Development of a prognostic naive bayesian classifier for successful treatment of nonunions.
predictive models permitting individualized prognostication for patients with fracture nonunion are lacking. The objective of this study was to train, test, and cross-validate a Bayesian classifier for predicting fracture-nonunion healing in a population treated with extracorporeal shock wave therapy. prospectively collected data from 349 patients with delayed fracture union or a nonunion were utilized to develop a naïve Bayesian belief network model to estimate site-specific fracture-nonunion healing in patients treated with extracorporeal shock wave therapy. Receiver operating characteristic curve analysis and tenfold cross-validation of the model were used to determine the clinical utility of the approach. predictors of fracture-healing at six months following shock wave treatment were the time between the fracture and the first shock wave treatment, the time between the fracture and the surgery, intramedullary stabilization, the number of bone-grafting procedures, the number of extracorporeal shock wave therapy treatments, work-related injury, and the bone involved (p < 0.05 for all comparisons). These variables were all included in the naïve Bayesian belief network model. a clinically relevant Bayesian classifier was developed to predict the outcome after extracorporeal shock wave therapy for fracture nonunions. The time to treatment and the anatomic site of the fracture nonunion significantly impacted healing outcomes. Although this study population was restricted to patients treated with shock wave therapy, Bayesian-derived predictive models may be developed for application to other fracture populations at risk for nonunion. prognostic Level II. See Instructions to Authors for a complete description of levels of evidence.


The reality of hospitalisation: Stories from family members of their hospital experience for adolescents and young adults living with and dying from cancer.
Abstract Background: Adolescents and Young Adults (AYA) with cancer are being disadvantaged within the present health care system. Some of the factors identified as leading to this disadvantage include medical issues specific to AYAs with cancer, delay in diagnosis, fragmented services, lack of access to clinical trials and psychosocial life stage issues Objective: A major study investigated the experience that accompanies the stages of diagnosis, treatment, dying and death of an AYA from the perspective of family members. This paper discusses the major theme of the reality of hospitalisation Methods: Narrative inquiry was the methodology for this study. The participants were a self-selected purposeful sample of 26 family members. Open-ended interviews were conducted to obtain a story of the experience of having an AYA family member live with and die of cancer. A meta-narrative of the family member's experience was developed by NVivo8. Results: In amongst the mass of data this study produced, a major theme to emerge was the experience 'of the reality of hospitalisation.' Within this theme issues regarding: the place of treatment; the hospital experience; not fitting in; and, confronting illness and death were revealed. Conclusion: While on the whole the cancer was treated with state of the art medicine, the experiences of the hospitalisation repeated consistently throughout this narrative reveals a failure to meet the higher order needs specific to adolelscents and young adults and their families As a result this cohort were exposed to a landscape which did not facilitate a therapeutic experience, as well as would be expected for children and older adults.


QTc Prolongation in Pediatric Patients with Diabetic Ketoacidosis.
To investigate the association between diabetic ketoacidosis (DKA) and prolonged QTc interval and to assess for correlation between DKA severity and QTc prolongation. Retrospective observational study in a pediatric hospital. Patients admitted with DKA diagnosed by laboratory criteria and an electrocardiogram (ECG) performed during a period of acidosis were identified using Looking Glass Clinical Analytics. Data including age, sex, pH, electrolytes, anion gap, and ECG variables were collected. Patients were excluded if they had a prior diagnosis of prolonged QTc or were taking QTc prolonging medications. Severity of DKA was classified as mild (pH 7.24-7.3), moderate (pH 7-7.24), or severe (pH <7). ECGs were read by a pediatric electrophysiologist and QTc interval was manually calculated utilizing the Bazett formula. Ninety-six patients were included (mean age 15.2 ± 4.2 years, pH 7.12 ± 0.12, bicarbonate 8.6 ± 3.7 mmol/L, potassium 5.3 ± 1.1 mEq/L). Mean QTc interval for all patients in DKA was 454 ± 32 msec. Mean QTc in the mild group was 441 ± 22 msec, moderate group 460 ± 36 msec, and severe group 461 ± 34 msec. There was a significant difference in QTc interval across DKA severity groups (P = .05). There was a significant association between higher anion gaps and greater QTc intervals (r = 0.21, P = .04). Thirty-one percent of pediatric patients with DKA demonstrated QTc prolongation on ECG. Severity of DKA and worsening acidosis were associated with increased prolongation of the QTc. Further study is required to evaluate the clinical impact of these findings.


Objective Identification of Simulated Cochlear Implant Settings in Normal-Hearing Listeners Via Auditory Cortical Evoked Potentials.
Providing cochlear implant (CI) patients the optimal signal processing settings during mapping sessions is critical for facilitating their speech perception. Here, we aimed to evaluate whether auditory cortical event-related potentials (ERPs) could be used to objectively determine optimal CI parameters. While recording neuroelectric potentials, we presented a set of acoustically vocoded consonants (aKa, aSHa, and aNa) to normal-hearing listeners (n = 12) that simulated speech tokens processed through four different combinations of CI stimulation rate and number of spectral maxima. Parameter settings were selected to feature relatively fast/slow stimulation rates and high/low number of maxima; 1800 pps/20 maxima, 1800/8, 500/20 and 500/8. Speech identification and reaction times did not differ with changes in either the number of maxima or stimulation rate indicating ceiling behavioral performance. Similarly, we found that conventional univariate analysis (analysis of variance) of N1 and P2 amplitude/latency failed to reveal strong modulations across CI-processed speech conditions. In contrast, multivariate discriminant analysis based on a combination of neural measures was used to create "neural confusion matrices" and identified a unique parameter set (1800/8) that maximally differentiated speech tokens at the neural level. This finding was corroborated by information transfer analysis which confirmed these settings optimally transmitted information in listeners' neural and perceptual responses. Translated to actual implant patients, our findings suggest that scalp-recorded ERPs might be useful in determining optimal signal processing settings from among a closed set of parameter options and aid in the objective fitting of CI devices.


Protective Prevention Effects on the Association of Poverty With Brain Development.
This study was designed to determine whether a preventive intervention focused on enhancing supportive parenting could ameliorate the association between exposure to poverty and brain development in low socioeconomic status African American individuals from the rural South. To determine whether participation in an efficacious prevention program designed to enhance supportive parenting for rural African American children will ameliorate the association between living in poverty and reduced hippocampal and amygdalar volumes in adulthood. In the rural southeastern United States, African American parents and their 11-year-old children were assigned randomly to the Strong African American Families randomized prevention trial or to a control condition. Parents provided data used to calculate income-to-needs ratios when children were aged 11 to 13 years and 16 to 18 years. When the participants were aged 25 years, hippocampal and amygdalar volumes were measured using magnetic resonance imaging. Household poverty was measured by income-to-needs ratios. Young adults' whole hippocampal, dentate gyrus, and CA3 hippocampal subfields as well as amygdalar volumes were assessed using magnetic resonance imaging. Of the 667 participants in the Strong African American Families randomized prevention trial, 119 right-handed African American individuals aged 25 years living in rural areas were recruited. Years lived in poverty across ages 11 to 18 years forecasted diminished left dentate gyrus (simple slope, -14.20; standard error, 5.22; P = .008) and CA3 (simple slope, -6.42; standard error, 2.42; P = .009) hippocampal subfields and left amygdalar (simple slope, -34.62; standard error, 12.74; P = .008) volumes among young adults in the control condition (mean [SD] time, 2.04 [1.88] years) but not among those who participated in the Strong African American Families program (mean [SD] time, 2.61 [1.77] years). In this study, we described how participation in a randomized clinical trial designed to enhance supportive parenting ameliorated the association of years lived in poverty with left dentate gyrus and CA3 hippocampal subfields and left amygdalar volumes. These findings are consistent with a possible role for supportive parenting and suggest a strategy for narrowing social disparities.


Targeting Ovarian Cancer Cells Overexpressing CD44 with Immunoliposomes Encapsulating Glycosylated Paclitaxel.
Paclitaxel (PTX) is one of the front-line drugs approved for the treatment of ovarian cancer. However, the application of PTX is limited due to the significant hydrophobicity and poor pharmacokinetics. We previously reported target-directed liposomes carrying tumor-selective conjugated antibody and encapsulated glycosylated PTX (gPTX-L) which successfully overcome the PTX limitation. The tubulin stabilizing activity of gPTX was equivalent to that of PTX while the cytotoxic activity of gPTX was reduced. In human ovarian cancer cell lines, SK-OV-3 and OVK18, the concentration at which cell growth was inhibited by 50% (IC50) for gPTX range from 15⁻20 nM, which was sensitive enough to address gPTX-L with tumor-selective antibody coupling for ovarian cancer therapy. The cell membrane receptor CD44 is associated with cancer progression and has been recognized as a cancer stem cell marker including ovarian cancer, becoming a suitable candidate to be targeted by gPTX-L therapy. In this study, gPTX-loading liposomes conjugated with anti-CD44 antibody (gPTX-IL) were assessed for the efficacy of targeting CD44-positive ovarian cancer cells. We successfully encapsulated gPTX into liposomes with the loading efficiency (LE) more than 80% in both of gPTX-L and gPTX-IL with a diameter of approximately 100 nm with efficacy of enhanced cytotoxicity in vitro and of convenient treatment in vivo. As the result, gPTX-IL efficiently suppressed tumor growth in vivo. Therefore gPTX-IL could be a promising formulation for effective ovarian cancer therapies.


Single-Cell Transcriptomics and In Situ Morphological Analyses Reveal Microglia Heterogeneity Across the Nigrostriatal Pathway.
Microglia are the resident immune effector cells of the central nervous system (CNS) rapidly reacting to various pathological stimuli to maintain CNS homeostasis. However, microglial reactions in the CNS may also worsen neurological disorders. Hence, the phenotypic analysis of microglia in healthy tissue may identify specific poised subsets ultimately supporting or harming the neuronal network. This is all the more important for the understanding of CNS disorders exhibiting regional-specific and cellular pathological hallmarks, such as many neurodegenerative disorders, including Parkinson's disease (PD). In this context, we aimed to address the heterogeneity of microglial cells in susceptible brain regions for PD, such as the nigrostriatal pathway. Here, we combined single-cell RNA-sequencing with immunofluorescence analyses of the murine nigrostriatal pathway, the most affected brain region in PD. We uncovered a microglia subset, mainly present in the midbrain, displaying an intrinsic transcriptional immune alerted signature sharing features of inflammation-induced microglia. Further, an in situ morphological screening of inferred cellular diversity showed a decreased microglia complexity in the midbrain when compared to striatum. Our study provides a resource for the identification of specific microglia phenotypes within the nigrostriatal pathway, which may be relevant in PD.


The effect of subcutaneous Insulin-like Growth Factor-1 (IGF-1) injection on rabbit auricular cartilage autograft viability.
Insulin-like Growth Factor-1 (IGF-1) is one of the significant substances affecting the growth and development of cartilage tissue in the body. The aim of this study is to evaluate the possible histopathological effects of local IGF-1 injection on the viability of rabbit auricular cartilage autografts. To this end, the single-piece and sliced cartilage tissues obtained from 20 albino rabbits' auricula were implanted in the subcutaneous pockets created on the back skins of the experimental animals. Every two weeks IGF-1 (10 mg/ml) injections were performed on the autograft implants of one group and normal saline (0.9%) injections were performed on the other group. Experimental animals were sacrificed at the end of the third month. A total of 34 tissue samples obtained after dissection were evaluated and scored histopathologically according to their cartilage viability, environmental reaction, and regenerative activities. The intergroup evaluation carried out for the single-piece and sliced cartilage grafts revealed that there was statistically more cartilage viability and less foreign-body reaction in the IGF-1 group than the normal saline group (p<0.05). While there was a statistically significant difference between the groups for single-piece grafts regarding regenerative activity (p<0.05), there was no significant difference for sliced grafts. The IGF-1 group, however, showed more activity. The results we obtained point out to the fact that IGF-1 increases the tissue viability of the implanted auricular autograft and it suppresses immune modulation effect.


Effects of Vessel Tortuosity on Coronary Hemodynamics: An Idealized and Patient-Specific Computational Study.
Although coronary tortuosity can influence the hemodynamics of coronary arteries, the relationship between tortuosity and flow has not been thoroughly investigated partly due to the absence of a widely accepted definition of tortuosity and the lack of patient-specific studies that analyze complete coronary trees. Using a computational approach we investigated the effects of tortuosity on coronary flow parameters including pressure drop, wall shear stress, and helical flow strength as measured by helicity intensity. Our analysis considered idealized and patient-specific geometries. Overall results indicate that perfusion pressure decreases with increased tortuosity, but the patient-specific results show that more tortuous vessels have higher physiological wall shear stress values. Differences between the idealized and patient-specific results reveal that an accurate representation of coronary tortuosity must account for all relevant geometric aspects, including curvature imposed by the heart shape. The patient-specific results exhibit a strong correlation between tortuosity and helicity intensity, and the corresponding helical flow contributes directly to the observed increase in wall shear stress. Therefore, helicity intensity may prove helpful in developing a universal parameter to describe tortuosity and assess its impact on patient health. Our data suggest that increased tortuosity could have a deleterious impact via a reduction in coronary perfusion pressure, but the attendant increase in wall shear stress could afford protection against atherosclerosis.


ERG expression in chondrogenic bone and soft tissue tumours.
We studied ERG expression in a large series of chondrogenic bone and soft tissue tumours to assess the value of ERG as a possible marker of chondroid/cartilaginous differentiation. Formalin-fixed, paraffin-embedded whole sections from 111 bone and soft tissue tumours with chondroid differentiation or a morphology that may mimic cartilaginous differentiation were retrieved. Immunohistochemistry was performed using anti-ERG monoclonal antibody directed against the N terminus. Nuclear staining was scored as negative (<5%), 1+ (5%-25%), 2+ (26%-50%), 3+ (>51%). Nuclear ERG expression was seen in all cases of soft tissue chondroma (8), chondromyxoid fibroma (7), chondroblastic osteosarcoma (6) and clear cell chondrosarcoma (1). 10/12 conventional chondrosarcomas were also positive for ERG. In cases of dedifferentiated chondrosarcoma, the well-differentiated component was positive in 7/9 cases, while all dedifferentiated foci were negative. In cases of mesenchymal chondrosarcoma, the hyaline cartilage component was positive in 2/4 cases, whereas the primitive component in all cases was negative. Variable positivity was identified in extraskeletal myxoid chondrosarcomas (4/9), chondroblastomas (3/8) and mixed tumours/myoepitheliomas (2/11). Only 1/12 chordoma was positive for ERG (1+). Interestingly, 15/17 enchondromas were negative for ERG. In this study, we further characterise the expression of ERG in mesenchymal tumours and found relatively constant nuclear ERG expression in selected chondrogenic tumours including conventional chondrosarcoma, chondromyxoid fibroma, chondroblastic osteosarcoma and clear cell chondrosarcoma. We also show that ERG may be a helpful ancillary tool in certain select diagnostic scenarios and that awareness of ERG expression in tumours with cartilaginous differentiation is important.


[Origin of ovarian epithelial inclusions and its relationship with the development of low-grade serous carcinoma].
To investigate the possible origin of ovarian epithelial inclusions and its relationship with the low-grade ovarian serous carcinoma. By comparatively evaluating the morphologic (secretory and ciliated cell distribution) and immunophenotypic [using paired box gene 8 (PAX8), tubulin, calretinin, and Ki-67 as first antibodies] attributes of ovarian epithelial inclusions, the normal tubal epithelium, and the ovarian tumors, all adnexal tissues from a total of 198 patients were studied, including 116 adnexae removed for non-neoplastic indications, 53 serous cystadenomas, 44 serous borderline tumors, and 41 low-grade serous carcinomas, which were collected from Qilu Hospital of Shandong University and University of Arizona in USA. Immunohistochemical single staining was used to detect the expressions of PAX8, tubulin, calretinin, and Ki-67 in the two groups, while immunohistochemical double staining of PAX8/calretinin was used to figure out the immunophenotype of various ovarian epithelial inclusions in a more intuitive way. With immunohistochemical single staining of PAX8 and calretinin, the vast majority (90%, 54/60) of ovarian surface epithelia displayed a mesothelial phenotype [calretinin(+), PAX8(-)], whereas 10% (6/60) of the cases displayed foci with tubal phenotype [calretinin(-), PAX8(+)]. In contrast, most (79%, 728/921) of the ovarian epithelial inclusions displayed a tubal phenotype, though 21% (193/921) of the ovarian epithelial inclusions showed a mesothelial phenotype. It was further proved by immunohistochemical double staining of PAX8/calretinin. Secretory and ciliated cells were found in the ovarian epithelial inclusions with tubal phenotype. There was a progressive increase in the secretory/ciliated cells ratio and proliferative index, from ovarian epithelial inclusions/cystadenomas to borderline tumors to low-grade serous carcinoma, according to the expression of tubulin and Ki-67. The findings make a strong argument that the ovarian epithelial inclusions displaying a tubal phenotype with PAX8(+), calretinin(-) is likely derived from fallopian tube rather than through Mullerian metaplasia from ovarian surface epithelium. The increasing trend of secretory/ciliated cells ratio and proliferative index from ovarian epithelial inclusions/cystadenomas to borderline tumors to low-grade serous carcinoma indicates that the latter is a clonal expansion of secretory cells. Genetic and molecular studies are needed to further confirm these findings.


Telomere content and risk of second malignant neoplasm in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.
Shorter constitutional telomere length has been associated with increased cancer incidence. Furthermore, telomere shortening is observed in response to intensive chemotherapy and/or ionizing radiation exposure. We aimed to determine whether less telomere content was associated with treatment-related second malignant neoplasms (SMN) in childhood cancer survivors. Using a nested case-control design, 147 cancer survivors with breast cancer, thyroid cancer, or sarcoma developing after treatment for childhood cancer (cases) were matched (1:1) with childhood cancer survivors without a SMN (controls). Cases and controls were matched by primary cancer diagnosis, years since diagnosis, age at the time of sample collection, years of follow-up from childhood cancer diagnosis, exposure to specific chemotherapy agents, and to specific radiation fields. We performed conditional logistic regression using telomere content as a continuous variable to estimate ORs with corresponding 95% confidence intervals (CI) for development of SMN. ORs were also estimated for specific SMN types, i.e., breast cancer, thyroid cancer, and sarcoma. There was an inverse relationship between telomere content and SMN, with an adjusted OR of 0.3 per unit change in telomere length to single-copy gene ratio (95% CI, 0.09-1.02; P = 0.05). Patients with thyroid cancer SMN were less likely to have more telomere content (OR, 0.04; 95% CI, 0.00-0.55; P = 0.01), but statistically significant associations could not be demonstrated for breast cancer or sarcoma. A relation between less telomere content and treatment-related thyroid cancer was observed, suggesting that shorter telomeres may contribute to certain SMNs in childhood cancer survivors.


A phase II study with cetuximab and radiation therapy for patients with surgically resectable esophageal and GE junction carcinomas: Hoosier Oncology Group G05-92.
On the basis of the promising activity of cetuximab and radiation therapy for head and neck cancers, we evaluated the efficacy of this regimen followed by surgery in patients with resectable esophageal cancer. This was a phase II, open-label, single-arm, multicenter study of patients with potentially resectable esophageal cancer. Patients received two weekly doses of cetuximab followed by weekly cetuximab combined with radiation therapy for 6 weeks. After a 6- to 8-week rest, patients' primary tumor was resected. The main objective was to evaluate pathologic complete response (pCR) rate in the primary tumor after cetuximab and radiation therapy. Thirty-nine patients completed the study. Most patients were men (93%), median age was 64 years, performance status was 0 to 1 (95%), patients had a histology of adenocarcinoma (78%), and tumors were located in the esophagus (63%). Grade 3 toxicities in more than 5% of patients included dysphagia (17%), anorexia and dehydration (7%), and dyspnea, fatigue, hypernatremia (5%). Grade 5 aspiration occurred in 2% (1 patient). Four patients died, two from disease progression, one from aspiration pneumonia postsurgery, and one from septic shock. Thirty-one patients (76%) underwent esophagectomy. The pCR rate was 36.6% by intention-to-treat and 48% for patients who underwent esophagectomy. The pCR by histology was 6 of 9 (67%) for squamous cell carcinomas and 9 of 32 (28%) for adenocarcinoma. Earlier-stage disease was associated with increased pCR (IIA 70%, IIB 29%, III 28%). Cetuximab and radiation therapy results in a pCR rate that seems at least comparable with that of chemotherapy and radiation therapy. This regimen may be better tolerated than preoperative chemotherapy and radiation therapy in patients with resectable esophageal cancers.


Inhomogeneous Quadriceps Femoris Hypertrophy in Response to Strength and Power Training.
Previous studies have reported inhomogeneous changes in quadriceps femoris (QF) cross-sectional area (CSA) in response to strength training. It is assumed that these differential changes in muscle shape influence the muscle's functional capacity during high-force and high-power movements. The purpose of the current study was to compare intermuscular and intramuscular QF adaptations to high-load strength training and fast-speed power training. Thirty-six non-strength-trained men were randomly assigned to four groups and completed 8 wk of parallel-depth heavy squat-lift training (HS-P), parallel-depth jump squat training (JS-P), volitional-depth jump squat training (JS-V), or no training (C). Quadriceps femoris, vastus lateralis (VL), intermedius (VI), medialis (VM), and rectus femoris (RF) CSA were measured in distal-, mid-, and proximal-thigh regions using extended field-of-view ultrasonography and compared using a 3 × 2 mixed-model MANOVA with Bonferroni post hoc tests (P < 0.05). Parallel-depth heavy squat-lift training and JS-P elicited similar changes in mid-CSA(QF) as well as summed CSA of the QF, VL, VI, and VM. Cross-sectional area of the VL (CSA(VL)) and CSA(VI) increased in both HS-P and JS-P at mid-thigh, but only JS-P significantly increased CSA proximally, and only HS-P significantly increased CSA distally. Cross-sectional area of the VM (CSA(VM)) increased in HS-P and JS-P distally, but only HS-P increased at mid-thigh. No hypertrophy was observed in RF at any location and no significant differences were observed between JS-P and JS-V. Parallel-depth heavy squat-lift training elicited greater proximal hypertrophy in each of the vasti muscles, whereas only JS-P elicited distal VL and VI hypertrophy. These observed inhomogeneous changes in CSA may alter the thigh's moment of inertia and moment arms of muscle "compartments," and the influence of elastic component force transmission on the muscular force expression. Such selective hypertrophy is speculated to be biomechanically beneficial to high-force or high-power movements used in training.


Beyond indicators: advances in global HIV monitoring and evaluation during the PEPFAR era.
Monitoring and evaluation (M&E) is fundamental to global HIV program implementation and has been a cornerstone of the President's Emergency Plan for AIDS Relief (PEPFAR). Rapid results were crucial to demonstrating feasibility and scalability of HIV care and treatment services early in PEPFAR. When national HIV M&E systems were nascent, the rapid influx of funds and the emergency expansion of HIV services contributed to the development of uncoordinated "parallel" information systems to serve donor demands for information. Close collaboration of PEPFAR with multilateral and national partners improved harmonization of indicators, standards, methods, tools, and reports. Concurrent PEPFAR investments in surveillance, surveys, program monitoring, health information systems, and human capacity development began to show signs of progress toward sustainable country-owned systems. Awareness of the need for and usefulness of data increased, far beyond discussions of indicators and reporting. Emphasis has turned toward ensuring the quality of data and using available data to improve the quality of care. Assessing progress toward an AIDS-free generation requires that the global community can measure the reduction of new HIV infections in children and adults and monitor the coverage, quality, and outcomes of highly efficacious interventions in combination. Building national M&E systems requires sustained efforts over long periods of time with effective leadership and coordination. PEPFAR, in close collaboration with its global and national partners, is well positioned to transform the successes and challenges associated with early rapid scale-up into future opportunities for sustainable, cost-effective, country-owned programs and systems.


Adaptation and Validation of Vocal Fatigue Index (VFI) to Malayalam Language.
The purpose of the present study was to translate and validate the English version of the Vocal Fatigue Index (VFI) in to Malayalam language. The English version of the VFI was translated into Malayalam language using parallel back translation. The translated version was content validated by three qualified Speech Language Pathologists. The final Malayalam version of the VFI was administered on 528 primary school teachers with and without self-reporting of voice problems. The internal consistency and test-retest reliability were determined using Cronbach's alpha and intraclass correlation coefficients. Independent sample t test was used to assess the difference in means. Receiver operating characteristic curves with sensitivity and specificity were calculated to set cut-off scores for three domains of Malayalam VFI. The results revealed that the Malayalam version of VFI has an excellent internal consistency across all the three factors of VFI; tiredness of voice and avoidance of voice use (α = 0.922), physical discomfort symptoms (α = 0.923), and improvement of symptoms with voice rest (α = 0.925). Independent sample t test revealed a significant difference (P ≤ 0.001) for total scores of three domains [tiredness and avoidance of voice use (factor 1), physical discomfort symptoms (factor 2), improvement in symptoms with voice rest (factor 3)] between teachers reporting voice problems and teachers not reporting voice problems. Cut-off scores for three different domains of the Malayalam VFI were set at ≥ 16.5 (80% sensitivity and 71.4% specificity) for factor 1, ≥ 6.5 (71.1% sensitivity and 70.1% specificity) for factor 2 and ≤ 7.5 (71.1% sensitivity and 69.9% specificity) for factor 3. The Malayalam VFI was found to have good internal consistency and reliability. Hence, it can be considered as a valid and reliable tool for identifying vocal fatigue symptoms and its severity among the Malayalam speaking community who report voice disorders.


Genetic characterization of the Indian cattle breeds, Ongole and Deoni (Bos indicus), using microsatellite markers - a preliminary study.
Molecular characterization of cattle breeds is important for the prevention of germplasm erosion by cross breeding. The Indian zebu cattle have their significant role in evolution of present day cattle breeds and development of some of the exotic breeds. Microsatellites are the best available molecular tools for characterization of cattle breeds. The present study was carried out to characterize two Indian cattle breeds, Ongole and Deoni, using microsatellite markers. Using 5 di- and 5 tri-nucleotide repeat loci, 17 Ongole and 13 Deoni unrelated individuals were studied. Of the ten loci, eight revealed polymorphism in both the breeds. The di-nucleotide repeat loci were found to be more polymorphic (100%) than tri-nucleotide repeat loci (60%). A total of 39 polymorphic alleles were obtained at 4.5 alleles per locus in Ongole and 4.1 in Deoni. The average expected heterozygosity was 0.46 (+/-0.1) and 0.50 (+/-0.1) in Ongole and Deoni breeds, respectively. The PIC values of the polymorphic loci ranged from 0.15 to 0.79 in Ongole and 0.13 to 0.80 in Deoni breeds. Six Ongole specific and three Deoni specific alleles were identified. The two breeds showed a moderate genetic relationship between themselves with a FST value of 0.117 (P = 0.01). This preliminary study shows that microsatellite markers are useful in distinguishing the two zebu breeds namely, Ongole and Deoni. Further studies of other zebu breeds using many microsatellite loci with larger sample sizes can reveal the genetic relationships of Indian breeds.


Age, waist circumference, and blood pressure are associated with skin microvascular flow motion: the Maastricht Study.
Skin microvascular flow motion (SMF)--blood flow fluctuation attributed to the rhythmic contraction and dilation of arterioles--is thought to be an important component of the microcirculation, by ensuring optimal delivery of nutrients and oxygen to tissue and regulating local hydraulic resistance. There is some evidence that SMF is altered in obesity, type 2 diabetes mellitus, and hypertension. Nevertheless, most studies of SMF have been conducted in highly selected patient groups, and evidence how SMF relates to other cardiovascular risk factors is scarce. Therefore, the aim of the present study was to examine in a population-based setting which cardiovascular risk factors are associated with SMF. We measured SMF in 506 participants of the Maastricht Study without prior cardiovascular event. SMF was investigated using Fourier transform analysis of skin laser Doppler flowmetry at rest within five frequency intervals in the 0.01-1.6-Hz spectral range. The associations with SMF of the cardiovascular risk factors age, sex, waist circumference, total-to-high-density lipoprotein cholesterol, fasting plasma glucose, 24-h SBP, and cigarette smoking were analysed by use of multiple linear regression analysis. Per 1 SD higher age, waist circumference and 24-h SBP, SMF was 0.16 SD higher [95% confidence interval (CI) 0.07, 0.25; P < 0.001), -0.14 SD lower (95% CI -0.25, -0.04; P = 0.01), and 0.16 SD higher (95% CI 0.07, 0.26; P < 0.001), respectively, in fully adjusted analyses. We found no significant associations of sex, fasting plasma glucose levels, total-to-high-density lipoprotein cholesterol ratio, or pack years of smoking with SMF. Age and 24-h SBP are directly, and waist circumference is inversely associated with SMF in the general population. The exact mechanisms underlying these findings remain elusive. We hypothesize that flow motion may be an important component of the microcirculation by ensuring optimal delivery of nutrients and oxygen to tissue and regulating local hydraulic resistance not only under physiological conditions but also under pathophysiological conditions when microcirculatory perfusion is reduced, such as occurs with ageing and higher blood pressure. In addition, obesity may result in an impaired flow motion with negative effects on the delivery of nutrients and oxygen to tissue and local hydraulic resistance.


High frequency stimulation of the anterior vermis modulates behavioural response to chronic stress: involvement of the prefrontal cortex and dorsal raphe?
Some evidence suggests that the cerebellum modulates affect via connectivities with mood-regulating corticolimbic structures, such as the prefrontal cortex and monoamine nuclei. In rats exposed to chronic unpredictable stress (CUS), we examined the neuro-behavioural effects of high frequency stimulation and surgical ablation/disconnection of the cerebellar vermis. CUS reduced sucrose preference, increased novelty-induced feeding suppression and passive coping. These depressive-like behaviours were associated with decreased cerebellar zif268 expression, indicating possible cerebellar involvement in stress pathology. These were paralleled by decreased vermal Purkinje simple and complex spiking activity and raphe serotonergic activity. Protracted (24-h) vermal stimulation reversed these behavioural deficits through serotonin-mediated mechanisms since this effect was abrogated by the serotonin-depleting agent pCPA. Vermal stimulation and disconnection lesion also enhanced serotonergic activity, but did not modify prefrontocortical pyramidal firing. This effect was likely mediated by 5-HT1A receptors (5-HT1AR). Indeed, acute vermal stimulation mimicked the effect of the 5-HT1AR agonist 8-OH-DPAT in inhibiting serotonergic activity, which was prevented by pre-treatment with the 5-HT1AR antagonist WAY100,635. These results demonstrate vermal involvement in depressive-type behaviour via its modulatory action on serotonergic neurons. They further suggest that vermal and mPFC stimulation may bestow therapeutic benefits via parallel pathways.


Health care utilization by people with HIV on release from provincial prison in Ontario, Canada in 2010: a retrospective cohort study.
Limited evidence suggests that at the time of release from prison, people with HIV face barriers to health care, which may contribute to worsening HIV clinical outcomes. We aimed to describe health care utilization for people with HIV released from provincial prison in Ontario in 2010, and to compare rates of use with prisoner and general population controls. We used Ontario's administrative health records and data from the Ontario Ministry of Community Safety and Correctional Services on all persons released from provincial prison in 2010. We matched each person with HIV released from provincial prison by age and sex with three controls in each of three groups: people with no HIV released from provincial prison, people with HIV in the general population, and people with no HIV in the general population. We compared rates of use of primary care, non-primary ambulatory care, emergency departments, and hospitalization in the year after the first release from provincial prison in 2010 and in the corresponding period for matched controls. We identified 330 persons with HIV released from provincial prison in 2010. Their median time to first HIV-ambulatory care visit after prison release was 177 days (SD 136-239). Compared to all control groups, people with HIV released from provincial prison had higher rates of primary care use, unscheduled emergency department visits and hospital admissions at 30, 90 and 365 days after release. People with HIV released from provincial prison have a long time to first contact with HIV ambulatory care, and higher rates of health care utilization across health care settings. Interventions are required to facilitate post-release linkage to care for this population.


Critical cap thickness and rupture in symptomatic carotid plaques: the oxford plaque study.
Advances in carotid plaque imaging could allow quantification of fibrous cap thickness in vivo. While a cap thickness <65 microm is the accepted definition of rupture-prone plaque in the coronary circulation, the threshold value for carotid plaques is unknown. We made detailed histological assessments of 526 carotid plaques from consecutive patients undergoing endarterectomy for symptomatic carotid stenosis. The thickness of the fibrous cap at the thinnest and most representative part was measured. Cap thickness could be measured reliably in 428 (81%) plaques. In the ruptured plaques (n=257), the median representative cap thickness was 300 microm (IQR 200 to 500 microm) and the median minimum cap thickness was 150 microm (80 to 210 microm; mean=181 microm), which is much greater than the mean cap thickness of 23 microm at the point of rupture that has been reported for coronary plaques. For nonruptured plaques, the median cap thickness values were 500 microm (300 to 700 microm) and 250 microm (180 to 400 microm), respectively. The optimum cut-offs for discriminating between ruptured and nonruptured plaques were a minimum cap thickness <200 microm (OR 5.00, 3.26 to 7.65, P<0.001), a representative cap thickness <500 microm (OR 3.38, 2.25 to 5.08, P<0.001), or a combination of both (OR 5.11, 3.19 to 8.19, P<0.001). Minimum and representative cap thickness were only modestly correlated (r(2)=0.30) and were both independently associated with cap rupture. Critical cap thickness is greater in carotid plaques than coronary plaques. Minimum and representative cap thicknesses were both independently associated with cap rupture. A combination of minimum cap thickness <200 microm and a representative cap thickness <500 microm identified ruptured plaques most reliably. Prospective imaging studies are required to establish whether these cut points predict clinical events in patients with asymptomatic carotid stenosis.


From dense monomer salt crystals to CO2 selective microporous polyimides via solid-state polymerization.
Fully aromatic polyimides are synthesized via solid-state polymerization of the corresponding monomer salts. The crystal structure of salts shows strong hydrogen bonding of the reactive groups and thereby paves the way for solid-state transformations. The polycondensation yields copies of the initial salt crystallite habits, accompanied by the development of a porosity especially suited for CO2.


Executive function and intelligence in the resolution of temporary syntactic ambiguity: an individual differences investigation.
In the current study, we examined the role of intelligence and executive functions in the resolution of temporary syntactic ambiguity using an individual differences approach. Data were collected from 174 adolescents and adults who completed a battery of cognitive tests as well as a sentence comprehension task. The critical items for the comprehension task consisted of object/subject garden paths (e.g., While Anna dressed the baby that was small and cute played in the crib), and participants answered a comprehension question (e.g., Did Anna dress the baby?) following each one. Previous studies have shown that garden-path misinterpretations tend to persist into final interpretations. Results showed that both intelligence and processing speed interacted with ambiguity. Individuals with higher intelligence and faster processing were more likely to answer the comprehension questions correctly and, specifically, following ambiguous as opposed to unambiguous sentences. Inhibition produced a marginal effect, but the variance in inhibition was largely shared with intelligence. Conclusions focus on the role of individual differences in cognitive ability and their impact on syntactic ambiguity resolution.


Obstetrical and neonatal outcomes after transfer of cleavage-stage and blastocyst-stage embryos derived from monopronuclear zygotes: a retrospective cohort study.
To evaluate the outcomes of embryo transfer with the use of monopronuclear (1PN) zygotes, and the risks of congenital malformations and postpartum developmental disorders. Retrospective cohort study. Tertiary-care academic medical center. This study included patients who underwent single embryo transfer of 1PN frozen-thawed cleavage- or blastocyst-stage embryos. Seventy-six singletons were assessed for congenital malformations and defects in psychomotor development. Monopronuclear frozen-thawed cleavage-stage or blastocyst embryos were compared with 2PN frozen-thawed cleavage-stage and blastocyst frozen embryos, in frozen-thawed embryo transfer (FET) cycles. Neonates from 2PN FET constituted the control group. Implantation rate (IR), clinical pregnancy rate (PR), miscarriage rate, live birth rate, congenital malformations, and motor and language development status were compared. The cohort comprised 186, 676, 133, and 502 patients consenting to FET with, respectively, 1PN cleavage-stage, 2PN cleavage-stage, 1PN blastocystocyst, and 2PN blastocystocyst embryos. The IR, PR, and live birth rate were lower in 1PN than with 2PN cleavage-stage FET, but similar between 1PN and 2PN blastocystocysts. Miscarriage rates did not differ significantly between 1PN and 2PN cleavage-stage or blastocystocyst FET. Risk of congenital malformations and defects in psychomotor development did not differ significantly within 2 years postpartum with the use of 1PN or 2PN FET. The present results suggest that the value of 1PN blastocyst FET is similar to that of 2PN blastocyst FET, without an increased risk of miscarriage rate, congenital malformations, or defects of psychomotor development.


LAD-1 is absent in a subset of junctional epidermolysis bullosa patients.
The anchoring filament protein LAD-1 has been recently identified as the target of autoantibodies in the acquired blistering disorder linear IgA bullous dermatosis. Because this protein appears to be involved in the process of dermal-epidermal cohesion, this study sought to determine the involvement of LAD-1 in the pathology of junctional epidermolysis bullosa (JEB). To this end, 44 patients with a variety of subtypes of JEB were analyzed by indirect immunofluorescence microscopy with antibodies to LAD-1, BP180, and laminin-5. We found that only patients with generalized atrophic benign epidermolysis bullosa (GABEB) contained LAD-1 defects. Of the 16 GABEB patients studied, 13 showed absent or greatly reduced expression of LAD-1 (including 2 patients with a peculiar interrupted staining pattern) and 3 patients showed defects of laminin-5 expression with normal LAD-1 expression. Patients who showed LAD-1 defects also showed abnormal expression of BP180. Keratinocytes were cultured from the skin of two GABEB patients and analyzed by indirect immunofluorescent microscopy. One culture demonstrated defects of BP180 and LAD-1 expression (which was also verified by radioimmunoprecipitation assay), and one culture showed decreased laminin-5 expression but normal BP180 and LAD-1 expression. Thus, these studies demonstrate that: (i) LAD-1 and BP180 are normally expressed in all subtypes of JEB except GABEB, (ii) the majority of GABEB patients show absent or near absent expression of both LAD-1 and BP180 but normal expression of laminin-5, and (iii) a smaller subset of GABEB patients show normal LAD-1 and BP180 expression but express persistent but reduced levels of laminin-5.


Allogeneic peripheral blood stem cell transplantation using normal patient-related pediatric donors.
Successful allogeneic peripheral blood progenitor cell (PBPC) transplantation has recently been reported by several transplant centers. This is a first report describing allogeneic PBPC transplantation in five patients using related pediatric donors between the ages of 4 and 13 years. Donors underwent 3 or 4 days of rhG-CSF treatment (6 micrograms/kg q 12 h) for stem cell peripheralization prior to PBPC collection, which was performed by continuous-flow apheresis on day 4 or 5. Venous access was exclusively by ante-cubital veins. A median of 2.2 times (range 1.4-3.6) the donor's total blood volume (TBV) was processed per procedure. In cases where the donor's TBV was < 2 liters, the blood cell separator was primed with human serum albumin (HSA-5%), and anticoagulation was performed using a combination of heparin (pre-apheresis bolus + continuous infusion (CI)) and/or ACD-A (CI at a reduced rate). The median number of CD34+ cells collected per kg of donor body weight (b.w.) and per liter of donor blood processed during each procedure was 128 x 10(4) (range 58 x 10(4)-314 x 10(4)). Between one and two aphereses were sufficient to collect a safe CD34+ cell engraftment dose of 3 or 4 x 10(6)/kg of recipient b.w. Two PBPC recipients were parents, and three were siblings. After freezing and thawing, the median number of CD34+ cells per kg of recipient b.w. thawed and transfused was 8.5 x 10(6) (range 3.2 x 10(6)-9.7 x 10(6)). The time to PMN > 1000/microliters was between 10 and 16 days (four out of five evaluable patients), and platelets > 20000/microliters were reached between day 13 and 14 post-transplantation (three out of five evaluable patients). Two out of three evaluable patients developed grades one and three acute GVHD, and one out of three developed chronic GVHD. Two patients died of sepsis and VOD at day 10 and 19, respectively. Two adult patients are alive and in cytogenetic and molecular remission of CML at +339 and +227 days post-allotransplantation. One 3-year-old girl with hemophagocytic lymphohistiocytosis is in remission at +304 days post-transplantation. Using pediatric donors for allogeneic PBPC transplantation appears to be safe, yields a sufficient amount of progenitors for prompt engraftment, and results in clinical outcome similar to adult PBPC allotransplantation.


Limb salvage vs amputation for critical ischemia. The role of vascular surgery.
Since 1980, 498 patients with 627 critically ischemic legs (rest pain, gangrene, ischemic ulcer, and ankle-brachial pressure index less than 0.40) were treated with revascularization regardless of operative risk or anticipated operative difficulty. Primary amputation was performed only when no graftable distal vessels were present (14 primary amputations [2.8%]) or in neurologically impaired, hopelessly nonambulatory patients. The mortality for revascularization was 2.3%, and the median hospital stay was 11 days. During follow-up, 41 limbs (7%) required amputation, 31 after failure of revascularization and 10 despite patent revascularizations. Renal failure had an adverse influence on limb salvage (67%) because of a significantly increased requirement for amputation despite patent revascularizations. We conclude aggressive limb revascularization in patients with critical lower-extremity ischemia results in low operative morbidity and mortality and excellent long-term limb salvage. Patients with critical leg ischemia and renal failure are at higher risk for limb loss than patients without renal failure.


Adeno-associated virus-mediated gene transfer leads to persistent hepatitis B virus replication in mice expressing HLA-A2 and HLA-DR1 molecules.
Hepatitis B virus (HBV) persistence may be due to impaired HBV-specific immune responses being unable to eliminate efficiently or cure infected hepatocytes. The immune mechanisms that lead to HBV persistence have not been completely identified, and no appropriate animal model is available for such studies. Therefore, we established a chronic HBV infection model in a mouse strain with human leukocyte antigen A2/DR1 (HLA-A2/DR1) transgenes and an H-2 class I/class II knockout. The liver of these mice was transduced with adeno-associated virus serotype 2/8 (AAV2/8) carrying a replication-competent HBV DNA genome. In all AAV2/8-transduced mice, hepatitis B virus surface antigen, hepatitis B virus e antigen, and HBV DNA persisted in serum for at least 1 year. Viral replication intermediates and transcripts were detected in the livers of the AAV-injected mice. The hepatitis B core antigen was expressed in 60% of hepatocytes. No significant inflammation was observed in the liver. This was linked to a higher number of regulatory T cells in liver than in controls and a defect in HBV-specific functional T-cell responses. Despite the substantial tolerance resulting from expression of HBV antigens in hepatocytes, we succeeded in priming functional HBV-specific T-cell responses in peripheral tissues, which subsequently reached the liver. This AAV2/8-HBV-transduced HLA-A2/DR1 murine model recapitulates virological and immunological characteristics of chronic HBV infection, and it could be useful for the development of new treatments and immune-based therapies or therapeutic vaccines for chronic HBV infections.


Arteriovenous fistula with associated aneurysms coexisting with dural arteriovenous malformation of the anterior inferior falx. Case report and review of the literature.
This 24-year-old man presented with an unusual case of a high-flow arteriovenous fistula (AVF). This lesion was similar to giant AVFs in children that have been previously described in the literature. In patients in whom abnormalities of the vein of Galen have been excluded and in whom presentation occurs after 20 years of age, a diagnosis of congenital AVF is quite unusual. The fistula in this case originated in an enlarged callosomarginal artery and drained into the superior sagittal sinus via a saccular vascular abnormality. Two giant aneurysmal dilations of the fistula were present. In an associated finding, a small falcine dural arteriovenous malformation (AVM) was also present. Arterial supply to the AVM arose from both external carotid arteries and the left vertebral artery, with drainage through an aberrant vein in the region of the inferior sagittal sinus into the vein of Galen. Craniotomy with exposure and trapping of the AVF was performed, with subsequent radiosurgical (linear accelerator) treatment of the dural AVM. Through this combination of microsurgical trapping of the AVF and radiotherapy of the dural AVM, an excellent clinical outcome was achieved.


Derivation and validation of a prognostic model for postoperative risk stratification of critically ill patients with faecal peritonitis.
Prognostic scores and models of illness severity are useful both clinically and for research. The aim of this study was to develop two prognostic models for the prediction of long-term (6 months) and 28-day mortality of postoperative critically ill patients with faecal peritonitis (FP). Patients admitted to intensive care units with faecal peritonitis and recruited to the European GenOSept study were divided into a derivation and a geographical validation subset; patients subsequently recruited to the UK GAinS study were used for temporal validation. Using all 50 clinical and laboratory variables available on day 1 of critical care admission, Cox proportional hazards regression was fitted to select variables for inclusion in two prognostic models, using stepwise selection and nonparametric bootstrapping sampling techniques. Using Area under the receiver operating characteristic curve (AuROC) analysis, the performance of the models was compared to SOFA and APACHE II. Five variables (age, SOFA score, lowest temperature, highest heart rate, haematocrit) were entered into the prognostic models. The discriminatory performance of the 6-month prognostic model yielded an AuROC 0.81 (95% CI 0.76-0.86), 0.73 (95% CI 0.69-0.78) and 0.76 (95% CI 0.69-0.83) for the derivation, geographic and temporal external validation cohorts, respectively. The 28-day prognostic tool yielded an AuROC 0.82 (95% CI 0.77-0.88), 0.75 (95% CI 0.69-0.80) and 0.79 (95% CI 0.71-0.87) for the same cohorts. These AuROCs appeared consistently superior to those obtained with the SOFA and APACHE II scores alone. The two prognostic models developed for 6-month and 28-day mortality prediction in critically ill septic patients with FP, in the postoperative phase, enhanced the day one SOFA score's predictive utility by adding a few key variables: age, lowest recorded temperature, highest recorded heart rate and haematocrit. External validation of their predictive capability in larger cohorts is needed, before introduction of the proposed scores into clinical practice to inform decision making and the design of clinical trials.


Stimulation of human neutrophil oxidative metabolism by nonopsonized Neisseria gonorrhoeae.
Nonopsonized gonococci possessing opacity-associated (Opa; previously PII) outer membrane proteins stimulate neutrophils to undergo a vigorous oxidative response when measured by luminol-dependent chemiluminescence (LDCL). In these studies, we characterized the mechanism of this stimulation. No gonococci that we tested induced measurable release of neutrophil superoxide anion (O2-) or hydrogen peroxide (H2O2) as measured by reduction of cytochrome c or the oxidation of scopoletin, respectively. Neutrophils pretreated with gonococci and then exposed to phorbol myristate acetate, the chemotactic peptide formylmethionylleucylphenylalanine, or opsonized zymosan released levels of neutrophil O2- and H2O2 comparable to controls, indicating that gonococci were not preventing or inhibiting neutrophil O2- or H2O2 release. To ascertain a possible explanation for these seemingly contradictory observations (i.e., induction of LDCL, but no release of O2- or H2O2), we further characterized the ability of Opa+ gonococci to stimulate LDCL. By using 1 mM azide and 4 U of horseradish peroxidase to monitor extracellular LDCL selectively and 2,000 U of catalase to monitor intracellular LDCL selectively, we determined that greater than 80% of total gonococcus-induced neutrophil LDCL occurred intracellularly. In addition, neutrophils stimulated with Opa+ gonococci showed a marked increase in O2 uptake and hexose monophosphate shunt activity. We conclude that Neisseria gonorrhoeae induces neutrophil oxidative metabolism without causing release of detectable amounts of reactive oxygen intermediates into the surrounding milieu. The gonococcus apparently directs oxidase assembly and activity to the phagolysosomal membrane. This could be a mechanism by which extracellular gonococci persist for extended periods in vivo in the presence of high concentrations of neutrophils.


Milk thistle in liver diseases: past, present, future.
Silybum marianum or milk thistle (MT) is the most well-researched plant in the treatment of liver disease. The active complex of MT is a lipophilic extract from the seeds of the plant and is composed of three isomer flavonolignans (silybin, silydianin, and silychristin) collectively known as silymarin. Silybin is a component with the greatest degree of biological activity and makes up 50% to 70% of silymarin. Silymarin is found in the entire plant but it is concentrated in the fruit and seeds. Silymarin acts as an antioxidant by reducing free radical production and lipid peroxidation, has antifibrotic activity and may act as a toxin blockade agent by inhibiting binding of toxins to the hepatocyte cell membrane receptors. In animals, silymarin reduces liver injury caused by acetaminophen, carbon tetrachloride, radiation, iron overload, phenylhydrazine, alcohol, cold ischaemia and Amanita phalloides. Silymarin has been used to treat alcoholic liver disease, acute and chronic viral hepatitis and toxin-induced liver diseases.


Benefits and Challenges of Remote Patient Monitoring as Perceived by Health Care Practitioners: A Systematic Review.
Background Remote patient monitoring (RPM), or telemonitoring, offers ways for health care practitioners to gather real-time information on the physiological conditions of patients. As telemedicine, and thus telemonitoring, is becoming increasingly relevant in today's society, understanding the practitioners' opinions is crucial. This systematic review evaluates the perspectives and experiences of health care practitioners with telemonitoring technologies. Methods A database search was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for the selection of articles measuring health care practitioners' perspectives and experiences with RPM technologies published between 2017 and 2021. Only articles written in English were included. No statistical analysis was performed and thus this is a qualitative review. Results A total of 1605 studies were identified after the initial search. After applying the inclusion and exclusion criteria of this review's authors, 13 articles were included in this review. In all, 2351 practitioners' perspectives and experience utilizing RPM technology in a variety of medical specialties were evaluated through close- and open-ended surveys. Recurring themes emerged for both the benefits and challenges. Common benefits included continuous monitoring of patients to provide prompt care, improvement of patient self-care, efficient communication, increased patient confidence, visualization of health trends, and greater patient education. Challenges comprised increased workload, higher patient anxiety, data inaccuracy, disorienting technology, financial issues, and privacy concerns. Conclusion Health care practitioners generally believe that RPM is feasible for application. Additionally, there is a consensus that telemonitoring strategies will become increasingly relevant. However, there are still drawbacks to the technology that need to be considered.


Membrane interaction of TNF is not sufficient to trigger increase in membrane conductance in mammalian cells.
Tumor necrosis factor TNF can trigger increases in membrane conductance of mammalian cells in a receptor-independent manner via its lectin-like domain. A lectin-deficient TNF mutant, lacking this activity, was able to bind to artificial liposomes in a pH-dependent manner, but not to insert into the bilayer, just like wild type TNF. A peptide mimicking the lectin-like domain, which can still trigger increases in membrane currents in cells, failed to interact with liposomes. Thus, the capacity of TNF to trigger increases in membrane conductance in mammalian cells does not correlate with its ability to interact with membranes, suggesting that the cytokine does not form channels itself, but rather interacts with endogenous ion channels or with plasma membrane proteins that are coupled to ion channels.


Factors associated with discontinuation of complementary and alternative medicine among Korean cancer patients.
The purpose of this study was to determine patient characteristics and other factors associated with discontinuation of complementary and alternative medicine (CAM) among cancer patients in Korea. A national, multicenter, cross-sectional survey of cancer patients was performed in which 674 of 2,661 patients were analyzed for their use of CAM after cancer diagnosis. Multiple logistic regression was used to identify the factors related to CAM discontinuation. Among the surveyed cancer patients, 25.3% (674 of 2,661) had used CAM, whereas 38.3% (258 of 674) of those with CAM experience had discontinued CAM therapy. The most frequently used form of CAM was herbs (43.5%). The major reasons for the discontinuation of CAM included absence of effects (23.9%), financial burden (22.9%), and physician opposition (13.7%). Other factors associated with the discontinuation of CAM included metastatic cancer (OR = 2.06), a long duration of cancer treatment (OR = 3.34), dissatisfaction (OR = 4.34), and side effects (OR = 4.23) of CAM therapy. For cancer patients to correctly employ CAM therapy, increase their satisfaction, and reduce their side effects, efforts should be made to analyze the cost effectiveness of CAM, and valid information must be provided to physicians and cancer patients.


Cloning and nucleotide sequence of the glpD gene encoding sn-glycerol-3-phosphate dehydrogenase of Pseudomonas aeruginosa.
Nitrosoguanidine-induced Pseudomonas aeruginosa mutants which were unable to utilize glycerol as a carbon source were isolated. By utilizing PAO104, a mutant defective in glycerol transport and sn-glycerol-3-phosphate dehydrogenase (glpD), the glpD gene was cloned by a phage mini-D3112-based in vivo cloning method. The cloned gene was able to complement an Escherichia coli glpD mutant. Restriction analysis and recloning of DNA fragments located the glpD gene to a 1.6-kb EcoRI-SphI DNA fragment. In E. coli, a single 56,000-Da protein was expressed from the cloned DNA fragments. An in-frame glpD'-'lacZ translational fusion was isolated and used to determine the reading frame of glpD by sequencing across the fusion junction. The nucleotide sequence of a 1,792-bp fragment containing the glpD region was determined. The glpD gene encodes a protein containing 510 amino acids and with a predicted molecular weight of 56,150. Compared with the aerobic sn-glycerol-3-phosphate dehydrogenase from E. coli, P. aeruginosa GlpD is 56% identical and 69% similar. A similar comparison with GlpD from Bacillus subtilis reveals 21% identity and 40% similarity. A flavin-binding domain near the amino terminus which shared the consensus sequence reported for other bacterial flavoproteins was identified.


Lipid peroxidation and some antioxidant enzymes in nasal polyp tissue.
Nasal polyp (NP) is considered an inflammatory condition in nasal and paranasal sinus cavities and is frequently encountered in otolaryngology clinics. Although the pathophysiology of nasal polyps is poorly understood, it seems likely that the epithelium may play a critical role in the genesis of inflammatory nasal disease. The aim of this study was to investigate the role of free radicals and antioxidant enzymes in NP and compare these findings with concha bullosa (CB). NP and CB were obtained from 27 and 23 patients, respectively. Glutathione peroxidase (GSH-Px), catalase (CAT), xanthine oxidase (XO) total (enzymic plus non-enzymic) superoxide scavenger activity (TSSA), non-enzymic superoxide scavenger activity (NSSA), superoxide dismutase (SOD), and MDA levels in NP and CB were measured. GSH-Px activiy was significantly lower in patients with NP than in the CB group. However, CAT, XO activities and MDA levels were significantly higher in patients with NP than in the CB group, but TSSA, NSSA and SOD activities were unchanged. Increases in the levels of tissue MDA in patients with NP compared to the CB group may indicate the presence of free radical damage in patients with nasal NP.


Beta-2 Microglobulin in Whole Unstimulated Saliva Can Effectively Distinguish Between Sjögren's Syndrome and Non-Autoimmune Sicca Symptoms.
This study aims to describe salivary beta-2 microglobulin (sB2M) levels in our setting and to assess the performance of sB2M for the diagnosis of Sjögren's syndrome (SS). This cross-sectional, comparative study included 192 SS patients (2 males, 190 females; mean age 53.1 years; range 23 to 84 years) and 64 healthy controls (1 male, 63 females; mean age 46.9 years; range 21 to 82 years). Patients were divided into three groups as those with primary SS, secondary SS, and sicca non-Sjögren's syndrome (snSS). sB2M was measured by enzyme-linked immunosorbent assay in whole unstimulated saliva (ng/mL). Differences in sB2M were evaluated using the Kruskal-Wallis test. Receiver operating curves were generated to determine the performance of sB2M for distinguishing between SS and non-autoimmune snSS groups, and between SS group and healthy controls. The primary SS and secondary SS groups had a significantly higher concentration of sB2M than the other two groups. There was no significant difference in the concentration of sB2M between primary SS and secondary SS groups, and neither between snSS group and healthy controls. The receiver operating curve analysis for distinguishing SS and snSS showed an area under the curve of 0.661 (95% confidence interval 0.590-0.728, p=0.0001) with an optimal cutoff value of 0.582 ng/mL. Sensitivity, specificity, positive predictive value, and negative predictive value were 68.7%, 59.3%, 20.2%, and 92.7%, respectively. The reported prevalence of SS in Mexico was considered when calculating the last two values. In our setting, sB2M effectively distinguished between SS patients and non-autoimmune sicca symptoms. Including sB2M in our conventional diagnostic arsenal may assist in the evaluation of patients in whom SS is suspected; however, further studies are needed to clarify this hypothesis.


Composite outcome measures in a pragmatic clinical trial of chronic heart failure management: A comparative assessment.
A number of composite outcomes have been developed to capture the perspective of the patient, clinician and objective measures of health in assessing heart failure outcomes. To date there has been a limited examination in the composition of these outcomes. Three commonly used scoring systems in heart failure trials: Packer's composite, Patient Journey and the African American Heart Failure Trial (A-HeFT) scores were compared in assessing outcomes from the Which heart failure intervention is most cost-effective & consumer friendly in reducing hospital care (WHICH(?)) Trial. Comparability and interpretability of these outcomes and the influence of each component to the final outcome were examined. Despite all three composite outcomes incorporating mortality, hospitalisation and quality of life (QoL), the contribution of each individual component to the final outcomes differed. The component with the most influence in deteriorating condition for the Packer's composite was hospitalisation (67.7%), while in Patient Journey it was QoL (61.5%) and for A-HeFT composite score it was mortality (45.4%). The contribution made by each component varied in subtle, but important ways. This study emphasises the importance of understanding the value system of the composite outcomes to enable meaningful interpretation of results.


Associations among computed tomographic measures of bone and muscle quality and biomechanical measures of tibiotarsal bone quality in laying hens.
The objectives of the current study were to quantify laying hen sternal carina (keel) and tibiotarsal bone and muscle quality using clinical CT, tissue level, and biomechanical measures; test associations among muscle transverse sectional area, bone mineral density, and biomechanical measures of bone quality; and determine whether CT measures of bone and muscle quality would be predictive of biomechanical measures of tibiotarsal bone quality. 60 40-week-old Hy-Line brown laying hens were used. Associations among CT imaging, tissue level, and biomechanical measures of tibiotarsal and keel bone and muscle quality were tested using multivariate correlational analyses. Bivariate and generalized regressions were performed to determine whether CT measures were predictive of biomechanical measures of tibiotarsal bone quality. Low positive correlations were identified between tibiotarsal muscle transverse-sectional area (cross-sectional area [CSA]) and bone mineral density (BMD) in the proximal location of the bone (r = -0.11 to 0.31). Tibiotarsal muscle CSA was also low to moderately correlated with biomechanical measures of bone quality (r = 0.20 to 0.41). Keel muscle CSA values were not correlated with keel BMD values, but they were correlated with biomechanical measures of tibiotarsal bone quality (r = 0.18 to 0.40). Keel CT measures of bone quality were not correlated with tibiotarsal CT measures of bone quality. At the proximal location, muscle CSA and tibiotarsal BMD were predictive of biomechanical failure load (F = 9.68, P = .0003muscle CSA; F = 9.13, P = .004tibiotarsal BMD). Findings supported using noninvasive CT measures of muscle and bone quality in longitudinal research studies evaluating the effects of interventions on laying hen welfare.


Coping strategies and quality of life in schizophrenia: cross-sectional study.
The modern psychiatric view of schizophrenia spectrum disorders and their treatment has led to an increasing focus on coping strategies and the quality of life of these patients. In the present study, the authors examined the relationship between demographic data, the severity of symptoms, coping strategies, and the quality of life in psychotic patients. It is important to study the inner experience and striving of these individuals as it has been linked to their well-being and treatment adherence. Psychiatric outpatients who met International Classification of Diseases, Tenth Revision criteria for a psychotic disorder (schizophrenia, schizoaffective disorder, or delusional disorder) were recruited in the study. Questionnaires measuring the coping strategies (The Stress Coping Style Questionnaire [SVF-78]), the quality of life (Quality of Life Satisfaction and Enjoyment Questionnaire [Q-LES-Q]), and symptom severity (objective and subjective Clinical Global Impression - objCGI; subjCGI) were assessed. The data were analyzed using one-way analysis of variance, Mann-Whitney U test, Pearson and Spearman correlation coefficients, and multiple regression analysis. A total of 109 psychotic patients were included in the study. The quality of life was significantly related to both the positive and negative coping strategies. The severity of disorder was highly negatively correlated with the quality of life score. The results of multiple stepwise regression analysis using the quality of life as a dependent variable showed that symptom severity (subjCGI, difference between subjCGI, and objCGI), negative coping strategies, positive coping strategies, and the difference between positive and negative coping strategies explain more than half variance. Our study suggests the importance of utilizing the positive coping strategies in improving the quality of life in patients with psychotic disorders.


Low back pain in relation to lumbar disc degeneration.
Cross-sectional magnetic resonance imaging (MRI) study. To study the relation of low back pain (LBP) to disc degeneration in the lumbar spine. Controversy still prevails about the relationship between disc degeneration and LBP. Classification of disc degeneration and symptoms varies, hampering comparison of study results. Subjects comprised 164 men aged 40-45 years-53 machine drivers, 51 construction carpenters, and 60 office workers. The data of different types of LBP, individual characteristics, and lifestyle factors were obtained from a questionnaire and a structured interview. Degeneration of discs L2/L3-L5/S1 (dark nucleus pulposus and posterior and anterior bulge) was assessed with MRI. An increased risk of LBP (including all types) was found in relation to all signs of disc degeneration. An increased risk of sciatic pain was found in relation to posterior bulges, but local LBP was not related to disc degeneration. The risks of LBP and sciatic pain were strongly affected by occupation. Low back pain is associated with signs of disc degeneration and sciatic pain with posterior disc bulges. Low back pain is strongly associated with occupation.


Genetic variant affecting the myosin light chain 2 related to familial hypertrophic cardiomyopathy.
Familial hypertrophic cardiomyopathy (FHCM) is a genetic disease characterized by left ventricle (LV) or interventricular septum hypertrophy. FHCM is a common heart disease (affecting 1 out of 500 individuals) associated with genetic variants in genes related to the sarcomere, including the MYL2 (myosin light chain 2) gene that is affected in 1 to 3% of the cases. As described in this report, the genetic mutation p.Gly87Ala, rs 397516399 in the MYL2 gene is likely pathogenic. Reported here is the case of a 37-year-old Colombian man with asymmetric septal hypertrophic cardiomyopathy and ventricular tachycardia. The man had progressive symptomatology, a family history of FHCM with a dominant inheritance pattern, a mother and 2 brothers with FHCM, and 2 brothers who died suddenly before the age of 35. A molecular panel of 17 genes for hypertrophic cardiomyopathy identified a heterozygous variant, p.Gly87Ala, of the MYL2 gene. This variant can be found in Ensembl, dbSNP, and ClinVar, where it has conflicting interpretations: it either has an uncertain significance or it is likely pathogenic. This is the first report of a Colombian case of FHCM secondary to a mutation in the MYL2 gene, highlighting the importance of molecular diagnosis, genetic counseling, and bioinformatic analysis in these patients.


Tetrahydrocurcumin and octahydrocurcumin, the primary and final hydrogenated metabolites of curcumin, possess superior hepatic-protective effect against acetaminophen-induced liver injury: Role of CYP2E1 and Keap1-Nrf2 pathway.
Acetaminophen (APAP) overdose-induced hepatotoxicity is tightly associated with oxidative stress. Tetrahydrocurcumin (THC) and octahydrocurcumin (OHC), the primary and final hydrogenated metabolites of curcumin (CUR), possess stronger antioxidant activity in vitro. The present study was performed to investigate the potential and mechanism of OHC and THC against APAP-induced hepatotoxicity in parallel to CUR. Our results showed that OHC and THC dose-dependently enhanced liver function (ALT and AST levels) and alleviated histopathological deterioration. Besides, OHC and THC significantly restored the hepatic antioxidant status by miring level of MDA and ROS, and elevated levels of GSH, SOD, CAT and T-AOC. In addition, OHC and THC markedly suppressed the activity and expressions of CYP2E1, and bound to the active sites of CYP2E1. Moreover, OHC and THC activated the Keap1-Nrf2 pathway and enormously enhanced the translational activation of Nrf2-targeted gene (GCLC, GCLM, NQO1 and HO-1) against oxidative stress, via inhibiting the expression of Keap1 and blocking the interaction between Keap1 and Nrf2. Particularly, OHC and THC exerted superior hepato-protective and antioxidant activities to CUR. In conclusion, OHC and THC possess favorable hepato-protective effect through restoring antioxidant status, inhibiting CYP2E1 and activating Keap1-Nrf2 pathway, which might represent promising antioxidants for the treatment of APAP-induced hepatotoxicity.


Steroid-free chemotherapy decreases risk of hepatitis B virus (HBV) reactivation in HBV-carriers with lymphoma.
Reactivation of hepatitis is one of the most serious complications of chemotherapy in lymphoma patients who are carriers of the hepatitis B virus (HBV). Glucocorticoids are linked to increased risk of HBV reactivation. This study seeks to clarify whether removal of glucocorticoids from chemotherapy regimens may decrease the risk of HBV reactivation. Eligible patients were seropositive for hepatitis B surface antigen (HBsAg) and had histologically proven non-Hodgkin's lymphomas for which intensive chemotherapy was indicated. Patients were randomized to receive either ACE (epirubicin, cyclophosphamide, and etoposide) or PACE (prednisolone + ACE). A total of 50 patients were enrolled, 25 each for the ACE and PACE arms. The cumulative incidence of HBV reactivation at 9 months after starting chemotherapy was 38% and 73% for ACE and PACE arm, respectively (P =.03). The degree of clinical hepatitis was significantly more severe in the PACE arm: 11 patients (44%) in the PACE and 3 patients (13%) in the ACE arm had ALT elevation more than 10-fold of normal (P =.025), and 7 patients (28%) in the PACE and 1 patient (4%) in the ACE arm had icteric hepatitis (P =.049). Complete remission of tumors occurred in 11 (46%) patients in the PACE and 8 (35%) patients in the ACE arm (P =.556). The estimated overall survival rate at 46 months was 68% in the PACE arm and 36% in the ACE arm, respectively (P =.18). In conclusion, steroid-free chemotherapy decreases the incidence and severity of HBV reactivation in HBsAg-positive lymphoma patients. However, further research is needed to evaluate whether steroid-free chemotherapy may confer a less satisfactory control of lymphoma.


Antiproliferative Effects of Pancratium Maritimum Extracts on Normal and Cancerous Cells.
Plants are an important natural source of compounds used in cancer therapy. Pancratium maritimum contains potential anti-cancer agents such as alkaloids. In this study, we investigated the anti-proliferative effects of P. maritimum extracts on MDA-MB-231 human epithelial adenocarcinoma cell line and on normal lymphocytes in vitro. Leaves, flowers, roots, and bulbs of P. maritimum were collected and their contents were extracted and diluted to different concentrations that were applied on MDA-MB-231 cells and normal human lymphocytes cell in vitro for different intervals. Cells viability, proliferation, cell cycle distribution, apoptosis, and growth were evaluated by flow cytometry and microscopy. Parametric unpaired t-test was used to compare effects of plant extracts on treated cell cultures with untreated control cell cultures. IC50 was also calculated. P. maritimum extract had profound effects on MDA-MB-321 cells. It inhibited cell proliferation in a dose- and time-dependent manner. The IC50 values were 0.039, 0.035, and 0.026 mg/ml after 48, 72, and 96 hours of treatment with 0.1 mg/ml concentration of bulb extract, respectively. Those values were 0.051 and 0.03 mg/ml after 72 and 96 hours for root extract, respectively, and 0.048 mg/ml after 96 hours for flower extract. There were no significant effects of P. maritimum bulb extracts on normal lymphocytes proliferation. P. maritimum extract has anti-proliferative effects on MDA-MB-231 cell line in vitro. The effects imply the involvement of mechanisms that inhibits cell growth and arresting cells at S and G2/M phases. Cyclin B1, Bcl-2, and Ki67 expression was also affected.


Measuring the context of care in an Australian acute care hospital: a nurse survey.
This study set out to achieve three objectives: to test the application of a context assessment tool in an acute hospital in South Australia; to use the tool to compare context in wards that had undergone an evidence implementation process with control wards; and finally to test for relationships between demographic variables (in particular experience) of nurses being studied (n = 422) with the dimensions of context. The Alberta Context Tool (ACT) was administered to all nursing staff on six control and six intervention wards. A total of 217 (62%) were returned (67% from the intervention wards and 56% from control wards). Data were analysed using Stata (v9). The effect of the intervention was analysed using nested (hierarchical) analysis of variance; relationships between nurses' experience and context was examined using canonical correlation analysis. Results confirmed the adaptation and fit of the ACT to one acute care setting in South Australia. There was no difference in context scores between control and intervention wards. However, the tool identified significant variation between wards in many of the dimensions of context. Though significant, the relationship between nurses' experience and context was weak, suggesting that at the level of the individual nurse, few factors are related to context. Variables operating at the level of the individual showed little relationship with context. However, the study indicated that some dimensions of context (e.g., leadership, culture) vary at the ward level, whereas others (e.g., structural and electronic resources) do not. The ACT also raised a number of interesting speculative hypotheses around the relationship between a measure of context and the capability and capacity of staff to influence it.We propose that context be considered to be dependent on ward- and hospital-level factors. Additionally, questions need to be considered about the unit of measurement of context in studies of knowledge implementation--is individual (micro), ward (meso) or hospital-level (macro) data most appropriate? The preliminary results also raise questions about how best to utilise this instrument in knowledge translation research.


Genome-wide analysis of functional sirtuin chromatin targets in yeast.
The sirtuins are a conserved family of NAD⁺-dependent histone/protein deacetylases that regulate numerous cellular processes, including heterochromatin formation and transcription. Multiple sirtuins are encoded by each eukaryotic genome, raising the possibility of cooperativity or functional overlap. The scope and variety of chromatin binding sites of the sirtuins in any specific organism remain unclear. Here we utilize the ChIP-seq technique to identify and functionally characterize the genome-wide targets of the sirtuins, Sir2, Hst1 to Hst4, and the DNA binding partner of Hst1, Sum 1, in Saccharomyces cerevisiae. Unexpectedly, Sir2, Hst1 and Sum1, but not the other sirtuins, exhibit co-enrichment at several classes of chromatin targets. These include telomeric repeat clusters, tRNA genes, and surprisingly, the open reading frames (ORFs) of multiple highly expressed RNA polymerase II-transcribed genes that function in processes such as fermentation, glycolysis, and translation. Repression of these target genes during the diauxic shift is specifically dependent on Sir2/Hst1/Sum1 binding to the ORF and sufficiently high intracellular NAD⁺ concentrations. Sir2 recruitment to the ORFs is independent of the canonical SIR complex and surprisingly requires Sum1. The shared Sir2/Hst1/Sum1 targets also significantly overlap with condensin and cohesin binding sites, where Sir2, Hst1, and Sum1 were found to be important for condensin and cohesin deposition, suggesting a possible mechanistic link between metabolism and chromatin architecture during the diauxic shift. This study demonstrates the existence of overlap in sirtuin function, and advances our understanding of conserved sirtuin-regulated functions, including the regulation of glycolytic gene expression and condensin loading.


Plant diversity and productivity experiments in european grasslands
At eight European field sites, the impact of loss of plant diversity on primary productivity was simulated by synthesizing grassland communities with different numbers of plant species. Results differed in detail at each location, but there was an overall log-linear reduction of average aboveground biomass with loss of species. For a given number of species, communities with fewer functional groups were less productive. These diversity effects occurred along with differences associated with species composition and geographic location. Niche complementarity and positive species interactions appear to play a role in generating diversity-productivity relationships within sites in addition to sampling from the species pool.


The impact of diet during adolescence on the neonatal health of offspring: evidence on the importance of preconception diet. The HUNT study.
Emerging evidence suggests that parents' nutritional status before and at the time of conception influences the lifelong physical and mental health of their child. Yet little is known about the relationship between diet in adolescence and the health of the next generation at birth. This study examined data from Norwegian cohorts to assess the relationship between dietary patterns in adolescence and neonatal outcomes. Data from adolescents who participated in the Nord-Trøndelag Health Study (Young-HUNT) were merged with birth data for their offspring through the Medical Birth Registry of Norway. Young-HUNT1 collected data from 8980 adolescents between 1995 and 1997. Linear regression was used to assess associations between adolescents' diet and later neonatal outcomes of their offspring adjusting for sociodemographic factors. Analyses were replicated with data from the Young-HUNT3 cohort (dietary data collected from 2006 to 2008) and combined with Young-HUNT1 for pooled analyses. In Young-HUNT1, there was evidence of associations between dietary choices, meal patterns, and neonatal outcomes, these were similar in the pooled analyses but were attenuated to the point of nonsignificance in the smaller Young-HUNT3 cohort. Overall, energy-dense food products were associated with a small detrimental impact on some neonatal outcomes, whereas healthier food choices appeared protective. Our study suggests that there are causal links between consumption of healthy and unhealthy food and meal patterns in adolescence with neonatal outcomes for offspring some years later. The effects seen are small and will require even larger studies with more state-of-the-art dietary assessment to estimate these robustly.


Dementia Risk and Financial Decision Making by Older Households: The Impact of Information.
The knowledge and reasoning ability needed to manage one's finances is a form of human capital. Alzheimer's disease and other dementias cause progressive declines in cognition that lead to a complete loss of functional capacities. In this paper we analyze the impact of information about cognitive decline on the choice of household financial decision-maker. Using longitudinal data on older married couples in a novel application of survival analysis, we find that as the financial decision maker's cognition declines, the management of finances is eventually turned over to his cognitively intact spouse, often well after difficulties handling money have already emerged. However, a memory disease diagnosis increases the hazard of switching the financial respondent by over 200 percent for couples who control their retirement accounts, like 401(k) accounts, relative to those who passively receive retirement income. This finding is consistent with a model of the value of information: households with the most to gain financially from preparation are most responsive to information about cognitive decline.


[Effect of CYP3A4*18B, CYP3A5*3 gene polymorphism on dosage and concentration of tacrolimus in renal transplant patients].
The effect of CYP3A4*18B and CYP3A5*3 on concentration/dosage x body surface area ratios (C/D'), adverse effects and acute rejection of tacrolimus in renal transplant patients were investigated. The CYP3A4*18B genotypes of 227 renal transplant patients were determined by PCR-RFLP method. The differences of C/D' ratios, adverse reactions and acute rejection were compared among all of the genotype groups treated with tacrolimus. The frequencies of CYP3A4*18 and CYP3A5*3 alleles in renal transplant patients were 30.8% and 74.2%, respectively. No significant association was found between the C/D's of tacrolimus and CYP3A4*18B genotypes when they were classified by two CYP3A5 genotypes (P > 0.05). While after the effects of CYP3A4*18B genotype were eliminated, the C/D' ratio of tacrolimus in patients with CYP3A5*1/*1 and *1/*3 genotype group was significantly lower than those with CYP3A5*3/*3 genotype groups (P < 0.01). There is no significant difference in adverse effects and acute rejection among different genotypes (P > 0.05).


Imaging of cAMP levels and protein kinase A activity reveals that retinal waves drive oscillations in second-messenger cascades.
Recent evidence demonstrates that low-frequency oscillations of intracellular calcium on timescales of seconds to minutes drive distinct aspects of neuronal development, but the mechanisms by which these calcium transients are coupled to signaling cascades are not well understood. Here we test the hypothesis that spontaneous electrical activity activates protein kinase A (PKA). We use live-cell indicators to observe spontaneous and evoked changes in cAMP levels and PKA activity in developing retinal neurons. Expression of cAMP and PKA indicators in neonatal rat retinal explants reveals spontaneous oscillations in PKA activity that are temporally correlated with spontaneous depolarizations associated with retinal waves. In response to short applications of forskolin, dopamine, or high-potassium concentration, we image an increase in cAMP levels and PKA activity, indicating that this second-messenger pathway can be activated quickly by neural activity. Depolarization-evoked increases in PKA activity were blocked by the removal of extracellular calcium, indicating that they are mediated by a calcium-dependent mechanism. These findings demonstrate for the first time that spontaneous activity in developing circuits is correlated with activation of the cAMP/PKA pathway and that PKA activity is turned on and off on the timescale of tens of seconds. These results show a link between neural activity and an intracellular biochemical cascade associated with plasticity, axon guidance, and neural differentiation.


Failure to engage spatial working memory contributes to age-related declines in visuomotor learning.
It is well documented that both cognitive and motor learning abilities decline with normative aging. Given that cognitive processes such as working memory are engaged during the early stages of motor learning [Anguera, J., Reuter-Lorenz, P., Willingham, D., & Seidler, R. Contributions of spatial working memory to visuomotor learning. Journal of Cognitive Neuroscience, 22(9), 1917-1930, 2010], age-related declines in motor learning may be due in part to reductions in cognitive ability. The present study examined whether age-related declines in spatial working memory (SWM) contribute to deficits in visuomotor adaptation. Young and older adult participants performed a visuomotor adaptation task that involved adapting manual aiming movements to a 30° rotation of the visual feedback display as well as an SWM task in an fMRI scanner. Young adults showed a steeper learning curve than older adults during the early adaptation period. The rate of early adaptation was correlated with SWM performance for the young, but not older, adults. Both groups showed similar brain activation patterns for the SWM task, including engagement of the right dorsolateral prefrontal cortex and bilateral inferior parietal lobules. However, when the SWM activation was used as a limiting mask, younger adults showed neural activation that overlapped with the early adaptation period, whereas older adults did not. A partial correlation controlling for age revealed that the rate of early adaptation correlated with the amount of activation at the right dorsolateral prefrontal cortex. These findings suggest that a failure to effectively engage SWM processes during learning contributes to age-related deficits in visuomotor adaptation.


Efficient pharmacokinetic modeling of complex clinical dosing regimens: the universal elementary dosing regimen and computer algorithm EDFAST.
Dosing regimens used in clinical practice are often complex, involving several different routes of administration, dose sizes, dosing rates, and dosing intervals and durations. A novel universal elementary dosing regimen (uedr), that allows general pharmacokinetic modeling of these clinical regimens, is presented and developed mathematically. The uedr concept is computationally efficient, mathematically exact, and logically simple, and can replace the disparate standard concepts and equations of elementary infusion, "bolus" injection, multiple injection, oral dosing, zero-order-release dosing, etc. An optimized computer algorithm (EDFAST) based on the uedr approach, that readily permits the creation of a single fast and versatile microcomputer program for the analysis of all complex dosing regimens in any set of linear compartmental models, is presented. This is of particular relevance to three areas of application in clinical pharmacokinetics: compartmental drug concentration or amount versus time course prediction (simulation) with known model parameter values; parameter estimation (curve-fitting) from measured concentration versus time data; and individualized complex dosing regimen calculation (optimization) for target sets of concentration-time points. Application examples that show the versatility of the uedr approach are presented in detail.


Alterations in tyrosine and protein kinetics produced by injury and branched chain amino acid administration in rats.
1. To determine whether the alterations in amino acid metabolism after injury were a result of changes in protein synthesis, whole body tyrosine and individual tissue protein kinetics were estimated 24 h after three different forms of stress in rats. 2. In addition, injured rats were either starved or infused with 180 mg of nitrogen/day (as branched chain amino acids or L-alanine) to ascertain whether the mechanism and degree of nitrogen sparing were unique to branched chain amino acid administration or whether they could be attributed to the infusion of alpha-amino nitrogen. 3. In the more catabolic types of injury, increased nitrogen loss during starvation appeared to be due to both an increased plasma amino acid appearance and a greater percentage being oxidized. Rates of tyrosine incorporation into whole body protein were also enhanced and could be explained in part by increases in the fractional synthesis rate of hepatic non-secretory protein. 4. Both branched chain amino acid and L-alanine administration reduced endogenous tyrosine oxidation and improved nitrogen balance. However, branched chain amino acid administration significantly increased amino acid incorporation into whole body protein and fractional synthetic rates of skeletal muscle, kidney and hepatic non-secretory protein. 5. It is concluded that the catabolic response to severe injury is consistent with increased rates of plasma amino acid appearance and branched chain amino acid administration spares body protein by improving amino acid utilization for whole body protein synthesis.


Diet-induced thermogenesis in patients with gastrointestinal cancer cachexia.
1. Indirect calorimetry has been used to measure resting energy expenditure (REE) and the thermogenic response to a test meal (diet-induced thermogenesis) in groups of weight-stable and weight-losing patients with gastrointestinal adenocarcinoma. Average daily intakes of energy and protein were computed from dietary assessment for the week before hospitalization. Results were compared with a control group of patients with benign gastrointestinal disease. 2. Weight-losing cancer patients had a significantly reduced mean total energy and protein intake. 3. There was no significant difference in REE between the groups when results were normalized in terms of metabolic body size (kJ/kg 0.75) and lean body mass (kJ/kg). 4. Diet-induced thermogenesis was reduced in weight-losing cancer patients. 5. It is suggested that the reduction of diet-induced thermogenesis in weight-losing cancer patients is another element of starvation adaptation, subsequent to their weight loss, and that altered thermogenesis does not contribute to the weight loss seen in cancer cachexia.