Evaluation of a lateral-flow nanoparticle fluorescence assay for TB infection diagnosis.

BACKGROUND: Programmatic management of TB infection is a critical component of the WHO End TB Strategy. Interferon-gamma release assays (IGRAs) overcome some limitations of the tuberculin skin test, but implementation of IGRA testing in low-resource settings is challenging.METHODS: In this feasibility study, we evaluated performance of a novel digital lateral-flow assay, the QIAreach® QuantiFERON® TB (QIAreach-QFT) test, against the QuantiFERON®-TB Gold Plus (QFT-Plus) assay. A population with a mix of risk factors for TB infection (111 donors) were sampled over multiple days. A total of 207 individual blood samples were tested according to the manufacturer´s instructions.RESULTS: The overall percentage agreement was 95.6% (two-sided 95% CI 91.8-98), with a positive percentage agreement (i.e., sensitivity) of 100% (95% CI 94.7-100) and a negative percentage agreement (i.e., specificity) of 95.6% (95% CI 90.6-98.4). All QFT-Plus positive specimens with TB1-Nil and TB2-Nil values less than 1 IU/ml tested positive on QIAreach-QFT.CONCLUSIONS: QIAreach QFT is a deployable, accurate testing solution for decentralised testing. It has the potential to overcome key hurdles for TB infection screening in high-burden settings thus helping to achieve the WHO End TB programme goals.

A new clinical presentation: breast implant pneumocapsule and pneumothorax following penetrating chest wall trauma.

Pneumothorax resulting from traumatic thoracic injury is a potentially life-threatening emergency requiring prompt recognition and management with an intercostal drain. A 34-year-old woman was brought into the emergency department after sustaining a stab injury to the right upper outer quadrant of the right breast. She described noticing a jelly-like substance from her wound, on the background of a prior cosmetic breast augmentation. On examination, it was noted that the right breast was significantly swollen. Computed tomography demonstrated a large right sided pneumothorax with associated punctured right breast implant, a 'pneumocapsule' and extensive subcutaneous emphysema of the breast. This case highlights that the fibrous tissue capsule around a breast implant can function as an anatomical space in continuity with the thoracic cavity, masking the diagnosis of pneumothorax in penetrating trauma.

Management of painful scar-tethered cutaneous nerves of the upper limb.

We report the results of treatment by division and proximal relocation of 44 painful, scar-tethered cutaneous nerves of the upper limb in 22 patients. In all patients, neuropathic pain had developed either following surgery or trauma, but without apparent direct nerve injury. The mean duration of pain symptoms prior to relocation was 17 (range 7-44) months. Adequate treatment involved relocation of 35 nerves at a first operation for each of the 22 patients, with six patients requiring further surgery to relocate 9 nerves. At a minimum follow-up of 6 months, nerve relocation resulted in complete resolution of all forms of pain at the primary site in 21/22 (95%) patients and no pain or hypersensitivity at the final relocation site in 19 of the 22 patients (86%).

Long term functional results from major limb replantations.

Replantation is now firmly established as a viable treatment option in traumatic limb amputation, yet there are few long-term studies describing the functional outcome of these cases. The purpose of the present study was to evaluate long-term results in a population of such patients to determine overall success and patient satisfaction. Since 1981, twenty macro-replants involving nineteen patients have been performed in our unit. All patients were reviewed by means of case note analysis, patient questionnaire, and follow-up clinical evaluation for functional outcome using the Tamai scoring system. Acute limb salvage was successful in 18/20 (90%) cases. One patient is still undergoing secondary reconstructive surgery and was unable to be assessed for final outcome leaving 17 replanted limbs that underwent full functional assessment. Overall functional results were good in 7/17 (41%) limbs, fair in 7/17 (41%) and poor in 3/17 (18%). The majority of patients (12/17) claimed to be highly or well satisfied with their outcome and eleven have returned to work since their injury. The current study of major limb replantation demonstrates favorable or acceptable long term functional outcomes in the majority of cases. High patient satisfaction rates even where results were poor emphasise the positive psychological impact of successful replantation.

Extensor indicis proprius opponensplasty - the burkhalter revisited.

The Extensor Indicis Proprius Opponensplasty although not widely exercised by hand surgeons has previously been shown to produce good results in the restoration of thumb opposition. Over the last 5 years the Extensor Indicis Proprius was selectively used in cases where the Flexor Digitorum Superficialis was unavailable or inappropriate. In a small case series operating on a total of six male patients with an average age of 32 and follow up of 12 months we have been impressed by the functional outcome and lack of donor site morbidity. The Extensor Indicis Proprius is expendable with minimal donor site morbidity, is of sufficient length and has an optimal line of pull to provide a superior mechanical advantage and a favourable torque when compared to Flexor Digitorum Superficialis.

Paediatric ride-on mower related injuries and plastic surgical management.

Lawnmower related injuries cause significant morbidity in children and young teenagers. The 'ride-on' mowers which are more powerful than the 'walk behind' mowers are becoming increasingly popular. The incidence and severity of injuries from either type of lawnmower appears to be steadily rising as is the burden placed on local plastic surgical and emergency services in managing the care of these patients. The aims of the study were to demonstrate changing trends in lawnmower-related injuries to children presenting to a single unit over a ten-year period and to identify any association between injury severity and machine subtype ('ride-on' versus 'walk-behind'). Hospital databases, theatre records and medical case notes were reviewed retrospectively of all patients under the age of 16 treated for lawnmower related injuries over a 10 year period from July 1998 to June 2008. Data gathered included patient demographics, injury site and severity, management (type and number of surgical procedures), length of hospital stay and outcome. Injury severity score was also calculated for each case. Controlling for estimated regional population changes, there was a significant increase in the number of ride-on mower related accidents in the time period 2003-2008, compared to the time period 1998-2003. Ride-on injuries had significantly higher injury severity scores, longer hospital stays and were more likely to involve amputations as compared with walk-behind injuries. Children can sustain significant injuries with unsafe lawnmower use. The current study demonstrates the increasing incidence of ride-on mower related injuries in children and identifies a greater morbidity associated with such injuries. Such presentations place intense demands on local plastic surgical services.

Botulinum toxin for treatment of glandular hypersecretory disorders.

SUMMARY: The use of botulinum toxin to treat disorders of the salivary glands is increasing in popularity in recent years. Recent reports of the use of botulinum toxin in glandular hypersecretion suggest overall favourable results with minimal side-effects. However, few randomised clinical trials means that data are limited with respect to candidate suitability, treatment dosages, frequency and duration of treatment. We report a selection of such cases from our own department managed with botulinum toxin and review the current data on use of the toxin to treat salivary gland disorders such as Frey's syndrome, excessive salivation (sialorrhoea), focal and general hyperhidrosis, excessive lacrimation and chronic rhinitis.

The role of endothelial dysfunction in the pathogenesis of impaired diabetic wound healing: a novel therapeutic target?

The global burden of diabetes is attributed to its multiple associated complications including impaired wound healing which can ultimately result in amputation. Peripheral vascular disease, infection, neuropathy and abnormal local cellular and cytokine activity are some of the traditionally cited pathological instigators of defective diabetic wound repair. Despite intensive research and subsequent advances in diabetic wound care technology a single treatment with measurable clinical impact has yet to be determined. The phenomenon of endothelial dysfunction as seen in atherosclerosis and recently identified as a characteristic of diabetic vasculature may contribute to impaired cutaneous healing in this group. Indicators of endothelial dysfunction have been demonstrated in diabetic wounds by a number of investigators. Successful results are being obtained with modifiers of endothelial function in the management of cardiovascular disease. We hypothesise that endothelial dysfunction plays a substantial contributory role in the pathogenesis of wound healing impairment of diabetes and holds potential as a target for therapeutic intervention.

Potential risk factors for undifferentiated connective tissue disease among women: implanted medical devices.

A case-control study was conducted among 205 women in Michigan and Ohio who were diagnosed with undifferentiated connective tissue disease (UCTD) to investigate the significance of self-reported past exposures to implanted silicone-containing or non-silicone-containing medical devices. The 205 UCTD cases were compared with 2,095 controls who were sampled by random digit dialing. When silicone-containing devices, including shunts and catheters, were analyzed collectively, a significant association was observed (odds ratio (OR) = 2.81, 95% confidence interval (CI): 1.34, 5.89). The odds ratio for exposure to breast implants was increased, but not significantly (OR = 2.22, 95% CI: 0.65, 7.57). Among the non-silicone-containing devices, artificial joints (OR = 5.01, 95% CI: 1.60, 15.71) and orthopedic metallic fixation devices (OR = 1.95, 95% CI: 1.05, 3.60) were associated with UCTD. The estimations of risk associated with implanted medical devices in UCTD cases were explored in a comparison with 660 scleroderma patients who were ascertained concurrently in Michigan and Ohio. In general, the associations that were observed with non-silicone-containing devices, and more specifically with the fixation devices, persisted in the comparison of UCTD cases with scleroderma patients. The studies conducted among populations in Michigan and Ohio are intended to stimulate new hypotheses, innovative approaches, and the fostering of understanding of the environmental determinants of autoimmune disease.

137Cs distribution and geochemistry of Lena River (Siberia) drainage basin lake sediments.

The Lena River is the second largest river that discharges into the Arctic Ocean. It is therefore important to determine not only the direct impact its discharge has on the 137Cs concentration of the Arctic, but also the potential its drainage basin has as a 137Cs source. 137Cs surface sediment concentrations and inventory values, which range from 4.97 to 338 Bq kg(-1) and 357 to 1732 Bq m(-2), respectively, were determined for the Lena River drainage basin lake samples, via gamma analysis. The average geochemical and mineralogical composition of a subset of samples was also determined using neutron activation analysis, X-ray diffraction and X-ray fluorescence spectrometry techniques. Results of these geochemical analyses allowed for the identification of key geochemical factors that influence the distribution of 137Cs in the Lena River drainage basin. 137Cs profiles indicate that Lena River drainage basin lacustrine sediments serve as a record of 137Cs fallout. Based on the downcore 137Cs, %illite, %smectite, %Al and %Mn distribution patterns, it was concluded that a small fraction of non-selectively bound 137Cs was remobilized at depth in some cores. Inconsistencies between the actual 137Cs fallout record and the 137Cs profiles determined for the lake sediments were attributed to 137Cs remobilization in subsurface sediments. In addition to establishing the agreement between the global atmospheric fallout record and the downcore 137Cs distribution patterns determined for these sediments, results indicate that 137Cs deposited during periods of maximum atmospheric release was buried and is not susceptible to surface erosion processes. However, mean 137Cs concentrations of the lacustrine surface sediments (125 Bq kg(-1)) are still significantly higher than those of the nearby Lena River estuary (11.22 Bq kg(-1)) and Laptev Sea (6.00 Bq kg(-1)). Our study suggests that the Lena River drainage basin has the potential to serve as a source of 137Cs to the adjacent Arctic Ocean.

Petroleum distillate solvents as risk factors for undifferentiated connective tissue disease (UCTD).

Occupational solvent exposure may increase the risk of connective tissue disease (CTD). The objective of this case-control study was to investigate the relation between undifferentiated connective tissue disease (UCTD) and solvent exposure in Michigan and Ohio. Women were considered to have UCTD if they did not meet the American College of Rheumatology classification criteria for any CTD but had at least two documented signs, symptoms, or laboratory abnormalities suggestive of a CTD. Detailed information on solvent exposure was ascertained from 205 cases, diagnosed between 1980 and 1992, and 2,095 population-based controls. Age-adjusted odds ratios (OR) and 95 percent confidence intervals (CI) were calculated for all exposures. Among 16 self-reported occupational activities with potential solvent exposure, furniture refinishing (OR = 9.73, 95 percent CI 1.48-63.90), perfume, cosmetic, or drug manufacturing (OR = 7.71, 95 percent CI 2.24-26.56), rubber product manufacturing (OR = 4.70, 95 percent CI 1.75-12.61), work in a medical diagnostic or pathology laboratory (OR = 4.52, 95 percent CI 2.27-8.97), and painting or paint manufacturing (OR = 2.87, 95 percent CI 1.06-7.76) were significantly associated with UCTD. After expert review of self-reported exposure to ten specific solvents, paint thinners or removers (OR = 2.73, 95 percent CI 1.80-4.16) and mineral spirits (OR = 1.81, 95 percent CI 1.09-3.02) were associated with UCTD. These results suggest that exposure to petroleum distillates increases the risk of developing UCTD.

Gelatinase-A (MMP-2), gelatinase-B (MMP-9) and membrane type matrix metalloproteinase-1 (MT1-MMP) are involved in different aspects of the pathophysiology of malignant gliomas.

Matrix metalloproteinases (MMPs) have been implicated as important factors in gliomas since they may both facilitate invasion into the surrounding brain and participate in neovascularization. We have tested the hypothesis that deregulated expression of gelatinase-A or B, or an activator of gelatinase-A, MT1-MMP, may contribute directly to human gliomas by quantifying the expression of these MMPs in 46 brain tumour specimens and seven control tissues. Quantitative RT-PCR and gelatin zymography showed that gelatinase-A in glioma specimens was higher than in normal tissue; these were significantly elevated in low grade gliomas and remained elevated in GBMs. Gelatinase-B transcript and activity levels were also higher than in normal brain and more strongly correlated with tumour grade. We did not see a close relationship between the levels of expression of MT1-MMP mRNA and amounts of activated gelatinase-A. In situ hybridization localized gelatinase-A and MT1-MMP transcripts to normal neuronal and glia, malignant glioma cells and blood vessels. In contrast, gelatinase-B showed a more restricted pattern of expression; it was strongly expressed in blood vessels at proliferating margins, as well as tumour cells in some cases. These data suggest that gelatinase-A, -B and MT1-MMP are important in the pathophysiology of human gliomas. The primary role of gelatinase-B may lie in remodelling associated with neovascularization, whereas gelatinase-A and MT1-MMP may be involved in both glial invasion and angiogenesis.

High levels of gelatinase-B and active gelatinase-A in metastatic glioblastoma.

PURPOSE: Extra-neural metastases from glioblastoma multiforme (GBM) are rare. Because gelatinases-A and -B have been implicated in tumor invasion/metastasis in non-neural tumors, we compared the expression of gelatinase-A and -B in 2 patients (both had a prior craniotomy performed) with extraneural metastases from GBM to expression levels in 24 other gliomas; 15 non-metastatic GBMs, 9 other lower grade gliomas, and 7 normal brain tissues. METHODS: The intracerebral tumor from both patients, patient # 1's extraneural metastases, 24 other gliomas, 1 sample of reactive astrocytes and 7 normal brain tissues were studied using gelatin zymography. The active form of gelatinases was confirmed by co-migration after activation with APMA. RESULTS: Expression of the latent form of gelatinase-A correlated with glioma grade (r = 0.486; p = 0.0053). Active gelatinase-A was found only in the 2 GBMs with extraneural metastases and patient # 1's cervical metastases. In contrast, latent gelatinase-B levels correlated more strongly with histologic grade (r = 0.577; p = 0.0009) (higher levels with higher grades). Very high levels of gelatinase-B were seen in both GBMs with extraneural metastases, a cervical extraneural metastases, and 2 GBMs without metastases. CONCLUSIONS: We observed that gelatinases-A and -B are present in most gliomas but we found active gelatinase-A only in the GBMs with extraneural metastases suggesting that the active form of this enzyme may determine the metastatic potential of GBMs. We propose that high levels of gelatinolytic activities are associated with intracerebral invasion and rarely, metastases of GBMs.

Molecular lysis of synovial lining cells by in vivo herpes simplex virus-thymidine kinase gene transfer.

Herpes simples virus thymidine kinase (HSV-TK) expression plasmid DNA was injected into the joint space of rabbits with antigen-induced arthritis (AIA). Purified plasmid DNA was able to mediate transfection of synovial lining cells and transient overexpression of HSV-TK in the context of active synovial inflammation. The pharmacodynamic distribution of intraarticular expression plasmid DNA was confined to the joint space. Arthritic rabbits treated with intraarticular expression plasmid DNA followed by intravenous ganciclovir (GCV, 5 mg/kg) twice daily for 3 days showed histologic evidence of synovial lining layer cytolysis when articular tissues were examined 21 days posttreatment. There was also a reduction in joint swelling in the TK-treated knees. No untoward clinical effects were observed in the rabbits and no evidence of cytolytic damage specific to the TK-GCV gene therapy was observed either in the articular cartilage or bone. The application of TK-GCV intraarticular gene therapy using purified expression plasmid DNA for the induction of synovial cytolysis may be applicable to the treatment of human inflammatory arthritis.

Racial differences in scleroderma among women in Michigan.

OBJECTIVE: To examine racial differences in disease onset, extent, manifestations, and survival among women with scleroderma. METHODS: A retrospective cohort study of women with scleroderma, diagnosed in Michigan between 1980 and 1991, was conducted. Clinical, laboratory, and demographic data were abstracted from the patients' medical records. RESULTS: A total of 514 women with scleroderma were identified: 117 (23%) were black and 397 (77%) were white. Among black women, the mean age at diagnosis was lower (44.5 years versus 51.5 years; P < 0.001) and diffuse disease was more common (49.6% versus 24.9%; P < 0.001) than among white women. The overall incidence of scleroderma was 14.1 per million per year: 22.5 per million per year in black women versus 12.8 per million per year in white women (P < 0.001). Pericarditis (P = 0.009), pulmonary hypertension (P < 0.001), pleural effusions (P = 0.01), myositis (P = 0.02), and an erythrocyte sedimentation rate >40 mm/hour (P < 0.001) were more frequent among black women, while white women were more likely to have digital infarctions (P < 0.001). Survival at 7 years from diagnosis was 72.5% among black women and 77.6% among white women. Age-adjusted survival was significantly reduced among black women (P = 0.033), most likely because of increased diffuse involvement. Survival among those with renal or pulmonary involvement was also significantly reduced. CONCLUSION: Black women with scleroderma were significantly more likely than white women to develop diffuse disease, be diagnosed at a younger age, have a higher incidence of inflammatory features, and have a worse age-adjusted survival rate.

Ultrasonic characterization of in vitro osteoarthritic articular cartilage with validation by confocal microscopy.

The majority of adults over the age of 65 y develop osteoarthritis (OA), a joint disease characterized by degeneration of articular cartilage and subchondral sclerosis. Early in the disease, the articular cartilage surface begins to change histologically from a smooth to a rough or fibrillated appearance. A prerequisite for any chondroprotective pharmacological intervention is detection of OA in its preclinical phase. Current diagnostic imaging modalities, such as radiographs or (nuclear) magnetic resonance imaging, either cannot directly image the cartilage surface or lack sufficient resolution to detect surface fibrillations. We have developed an ultrasonic technique that can be used to characterize these surface fibrillations directly. We present our in vitro results with validation by laser-based confocal microscopic imaging.

The epidemiology of scleroderma among women: assessment of risk from exposure to silicone and silica.

OBJECTIVE: To investigate the relationship between exposure to silicone (including breast implants) and silica and the development of scleroderma (systemic sclerosis, SSc) among women. METHODS: A population based case-control study was conducted among women in Michigan. 274 confirmed cases of SSc diagnosed between 1985 and 1991 were identified by contacting rheumatologists, hospitals, and a scleroderma support group. These cases and 1184 controls were interviewed by telephone to ascertain past exposures to silicone or silica. RESULTS: Silicone in the form of breast implants was not associated with significantly increased risk of SSc (adjusted odds ratio, 1.30; 95% confidence interval, 0.27 to 6.23). Among 20 other potential silicone exposure surveyed, self-reported exposure to silicone based glues, sealants, and caulks, manufacture or repair of windows or windshields, repairing or frequently using photocopy machines, consumption of simethicone-containing antacids, and implanted medication delivery pumps were significantly associated with SSc. However, blinded assessment of all job and hobby descriptions in terms of their potential for silicone exposure failed to support the first 3 associations, antacid consumption may have been confounded by esophageal dysmotility before the diagnosis of SSc, and other silicone containing device categories (pacemakers, central nervous system shunts, other shunts and catheters) were not significantly associated with SSc. Surgically implanted metallic fixation devices were associated with significantly reduced risk for SSc. No association was detected between SSc and silica dust exposure. CONCLUSION: Consistent with other studies, we found no increased risk of SSc among women with silicone breast implants, equivocal evidence of risk from other silicone exposures, and no evidence of risk from silica exposure.

The use of trained patient educators with rheumatoid arthritis to teach medical students.

OBJECTIVE: To assess whether patients with rheumatoid arthritis (RA) trained as educators can enhance the integration of clinical and basic science education among second-year medical students during their rheumatology sequence. METHODS: Twenty patients with RA and strong communication skills were extensively trained to teach students how to perform the whole-body joint examination. Each arthritis educator taught three 2-hour small group sessions and participated in a concluding 2-hour panel discussion with the entire class. Changes in student knowledge and attitudes were assessed in a pre-post evaluation design. RESULTS: There were statistically and educationally significant gains in knowledge, confidence, and attitudes related to psychosocial aspects of arthritis in each of the 2 years the program was implemented. One-year followup data indicated substantial retention of these gains. CONCLUSIONS: Patients trained in arthritis education can effectively teach fundamental musculoskeletal examination skills and encourage the development of sensitivity to the impact of chronic arthritis on the daily life of other patients.

Mechanisms of drug-induced lupus. II. T cells overexpressing lymphocyte function-associated antigen 1 become autoreactive and cause a lupuslike disease in syngeneic mice.

Current theories propose that systemic lupus erythematosus develops when genetically predisposed individuals are exposed to certain environmental agents, although how these agents trigger lupus is uncertain. Some of these agents, such as procainamide, hydralazine, and UV-light inhibit T cell DNA methylation, increase lymphocyte function-associated antigen 1 (LFA-1) (CD11a/CD18) expression, and induce autoreactivity in vitro, and adoptive transfer of T cells that are made autoreactive by this mechanism causes a lupuslike disease. The mechanism by which these cells cause autoimmunity is unknown. In this report, we present evidence that LFA-1 overexpression is sufficient to induce autoimmunity. LFA-1 overexpression was induced on cloned murine Th2 cells by transfection, resulting in autoreactivity. Adoptive transfer of the transfected, autoreactive cells into syngeneic recipients caused a lupuslike disease with anti-DNA antibodies, an immune complex glomerulonephritis and pulmonary alveolitis, similar to that caused by cells treated with procainamide. These results indicate that agents or events which modify T cell DNA methylation may induce autoimmunity by causing T cell LFA-1 overexpression. Since T cells from patients with active lupus have hypomethylated DNA and overexpressed LFA-1, this mechanism could be important in the development of human autoimmunity.

The roles of tissue inhibitors of metalloproteinases in tissue remodelling and cell growth.

Tissue inhibitors of metalloproteinases (TIMPs) are secreted proteins that block the activities of the extracellular matrix (ECM)-degrading metalloproteinases (MMPs). As key determinants of ECM integrity and turnover, TIMPs are involved in the establishment and maintenance of tissue architecture and may indirectly influence ECM-dependent cells signaling. In addition, TIMPs exert both positive and negative effects on cell growth through mechanisms that are independent of MMP inhibition. The three members of the mammalian TIMP family differ in structure, biochemical properties and expression, suggesting that they have distinct physiological roles. Here, we review recent advances in our understanding of TIMP protein function and gene regulation. We discuss the potential relevance of MMPs and TIMPs in obesity with regard to effects on the processing of tumor necrosis factor-alpha.