetic disorder, is the third most common cause of mental retardation. The following is a case of a 6-year-old boy with fragile X syndrome and its characteristic cognitive and behavioral symptomatology, including attention deficit hyperactivity disorder. In addition, this child experienced initial insomnia and nocturnal enuresis, problems not previously reported with fragile X. Previous pharmacological treatment of the syndrome's behavioral difficulties and attention deficit has included stimulants, folic acid, and neuroleptics. This is the first report of the successful use of imipramine. Imipramine also improved the boy's insomnia and enuresis, whereas methylphenidate caused an overall worsening of his condition.

Gender differences in adolescent psychiatric outpatient substance use: associated behaviors and feelings.

OBJECTIVE: To investigate gender differences in substance use and associated high-risk behaviors and feeling states in 220 adolescent psychiatric outpatients. METHOD: One hundred seven females and 113 males with a mean age of 15.6 (SD +/- 1.4), seen in a tertiary care center adolescent psychiatry clinic, completed scales tapping substance use and associated feelings and behaviors. Approximately half had used nicotine and alcohol, one third had used marijuana, and 10% reported narcotic use. RESULTS: Conduct disorder behavior, suicidality, and impulsivity scale scores decreased with age in females while marijuana use, conduct disorder behavior, and Hypophoria scale scores increased with age in males. Alcohol use in males, as contrasted with females, correlated more significantly with other substance use and high-risk behaviors. Suicidality tended to correlate more with polysubstance use in females and with sexual behaviors in females only. Substance use correlated with the Impulsivity and Need scale scores in males and scores on the Sociopathy scale in females. CONCLUSIONS: Substance use in males correlates with high-risk behaviors and is associated with feelings of impulsivity and need. Substance use correlates with self-destructive behaviors and sociopathic feelings in females. There is evidence of more persistent high-risk behaviors, including substance use, in males than in females.

Effects of cromakalim on bradykinin-, histamine- and substance P-induced airway microvascular leakage in the guinea-pig.

The effects of cromakalim on the increase in microvascular permeability induced by histamine, substance P or bradykinin in guinea-pig airways were studied in vivo. Extravasation of i.v. injected Evans blue dye was used as an index of permeability. We also studied the effects of cromakalim on the contractile effect of substance P, histamine or bradykinin on the isolated guinea-pig main bronchus and on the contractile response of isolated guinea-pig main bronchi to electrical field stimulation. Cromakalim (30 to 300 micrograms.kg-1) did not inhibit the increase in microvascular permeability induced by histamine (30 micrograms.kg-1) in guinea-pig airways and potentiated (30 and 100 micrograms.kg-1) the effects of substance P (0.3 microgram.kg-1) in trachea, main bronchi and proximal intrapulmonary airways. In contrast, cromakalim (30 and 300 micrograms.kg-1) reduced the increase in microvascular permeability induced by bradykinin (0.3 microgram.kg-1). However, a significant potentiation of the effects of bradykinin was observed with cromakalim (100 micrograms.kg-1) in main bronchi and intrapulmonary airways. In the isolated guinea-pig main bronchus, the contractile effects of bradykinin, histamine and substance P were not modified by cromakalim (10(-5) M). Conversely, cromakalim (10(-5) M) significantly reduced both cholinergic and noncholinergic contractile responses induced by electrical field stimulation of the isolated guinea-pig main bronchus. In conclusion, cromakalim can partially inhibit the increase in microvascular permeability induced by i.v. bradykinin. It is suggested that this effect might occur through inhibition of the nonadrenergic noncholinergic excitatory (NANC) nerves preventing release by bradykinin of inflammatory neuropeptides such as substance P.