Systematic review: hand activity and ultrasound of the median nerve.

BACKGROUND: Ultrasound is an established method of viewing the median nerve in the carpal tunnel syndrome (CTS). There is some evidence to suggest that immediate changes may occur in the median nerve before and after hand activity. The evidence for the validity and reliability of ultrasound for testing acute changes in the median nerve has not been systematically reviewed to date. AIMS: To evaluate the evidence for visible change in ultrasound appearance of the median nerve after hand activity. METHODS: A literature search was designed, and three reviewers independently selected published research for inclusion. Two reviewers independently appraised papers using the Evidence Based Library and Information Practice (EBLIP) appraisal checklist, while the third reviewer resolved discrepancies between appraisals. RESULTS: Ten studies were appraised and the results showed an increase in median nerve cross-sectional area following activity, with a return to normal size within 1 h following activity. Both healthy individuals and those diagnosed with CTS participated, all were small convenience samples. Ultrasonographic measurements of the median nerve were reliable in the four studies reporting this, and the studies demonstrated high quality. CONCLUSIONS: Good-quality evidence as identified by the EBLIP appraisal checklist suggests that following hand activity, the median nerve changes in size in the carpal tunnel. The results may not be generalizable to all people and activities due to the use of small convenience sampling and narrow range of activities studied, in all of the studies appraised.

Cemented or cementless humeral fixation in reverse total shoulder arthroplasty? a systematic review.

AIMS: To date, there is insufficient evidence available to compare the outcome of cemented and uncemented fixation of the humeral stem in reverse shoulder arthroplasty (RSA). METHODS: A systemic review comprising 41 clinical studies was performed to compare the functional outcome and rate of complications of cemented and uncemented stems in RSA. These included 1455 cemented and 329 uncemented shoulders. The clinical characteristics of the two groups were similar. Variables were compared using pooled frequency-weighted means and relative risk ratios (RR). RESULTS: Uncemented stems had a significantly higher incidence of early humeral stem migration (p < 0.001, RR 18.1, 95% confidence interval (CI) 5.0 to 65.2) and non-progressive radiolucent lines (p < 0.001, RR 2.4, 95% CI 1.7 to 3.4), but a significantly lower incidence of post-operative fractures of the acromion compared with cemented stems (p = 0.004, RR 14.3, 95% CI 0.9 to 232.8). There was no difference in the risk of stem loosening or revision between the groups. The cemented stems had a greater relative risk of infection (RR 3.3, 95% CI 0.8 to 13.7), nerve injury (RR 5.7, 95% CI 0.7 to 41.5) and thromboembolism (RR 3.9, 95% CI 0.2 to 66.6). The functional outcome and range of movement were equivalent in the two groups. DISCUSSION: RSA performed with an uncemented stem gives them equivalent functional outcome and a better complication profile than with a cemented stem. The natural history and clinical relevance of early stem migration and radiolucent lines found with uncemented stems requires further long-term study. TAKE HOME MESSAGE: This study demonstrates that uncemented stems have at least equivalent clinical and radiographic outcomes compared with cemented stems when used for reverse total shoulder arthroplasty.

The functional range of motion of the finger joints.

The purpose of this study was to measure the functional range of motion of the finger joints needed to perform activities of daily living. Using the Sollerman hand grip function test, 20 activities were assessed in ten volunteers. The active and passive range of motion was measured with a computerized electric goniometer. The position of each finger joint was evaluated in the pre-grasp and grasp positions. The functional range of motion was defined as the range required to perform 90% of the activities, utilizing the pre-grasp and grasp measurements. The functional range of motion was 19°-71°, 23°-87°, and 10°-64° at the metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints, respectively. This represents 48%, 59%, and 60% of the active motion of these joints, respectively. There was a significant difference in the functional range of motion between the joints of the fingers, with the ulnar digits having greater active and functional range. The functional range of motion is important for directing indications for surgery and rehabilitation, and assessing outcome of treatment.

Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas.

BACKGROUND: Cytotoxic chemotherapy remains the main systemic therapy for gastro-oesophageal adenocarcinoma, but resistance to chemotherapy is common, resulting in ineffective and often toxic treatment for patients. Predictive biomarkers for chemotherapy response would increase the probability of successful therapy, but none are currently recommended for clinical use. We used global gene expression profiling of tumour biopsies to identify novel predictive biomarkers for cytotoxic chemotherapy. METHODS: Tumour biopsies from patients (n=14) with TNM stage IB-IV gastro-oesophageal adenocarcinomas receiving platinum-based combination chemotherapy were used as a discovery cohort and profiled with Affymetrix ST1.0 Exon Genechips. An independent cohort of patients (n=154) treated with surgery with or without neoadjuvant platinum combination chemotherapy and gastric adenocarcinoma cell lines (n=22) were used for qualification of gene expression profiling results by immunohistochemistry. A cisplatin-resistant gastric cancer cell line, AGS Cis5, and the oesophageal adenocarcinoma cell line, OE33, were used for in vitro validation investigations. RESULTS: We identified 520 genes with differential expression (Mann-Whitney U, P<0.020) between radiological responding and nonresponding patients. Gene enrichment analysis (DAVID v6.7) was used on this list of 520 genes to identify pathways associated with response and identified the adipocytokine signalling pathway, with higher leptin mRNA associated with lack of radiological response (P=0.011). Similarly, in the independent cohort (n=154), higher leptin protein expression by immunohistochemistry in the tumour cells was associated with lack of histopathological response (P=0.007). Higher leptin protein expression by immunohistochemistry was also associated with improved survival in the absence of neoadjuvant chemotherapy, and patients with low leptin protein-expressing tumours had improved survival when treated by neoadjuvant chemotherapy (P for interaction=0.038). In the gastric adenocarcinoma cell lines, higher leptin protein expression was associated with resistance to cisplatin (P=0.008), but not to oxaliplatin (P=0.988) or 5fluorouracil (P=0.636). The leptin receptor antagonist SHLA increased the sensitivity of AGS Cis5 and OE33 cell lines to cisplatin. CONCLUSIONS: In gastro-oesophageal adenocarcinomas, tumour leptin expression is associated with chemoresistance but a better therapy-independent prognosis. Tumour leptin expression determined by immunohistochemistry has potential utility as a predictive marker of resistance to cytotoxic chemotherapy, and a prognostic marker independent of therapy in gastro-oesophageal adenocarcinoma. Leptin antagonists have been developed for clinical use and leptin and its associated pathways may also provide much needed novel therapeutic targets for gastro-oesophageal adenocarcinoma.

The radiological spectrum of pulmonary lymphoproliferative disease.

Pulmonary lymphoproliferative disorders (LPD) are characterised by abnormal proliferation of indigenous cell lines or infiltration of lung parenchyma by lymphoid cells. They encompass a wide spectrum of focal or diffuse abnormalities, which may be classified as reactive or neoplastic on the basis of cellular morphology and clonality. The spectrum of reactive disorders results primarily from antigenic stimulation of bronchial mucosa-associated lymphoid tissue (MALT) and comprises three main entities: follicular bronchiolitis, lymphoid interstitial pneumonia and (more rarely) nodular lymphoid hyperplasia. Primary parenchymal neoplasms are most commonly extranodal marginal zone lymphomas of MALT origin (MALT lymphomas), followed by diffuse large B-cell lymphomas (DLBCLs) and lymphomatoid granulomatosis (LYG). Secondary lymphomatous parenchymal neoplasms (both Hodgkin and non-Hodgkin lymphomas) are far more prevalent than primary neoplasms. Acquired immune deficiency syndrome (AIDS)-related lymphoma (ARL) and post-transplantation lymphoproliferative disorder (PTLD) may also primarily affect the lung parenchyma. Modern advances in treatments for AIDS and transplant medicine are associated with an increase in the incidence of LPD and have heightened the need to understand the range of imaging appearance of these diseases. The multidetector CT (MDCT) findings of LPD are heterogeneous, thereby reflecting the wide spectrum of clinical manifestations of these entities. Understanding the spectrum of LPD and the various imaging manifestations is crucial because the radiologist is often the first one to suggest the diagnosis and has a pivotal role in differentiating these diseases. The current concepts of LPD are discussed together with a demonstration of the breadth of MDCT patterns within this disease spectrum.

Pharmacodynamics, pharmacokinetics, and safety of AM211: a novel and potent antagonist of the prostaglandin D2 receptor type 2.

The prostaglandin D(2) receptor type 2 (DP2) and its ligand, PGD(2), have been implicated in the development of asthma and other inflammatory diseases. The authors evaluated the pharmacodynamics, pharmacokinetics and safety of [2'-(3-benzyl-1-ethyl-ureidomethyl)-6-methoxy-4'-trifluoromethyl-biphenyl-3-yl]-acetic acid sodium salt (AM211), a novel and potent DP2 antagonist, in healthy participants. Single and multiple doses of AM211 demonstrated dose-dependent inhibition of eosinophil shape change in blood with near-complete inhibition observed at trough after dosing 200 mg once daily for 7 days. Maximum plasma concentrations and exposures of AM211 increased in a greater-than-dose-proportional manner after single and multiple dosing. After multiple dosing, the exposures on day 7 were higher than on day 1 with accumulation ratio values ranging from 1.4 to 1.5. Mean terminal half-life values ranged from 14 to 25 hours across the dose range of 100 to 600 mg. AM211 was well tolerated at all doses in both the single- and multiple-dose cohorts. These data support additional clinical studies to evaluate AM211 in asthma and other inflammatory diseases.

Pharmacokinetic and pharmacodynamic characterization of an oral lysophosphatidic acid type 1 receptor-selective antagonist.

Lysophosphatidic acid (LPA) is a bioactive phospholipid that signals through a family of at least six G protein-coupled receptors designated LPA1₋6. LPA type 1 receptor (LPA1) exhibits widespread tissue distribution and regulates a variety of physiological and pathological cellular functions. Here, we evaluated the in vitro pharmacology, pharmacokinetic, and pharmacodynamic properties of the LPA1-selective antagonist AM095 (sodium, {4'-[3-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-acetate) and assessed the effects of AM095 in rodent models of lung and kidney fibrosis and dermal wound healing. In vitro, AM095 was a potent LPA1 receptor antagonist because it inhibited GTPγS binding to Chinese hamster ovary (CHO) cell membranes overexpressing recombinant human or mouse LPA1 with IC50 values of 0.98 and 0.73 µM, respectively, and exhibited no LPA1 agonism. In functional assays, AM095 inhibited LPA-driven chemotaxis of CHO cells overexpressing mouse LPA1 (IC50= 778 nM) and human A2058 melanoma cells (IC50 = 233 nM). In vivo, we demonstrated that AM095: 1) had high oral bioavailability and a moderate half-life and was well tolerated at the doses tested in rats and dogs after oral and intravenous dosing, 2) dose-dependently reduced LPA-stimulated histamine release, 3) attenuated bleomycin-induced increases in collagen, protein, and inflammatory cell infiltration in bronchalveolar lavage fluid, and 4) decreased kidney fibrosis in a mouse unilateral ureteral obstruction model. Despite its antifibrotic activity, AM095 had no effect on normal wound healing after incisional and excisional wounding in rats. These data demonstrate that AM095 is an LPA1 receptor antagonist with good oral exposure and antifibrotic activity in rodent models.

Pharmacodynamics and pharmacokinetics of AM103, a novel inhibitor of 5-lipoxygenase-activating protein (FLAP).

The 5-lipoxygenase-activating protein (FLAP) gene and an increase in leukotriene (LT) production are linked to the risk of asthma, myocardial infarction, and stroke. We evaluated the pharmacodynamics, pharmacokinetics, and tolerability of 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (AM103), a novel FLAP inhibitor, in healthy subjects. Single and multiple doses of AM103 demonstrated dose-dependent inhibition of blood LTB(4) production and dose-related inhibition of urinary LTE(4). After a single oral dose (50-1,000 mg) of AM103, the maximum concentration (C(max)) and area under the curve (AUC) in plasma increased in a dose-dependent manner. After multiple-dose administration (50-1,000 mg once daily for 11 days), there were no significant differences in the pharmacokinetic parameters between the first and last days of treatment. AM103 was well tolerated at all doses in both the single- and multiple-dose cohorts. Further clinical trials with AM103 in inflammatory diseases are warranted.

An association between lunate morphology and scaphoid-trapezium-trapezoid arthritis.

The purpose of this study was to determine if an association exists between scaphoid-trapezium-trapezoid arthritis and lunate morphology. Plain neutral posteroanterior radiographs were evaluated for 48 patients with STT arthritis and 96 patients from a control group. Lunate type was determined using capitate-triquetrum (C-T) distance. A type I lunate was defined as a C-T distance < or =2 mm. A type II lunate was defined as a C-T distance > or =4 mm. Lunate type was recorded and compared between those with STT arthritis and a control group. The groups were similar with regard to age, gender and handedness. Type II lunates were found in 83% of cases with STT arthritis and in 64% of controls. STT OA was associated with type II lunate wrists (P = 0.02; OR = 0.35; CI: 0.15-0.82). We postulate that variations in scaphoid motion secondary to lunate morphology may contribute to the development of STT OA.

Effect of scaphoid and triquetrum excision after limited stabilisation on cadaver wrist movement.

This study assessed the effect of excision of the scaphoid and triquetrum on the range of motion of the embalmed cadaver wrist joint after midcarpal stabilisation. The range of motion was measured in 12 cadaver wrists before and after stabilisation of the joints between the lunate, capitate, triquetrum and hamate. This was measured again following resection of the scaphoid and then the triquetrum. Scaphoid excision after four-corner stabilisation increased the radioulnar (RU) arc by 12 degrees and the flexion-extension (F-E) arc by 10 degrees. Subsequent excision of the triquetrum, to produce a three-corner stabilisation, further increased the RU arc by 7 degrees and the F-E arc by 6 degrees. Three-corner stabilisation with excision of scaphoid and triquetrum improved wrist motion in embalmed cadavers.

A history of carpal tunnel syndrome.

Carpal tunnel syndrome is the commonest entrapment neuropathy seen in clinical practice. The history of its aetiology and diagnosis gives an interesting insight into how the condition has evolved to also become the best understood neuropathy.

Clinical Results of Coracoacromial Ligament Transfer in Acromioclavicular Dislocations: a Review of Published Literature

Acromioclavicular joint dislocations are common injuries; which typically occur with trauma in young men. Treatment recommendations for these injuries are highly variable and controversial. There are greater than 100 surgical techniques described for operative treatment of this injury. One of the most widely recommended methods of surgical recons- truction for acromioclavicular joint dislocations is to utilize the coracoacromial ligament for stabilization of the distal clavicle. Several modifications of this procedure have been described which have involved adjunct coracoclavicular fixation or fixation across acromioclavicular joint. Although the literature is replete with descriptive papers; there is paucity of studies evaluating the surgical outcome of this procedure. We systematically reviewed the eng language published literature in peer reviewed journals (Medline; EMBASE; SCOPUS) and assigned a level of evidence for available studies. We critically reviewed each paper for the flaws and biases and then evaluated the comparable clinical outcomes for various procedures and their modifications. The published literature consists entirely of case series (Level IV evidence) with variability in surgical technique and outcome measures. On review there is low level evidence to support the use of coracoacromial ligament for acromioclavicular dislocation but it has been associated with high rate of deformity recurrence. Adjunct fixation does not improve clinical results when compared to isolated coracoacromial ligament transfer. This is in part because of the high incidence of fixation related complications. Similar results are reported with coracoacromial ligament reconstruction for acute and chronic cases. The development of secon- dary acromioclavicular joint symptoms with distal clavicle retention is poorly reported with the incidence rate varying from 12to 32. Despite this; the retention or excision of distal clavicle did not affect overall clinical results except in the patients with pre existing acromioclavicular joint osteoarthritis who have inferior results with retention of distal end of clavicle. Further well designed clinical trials with validated outcome measures are required to fully evaluate the clinical results of this procedure

Distal biceps tendon anatomy: a cadaveric study.

BACKGROUND: The anatomy of the distal biceps tendon and aponeurosis has not been studied in detail. METHODS: Seventeen cadaver elbows were dissected with loupe magnification to identify the details of the distal biceps tendon and the lacertus fibrosus. RESULTS: In ten of the seventeen specimens, the distal biceps tendon was in two distinct parts, each a continuation of the long and short heads of the muscle. The remaining seven specimens showed interdigitation of the muscle distally. The tendon continued from each muscle belly. The short head inserted distal to the radial tuberosity and was positioned to be a more powerful flexor of the elbow, while the tendon of the long head inserted on the tuberosity further from the axis of rotation of the forearm and was positioned to be a stronger supinator. The bicipital aponeurosis consisted of three layers and completely encircled the ulnar forearm flexor muscles. The aponeurosis may be important in stabilizing the tendons distally. CONCLUSIONS: The double tendon insertion may allow an element of independent function of each portion of the biceps, and, during repair of an avulsion, the surgeon should ensure correct orientation of both tendon components.

Management of Mason type-III radial head fractures with a titanium prosthesis, ligament repair, and early mobilization. Surgical technique.

BACKGROUND: Radial head fractures often occur in association with other elbow fractures and soft-tissue injuries. Radial head replacement is indicated for irreparable radial head fractures associated with elbow instability. The purpose of this study was to analyze the results after treatment of such injuries with a titanium radial head prosthesis, repair of torn collateral ligaments, and early mobilization of the elbow. MATERIALS: Sixteen patients with sixteen Mason type-III radial head fractures and collateral ligament injury were treated with use of a titanium radial head prosthesis over a five-year period at the Royal Adelaide Hospital and Modbury Public Hospital in South Australia. The surgery was performed acutely in ten patients and was delayed an average of thirty-seven days (range, fifteen to seventy-nine days) in six. All patients were followed clinically and radiographically for a mean of 2.8 years (range, 1.2 to 4.3 years). RESULTS: Eight patients had an excellent result; five, a good result; and three, a fair result, according to the Mayo Elbow Performance Score. The three fair results occurred in patients with delayed surgery. The mean flexion contracture was 15 degrees (range, 0 degrees to 42 degrees ), with an average loss of 10 degrees (range, 0 degrees to 25 degrees ) of full flexion compared with that of the contralateral elbow. Both pronation and supination decreased an average of 12 degrees (range, 0 degrees to 45 degrees ) compared with that of the contralateral forearm. CONCLUSIONS: The results of treatment of Mason type-III radial head fractures with a monoblock titanium radial head prosthesis and soft-tissue reconstruction are satisfactory. Early mobilization of the elbow is important for the restoration of elbow range of motion and function.

HRCT diagnosis of diffuse parenchymal lung disease: inter-observer variation.

BACKGROUND: This study was designed to measure inter-observer variation between thoracic radiologists in the diagnosis of diffuse parenchymal lung disease (DPLD) using high resolution computed tomography (HRCT) and to identify areas of difficulty where expertise, in the form of national panels, would be of particular value. METHODS: HRCT images of 131 patients with DPLD (from a tertiary referral hospital (n = 66) and regional teaching centres (n = 65)) were reviewed by 11 thoracic radiologists. Inter-observer variation for the first choice diagnosis was quantified using the unadjusted kappa coefficient of agreement. Observers stated differential diagnoses and assigned a percentage likelihood to each. A weighted kappa was calculated for the likelihood of each of the six most frequently diagnosed disease entities. RESULTS: Observer agreement on the first choice diagnosis was moderate for the entire cohort (kappa = 0.48) and was higher for cases from regional centres (kappa = 0.60) than for cases from the tertiary referral centre (kappa = 0.34). 62% of cases from regional teaching centres were diagnosed with high confidence and good observer agreement (kappa = 0.77). Non-specific interstitial pneumonia (NSIP) was in the differential diagnosis in most disagreements (55%). Weighted kappa values quantifying the likelihood of specific diseases were moderate to good (mean 0.57, range 0.49-0.70). CONCLUSION: There is good agreement between thoracic radiologists for the HRCT diagnosis of DPLD encountered in regional teaching centres. However, cases diagnosed with low confidence, particularly where NSIP is considered as a differential diagnosis, may benefit from the expertise of a reference panel.

Early thymocyte development is regulated by modulation of E2A protein activity.

The E2A gene encodes the E47 and E12 basic helix-loop-helix (bHLH) transcription factors. T cell development in E2A-deficient mice is partially arrested before lineage commitment. Here we demonstrate that E47 expression becomes uniformly high at the point at which thymocytes begin to commit towards the T cell lineage. E47 protein levels remain high until the double positive developmental stage, at which point they drop to relatively moderate levels, and are further downregulated upon transition to the single positive stage. However, stimuli that mimic pre-T cell receptor (TCR) signaling in committed T cell precursors inhibit E47 DNA-binding activity and induce the bHLH inhibitor Id3 through a mitogen-activated protein kinase kinase-dependent pathway. Consistent with these observations, a deficiency in E2A proteins completely abrogates the developmental block observed in mice with defects in TCR rearrangement. Thus E2A proteins are necessary for both initiating T cell differentiation and inhibiting development in the absence of pre-TCR expression. Mechanistically, these data link pre-TCR mediated signaling and E2A downstream target genes into a common pathway.

The effect of a standard activity on the size of the median nerve as determined by ultrasound visualization.

The purpose of this study was to determine whether a standardized hand activity would produce changes in the cross-sectional diameter of the median nerve. Ultrasound measures of proven reliability of the cross-sectional diameter of the median nerve in the wrist were taken. These measures were taken before activity and immediately after the activity, after 5 minutes, and after 10 minutes. The median nerves of 40 normal subjects showed an increase in cross-sectional diameter immediately after hand activity then returned to a size close to the preactivity size within 10 minutes. The cross-sectional area of the carpal canal did not change significantly after the hand activity was performed. Female gender and body mass index over 25 were associated with significantly larger size increases in the median nerve. This preliminary study suggests that ultrasound is sensitive to the effects of activity upon the hand.