Decoupling transcription factor expression and activity enables dimmer switch gene regulation.

Gene-regulatory networks achieve complex mappings of inputs to outputs through mechanisms that are poorly understood. We found that in the galactose-responsive pathway in Saccharomyces cerevisiae, the decision to activate the transcription of genes encoding pathway components is controlled independently from the expression level, resulting in behavior resembling that of a mechanical dimmer switch. This was not a direct result of chromatin regulation or combinatorial control at galactose-responsive promoters; rather, this behavior was achieved by hierarchical regulation of the expression and activity of a single transcription factor. Hierarchical regulation is ubiquitous, and thus dimmer switch regulation is likely a key feature of many biological systems. Dimmer switch gene regulation may allow cells to fine-tune their responses to multi-input environments on both physiological and evolutionary time scales.

Targeting cancer metastasis with antibody therapeutics.

Cancer metastasis, the spread of disease from a primary to a distal site through the circulatory or lymphatic systems, accounts for over 90% of all cancer related deaths. Despite significant progress in the field of cancer therapy in recent years, mortality rates remain dramatically higher for patients with metastatic disease versus those with local or regional disease. Although there is clearly an urgent need to develop drugs that inhibit cancer spread, the overwhelming majority of anticancer therapies that have been developed to date are designed to inhibit tumor growth but fail to address the key stages of the metastatic process: invasion, intravasation, circulation, extravasation, and colonization. There is growing interest in engineering targeted therapeutics, such as antibody drugs, that inhibit various steps in the metastatic cascade. We present an overview of antibody therapeutic approaches, both in the pipeline and in the clinic, that disrupt the essential mechanisms that underlie cancer metastasis. These therapies include classes of antibodies that indirectly target metastasis, including anti-integrin, anticadherin, and immune checkpoint blocking antibodies, as well as monoclonal and bispecific antibodies that are specifically designed to interrupt disease dissemination. Although few antimetastatic antibodies have achieved clinical success to date, there are many promising candidates in various stages of development, and novel targets and approaches are constantly emerging. Collectively, these efforts will enrich our understanding of the molecular drivers of metastasis, and the new strategies that arise promise to have a profound impact on the future of cancer therapeutic development. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Why not the best? Social anxiety symptoms and perfectionism among Israeli Jews and Arabs: a comparative Study.

BACKGROUND: Social Anxiety Disorder (SAD) has been repeatedly shown to be very prevalent in the Western society and is characterized by low self-esteem, pessimism, procrastination and also perfectionism. Very few studies on SAD have been done in the Middle East or in Arab countries, and no study tackled the relationship between social anxiety symptoms and perfectionism in non-Western samples. METHODS: We examined social anxiety symptoms and perfectionism in a group of 132 Israeli Jewish (IJ) and Israeli Arab (IA) students. Subjects completed the Liebowitz Social Anxiety Scale (LSAS), the Multidimensional Perfectionism Scale (MPS), the Negative Automatic Thoughts Questionnaire (ATQ-N), the Positive Automatic Thoughts Questionnaire (ATQ-P) and a socio-demographic questionnaire. RESULTS: The rate of SAD in our sample according to a LSAS score of 60 or more was 17.2% (IJ=13.8%, IA=19%, ns). The correlation between perfectionism and the LSAS was high in both groups, and in particular in the IJ group. The IA group had higher scores of social avoidance, of ATQ-P and of two of the MPS subscales: parental expectations and parental criticism. Concern over mistakes and negative automatic thoughts positively predicted social fear in the IJ group, whereas in the IA group being female, religious and less educated positively predicted social fear. Negative automatic thoughts and age positively predicted social avoidance in the IJ group. In general, the IJ and IA subjects showed higher social anxiety, higher ATQ-N scores and lower parental expectations as compared with non-clinical US samples. CONCLUSIONS: Social anxiety symptoms and perfectionism are prevalent in Arab and Jewish students in Israel and seem to be closely related. Further studies among non-western minority groups may detect cultural influences on social anxiety and might add to the growing body of knowledge on this intriguing condition.

A painful train of events: increased prevalence of fibromyalgia in survivors of a major train crash.

OBJECTIVES: To evaluate the prevalence of fibromyalgia in survivors of a major train crash in southern Israel, three years after the event. METHODS: Survivors were contacted by mail and telephone. Individuals consenting to participate in the study underwent physical examination, including a tender point count and dolorimetry, as well as extensive evaluation of parameters relating to quality of life, presence of widespread pain, fatigue, physical and social function, posttraumatic symptoms and symptoms related to anxiety, dissociation, depression, somatisation, etc. RESULTS: Fifteen percent of survivors participating in the study met ACR criteria for the classification of fibromyalgia. Significantly lower rates of physical and emotional functioning were found among survivors with fibromyalgia compared with those not meeting the classification criteria. Survivors with fibromyalgia rated significantly higher on scales of somatisation, obsessive-compulsive ideation, interpersonal sensitivity, depression, anger and hostility, phobic and general anxiety, paranoid ideation and psychoticism. Survivors with fibromyalgia also rated significantly higher on scales of posttraumatic symptoms including intrusion, avoidance and arousal. These individuals also rated significantly higher on the Peritraumatic Dissociative Experiences Questionnaire (PDE-Q) and the Dissociative Experiences Scale (Hebrew version) (DES-H). CONCLUSION: Fibromyalgia was found to be highly prevalent, three years after a major train crash, among individuals exposed to the combination of physical injury and extreme stress. This finding is in accordance with previous data regarding the association of fibromyalgia with both physical and emotional trauma and calls attention to studying the underlying susceptibility factors which may partake in this association.

A case of mirtazapine-induced spontaneous orgasms in a female patient.

This is a case report of a 51-year-old woman admitted as a psychiatric outpatient with symptoms of moderate to severe depression and anxiety. She had received anti-depressants prior to her admission. The patient did not have a medical history of mania or hypomania, and did not complain of any sexual side-effects when taking prior medications. She was diagnosed in our clinic with mixed anxiety-depressive disorder. Due to lack of improvement she was commenced on mirtazapine and after three days complained of spontaneous orgasms and increased libido. The sexual symptoms resolved gradually after a few days and reappeared upon every dosage increase. On discontinuation of mirtazapine the side effects subsided. To the best of the author's knowledge this is the first report of spontaneous orgasms following treatment with mirtazapine.

Polymorphisms in the dopamine D4 receptor gene (DRD4) contribute to individual differences in human sexual behavior: desire, arousal and sexual function.

Although there is some evidence from twin studies that individual differences in sexual behavior are heritable, little is known about the specific molecular genetic design of human sexuality. Recently, a specific dopamine D4 receptor (DRD4) agonist was shown in rats to induce penile erection through a central mechanism. These findings prompted us to examine possible association between the well-characterized DRD4 gene and core phenotypes of human sexual behavior that included desire, arousal and function in a group of 148 nonclinical university students. We observed association between the exon 3 repeat region, and the C-521T and C-616G promoter region SNPs, with scores on scales that measure human sexual behavior. The single most common DRD4 5-locus haplotype (19%) was significantly associated with Desire, Function and Arousal scores. The current results are consistent with animal studies that show a role for dopamine and specifically the DRD4 receptor in sexual behavior and suggest that one pathway by which individual variation in human desire, arousal and function are mediated is based on allelic variants coding for differences in DRD4 receptor gene expression and protein concentrations in key brain areas.

[Female sexual dysfunction (FSD)].

Recent research suggests that a large number of women are dissatisfied with their sexual life due to sexual dysfunction. The accepted definitions of female sexual dysfunction are based on the human sexual response cycle described by Masters and Johnson and later elaborated by Kaplan. Their work formed the basis for the diagnostic systems of both the ICD-10 and DSM IV. Female sexual dysfunction may appear as lack of sexual desire, sexual pain, and arousal or orgasmic dysfunction. Although these problems are very common in women and more common than in males, for many years this field of interest was neglected both scientifically and clinically. In the past, only psychological and sexological forms of therapy were suggested. It is now better understood that, as in many other areas, the junction between the body and the mind, is responsible for many sex problems in women. Furthermore, multi professional team work is needed to treat these problems in order to enhance better quality of life for individuals and couples. This editorial calls for better education and research in this important field.

Subtalar distraction arthrodesis using a ramp cage.

Subtalar distraction bone block arthrodesis has been described to treat late complications of displaced calcaneal fractures. A "ramp cage" can be used to restore the talocalcaneal relationship by providing stable correction in the coronal and sagittal dimensions.

The anatomy of tibial eminence fractures: arthroscopic observations following failed closed reduction.

BACKGROUND: Failed manipulative reduction of avulsion fractures of the tibial insertion of the anterior cruciate ligament has been attributed to interposition of soft tissues, particularly the anterior horn of the medial meniscus. The objectives of the present report were (1) to show that the failure to reduce Meyers and McKeever type-III tibial eminence fractures was not due to interposition of soft tissues and (2) to discuss the relevance of the finding that the anterior third of the lateral meniscus was attached to the avulsed anterior cruciate ligament insertion site in all patients studied. METHODS: Twelve patients who had had a failed manipulative reduction of a type-III tibial eminence fracture underwent arthroscopic reduction and fixation of the avulsed fragment. RESULTS: A number of consistent findings were noted. The avulsed intercondylar eminence was displaced superiorly into the intercondylar notch. Attached to this fragment was not only the anterior cruciate ligament, but also, in all cases, the anterior horn of the lateral meniscus. The anterior third of the lateral meniscus had been torn from its tibial attachment and displaced together with the osseous fragment into the intercondylar notch. No interposition of bone or soft tissue was observed. Reduction of the osseous fragment was facilitated by traction on, or sutures passed around, the anterior horn of the lateral meniscus. Standard fixation methods were utilized. CONCLUSIONS: The concept that avulsion fractures of the tibial insertion of the anterior cruciate ligament cannot be reduced by manipulation because of soft-tissue interposition was not supported by the findings of the present study. The attachment of the anterior horn of the lateral meniscus to the avulsed tibial insertion of the anterior cruciate ligament may not be an irrelevant incidental finding. The observation that the displaced osseous fragment was attached simultaneously to the anterior cruciate ligament and to the anterior horn of the lateral meniscus, both pulling in different directions, may explain why type-III tibial eminence fractures are irreducible by manipulation.

Glyceryl trinitrate ointment as a potential treatment for primary vaginismus.

A Muslim Bedouin couple presented with difficulty in engaging in sexual intercourse, because of primary vaginismus. The couple rejected behavioral-cognitive therapy on ethnic. Topical application of nitroglycerin ointment to the vagina enabled the couple to enjoy a satisfactory sexual relationship.

Collapsing the tibial bone tunnel in hamstring autograft reconstruction of the anterior cruciate ligament.

The use of double staples is an accepted method for fixation of hamstring anterior cruciate ligament (ACL) grafts at the distal tibial site. In the last year, we have modified the 2-staple technique that we have been using for distal tibial fixation of our double loop hamstring ACL autografts. Previously, we had impacted the graft with 2 toothed staples onto the cortex distal to the opening of the tibial tunnel. The modification we report here involves driving the proximal staple into the tibial tunnel roof, thus collapsing the tunnel onto the tendon during fixation. The distal staple is introduced in the usual manner. Clinical follow-up including subjective and objective KT-1000 arthrometry has indicated no difference in the early results compared with the former staple technique. Radiologic follow-up showed tunnel obliteration and filling in the area of the proximal staple, suggesting early graft incorporation in callus. While early results are encouraging, long-term follow-up and pullout studies will be reported. It would appear that collapsing the bony tunnel by the proximal staple may be a simple method of providing fracture callus to increase the stiffness of the tibial graft fixation, with no major or minor complications. Animal experiments are being carried out to objectively define the mechanical advantage of the graft incorporation by callus.

Double-blind placebo-controlled pilot study of paroxetine for specific phobia.

Drugs are not recognized as a standard treatment for specific phobia, despite its apparent similarities to other kinds of phobia. Reluctance on the part of patients and clinicians to see the disorder as more than normal anxiety may explain the apparent resistance to pharmacotherapy. Eleven patients fulfilling DSM-IV criteria for specific phobia were randomized to 4 weeks of double-blind treatment with placebo or paroxetine up to 20 mg/day. They were assessed weekly with the Fear Questionnaire and the Hamilton Rating Scale for Anxiety. Paroxetine showed significant superiority in reducing all measures (ANCOVA for reductions in phobia scores F=7.9, P=0.02). One out of six patients responded to placebo, compared to three out of five patients on paroxetine. This new therapeutic option (i.e. drug treatment) for specific phobia deserves further examination in a larger trial.

Enhancement of CO2-induced anxiety in healthy volunteers with the serotonin antagonist metergoline.

OBJECTIVE: The mechanism of action of CO2-induced anxiety is unknown and has been little studied. The authors studied healthy volunteers for the possible influence of serotonin (5-HT) on CO2-induced anxiety. METHOD: Fourteen healthy volunteers received two vital capacity inhalations each of 35% CO2 and of air, preceded once by placebo and once by the 5-HT antagonist metergoline in a double-blind, randomized crossover design. RESULTS: Mean National Institute of Mental Health self-rating anxiety subscale scores increased nonsignificantly after CO2 inhalation; this effect was significantly enhanced by the administration of metergoline. CONCLUSIONS: The authors hypothesize that 5-HT may inhibit CO2-induced anxiety, a function that is lessened by metergoline.

[Alcoholic delirium: warning signs and diagnosis].

Lately an increasing number of physicians are asked to diagnose and treat physical and mental disorders caused by alcohol abuse, a phenomena which had been quite rare in Israel until recently. Early diagnosis and efficient treatment are essential for the management of alcohol-dependent patients. Primary care physicians and hospital personnel should be more alert to the growing numbers of alcohol abusers and to their appropriate diagnosis and treatment. This article describes and summarizes the symptoms of alcohol withdrawal in general, and alcoholic delirium in particular. Problems in diagnosis and treatment are illustrated by typical cases, pointing out early clinical warning signs and suggesting some treatment guidelines.

[Comparison between every-day and every-3-days fluoxetine in young, moderately depressed out-patients].

Fluoxetine is now a well-known and often-used specific serotonin reuptake inhibitor (SSRI) and antidepressant. It has a very long active half-life, from 2-16 days. Our hypothesis was that sufficient therapeutic effectiveness would be achieved by prescribing the drug less frequently than once a day. To establish whether there is a difference between fluoxetine given daily or every 3 days, we assigned 25 outpatients with mild to moderate, acute major depressions (DSM-IV) to receive fluoxetine (20 mg), either each day or every 3 days. The study was open-labelled, using for assessment the HAM-D, GHQ-28 side-effect checklist and clinical judgment questionnaires. Follow-up lasted 6 months. Results indicated no differences in the clinical outcomes, except for slightly fewer side-effects in the study group. Although the open label design limits drawing definitive conclusions, our preliminary results provide more information, and support our hypothesis that low-dosage fluoxetine is beneficial. However, more comprehensive, double-blind studies are necessary to confirm our preliminary results.

[Bacterial culture of chip tissue of enucleated prostates].

To assess the prevalence of infection and colonization of the prostate by bacteria, chip tissue samples from 166 patients undergoing retropubic prostatectomy were submitted for bacterial tissue culture. In 28 patients with an indwelling catheter before surgery, E. coli, Klebsiella, Pseudomonas and Enterobacter were the commonest species encountered, the first the most common. In only 7 patients (20%) who didn't have an indwelling catheter before operation was the culture positive. We confirmed that the longer the time the catheter was indwelling before surgery, the greater the likelihood of positive cultures. However, postoperative outcome and morbidity were not related to culture results. We conclude that even though it is worth trying to sterilize the urine and prostate before prostatectomy, the effect on the postoperative outcome is minimal when proper antimicrobial therapy is given perioperatively.

[Capgras' syndrome].

We present 3 cases of Capgras' syndrome-a delusional disorder in which the patient believes that 1 (or more) of his acquaintances has been replaced by an imposter who appears as a double. 2 were schizophrenics and 1 had depression with psychotic features. This syndrome is rare in our practice, but we do not know if this is due to lack of awareness of the condition, or to the possibility that it is a culture-related syndrome. We suggest that although the syndrome has lost some of it's significance, it is still worth making the diagnosis because of the medical and psychological implications this condition carries.