Social support and fear-inhibition: an examination of underlying neural mechanisms.

Recent work has demonstrated that reminders of those we are closest to have a unique combination of effects on fear learning and represent a new category of fear inhibitors, termed prepared fear suppressors. Notably, social-support-figure images have been shown to resist becoming associated with fear, suppress conditional-fear-responding and lead to long-term fear reduction. Due to the novelty of this category, understanding the underlying neural mechanisms that support these unique abilities of social-support-reminders has yet to be investigated. Here, we examined the neural correlates that enable social-support-reminders to resist becoming associated with fear during a retardation-of-acquisition test. We found that social-support-figure-images (vs stranger-images) were less readily associated with fear, replicating prior work, and that this effect was associated with decreased amygdala activity and increased ventromedial prefrontal cortex (VMPFC) activity for social-support-figure-images (vs stranger-images), suggesting that social-support-engagement of the VMPFC and consequent inhibition of the amygdala may contribute to unique their inhibitory effects. Connectivity analyses supported this interpretation, showing greater connectivity between the VMPFC and left amygdala for social-support-figure-images (vs stranger-images).

Amino acid-induced translation of TOP mRNAs is fully dependent on phosphatidylinositol 3-kinase-mediated signaling, is partially inhibited by rapamycin, and is independent of S6K1 and rpS6 phosphorylation.

Vertebrate TOP mRNAs contain an oligopyrimidine tract at their 5' termini (5'TOP) and encode components of the translational machinery. Previously it has been shown that they are subject to selective translational repression upon growth arrest and that their translational behavior correlates with the activity of S6K1. We now show that the translation of TOP mRNAs is rapidly repressed by amino acid withdrawal and that this nutritional control depends strictly on the integrity of the 5'TOP motif. However, neither phosphorylation of ribosomal protein (rp) S6 nor activation of S6K1 per se is sufficient to relieve the translational repression of TOP mRNAs in amino acid-starved cells. Likewise, inhibition of S6K1 activity and rpS6 phosphorylation by overexpression of dominant-negative S6K1 mutants failed to suppress the translational activation of TOP mRNAs in amino acid-refed cells. Furthermore, TOP mRNAs were translationally regulated by amino acid sufficiency in embryonic stem cells lacking both alleles of the S6K1 gene. Inhibition of mTOR by rapamycin led to fast and complete repression of S6K1, as judged by rpS6 phosphorylation, but to only partial and delayed repression of translational activation of TOP mRNAs. In contrast, interference in the phosphatidylinositol 3-kinase (PI3-kinase)-mediated pathway by chemical or genetic manipulations blocked rapidly and completely the translational activation of TOP mRNAs. It appears, therefore, that translational regulation of TOP mRNAs, at least by amino acids, (i) is fully dependent on PI3-kinase, (ii) is partially sensitive to rapamycin, and (iii) requires neither S6K1 activity nor rpS6 phosphorylation.

Sexual dimorphism matches photoreceptor performance to behavioural requirements.

Differences in behaviour exist between the sexes of most animal species and are associated with many sex-specific specializations. The visual system of the male housefly is known to be specialized for pursuit behaviour that culminates in mating. Males chase females using a high-acuity region of the fronto-dorsal retina (the 'love spot') that drives sex-specific neural circuitry. We show that love spot photoreceptors of the housefly combine better spatial resolution with a faster electrical response, thereby allowing them to code higher velocities and smaller targets than female photoreceptors. Love spot photoreceptors of males are more than 60% faster than their female counterparts and are among the fastest recorded for any animal. The superior response dynamics of male photoreceptors is achieved by a speeding up of the biochemical processes involved in phototransduction and by a tuned voltage-activated conductance that boosts the membrane frequency response. These results demonstrate that the inherent plasticity of phototransduction facilitates the tuning of the dynamics of visual processing to the requirements of visual ecology.

Overexpression of poly(A)-binding protein down-regulates the translation or the abundance of its own mRNA.

Poly(A)-binding protein (PABP) mRNA is subject to autoregulation through a 61 nucleotides long A-rich sequence in its 5' untranslated region (UTR). Here, we show that this mode of regulation is exerted in a cell type-specific manner. Thus, overexpression of PABP in mouse NIH 3T3 fibroblasts represses the translation of the respective endogenous mRNA or that of a chimeric mRNA containing just the 5' UTR of PABP mRNA. In contrast, ectopic expression of PABP in human embryonic kidney 293 cells down-regulates the abundance of the endogenous PABP mRNA, rather than affecting its translational efficiency. Transfection experiments with chimeric constructs suggest that the lack of translational autoregulation of endogenous PABP mRNA in these cells appears to reflect the presence of an overriding regulatory element outside the A-rich region.

Noise and its effects on photoreceptor temporal contrast sensitivity at low light levels.

We studied photoreceptors in the locust (Schistocerca americanus) visual system to determine the extent to which quantal noise and intrinsic neural noise limit temporal sensitivity. Typical computational models of the temporal contrast sensitivity function are deterministic, reflect only filter characteristics, and lack explicit noise sources [J. Opt. Soc. Am. 58, 1133 (1968); Vision Res. 32, 1373 (1992)]. We report here that the temporal contrast sensitivity function, at low light levels, is not simply the reflection of a filter function. Our evidence suggests that, at low backgrounds, noise, in conjunction with temporal filtering, plays a role in shaping the temporal contrast sensitivity function. At a given low adaptation level, quantal noise limits sensitivity at low temporal frequencies, while intrinsic noise limits sensitivity at relatively higher temporal frequencies.

The expression of poly(A)-binding protein gene is translationally regulated in a growth-dependent fashion through a 5'-terminal oligopyrimidine tract motif.

Poly(A)-binding protein (PABP) is an important regulator of gene expression that has been implicated in control of translation initiation. Here we report the isolation and the initial structural and functional characterization of the human PABP gene. Delineation of the promoter region revealed that it directs the initiation of transcription at consecutive C residues within a stretch of pyrimidines. A study of the translational behavior of the corresponding mRNA demonstrates that it is translationally repressed upon growth arrest of cultured mouse fibroblasts and translationally activated in regenerating rat liver. Furthermore, transfection experiments show that the first 32 nucleotides of PABP mRNA are sufficient to confer growth-dependent translational control on a heterologous mRNA. Substitution of the C residue at the cap site by purines abolishes the translational control of the chimeric mRNA. These features have established PABP mRNA as a new member of the terminal oligopyrimidine tract mRNA family. Members of this family are known to encode for components of the translational apparatus and to contain an oligopyrimidine tract at the 5' terminus (5'TOP). This motif mediates their translational control in a growth-dependent manner.

Diagnostic laparoscopy in primary and secondary infertility.

PURPOSE: Our purpose was to compare the diagnostic efficacy of laparoscopy between primary and secondary infertility and to define a subgroup in which the positive findings are low. METHODS: A retrospective review of the cases of 206 infertile women who underwent laparoscopy was conducted. RESULTS: Eighty-two (39.8%) patients were found to have evidence of pelvic disease--20 (22.2%) with primary infertility and 62 (54.3%) with secondary infertility. The ratio of positive findings in secondary infertility was significant in comparison with the positive findings in primary infertility. In only 3 of the 20 patients with primary infertility was there no history of an abdominal operation, pelvic inflammatory disease, or an abnormal hysterosalpingography. Of the 62 women who suffered secondary infertility and had positive findings in laparoscopy, 15 had no history of suspect findings. CONCLUSIONS: The diagnostic yield of laparoscopy for primary infertility in the absence of indications of mechanical factors is low. Therefore the need for diagnostic laparoscopy in these cases should be reconsidered.

The value of screening for psychiatric disorders in rheumatology referrals.

BACKGROUND: Musculoskeletal complaints are common and often unexplained and often lead to rheumatology referrals. The prevalence of psychiatric disease in patients with musculoskeletal complaints is unknown. OBJECTIVES: To determine the prevalence of common psychiatric disorders among patients referred to a rheumatology clinic and the likelihood of establishing a rheumatic diagnosis if a psychiatric disorder is present. DESIGN: Prospective diagnostic survey. SETTING: Two hospital-based rheumatology clinics and a general medicine clinic. PARTICIPANTS: A consecutive sample of newly referred patients (n = 185) and their rheumatologists (n = 9). INTERVENTION: Before their visit, all patients filled out a self-administered version of PRIME-MD (Primary Care Evaluation of Mental Disorders), a questionnaire that makes Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition: Primary Care Version, diagnoses of depressive, anxiety, and somatoform disorders. After the visit, the study rheumatologists, who were unaware of the PRIME-MD results, completed a questionnaire regarding their diagnostic assessment. These patients were compared with 210 patients with musculoskeletal complaints who were cared for in a general medicine clinic. MAIN OUTCOME MEASURES: Psychiatric and rheumatic disorders. RESULTS: Compared with patients with musculoskeletal complaints in a general medicine clinic, patients referred to a rheumatology clinic had a higher prevalence of psychiatric disease (40% vs 29%; P = .008), had an almost 2-fold higher prevalence of anxiety disorders, and were more likely to have multiple psychiatric disorders (odds ratio = 2.70, 95% confidence interval = 1.50-5.00). The likelihood of a psychiatric disorder differed among patients with connective tissue disease, nonsystemic articular or periarticular disorders, and nonarticular disorders (27%, 38%, 55%, respectively; P = .006). In a best-fitting logistic regression model, psychiatric disorders markedly decreased the likelihood of a connective tissue disease (odds ratio = 0.24, 95% confidence interval = 0.09-0.62). CONCLUSIONS: Forty percent of patients referred to a rheumatology clinic in this study had a psychiatric disorder, and its presence predicted a lower likelihood of a connective tissue disease. Prospective studies are needed to determine if screening for psychiatric disease before referring patients with unexplained musculoskeletal complaints would reduce costs or improve recognition of potentially treatable psychiatric disorders.

Modulation of human T-lymphocyte plasma membrane Ca2+ permeability by imidazole antimycotics.

The role of cytochrome P-450 in the regulation of plasma membrane Ca+2 permeability of human peripheral T-lymphocytes by intracellular Ca+2 was examined. We assessed the effect of imidazole inhibitors of cytochrome P-450 on the intracytoplasmic free Ca+2 ([Ca+2]i) response generated using the microsomal ATPase inhibitor thapsigargin (THG) to deplete the intracellular Ca+2 stores. Econazole, miconazole and clotrimazole dramatically inhibited the THG mediated increase in [Ca+2]i and induced an increase in [Ca+2]i themselves. This inhibitory effect was previously observed in other cell systems and was attributed to inhibition of cytochrome P-450 by these agents. However, we evaluated a variety of structurally dissimilar P-450 inhibitors and found that none affected [Ca+2]i, indicating that the mechanism of imidazole action does not involve P-450.

Histochemical localization of acetylcholinesterase in the lateral eye and brain of Limulus polyphemus: might acetylcholine be a neurotransmitter for lateral inhibition in the lateral eye?

The distribution of acetylcholinesterase (AChE) in the lateral eye and brain of the horseshoe crab was investigated with histochemical means using standard controls to eliminate butyrylcholinesterase and nonspecific staining. Intense staining was observed in the neural plexus of the lateral compound eye, in the lateral optic nerve, and in various neuropils of the brain. Nerve fibers with moderate to weak staining were widespread in the brain. No somata were stained in either the lateral eye or the brain. The distribution of acetylcholinesterase in the supraesophageal ganglia and nerves of the giant barnacle was also investigated for comparison. Although both the median optic nerve of the barnacle and the lateral optic nerve of the horseshoe crab appear to contain the fibers of histaminergic neurons, only the lateral optic nerve of the horseshoe crab shows AChE staining. Other parts of the barnacle nervous system, however, showed intense AChE staining. These results along with the histochemical controls eliminate the possibility that some molecule found in histaminergic neurons accounted for the AChE staining but support the possibility that acetylcholine might be involved as a neurotransmitter in lateral inhibition in the horseshoe crab retina. Two reasonable neurotransmitter candidates for lateral inhibition, histamine and acetylcholine, must now be investigated.

Ureteric jet examination by color Doppler ultrasound versus IVP for the assessment of ureteric patency following pelvic surgery--a pilot study.

During the study period 228 women underwent major gynecological surgery in our department. Of these, 25 were selected for the study because of suspected post-operative ureteric obstruction. Post-operatively, both intravenous pyelography (IVP) and ureteric jet examination by the means of color Doppler ultrasound were performed in the study group. The aims were to exclude iatrogenic ureteric occlusion and to test the reliability of ureteric jet examination with ultrasound, as compared with IVP, as a diagnostic test for ureteric obstruction. In 19 patients both IVP and jet examination were normal. In the remaining six patients, jet was negative either uni- or bi-laterally. Of these six, only two obstructions were diagnosed using IVP. This test was associated with a positive predictive value of 33.3%, negative predictive value of 100%, sensitivity of 100%, specificity of 88.6%, false negative of 0% and a false positive of 17.4%. It is concluded that the results suggest that color Doppler ultrasound may be a good screening test for ureteric occlusion following pelvic surgery. Whenever a jet test is negative, further evaluation by IVP is required.

Human gammaglobulin use in the treatment of severe thrombocytopenia associated with sarcoidosis.

Thrombocytopenia associated with sarcoidosis is an uncommon, yet potentially lethal, complication. The traditional treatment for the thrombocytopenia has been steroid therapy followed by splenectomy if steroid therapy fails. The use of human immunoglobulin as a potential therapy in a patient afflicted with thrombocytopenia and sarcoidosis is reviewed.

Cocaine: maternal use during pregnancy and its effect on the mother, the fetus, and the infant.

Cocaine was previously regarded as a soft drug causing only mild damage. Its use during pregnancy, however, creates a variety of grave medical problems which necessitate immediate attention not only on the part of internists and psychiatrists but also, and more particularly, by obstetricians and pediatricians. The pregnancy of a cocaine-using woman must be carefully managed and regarded as a high-risk one. This in view of the numerous obstetric risks caused by the drug, notably premature separation of the placenta, increased incidence of stillbirths, congenital malformations, premature births, and intrauterine growth retardation. The neonatal monitoring must be focused on prevention of complications resulting from the withdrawal syndrome and associated conditions such as pneumonia, severe weight loss, and contagion from the mother. Moreover, efforts must be made to ensure a strict observation of the infant outside the hospital in view of the far greater incidence of idiopathic infant death in such cases. Owing to the sharp rise of the regular and occasional use of the drug and since pregnant women tend on anamnesis to deny any drug taking, we recommend a test of maternal urine for cocaine and other drugs whenever a suspicion to this effect arises. It is also advisable to test for the presence of such drugs in the urine of the neonate in cases of reasonable suspicion of maternal use during pregnancy, though a negative outcome of the urine test naturally does not rule out a possible use. Strict monitoring of positive cases, accompanied by preventive treatment, may contribute a great deal toward a reduction of perinatal morbidity and mortality associated with cocaine use use.

The effect of disopyramide on uterine contractions during pregnancy.

To evaluate the effect of disopyramide on uterine contractions during pregnancy, the drug was given for 48 hours to 10 women with indications for labor induction. Placebo was given to 10 other women with the same indications for induction. During the study period, regular uterine contractions occurred in 10 women in the study group, as compared with none in the control group (p less than 0.0001). Eight women in the study group were delivered of infants within 48 hours, as compared with none in the control group (p less than 0.0001). The mean time until the appearance of regular uterine contractions in the study group (4.15 +/- 1.76 hours) was significantly shorter (p less than 0.001) than that in the control group (56.13 +/- 5.28 hours). Patients who were not delivered of infants within 48 hours received other medications (prostaglandin E2, oxytocin). The mean maternal blood level of disopyramide at the time of appearance of uterine contractions was 1.52 +/- 0.9 mg/ml. The mean maternal level at delivery was 0.93 +/- 0.43 mg/ml and the cord blood level at the time of delivery was 0.33 mg/ml (cord blood/maternal level ratio = 0.36, r = 0.73, p less than 0.05). These results indicate that disopyramide should not be used in pregnancy for antiarrhythmic purposes because it may induce uterine contractions and delivery.

The management of breast carcinoma in pregnancy and lactation.

Until recent years, the prognosis for breast cancer in pregnancy and lactation was regarded as grave. The current new data suggest that pregnant women with early breast carcinoma may be treated in the same way as nonpregnant women without affecting pregnancy. However, women with breast cancer in their first trimester of pregnancy and in whom axillary lymph nodes are involved, should receive chemotherapy and have their pregnancy terminated. Toward the end of pregnancy, adjuvant therapy, when needed, can be delayed until after delivery. In patients with advanced disease pregnancy should be terminated and subsequent treatment initiated. During lactation, diagnosis of breast carcinoma requires suppression of lactation by means other than estrogens. The carcinoma will be treated by standard methods. After radical mastectomy for breast cancer, subsequent pregnancies are allowed but should be delayed until the period of greatest risk has passed.