The effects of indomethacin on the generalized shwartzman reaction.

The antiflammatory drug indomethacin, an inhibitor of prostaglandin synthesis, prevents the generalized Shwartzman reaction produced in rabbits by two intravenous injections of bacterial endotoxin. Indomethacin has this effect if given before the first but not the second injection of endotoxin. Measurements of circulating white blood cells, platelets, partial thromboplastin time, prothrombin time, fibrinogen, plasminogen, and soluble fibrin were made at several times after either the first or second injection of endotoxin treated and nontreated rabbits. Four hours after the first injection of endotoxin, leukopenia and thrombocytopenia were somewhat greater in treated rabbits and the prolongation of the activated partial thromboplastin time was shortened. Twenty-one hours after injection of endotoxin, leukocytosis and elevation of plasma fibrinogen were not as great in treated animals. Four hours following the second injection of endotoxin a decrease in fibrinogen, prolongation of the prothrombin time, and the elaboration of soluble fibrin were consistently found in rabbits with the generalized Shwartzman reaction. In treated rabbits, none of these changes occurred. Indomethacin prevents the generalized Shwartzman reaction by preventing the development of the prepared state in this endotoxin model.     

Psychosocial factors related to long-term survival with HIV/AIDS

Only a few studies of long-term survivors of AIDS (those who survive more than twice the median expected time) have been done but these reveal a constellation of psychological characteristics including, but not limited to, those with active coping, social support, life involvement, ability to communicate, and active collaboration with one's doctor. Another related literature consists of longitudinal studies following people infected with the HIV virus to determine whether psychological characteristics are related to disease progression. These studies have focused on coping, depression, negative expectancies and social support as predictors. This article reviews and integrates the two bodies of literature combining the variables identified into four psychosocial strategies related to longer survival with HIV/AIDS: following healthy self care; maintaining connectedness; having a sense of meaning or purpose in life; and maintaining perspective. Affect, beliefs, and behaviour are all seen as important. Biological variables, SES and psychological resources that the person brings to the situation and external stresses are seen as important variables to consider in prediction studies. The pathways through which these four strategies may operate (both psychological and biological) to impact on health are discussed. Psychological pathways include distress and behavioural disengagement, while biological pathways involve the sympathetic nervous system, neuroendocrine and immune mediation. Finally suggestions for future research are given.     

Clamp loading,unloading and intrinsic stability of the PCNA, β and gp45 sliding clamps of human,E. coli and T4 replicases

Background: The high speed and processivity of replicative DNA polymerases reside in a processivity factor which has been shown to be a ring-shaped protein. This protein (‘sliding clamp’) encircles DNA and tethers the catalytic unit to the template. Although in eukaryotic, prokaryotic and bacteriophage-T4 systems, the processivity factors are ring-shaped, they assume different oligomeric states. The Escherichia coli clamp (the β subunit) is active as a dimer while the eukaryotic and T4 phage clamps (PCNA and gp45, respectively) are active as trimers. The clamp can not assemble itself on DNA. Instead, a protein complex known as a clamp loader utilizes ATP to assemble the ring around the primer-template. This study compares properties of the human PCNA clamp with those of E. coli and T4 phage. Results: The PCNA ring is a stable trimer down to a concentration below 100 nm (K_d ≈ 21 nm ). On DNA, the PCNA clamp slides freely and dissociates from DNA slowly (t_1/2 ≈ 24 min). β is more stable in solution (K_d < 60 pm ) and on DNA (t_1/2 ≈ 1 h) than PCNA which may be explained by its simpler oligomeric state. The T4 gp45 clamp is a much less stable trimer than PCNA (K_d ≈ 250 nm ) and requires association with the polymerase to stabilize it on DNA as observed previously. The consequence of this cooperation between clamp and polymerase is that upon finishing a template and dissociation of the polymerase from DNA, the gp45 clamp spontaneously dissociates from DNA without assistance. However, the greater stability of the PCNA and β clamps on DNA necessitates an active process for their removal. The clamp loaders (RF-C and γ complex) were also capable of unloading their respective clamps from DNA in the presence of ATP. Conclusions: The stability of the different clamps in solution correlates with their stability on DNA. Thus, the low stability of the T4 clamp explains the inability to isolate gp45 on DNA. The stability of the PCNA and β clamps predicts they will require an unloading factor to recycle them on and off DNA during replication. The clamp loaders of PCNA and β double as clamp unloaders presumably for the purpose of clamp recycling.     

Extracellular matrix-modulated differential invasion of human meningioma cell lines in vitro

The in vitro invasive behaviour of six meningioma cell lines of various histological sub-type and grade was assessed using Boyden chemotaxis chambers ('Transwell' units) precoated with various extracellular matrix proteins. The cell lines included a benign meningothelial (IPGS), two benign transitional (IPCBR and IPGC), one atypical (IPIH) and two malignant (IPSE and IPIR) meningiomas. IPGC was a recurrent tumour. The results showed that IPCBR was most invasive through laminin and vitronectin. IPIH was moderately invasive through collagen type IV, laminin, vitronectin and fibronectin. However, both IPSE and IPIR were less invasive than IPIH whereas, IPGS was least invasive of all. Moreover, laminin was the most permissive extracellular matrix protein for most cell lines and collagen type IV, the least permissive. These results show that there is a differential in vitro invasive behaviour of cell lines derived from different histological types of meningiomas according to extracellular matrix substrate and suggests that invasion and migration of meningiomas in situ might be modulated by various extracellular components.     

Movements resembling orientation or avoidance elicited by electrical stimulation of the superior colliculus in rats

Some studies have reported that stimulation of the superior colliculus in rats produces orienting responses, as it does in a number of species. However, other studies have reported movements resembling avoidance and escape, which are not characteristic of collicular stimulation in other mammals. This apparent discrepancy was investigated by systematically recording the effects on head and body movements of electrical stimulation at a large number of sites throughout the superior colliculus (SC) and surrounding structures. It was found that the nature of the movements observed depended on the location of the stimulating electrode. Contralateral head and body movements resembling orienting and approach were obtained from sites in the intermediate and deep layers in rostral colliculus, the intermediate white layer and immediately surrounding tissue in central colliculus, and in all layers except deep white in caudal colliculus. At the remaining responsive sites, movements resembling avoidance and escape were obtained. The most common response was an ipsilateral cringelike movement of the body that developed into ipsilateral locomotion, followed by running and jumping as the current was increased. These movements were obtained from sites in the superficial and intermediate layers rostrally; from the intermediate gray and the medial superficial and deep layers in central colliculus; and from the deep layers and underlying tegmentum caudally. The distributions of sites, together with evidence from other studies, suggested the following conclusions: Within the superficial layers, avoidance responses were obtained from a region of the superior colliculus that appeared to represent the upper visual field, whereas orienting responses were obtained from a region apparently representing the lower visual field. Stimulation of the area containing the cells of origin of the predorsal bundle produced orientation and approach movements, whereas the avoidance and escape movements were probably mediated by parts of the ipsilateral descending pathway. The stimulation-induced avoidance and escape may reflect the importance of such responses to visual "events," particularly in the upper part of the visual field, in animals, like rats, with many predators.     

Management of cervicofacial lymphatic malformations requires a multidisciplinary approach

Background/PurposeCervicofacial lymphatic malformations (CFLM) are rare, potentially life-threatening vascular anomalies, yet reports on multidisciplinary treatment strategies are lacking. We evaluated outcomes for CFLMs following sclerotherapy, surgical resection, and/or medical management.MethodsWe identified children with a CFLM at a vascular anomalies center from 2004 to 2019. Exclusion criteria: retro-orbital malformations, untreated malformations, patients without follow-up. Primary clinical outcome was contour improvement, with significance defined as LM volume reduction of > 50% by cross-sectional imaging.ResultsSixty-three children met inclusion criteria: 35 with macrocystic CFLMs, six with microcystic CFLMs, and 22 with mixed-type malformations. Mean post-intervention follow-up was 27.5 months. Fifty-eight patients underwent sclerotherapy (median: two treatments). Doxycycline and/or bleomycin were used in 95% of patients. After sclerotherapy, 97% of macrocystic CFLMs improved significantly compared to 82% of mixed and 67% of microcystic lesions. Sixteen children underwent surgical resection with 75% significantly improving; two additional patients were successfully treated with sclerotherapy after debulking surgery. Six children received sirolimus for microcystic disease, of which 33% significantly improved.ConclusionSclerotherapy is very effective for macrocystic components of CFLMs, albeit less so for microcystic disease. Microcystic CFLMs frequently require surgical resection. Sirolimus is a helpful therapeutic adjunct, particularly for microcystic lesions, but more study is needed.Level of EvidenceLevel II, prognosis study     

An Exploration of Dyadic Relationship Approach-Avoidance Goals and Relationship and Sexual Satisfaction in Couples Coping with Endometriosis

Endometriosis affects women of reproductive age and is associated with higher levels of sexual and relational distress. Despite the relational context of endometriosis, the research pertaining to dyadic relationship goals is lacking. An exploration of the relationship goals of couples coping with endometriosis can facilitate the understanding of potential protective mechanisms that mitigate the relational components of the condition. Guided by the approach-avoidance theoretical framework, the current cross-sectional study aimed to examine the role relationship goals play in sexual and relationship satisfaction in couples coping with endometriosis. Approach goals relate to the pursuit of a positive outcomes, whereas avoidance goals relate to the avoidance of negative outcomes. Women with endometriosis and their partners (N?=?61) completed an online survey measuring relationship goals and relationship and sexual satisfaction. The study results indicated that, for women, their own and their partner’s higher relationship approach goals were linked to higher sexual satisfaction. For partners of women with endometriosis, their own higher relationship approach goals were associated with their own higher relationship satisfaction. Higher relationship avoidance goals in both women with endometriosis and partners were associated with higher relationship satisfaction. The study’s findings highlight relationship goals as relevant to the relational and sexual experience of couples coping with endometriosis. When treating women with endometriosis, the inclusion of partners and consideration of factors beyond the physical illness are important for a holistic management approach.

     

Active-specific immunotherapy for melanoma

Twenty-five patients with metastatic melanoma were treated with a therapeutic vaccine ("theraccine") consisting of allogeneic melanoma lysates and a novel adjuvant, DETOX (Ribi ImmunoChem Research, Inc, Hamilton, MT). Each patient received 200 antigenic units (20 x 10(6) tumor cell equivalents) subcutaneously on weeks 1, 2, 3, 4, and 6. Clinical responses included one complete remission, three partial remissions, and a long-term (17-month) stability. Two other patients had mixed responses, with partial remissions of numerous subcutaneous nodules. Sites of responsive disease included primarily the skin, but ileal, breast, and a liver metastasis also responded. Removal of residual lesions in patients with partial remissions, whose other lesions had disappeared during treatment, led to long disease-free survivals. The median duration of remission was 17 months, with four of the five responders alive for at least 24 months after treatment. An increase in precursors of cytolytic T cells (CTLs) correlated with clinical outcome, when complete, partial, and mixed responses and long-term stability were considered. The CTLs recognized melanoma-associated antigens on many cell lines, but not other types of tumor or normal lymphocytes. Skin-test reactivity to melanoma antigens and serum antibodies against the melanoma cells was unrelated to clinical response. Toxicity was minimal, restricted largely to minor soreness at the site of injection. Only five patients, four of whom were treated with repeated courses, developed severe granulomas. These results confirm that active-specific immunization with allogeneic lysates of melanoma administered with the adjuvant DETOX can induce immunity to melanoma, and can induce regressions of disease in a proportion of patients with metastatic disease with little toxicity.