Fibroblasts regulate tissue homeostasis, coordinate inflammatory responses, and mediate tissue damage. In rheumatoid arthritis (RA), synovial fibroblasts maintain chronic inflammation which leads to ...joint destruction. Little is known about fibroblast heterogeneity or if aberrations in fibroblast subsets relate to pathology. Here, we show functional and transcriptional differences between fibroblast subsets from human synovial tissues using bulk transcriptomics of targeted subpopulations and single-cell transcriptomics. We identify seven fibroblast subsets with distinct surface protein phenotypes, and collapse them into three subsets by integrating transcriptomic data. One fibroblast subset, characterized by the expression of proteins podoplanin, THY1 membrane glycoprotein and cadherin-11, but lacking CD34, is threefold expanded in patients with RA relative to patients with osteoarthritis. These fibroblasts localize to the perivascular zone in inflamed synovium, secrete proinflammatory cytokines, are proliferative, and have an in vitro phenotype characteristic of invasive cells. Our strategy may be used as a template to identify pathogenic stromal cellular subsets in other complex diseases.
Seafloor sediment flows (turbidity currents) are among the volumetrically most important yet least documented sediment transport processes on Earth. A scarcity of direct observations means that basic ...characteristics, such as whether flows are entirely dilute or driven by a dense basal layer, remain equivocal. Here we present the most detailed direct observations yet from oceanic turbidity currents. These powerful events in Monterey Canyon have frontal speeds of up to 7.2 m s
, and carry heavy (800 kg) objects at speeds of ≥4 m s
. We infer they consist of fast and dense near-bed layers, caused by remobilization of the seafloor, overlain by dilute clouds that outrun the dense layer. Seabed remobilization probably results from disturbance and liquefaction of loose-packed canyon-floor sand. Surprisingly, not all flows correlate with major perturbations such as storms, floods or earthquakes. We therefore provide a new view of sediment transport through submarine canyons into the deep-sea.
Deposits of Ig and complement are abundant in affected joints of patients with rheumatoid arthritis (RA) and in animal models of RA in which antibodies are demonstrably pathogenic. To identify ...molecular targets of the Igs deposited in arthritic joints, which may activate local inflammation, we used a combination of mass spectrometry (MS) and protein microarrays. Immune complexes were affinity-purified from surgically removed joint tissues of 26 RA and osteoarthritis (OA) patients. Proteins complexed with IgG were identified by proteomic analysis using tandem MS. A striking diversity of components of the extracellular matrix, and some intracellular components, copurified specifically with IgG from RA and OA tissues. A smaller set of autoantigens was observed only in RA eluates. In complementary experiments, IgG fractions purified from joint immune complexes were tested on protein microarrays against a range of candidate autoantigens. These Igs bound a diverse subset of proteins and peptides from synovium and cartilage, different from that bound by normal serum Ig. One type of intracellular protein detected specifically in RA joints (histones H2A/B) was validated by immunohistology and found to be deposited on the cartilage surface of RA but not OA joints. Thus, autoantibodies to many determinants (whether deposited as "neoantigens" or normal constituents of the extracellular matrix) have the potential to contribute to arthritic inflammation.
Since the advent of disease-modifying antirheumatic drugs for rheumatoid arthritis, orthopedic surgeons see fewer patients in the office who require hand surgery. However, a significant number of ...patients still seek surgical intervention to improve pain and function. These patients often present with isolated soft tissue pathologies, but even bone and joint pathology require meticulous soft tissue handling in this cohort. This review highlights the principles and techniques relevant to the management of soft tissue deformity in rheumatoid hand and wrist surgery, as exposure in training and practice continues to decrease.
Carpal Tunnel Syndrome Katz, Jeffrey N; Simmons, Barry P
The New England journal of medicine,
06/2002, Letnik:
346, Številka:
23
Journal Article
Recenzirano
A 64-year-old woman has a three-month history of intermittent numbness, tingling, and burning pain in the three radial digits of both hands. These symptoms awaken her several times each night. She ...has no atrophy of the thenar muscles. How should she be evaluated and treated?
Foreword
This
Journal
feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors' clinical recommendations.
Stage
A 64-year-old, right-handed, retired woman presents with intermittent numbness, tingling, and burning pain in the three radial digits of both hands. She has had these symptoms for three months, and they awaken her several times each night. She has no atrophy of the thenar muscles. Sensation to light touch is intact. How should she be evaluated and treated?
The Clinical Problem
Hand, finger, or wrist symptoms account for 2.7 million office visits to physicians for new problems per year in the United States.
1
The differential diagnosis of discomfort of the hand and wrist includes entrapments of the nerves (such . . .
Background: Silastic metacarpophalangeal arthroplasty (SMPA) has proven to be a durable option for end-stage arthritis in the non-thumb digits, while fusion has been the mainstay procedure for the ...thumb metacarpophalangeal joint (MP). Few studies exist to comment on the viability of thumb MP arthroplasty. This study reports both survival and objective outcomes following SMPA of the thumb. Methods: In an institutional review board-approved retrospective study, we identified 18 patients who underwent thumb SMPA at a tertiary academic center by 3 board-certified hand surgeons. Primary outcome measures were implant survival and post-operative complications. Secondary outcomes measures were quick Disabilities of the Arm, Shoulder, and Hand (quickDASH) scores, brief Michigan Hand Questionnaire (bMHQ), and postoperative pain as rated by the numerical rating scale. Results: Mean quickDASH and bMHQ scores at final follow-up were 35.6 and 70.6, respectively. The most common short-term complication was clinical deformity, followed by instability. The sole long-term complication was an implant dislocation in a previously asymptomatic patient. All patients reported reduction in pain. Three patients were indicated for revision surgery, 2 for persistent instability, and 1 for implant dislocation. Primary survivorship was 83% at mean follow-up of 5.8 years. Conclusions: Thumb SMPA is a viable option for end-stage arthritis. Pain relief in our series was unanimous. Among those that reported persistent symptoms or required revision, a majority had one or more key preoperative risk factors for failure as currently reported in literature. Larger, prospective series are needed to prove superior longevity and functional outcomes of thumb SMPA versus fusion.
Submarine canyons are conduits for episodic and powerful sediment density flows (commonly called turbidity currents) that move globally significant amounts of terrestrial sediment and organic carbon ...into the deep sea, forming some of the largest sedimentary deposits on Earth. The only record available for most turbidity currents is the deposit they leave behind. Therefore, to understand turbidity current processes, we need to determine the degree to which these flows are represented by their deposits. However, linking flows and deposits is a major long-standing scientific challenge. There are few detailed measurements from submarine turbidity currents in action, and even fewer direct measurements that can be compared to resulting seabed deposits. Recently, an extensive array of moorings along Monterey Canyon, offshore California, took measurements and samples during sediment density flow events, providing the most comprehensive dataset to date of turbidity current flows and their deposits. Here, we use sediment trap samples, velocity measurements, and seafloor cores to document how sand is transported through a submarine canyon, and how the transported sediment is represented in seafloor deposits. Sediment trap samples from events contain primarily fine to medium-grained sand with sharp bases, normal grading, and muddy tops. Sediment captured from the water column during the flow shows normal grading, which is broadly consistent with the initial peak and waning of flow velocities measured at a single height within the flow, and may be enhanced by collapsing flows. Flow events contain coarser sand concentrated toward the seafloor and larger grain sizes on the seafloor or in the dense near-bed layer, possibly representative of stratified flows. Although flow velocity varies, sand grain sizes in sediment traps are similar over distances of 50 km down-canyon, suggesting that grain size is an unfaithful record of down-canyon changes in maximum flow speeds. Sand transported within flow events and sampled in sediment traps is similar to sand sampled from the seafloor shortly after the events, but traps do not contain pebbles and gravel common in seabed deposits. Seabed deposits thus appear to faithfully record the sand component that is transported in the water column during sub-annual turbidity currents.
Aprospective, community-based, observational study of the outcome of surgical and nonoperative management was conducted. The study included 429 patients with carpal tunnel syndrome recruited in ...physicians' offices throughout Maine. Patients were assessed at baseline and at 6, 18, and 30 months following presentation using validated scales that measured symptom severity, functional status, and satisfaction. Seventy-seven percent of eligible survivors from the original cohort were monitored for 30 months. Surgically treated patients demonstrated improvements of 1.2 to 1.6 points on the 5-point Symptom Severity and Functional Status scale (23% to 45% improvement in scores), which persisted over the 30-month follow-up period. The nonoperatively managed patients showed little change in clinical status at 6, 18, and 30 months. While workers' compensation recipients had worse outcomes than nonrecipients, 36 of 68 (53%) workers' compensation recipients were completely or very satisfied with the results of the procedure 30 months after surgery. There were no significant differences in outcome between patients treated with endoscopic versus open carpal tunnel release. Among worker's compensation recipients, 12 of 68 (18%) surgical patients and 4 of 32 (13%) nonoperatively treated patients remained out of work because of carpal tunnel syndrome at 30 months. Thus, carpal tunnel surgery offered excellent symptom relief and functional improvement in this prospective community-based sample, irrespective of the surgical approach, even in workers' compensation recipients. Work absence remained high in both surgically and nonoperatively managed workers' compensation recipients.
In patients with rheumatoid arthritis (RA), it is unclear what determines satisfaction with metacarpophalangeal (MCP) joint replacement surgery. Previous studies have focused primarily on objective ...outcomes, such as range of motion (ROM) or strength, although some subjective measures have been examined. We investigate which outcomes most strongly correlate with patient satisfaction.
We assembled a retrospective cohort of 26 RA patients who received a total of 160 MCP silastic spacer implants. Patients answered a telephone survey, and 18/26 patients were examined. The strength of association between specific outcome variables and patient satisfaction with surgery was measured using Spearman correlations.
Patients had a mean age of 64.8 years and 77% were female. The mean time since surgery was 5.5 years. The strongest determinant of patient satisfaction was postoperative hand appearance (Spearman r > or = 0.60). Pain was also highly correlated with satisfaction with surgery (Spearman r > or = 0.46). Ability to perform activities of daily living and portions of the Jebsen Hand Function Test were moderately correlated with patient satisfaction. Most other measures of hand strength and ROM showed only minimal correlation with patients' overall satisfaction with surgery.
Overall satisfaction with silastic spacer surgery in this cohort of RA patients was most influenced by postoperative hand appearance and by pain. While objective measures of surgical outcomes are valuable reflections of technical success, they are not important determinants of patient satisfaction. The criteria used to assess MCP arthroplasty results should be revised to better capture the outcomes that appear to matter most to patients.
A novel series of selective negative allosteric modulators (NAMs) for metabotropic glutamate receptor 5 (mGlu5) was discovered from an isothiazole scaffold. One compound of this series, ...(1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide (24), demonstrated satisfactory pharmacokinetic properties and, following oral dosing in rats, produced dose-dependent and long-lasting mGlu5 receptor occupancy. Consistent with the hypothesis that blockade of mGlu5 receptors will produce analgesic effects in mammals, compound 24 produced a dose-dependent reduction in paw licking responses in the formalin model of persistent pain.
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