Whole-exome sequencing of cell-free DNA and circulating tumor cells in multiple myeloma.

Liquid biopsies including circulating tumor cells (CTCs) and cell-free DNA (cfDNA) have enabled minimally invasive characterization of many cancers, but are rarely analyzed together. Understanding the detectability and genomic concordance of CTCs and cfDNA may inform their use in guiding cancer precision medicine. Here, we report the detectability of cfDNA and CTCs in blood samples from 107 and 56 patients with multiple myeloma (MM), respectively. Using ultra-low pass whole-genome sequencing, we find both tumor fractions correlate with disease progression. Applying whole-exome sequencing (WES) to cfDNA, CTCs, and matched tumor biopsies, we find concordance in clonal somatic mutations (~99%) and copy number alterations (~81%) between liquid and tumor biopsies. Importantly, analyzing CTCs and cfDNA together enables cross-validation of mutations, uncovers mutations exclusive to either CTCs or cfDNA, and allows blood-based tumor profiling in a greater fraction of patients. Our study demonstrates the utility of analyzing both CTCs and cfDNA in MM.

Biogeochemical consequences of rapid microbial turnover and seasonal succession in soil.

Soil microbial communities have the metabolic and genetic capability to adapt to changing environmental conditions on very short time scales. In this paper we combine biogeochemical and molecular approaches to reveal this potential, showing that microbial biomass can turn over on time scales of days to months in soil, resulting in a succession of microbial communities over the course of a year. This new understanding of the year-round turnover and succession of microbial communities allows us for the first time to propose a temporally explicit N cycle that provides mechanistic hypotheses to explain both the loss and retention of dissolved organic N (DON) and inorganic N (DIN) throughout the year in terrestrial ecosystems. In addition, our results strongly support the hypothesis that turnover of the microbial community is the largest source of DON and DIN for plant uptake during the plant growing season. While this model of microbial biogeochemistry is derived from observed dynamics in the alpine, we present several examples from other ecosystems to indicate that the general ideas of biogeochemical fluxes being linked to turnover and succession of microbial communities are applicable to a wide range of terrestrial ecosystems.

The health benefits of omega-3 polyunsaturated fatty acids: a review of the evidence.

The UK dietary guidelines for cardiovascular disease acknowledge the importance of long-chain omega-3 polyunsaturated fatty acids (PUFA) - a component of fish oils - in reducing heart disease risk. At the time, it was recommended that the average n-3 PUFA intake should be increased from 0.1 to 0.2 g day(-1). However, since the publication of these guidelines, a plethora of evidence relating to the beneficial effects of n-3 PUFAs, in areas other than heart disease, has emerged. The majority of intervention studies, which found associations between various conditions and the intake of fish oils or their derivatives, used n-3 intakes well above the 0.2 g day(-1) recommended by Committee on Medical Aspects of Food Policy (COMA). Furthermore, in 2004, the Food Standards Agency changed its advice on oil-rich fish creating a discrepancy between the levels of n-3 PUFA implied by the new advice and the 1994 COMA guideline. This review will examine published evidence from observational and intervention studies relating to the health effects of n-3 PUFAs, and discuss whether the current UK recommendation for long-chain n-3 PUFA needs to be revisited.

The impact of long-chain n-3 polyunsaturated fatty acids on human health.

A considerable literature has been published on the health benefits of fish, oil-rich fish and fish oils and their constituent long-chain (LC) n-3 PUFA. Evidence from epidemiological studies highlights the cardioprotective attributes of diets rich in fish, especially oil-rich fish. Data from intervention trials are consistent in suggesting that LC n-3 PUFA lower the risk of CVD, probably by the multiple mechanisms of lowering serum triacylglycerols, improving the LDL:HDL ratio, anti-arrhythmic effects on heart muscle, improved plaque stability, anti-thrombotic effects and reduced endothelial activation. Research indicates LC n-3 PUFA provision has an impact during development, and there is preliminary evidence that docosahexaenoic acid supplementation during pregnancy could optimise brain and retina development in the infant. LC n-3 PUFA are also postulated to ameliorate behavioural and mental health disturbances such as depression, schizophrenia, dementia and attention deficit hyperactivity disorder. However, despite some positive evidence in each of these areas, use of LC n-3 PUFA in these conditions remains at the experimental stage. In the case of immune function, there is little doubt that LC n-3 PUFA have a positive effect. Although intervention trials in rheumatoid arthritis show strong evidence of benefit, evidence for efficacy in other inflammatory conditions, including Crohn's disease, ulcerative colitis, psoriasis, lupus, multiple sclerosis, cystic fibrosis and asthma, is inconsistent or inadequate. More promising evidence in some conditions may come from studies which attempt to modify the fetal environment using LC n-3 PUFA supplementation during pregnancy.

The health benefits of omega-3 polyunsaturated fatty acids: a review of the evidence.

The UK dietary guidelines for cardiovascular disease acknowledge the importance of long-chain omega-3 polyunsaturated fatty acids (PUFA) - a component of fish oils - in reducing heart disease risk. At the time, it was recommended that the average n-3 PUFA intake should be increased from 0.1 to 0.2 g day(-1). However, since the publication of these guidelines, a plethora of evidence relating to the beneficial effects of n-3 PUFAs, in areas other than heart disease, has emerged. The majority of intervention studies, which found associations between various conditions and the intake of fish oils or their derivatives, used n-3 intakes well above the 0.2 g day(-1) recommended by Committee on Medical Aspects of Food Policy (COMA). Furthermore, in 2004, the Food Standards Agency changed its advice on oil-rich fish creating a discrepancy between the levels of n-3 PUFA implied by the new advice and the 1994 COMA guideline. This review will examine published evidence from observational and intervention studies relating to the health effects of n-3 PUFAs, and discuss whether the current UK recommendation for long-chain n-3 PUFA needs to be revisited.

Therapeutic approaches to raising plasma HDL-cholesterol levels.

Epidemiologic data from the Framingham and Prospective Cardiovascular Munster studies, demonstrating an inverse correlation between the plasma concentration of HDLs and the incidence of cardiovascular disease, have driven research to explore precisely how HDLs confer this cardioprotective effect. HDLs are anti-inflammatory, antithrombogenic and have vasoactive effects, as well as being efficient cholesterol acceptors enabling the removal of cholesterol from peripheral tissues, all functions that are likely to protect the vasculature. The first part of this article will review the clinical evidence in support of the pleiotropic effects of HDLs, along with laboratory-based investigations of the molecular mechanisms of action. As the evidence of clinical benefits of raising plasma HDL concentration has increased, so has the number of strategies currently being considered to achieve this goal. The second part of this article will review three current strategies: infusion of HDL-like products, comparing physicopharmacologic characteristics of the two commercial products currently under trial; the use of fibrates to raise plasma HDLs (although fibrates primarily reduce triglyceride levels, certain derivatives are able to induce significant increases in plasma HDLs); and the use of drugs that inhibit cholesterol ester transfer protein (these drugs increase plasma HDL concentration either alone or as an adjunct therapy with statins). The clinical efficacy and mechanism of action of fibrates and inhibitors of cholesterol ester transfer protein will be reviewed.

Temporal variation in community composition, pigmentation, and F(v)/F(m) of desert cyanobacterial soil crusts.

Summers on the Colorado Plateau (USA) are typified by harsh conditions such as high temperatures, brief soil hydration periods, and high UV and visible radiation. We investigated whether community composition, physiological status, and pigmentation might vary in biological soil crusts as a result of such conditions. Representative surface cores were sampled at the ENE, WSW, and top microaspects of 20 individual soil crust pedicels at a single site in Canyonlands National Park, Utah, in spring and fall of 1999. Frequency of cyanobacterial taxa, pigment concentrations, and dark adapted quantum yield [F(v)/F(m)] were measured for each core. The frequency of major cyanobacterial taxa was lower in the fall compared to spring. The less-pigmented cyanobacterium Microcoleus vaginatus showed significant mortality when not in the presence of Nostoc spp. and Scytonema myochrous (Dillw.) Agardh. (both synthesizers of UV radiation-linked pigments) but had little or no mortality when these species were abundant. We hypothesize that the sunscreen pigments produced by Nostoc and Scytonema in the surface of crusts protect other, less-pigmented taxa. When fall and spring samples were compared, overall cyanobacterial frequency was lower in fall, while sunscreen pigment concentrations, chlorophyll a concentration, and F(v)/F(m) were higher in fall. The ratio of cyanobacterial frequency/chlorophyll a concentrations was 2-3 times lower in fall than spring. Because chlorophyll a is commonly used as a surrogate measure of soil cyanobacterial biomass, these results indicate that seasonality needs to be taken into consideration. In the fall sample, most pigments associated with UV radiation protection or repair were at their highest concentrations on pedicel tops and WSW microaspects, and at their lowest concentrations on ENE microaspects. We suggest that differential pigment concentrations between microaspects are induced by varying UV radiation dosage at the soil surface on these different microaspects.

Photochemical generation and matrix-isolation detection of dimethylvinylidene.

We report the spectroscopic characterization of dimethylvinylidene, (CH3)2C=C:, generated within an argon matrix at 14 K from a bisperoxyester precursor. The carbene was identified by comparison of the experimental IR spectrum with vibrational frequencies computed at the B3LYP/6-31G(d) level. Chemical trapping of the carbene within a 9% CO/Ar matrix to form dimethylpropadienone supports this analysis. Additional products produced during photolysis were identified by comparison to the appropriate computed vibrational frequencies. The potential energy surface of dimethylvinylidene and its intramolecular rearrangement products, 2-butyne and methylcyclopropene, were also investigated computationally at the B3LYP/6-31G(d) level. A spin-state analysis of this carbene using a variety of computational methods (CCSD(T), B3LYP, MP2) indicates the singlet state is more stable than the triplet by approximately 45 kcal mol-1. We anticipate the bisperoxyester precursor used here will be a convenient and general way for initiating future studies of alkylvinylidenes under matrix-isolation conditions.

Supply and segregation of nursing home beds in Chicago communities.

OBJECTIVE: Previous research suggests that a shortage of nursing home beds in Latino communities and segregation within facilities in urban settings may contribute to low utilization patterns that both Latino and African American elders exhibit. In order to explore structural barriers to nursing home care for African American and Latino families, this study examines the supply and ethnoracial composition of nursing homes in Chicago communities. DESIGN: With data from the 1990 US Census of Population and Illinois' 1994 Long-Term Care Facility Survey, regression was used to determine if Latino nursing home residents in Chicago follow neighborhood residential patterns in the same way that African American nursing home residents do. Next the availability of nursing home beds by ethnoracial community is examined using analysis of variance. Finally, we present correlations between the racial/ethnic composition of Chicago's facilities, community demographics and facility characteristics that have been associated with quality outcomes. RESULTS: Both African American and Latino nursing home residents follow residential housing patterns, tending to reside in facilities located in their own communities. Latino communities have the fewest beds. However, Latinos appear to be more mobile in their utilization of nursing facilities in other communities than either African Americans or whites and tend to reside in smaller homes with fewer Medicaid recipients. CONCLUSION: Health policy makers must actively address racial and ethnic differences in access to long-term care or risk reinforcing the effects of poverty and segregation. In order to ensure that Latino elders living alone are not going without needed care city leaders must promote a range of culturally sensitive alternatives to nursing home care within Latino communities while promoting geographic mobility for African Americans.

Concentrated poverty and nursing home bed supply in Chicago.

This study explores whether poverty areas of Chicago have fewer nursing home beds and unique staffing patterns. Using 1990 census data and Illinois's 1994 Long-Term Care Facility Survey, census tracts were compared by need for long-term care, bed supply, and nursing home characteristics. While facilities cluster on the north side, and the number of beds follow the elderly, the supply of beds per elderly is actually greater in tracts with high proportions of poverty, disability, and African American residents due, in part, to the predominance of larger facilities. Ironically, economic segregation may work together with Medicaid's policy of serving the poorest to increase the supply of beds to those who might otherwise remain unserved. Nursing homes in the poorest communities have high percentages of Medicaid residents, are larger, and employ fewer staff per resident; homes with a high Medicaid population are more likely to employ LPNs, which may reflect labor supply differences.

An office systems approach to cancer prevention in primary care.

PURPOSE: The provision of preventive services holds a central place in primary care. Achievement of prevention standards offers a challenge. The authors address the efficacy of an office systems approach to improving cancer prevention and early detection services, provide a guide to assessing the appropriateness of office systems dissemination in practices targeted for improvement, and describe the range of dissemination strategies available. OVERVIEW: Preventive service office systems depend on establishing practice routines, using tools such as flow sheets, and sharing responsibilities among practice clinicians, staff, and patients. Systems have been shown to be efficacious in a variety of settings. Computers provide a significant enhancement to paper-based tools. Some practices develop office systems themselves, whereas others require external support. Before attempting to disseminate preventive services offices systems, disseminators should ensure that adequate assistance can be provided, that assistance follows a format that is acceptable to target practices, and that target practices are receptive to assistance and able to cooperate. Dissemination strategies include journal articles, continuing education programs, manuals and tool kits, facilitation, and academic detailing. The relative expense and efficacy of these approaches require further assessment. CLINICAL IMPLICATIONS: Office systems hold promise in enhancing provision of cancer prevention services in primary care. The practice should be approached as a team, and should include practice clinicians as well as nonclinical staff members. Current research should provide answers over the next few years about the cost-effectiveness of various approaches and the most feasible ways to promote dissemination to practices that need it.

The accuracy of femoral intramedullary guides in total knee arthroplasty.

Of the technical factors important in achieving a successful total knee arthroplasty, limb alignment has been demonstrated to be most influential in determining implant survival. Intramedullary femoral guide systems rely on placement of the intramedullary rod along the anatomic axis of the femur. In this article, the accuracy of the femoral intramedullary guide is investigated using radiographs and a mathematical model. The femoral anatomic axis was drawn on 40 consecutive, preoperative, 3-ft standing radiographs. Using a mathematical model, the potential angular error in the distal femoral cut from aberrant placement of the intramedullary rod was estimated. Calculated values correlated with measured values from plain radiographs and an intramedullary guide template. The anatomic axis was found to exit the distal femur at an average of 6.6 mm medial to the center of the femoral notch. Substantial malalignment error resulted from minor malposition of the intramedullary rod. Most books and diagrams demonstrating the use of intramedullary guides indicate that the entry point is at the center of the femoral notch. These results show that the true entry point is medial to the center of the notch, and rod placement error results in excessive valgus alignment. Preoperative drawing of the anatomic axis on a 3-ft or 18-inch anteroposterior radiograph is recommended. The results both demonstrate the importance of correct use of the guide and heighten cognizance among surgeons performing total knee arthroplasty as to the limitations of the intramedullary guides.

Synovial chondromatosis of the metacarpophalangeal joint: case report and review of the literature.

Intra-articular synovial chondromatosis in the hand is rare but should be considered in the differential diagnosis of a swollen, stiff or painful joint. Other possible diagnoses include osteoarthritis, rheumatoid arthritis, gout, trauma and chronic infection, and unless enchondral ossification of loose bodies is seen the diagnosis of synovial chondromatosis may not be made preoperatively. A 69-year-old man with synovial chondromatosis of the metacarpophalangeal joint is reported. The joint was swollen and tender. He had not sustained trauma and there was no evidence of arthritis, involvement of other joints or infection. Complete synovectomy with removal of all loose bodies was successful and his symptoms resolved. Intra-articular synovial chondromatosis is a benign condition, but spontaneous resolution is the exception and surgical synovectomy remains the most effective treatment.

The vacuum arthrogram in the shoulder: correlation with rotator cuff disease.

Plain radiographs of the shoulder can demonstrate a vacuum arthrogram delineating the articular surfaces. In a review of 122 consecutive arthrograms with radiographic contrast injections, there were 25 vacuum arthrograms on the preceding plain films. We have found the presence of a vacuum arthrogram to be an accurate predictor of an intact rotator cuff, with a specificity of 0.98 and a positive predictive value of 0.96.

Full-thickness rotator cuff tears. A biomechanical comparison of suture versus bone anchor techniques.

We performed a biomechanical comparison of two rotator cuff repair techniques using fresh-frozen human cadavers. Nine pairs of cadaveric shoulders had standardized full-thickness tears made at the supraspinatus tendon insertion. One of each pair of the cadaveric shoulders was repaired by pulling the tendon into a bone trough in the humeral head using standard sutures. The remaining half of the pairs was repaired using anchor sutures. The repairs were tested using a servohydraulically operated material testing system. The anchor suture repair was significantly stronger than the standard suture technique irrespective of bone quality. Failure occurred predominantly through bone in the suture repairs and as a result of suture breakage in the anchor repairs. The anchors should be placed into the edge of the subchondral bone adjacent to the articular surface. The surgeon should direct the anchor so that the direction of the pull is approximately 90 degrees to the anchor, with the humerus at 30 degrees of abduction.

Compression of the deep branch of the peroneal nerve by the extensor hallucis brevis muscle: a variation of the anterior tarsal tunnel syndrome.

Anterior tarsal tunnel syndrome is a rare condition in which the deep peroneal nerve is trapped below the extensor retinaculum at the ankle. The authors report a variation of this condition: a 67-year-old woman who had anterior tarsal tunnel syndrome caused by entrapment of the deep peroneal nerve by the extensor hallucis brevis muscle. Conservative treatment was unsuccessful, but surgical decompression of the nerve provided immediate improvement, and by 2 weeks postoperatively she had no residual pain or paresthesia, although there was some numbness in the first web space.

The excimer laser in orthopaedics.

This review details clinical and laboratory experience with the 308 nm XeCl excimer laser. This ultraviolet laser is not approved yet for use in arthroscopy, but has been shown to be extremely proficient for debridement of degenerate articular cartilage and meniscus. It has fewer advantages than conventional techniques for synovectomy, meniscectomy, and lateral release. Preliminary in vitro and in vivo studies were performed to investigate the character of laser-irradiated articular cartilage and to search for evidence of regeneration. A model of arthritis was created in rabbits to test the effects of the laser. Partial-thickness cuts in articular cartilage also were irradiated to test for cartilage regeneration. In vitro results indicated that the cartilage was sealed, with only a negligible loss in thickness. The results of live rabbit studies initially showed a similar sealing under scanning electron and light microscopy; however, it tended to break down in time. The results of autoradiographic and histologic studies showed no evidence of cartilage regeneration. Recent evidence suggests that the laser may adversely affect chondrocyte vitality in a region beyond the region of visible damage. There is no evidence to suggest that the laser is mutagenic.

Disruption of the ankle syndesmosis: biomechanical study of the ligamentous restraints.

We investigated the relative importance to stability of the four component ligaments of the distal tibiofibular syndesmosis. Eight fresh-frozen cadaver specimens were tested on a hydraulic test system during sequential cutting of the ligaments. The percentage resistance to 2 mm of diastasis was measured for the four ligaments. The anterior inferior tibiofibular ligament provided 35%, interosseous ligament 22%, superficial posterior inferior tibiofibular 9%, and deep posterior inferior tibiofibular 33%. These results have clinical implications with regard to injury. Damage to the syndesmosis should be assessed anteriorly and posteriorly at the time of examination. The interosseous ligament can be visualized arthroscopically.

Disruption of the ankle syndesmosis: diagnosis and treatment by arthroscopic surgery.

Over a 10-year period, 19 patients were seen who had the clinical features of disruption of the syndesmotic ligaments of the ankle. Seventeen of these were available for follow-up by history and 13 by physical examination. The patients underwent an arthroscopy for persistent symptoms an average of 2 years following the injury. Preoperatively the patients had a positive external rotation stress test. A triad of pathological features was found: disruption of the posterior inferior tibiofibular ligament; rupture of the interosseous ligament; and chondral fracture of the posterolateral portion of the tibial plafond. Arthroscopic resection of the torn portion of the interosseous ligament and the chondral pathology successfully relieved the symptoms in most of the patients. There was a statistically significant improvement in pain, swelling, stiffness, stability, limp, and activity levels. The external rotation stress test was converted to negative. Patients with persistent pain following a syndesmotic disruption of the ankle can benefit substantially by removal of the intraarticular pathology associated with such injuries. Residual instability of the syndesmosis itself did not seem to be a problem.

Risk factors for anemia in young children in rural Malawi.

Anemia is an increasingly recognized health problem in African children. To determine the prevalence of and risk factors for anemia in young children, we enrolled 252 pregnant women and studied their newborn infants in Mangochi District in southern Malawi. At the first follow-up visit after birth at approximately two months of age, the mean hematocrit value of the 252 infants was 29.5%, and 64 infants (25%) were anemic (hematocrit value < 25%). Placental malaria infection was the strongest risk factor for an infant having anemia at the first follow-up (relative risk = 2.0, P = 0.003). Infants who had Plasmodium falciparum parasitemia at the first follow-up had lower hematocrit values than infants without parasitemia (median 28% versus 31%; P = 0.02). Neither the mother's hematocrit at enrollment, her hematocrit at delivery, sex of the infant, nor fever illness in the infant was associated with having a hematocrit less than 25% at the first follow-up. Although infants with hematocrit values less than 25% were more likely than infants with higher hematocrit values to die during the first year of life, this difference was not statically significant (relative risk = 1.7, P = 0.15). In rural Malawi, anemia commonly affects young infants, is acquired early in life, and is probably a risk factor for death in infancy. Strategies to reduce anemia in infants must address P. falciparum infection, both during pregnancy and in the first few months of life.