Treatment durability and virological response in treatment-experienced HIV-positive patients on an integrase inhibitor-based regimen: an Australian cohort study.
Background: Integrase inhibitors (INSTI) are a newer class of antiretroviral (ARV) drugs that offer additional treatment options for experienced patients. Our aim is to describe treatment durability and virological outcomes in treatment-experienced HIV-positive patients using INSTI-based regimens. Methods: All patients in the Australian HIV Observational Database who had received an INSTI-based regimen ≥ 14 days as well as previous therapy were included in the study. We defined two groups of treatment-experienced patients: (1) those starting a second-line regimen with INSTI; and (2) highly experienced patients, defined as having prior exposure to all three main ARV classes, nucleoside reverse transcriptase inhibitor, nonnucleoside reverse transcriptase inhibitors and protease inhibitors, before commencing INSTI. Survival methods were used to determine time to viral suppression and treatment switch, stratified by patient treatment experience. Covariates of interest included age, gender, hepatitis B and C co-infection, previous antiretroviral treatment time, patient treatment experience and baseline viral load. Results: Time to viral suppression and regimen switching from INSTI initiation was similar for second-line and highly experienced patients. The probability of achieving viral suppression at 6 months was 77.7% for second-line patients and 68.4% for highly experienced patients. There were 60 occurrences of regimen switching away from INSTI observed over 1274.0 person-years, a crude rate of 4.71 (95% CI: 3.66-6.07) per 100 person-years. Patient treatment experience was not a significant factor for regimen switch according to multivariate analysis, adjusting for relevant covariates. Conclusions: We found that INSTI-based regimens were potent and durable in experienced HIV-positive patients receiving treatment outside clinical trials. These results confirm that INSTI-based regimens are a robust treatment option.


A Comparison of DSM-5 and DSM-IV Diagnostic Criteria for Posttraumatic Stress Disorder in Traumatized Refugees.
The aim of this study was to compare the prevalence rate and factor structure of posttraumatic stress disorder (PTSD) based on the diagnostic criteria of the fourth and fifth editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; DSM-5; American Psychiatric Association, , ) in traumatized refugees. There were 134 adult treatment-seeking, severely and multiply traumatized patients from various refugee backgrounds were assessed in their mother tongue using a computerized set of questionnaires consisting of a trauma list, the Posttraumatic Diagnostic Scale, and the new PTSD items that had been suggested by the DSM-5 Task Force of the American Psychiatric Association. Using DSM-IV, 60.4% of participants met diagnostic criteria for PTSD; using DSM-5, only 49.3% fulfilled all criteria (p < .001). Confirmatory factor analysis of DSM-IV and DSM-5 items showed good and comparable model fits. Furthermore, classification functions in the DSM-5 were satisfactory. The new Cluster D symptoms showed relatively high sensitivity, specificity, positive predictive power, and negative predictive power. The DSM-5 symptom structure appears to be applicable to traumatized refugees. Negative alterations in cognitions and mood may be especially useful for clinicians, not only to determine the extent to which an individual refugee is likely to meet criteria for PTSD, but also in providing targets for clinical intervention.


Radiographic structural abnormalities associated with premature, natural hip-joint failure.
Significant controversy exists regarding the causes of premature, natural hip-joint failure. Identification of these causes may guide future investigations targeting prevention of this disorder. The aims of this study were to: (1) determine and characterize structural abnormalities associated with premature, natural hip-joint failure, and (2) analyze disease progression in the contralateral hips of patients with femoroacetabular impingement deformities. We analyzed 604 patients (710 hips) from three different medical centers who underwent primary total hip arthroplasty at or before fifty years of age (average age, forty years). Three hundred fourteen patients (52%) were male, and 290 patients (48%) were female. The diagnoses associated with premature hip failure varied, but osteoarthritis and osteonecrosis were most common. Radiographic abnormalities associated with developmental hip dysplasia and femoroacetabular impingement were associated with the majority of osteoarthritic hips. Hips with femoroacetabular impingement deformities demonstrated distinct structural anatomy relative to asymptomatic hips, with a high prevalence of bilateral deformities. In a subgroup of seventy patients with femoroacetabular impingement deformities, contralateral radiographic disease progression or the need for total hip arthroplasty was observed in 73% of hips. Osteoarthritis and osteonecrosis are the major causes of premature hip-joint failure in young patients. Femoroacetabular impingement abnormalities are usually bilateral and are commonly associated with progression of the disease to the contralateral hip.


BioShell-Threading: versatile Monte Carlo package for protein 3D threading.
The comparative modeling approach to protein structure prediction inherently relies on a template structure. Before building a model such a template protein has to be found and aligned with the query sequence. Any error made on this stage may dramatically affects the quality of result. There is a need, therefore, to develop accurate and sensitive alignment protocols. BioShell threading software is a versatile tool for aligning protein structures, protein sequences or sequence profiles and query sequences to a template structures. The software is also capable of sub-optimal alignment generation. It can be executed as an application from the UNIX command line, or as a set of Java classes called from a script or a Java application. The implemented Monte Carlo search engine greatly facilitates the development and benchmarking of new alignment scoring schemes even when the functions exhibit non-deterministic polynomial-time complexity. Numerical experiments indicate that the new threading application offers template detection abilities and provides much better alignments than other methods. The package along with documentation and examples is available at: http://bioshell.pl/threading3d.


[Clinical characteristics, course and diagnosis of chronic progressive liver diseases in patients with a history of acute viral hepatitis].
Based on examination of 144 patients with chronic active hepatitis (CAH) and liver cirrhosis (LC) with a history of acute virus hepatitis (AVH) it was established that chronic progressive liver injuries of virus etiology with and without HB-antigenemia are characterized by the diversity of the clinico-laboratory findings determined by the involvement, in addition to the liver, of many organs and systems. The following variants of chronic AVH were recognized: (1) early development of chronic progressive liver injury due to AVH (40.4% of cases); (2) late occurrence of chronic progressive liver injury after a latent period of varying duration, namely up to 21-30 years and more (59% of cases). Late recognition of CAH and LC in patients with a history of AVH was caused, on the one hand, by a high rate of chronic progressive liver injuries after a long-term period, and on the other hand, by erroneous evaluation of extrahepatic lesions, which were the first symptoms of a chronic condition in many patients. Hepatitis virus B markers were detected in the blood serum of 44.5% of patients with CAH and LC with a history of AVH, mostly in men (55.3%) versus women (34.9%). In view of the difficulties of verifying liver injuries of virus etiology based on the laboratory research methods alone, one should be guided by a clinico-epidemiological approach to a study of CAH and LC etiology.


Evolving brand-name and generic drug competition may warrant a revision of the Hatch-Waxman Act.
The evolution of pharmaceutical competition since Congress passed the Hatch-Waxman Act in 1984 raises questions about whether the act's intended balance of incentives for cost savings and continued innovation has been achieved. Generic drug usage and challenges to brand-name drugs' patents have increased markedly, resulting in greatly increased cost savings but also potentially reduced incentives for innovators. Congress should review whether Hatch-Waxman is achieving its intended purpose of balancing incentives for generics and innovation. It also should consider whether the law should be amended so that some of its provisions are brought more in line with recently enacted legislation governing approval of so-called biosimilars, or the corollary for biologics of generic competition for small-molecule drugs.


Prospective study of hemoglobin A1c and incident carotid artery plaque in Chinese adults without diabetes.
Diabetes has been reported to be associated with carotid artery plaque (CAP). However, it remains unclear whether hemoglobin A1c (HbA1c) level, a marker for long-term glycemic status, is associated with altered CAP risk in individuals with fasting blood glucose (FBG) concentrations below the current cutoff for diabetes. Included were 16,863 Chinese adults (aged 18 years or more; 9855 men and 7008 women) with fasting blood glucose < 7.0 mmol/L at baseline (2013). Both HbA1c level and CAP (assessed via ultrasound B-mode imaging) were annually assessed during 2014-2018. All the participants were further classified into three groups based on baseline HbA1c level: ≤ 5.6%, 5.7-6.4%, and ≥ 6.5%. We used Cox proportional-hazards model to evaluate the association between HbA1c level and incident CAP, adjusting for a series of potential confounders. During 5 years of follow up, 3942 incident CAP cases were identified. Individuals with higher baseline HbA1c had higher future risk of CAP (p-trend < 0.001). In the full-adjusted model, each percent increase of HbA1c was associated with a 56% (HR = 1.56, 95% CI 1.37, 1.78) higher risk of CAP. Excluding participants with chronic inflammation, as assessed by high-sensitivity C-reactive protein and white blood cell, and those with FBG ≥ 5.6 mmol/L at baseline generated similar results. Elevated HbA1c level was associated with high risk of developing CAP in Chinese adults without FBG defined diabetes.


Factors Associated With Medical School Graduates' Intention to Work With Underserved Populations: Policy Implications for Advancing Workforce Diversity.
Given projected U.S. physician shortages across all specialties that will likely impact underserved areas disproportionately, the authors sought to explore factors most correlated with medical school graduates' intention to work with underserved populations (IWUP). Data from the 2010-2012 Association of American Medical Colleges Medical School Graduation Questionnaire (n = 40,846) were analyzed. Variables (demographics, career preference, debt burden, intention to enter loan forgiveness programs) were examined using chi-square tests and logistic regression models. Respondents included 49.5% (20,228/40,846) women, 16.6% (6,771/40,837) underrepresented minorities (URMs), and 32.4% (13,034/37,342) with primary care intent. The median educational debt was $160,000. Respondents who were women (adjusted odds ratio [aOR] 1.59, 95% confidence interval [CI] 1.49, 1.70), URMs (aOR 2.50, 95% CI 2.30, 2.72), intended to enter loan forgiveness programs (aOR 2.44, 95% CI 2.26, 2.63), intended to practice primary care (aOR 1.65, 95% CI 1.54, 1.76), and intended to emphasize nonclinical careers (aOR 1.23, 95% CI 1.11, 1.37) had greater odds of reporting IWUP. Among those who chose specialties and careers with a nonclinical emphasis, and among those with greater burdens of educational and consumer debt, URMs were nearly twice as likely as other minorities and whites to report IWUP. Findings suggest physician characteristics that may be associated with filling workforce gaps in underserved areas. Restructuring financial incentive programs to support physician leaders and specialists with characteristics associated with IWUP may complement similar policies in primary care and could have key impacts on health equity in underserved areas.


Validation and calibration of food-frequency questionnaire measurements in the Northern Sweden Health and Disease cohort.
To evaluate the reproducibility of, and to compare and calibrate, diet measures by the Northern Sweden 84-item food-frequency questionnaire (FFQ) with measures from 24-hour diet recalls (24-HDR). Randomly selected respondents from the EPIC (diet-cancer) and MONICA (diet-cardiovascular disease) study cohort in Northern Sweden were invited to answer the FFQ twice over a one-year interval (FFQ1 and FFQ2), and to complete ten 24-hour recalls (reference method) in the months between. Plasma beta-carotene concentrations were determined from a subset of 47 participants. Västerbotten and Norrbotten, Northern Sweden. Ninety-six men and 99 women, who completed the study. The reproducibility of the FFQ was high in terms of both mean energy and nutrient intakes and relative ranking of participants by intake levels (median Pearson correlation of 0.68). Moderately higher food intake frequencies were recorded by FFQ1 compared with 24-hour recalls for dairy products, bread/cereals, vegetables, fruits and potato/rice/pasta, whereas meat, fish, sweet snacks and alcoholic beverage intakes were lower. The median Spearman coefficient of correlation between FFQ1 and the average of ten 24-HDR measurements was 0.50. Daily energy and nutrient intakes were similar for FFQ1 and 24-HDR measurements, except for fibre, vitamin C, beta-carotene and retinol (FFQ1>24-HDR) and sucrose and cholesterol Pearson coefficients of correlation between FFQ1 and 24-HDR corrected for attenuation due to residual day-to-day variation in the 24-HDR measurements ranged from 0.36 to 0.79 (median 0.54). Adjustment for energy had only very moderate effects on the correlation estimates. Calibration coefficients estimated by linear regression of the 24-HDR on the FFQ1 measurements varied between 0.30 and 0.59 for all nutrients except alcohol, which had calibration coefficients close to 1.0. These low calibration coefficients indicate that relative risk estimates corresponding to an absolute difference in dietary intake levels measured by the FFQ will generally be biased towards 1.0. Plasma beta-carotene levels had a Pearson coefficient of correlation of 0.47 with the 24-HDR measurements, and of 0.23 with FFQ1 measurements. The Northern Sweden FFQ measurements have good reproducibility and an estimated level of validity similar to that of FFQ measurements in other prospective cohort studies. The results from this study will form the basis for the correction of attenuation and regression dilution biases in relative risk estimates, in future studies relating FFQ measurements to disease outcomes.


Osteopontin-positive infiltrating tumor-associated macrophages in bulky ampullary cancer predict survival.
Tumor-associated macrophages (TAMs) promote cancer cell proliferation and distant metastases. Osteopontin (OPN) is overexpressed in several human cancer cells and in TAMs. Therefore, we set out to determine the role of OPN-expressing macrophages in cancer. In 100 ampullary cancers, diffuse cytoplasmic positivity for OPN was found in infiltrating TAMs in 36 patients and marginal TAMs in 32 patients; OPN(+) macrophages were absent in 32 patients. Expression patterns of OPN in TAMs were associated with pancreatic invasion, tumor stage, TNM stage, lymphovascular invasion and recurrence with peritoneal carcinomatosis. Patients were stratified according to a median tumor size of 2 cm. Patients with tumor sizes ≥2 cm and OPN(+) infiltrating TAMs had a poorer disease-specific survival rate than those with OPN(+) marginal TAMs. Macrophage-associated cytokine expression in ampullary cancer cells was also assessed; levels of macrophage migration inhibitory factor (MIF) in cancer cells were higher than in normal duodenal mucosa. Specimens from ampullary cancer patients at National Cheng Kung University Hospital were collected for immunohistochemistry. Plasma OPN was measured by enzyme-linked immunosorbent assay. Tumor and normal epithelial cells from fresh tissues were separated by laser-assisted microdissection for reverse-transcription polymerase chain reaction and quantitative real-time PCR analyses. Expression of OPN and location of TAMs in bulky ampullary cancer predict recurrence. In addition, cytoplasmic staining of MIF is enhanced in ampullary cancer cells. Patients with bulky tumor, OPN(+) infiltrating TAMs and MIF expression had a worst disease-specific survival.


In vivo spectroscopy: optical fiber probes for clinical applications.
Fiber optic probe-based in vivo spectroscopy techniques are fast and highly objective methods for intraoperative diagnoses and minimally invasive surgical interventions for all procedures where endoscopic observations are carried out for cancers of different types. The Raman spectral features provide molecular fingerprint-type information and can reveal the subjects' pathological state in label-free manner, making endoscopy multiplexed fiber optic probe-based devices with the potential for translation from bench to bedside for routine applications. This review provides a general overview of different fiber-optic probes for in vivo measurements with emphasis on Raman spectroscopy for biomedical application. Various aspects such as fiber-optic probe, radiation source, detector, and spectrometer for extracting optimum spectral features have also been discussed. Optical spectroscopy-based fiber probe systems with 'Chip-on-Tip' technology, combined with machine learning, can in the near future, become a complementary diagnostic tool to magnetic resonance imaging (MRI), computed tomography (CT) scan, ultrasound, etc. Hyperspectral imaging and fluorescence-based devices are in the advanced stage of technology readiness level (TRL), and with advances in lasers and miniature spectroscopy systems, probe-based Raman devices are also coming up.


Home phototherapy treatment of neonatal jaundice.
A home phototherapy program for healthy, term newborns with hyperbilirubinemia (n = 62) was implemented, and results were compared prospectively with a group of term neonates who met enrollment criteria but were treated in-hospital (n = 55). The purpose of the study was to prospectively assess the feasibility, safety, and effectiveness of home phototherapy in treating uncomplicated neonatal jaundice. Infants were required to be greater than 24 hours old and to weigh at least 2,270 g (5 lb). Enrolling physicians were instructed to select infants whose clinical diagnoses and bilirubin levels allowed an adequate margin of error for a trial of home phototherapy and whose parents were capable of managing the added responsibilities of home therapy. At the time the phototherapy equipment was delivered and set up in their home, parents received extensive instruction, including how to record pertinent ongoing data on a home flow sheet. Serum bilirubin levels were measured at least daily. The preponderant diagnosis listed by enrolling physicians was "physiologic jaundice." No parent reported significant complications, and no infant required rehospitalization. Bilirubin levels decreased as rapidly in the home group as in the hospitalized control group, and duration of treatment averaged 2.8 days. About $18,000 was saved by treating these 62 infants at home compared with in-hospital costs in our community. We found home phototherapy to be a feasible, safe, and effective alternative to in-hospital phototherapy for otherwise healthy, jaundiced infants with motivated and capable parents.


The Effect of Ebola Virus Disease on Maternal and Child Health Services and Child Mortality in Sierra Leone, 2014-2015: Implications for COVID-19.
During Sierra Leone's 2014-2015 Ebola virus disease (EVD) epidemic, early reports warned of health system collapse and potential effects on other-cause mortality. These same warnings are reverberating during the COVID-19 pandemic. Consideration of the impacts of EVD on maternal and child health services from facility data can be instructive during COVID-19. We surveyed all peripheral healthcare units (PHUs) in Sierra Leone in October 2014 and March 2015 to assess closures, staffing, amenities, medicines, supplies, and service utilization during May 2014-January 2015 and October 2013-January 2014. We report PHU characteristics and service utilization changes for equivalent 4-month periods during the epidemic and the prior year. We present utilization changes by district and service type, and model excess child mortality. PHU closures (-8%) and staff attrition (-3%) were limited, but many facilities lacked amenities, medicines, and supplies. Utilization of preventive and scheduled services fell more than individualized, clinical care interventions, aside from malaria treatment which declined significantly. Ebola virus disease intensity in districts was weakly associated with utilization, aside from two districts that were severely affected. Modeling suggests utilization declines resulted in 6,782 excess under-five deaths (an increase of 21%) between 2014 and 2015. Ebola virus disease negatively affected service provision, but utilization declined relatively more, particularly for preventive and scheduled interventions. Although these findings are specific to Sierra Leone's EVD epidemic, they illustrate the magnitude of possible effects in other settings due to COVID-19-induced service disruptions, where collateral impacts on child mortality from other preventable causes may far outweigh COVID-19 mortality.


["Tendon" action of two-joint muscles during human locomotion: transfer of mechanical energy between links in shock-absorbing and push-off phases].
We hale evaluated experimentally the amounts of the mechanical energy transferred by the two-joint muscles between the links of legs during squat vertical jumps and landings after jumping down from a height of 0.5. The experiments have been conducted on file healthy subjects in the course of locomotions. The coordinates of markers attached to the subjects' bodies and the ground reaction forces have been registered. The energy transferred by the two-joint muscles from and to the links forming each joint has been determined by integration of the difference between the power developed in the joint by the control moment and the total power of the muscles serving the given joint. It has been shown, that at squat vertical jump (the push-off phase) the two-joint muscles transfer mechanical energy from the proximal links of the leg to the distal ones: from pelvis to shank (by the rectus femoris m.), and from thigh to foot (by the gastrocnemius m.). At landing (the shock-absorbing phase) the two-joint muscles transfer energy from the distal to proximal links: from foot to thigh (by the gastrocnemius m.), and from shank to pelvis (by the rectus femoris m.). Thus the one-joint muscles of the proximal links compensate for the deficiency in the force developed by the one-joint muscles of the distal links due to the "tendon action" of the two-joint muscles. During push-off, the muscles of the proximal links contribute to increase in the energy of the distal links, and in the shock-absorbing phase, to its dissipation.


Evaluation of Children's Screen Viewing Time and Parental Role in Household Context.
Limited screen time has been recommended by the American Academy of Pediatrics for all children and no screen time for children under 2 years of age. With the advancement in technology, the prevalence and detrimental effects of excess screen time on children has become a global problem that can lead to health issues such as obesity and other cardiovascular diseases among both adults and children. This article examines the drivers of screen-related sedentary behavior within the home context and reports on parents' attitude in supporting children's associated behavior. The study implemented a mixed method approach of online questionnaire and face-to-face interviews. A total of 140 questionnaires, 10 semistructured interviews, and responses from parents were used to evaluate children's behavior toward screen use and parents' perception. The analysis of the article has shown that parents are concerned about their children's screen time during weekends and holidays with a significant correlation between the number of hours their children spend on on-screen activities and their level of concern (P < .01). Also, for the same P value (P < .01), it has been found that there is a statistically significant positive relationship between children's screen time and their food and beverages consumption. Children's use of screen technology is becoming a challenge for parents as they present barriers to healthy physical activities. From the parents' viewpoint, there is a need to change the screen use habit and this requires an appropriate intervention that promotes gratifying measures to induce more active behaviors to displace screen viewing.


Angiopoietin-2 is associated with albuminuria and microinflammation in chronic kidney disease.
Although cardiovascular disease (CVD) is the leading cause of mortality in patients with chronic kidney disease (CKD), the pathophysiology is not thoroughly understood. Given that elevated albuminuria or circulating angiopoietin-2 associates with CVD and mortality in CKD patients, we were intrigued by the relationship between albuminuria and angiopoietin-2. A total of 416 patients with CKD stages 3 to 5 were stratified by urine albumin-creatinine ratio as normoalbuminuria (<30 mg/g), microalbuminuria (30-300 mg/g), or macroalbuminuria (>300 mg/g). The levels of plasma angiopoietin-2 and vascular endothelial growth factor (VEGF) increased, and soluble Tie-2 decreased in the subgroups of albuminuria; whereas angiopoietin-1 did not change. Linear regression showed a positive correlation between urine albumin-creatinine ratio (ACR) and plasma angiopoietin-2 (correlation coefficient r = 0.301, 95% confidence interval 0.211-0.386, P<0.0001), but not between ACR and VEGF or soluble Tie-2. Multivariate linear regression analysis showed that plasma angiopoietin-2 was independently associated with ACR (P = 0.025). Furthermore, plasma angiopoietin-2 was positively correlated with high sensitive C-reactive protein (r = 0.114, 95% confidence interval 0.018-0.208, P = 0.020). In conclusion, plasma angiopoietin-2 was associated with albuminuria and markers of systemic microinflammation in CKD patients. Although previous evidence has shown that angiopoietin-2 destabilizes vasculature and induces inflammation in different scenarios, further study will be required to delineate the role of angiopoietin-2 in albuminuria and microinflammation in CKD patients.


Monitoring of co-trimoxazole concentrations in serum during treatment of pneumocystis carinii pneumonia.
The purpose of this prospective randomized open trial was to investigate the impact of monitoring concentrations in serum on the efficacy and side effects of high-dose co-trimoxazole therapy. Forty consecutive patients with microscopically confirmed Pneumocystis carinii pneumonia were enrolled. Therapy was started with 5 and 25 mg of trimethoprim and sulfamethoxazole, respectively, per kg of body weight given every 6 h for 2 days and continued every 8 h either with (group A) or without (group B) monitoring and dose adjustments according to sulfamethoxazole levels in serum (target, 150 to 200 micrograms/ml) for a total of 21 days. Only 7 of 19 patients (83%). Patients who were treated for the full period and patients for whom co-trimoxazole was prematurely stopped had similar concentrations of sulfamethoxazole (157 +/- 52 versus 155 +/- 47 micrograms/ml) and trimethoprim (5.0 +/- 1.4 versus 5.6 +/- 1.0 microgram/ml). Concentrations of sulfamethoxazole and trimethoprim in group A (158 +/- 39 and 5.6 +/- 1.8 micrograms/ml, respectively) did not differ from those in group B (153 +/- 57 and 5.1 +/- 1.6 micrograms/ml, respectively), and the average daily maintenance doses for groups A (75.4 mg/kg plus 15.1 mg/kg) and B (76.4 mg/kg plus 15.3 mg/kg) were nearly identical. Although the average sulfamethoxazole concentrations were maintained within the target zone in the monitoring group (day 5, 160 +/- 44 micrograms/ml; day 10, 160 +/- 41 micrograms/ml; day 15, 168 +/- micrograms/ml; and day 21, 157 +/- 95 micrograms/ml), only 28% of the individual sulfamethoxazole levels were within the target range of 150 to 200 micrograms/ml after the dose adjustments (32% in group B without intervention). Response rates were similar in both groups. Complete response or improvement was observed in 18 of 19 (group A) and 19 of 21 (group B) patients. The method used for monitoring sulfamethoxazole levels with subsequent dose adjustment did not allow us to reliably achieve the target concentrations and did not significantly alter the incidence of side effects or the efficacy of the therapy.


Conformational dynamics of the ABC transporter McjD seen by single-molecule FRET.
ABC transporters utilize ATP for export processes to provide cellular resistance against toxins, antibiotics, and harmful metabolites in eukaryotes and prokaryotes. Based on static structure snapshots, it is believed that they use an alternating access mechanism, which couples conformational changes to ATP binding (outward-open conformation) and hydrolysis (inward-open) for unidirectional transport driven by ATP Here, we analyzed the conformational states and dynamics of the antibacterial peptide exporter McjD from Escherichia coli using single-molecule Förster resonance energy transfer (smFRET). For the first time, we established smFRET for an ABC exporter in a native-like lipid environment and directly monitor conformational dynamics in both the transmembrane- (TMD) and nucleotide-binding domains (NBD). With this, we unravel the ligand dependences that drive conformational changes in both domains. Furthermore, we observe intrinsic conformational dynamics in the absence of ATP and ligand in the NBDs. ATP binding and hydrolysis on the other hand can be observed via NBD conformational dynamics. We believe that the progress made here in combination with future studies will facilitate full understanding of ABC transport cycles.


Persons with multiple disabilities engage in stimulus choice and postural control with the support of a technology-aided program.
Technology-aided programs have been reported to help persons with disabilities develop adaptive responding and control problem behavior/posture. This study assessed one such program in which choice of stimulus events was used as adaptive responding for three adults with multiple disabilities. A computer system presented the participants stimulus samples. For each sample, they could perform a choice response (gaining access to the related stimulus whose length they could extend) or abstain from responding (making the system proceed to the next sample). Once choice responding had strengthened, the program also targeted the participants' problem posture (i.e., head and trunk forward bending). The stimulus exposure gained with a choice response was interrupted if the problem posture occurred. All three participants successfully (a) managed choice responses and access to preferred stimuli and (b) gained postural control (i.e., reducing the problem posture to very low levels). The practical implications of those results are discussed.


Development, reliability, and validity of PRESTO: a new high-variability sentence recognition test.
There is a pressing need for new clinically feasible speech recognition tests that are theoretically motivated, sensitive to individual differences, and access the core perceptual and neurocognitive processes used in speech perception. PRESTO (Perceptually Robust English Sentence Test Open-set) is a new high-variability sentence test designed to reflect current theories of exemplar-based learning, attention, and perception, including lexical organization and automatic encoding of indexical attributes. Using sentences selected from the TIMIT (Texas Instruments/Massachusetts Institute of Technology) speech corpus, PRESTO was developed to include talker and dialect variability. The test consists of lists balanced for talker gender, keywords, frequency, and familiarity. To investigate the performance, reliability, and validity of PRESTO. In Phase I, PRESTO sentences were presented in multitalker babble at four signal-to-noise ratios (SNRs) to obtain a distribution of performance. In Phase II, participants returned and were tested on new PRESTO sentences and on HINT (Hearing In Noise Test) sentences presented in multitalker babble. Young, normal-hearing adults (N = 121) were recruited from the Indiana University community for Phase I. Participants who scored within the upper and lower quartiles of performance in Phase I were asked to return for Phase II (N = 40). In both Phase I and Phase II, participants listened to sentences presented diotically through headphones while seated in enclosed carrels at the Speech Research Laboratory at Indiana University. They were instructed to type in the sentence that they heard using keyboards interfaced to a computer. Scoring for keywords was completed offline following data collection. Phase I data were analyzed by determining the distribution of performance on PRESTO at each SNR and at the average performance across all SNRs. PRESTO reliability was analyzed by a correlational analysis of participant performance at test (Phase I) and retest (Phase II). PRESTO validity was analyzed by a correlational analysis of participant performance on PRESTO and HINT sentences tested in Phase II, and by an analysis of variance of within-subject factors of sentence test and SNR, and a between-subjects factor of group, based on level of Phase I performance. A wide range of performance on PRESTO was observed; averaged across all SNRs, keyword accuracy ranged from 40.26 to 76.18% correct. PRESTO accuracy at retest (Phase II) was highly correlated with Phase I accuracy (r = 0.92, p < 0.001). PRESTO scores were also correlated with scores on HINT sentences (r = 0.52, p < 0.001). Phase II results showed an interaction between sentence test type and SNR [F(3, 114) = 121.36, p < 0.001], with better performance on HINT sentences at more favorable SNRs and better performance on PRESTO sentences at poorer SNRs. PRESTO demonstrated excellent test/retest reliability. Although a moderate correlation was observed between PRESTO and HINT sentences, a different pattern of results occurred with the two types of sentences depending on the level of the competition, suggesting the use of different processing strategies. Findings from this study demonstrate the importance of high-variability materials for assessing and understanding individual differences in speech perception.


Application of regulations to cosmetic lasers in private practice.
Recent years have seen a growth in the number of non-NHS premises, for example beauty salons, offering cosmetic laser treatments such as laser hair removal. By law, such practices are subject to registration and monitoring by Health Authorities. However, a national consensus on appropriate standards is urgently required, particularly on interpretation of the legal requirements for medical direction and operator training, in order to ensure consistency of standards in private practice with lasers across the country. This paper outlines the difficulties experienced in the inspection and registration process, and makes recommendations on appropriate interim standards, pending formal guidance from professional bodies and the promulgation of revised regulations. Until such guidance is in place, it may be wise for Health Authorities to include within their inspection protocols a requirement that applicants for laser registrations produce a statement as to the exact form which medical direction of laser treatment will take, to enable the Health Authority to consider and take advice on its suitability. Similarly a requirement that laser operators are state-registered health professionals will ensure that these potentially hazardous devices are only used by properly qualified operators, whilst professional bodies work towards a consensus on minimum training standards.


Predictive Uncertainty Underlies Auditory Boundary Perception.
Anticipating the future is essential for efficient perception and action planning. Yet the role of anticipation in event segmentation is understudied because empirical research has focused on retrospective cues such as surprise. We address this concern in the context of perception of musical-phrase boundaries. A computational model of cognitive sequence processing was used to control the information-dynamic properties of tone sequences. In an implicit, self-paced listening task (N = 38), undergraduates dwelled longer on tones generating high entropy (i.e., high uncertainty) than on those generating low entropy (i.e., low uncertainty). Similarly, sequences that ended on tones generating high entropy were rated as sounding more complete (N = 31 undergraduates). These entropy effects were independent of both the surprise (i.e., information content) and phrase position of target tones in the original musical stimuli. Our results indicate that events generating high entropy prospectively contribute to segmentation processes in auditory sequence perception, independently of the properties of the subsequent event.


Bone marrow cultures for the diagnosis of mycobacterial and fungal infections in patients infected with the human immunodeficiency virus.
University medical center. To determine the value of bone marrow cultures for mycobacteria and fungi in patients infected with the human immunodeficiency virus (HIV). Retrospective review of charts and laboratory records. From 1992-1996, 1225 bone marrow specimens were submitted for mycobacterial and fungal cultures. The number of specimens submitted,declined sharply from 435 in 1992 to 94 in 1996 (P = 0.002 for trend). The yield remained stable. Thirty-one of 1225 specimens grew mycobacteria or fungi; 26 isolates were from 24 HIV-infected patients. These 24 patients were infected with Mycobacterium avium complex (19), M. tuberculosis (one), M. chelonae (one), Histoplasma capsulatum (two), and Cryptococcus neoformans (one). All 24 HIV-infected patients had a culture submitted from at least one other site within 4 weeks of the positive bone marrow culture. The identical organism was grown from another site (usually blood) in 18 of these 24 patients. The bone marrow culture provided the only positive result in six patients and the first positive result in eight patients. Utilization of bone marrow cultures for mycobacteria and fungi declined at our institution. Bone marrow and blood cultures were highly concordant. However, the majority of positive bone marrow cultures provided useful information.


Chimeric beta-defensin analogs, including the novel 3NI analog, display salt-resistant antimicrobial activity and lack toxicity in human epithelial cell lines.
Human beta-defensins (hBDs) are crucial peptides for the innate immune response and are thus prime candidates as therapeutic agents directed against infective diseases. Based on the properties of wild-type hBD1 and hBD3 and of previously synthesized analogs (1C, 3I, and 3N), we have designed a new analog, 3NI, and investigated its potential as an antimicrobial drug. Specifically, we evaluated the antimicrobial activities of 3NI versus those of hBD1, hBD3, 1C, 3I, and 3N. Our results show that 3NI exerted greater antibacterial activity against Pseudomonas aeruginosa, Escherichia coli, and Enterococcus faecalis than did hBD1 and hBD3, even with elevated salt concentrations. Moreover, its antiviral activity against herpes simplex virus 1 was greater than that of hBD1 and similar to that of hBD3. Subsequently, we investigated the cytotoxic effects of all peptides in three human epithelial carcinoma cell lines: A549 from lung, CaCo-2 from colon, and Capan-1 from pancreas. None of the analogs significantly reduced cell viability versus wild-type hBD1 and hBD3. They did not induce genotoxicity or cause an increase in the number of apoptotic cells. Using confocal microscopy, we also investigated the localization of the peptides during their incubation with epithelial cells and found that they were distributed on the cell surface, from which they were internalized. Finally, we show that hBD1 and hBD3 are characterized by high resistance to serum degradation. In conclusion, the new analog 3NI seems to be a promising anti-infective agent, particularly given its high salt resistance--a feature that is relevant in diseases such as cystic fibrosis.


Dietary reference intakes for DHA and EPA.
Various organizations worldwide have made dietary recommendations for eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and fish intake that are primarily for coronary disease risk reduction and triglyceride (TG) lowering. Recommendations also have been made for DHA intake for pregnant women, infants, and vegetarians/vegans. A Dietary Reference Intake (DRI), specifically, an Adequate Intake (AI), has been set for alpha-linolenic acid (ALA) by the Institute of Medicine (IOM) of The National Academies. This amount is based on an intake that supports normal growth and neural development and results in no nutrient deficiency. Although there is no DRI for EPA and DHA, the National Academies have recommended that approximately 10% of the Acceptable Macronutrient Distribution Range (AMDR) for ALA can be consumed as EPA and/or DHA. This recommendation represents current mean intake for EPA and DHA in the United States ( approximately 100mg/day), which is much lower than what many groups worldwide are currently recommending. Global recommendations for long-chain omega-3 fatty acids underscore the pressing need to establish DRIs for DHA and EPA because DRIs are recognized as the "official" standard by which federal agencies issue dietary guidance or policy directives for the health and well-being of individuals in the United States and Canada. Because of the many health benefits of DHA and EPA, it is important and timely that the National Academies establish DRIs for the individual long-chain (20 carbons or greater) omega-3 fatty acids.


Stress in ASL: empirical evidence and linguistic issues.
The study of signed languages provides an opportunity to identify those characteristics of language that are universal and to investigate the effect of production modality (signed vs. spoken) on the grammar. Over time, American Sign Language (ASL) has accommodated itself to the production and perception requirements of the manual/visual modality, resulting in a prosodic system that is comparable in function to spoken languages but different in means of expression. The present focus is on phrasal prominence in ASL. I review the marking of stress and phrase boundaries in ASL, and discuss prominence assignment at the phrasal level, with brief mention of lexical stress. At the kinematic level, there is a modality effect in marking of linguistic prominence but no modality effect with respect to marking phrase position. Of significance is the fact that ASL lacks phrasal prominence plasticity, that is the ability to move prominence to mark focus in a sentence location other than phrase final. I review the typological implications of how ASL handles prominence as compared to other languages.


Baroreflex deficiency induces additional impairment of vagal tone, diastolic function and calcium handling proteins after myocardial infarction.
Baroreflex dysfunction has been considered an important mortality predictor after myocardial infarction (MI). However, the impact of baroreflex deficiency prior to MI on tonic autonomic control and cardiac function, and on the profile of proteins associated with intracellular calcium handling has not yet been studied. The aim of the present study was to analyze how the impairment of baroreflex induced by sinoaortic denervation (SAD) prior to MI in rats affects the tonic autonomic control, ventricular function and cardiomyocyte calcium handling proteins. After 15 days of following or SAD surgery, rats underwent MI. Echocardiographic, hemodynamic, autonomic and molecular evaluations were performed 90 days after MI. Baroreflex impairment led to additional damage on: left ventricular remodeling, diastolic function, vagal tonus and intrinsic heart rate after MI. The loss of vagal component of the arterial baroreflex and vagal tonus were correlated with changes in the cardiac proteins involved in intracellular calcium homeostasis. Furthermore, additional increase in sodium calcium exchanger expression levels was associated with impaired diastolic function in experimental animals. Our findings strongly suggest that previous arterial baroreflex deficiency may induce additional impairment of vagal tonus, which was associated with calcium handling proteins abnormalities, probably triggering ventricular diastolic dysfunction after MI in rats.


Is tobacco a risk factor for chronic pancreatitis and alcoholic cirrhosis?
In a case control study alcohol intake and tobacco use were assessed between 1975 and 1987 in 103 male patients suffering from alcoholic cirrhosis of the liver, in 145 patients with chronic pancreatitis, and in 264 control subjects. The patients with chronic pancreatitis were significantly younger than the patients with cirrhosis (mean (SD) age 41.92 (2.4) v 60.9 (11.6) years). Among the patients with chronic pancreatitis, 94% were both smokers and drinkers compared with 83% of patients with cirrhosis of the liver. The relative risks for each disease were calculated by conditional multiple logistic regression. Whereas daily intake of alcohol was a major risk factor for both cirrhosis of the liver and chronic pancreatitis, smoking was significantly related only to the risk of having chronic pancreatitis. Moreover, the mean age at onset of pancreatitis was lower among smokers.


A Comparison of Clinicopathologic Outcomes and Patterns of Lymphatic Spread Across Neoadjuvant Chemotherapy, Neoadjuvant Chemoradiotherapy, and Neoadjuvant Immunochemotherapy in Locally Advanced Esophageal Squamous Cell Carcinoma.
Neoadjuvant chemoradiotherapy (NCRT) is recommended as the treatment standard for locally advanced esophageal squamous cell carcinoma (ESCC). The use of immunotherapy in the neoadjuvant setting has gained attention. Multiple, clinical trials have explored the efficacy and safety of neoadjuvant immunochemotherapy (NICT). We evaluated the differences in clinicopathologic outcomes and the patterns of lymphatic spread among patients receiving neoadjuvant chemotherapy (NCT), NCRT, and NICT before esophagectomy for locally advanced ESCC. A total of 702 patients with ESCC who completed transthoracic esophagectomy followed neoadjuvant therapy were included. Pathological characteristics, including pathologic complete response (pCR), tumor regression grade (TRG) score and patterns of lymphatic spread, were evaluated. Compared with the NCT group, the NCRT group and NICT group had an advantage in pathological response (P < 0.05). The pCR rate was 8.1% in the NCT group, 29.9% in the NCRT group, and 23.6% in the NICT group. The TRG score (P < 0.05) and pathologic T stage (P < 0.05) in the NCT group were significantly higher. Compared with NICT, NCRT can significantly reduce the rate of lymph node metastasis rate in station 1R (0 vs. 3.4%, P < 0.05) and 2R (1.1% vs. 6.8%, P < 0.05). Subgroup analysis according to the tumor location distribution showed that NICT group had higher lymph node metastasis rate in station 2R (9.1%) in middle thoracic cases (P < 0.05) and in station 18 (7.5%) (P < 0.05) in lower thoracic cases. NCRT or NICT followed by surgery may result in a promising pCR rate and show a better performance in therapeutic response of primary lesion. For patients with lymph node metastasis in station 1R and 2R, NCRT should be the optimal preoperative treatment strategy.


Solid phase extraction of large volume of water and beverage samples to improve detection limits for GC-MS analysis of bisphenol A and four other bisphenols.
Solid phase extraction (SPE) of large volumes of water and beverage products was investigated for the GC-MS analysis of bisphenol A (BPA), bisphenol AF (BPAF), bisphenol F (BPF), bisphenol E (BPE), and bisphenol B (BPB). While absolute recoveries of the method were improved for water and some beverage products (e.g. diet cola, iced tea), breakthrough may also have occurred during SPE of 200 mL of other beverages (e.g. BPF in cola). Improvements in method detection limits were observed with the analysis of large sample volumes for all bisphenols at ppt (pg/g) to sub-ppt levels. This improvement was found to be proportional to sample volumes for water and beverage products with less interferences and noise levels around the analytes. Matrix effects and interferences were observed during SPE of larger volumes (100 and 200 mL) of the beverage products, and affected the accurate analysis of BPF. This improved method was used to analyse bisphenols in various beverage samples, and only BPA was detected, with levels ranging from 0.022 to 0.030 ng/g for products in PET bottles, and 0.085 to 0.32 ng/g for products in cans.


Resistance and tolerance in a host plant-holoparasitic plant interaction: genetic variation and costs.
Host organisms are believed to evolve defense mechanisms (i.e., resistance and/or tolerance) under selective pressures exerted by natural enemies. A prerequisite for the evolution of resistance and tolerance is the existence of genetic variation in these traits for natural selection to act. However, selection for resistance and/or tolerance may be constrained by negative genetic correlations with other traits that affect host fitness. We studied genetic variation in resistance and tolerance against parasitic infection and the potential fitness costs associated with these traits using a novel study system, namely the interaction between a flowering plant and a parasitic plant. In this system, parasitic infection has significant negative effects on host growth and reproduction and may thus act as a selective agent. We conducted a greenhouse experiment in which we grew host plants, Urtica dioica, that originated from a single natural population and represented 20 maternal families either uninfected or infected with the holoparasitic dodder, Cuscuta europaea. that originated from the same site. We calculated correlations among resistance, tolerance, and host performance to test for costs of resistance and tolerance. We measured resistance as parasite performance (quantitative resistance) and tolerance as the slopes of regressions relating the vegetative and reproductive biomass of host plants to damage level (measured as parasite biomass). We observed significant differences among host families in parasite resistance and in parasite tolerance in terms of reproductive biomass, a result that suggests genetic variation in these traits. Furthermore, we found differences in resistance and tolerance between female and male host plants. In addition, the correlations indicate costs of resistance in terms of host growth and reproduction and costs of tolerance in terms of host reproduction. Our results thus indicate that host tolerance and resistance can evolve as a response to infection by a parasitic plant and that costs of resistance and tolerance may be one factor maintaining genetic variation in these traits.


Intersection of group I CD1 molecules and mycobacteria in different intracellular compartments of dendritic cells.
Human CD1a, CD1b, and CD1c molecules can present mycobacterial glycolipids to T cells. Because phagosomes containing viable mycobacteria represent early endosomal compartments, we studied where mycobacterial glycolipids intersect with CD1 molecules in infected APC. CD1b and CD1c, but not CD1a, localized to late endosomes/lysosomes. CD1a and CD1c were predominantly expressed on the cell surface and in mycobacterial phagosomes of the early endosomal stage. In contrast, CD1b was present in a subset of mycobacterial phagosomes representing mature phagolysosomes. Released mycobacterial glycolipids including lipoarabinomannan and phosphatidylinositol mannosides were transported from the phagosome into late endosomes/lysosomes and to uninfected bystander cells. The macrophage mannose receptor, which has been implicated in glycolipid uptake by APC for CD1b-mediated presentation, was absent from mycobacterial phagosomes and may therefore not be involved in trafficking of glycolipids between phagosomes and late endosomes/lysosomes. In conclusion, all three CD1 molecules have access to mycobacteria and glycolipids thereof, but at different intracellular sites. This allows sampling by CD1a, CD1b, and CD1c of mycobacterial glycolipids from different intracellular sites of the infected cell, which has important implications for processing and presentation of such Ags during mycobacterial infections.


Age-job satisfaction relationship for Japanese public school teachers: a comparison of teachers' labor union members and professional and technical employee members of private company labor unions.
This study investigated the characteristics of the age-job satisfaction relationship for public school teachers. Past studies examining this relationship have found both linear and non-linear relationships. However, such studies have yet to examine these relationships by comparing job satisfaction of teachers with that of company employees in the same cultural context. In order to investigate the characteristics of Japanese teachers' working environment, we examined how different the age-job satisfaction relationships were between teachers and company employees. We conducted hierarchical polynomial regression analyses with four job satisfaction variables to compare the age-job satisfaction relationships of Japanese public elementary, junior and high school teachers with Japanese professional and technical workers who belonged to their respective labor unions. 1) Among teachers, the effects of age on overall job satisfaction and satisfaction with pay were significantly negative, and the effects of age on satisfaction with human relationships and working hours were not significant. 2) Among company employees, these four kinds of satisfactions had U shaped relationships with age. 3) Compared to company employees, teachers showed higher intrinsic satisfaction and lower extrinsic satisfaction. The age-job satisfaction relationship for teachers decreases with age. This result may be explained by the excessive workload of Japanese teachers, a characteristic of their working environment. Elderly teachers' burnout may be related to this characteristic. It may be necessary for elderly teachers to be supported in order to enhance their job satisfaction, especially extrinsic satisfaction.


Sudden death in epilepsy, surgery, and seizure outcomes: the interface between heart and brain.
A significant body of literature suggests that sudden unexpected death in epilepsy (SUDEP) has a cardiac mechanism. Although a correlation has been established between freedom from seizures and reduced SUDEP risk, the exact relationship between seizure outcomes following epilepsy surgery and SUDEP is still being studied. Emerging evidence suggests that seizure outcomes following epilepsy surgery and risk for SUDEP may both be governed by a common underlying biologic process linked to cardiac changes and autonomic dysregulation.


Conformational Properties of Aromatic Amides Bearing Imidazole Ring and Acid-Induced Trans-Cis Amide Switching.
Aromatic amides bearing secondary amide bond exist in trans conformation both in the crystal and in solution, whereas the conformation of the N-methylated derivatives is cis in the crystal and predominantly cis in various solvents. The cis conformational preference of N-alkylated benzanilide provides access to aromatic foldamers such as oligo(N-alkyl-p-benzamide)s, which adopt dynamic helical structures. Here, the conformational properties of imidazole-substituted amide in the crystal and in solution were examined. Imidazole-substituted amides 2a and 4a existed mainly in the cis conformation in solution. The ratio of the cis conformer of N-methyl-N-(1-methyl-1H-imidazol-4-yl)benzamide (4a) was smaller than that of N,1-dimethyl-N-phenyl-1H-imidazole-2-carboxamide (2a) or N-methylbenzanilide, but the introduction of a substituent strongly affected the conformer ratio. Compounds 6a and 7a bearing an electron-withdrawing group on the imidazole ring existed predominantly in trans form. On the other hand, the introduction of an electron-withdrawing group on the phenyl ring or a bulky substituent on the amide nitrogen of 4a increased the ratio of cis conformer. Further, the major conformer of N-alkylated N-imidazolylamides was switched from cis to trans by the addition of acid. These results suggest that imidazole-substituted amides might be applicable as conformational switches in aromatic foldamers to enable environment-dependent structural change.


Function of chalcone reductase gene CHR1 in soybean.
To verify the function of chalcone reductase gene (CHR1) in soybean Daidzein synthesis, CHR1 gene in soybean was cloned, and an RNAi expression vector pCPB-CHR1-RNAi was constructed. Four transformed plants in T0 generation and thirteen transformed plants in T1 generation of soybean "Jinong28" were obtained by agrobacterium-mediated genetic transformation, in which transcriptions of CHR1 gene were depressed. Southern blotting showed the functional fragment of pCPB-CHR1-RNAi was integrated into the genome of recipient soybean in the form of a single copy. Detection of the transcription of CHR1 gene using quantitative real-time PCR (qRT-PCR) showed that the expression of CHR1 gene in transformed plants decreased 60%-99% compared to the recipient soybean, while the content of isoliquiritigenin, the precursors of daidzein, decreased 38.7%. These results indicate that RNA interference can suppress the transcription of CHR1 gene expression successfully.


Imidazole-imidazole pair as a minor groove recognition motif for T:G mismatched base pairs.
The T:G mismatched base pair is associated with many genetic mutations. Understanding its biological consequences may be aided by studying the structural perturbation of DNA caused by a T:G base pair and by specific probing of the mismatch using small molecular ligands. We have shown previously that AR-1-144, a tri-imidazole (Im-Im-Im) minor groove binder, recognizes the sequence CCGG. NMR structural analysis of the symmetric 2:1 complex of AR-1-144 and GAACCGGTTC revealed that each AR-1-144 binds to four base pairs with the guanine N2 amino group forming a bifurcated hydrogen bond to a side-by-side Im/Im pair. We predicted that the free G-N2 amino group in a T:G wobble base pair can form two individual hydrogen bonds to a side-by-side Im/Im pair. Thus an Im/Im pair may be a good recognition motif for a T:G base pair in DNA. Cooperative and tight binding of an AR-1-144 homodimer to GAACTGGTTC permits a detailed structural analysis by 2D NOE NMR refinement and the refined structure confirms our prediction. Surprisingly, AR-1-144 does not bind to GAATCGGTTC. We further show that both the Im-Im-Im/Im-Py-Im heterodimer and the Im-Im-Im/Im-Im-Im homodimer bind strongly to the CACGGGTC + GACTCGTG duplex. These results together suggest that an Im/Im pair can specifically recognize a single T:G mismatch. Our results may be useful in future design of molecules (e.g. linked dimers) that can recognize a single T:G mismatch with specificity.


[Hypokalemic Paresis in Adolescent: A Case Report].
Familial hypokalaemic periodic paralysis is a rare autosomal dominant neuromuscular disease characterized by episodic attacks of flaccid paralysis with concomitant hypokalaemia. We present a case of a 15-year-old male adolescent observed in the pediatric emergency department by flaccid paresis of the 4 limbs of sudden onset and progressive worsening. In the anamnesis, corticosteroid and antihistamine intake were observed on the previous day for urticaria and family history of transient episodes of flaccid paralysis in adolescence, asymptomatic after the fourth decade of life, without an established diagnosis. Diagnostic tests revealed hypokalaemia (K + < 2.4 mEq/L), without hypokaluria and without other changes. Symptomatology resolution after supplementation with potassium was verified until normalization of kaliemia. Flaccid paralysis is a rare form of presentation of hypokalaemia. Several etiologies may be involved in the child or adolescent presenting with acute flaccid paralysis. The description of this case draws attention to the importance of the knowledge of this entity, because if recognized and treated properly, patients usually recover without sequelae.


Hypertension and Decreased Glomerular Filtration Rate Among Commercial Drivers.
Chronic Kidney Disease (CKD) is of high clinical importance due to cost of outcomes such as kidney transplantation. However, CKD is an overlooked disorder among commercial drivers. The present study aimed to evaluate hypertension and Glomerular Filtration Rate (GFR) among commercial drivers. In this cross-sectional study, a total of 903 commercial drivers referred for obtaining their health license were recruited. After obtaining informed consent, a questionnaire consisted of demographic characteristics was completed. Blood pressure, level of lipid profile, blood sugar, blood urea nitrogen, and plasma creatinine were measured. Chi-square and independent T-test were used for data analysis. All participants were male. The mean ( ± SD) age and Body mass index were 42 ± (10) years and 27 ± (4) kg/m2, respectively. Of 903 studied cases 40 (4%) had GFR < 60. Increased age and high blood pressure had a significant association with reduced GFR (P < .0001). The ones with sleep apnea were more likely to have GFR < 60, however, the association was not statistically significant after adjusting for related risk factors. Older age and hypertension are considered as risk factors for CKD among commercial drivers. Obstructive sleep apnea also should be kept in mind as a possible risk factor that requires further elucidation and management.


[Analysis of P/N leak subtraction of pClamp acquisition software].
Using blind whole cell recording technique on rat hippocampal slices, the function and mechanisms of P/N leak subtraction of Clampex program in pClamp acquisition software were studied. The ways of picking up sub-pulse current and properly selecting parameters, including time course, polarization, sub-holding potential, numbers and location of P/N sub-pulse were analyzed in detail. Our results indicate that voltage-gated ion channel currents recorded by Clampex will be more accurate and reproducible by properly using P/N leak subtraction.


Auxological and endocrine phenotype in a population-based cohort of patients with PROP1 gene defects.
Multiple pituitary hormone deficiency (MPHD) may result from defects of transcription factors that govern early pituitary development. We aimed to establish the prevalence of HESX1, PROP1, and POU1F1 gene defects in a population-based cohort of patients with MPHD and to analyse the phenotype of affected individuals. Genomic analysis was carried out on 74 children and adults with MPHD from the Czech Republic (including four sibling pairs). Phenotypic data were collected from medical records and referring physicians. One patient carried a heterozygous mutation of POU1F1 (71C > T), and 18 patients (including three sibling pairs) had a PROP1 mutation (genotypes 150delA/301delGA/9/, 301delGA/301-delGA/8/, or 301delGA/349T > A/1/). A detailed longitudinal phenotypic analysis was performed for patients with PROP1 mutations (n = 17). The mean ( +/-s.d.) birth length SDS of these patients (0.12 +/- 0.76) was lower than expected based on their mean ( +/-s.d.) birth weight SDS (0.63 +/- 1.27; P = 0.01). Parental heights were normal. The patients' mean ( +/-s.d.) height SDS declined to -1.5 +/- 0.9, -3.6 +/- 1.3 and -4.1 +/- 1.2 at 1.5, 3 and 5 years of age, respectively. GH therapy, initiated at 6.8 +/- 3.2 years of age (mean dose: 0.022 mg/kg per day), led to substantial growth acceleration in all patients. Mean adult height (n = 7) was normal when adjusted for mid-parental height. ACTH deficiency developed in two out of seven young adult patients. PROP1 defects are a prevalent cause of MPHD. We suggest that testing for PROP1 mutations in patients with MPHD might become standard practice in order to predict risk of additional pituitary hormone deficiencies.


[Polyfunctional endometrial adenocarcinoma producing melatonin, noradrenaline and chorionic gonadotropin].
Highly differentiated endometrial adenocarcinoma is described in which the cells of the APUD-system (apudocytes) producing melatonin, noradrenaline and chorionic gonadotropin are detected histochemically and immunohistochemically. The disturbance of lipid metabolism in the patient is attributed to the hyperproduction of noradrenaline and melatonin exerting a mobilizing effect on lipid metabolism.


Nanoparticle-assisted pyrrolidonyl arylamidase assay for a culture-free Group A Streptococcus pyogenes detection with image analysis.
Existing techniques for the detection of Group A Streptococcus pyogenes (GAS) have drawbacks in rapidness, accuracy or in high-cost. Considering the clinical importance of GAS, we have developed a culture-free detection method based on pyrrolidonyl arylamidase (PYR) activity with the aid of magnetic gold nanoparticles (AuNPs). GAS is the reason for pharyngitis and sampling starts from the throat with cotton swabs. After swab sampling, the target was collected with antibody modified magnetic AuNPs and transferred into 500 μL of PYR-broth without any antigen extraction or pure colony isolation. Then, the assay was finished by adding 25 μL of 4-(dimethylamino)-cinnamaldehyde (DMACA) reagent after 4-h incubation. A red color formation was evaluated as the presence of GAS comparing to blank, however, image analysis was employed for the interpretation of color changes clearly. For this purpose, a formula related to image data was proposed and analytical validation parameters were defined. Thus, the correlation was found to be linear with the R2 of 0.9685 between the log of bacteria concentration and the image data with the limit of detection of 3.3 × 102 CFU/mL of GAS. In addition, the assay worked efficiently in the abundance interference of Enterococcus faecalis. The results represent a new feature to nanoparticles eliminating the selective growth media for a bacteria and this study provided a detection with intact cells of bacteria without any antigen or DNA/RNA extraction. The proposed work has been the most similar to the gold standard but a faster method in this field.


Deletion of 5q as a rare abnormality in chronic lymphocytic leukemia.
Deletions of the long arm of chromosome 5 [del(5q)] are frequent chromosome aberrations with known prognosis in myelodysplastic syndromes and acute myeloid leukemia (AML). However, in chronic lymphocytic leukemia (CLL), they are rare and have been reported only as karyotypic results without known prognosis. In the present study, we report a novel conventional and molecular cytogenetic study of two CLL patients carrying interstitial del(5q) in order to contribute to the identification of rare recurrent aberrations and their prognostic impact in CLL. Karyotypic and fluorescence in situ hybridization analysis that used probes for the most common aberrations of CLL demonstrated that del(5q) was the sole chromosome abnormality in both patients at the time of diagnosis. None of these patients had a history of exposure to chemotherapy or radiotherapy. Both patients had disease that was still staged as Binet A at 28 and 18 months after diagnosis, respectively, without receiving any therapy because of their good clinical condition. Therefore, it could be suggested that del(5q) may not be associated with an adverse prognosis in CLL and is not related with therapy-induced chromosome changes. Further studies are required to elucidate the prognostic value of these deletions in more CLL patients, which could be advisable for prognostic and therapeutic purposes, as well as to identify candidate genes that may potentially play a role in the pathogenesis of CLL.


Tree-inspired radially aligned, bimodal graphene frameworks for highly efficient and isotropic thermal transport.
Highly-oriented, interconnected graphene frameworks have been considered as promising candidates to realize high-performance thermal management in microelectronics. However, the obvious thermal boundary resistance and anisotropic heat conduction still remain major bottlenecks for efficient heat dissipation. Herein, a biomimetic design enabled by radially aligned, bimodal graphene frameworks (RG-Fin) is proposed to achieve highly efficient and isotropic thermal transport. An interconnected RG skeleton is prepared via a radial ice-template method, serving as the primary expressway for isotropic heat conduction. Tree-leaf-like graphene nanofins are vertically grown on the RG surface to provide additional thermal pathways for bimodal phonon transportation, which can reduce the thermal boundary resistance without degrading the thermal properties of the skeleton. An RG-Fin composite exhibits a superior thermal conductivity of 4.01 W m-1 K-1 (almost 20 times that of a polymer) at an ultralow loading of 1.53 vol%, demonstrating an exceptionally large thermal conductivity enhancement efficiency of 1247%, which far exceeds those of graphene-based polymer composites. Further theoretical analysis and finite element simulations reveal the critical role of the nanofins in significantly decreasing the thermal boundary resistance (by almost 27-fold). Finally, the practical thermal management of running a CPU module is demonstrated, in which the heating-up rate of the RG-Fin composite is ∼2.0 times that of a pure polymer. This strategy provides an innovative avenue for designing radially aligned networks to realize isotropic and efficient thermoconductive composites for thermal management.


Inhibition of retinoic acid signaling in proximal tubular epithelial cells protects against acute kidney injury.
Retinoic acid receptor (RAR) signaling is essential for mammalian kidney development but, in the adult kidney, is restricted to occasional collecting duct epithelial cells. We now show that there is widespread reactivation of RAR signaling in proximal tubular epithelial cells (PTECs) in human sepsis-associated acute kidney injury (AKI) and in mouse models of AKI. Genetic inhibition of RAR signaling in PTECs protected against experimental AKI but was unexpectedly associated with increased expression of the PTEC injury marker Kim1. However, the protective effects of inhibiting PTEC RAR signaling were associated with increased Kim1-dependent apoptotic cell clearance, or efferocytosis, and this was associated with dedifferentiation, proliferation, and metabolic reprogramming of PTECs. These data demonstrate the functional role that reactivation of RAR signaling plays in regulating PTEC differentiation and function in human and experimental AKI.


Overexpression of ABCB transporter genes confer multiple insecticide tolerances in Bactrocera dorsalis (Hendel) (Diptera: Tephritidae).
Bactrocera dorsalis is a notable invasive pest that has developed resistance to several commonly used insecticides in the field, such as avermectin, beta-cypermethrin and malathion. Investigating the mechanisms of insecticide resistance in this pest is of paramount importance for ensuring its effective control. The ATP-binding cassette transporter subfamily B (ABCB) genes, responsible for encoding transmembrane efflux transporters, represent a potential source of insecticide detoxification activity or transportation that remains largely unexplored in B. dorsalis. In this study, seven BdABCB genes were identified and comprehensive analyzed based on the latest genome and transcriptome dataset. Subsequently, we characterized the expression profiles of these genes across different development stages and tissues, as well as under different insecticide exposures. The results showed that the BdABCB genes were expressed at all stages in B. dorsalis, with BdABCB2 and BdABCB7 being highly expressed in the pupal stage, while BdABCB5 and BdABCB6 were highly expressed in the larval stage. Besides, the BdABCBs were highly expressed in the detoxification metabolic tissues. Among them, BdABCB5 and BdABCB6 were significantly overexpressed in the midgut and Malpighian tubules, respectively. Furthermore, with the exception of BdABCB6, the expression levels of the other six BdABCBs were significantly up-regulated following induction with avermectin, beta-cypermethrin and malathion. Six BdABCBs (BdABCB1-5 and BdABCB7) were knocked down by RNA interference, and the interference efficiencies were 46.58%, 39.50%, 45.60%, 33.74%, 66.37% and 63.83%, respectively. After injecting dsBdABCBs, the mortality of flies increased by 25.23% to 39.67% compared to the control upon exposure to the three insecticides. These results suggested that BdABCBs play crucial roles in the detoxification or tolerance of B. dorsalis to multiple insecticides.


Suckling CD1 mice as an animal model for studies of Legionella pneumophila virulence.
On the assumption that specific host defences are lower in newborn and infant animals, the susceptibility of CD1 suckling mice to Legionella pneumophila was studied with the hypothesis that this model could detect consistent differences in virulence among Legionella isolates from various clinical and environmental sources. Mice 3-14 days old were indeed markedly susceptible to intraperitoneal challenge with fresh clinical isolates, but not to serially subcultured or type collection strains of L. pneumophila. For example, intraperitoneal inoculation of 10(7) cells of a fresh clinical isolate of L. pneumophila (strain Monza 3) caused 60% mortality of suckling mice in 1 day whereas the same number of cells of a culture-attenuated derivative (strain Monza 3p50) caused <10% mortality in >15 days. Lethal infection by the 'virulent' Monza 3 strain was strictly dependent on mouse age (no death was observed in mice >26 days old), required the inoculation of viable cells and was not related to endotoxin production. The 'virulent' L. pneumophila strain was cleared from mouse lungs less rapidly, while adhering to, and being internalised into the peritoneal exudate cells (PEC) of suckling mice to a greater extent, than the avirulent derivative, as shown by immunofluorescence and confocal microscopy. The Monza 3 strain also induced the production by PEC in vivo of 5-to-10 times more tumour necrosis factor-alpha (TNF-alpha) mRNA than the Monza 3p50 strain. Overall, suckling CD1 mice appear to provide a promising, easily handled, highly reproducible and relatively inexpensive animal model for studies of the virulence of L. pneumophila, and possibly, of the role of pro-inflammatory cytokine production in this phenomenon.


The tumor microenvironment as driver of stemness and therapeutic resistance in breast cancer: New challenges and therapeutic opportunities.
Breast cancer (BC), the second most common cause of cancer-related deaths, remains a significant threat to the health and wellness of women worldwide. The tumor microenvironment (TME), comprising cellular components, such as cancer-associated fibroblasts (CAFs), immune cells, endothelial cells and adipocytes, and noncellular components such as extracellular matrix (ECM), has been recognized as a critical contributor to the development and progression of BC. The interplay between TME components and cancer cells promotes phenotypic heterogeneity, cell plasticity and cancer cell stemness that impart tumor dormancy, enhanced invasion and metastasis, and the development of therapeutic resistance. While most previous studies have focused on targeting cancer cells with a dismal prognosis, novel therapies targeting stromal components are currently being evaluated in preclinical and clinical studies, and are already showing improved efficacies. As such, they may offer better means to eliminate the disease effectively. In this review, we focus on the evolving concept of the TME as a key player regulating tumor growth, metastasis, stemness, and the development of therapeutic resistance. Despite significant advances over the last decade, several clinical trials focusing on the TME have failed to demonstrate promising effectiveness in cancer patients. To expedite clinical efficacy of TME-directed therapies, a deeper understanding of the TME is of utmost importance. Secondly, the efficacy of TME-directed therapies when used alone or in combination with chemo- or radiotherapy, and the tumor stage needs to be studied. Likewise, identifying molecular signatures and biomarkers indicating the type of TME will help in determining precise TME-directed therapies.


[GRADE guidelines: 1. Introduction - GRADE evidence profiles and summary of findings tables].
This article is the first of a series providing guidance for the use of the GRADE system of rating quality of evidence and grading strength of recommendations in systematic reviews, health technology assessments, and clinical practice guidelines addressing alternative management options. The GRADE process begins with asking an explicit question, including specification of all important outcomes. After the evidence has been collected and summarised, GRADE provides explicit criteria for rating the quality of evidence that include study design, risk of bias, imprecision, inconsistency, indirectness, and magnitude of effect. Recommendations are characterised as strong or weak (alternative terms: conditional or discretionary) according to the quality of the supporting evidence and the balance between desirable and undesirable consequences of the alternative management options. GRADE suggests summarising evidence in succinct, transparent, and informative Summary of Findings tables that show the quality of evidence and the magnitude of relative and absolute effects for each important outcome and/or as evidence profiles that provide, in addition, detailed information about the reason for the quality of evidence rating. Subsequent articles in this series will address GRADE's approach to formulating questions, assessing quality of evidence, and developing recommendations.


Sci-Hi-C: A single-cell Hi-C method for mapping 3D genome organization in large number of single cells.
The highly dynamic nature of chromosome conformation and three-dimensional (3D) genome organization leads to cell-to-cell variability in chromatin interactions within a cell population, even if the cells of the population appear to be functionally homogeneous. Hence, although Hi-C is a powerful tool for mapping 3D genome organization, this heterogeneity of chromosome higher order structure among individual cells limits the interpretive power of population based bulk Hi-C assays. Moreover, single-cell studies have the potential to enable the identification and characterization of rare cell populations or cell subtypes in a heterogeneous population. However, it may require surveying relatively large numbers of single cells to achieve statistically meaningful observations in single-cell studies. By applying combinatorial cellular indexing to chromosome conformation capture, we developed single-cell combinatorial indexed Hi-C (sci-Hi-C), a high throughput method that enables mapping chromatin interactomes in large number of single cells. We demonstrated the use of sci-Hi-C data to separate cells by karytoypic and cell-cycle state differences and to identify cellular variability in mammalian chromosomal conformation. Here, we provide a detailed description of method design and step-by-step working protocols for sci-Hi-C.


Pre- and postnatal brain hemodynamics in pregnancies at term: correlation with Doppler ultrasound, birthweight, and adverse perinatal outcome.
To elucidate the correlation between pre- and postnatal cerebral Doppler in pregnancies close to term and to explore whether they are associated with perinatal outcome. Prospective study on singleton pregnancies at 36-37 weeks of gestation. The primary outcome was a composite score of perinatal morbidity, while secondary outcomes were adverse intra-partum outcome and abnormal acid-base status. All pregnancies underwent ultrasound assessment of umbilical artery (UA), middle cerebral artery (MCA), uterine arteries (UtAs) pulsatility index (PI), and cerebroplacental ratio (CPR). At birth, neonatal MCA PI was measured 72 h from delivery and correlated with prenatal Doppler, primary and secondary outcomes. Fisher's test and multivariate logistic regression analysis were used to analyze the data. One hundred and sixty-six fetuses with both pre- and postnatal Doppler assessment of the MCA were included in the study. The risk of composite perinatal morbidity was higher in fetuses (OR: 5.7, 95% CI 2.2-14.6) and newborns (OR: 4.1, 95% CI 1.8-9.6) with fetal MCA PI < 10th centile. Likewise, the incidence of abnormal acid-base status was higher both in fetuses (20 versus 4.2%, p = .026) and newborns (17.1 versus 3.2%, p = .001) with a low MCA PI before and at birth, respectively. At logistic regression analysis, fetal and neonatal MCAPI were independently associated with composite perinatal morbidity and abnormal acid-base status, but not with adverse intra-partum outcome. In small for gestational age (SGA) fetuses, the incidence of composite perinatal morbidity was higher in fetuses and new-borns presenting compared to those not presenting with an MCA PI < 10th centile (61.5 versus 20%, p = .003 and 52.6% versus 7.1%, p = .008, respectively), while such association was lost when considering non-SGA fetuses. A low MCA PI is associated with adverse perinatal outcome in pregnancies at term and tends to persist after birth.


Provider Counseling About and Risk Perception for Future Chronic Disease Among Women with Gestational Diabetes and Preeclampsia.
Background: Women diagnosed with gestational diabetes or preeclampsia are at a greater risk of developing future type 2 diabetes mellitus, high blood pressure, and cardiovascular disease. Increased perception of future chronic disease risk is positively associated with making health behavior changes, including in pregnant women. Although gestational diabetes is a risk factor for type 2 diabetes, few women have heightened risk perception. Little research has assessed receipt of health advice from a provider among women with preeclampsia and its association with risk perception regarding future risk of high blood pressure and cardiovascular disease. Among women with recent diagnoses of preeclampsia or gestational diabetes, we assessed associations between receipt of health advice from providers, psychosocial factors, and type of pregnancy complication with risk perception for future chronic illness. Methods: We conducted a cross-sectional analysis among 79 women diagnosed with preeclampsia and/or gestational diabetes using surveys and medical record abstraction after delivery and at 3 months postpartum. Results: Overall, fewer than half of the 79 women with preeclampsia and gestational diabetes reported receiving health advice from a provider, and women with preeclampsia were significantly less likely to receive counseling as compared with women with gestational diabetes (odds ratio 0.23). We did not identify a difference in the degree of risk perception by pregnancy complication or receipt of health advice. There were no significant differences in risk perception based on age, race, education, or health insurance coverage. Conclusions: We demonstrated that women with preeclampsia and gestational diabetes are not routinely receiving health advice from providers regarding future chronic disease risk, and that women with preeclampsia are less likely to be counseled on their risk, compared with women with gestational diabetes. Provider and patient-centered interventions are needed to improve postpartum care and counseling for women at high risk for chronic disease based on recent pregnancy complications.


L-type calcium channel blocker ameliorates diabetic encephalopathy by modulating dysregulated calcium homeostasis.
Diabetic encephalopathy is a complication of diabetes characterized by impaired cognitive functions. The objective of the present study was to examine the beneficial effect of the calcium channel blocker, nimodipine, on diabetes-induced cognitive deficits and altered calcium homeostasis in the cerebral cortex. Diabetes was induced in mice by intraperitoneal injection of streptozotocin (40 mg/kg body wt) for 5 days. Nimodipine (10 mg/kg body weight) was administered intraperitoneally to the animals every 48 hr for 8 weeks. A significant impairment in spatial learning and memory was observed in diabetic animals, which was reversed by nimodipine treatment. Diabetic animals showed increased CaV1.2 mRNA and protein expression, which might be responsible for enhanced synaptosomal calcium uptake. Nimodipine treatment was found to lower CaV1.2 mRNA, protein expression, and calcium uptake. Mitochondrial Ca(2+) uptake was reduced in diabetic brains, which was reversed with nimodipine treatment. Plasma membrane and sarcoplasmic reticulum Ca(2+) -ATPase activity was found to be significantly decreased in diabetic animals, whereas nimodipine supplementation restored the activity of both Ca(2+) -ATPases nearly to control values. Nimodipine treatment was shown to normalize intracellular free Ca(2+) levels in diabetic animals. Nimodipine was shown to attenuate increased calpain activity measured in terms of hydrolysis of fluorogenic substrate and αII-spectrin degradation. Nimodipine supplementation also reduced reactive oxygen species production and lipid peroxidation in diabetic animals. The data suggests that L-type calcium channel blocker is beneficial in preventing cognitive deficits associated with diabetic encephalopathy through modulation of dysregulated calcium homeostasis.


Weekly high-dose cisplatin is a feasible treatment option: analysis on prognostic factors for toxicity in 400 patients.
In the present study we describe the toxicity of weekly high-dose (70-85 mg x m(-2)) cisplatin in 400 patients (203 men, 197 women; median age 54 years) with advanced solid tumours treated in the period 1990-2001 who took part in phase I/II trials, investigating the feasibility and efficacy of weekly cisplatin alone, or in combination with paclitaxel or etoposide. Cisplatin was administered in 250 ml NaCl 3% over 3 h, for six intended administrations. The mean number of administrations was 5.3 (range, 1-6 administrations). Reasons not to complete six cycles were disease progression (7.5%), haematological toxicity (9%), nephrotoxicity (7%), ototoxicity (2.5%), neurotoxicity (1%), gastrointestinal toxicity (1%), cardiovascular complications (0.5%) or a combination of reasons including noncompliance and patient's request (5.5%). Logistic regression analysis was used to evaluate baseline parameters for prognostic value regarding toxicity. Leukopenia correlated with etoposide cotreatment, and thrombocytopenia with cisplatin dose and prior (platinum-based) chemotherapy. Risk factors for nephrotoxicity were older age, female gender, smoking, hypoalbuminaemia and paclitaxel coadministration. Neurotoxicity >grade 1 (11% of patients) was associated with prior chemotherapy and paclitaxel coadministration. Symptomatic hearing loss occurred in 15% with anaemia as the predisposing factor. We conclude that weekly high-dose cisplatin administered in hypertonic saline is a feasible treatment regimen.


Illustrating potential efficiency gains from using cost-effectiveness evidence to reallocate Medicare expenditures.
The Centers for Medicare & Medicaid Services does not explicitly use cost-effectiveness information in national coverage determinations. The objective of this study was to illustrate potential efficiency gains from reallocating Medicare expenditures by using cost-effectiveness information, and the consequences for health gains among Medicare beneficiaries. We included national coverage determinations from 1999 through 2007. Estimates of cost-effectiveness were identified through a literature review. For coverage decisions with an associated cost-effectiveness estimate, we estimated utilization and size of the "unserved" eligible population by using a Medicare claims database (2007) and diagnostic and reimbursement codes. Technology costs originated from the cost-effectiveness literature or were estimated by using reimbursement codes. We illustrated potential aggregate health gains from increasing utilization of dominant interventions (i.e., cost saving and health increasing) and from reallocating expenditures by decreasing investment in cost-ineffective interventions and increasing investment in relatively cost-effective interventions. Complete information was available for 36 interventions. Increasing investment in dominant interventions alone led to an increase of 270,000 quality-adjusted life-years (QALYs) and savings of $12.9 billion. Reallocation of a broader array of interventions yielded an additional 1.8 million QALYs, approximately 0.17 QALYs per affected Medicare beneficiary. Compared with the distribution of resources prior to reallocation, following reallocation a greater proportion was directed to oncology, diagnostic imaging/tests, and the most prevalent diseases. A smaller proportion of resources went to cardiology, treatments (including drugs, surgeries, and medical devices, as opposed to nontreatments such as preventive services), and the least prevalent diseases. Using cost-effectiveness information has the potential to increase the aggregate health of Medicare beneficiaries while maintaining existing spending levels.


Osteonecrosis in retrieved femoral heads after failed resurfacing arthroplasty of the hip.
We present the histological findings of bone retrieved from beneath the femoral components of failed metal-on-metal hip resurfacing arthroplasties. Of a total of 377 patients who underwent resurfacing arthroplasty, 13 required revision; for fracture of the femoral neck in eight, loosening of a component in three and for other reasons in two. None of these cases had shown histological evidence of osteonecrosis in the femoral bone at the time of the initial implantation. Bone from the remnant of the femoral head showed changes of osteonecrosis in all but one case at revision. In two cases of fracture which occurred within a week of implantation, the changes were compatible with early necrosis of the edge of the fracture. In the remaining six fractures, there were changes of established osteonecrosis. In all but one of the non-fracture cases, patchy osteonecrosis was seen. We conclude that histological evidence of osteonecrosis is a common finding in failed resurfaced hips. Given that osteonecrosis is extensive in resurfaced femoral heads which fail by fracture, it is likely to play a role in the causation of these fractures.


Gliomatosis cerebri: clinical characteristics, management, and outcomes.
Gliomatosis cerebri is a rare diffusely infiltrating primary neoplastic glial process of the brain. Our objective is to review clinical presentation, management, and outcome in a large single institution series of gliomatosis cerebri patients. 54 consecutive gliomatosis cerebri cases presenting to Mayo Clinic Rochester between 1991 and 2008 were retrospectively reviewed. Inclusion criteria included involvement of at least three cerebral lobes, lack of a single discrete mass and pathological confirmation of diffuse glioma. Median overall survival (OS) was 18.5 months. Age, gender, presenting symptoms, and contrast enhancement did not correlate significantly with survival, though there was a trend toward decreased overall survival in patients above the median age of 46 years. Karnofsky performance score <70 was associated with poor OS (median 9.5 vs. 20.5 months, p = 0.02). Higher histologic grade was associated with poor progression-free survival (PFS; median for WHO grades II, III, and IV: 21.5, 6.5, and 4 months; p = 0.03) and OS (median 34, 15.5, and 8.5 months; p < 0.05). Radiation therapy was strongly associated with better prognosis (PFS 16.5 vs. 4.5 months, p < 0.01; OS 27.5 vs. 6.5, p < 0.01), but chemotherapy was not. Gliomatosis cerebri patients have a poor prognosis. Lower KPS upon presentation and higher histologic grade predict decreased survival. Surgery's role is limited beyond biopsy for diagnostic purposes. Radiotherapy appears beneficial, although selection bias could be present in this retrospective study. Chemotherapy's value is not as clear but this must be interpreted with caution given variable treatment regimens in this series.


[Philosophical aspects of the theory of adaptation].
This paper discusses the general concepts of the problem of adaptation from the dialectic point of view which, according to F. Engels, is the most important pattern of thinking in natural sciences. Dialectics provides an analog and therefore a method for interpreting developmental processes, universal relationships in nature, transition from one area of research to another. From the point of view of dialectic laws adaptation acts as a contradictory process of habituation to various environments. The contradictory pattern of the adaptive process and its result is very distinct in terms of heredity and variability. A logical enlargement of the concept of adaptation is the transition to the study of homeostasis which is assumed to be its mechanism, a property which has developed in the course of evolution and fixed in heredity. This adaptive property is contradictory in its essence because homeostasis is a unity of stability and instability, a fluctuating constancy. In addition to the law of constancy of the inner melieu, there is a law of homeostatic deviations. This concept can be understood through an analysis of the system theory that includes a continuous variation and conservation of structure which indicates its ordered oscillation, that is, its rhythmicity. This clarifies the relationship between homeostasis and biological rhythmicity as a method of maintaining the former. Thus, a consistent analysis of the problem of adaptation can help identify transition from one area of research to another, specifically to the study of oscillatory processes in living systems, including such oscillatory processes that have characteristics of universality and necessity. Such processes are biological rhythms with a period of about 24 hours, that is, circadian rhythms.


Tissue synchronisation imaging accurately measures left ventricular dyssynchrony and predicts response to cardiac resynchronisation therapy.
Tissue synchronisation imaging (TSI) is a new technique to assess left ventricular (LV) dyssynchrony. The value of using TSI to automatically assess LV dyssynchrony compared with manual assessment of LV dyssynchrony from colour-coded tissue Doppler imaging (TDI), and to evaluate the value of TSI to predict response to cardiac resynchronisation therapy (CRT). 60 symptomatic patients with heart failure with depressed LV ejection fraction (LVEF) and QRS >120 ms were evaluated clinically and echocardiographically at baseline and after 6 months of CRT. LV dyssynchrony was measured manually using velocity tracings from the colour-coded TDI and automatically using TSI. LV volumes and LVEF were assessed from two-dimensional echocardiography. Clinical responders had to exhibit an improvement in New York Heart Association functional class by > or =1 score and an improvement by > or =25% in 6 min walking distance after 6 months. Reverse LV remodelling was defined as a reduction of > or =15% LV end-systolic volume. An excellent correlation was observed between LV dyssynchrony measured manually and automatically derived by TSI (r = 0.95, p<0.001). 34 patients showed clinical response after 6 months of CRT and 32 patients showed reverse remodelling. Baseline characteristics were comparable between responders and non-responders, except for more extensive LV dyssynchrony in the responders: 78 (26) vs 29 (29) ms (p<0.001) as assessed manually, and 79 (29) vs 28 (27) ms (p<0.001) as assessed with TSI. Using a cut-off value of 65 ms to define extensive LV dyssynchrony, TSI had a sensitivity of 81% with a specificity of 89% to predict reverse LV remodelling. TSI allows automatic and reliable assessment of LV dyssynchrony and predicts reverse LV remodelling after CRT.


Adjuvant therapy of colon cancer.
Colon cancer is an important cause of cancer-related mortality. A series of clinical trials of adjuvant systemic therapy have been performed in attempt to establish means to improve outcome in this disease. By the early 1990s, a role for 5-fluorouracil (5-FU)-based chemotherapy in stage III colon cancer had been firmly established. The precise role for chemotherapy in stage II disease remains under investigation. Progress continues toward optimizing the schedule and duration of systemic therapy, allowing for maximal efficacy with a minimum of toxicity. It appears that approximately 6 months of 5-FU and leucovorin are as effective as more prolonged regimens. Levamisole does not appear to add to the benefit of 5-FU and leucovorin. Several newer agents such as the oral fluorinated pyrimidines, irinotecan (CPT-11) and oxaliplatin have demonstrated activity in metastatic colon cancer and hold promise as potentially effective drugs to be tested in the adjuvant setting.


Bioelectrochemical enzyme immunoassay of human choriogonadotropin with magnetic electrodes.
We describe an amperometric technique for quantification of an enzyme immunoassay in which we use a magnetic working electrode, both to separate bound and free analyte and to monitor the electrochemical response. We used a "two-site" immunometric assay with monoclonal antibodies for human choriogonadotropin (hCG) as a model system in which magnetic particles were used as the solid phase. Separation of bound and free label is readily achieved by localizing the particles at the electrode. Activity of the bound enzyme in the environment of the electrode is determined electrochemically, permitting rapid quantification of the analyte without the need for a separate incubation step to measure enzyme activity. The sensitivity of the system is 150 int. units of hCG per litre (1st Int. Ref. Preparation). Correlation between the amperometric measurement of urinary hCG and data for an immunoradiometric assay was r = 0.9. The assay is rapid, requiring a total assay time for each sample of 20 min, which includes 15 min for antibody/antigen binding.