How to recognize and treat specific low back pain?

A wide variety of mechanical and non-mechanical disorders are associated with the clinical symptom of low back pain. Mechanical disorders are the cause of the vast majority of low back pain. Despite this frequency, the specific cause of mechanical low back pain can not be elucidated in spite of extensive diagnostic evaluation in a majority of individuals. Specific causes of low back pain are associated with less frequently occurring systemic illnesses including rheumatic, infectious, neoplastic, gynaecological and vascular disorders. The diagnostic process is more successful in identifying systemic disorders as the specific cause of low back pain. Non-surgical management is effective therapy with most patients with mechanical disorders of any form. Systemic illnesses require interventions directed specifically at healing the affected organ system.     

Analysis of the process of localization of fertilin to the sperm posterior head plasma membrane domain during sperm maturation in the epididymis

Fertilin is a heterodimeric (subunits alpha and beta) sperm plasma membrane protein. Both subunits belong to the ADAM protein family of surface proteins that contain a disintegrin and a metalloprotease domain. Fertilin functions in sperm-egg fusion by binding the sperm to the egg plasma membrane via a binding site in the disintegrin domain of fertilin beta. On testicular sperm of guinea pig, fertilin is distributed on the plasma membrane over the entire sperm head, but is found only on the posterior head once sperm have passed through the epididymis. This redistribution of fertilin to the posterior head can be partially mimicked in vitro if testicular sperm are briefly treated with trypsin. In this study we used immunofluorescence and digital image analysis to analyze how fertilin becomes restricted to the posterior head. We found that fertilin became restricted to the posterior head by migration of anterior head fertilin molecules into the posterior head domain. Comparison of immunofluorescence patterns and immunoblots of fertilin from seven regions of the epididymis showed a temporal correlation between the beginning of fertilin's migration to the posterior head and the proteolytic processing of the full-length fertilin beta precursor (the 85-kDa pro-beta form) to a 75-kDa intermediate, pro-beta*. Completion of the migration coincided with the further cleavage of pro-beta* to the 25- to 28-kDa mature form. Our data suggest that the cleavage of fertilin pro-beta to pro-beta* may initiate fertilin's migration into the posterior head domain and, after localization to that membrane domain, pro-beta* is cleaved to mature beta. We also report evidence that a common mechanism may be used to change the localization pattern of other sperm surface molecules. Other surface proteins were shown to become localized to either the posterior or the anterior head membrane domains on sperm at the same time fertilin became localized to the posterior head. These restrictions of surface protein localizations were also shown to immediately precede the development of the sperm's ability to swim and undergo the acrosome reaction, and thus redistribution of surface proteins may be necessary before sperm become functional.     

DARPP-32: regulator of the efficacy of dopaminergic neurotransmission

Dopaminergic neurons exert a major modulatory effect on the forebrain. Dopamine and adenosine 3',5'-monophosphate-regulated phosphoprotein (32 kilodaltons) (DARPP-32), which is enriched in all neurons that receive a dopaminergic input, is converted in response to dopamine into a potent protein phosphatase inhibitor. Mice generated to contain a targeted disruption of the DARPP-32 gene showed profound deficits in their molecular, electrophysiological, and behavioral responses to dopamine, drugs of abuse, and antipsychotic medication. The results show that DARPP-32 plays a central role in regulating the efficacy of dopaminergic neurotransmission.     

Evocation and characterization of percepts of apparent motion on the face

The percepts evoked by sequential stimulation of sites in close spatial proximity (< or = 2.5 cm) on the face were studied. Both method-of-limits and magnitude-estimation procedures were used to identify and characterize alterations in the percepts produced by systematic changes in the temporal and spatial parameters of the sequence. Each site was stimulated by a vertically oriented row of miniature vibrating probes. Apparent motion was consistently perceived when the delay between the onsets of sequentially activated rows (interstimulus onset interval, or ISOI) fell within a relatively narrow range of values, the lower limit of which approximated 5 msec. Both the upper limit and the perceived smoothness and continuity of the motion percepts (goodness of motion) increased with the duration for which each row stimulated the skin over the range evaluated, 15-185 msec. For the successive activation of only two rows, goodness of motion was not influenced by changes in their separation from 0.4 to 2.5 cm. The ISOI values at which magnitude estimates of goodness of motion were highest increased with the duration for which each row stimulated the skin. As such, maximum goodness of motion decreased with increases in the apparent velocity of motion. When the number of sequentially activated rows was increased from two to four or more, the quality of the motion percepts improved. For the successive activation of multiple closely spaced rows, values of ISOI at which numerical estimates of goodness of motion were highest approximated integral fractions of the duration for which each row stimulated the skin. In this situation, the probes rose and fell in a regular, step-locked rhythm to simulate an edge-like or rectangular object moving across the skin. The goodness of motion so attained was relatively independent of the apparent velocity of motion.     

Activity Counseling Trial (ACT): rationale, design, and methods. Activity Counseling Trial Research Group

The Activity Counseling Trial (ACT) is a multicenter, randomized controlled trial to evaluate the effectiveness of interventions to promote physical activity in the primary health care setting. ACT has recruited, evaluated, and randomized 874 men and women 35-75 yr of age who are patients of primary care physicians. Participants were assigned to one of three educational interventions that differ in amount of interpersonal contact and resources required: standard care control, staff-assisted intervention, or staff-counseling intervention. The study is designed to provide 90% power in both men and women to detect a 1.1 kcal.kg-1.day-1 difference in total daily energy expenditure between any two treatment groups, and over 90% power to detect a 7% increase in maximal oxygen uptake, the two primary outcomes. Primary analyses will compare study groups on mean outcome measures at 24 months post-randomization, be adjusted for the baseline value of the outcome measure and for multiple comparisons, and be conducted separately for men and women. Secondary outcomes include comparisons between interventions at 24 months of factors related to cardiovascular disease (blood lipids/lipoproteins, blood pressure, body composition, plasma insulin, fibrinogen, dietary intake, smoking, heart rate variability), psychosocial effect, and cost-effectiveness, and at 6 months for primary outcome measures. ACT is the first large-scale behavioral intervention study of physical activity counseling in a clinical setting, includes a generalizable sample of adult men and women and of clinical setting, and examines long-term (24 months) effects. ACT has the potential to make substantial contributions to the understanding of how to promote physical activity in the primary health care setting.     

COFFEE: an objective function for multiple sequence alignments

MOTIVATION: In order to increase the accuracy of multiple sequence alignments, we designed a new strategy for optimizing multiple sequence alignments by genetic algorithm. We named it COFFEE (Consistency based Objective Function For alignmEnt Evaluation). The COFFEE score reflects the level of consistency between a multiple sequence alignment and a library containing pairwise alignments of the same sequences. RESULTS: We show that multiple sequence alignments can be optimized for their COFFEE score with the genetic algorithm package SAGA. The COFFEE function is tested on 11 test cases made of structural alignments extracted from 3D_ali. These alignments are compared to those produced using five alternative methods. Results indicate that COFFEE outperforms the other methods when the level of identity between the sequences is low. Accuracy is evaluated by comparison with the structural alignments used as references. We also show that the COFFEE score can be used as a reliability index on multiple sequence alignments. Finally, we show that given a library of structure-based pairwise sequence alignments extracted from FSSP, SAGA can produce high-quality multiple sequence alignments. The main advantage of COFFEE is its flexibility. With COFFEE, any method suitable for making pairwise alignments can be extended to making multiple alignments. AVAILABILITY: The package is available along with the test cases through the WWW: http://www. ebi.ac.uk/cedric CONTACT: cedric.notredame@ebi.ac.uk     

Dose-intensive melphalan with blood stem-cell support for the treatment of AL (amyloid light-chain) amyloidosis: survival and responses in 25 patients

AL (amyloid light-chain) amyloidosis is an uncommon plasma cell disorder in which depositions of amyloid light-chain protein cause progressive organ failure and death in a median of 13 months. Autologous stem-cell transplantation is effective therapy for multiple myeloma and therefore, we evaluated its efficacy for AL amyloidosis. Patients with adequate cardiac, pulmonary, and renal function had stem cells mobilized with granulocyte-colony stimulating factor and were treated with dose-intensive intravenous melphalan (200 mg/m2). Response to therapy was determined by survival and improvement of performance status, complete response or persistence of the clonal plasma cell disorder, and change in the function of organs involved with amyloid at baseline. We enrolled 25 patients with a median age of 48 years (range, 29-60), all of whom had biopsy-proven amyloidosis with clonal plasma cell disorders. Twenty-two (88%) were Southwest Oncology Group performance status 1 or 2 within a year of diagnosis, and 16 (64%) had received no prior therapy. Predominant amyloid-related organ involvement was cardiac (n = 8), renal (n = 7), hepatic (n = 6), neuropathic (n = 3), and lymphatic (n = 1). Fifteen patients had one or two organ systems involved, whereas 10 had three or more involved. With a median follow-up of 24 months (12-38), 17 of 25 patients (68%) are alive, and the median survival has not been reached. Thirteen of 21 patients (62%) evaluated 3 months posttransplant had complete responses of their clonal plasma cell disorders. Currently, two thirds of the surviving patients (11 of 17) have experienced improvements of amyloid-related organ involvement in all systems, whereas 4 of 17 have stable disease. The improvement in the median performance status of the 17 survivors at follow-up (0 [range, 0-3]) is statistically significant versus baseline (2 [range, 1-3]; P < . 01). Significant negative prognostic factors with respect to overall survival include amyloid involvement of more than two major organ systems and predominant cardiac involvement. Three patients have experienced relapses of the clonal plasma cell disorder at 12 and 24 months. Dose-intensive therapy should currently be considered as the preferred therapy for patients with AL amyloidosis who meet functional criteria for autologous transplantation.