Scaling up self-assembly: bottom-up approaches to macroscopic particle organization.

This review presents an overview of recent work in the field of non-Brownian particle self-assembly. Compared to nanoparticles that naturally self-assemble due to Brownian motion, larger, non-Brownian particles (d > 6 µm) are less prone to autonomously organize into crystalline arrays. The tendency for particle systems to experience immobilization and kinetic arrest grows with particle radius. In order to overcome this kinetic limitation, some type of external driver must be applied to act as an artificial "thermalizing force" upon non-Brownian particles, inducing particle motion and subsequent crystallization. Many groups have explored the use of various agitation methods to overcome the natural barriers preventing self-assembly to which non-Brownian particles are susceptible. The ability to create materials from a bottom-up approach with these characteristics would allow for precise control over their pore structure (size and distribution) and surface properties (topography, functionalization and area), resulting in improved regulation of key characteristics such as mechanical strength, diffusive properties, and possibly even photonic properties. This review will highlight these approaches, as well as discuss the potential impact of bottom-up macroscale particle assembly. The applications of such technology range from customizable and autonomously self-assembled niche microenvironments for drug delivery and tissue engineering to new acoustic dampening, battery, and filtration materials, among others. Additionally, crystals made from non-Brownian particles resemble naturally derived materials such as opals, zeolites, and biological tissue (i.e. bone, cartilage and lung), due to their high surface area, pore distribution, and tunable (multilevel) hierarchy.

Ambient hypoxia enhances the loss of muscle mass after extensive injury.

Hypoxia induces a loss of skeletal muscle mass and alters myogenesis in vitro, but whether it affects muscle regeneration in vivo following injury remains to be elucidated. We hypothesized that hypoxia would impair the recovery of muscle mass during regeneration. To test this hypothesis, the soleus muscle of female rats was injured by notexin and allowed to recover for 3, 7, 14, and 28 days under normoxia or hypobaric hypoxia (5,500 m) conditions. Hypoxia impaired the formation and growth of new myofibers and enhanced the loss of muscle mass during the first 7 days of regeneration, but did not affect the final recovery of muscle mass at 28 days. The impaired regeneration under hypoxic conditions was associated with a blunted activation of mechanical target of rapamycin (mTOR) signaling as assessed by p70(S6K) and 4E-BP1 phosphorylation that was independent of Akt activation. The decrease in mTOR activity with hypoxia was consistent with the increase in AMP-activated protein kinase activity, but not related to the change in regulated in development and DNA response 1 protein content. Hypoxia increased the mRNA levels of the atrogene muscle ring finger-1 after 7 days of regeneration, though muscle atrophy F box transcript levels remained unchanged. The increase in MyoD and myogenin mRNA expression with regeneration was attenuated at 7 days with hypoxia. In conclusion, our results support the notion that the enhanced loss of muscle mass observed after 1 week of regeneration under hypoxic conditions could mainly result from the impaired formation and growth of new fibers resulting from a reduction in protein synthesis and satellite cell activity.

Sex and age differences in lipid response to chronic infection with the hepatitis C virus in the United States National Health and Nutrition Examination Surveys.

Low levels of serum lipids were reported in subjects chronically infected with the hepatitis C virus (HCV) and correlated with poorer clinical outcomes. Whether HCV 'hypo-lipidemia' is constant across age, sex and race has not been systematically explored. We therefore investigated the association between HCV infection and serum lipid levels in two independent National Health and Nutrition Examination Survey (NHANES) cohorts. HCV antibody status and serum lipid levels were obtained from 14 369 adults from NHANES 1999-2006 and 12 261 from NHANES III (enrolled in 1988-1994). In multivariable models, the prevalence of HCV-associated hypo-low density lipoprotein-cholesterol was highest among women >50 years of age in both NHANES 1999-2006 (OR: 10.51, 95% CI: 2.86, 38.62) and III (OR: 24.21, 95% CI: 6.17, 94.92), but among women <50 years of age, the odds ratios were 3.01 (95% CI: 1.00, 9.04) for NHANES 1999-2006 and 0.52 (95% CI: 0.14, 1.88) for III, respectively. HCV by age interaction among women was significant in both cohorts (P < 0.001 and P = 0.004, respectively). Among men, the odds ratios of HCV-associated hypo-LDL-cholesterol were 2.74 (95% CI: 1.55, 4.85) in NHANES 1999-2006 and 3.84 (95% CI: 1.66, 8.88) in III, respectively, with no significant age effects. Similar patterns were observed for total-cholesterol, but no significantly discernable patterns for high density lipoprotein-cholesterol and triglycerides. Results show that HCV infection is associated with lower total- and LDL-cholesterol in two US population-based cohorts, and this relationship varies significantly by age and sex, suggesting a possible influence of sex hormones on host lipid response to HCV infection.

Nitrogenous nutrition of marine phytoplankton in nutrient-depleted waters.

Variability in the small-scale temporal and spatial patterns in nitrogenous nutrient supply, coupled with an enhanced uptake capability for nitrogenous nutrients induced by nitrogen limitation, make it possible for phytoplankton to maintain nearly maximum rates of growth at media nutrient concentrations that cannot be quantified with existing analytical techniques.

The use of single-nucleotide polymorphism maps in pharmacogenomics.

Single-nucleotide polymorphisms (SNPs), common variations among the DNA of individuals, are being uncovered and assembled into large SNP databases that promise to enable the dissection of the genetic basis of disease and drug response (i.e., pharmacogenomics). Although great strides have been made in understanding the diversity of the human genome, such as the frequency, distribution, and type of genetic variation that exists, the feasibility of applying this information to uncover useful pharmacogenomic markers is uncertain. The health care industry is clamoring for access to SNP databases for use in research in the hope of revolutionizing the drug development process. As the reality of using SNPs to uncover drug response markers is rarely addressed, this review discusses practical issues, such as patient sample size, SNP density and genome coverage, and data interpretation, that will be important for determining the applicability of pharmacogenomic information to medical practice.

Thermal expansion effects and heat conduction in granular materials.

In this paper, we report results and analysis on a simulation study of the effects of thermal expansion in granular systems. We show that these effects impact the force distribution inside a two-dimensional system of disks that are subject to thermal heating under two different boundary conditions. A significant increase in the average force is observed for steel particles confined within a box with fixed walls at temperature rises of 50 degrees C and 100 degrees C, respectively. As previously noted in the literature, thermal expansion also induces compaction. The results show that a systematic and controllable increase in granular packing can be induced by simply raising and then lowering the temperature, without the input of mechanical energy in agreement with previous experimental observations. We find that the evolution of the packing fraction is well described by a fractional relaxation model, which follows the Mittag-Leffler law.

Melastatin expression and prognosis in cutaneous malignant melanoma.

PURPOSE: Melastatin (MLSN-1), a novel melanocyte-specific gene recently identified using a genomic approach, is expressed in murine and human melanoma cells at levels inversely proportional to metastatic rates in vivo. We studied the relationship between expression of melastatin mRNA in the primary cutaneous tumor and prognosis in patients with localized malignant melanoma. PATIENTS AND METHODS: Melastatin mRNA was evaluated by in situ hybridization in primary cutaneous melanoma from 150 patients with localized disease (American Joint Committee on Cancer [AJCC] stage I and II). Multivariate Cox proportional hazards regression analysis was performed to assess the prognostic utility of melastatin mRNA expression while adjusting for other prognostic indicators. RESULTS: Uniform melastatin mRNA expression in the primary tumor was correlated with prolonged disease-free survival (P < .0001). Multivariate analysis revealed that melastatin status, mitotic rate, and tumor thickness influence disease-free survival independently. The 8-year disease-free survival rate in AJCC stage I patients whose tumors diffusely expressed melastatin mRNA was 100%, whereas in stage I patients with melastatin loss, the disease-free survival rate was 77% +/- 15% (median +/- SE). In patients with stage II disease whose tumors diffusely expressed melastatin mRNA, the 8-year disease-free survival rate was 90% +/- 7%, whereas in patients with melastatin loss, the disease-free survival rate was 51% +/- 8%. CONCLUSION: Downregulation of melastatin mRNA in the primary cutaneous tumor is a prognostic marker for metastasis in patients with localized malignant melanoma and is independent of tumor thickness and other variables. Used in combination, melastatin status and tumor thickness allow for the identification of subgroups of patients at high and low risk of developing metastatic disease.

Identification of false positive exercise tests with use of electrocardiographic criteria: a possible role for atrial repolarization waves.

Atrial repolarization waves are opposite in direction to P waves, may have a magnitude of 100 to 200 mu V and may extend into the ST segment and T wave. It was postulated that exaggerated atrial repolarization waves during exercise could produce ST segment depression mimicking myocardial ischemia. The P waves, PR segments and ST segments were studied in leads II, III, aVF and V4 to V6 in 69 patients whose exercise electrocardiogram (ECG) suggested ischemia (100 mu V horizontal or 150 mu V upsloping ST depression 80 ms after the J point). All had a normal ECG at rest. The exercise test in 25 patients (52% male, mean age 53 years) was deemed false positive because of normal coronary arteriograms and left ventricular function (5 patients) or normal stress single photon emission computed tomographic thallium or gated blood pool scans (16 patients), or both (4 patients). Forty-four patients with a similar age and gender distribution, anginal chest pain and at least one coronary stenosis greater than or equal to 80% served as a true positive control group. The false positive group was characterized by 1) markedly downsloping PR segments at peak exercise, 2) longer exercise time and more rapid peak exercise heart rate than those of the true positive group, and 3) absence of exercise-induced chest pain. The false positive group also displayed significantly greater absolute P wave amplitudes at peak exercise and greater augmentation of P wave amplitude by exercise in all six ECG leads than were observed in the true positive group.(ABSTRACT TRUNCATED AT 250 WORDS)

Large scale association analysis for identification of genes underlying premature coronary heart disease: cumulative perspective from analysis of 111 candidate genes.

BACKGROUND: to date, only three groups have reported data from large scale genetic association studies of coronary heart disease using a case control design. METHODS AND RESULTS: to extend our initial report of 62 genes, we present data for 210 polymorphisms in 111 candidate genes genotyped in 352 white subjects with familial, premature coronary heart disease (onset age for men, 45; for women, 50) and a random sample of 418 population based whites. Multivariate logistic regression analysis was used to compare the distributions of genotypes between cases and the comparison group while controlling for age, sex, body mass, diabetes, and hypertension. Significant associations were found with polymorphisms in thrombospondin-4 (THBS4), thrombospondin-2 (THBS2) and plasminogen activator inhibitor-2 (PAI2), the strongest being with the A387P variant in THBS4 (p = 0.002). The THBS2 and THBS4 associations have since been replicated. We evaluated polymorphisms in 40 genes previously associated with coronary heart disease and found significant (p<0.05) associations with 10: ACE, APOE, F7, FGB, GP1BA, IL1RN, LRP1, MTHFR, SELP, and THPO. For five of these genes, the polymorphism associated in our study was different from that previously reported, suggesting linkage disequilibrium as an explanation for failure to replicate associations consistently across studies. We found strong linkage disequilibrium between polymorphisms within and between genes, especially on chromosome 1q22-q25, a region containing several candidate genes. CONCLUSIONS: despite known caveats of genetic association studies, they can be an effective means of hypothesis generation and complement classic linkage studies for understanding the genetic basis of coronary heart disease.

Phase diagrams for cohesive particle mixing and segregation.

By taking a discrete view of cohesion, we develop a particle-level model which can accurately predict the extent of particle mixing and segregation in cohesive (wet) granular systems. Our model is based on a discrete characterization tool and is used to generate phase diagrams of the predicted particle behavior. These phase diagrams exhibit both mixed and segregated phases where the boundary is determined by the mechanical and surface properties of the particles, such that manipulation of surface properties and/or size/density ratios provides a method to control cohesive particle mixing and segregation. A detailed description of the phase diagram development process as well as quantitative validation of the theoretical results are reported here.

Personalized medicine: revolutionizing drug discovery and patient care.

Advances in human genome research are opening the door to a new paradigm for practising medicine that promises to transform healthcare. Personalized medicine, the use of marker-assisted diagnosis and targeted therapies derived from an individual's molecular profile, will impact the way drugs are developed and medicine is practiced. Knowledge of the molecular basis of disease will lead to novel target identification, toxicogenomic markers to screen compounds and improved selection of clinical trial patients, which will fundamentally change the pharmaceutical industry. The traditional linear process of drug discovery and development will be replaced by an integrated and heuristic approach. In addition, patient care will be revolutionized through the use of novel molecular predisposition, screening, diagnostic, prognostic, pharmacogenomic and monitoring markers. Although numerous challenges will need to be met to make personalized medicine a reality, with time, this approach will replace the traditional trial-and-error practice of medicine.

Limit setting on drug abuse in methadone maintenance patients.

In this prospective study the authors examined the effects of setting limits on continued drug abuse in patients receiving methadone maintenance. Subjects were randomly assigned either to structured treatment (drug use exceeding set limits resulted in methadone withdrawal) or to unstructured treatment (no consequences attended continued drug use). The structured treatment resulted in significantly less drug use and greater retention in the program. The authors conclude that these results confirm the importance of external structure in the treatment of addiction-related psychopathology.

Relationship between lesion formation and permeability of rat gastric mucosa to H+ and other cations.

The relationship between lesion formation and ionic permeability has been investigated in rat gastric mucosa in vivo. Changes in these parameters were measured in the mucosa treated topically with prostaglandins E2 and A2 and/or aspirin. Particular attention was paid to the net flux of H+ ions across the gastric mucosa. The effect of aspirin concentrations of 5 mM, 20 mM and '40 mM' (the latter, a suspension in a saturated solution) was investigated. Aspirin concentrations of 20 mM and '40 mM' produced a marked increase in lesion formation and increased the net mucosal to serosal flux of H+ ions. Aspirin 5 mM produced a significant increase in lesion formation but did not cause a significant change in net H+ ion flux. This result suggests that aspirin can have a direct irritant effect on the gastric mucosa and that the back diffusion of H+ ions is not a pre-requisite for the development of overt mucosal ulceration. The effect of topically applied prostaglandin E2 (PGE2) on aspirin-induced gastric mucosal damage was investigated. Concentrations of PGE2 of 10(-5) M and 10(-4) M ameliorated aspirin-induced damage, but these changes were not necessarily accompanied by a significant reduction in net H+ ion flux. Again, this result is not consistent with a direct relationship between lesion formation and mucosal permeability to H+ ions. Since PGA2 did not ameliorate aspirin-induced mucosal damage, the protective effect of PGE2 could not be attributed to its conversion to PGA2 in the acidic environment of the gastric lumen. 5 Changes in gastric mucosal potential difference (p.d.) and net fluxes of Na+ and K+ ions may occur without a concomitant change in the permeability of the gastric mucosa to acid back-diffusion. Thus, the assumption cannot be made that a change in the permeability of the gastric mucosa to one particular ion reflects a general increase in ionic permeability.

Can heparin cause adult respiratory distress syndrome by a similar mechanism as heparin-associated thrombocytopenia?

A 62-year-old woman who underwent an aortic valve replacement for severe aortic valve stenosis developed postoperative thrombocytopenia and adult respiratory distress syndrome, simultaneously. Both complications resolved promptly after discontinuing heparin therapy. The presence of a heparin-related antiplatelet antibody was detected by in vitro testing. The time course of clinical events suggests the possibility of a heparin-induced, immune-mediated injury to both the pulmonary vascular endothelium and the platelet membrane as an underlying pathophysiologic mechanism.

A comparison of methods to interpret the basal body temperature graph.

Specific criteria are given for several methods of determining the basal body temperature shift. The specific criteria selected have been coded for a uniform interpretation by computer, and interpretations have been compared for 8496 charts. Our results indicate that the method that defines the temperature shift as 0.3 degrees F or more above the running low average for at least 3 consecutive days provides the best concurrent chart interpretation method. A method that creates a smoothed curve that transects the average of all temperatures on a completed graph provides a good retrospective method for identifying the temperature shift. Both the temperature averaging technique and curve smoothing technique identified a temperature shift in more than 95% of the charts with complete temperature readings.

PIP: Cycle lengths under 40 days on 8496 temperature charts submitted by 1376 clients of the cervical mucus-basal body temperature (BBT) program of southwest Pennsylvania from 1973-79 were analyzed to compare various techniques of interpreting the BBT graphs. Clients ranged in age from 16-46; average age was 26. A subset of 5210 charts was selected for analysis of methods requiring more information. Techniques used to identify the thermal shift of biphasic cycles include single-point techniques, of which the most widely used is the overline (COV) which uses the highest of the normal temperatures in the low phase as the reference point, temperature averaging (AVE), and the smoothed curve (SMC) technique, which utilizes the average of all temperatures in the cycle. A computer program was developed for chart analysis. In the total sample, the largest number of biphasic cycles, 93.5%, occurred with the AVE technique using 2 degrees Fahrenheit as the criterion for identifying the temperature shift. A definition of 4 degrees Fahrenheit thermal shift produced only 78.1% biphasic curves. The criterion of 2 degrees thermal shift produced a significantly greater proportion of charts with a long postovulatory phase than would be expected without evidence of pregnancy. The criterion of 3 degrees Fahrenheit appears to provide the distribution of charts that most closely resembles the expected distribution in a population resembling the sample group. The proportion of biphasic charts identified with the COV technique, 64.9%, is lower than for any of the AVE techniques. The ratio of biphasic charts with COV increases to 76.2% when only the last 6 temperatures before the thermal shift are considered. The SMC method produced a high proportion, 96.9%, of biphasic charts, but requires a completed chart because it employs the mean of all temperatures in the cycle. The AVE technique based on a 3 degree Fahrenheit rise for 3 days, which can be used concurrently to interpret the graph, compares favorably with the strictly retrospective SMC technique. Both methods identified a temperature shift in over 95% of charts with complete temperature readings.

Innominate osteotomy in adolescents and adults who have acetabular dysplasia.

The results were evaluated for twenty-eight adolescents and adults (thirty-one hips) who had had a Salter innominate osteotomy because of acetabular dysplasia and pain in the hip. The mean age at the time of the index operation was twenty-two years, and the mean duration of radiographic follow-up was seventy-one months. Radiographs were available for twenty-five patients (twenty-eight hips) at the most recent follow-up evaluation. The radiographic evaluation included determination of the acetabular angle, the center-edge angle, the coverage of the femoral head, the height of the joint space, and the Shenton line. Compared with the preoperative measurements, the acetabular angle had decreased by a mean of 10.0 degrees, the center-edge angle had increased by a mean of 13.2 degrees, and the coverage of the femoral head had increased by a mean of 15 per cent (p < 0.001 for all three values). The height of the joint space had decreased but, with the numbers available, this change was not significant. The Harris hip scores, determined for twenty patients (twenty-one hips), improved from a mean of 71.2 points preoperatively to a mean of 88.3 points at the latest follow-up evaluation (p < 0.001). A questionnaire, completed by twenty-seven patients (thirty hips), revealed that twenty-one patients (78 per cent) were satisfied with the result of the operation; twenty-two patients (81 per cent) said that they would recommend this procedure to others who had a similar condition. The pain score (with 1 point indicating mild pain and 5 points indicating severe pain) improved from a mean of 3.7 points preoperatively to a mean of 2.5 points at the latest follow-up evaluation (p < 0.001). There were six postoperative complications. One patient had a non-union; one, an infection; one, heterotopic bone; and three, numbness. Two of these patients subsequently had a total hip arthroplasty at ninety-eight and 150 months, and one patient had a Chiari osteotomy at twenty-two months. Our findings demonstrate that the Salter innominate osteotomy provides notable clinical improvement as well as improvements in the radiographic measurements of the hip in patients who have acetabular dysplasia.

Fibular hemimelia: comparison of outcome measurments after amputation and lengthening.

BACKGROUND: Treatment of fibular hemimelia includes either Syme or Boyd amputation with early prosthetic fitting or tibial lengthening. Numerous studies have documented the success of both procedures. The purpose of our study was to compare the outcome after amputation with that after tibial lengthening, specifically with regard to activity restrictions, pain, satisfaction, complications, number of procedures, and cost, in children with fibular hemimelia. METHODS: Thirty limbs in twenty-five patients treated with either an amputation or a lengthening procedure and followed for at least two years were studied. Fifteen patients underwent amputation, and ten patients underwent lengthening of the tibia. The mean age was 1.2 years at the time of amputation and 9.7 years at the time of initial lengthening. The mean duration of follow-up was 6.9 years after the amputations and 7.1 years after the lengthening procedures. RESULTS: The patients who underwent amputation were able to perform more activities than those who had a lengthening (mean activity score, 0 compared with 1.2 points; p<0.05), and they had less pain (mean pain score, 0.2 compared with 1.2 points; p = 0.091), were more satisfied and had a lower complication rate (0.37 compared with 1.91; p<0.05). The patients who underwent amputation also had fewer procedures (1.9 compared with 7.0; p<0.05), at a lower cost ($7016 compared with $26,900; p<0.05), than those who had a lengthening. Lengthening was successful in equalizing limb lengths; the mean limb-length discrepancy, assessed in nine of eleven limbs, was 0.7 centimeter. CONCLUSIONS: This study demonstrated that children who undergo early amputation are more active, have less pain, are more satisfied, have fewer complications, undergo fewer procedures, and incur less cost than those who undergo lengthening. This was true even though good results were obtained with the lengthening procedures and most patients achieved limb-length equality, were able to walk, had minimal pain, and were quite active.

The relationship between tight hamstrings and lumbar hypolordosis in children with cerebral palsy.

STUDY DESIGN: Retrospective clinical and radiographic review. OBJECTIVE: To assess the influence of tight hamstrings on the sagittal alignment of the thoracic and lumbar spine in children with cerebral palsy. SUMMARY OF BACKGROUND DATA: It is postulated that tight hamstrings may produce a hypolordosis of the lumbar spine. The abnormal sagittal contour of the spine may lead to increased stresses in the lumbar spine and subsequent pain and disability. This is of special concern in children with cerebral palsy who often have shortened spastic hamstring muscles. METHODS: Twenty-one patients were evaluated, with a mean age of 9.4 years. Standing and sitting lateral spine films were obtained and the lumbar lordosis and thoracic kyphosis were measured using the Cobb method. The popliteal angle was measured to assess hamstring tightness, such that a large popliteal angle indicates tight hamstrings. RESULTS: We found a statistically significant correlation between the sitting lumbar curve and popliteal angle (Pearson correlation value -0.77, P < 0.01). As the popliteal angle increased, the amount of lumbar lordosis decreased. This correlation was less significant when the patient was standing (Pearson correlation value -0.59). CONCLUSION: This study demonstrates that there is a correlation between tight hamstrings, as measured by the popliteal angle, and decreasing lumbar lordosis, especially when sitting.

Surgery-associated factor VIII inhibitors in patients without hemophilia.

The acquisition of antibodies to factor VIII (ie, factor VIII protein) by patients without hemophilia is associated with conditions such as pregnancy, lymphoma, and autoimmune disorders. We present three patients who acquired factor VIII antibodies in the postoperative setting. Preoperatively, none gave a history of bleeding even with past surgeries and all had normal coagulation tests. Within days of surgery (bowel resection, cholecystectomy, coronary bypass), a bleeding diathesis emerged with prolonged partial thromboplastin time, decreased factor VIII levels, and demonstrable factor VIII antibodies. All patients required multiple blood transfusions and urgent reexploration for hemostatic control. All were treated with high dose human factor VIII infusions, corticosteroids, and various forms of immunosuppression. We wish to raise awareness of surgery as a precipitating cause of acquired hemophilia, which is something to be considered with unusual postoperative bleeding. This syndrome is remarkable for its abrupt onset within days of surgery, dramatic bleeding, subsequent persistence, but potential reversal by immunosuppression.