Mortality and risk of cancer in systemic connective tissue diseases

The systemic connective tissue diseases represent a broad spectrum of multiorgan disorders. This report reviews our current knowledge of mortality and the risk of cancer in these diseases. The relationship between clinical manifestations and reduced survival in systemic sclerosis, systemic lupus erythematosus and polyarteritis nodosa is addressed in detail. Moreover, we outline the increased risks of cancer in dermatomyositis and lymphoma in primary Sj?gren's syndrome, as well as cancer of the bladder in patients with Wegener's granulomatosis who have been treated with cyclophosphamide. Finally, the conflicting results regarding mortality in temporal arteritis are discussed.     

Immunoregulatory circuits and potential treatment of connective tissue diseases

Thirteen new (1-13) and seven known (14-20) steroid glycosides were isolated from Henricia downeyae, collected from the offshore waters of the northern Gulf of Mexico. Ethanolic extracts of these starfish caused growth inhibition in bacteria and fungi, potent antifouling activity against barnacle and bryozoan larvae, and feeding deterrent activity against a marine fish. The known compounds are typical glycosides found in several species of the family Echinasteridae, i.e., Echinaster sp. and Henricia laeviuscola. One of the new compounds belongs to this group, whereas the remaining 12 new compounds represent a novel series of steroid glycosides which have aglycons with structural similarities to the "asterosaponins". They possess a delta 9(11) 3 beta, 6 alpha-dihydroxysteroidal aglycon with 23-oxo or 22,23-epoxy functionalities and often a 20-hydroxyl group in the side chain. The sulfate is located at C-6 and the saccharide moiety at C-3, in contrast with the asterosaponins which have the sulfate at C-3 and the oligosaccaride moiety at C-6. All the new compounds contain a glucuronic acid unit, which is uncommon among steroid glycosides from echinoderms. The structures of the new compounds, isolated in amounts ranging from 3.4 to 0.9 mg, were determined by interpretation of their spectral data and by comparison with spectral data of known compounds.     

Conjugated equine estrogens alone, but not in combination with medroxyprogesterone acetate, inhibit aortic connective tissue remodeling after plasma lipid lowering in female monkeys

The objective of this study was to determine the arterial responses to plasma lipid lowering alone or in combination with (1) estrogen replacement therapy or (2) hormone replacement therapy in surgically postmenopausal female monkeys with preexisting atherosclerosis. Eighty-eight female cynomolgus macaques were ovariectomized, fed an atherogenic diet for 24 months, and then assigned by randomized stratification into 4 groups. One group (baseline, n=20) was necropsied at the end of the atherogenic diet period; the remaining 3 groups were fed a plasma lipid-lowering diet (regression) for 30 months. These regression groups were control (diet only), CEE (receiving conjugated equine estrogens alone), and CEE+MPA (receiving CEE and continuous medroxyprogesterone acetate). A previous report described coronary artery functional and histological results; the present report describes biochemical and histological results from the abdominal aorta. Aortic plaque size was not different between groups, similar to previous findings in the coronary arteries. Aortic cholesterol content (milligrams per gram lipid-free dry weight) was lower in the regression groups compared with baseline, both for free cholesterol (mean, control=19.1, CEE=15.7, CEE+MPA=14.4, and baseline=32.7; P<0.001) and for esterified cholesterol (mean, control=18.9, CEE=15.4, CEE+MPA=14.2, and baseline=58.7; P<0.001). This cholesterol efflux could lead to increased plaque stability without changing the physical size of the lesion. Alterations in aortic connective tissue composition were observed in the regression groups. When expressed as a percentage of the lipid-free tissue weight, the aortic elastin content of the control (mean=14.9) and the CEE+MPA (mean=14.0) groups was lower than that of the baseline group (mean=19.0), which was not different from that of the CEE group (mean=15.8). Aortic collagen content, as estimated by hydroxyproline content per milligram of lipid-free tissue, was higher in the control group (mean=67.4) and the CEE+MPA group (mean=66.1) than in the baseline group (mean=56.2; P<0.05). Collagen content of the CEE group (mean=58.9) was not different from that of the baseline group. When the regression groups were considered separately, the aortic collagen content of the CEE group was lower than that of the control group (P<0.05) and tended to be lower than that of the CEE+MPA group (P=0.10), suggesting that CEE therapy (but not CEE+MPA) inhibits potentially detrimental connective tissue alterations that accompany lesion regression. These results have implications for combinations of lipid-lowering and hormone replacement therapies in relation to vascular remodeling and abdominal aortic aneurysm development.     

Genetic diseases of the extracellular matrix: more than just connective tissue disorders

The rapidly increasing knowledge about the molecular biology of the extracellular matrix has changed the concepts for the pathomechanisms of heritable connective tissue diseases. The spectrum of genetic matrix disorders is much broader than previously thought and now also includes diseases of organs such as the kidney, eye, and muscles. In addition, evidence is emerging that certain "acquired" diseases may be inherited, and that defects in signal transduction and patterning genes contribute to the pathology of connective tissue disorders. The phenotypes of genetic matrix disorders are determined by basic biological characteristics of the extracellular matrix. (a) The extracellular matrix occurs ubiquitously and is important for organ development and functions. (b) Matrix macromolecules are often large oligomers that polymerize into suprastructures at several hierarchic levels. They form insoluble fibrils or filaments that are further assembled into tissue suprastructures, for example, bundles or networks of fibrils. (c) Matrix suprastructures share characteristics with metal alloys. Tissue-specific mixtures of matrix molecules form specific arrays that differ from those of the pure components. Therefore the phenotypes of matrix diseases reflect a cascade of pathological events disturbing alloy formation, such as abnormal protein synthesis and folding, defective fibrillogenesis, and bundling, all capable of leading to abnormal cell-matrix interactions.     

Mutations in the COCH gene are a frequent cause of autosomal dominant progressive cochleo-vestibular dysfunction, but not of Meniere's disease

The COCH gene is the only gene identified in man that causes autosomal dominantly inherited hearing loss associated with vestibular dysfunction. The condition is rare and only five mutations have been reported worldwide. All affected families showed a similar progressive hearing loss and vestibular dysfunction. Since Meniere's disease-like symptoms have also been described in some families, it was suggested that COCH mutations might be present in some patients diagnosed with Meniere's disease. In this study, using a Japanese population, we performed a COCH mutation analysis in 23 patients from independent families with autosomal dominant hearing impairment, four of whom reported vestibular symptoms, and also in 20 Meniere's patients. While a new point mutation, A119 T, was found in a patient with autosomal dominant hearing loss and vestibular symptoms, no mutations were found in the Meniere's patients. Like all other previously identified COCH mutations, the mutation identified here is a missense mutation located in the FCH domain of the protein. The current mutation is located in close spatial proximity to W117, in which a mutation (W117R) had previously been associated with autosomal dominant hearing loss. Model building suggests that, like the W117R mutation, the A119 T mutation does not affect the structural integrity of the FCH domain, but may interfere with the interaction with a yet unknown binding partner. We conclude that mutations in the COCH gene are responsible for a significant fraction of patients with autosomal dominantly inherited hearing loss accompanied by vestibular symptoms, but not for dominant hearing loss without vestibular dysfunction, or sporadic Meniere's disease.     

Ultrastructure of sea urchin tube feet. Evidence for connective tissue involvement in motor control

An analysis of the ultrastructure of the tube feet of three species of sea urchins (Strongylocentrotus franciscanus, Arbacia lixula and Echinus esculentus) revealed that the smooth muscle, although known to be cholinoceptive, receives no motor innervation. The muscle fibers are attached to a double layer of circular and longitudinal connective tissue which surrounds the muscle layer and contains numerous bundles of collagen fibers. On its outside, the connective tissue cylinder is invested by a basal lamina of the outer epithelium to which numerous nerve terminals are attached. These are part of a nerve plexus which surrounds the connective tissue cylinder. The plexus itself is an extension of a longitudinal nerve that extends the whole length of the tube foot. It is composed of axons, but nerve cell bodies and synapses are conspicuously lacking, suggesting that the axons and terminals derive from cells of the radial nerve. Processes of the epithelial cells penetrate the nerve plexus and attach to the basal lamina. There is no evidence that the epithelial cells function as sensory cells. On the basis of supporting evidence it is suggested that the transmitter released by the nerve terminals diffuses to the muscle cells over a distance of several microns and in doing so affects the mechanical properties of the connective tissue.     

Interleukin 1 beta, but not tumor necrosis factor, enhances neurogenic vasodilatation in the rat skin: involvement of nitric oxide

In phenobarbitone-anesthetized rats the effects of interleukin 1 beta (IL-1 beta) and tumor necrosis factors (TNFs) were examined on the capsaicin-induced increase of plantar cutaneous blood flow in the rat hind paw as measured by laser Doppler flowmetry. IL-1 beta (0.5-500 pg) or TNF alpha or TNF beta (50-500 pg) was injected subcutaneously into the left paws, while the right paws received vehicle (10 microL) only. IL-1 beta was without effect on blood flow by its own but dose dependently enhanced the hyperemia due to capsaicin (0.3 microgram). TNFs failed to enhance the capsaicin-induced vasodilatation although 5000 pg TNF alpha produced a transient increase of local blood flow. Indomethacin (10 mg/kg, i.p.) did not alter the capsaicin-induced vasodilatation but prevented IL-1 beta (50 pg) from augmenting the hyperemic response to capsaicin. Likewise, blockade of nitric oxide formation by NG-nitro-L-arginine methyl ester (L-NAME) failed to affect the capsaicin-evoked vasodilatation but abolished its amplification by IL-1 beta. Systemic pretreatment with a neurotoxic dose of capsaicin reduced the capsaicin-induced hyperemia and prevented the facilitatory effect of IL-1 beta. The hyperemia evoked by intraplantar calcitonin gene related peptide (0.038-3.8 ng) was not altered by IL-1 beta (50 pg). These data indicate that IL-1 beta but not TNF enhances the cutaneous hyperemic response to capsaicin. This proinflammatory action arises from sensitization of afferent nerve endings and depends on nitric oxide and cyclooxygenase products as essential intermediates.     

Hippocampal involvement in the acquisition of relational associations, but not in the expression of a transitive inference task in mice.

The hippocampus (HC) has been suggested to play a role in transitive inference (TI) on an ordered sequence of stimuli. However, it has remained unclear whether HC is involved in the expression of TI, or rather contributes to TI through its role in the acquisition of the sequence of elements (Frank, Rudy, & O'Reilly, 2003). Presently, the authors compared the effects of excitotoxic dorsal HC lesions in C57BL mice that received surgery before or after they were trained to discriminate between pairs of visual stimuli. Performance on a subsequent TI task was worse in mice with pretraining lesions than in those with posttraining lesions, which showed similar performance to shams without lesions. This indicates that HC is not involved in the expression of TI, but may merely help to acquire the underlying representations required for TI. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The t(11;18)(q21;q21) chromosome translocation is a frequent and specific aberration in low-grade but not high-grade malignant non-Hodgkin's lymphomas of the mucosa-associated lymphoid tissue (MALT-) type

Primary extranodal malignant non-Hodgkin's lymphoma arising from the mucosa-associated lymphoid tissue (MALT-type lymphoma) represents a subtype of B-cell lymphoid malignancies with distinct clinicopathological features and is often associated with a favorable prognosis. Unlike the situation in nodal non-Hodgkin's lymphoma of B-cell lineage, few data are still available concerning the chromosomal constitution of MALT-type lymphomas. Until now, cytogenetic data from 29 low-grade MALT lymphomas with karyotypic alterations have been reported from different institutions, and virtually no data were available for high-grade MALT-type lymphomas. We have analyzed the cytogenetics of 44 MALT lymphomas arising in the stomach, parotid gland, thyroid gland, lung, breast, and conjunctiva. Clonal chromosome aberrations have been detected in 13 of 20 (65%) low-grade and 20 of 24 (83%) high-grade tumors. More than half of the low-grade lymphomas with abnormal karyotypes (7 of 13 cases, 53%) displayed clonal t(11;18)(q21;q21), thus specifically associating this translocation with MALT-type lymphomas for the first time in a larger series. In contrast, t(11;18) was not found in a single case of 20 high-grade MALT-type lymphomas with abnormal karyotypes, nor were translocations t(14;18) or t(3;14), characterizing about 10-35% of primary nodal large cell lymphomas. Instead, these lymphomas were associated with t(8;14)(q24;q32) in three cases, frequent deletions in the long arm of chromosome 6, and partial or whole gains of chromosomes 3, 7, 17, 18, and 21.     

Dorsal hippocampus involvement in trace fear conditioning with long, but not short, trace intervals in mice.

Placing a "trace" interval between a warning signal and an aversive shock makes consolidation of the memory for trace conditioning hippocampus dependent. To determine the trace at which memory consolidation requires the hippocampus, mice were trained with 0-s, 1-s, 3-s, or 20-s trace intervals and tested for freezing to context and tone. Posttraining dorsal hippocampus (DH) lesions decreased context conditioning regardless of trace interval. However, DH lesions attenuated only the 20-s trace tone freezing. Like eyeblink conditioning, the DH is necessary for trace fear conditioning only at long trace intervals, but the time scale for the effective interval in fear conditioning is about 40 times longer. Manipulations that alter trace fear conditioning with short trace intervals probably do not reflect altered DH function. Given this difference in time scale along with the use of posttraining DH lesions, hippocampus dependency of trace conditioning is not related to a bridging function or response timing. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Happily hopeless: Adaptation to a permanent, but not to a temporary, disability.

Objective: The authors tracked patients with either irreversible or reversible colostomies over a 6-month period, beginning a week after the procedure, to examine how they adapted hedonically over time. Based on prior research and theorizing, the authors hypothesized that, paradoxically, those with irreversible colostomies would adapt more fully, and become happier, than would those with colostomies that were potentially reversible. Design: The authors contacted 107 patients who had recently received either a colostomy or ileostomy. The initial interviews were conducted while patients were still in the hospital recovering from their surgery. Consenting participants were mailed surveys at three time points: 1 week after release from the hospital, 1 month after release, and 6 months after release. Main Outcome Measures: The surveys included measures of life satisfaction and perceived quality of life. Results: As predicted, overall life satisfaction and quality of life increased with time for patients with permanent, but not temporary, ostomies. Conclusion: These findings suggest that knowing an adverse situation is temporary can interfere with adaptation, leading to a paradoxical situation in which people who are better off objectively are worse off subjectively. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Evidence for involvement of Bax and p53, but not caspases, in radiation-induced cell death of cultured postnatal hippocampal neurons

This paper unfolds the events, the people and the times that led up to the founding of AChemS and fashioned its character during its early formative years. It describes the path over which AChemS came, going from the original assertions and denials for the need of such an organization to its later inception and nascent development. This narration highlights such topics as the debate over the need for AChemS, the role of National Science Foundation in the founding of AChemS, the derivation of the Association's name, the choice of Sarasota and the Hyatt House as the meeting site, the generation of the programs for the early annual meetings, the adoption of the bylaws, the process of incorporation and tax deferment, and the birth of the Givaudan Lectureship. Most emphatically highlighted, however, is the enthusiasm, commitment and hard work that the members of the chemosensory research community displayed in bringing AChemS to fruition.     

Heparin attenuates bleomycin but not silica-induced pulmonary fibrosis in mice: possible relationship with involvement of myofibroblasts in bleomycin, and fibroblasts in silica-induced fibrosis

The metal alloys which were investigated histopathologically in the first part of this study, were examined with respect to their allergic potentials using the patch test. Results from 60 subjects (aged 17-23) were evaluated following exposure to nickel sulphate, potassium dichromate, silver nitrate, cobalt nitrate, copper sulphate, palladium chloride, platinum chloride and gold chloride. Nickel sulphate produced the most vigorous allergic response whereas gold chloride showed the least of all. The remaining solutions were ranked in decreasing order of severity as follows: potassium dichromate, cobalt nitrate, silver nitrate, copper sulphate, palladium chloride and platinum chloride. Patch testing is indicated in any patient with a history of allergy or sensitivity to a metal. The use of nickel containing alloys in such patients should also be avoided.     

Buspirone, but not sumatriptan, induces miosis in humans: relevance for a serotoninergic pupil control

BACKGROUND AND OBJECTIVE: Drugs that act on the serotoninergic system have been shown to influence the pupil size. However, the 5-hydroxytryptamine (5-HT) receptor type or subtype that affects pupil diameter has not been defined in humans. With a placebo-controlled, double-blind randomized design, we investigated in healthy volunteers the effect on pupil size of buspirone and sumatriptan, which mainly act on 5-HT1A- and the 5-HT1-like receptors, respectively. METHODS: The pupil area was measured by means of a videopupillometer before and after a single oral administration of placebo or of three different doses of active drugs. Heart rate and arterial blood pressure were recorded after pupil area measurement. RESULTS: Buspirone (5, 10, and 20 mg) caused a dose-dependent miosis. Sumatriptan (50, 100, and 200 mg) did not affect the pupil size. Twenty milligrams of buspirone reduced the mydriasis induced by pretreatment with homatropine eyedrops. A 20 mg dose of buspirone reduced blood pressure without change in heart rate, whereas buspirone, at doses lower than 20 mg, and sumatriptan did not affect heart rate and blood pressure. CONCLUSIONS: This study suggests that buspirone, but not sumatriptan, the selective agonist of 5-HT1-like receptors, causes miosis in humans by activation of 5-HT1A receptors, possibly located in the central nervous system where they inhibit iris sympathetic pathways. Measurement of pupil size seems to provide a valuable and sensitive index of 5-HT1A receptor function in humans.     

Evidence for the involvement of inositol trisphosphate but not cyclic nucleotides in visual transduction in Hermissenda eye

Although several second messengers are known to be involved in invertebrate photoresponses, the mechanism underlying invertebrate phototransduction remains unclear. In the present study, brief injection of inositol trisphosphate into Hermissenda photoreceptors induced a transient Na+ current followed by burst activity, which accurately reproduced the native photoresponse. Injection of Ca2+ did not induce a significant change in the membrane potential but potentiated the native photoresponse. Injection of a Ca2+ chelator decreased the response amplitude and increased the response latency. Injection of cGMP induced a Ca2+-dependent, transient depolarization with a short latency. cAMP injection evoked Na+-dependent action potentials without a rise in membrane potential. Taken together, these results suggest that phototransduction in Hermissenda is mediated by Na+ channels that are directly activated by inositol trisphosphate without mobilization of cytosolic Ca2+.     

Development of sibling inbred sea urchins: normal embryogenesis, but frequent postembryonic malformation, arrest and lethality

BACKGROUND: It has been suggested that within the growth plate, the final volume and shape of hypertrophic chondrocytes are important variables in determining the rate of longitudinal bone growth. To better understand the organization and regulation of chondrocytic hypertrophy as related to longitudinal bone growth, the beginning and end, and the location and magnitude of chondrocytic volume and shape changes during the hypertrophic process were defined in the proximal tibial growth plate of 35-day-old rats. METHODS: In this study we used two different approaches, a stereological analysis of chondrocytes in unbiasedly defined, narrow growth plate strata, and a serial section reconstruction and measurement of individual cells. In both experiments chondrocytes were preserved using optimal chemical fixation. Proliferating chondrocytes were identified using bromodeoxyuridine labelling, and the rate of longitudinal bone growth was determined using oxytetracycline labelling. RESULTS: In both studies, immediately following cell division in the proliferative zone, chondrocytic volume gradually increased toward the mid-point of the growth plate. During this phase of about 30 hours, approximately 20% of the final cell volume was obtained. During the following 20 hours the remaining 80% was acquired. The estimated rate of cell volume increased changed from approximately 50 microns 3/hr during the first 30 hours to about 800 microns 3/hr during the last 20 hours. The increase in cell volume resulted in an increase in both the vertical and the horizontal chondrocytic diameters. Cell parameters did not change during the final five hours of the maturation process. CONCLUSIONS: In this study we demonstrated that chondrocytic enlargement starts immediately following cell division in the proliferative zone, and that chondrocytic enlargement consists of two morphologically distinguishable phases. The transition point between the first and the second phase of chondrocytic enlargement corresponded with the junction between the proliferative zone and the maturation zone.