Comparison of the duration of hospital stay after laparoscopic or open distal pancreatectomy: randomized controlled trial.
Studies have suggested that laparoscopic distal pancreatectomy (LDP) is advantageous compared with open distal pancreatectomy (ODP) regarding hospital stay, blood loss and recovery. Only one randomized study is available, which showed enhanced functional recovery after LDP compared with ODP. Consecutive patients evaluated at a multidisciplinary tumour board and planned for standard distal pancreatectomy were randomized prospectively to LDP or ODP in an unblinded, parallel-group, single-centre superiority trial. The primary outcome was postoperative hospital stay. Of 105 screened patients, 60 were randomized and 58 (24 women, 41 per cent) were included in the intention-to-treat analysis; there were 29 patients of mean age 68 years in the LDP group and 29 of mean age 63 years in the ODP group. The main indication was cystic pancreatic lesions, followed by neuroendocrine tumours. The median postoperative hospital stay was 5 (i.q.r. 4-5) days in the laparoscopic group versus 6 (5-7) days in the open group (P = 0·002). Functional recovery was attained after a median of 4 (i.q.r. 2-6) versus 6 (4-7) days respectively (P = 0·007), and duration of surgery was 120 min in both groups (P = 0·482). Blood loss was less with laparoscopic surgery: median 50 (i.q.r. 25-150) ml versus 100 (100-300) ml in the open group (P = 0·018). No difference was found in the complication rates (Clavien-Dindo grade III or above: 4 versus 8 patients respectively). The rate of delayed gastric emptying and clinically relevant postoperative pancreatic fistula did not differ between the groups. LDP is associated with shorter hospital stay than ODP, with shorter time to functional recovery and less bleeding. Registration number: ISRCTN26912858 ( www.isrctn.com).


Linearly coded profilometry with a coding light that has isosceles triangle teeth: even-number-sample decoding method.
A new triangulation-based optical profilometry-linearly coded profilometry (LCP)-is presented. In this method, a linear coding technique is introduced. It uses a periodic sawtoothlike structure light to code the surface being measured and the phase-shifting technique to decode the profile. A coding light that has isosceles triangle teeth is proposed. To realize the decoding, at least three samples are needed. When more than three samples are used, higher accuracy can be obtained. A decoding method of LCP with an even number of samples is provided. This method has been realized in my laboratory and the experimental results verify the reliability of LCP. Because the coding method used in LCP is simpler than that used in phase-measuring profilometry, LCP has a faster measuring speed.


Lymphocytes in beta-thalassemia/HbE: subpopulations and mitogen responses.
Lymphocyte subpopulations and proliferative responses to mitogens of 24 beta-thalassemia/HbE patients were studied and compared with those of 23 healthy controls. Results of the study were analyzed in correlation with clinical aspects i.e. severity of disease (anemia), frequency of infections and iron status. T(CD3+) lymphocytes were found to increase in thalassemic patients compared to normal controls. The CD4+ or CD8-positive lymphocytes and CD4/CD8 ratio were not statistically different from normals. Without mitogen, lymphocytes from thalassemic patients incorporated more [3H]Tdr than those from normal controls. Stimulation index (SI) of these cells after various mitogens were lower than in normal subjects. The observations were more obvious in patients with severe disease (severe anemia) and those who had frequent infections. These findings suggest that lymphocytes from thalassemic patients are activated in vivo. Whether these cells are less efficient in response to new or previously unexposed antigens remains to be proven.


(R)-3-hydroxybutyrate dehydrogenase: selective phosphatidylcholine binding by the C-terminal domain.
(R)-3-Hydroxybutyrate dehydrogenase (BDH) is a lipid-requiring mitochondrial enzyme that has a specific requirement of phosphatidylcholine (PC) for function. The C-terminal domain (CTBDH) of human heart BDH (residues 195-297) has now been expressed in Escherichia coli as a chimera with a soluble protein, glutathione S-transferase (GST), yielding GST-CTBDH, a novel fusion protein that has been purified and shown to selectively bind to PC vesicles. Both recombinant human heart BDH (HH-Histag-BDH) and GST-CTBDH (but not GST) form well-defined protein-lipid complexes with either PC or phosphatidylethanolamine (PE)/diphosphatidylglycerol (DPG) vesicles (but not with digalactosyl diglyceride vesicles) as demonstrated by flotation in sucrose gradients. The protein-PC complexes are stable to 0.5 M NaCl, but complexes of either HH-Histag-BDH or GST-CTBDH with PE/DPG vesicles are dissociated by salt treatment. Thrombin cleavage of GST-CTBDH, either before or after reconstitution with PC vesicles, yields CTBDH (12 111 Da by MALDI mass spectrometry) which retains lipid binding without attached GST. The BDH activator, 1-palmitoyl-2-(1-pyrenyl)decanoyl-PC (pyrenyl-PC), at <2.5% of total phospholipid in vesicles, efficiently quenches a fraction (0.36 and 0.47, respectively) of the tryptophan fluorescence of both HH-Histag-BDH and GST-CTBDH with effective Stern-Volmer quenching constants, (K(Q))(eff), of 11 and 9.3 (%)(-)(1), respectively (half-maximal quenching at approximately 0.1% pyrenyl-PC). Maximal quenching by pyrenyl-PC obtains at approximately stoichiometric pyrenyl-PC to protein ratios, reflecting high-affinity interaction of pyrenyl-PC with both HH-Histag-BDH and GST-CTBDH. The analogous pyrenyl-PE effects a similar maximal quenching of tryptophan fluorescence for both proteins but with approximately 15-fold lower (K(Q))(eff) (half-maximal quenching at approximately 1.5% pyrenyl-PE) referable to nonspecific interaction of pyrenyl-PE with HH-Histag-BDH or GST-CTBDH. Thus, the 103-residue CTBDH constitutes a PC-selective lipid binding domain of the PC-requiring BDH.


[A white lesion of the oral mucosa: leukoplakia?].
In three patients, two men aged 50 and 44 years and a woman aged 56 years, an apparently identical white lesion of the oral mucosa was found. The first patient appeared to have an irritation due to vigorous toothbrushing, which disappeared after reducing the brushing frequency and using a soft brush, the second patient had a lichen planus, for which a wait and see policy was adopted, and the third patient had verrucous hyperplasia with dysplasia which was treated by CO2-laser evaporation. Oral leukoplakia occurs frequently together with other white lesions. Leukoplakia is a diagnosis by exclusion and the term should be used as a clinical diagnosis only. When a biopsy is taken, the term leukoplakia is replaced by the diagnosis obtained histologically. About 5% of leukoplakias progress to cancer in a mean observation period of 5 years. Sufficient knowledge of the nomenclature and clinical characteristics of oral white lesions may contribute to the prevention of malignancies and unnecessary referral to a medical specialist.


Differential impact of telomere dysfunction on initiation and progression of hepatocellular carcinoma.
Telomere maintenance and telomerase reactivation are near universal features of human hepatocellular carcinoma (HCC), yet the shorter telomeres and highly abnormal cytogenetic profiles of HCC suggest that telomere erosion and dysfunction may be operative during the formative stages of tumorigenesis. Previous studies have established that the cancer-enhancing or suppressing impact of telomere dysfunction is highly dependent on several parameters including cell type, tumor stage, and p53 status. Here, to understand better the pathogenetic role of telomere dysfunction in the initiation and progression in human HCC, we have used three mechanistically distinct liver cancer-prone model systems (urokinase plasminogen activator transgenic mice, carbon tetrachloride exposure, and diethylnistrosamine treatment) in the context of successive generations of telomerase-deficient mice null for the telomerase RNA component, mTERC. Across all of the HCC model systems, telomere dysfunction suppressed both the incidence and growth of HCC lesions, a trend that mirrored the level of intratumoral proliferative arrest and apoptosis. On the histological level, telomere dysfunction was associated with a significant increase in the number of early stage neoplastic lesions and a reciprocal decline in the occurrence of high-grade malignancies. These genetic data in the mouse indicate that telomere dysfunction exerts an opposing role in the initiation versus progression of HCC and provide a framework for understanding the intimate link among chronic liver disease, chromosomal instability, and increased HCC in humans.


Electron paramagnetic resonance studies on Pseudomonas nitrosyl nitrite reductase. Evidence for multiple species in the electron paramagnetic resonance spectra of nitrosyl haemoproteins.
The e.p.r. spectra of reduced 14NO- and 15NO-bound Pseudomonas nitrite reductase have been investigated at pH 5.8 and 8.0 in four buffer systems. At pH 8.0, absorption spectra indicated that only the haem d1 was NO-bound, but, although quantification of the e.p.r. signals in all cases accounted for NO bound the the haem d1 in both subunits of the enzyme, the precise form of the signals varied with buffer and temperature. A rhombic species, with gx = 2.07, gz = 2.01 and gy = 1.96, represented in the low-temperature spectra seen in all the buffers was converted at high temperatures (approx. 200K) into a form showing a reduced anisotropy. Hyperfine splitting on the gz component of this rhombic signal indicated a nitrogen atom trans to NO and it is proposed that histidine provides the endogenous axial ligand for haem d1. At pH 5.8, absorption spectra indicated NO binding to both haems c and d1 and e.p.r. quantifications accounted for NO-bound haems c and d1 in both enzyme subunits. The e.p.r. spectra at pH 5.8 were generally similar to those at pH 8.0 with respect to g-values and hyperfine coupling constants, but were broader with less well defined hyperfine splittings. As at pH 8, rhombic signals present in spectra at low temperatures were converted to less anisotropic forms at high temperatures. The results are discussed in relation to work on model nitrosyl-protohaem complexes [Yoshimura, Ozaki, Shintani & Watanabe (1979) Arch. Biochem, Biophys. 193, 301-313]. No. e.p.r. signal was observed from oxidized NO-bound Pseudomonas nitrite reductase at pH 6.0, over the temperature range 6-100K.


2',5'-Oligoadenylate-dependent RNAse located in nuclei: biochemical characterization and subcellular distribution of the nuclease in human and murine cells.
A cellular fractionation procedure allowed the rapid preparation of membraneless nuclei which contained a 2',5'-oligoadenylate (2-5A)-binding activity which was not due to cytoplasmic contaminants. Purified nuclei prepared from human lymphocytic leukaemia cells and mouse fibroblasts were found to contain 20-22% of the total cellular enzyme. In contrast with the cytoplasmic enzyme which was only present in a 2-5A-free form, 75% of the 2-5A-binding activity was found in the nuclei after a denaturing-renaturing procedure as the 2-5A-binding site was masked. Although the purification of nuclei from mouse fibroblasts was less effective, it appeared that, in confluent and growing cells, 50% and 75% respectively of the 2-5A-binding site was masked. Additional findings obtained by partial proteolysis and two-dimensional gel analysis provided definitive data on the nuclear location of this enzyme. Study of the nuclear 2-5A-dependent RNAase with a 2-5A-masked site could lead to an understanding of the molecular pathway involved in single-stranded RNA stability.


MicroRNAs regulate pituitary development, and microRNA 26b specifically targets lymphoid enhancer factor 1 (Lef-1), which modulates pituitary transcription factor 1 (Pit-1) expression.
To understand the role of microRNAs (miRNAs) in pituitary development, a group of pituitary-specific miRNAs were identified, and Dicer1 was then conditionally knocked out using the Pitx2-Cre mouse, resulting in the loss of mature miRNAs in the anterior pituitary. The Pitx2-Cre/Dicer1 mutant mice demonstrate growth retardation, and the pituitaries are hypoplastic with an abnormal branching of the anterior lobe, revealing a role for microRNAs in pituitary development. Growth hormone, prolactin, and thyroid-stimulating hormone β-subunit expression were decreased in the Dicer1 mutant mouse, whereas proopiomelanocortin and luteinizing hormone β-subunit expression were normal in the mutant pituitary. Further analyses revealed decreased Pit-1 and increased Lef-1 expression in the mutant mouse pituitary, consistent with the repression of the Pit-1 promoter by Lef-1. Lef-1 directly targets and represses the Pit-1 promoter. miRNA-26b (miR-26b) was identified as targeting Lef-1 expression, and miR-26b represses Lef-1 in pituitary and non-pituitary cell lines. Furthermore, miR-26b up-regulates Pit-1 and growth hormone expression by attenuating Lef-1 expression in GH3 cells. This study demonstrates that microRNAs are critical for anterior pituitary development and that miR-26b regulates Pit-1 expression by inhibiting Lef-1 expression and may promote Pit-1 lineage differentiation during pituitary development.


JAK2 V617F mutation and associated chromosomal alterations in primary and secondary myelofibrosis and post-HCT outcomes.
JAK2 V617F is the most common driver mutation in primary or secondary myelofibrosis for which allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment. Knowledge of the prognostic utility of JAK2 alterations in the HCT setting is limited. We identified all patients with MF who received HCT between 2000 and 2016 and had a pre-HCT blood sample (N = 973) available at the Center of International Blood and Marrow Transplant Research biorepository. PacBio sequencing and single nucleotide polymorphism-array genotyping were used to identify JAK2V617F mutation and associated mosaic chromosomal alterations (mCAs), respectively. Cox proportional hazard models were used for HCT outcome analyses. Genomic testing was complete for 924 patients with MF (634 primary MF [PMF], 135 postpolycythemia vera [PPV-MF], and 155 postessential thrombocytopenia [PET-MF]). JAK2V617F affected 562 patients (57.6% of PMF, 97% of PPV-MF, and 42.6% of PET-MF). Almost all patients with mCAs involving the JAK2 region (97.9%) were JAK2V617-positive. In PMF, JAK2V617F mutation status, allele burden, or identified mCAs were not associated with disease progression/relapse, nonrelapse mortality (NRM), or overall survival. Almost all PPV-MF were JAK2V617F-positive (97%), with no association between HCT outcomes and mutation allele burden or mCAs. In PET-MF, JAK2V617F high mutation allele burden (≥60%) was associated with excess risk of NRM, restricted to transplants received in the era of JAK inhibitors (2013-2016; hazard ratio = 7.65; 95% confidence interval = 2.10-27.82; P = .002). However, allele burden was not associated with post-HCT disease progression/relapse or survival. Our findings support the concept that HCT can mitigate the known negative effect of JAK2V617F in patients with MF, particularly for PMF and PPV-MF.


Active glycerol uptake is a mechanism underlying halotolerance in yeasts: a study of 42 species.
A comparison of 42 yeast species with respect to growth in the presence of high NaCl concentration and characteristics of glycerol uptake is presented. The yeast species were classified into four classes on the basis of their ability to grow in the presence of 1, 2, 3 or 4 M NaCl. Considering that two different types of active-transport systems for glycerol uptake have been described, Na+/glycerol and H+/glycerol symports, glycerol transport was investigated by testing for proton uptake upon glycerol addition in cells incubated in the absence and in the presence of NaCl. Only strains belonging to the two higher classes of salt tolerance showed constitutive active glycerol uptake, and could accumulate glycerol internally against a concentration gradient. Five of these strains exhibited a H+/glycerol symport. All the other strains showed evidence of the activity of a salt-dependent glycerol uptake similar to that described in the literature for Debraryomyces hansenii. The strains within the two lower classes of salt tolerance showed, to varying degrees, glycerol active uptake only when glycerol was used as the carbon and energy source, suggesting that this uptake system is involved in glycerol catabolism. The results within this work suggest that active glycerol uptake provides a basis for high halotolerance, helping to maintain a favourable intracellular concentration of glycerol. The relation between the constitutive expression of such carriers and a higher level of salt-stress resistance suggests that this may be an evolutionary advantage for growth under such conditions.


Pollination modulates expression of the PPAL gene, a pistil-specific beta-expansin.
Using differential screening we isolated a pistil-specific cDNA clone corresponding to a 1.2 kb mRNA and encoding a 32.5 kDa protein. The amino acid sequence shared similarity with that of group-I grass pollen allergens, which are known to have expansin activity. This clone, which later showed to share homology also with beta-expansins, was named PPAL. The PPAL mRNA was specifically expressed in the secretory zone of the stigma and in the epidermal layer of the placenta. The accumulation level of the transcript increased during pollination, and the protein was secreted in the stigmatic exudate of the tobacco flower. We suggest here that PPAL is a new expansin, acting as a cell-wall-loosening agent during pollination.


Ageing under unequal circumstances: a cross-sectional analysis of the gender and socioeconomic patterning of functional limitations among the Southern European elderly.
In a context of population ageing, it is a priority for planning and prevention to understand the socioeconomic (SE) patterning of functional limitations and its consequences on healthcare needs. This paper aims at measuring the gender and SE inequalities in functional limitations and their age of onset among the Southern European elderly; then, we evaluate how functional status is linked to formal and informal care use. We used Portuguese, Italian and Spanish data from the Survey of Health, Ageing and Retirement in Europe (SHARE) of 2011 (n = 9233). We constructed a summary functional limitation score as the sum of two variables: i) Activities of Daily Living (ADL) and ii) Instrumental Activities of Daily Living (IADL). We modelled the functional limitation as a function of age, gender, education, subjective poverty, employment and marital status using multinomial logit models. We then estimated how functional limitation affected informal and formal care demand using negative binomial and logistic models. Women were 2.3 percentage points (pp) more likely to experience severe functional limitation than men, and overcame a 10% probability threshold of suffering from severe limitation around 5 years earlier. Subjective poverty was associated with a 3.1 pp. higher probability of severe functional limitation. Having a university degree reduced the probability of severe functional limitation by 3.5 pp. as compared to none educational level. Discrepancies were wider for the oldest old: women aged 65-79 years old were 3.3 pp. more likely to suffer severe limitations, the excess risk increasing to 15.5 pp. among those older than 80. Similarly, educational inequalities in functional limitation were wider at older ages. Being severely limited was related with a 32.1 pp. higher probability of receiving any informal care, as compared to those moderately limited. Finally, those severely limited had on average 3.2 hospitalization days and 4.6 doctor consultations more, per year, than those without limitations. Functional limitations are unequally distributed, hitting women and the worse-off earlier and more severely, with consequences on care needs. Considering the burden on healthcare systems and families, public health policies should seek to reduce current inequalities in functional limitations.


Cardiometabolic risk profile of young and old adults with diabetes: Pooled, cross-sectional analysis of 42 national health surveys.
To compare levels of cardiometabolic risk factors in young and old adults with diabetes. Pooled analysis of 42 STEPS Surveys (n = 133,717). Diabetes was defined as self-reported diagnosis or fasting plasma glucose ≥ 126 mg/dl. There were two age groups: < 40 and ≥ 40 years. We summarized the mean levels of four cardiometabolic risk factors by country, sex and age group. In 11 (men) and seven countries (women), the mean BMI seemed higher in young versus old adults; largest difference was found in men in Qatar (∼6 kg/m2). For waist circumference, such pattern was observed in two (men) and in three (women) countries; largest difference in men in Tuvalu (∼7 cm). Regarding systolic blood pressure, in one country (Myanmar) the mean was higher in young men with ∼8 mmHg difference. Women in the oldest group always had higher mean systolic blood pressure. For total cholesterol, in 13 (men) and five (women) countries the mean was higher in young adults (difference was always <1 mmol/l). Levels of cardiometabolic risk factors in young versus old adults with diabetes were heterogenous across 42 countries and depended on the risk factor. This calls to monitor cardiometabolic risk factors in young adults with diabetes.


Health in crises. Migration, austerity and inequalities in Greece and Europe: introduction to the supplement.
This introduction summarizes and discusses the main findings of the supplement 'Health in crises. Migration, austerity and inequalities in Greece and Europe' to the European Journal of Public Health. The supplement applies data from the ESS (2014) health module in combination with the MIGHEAL study, which is a new source of data on the Greek population specially designed to examine health inequalities among and between migrants and natives. This has enabled the authors of the nine articles that constitute this supplement to address several pressing issues about the distribution of health and its determinants in Greece and other European countries. The main finding of the present supplement is the exceptionally high rates of reported depressive symptoms across the whole population residing in Greece and particularly among women. Levels of unmet need for healthcare were also found to be alarmingly high in Greece compared with other European countries, suggesting that the crisis and subsequent austerity policies may have impacted the provision of healthcare services and access to healthcare for broad sections of the population, whether native or migrant.


Germline variants and phenotypic spectrum in a Canadian cohort of individuals with diffuse gastric cancer.
CDH1 pathogenic variants (pvs) cause most cases of inherited diffuse gastric cancer (dgc), but have low detection rates and vary geographically. In the present study, we examined hereditary causes of dgc in patients in Ontario. CDH1 testing through single-site or multi-gene panels was conducted for patients with dgc meeting the 2015 International Gastric Cancer Linkage Consortium (igclc) criteria, or with isolated dgc at less than 50 years of age, or with a strong family history of cancer identified at the Zane Cohen Centre (zcc). All CDH1-positive patients at zcc, regardless of cancer history, were summarized. In 15 of 85 patients with dgc (17.6%), a pv or likely pv was identified through CDH1 single-site (n = 43) or multi-gene panel (n = 42) testing. The detection rate was 9.4% overall (8 of 85) and 11% using igclc criteria (7 of 65). No CDH1 pvs were identified in patients with isolated dgc at less than 40 years of age, but 1 pv was identified in a patient with isolated dgc at less than 50 years of age. Multi-gene panels identified 9 pvs (21.4%), including CDH1, STK11, ATM, BRCA2, MLH1, and MSH2. Review of 81 CDH1 carriers identified 10% with dgc (median age: 48 years; range: 38-59 years); 41% were unaffected (median age: 53 years; range: 26-89 years). Observed malignancies other than dgc or lobular breast cancer (lbc) included colorectal, gynecologic, kidney or bladder, prostate, testicular, and ductal breast cancers. Lobular-breast cancer was seen only in 3 families. In Ontario, the detection rate of CDH1 pvs in patients with dgc was low: no pvs were identified in patients with isolated dgc at less than 40 years of age, and 1 was identified in a patient with isolated dgc at less than 50 years of age. Isolated lbc with no dgc was observed in CDH1-positive families, as were pathology-confirmed nondgc or non-lbc malignancies, which had not previously been reported. Given a phenotype that overlaps with other hereditary conditions, multi-gene panels are recommended for all patients with dgc at less than 50 years of age and for those meeting igclc criteria.


Development of a Chronic Canine Ovariohysterectomy Model to Evaluate Vaginal Cuff Healing Using Two Closure Systems.
Background and Purpose. This study established a suitable animal model of ovariohysterectomy; characterized the course and pattern of vaginal healing after ovariohysterectomy; and compared healing obtained after closure of the vaginal cuff with a novel cuff-closure device (Zip-stitch® clips) and VICRYL® sutures. Research Design and Study Sample. This prospective, randomized, controlled, blinded animal study was conducted in 27 mongrel hounds according to an IACUC-approved protocol. Each animal underwent ovariohysterectomy followed by vaginal cuff closure with Zip-stitch or VICRYL. At two or six weeks, animals were sacrificed for gross and histological analysis. Data Collection. The primary endpoint was the difference in the fraction of vaginal cuff healed six weeks after application of the closure device. Secondary endpoints included histopathologic cellular and tissue responses, including inflammation, necrosis, infection, and vascular and muscle changes. Results. In the test group, there were two distinct locations where fibrotic or granular tissue fusion between the anterior and posterior vaginal walls was observed: in tissue "captured" by a clip or in tissue around the clip. The fraction of the vaginal cuff healed was similar in animals treated with Zip-stitch clips and those treated with sutures at six weeks (68±10% vs 67±18%; P=.148, test for non-inferiority) after surgery. The test article performed similarly or better than the control article in terms of the intensity or extent of the secondary endpoints. Conclusions. Subject to further confirmation, this study supports Zip-stitch clips as a method to maintain immediate post-operative approximation of the vaginal cuff leading to healing but did not achieve statistical significance in its primary endpoint.


Prognostic factors of cataract surgery in patients with uveitis.
To evaluate the long-term visual outcomes of patients with uveitis undergoing cataract surgery and to identify possible factors influencing the visual prognosis and the development of postoperative complications. Retrospective study of all patients with uveitis who underwent cataract surgery between January 2015 and February 2020 in our tertiary referral center. A total of 78 eyes from 78 patients were included in the study. The best-corrected visual acuity (BCVA) improved in 86% of patients, and a BCVA of 0.5 or better was achieved in 57 (73%) patients. A significant correlation was shown between the preoperative and postoperative BCVA (Spearman r = 0.521, p < 0.01). Final BCVA differed between diverse anatomical uveitis entities (p = 0.047), and anterior uveitis demonstrated the best outcomes. Chronic uveitis resulted in a worse final BCVA than acute recurrent uveitis (p = 0.001). The presence of CME any time before the surgery and intermediate uveitis were associated with worse visual prognosis, while systemic therapy for uveitis before surgery and iris manipulation during surgery were not related to visual outcomes. Postoperative development of cystoid macular edema (CME) was closely associated with preexisting CME (p < 0.001) and intermediate uveitis (p = 0.01). Visual results of cataract surgery in patients with uveitis were beneficial, but limited visual outcomes were more frequently observed in patients with chronic uveitis and intermediate uveitis with a history of CME. In consequence, prevention, or adequate treatment of CME, especially in patients with intermediate uveitis, might result in better visual results of their cataract surgery.


Comparison of sequence reads obtained from three next-generation sequencing platforms.
Next-generation sequencing technologies enable the rapid cost-effective production of sequence data. To evaluate the performance of these sequencing technologies, investigation of the quality of sequence reads obtained from these methods is important. In this study, we analyzed the quality of sequence reads and SNP detection performance using three commercially available next-generation sequencers, i.e., Roche Genome Sequencer FLX System (FLX), Illumina Genome Analyzer (GA), and Applied Biosystems SOLiD system (SOLiD). A common genomic DNA sample obtained from Escherichia coli strain DH1 was applied to these sequencers. The obtained sequence reads were aligned to the complete genome sequence of E. coli DH1, to evaluate the accuracy and sequence bias of these sequence methods. We found that the fraction of "junk" data, which could not be aligned to the reference genome, was largest in the data set of SOLiD, in which about half of reads could not be aligned. Among data sets after alignment to the reference, sequence accuracy was poorest in GA data sets, suggesting relatively low fidelity of the elongation reaction in the GA method. Furthermore, by aligning the sequence reads to the E. coli strain W3110, we screened sequence differences between two E. coli strains using data sets of three different next-generation platforms. The results revealed that the detected sequence differences were similar among these three methods, while the sequence coverage required for the detection was significantly small in the FLX data set. These results provided valuable information on the quality of short sequence reads and the performance of SNP detection in three next-generation sequencing platforms.


Risk stratification and prevention of sudden death in patients with heart failure.
For almost the past decade, recommendations for the use of implantable cardioverter defibrillators (ICDs) for primary prevention of sudden cardiac death have been based upon the left ventricular ejection fraction (LVEF). Current guidelines recommend an ICD for heart failure patients with LVEF ≤35% and NYHA functional class of II or III; however, because the majority of heart failure patients who qualify for ICD implantation based on these criteria will never have an event requiring ICD therapy over several years of follow-up, additional methods of risk stratification for sudden death are clearly needed. Additionally, most of the nearly 300,000 cardiac arrests that occur each year occur in patients without heart failure or significant left ventricular dysfunction. To improve the identification of patients at risk for sudden death, several criteria other than ejection fraction have been proposed and studied. Markers of autonomic tone, including heart rate turbulence and QT dynamicity, have shown some ability to predict total mortality but not arrhythmic events. Microvolt T-wave alternans testing was initially thought to be highly predictive of life-threatening arrhythmias, but prospective large sub-studies of the MADIT II and SCD-HeFT trials have failed to show a predictive value for T-wave alternans testing. Newer markers for risk are based upon the detection of myocardial fibrosis, which forms the substrate for re-entrant and malignant ventricular tachyarrhythmias. Markers of collagen turnover or quantification of myocardial scar by MRI may hold the best promise for identifying patients at highest risk for sudden cardiac death and may also identify patients at high risk but with an ejection fraction above 35%, who are not currently recommended for ICD implantation.


The transcription factor 7-like 2 (TCF7L2) polymorphism may be associated with focal arteriolar narrowing in Caucasians with hypertension or without diabetes: the ARIC Study.
Transcription factor 7-like 2 (TCF7L2) has emerged as a consistently replicated susceptibility gene for type 2 diabetes, however, whether the TCF7L2 gene also has similar effects on the retinal microvasculature is less clear. We therefore aimed to investigate the association between the transcription factor 7-like 2 (TCF7L2) rs7903146 polymorphism and retinal microvascular phenotypes in the Atherosclerosis Risk in Communities (ARIC) Study (1993-1995). This was a population-based, cross-sectional study of 10,320 middle-aged African American (n = 2,199) and Caucasian (n = 8,121) men and women selected from four United States communities to examine the association between TCF7L2 rs7903146 polymorphism and retinal microvascular signs (retinopathy, focal arteriolar narrowing, arteriovenous nicking, arteriolar and venular calibers). Photographs on one randomly selected eye were graded for presence of retinal microvascular signs and used to measure retinal vessel calibres. After adjusting for age, sex, study center, mean arterial blood pressure, total serum cholesterol, triglycerides, and other covariates, few associations of TCF7L2 rs7903146 and retinal microvascular signs were noted. TCF7L2 rs7903146 T risk allele was significantly associated with focal arteriolar narrowing in Caucasians with hypertension [odds ratio (OR)CT vs. CC (95% CI) = 1.25 (1.09-1.44); ORTT vs. CC = 1.56 (1.18-2.06); P = 0.002] and in Caucasians without diabetes [OR CT vs. CC = 1.18 (1.06-1.32); OR TT vs. CC = 1.40 (1.12, 1.75); P = 0.003]. No significant association of the TCF7L2 rs7903146 polymorphism and retinal vascular signs was noted among African American individuals. TCF7L2 rs7903146 is not consistently associated with retinal microvascular signs. However, we report an association between the TCF7L2 rs7903146 polymorphism and focal arteriolar narrowing in Caucasians with hypertension or without diabetes. Further research in other large, population-based studies is needed to replicate these findings.


[Functional prediction of KIAA0101 gene in human non-small cell lung cancer].
To predict the function of KIAA0101 gene over-expressed in human non-small cell lung cancer by bioinformatics methods. The gene expression profiles of the lung cancer tissues and the adjacent normal tissues were compared by dChip software analysis, and the differential genes coexpressed with KIAA0101 gene were identified. The biological functions of these genes were analyzed using the Database for Annotation, Visualization and Integrated Discovery (DAVID), Gene Ontology (GO) and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), and the common transcription factors of these genes were predicted using Gene Annotation Tool to Help Explain Relationships (GATHER). Nine genes were found to have at least two-fold overexpressions in the lung cancer tissues in comparison with the expression level in the adjacent normal tissues, and showed similar pattern of expression variations in the lung cancer tissue. Most of these genes had the E2F1 binding sites in the promoter region. KIAA0101 gene may participate in the cell cycle regulation of the non-small cell lung cancer, and the expression levels of the 9 genes identified may be regulated by the transcription factor E2F1.


Evolutionary relationships of the metazoan beta gamma-crystallins, including that from the marine sponge Geodia cydonium.
beta gamma-crystallins are one major component of vertebrate lenses. Here the isolation and characterization of a cDNA, coding for the first beta gamma-crystallin molecule from an invertebrate species, the marine sponge Geodia cydonium, is described. The size of the transcript as determined by Northern blotting was 0.7 kb in length. The deduced amino acid sequence consists of 163 aa residues and comprises four repeated motifs which compose the two domains of the beta gamma-crystallin. Motif 3 contains the characteristic beta gamma-crystallin 'Greek key' motif signature, while in each of the three other repeats, one aa residue is replaced by an aa with the same physico-chemical property. The sponge peptide shows striking similarities to vertebrate beta gamma-crystallins. Analysis by neighbour joining of the sponge motifs with the two motifs present in spherulin 3a of Physarum polycephalum shows that motif 4 of the sponge beta gamma-crystallin was added as the last single sequence to the tree. The data support the view that the beta gamma-crystallin superfamily, present in eukaryotes, evolved from a common ancestor including also the sponge beta gamma-crystallin.


[Procedure for Latrodectus reproduction in the laboratory setting and the preparation of the first Russian matrix from its venom to manufacture homeopathic remedies with antiparasitic activity].
The investigation was undertaken to study the biology and ecology of Latrodectus, the possibilities of its importation to Russia from other countries, to breed Latrodectus in the laboratory setting, and to design the first homeopathic matrix of Latrodectus to manufacture homeopathic remedies. The authors were the first to devise a method for Latrodectus breeding in the laboratory setting of Moscow and its vicinities. The Latrodectus bred in the laboratory is suitable to manufacture drugs and in captivity they do not lose its biological activity. The authors were the first to prepare a homeopathic Latrodectus matrix for homeopathic medicines, by using the new Russian extragent petroleum. Chromatography mass spectrometry was used to identify more than a hundred chemical compounds in the Russian petroleum. The biological activity of the petroleum Latrodectus matrix for the manufacture of homeopathic remedies was highly competitive with that of the traditional Latrodectus venom matrix made using ethyl alcohol. The homeopathic Latrodectus matrix made using glycerol lost its biological activity because of glycerol. The biological activity of homeopathic matrixes made from Latrodectus inhabiting the USA, Uzbekistan, and the south of Russia and from that bred in the laboratory was studied. The homeopathic matrix made from the Latrodectus living in the Samarkand Region, Republic of Uzbekistan, has the highest biological activity.


Adipose Tissue LPL Methylation is Associated with Triglyceride Concentrations in the Metabolic Syndrome.
DNA methylation is one of the epigenetic mechanisms that regulate gene expression. DNA methylation may be modified by environmental and nutritional factors. Thus, epigenetics could potentially provide a mechanism to explain the etiology of metabolic disorders, such as metabolic syndrome (MetS). The aim of this study was to analyze the level of DNA methylation of several lipoprotein lipase (LPL)-promoter-CpG dinucleotides in a CpG island region and relate this to the gene and protein expression levels in human visceral adipose tissue (VAT) from individuals with and without MetS. VAT samples were collected from laparoscopic surgical patients without and with MetS, and levels of LPL mRNA, LPL protein, and LPL DNA methylation were measured by qPCR, western blot, and pyrosequencing. Biochemical and anthropometric variables were analyzed. Individuals included in a subset underwent a dietary fat challenge test, and levels of postprandial triglycerides were determined. We found higher levels of DNA methylation in MetS patients but lower gene expression and protein levels. There was a negative association between LPL methylation and LPL gene expression. We found a positive association between LPL methylation status and abnormalities of the metabolic profile and basal and postprandial triglycerides, whereas LPL gene expression was negatively associated with these abnormalities. We demonstrate that LPL methylation may be influenced by the degree of metabolic disturbances and could be involved in triglyceride metabolism, promoting hypertriglyceridemia and subsequent associated disorders, such as MetS.


Effects of premium discount on workers' compensation claims in agriculture in Finland.
The objective of this study was to measure changes in injury claim rates after a premium discount program was implemented in the Finnish farmers' workers' compensation insurance. We focused on measures that could indicate whether the changes occurred in the true underlying injury rate, or only in claims reporting. Monthly injury claim rates were constructed at seven disability duration levels from January 1990 to December 2003. We conducted interrupted time series analyses to measure changes in the injury claim rates after the premium discount was implemented on July 1, 1997. Three additional policy change indicators were included in the analyses. The overall injury claim rate decreased 10.2%. Decreases occurred at four severity levels (measured by compensated disability days): 0 days (16.3%), 1-6 days (14.1%), 7-13 days (19.5%), and 14-29 days (8.4%). No changes were observed at higher severity levels. Minor injuries had a seasonal pattern with higher rates in summer months while severe injuries did not have a seasonal pattern. The premium discount decreased the overall claim rate. Decreases were observed in all categories up to 29 disability days. This pattern suggests that under-reporting contributes to the decrease but may not be the only factor. The value of the premium discount is lower than the value of a lost-time claim, so there was no financial reason to under-report lost-time injuries. Under-reporting would be expected to be greatest in the 0 day category, but that was not the case. These observations suggest that in addition to under-reporting, the premium discount may also have some preventive effect.


[Growth of Escherichia coli cell culture and frequency of mutation, induced by N-methyl-N'-nitro-N-nitrosoguanidine].
The rate of Escherichia coli mutation with N-methyl-N'-nitro-N-nitrosoguanidine was found to depend on the age of the culture and the pH value of the incubation medium. The mutability of late-logarithmic cells was higher than that of mid-logarithmic cells. Rifampicin, a transcription inhibitor, enhanced the mutagenic action of MNNG on cells from the late logarithmic and early stationary phases suspended in a medium with a pH of 7.4, and on cells from the mid-logarithmic phase suspended in a medium with a pH of 6.5. Conversely, streptomycin decreased the frequency of induced mutations in cells from the late logarithmic and early stationary phases suspended in the medium with a pH of 7.4, and in cells from the mid-logarithmic and early stationary phases suspended in the medium with a pH of 6.5. These data were interpreted as showing that the repair of premutational DNA lesions induced by MNNG depends on the level of DNA transcription and translation.


Changes in ventilation and its components in normal subjects during sleep.
Non-invasive measurements were made of ventilation, its derivatives, the contributions of abdomen and rib cage and arterial oxygen saturation in six healthy normal men whilst awake and during sleep. Minute ventilation fell significantly during slow wave (SW) sleep and rapid eye movement (REM) sleep (awake = 6.3 1 min-1, SW sleep = 5.7 1 min-1, REM sleep = 5.4 1 min-1; p less than 0.04). Mean inspiratory flow also fell significantly but timing was unchanged. The abdominal (diaphragmatic) contribution to ventilation fell very significantly during SW sleep but returned to awake levels during REM sleep (awake 54%, SW sleep 38%, REM sleep 56%; p less than 0.007). There were also significant falls in arterial oxygen saturation during SW and REM sleep (awake 97.3%, SW sleep 96.5%, REM sleep 96.2%; p less than 0.002). These falls represent reductions in arterial oxygen tension similar to those seen in patients with chronic airways obstruction and can be accounted for entirely by the associated reduction in ventilation.


Hyperglycemia-induced metabolic compensation inhibits metformin sensitivity in ovarian cancer.
Increasing interest in repurposing the diabetic medication metformin for cancer treatment has raised important questions about the translation of promising preclinical findings to therapeutic efficacy, especially in non-diabetic patients. A significant limitation of the findings to date is the use of supraphysiologic metformin doses and hyperglycemic conditions in vitro. Our goals were to determine the impact of hyperglycemia on metformin response and to address the applicability of metformin as a cancer therapeutic in non-diabetic patients. In normoglycemic conditions, lower concentrations of metformin were required to inhibit cell viability, while metformin treatment in hyperglycemic conditions resulted in increased glucose uptake and glycolytic flux, contributing to cell survival. Mechanistically, maintenance of c-Myc expression under conditions of hyperglycemia or via gene amplification facilitated metabolic escape from the effects of metformin. In vivo, treatment of an ovarian cancer mouse model with metformin resulted in greater tumor weight reduction in normoglycemic vs. hyperglycemic mice, with increased c-Myc expression observed in metformin-treated hyperglycemic mice. These findings indicate that hyperglycemia inhibits the anti-cancer effects of metformin in vitro and in vivo. Furthermore, our results suggest that metformin may elicit stronger responses in normoglycemic vs. hyperglycemic patients, highlighting the need for prospective clinical testing in patients without diabetes.


A review of barriers to utilization of the medicare hospice benefits in urban populations and strategies for enhanced access.
Disparities in access to health care extend to end-of-life care. Lack of access to hospice mirrors lack of access to health maintenance and primary care. Patients who are served by hospice nationally are disproportionately white and likely to reside in economically stable communities. In many urban low-income communities, less than 5% of decedents receive hospice care in the last 6 months of life. This review focuses on barriers to palliative care and hospice in urban, predominantly low-income communities, including cultural and reimbursement factors and the paucity of hospice providers, outreach projects, and in-patient hospice beds in urban communities. This review will also address some strategies that are being implemented by hospices locally and nationally to overcome demographic barriers to hospice care.


A comparison of cancer burden and research spending reveals discrepancies in the distribution of research funding.
Ideally, the distribution of research funding for different types of cancer should be equitable with respect to the societal burden each type of cancer imposes. These burdens can be estimated in a variety of ways; "Years of Life Lost" (YLL) measures the severity of death in regard to the age it occurs, "Disability-Adjusted Life-Years" (DALY) estimates the effects of non-lethal disabilities incurred by disease and economic metrics focus on the losses to tax revenue, productivity or direct medical expenses. We compared research funding from the National Cancer Institute (NCI) to a variety of burden metrics for the most common types of cancer to identify mismatches between spending and societal burden. Research funding levels were obtained from the NCI website and information for societal health and economic burdens were collected from government databases and published reports. We calculated the funding levels per unit burden for a wide range of different cancers and burden metrics and compared these values to identify discrepancies. Our analysis reveals a considerable mismatch between funding levels and burden. Some cancers are funded at levels far higher than their relative burden suggests (breast cancer, prostate cancer, and leukemia) while other cancers appear underfunded (bladder, esophageal, liver, oral, pancreatic, stomach, and uterine cancers). These discrepancies indicate that an improved method of health care research funding allocation should be investigated to better match funding levels to societal burden.


Elbow joint loads during simulated activities of daily living: implications for formulating recommendations after total elbow arthroplasty.
Overloading of the elbow joint prosthesis following total elbow arthroplasty can lead to implant failure. Joint moments during daily activities are not well contextualized for a prosthesis's failure limits, and the effect of the current postoperative instruction on elbow joint loading is unclear. This study investigates the difference in elbow joint moments between simulated daily tasks and between flexion-extension, pronation-supination, and varus-valgus movement directions. Additionally, the effect of the current postoperative instruction on elbow joint load is examined. Nine healthy participants (age 45.8 ± 17 years, 3 males) performed 8 tasks; driving a car, opening a door, rising from a chair, lifting, sliding, combing hair, drinking, emptying cup, without and with the instruction "not lifting more than 1 kg." Upper limb kinematics and hand contact forces were measured. Elbow joint angles and net moments were analyzed using inverse dynamic analysis, where the net moments are estimated from movement data and external forces. Peak elbow joint moments differed significantly between tasks (P < .01) and movement directions (P < .01). The most and least demanding tasks were, rising from a chair (13.4 Nm extension, 5.0 Nm supination, and 15.2 Nm valgus) and sliding (4.3 Nm flexion, 1.7 Nm supination, and 2.6 Nm varus). Net moments were significantly reduced after instruction only in the chair task (P < .01). This study analyzed elbow joint moments in different directions during daily tasks. The outcomes question whether postoperative instruction can lead to decreasing elbow loads. Future research might focus on reducing elbow loads in the flexion-extension and varus-valgus directions.


[Development of lymphocyte subsets in tumor patients after subcutaneous administration of mistletoe extracts].
In order to exclude the possibility that mistletoe therapy may result in immunosuppression, as indicated by a significant reduction of defined lymphocyte subsets, peripheral blood cells of 23 tumour patients were treated subcutaneously with increasing concentrations of aqueous mistletoe extracts (Helixor(R)). Within an observation period of 7 months, the relative amount of lymphocytes and the number of natural killer (NK) cells increased while the number of lymphocyte subsets (i. e. CD19+ B cells, CD4+ T helper cells, CD8+ CD28- suppressor cells, CD8+ CD28+ cytotoxic cells) and the proportion of CD25+ (activated) cells within T cells showed a statistically remarkable trend; due to the multiple test problem of statistical evaluation this trend is not allowed to be termed significant. The leucocytes decreased insignificantly within the observation period. However, we were unable to verify a suggested increase of defined lymphocyte subsets within 2-3 months after the onset of mistletoe treatment. Nevertheless, for the parameters CD19+ B cells, CD4+ T helper cells, CD8+ cells, CD8+ CD28+ cytotoxic cells and CD16+/CD56+ NK cells we observed statistically remarkable peaks within die 2nd and 3rd month of therapy, confirming the hypothesis. The responses to the extracts were obviously interindividually different; the immune responses especially of patients with a lower number of peripheral T cells were less significant as compared to those of patients with adequate T cell numbers. Surprisingly, even an increase of the drug concentration >3 ng mistletoe lectin (as determined within the whole plant extract) per kg body weight enhanced the number of CD4+ T helper cells. A decreased immunological reaction on mistletoe extracts was shown especially for patients with a reduced number of peripheral T cells, whereas patients with normal T-cell number were more reactive.


Treatment of older patients with chronic lymphocytic leukemia: key questions and current answers.
Despite the advanced age at onset, chronic lymphocytic leukemia (CLL) shortens the life expectancy of the majority of newly diagnosed patients. The management of elderly patients with CLL is more complex than that of younger patients due to the greater frequency of comorbidities and functional impairment as well as reduced organ function. Many of the recent advances in the care of CLL patients (prognostication, more intense combination therapy regimens) are of unclear relevance for elderly patients. This review addresses 5 key questions in the management of elderly patients with CLL: (1) why is classifying the "fitness" of CLL patients necessary; (2) what criteria should be used to classify patient fitness; (3) when should elderly patients be treated; (4) how should therapy be selected for elderly patients; and (5) which therapy is best (for this patient)?


Switching interlayer magnetic order in bilayer CrI3 by stacking reversal.
CrI3, a hot two-dimensional (2D) magnet, exhibits complex magnetism depending on the number of layers and interlayer stacking patterns. For bilayer CrI3, the interlayer magnetism can be tuned between ferromagnetic (FM) and antiferromagnetic (AFM) order by manipulating the stacking order. However, the stacking is mostly modified through translation between the layers, while the effect of rotation between the layers on the interlayer magnetic order has not yet been fully investigated. Here, we considered three energetically stable stacking patterns R3̄, C2/m and AA in bilayer CrI3, and their reversed counterparts R3̄-r, C2/m-r and AA-r through rotating one layer by 180° with respect to the other layer. Our first-principles calculations suggest that the interlayer magnetic ground state can be switched from AFM to FM (or FM to AFM) by reversing the stacking pattern. A detailed microscopic analysis was carried out by magnetic force theory calculations on C2/m stacking which favors AFM and C2/m-r stacking which favors FM. The interlayer magnetic interactions and the origin of the magnetic order change were revealed through specific orbital analysis. Our work demonstrates that stacking rotation can also tune the interlayer magnetism of CrI3 and provides insight into its interlayer magnetic properties at the microscopic level.


Increasing social interaction using prelinguistic milieu teaching with nonverbal school-age children with autism.
Children with autism display marked deficits in initiating and maintaining social interaction. Intervention using play routines can create a framework for developing and maintaining social interaction between these children and their communication partners. Six nonverbal 5- to 8-year-olds with autism were taught to engage in social interaction within salient play routines. Prelinguistic milieu teaching (PMT) techniques were used to teach the children to communicate intentionally during these routines. Intervention focused on the children's social interaction with an adult. The effects of intervention were evaluated using a multiple baseline design across participants. At study onset, the participants demonstrated few consistent interaction with others. With intervention, all of the children improved their ability to sustain social interactions, as evidenced by an increase in the number of communicative interactions during play routines. Participants also increased their overall rate of initiated intentional communication. Development of intentional prelinguistic communication within salient social routines creates opportunities for an adult to teach social and communication skills to young school-age children with autism who function at a nonverbal level.


The emerging epidemic of heart failure with preserved ejection fraction.
Heart failure with preserved ejection fraction (HFpEF), which currently represents approximately 50 % of heart failure (HF) cases, is common and associated with high morbidity and mortality. Understanding the epidemiology of HFpEF has been difficult due to the challenges in HFpEF diagnosis and the heterogeneous etiologies and pathophysiologies that underlie HFpEF. Nevertheless, several high-quality epidemiology and observational registry studies of HFpEF demonstrate that an increasing prevalence of HFpEF in both the outpatient and inpatient settings, coupled with a lack of evidence-based effective treatments for HFpEF, is resulting in an emerging epidemic of HFpEF. In this review, we discuss the emerging HFpEF epidemic, focusing on: (1) reasons for the rising prevalence of HFpEF; (2) the abnormalities in cardiac structure and function that dictate the transition from risk factors to HFpEF; (3) novel HFpEF mechanisms that may underlie the increase in HFpEF prevalence; (4) prognosis of HFpEF; and (5) risk prediction in HFpEF. We conclude with 10 unanswered questions onHFpEF epidemiology thatwill be important areas for future investigation.


Conceiving THz endometrial ablation: feasibility, requirements and technical challenges.
Shallow-ablation of endometrial lining using microwaves has been traditionally indicated as a minimally invasive treatment option for dysfunctional uterine bleeding (DUB). Known as microwave endometrial ablation (MEA), relevant procedure is used as an alternative to hysterectomy considering its safety, simplicity and effectiveness. In lieu of the prevailing MEA techniques, it is attempted in this study to foresee the possibility of conceiving an alternative and a newer option on endometrial ablation using mm-wave/THz frequencies. Commensurate with this motivated impetus, objectively considered are merits and design issues of using electromagnetic (EM) spectrum of mm-wave/THz region toward optimal conversion of EM energy into a thermal ablative source so that, the basal layer of endometrium can be effectively destroyed in surgical contexts as necessary. Hence, the feasibility of designing appropriate TEA applicators for controlled and safe procedures so as to ablate just the unwanted tissues within a localized zone of energy field is addressed. Lastly, a quantitative analysis on the interaction of THz EM-energy versus the lossy dielectric characteristics of endometrial medium is indicated to model the underlying (THz-energy)-to-(thermal energy) transduction. Relevant prospects of conceiving TEA and the associated pros and cons are identified specific to the prospects of feasibility, requirement considerations and technical challenges.


Hierarchical graph representations in digital pathology.
Cancer diagnosis, prognosis, and therapy response predictions from tissue specimens highly depend on the phenotype and topological distribution of constituting histological entities. Thus, adequate tissue representations for encoding histological entities is imperative for computer aided cancer patient care. To this end, several approaches have leveraged cell-graphs, capturing the cell-microenvironment, to depict the tissue. These allow for utilizing graph theory and machine learning to map the tissue representation to tissue functionality, and quantify their relationship. Though cellular information is crucial, it is incomplete alone to comprehensively characterize complex tissue structure. We herein treat the tissue as a hierarchical composition of multiple types of histological entities from fine to coarse level, capturing multivariate tissue information at multiple levels. We propose a novel multi-level hierarchical entity-graph representation of tissue specimens to model the hierarchical compositions that encode histological entities as well as their intra- and inter-entity level interactions. Subsequently, a hierarchical graph neural network is proposed to operate on the hierarchical entity-graph and map the tissue structure to tissue functionality. Specifically, for input histology images, we utilize well-defined cells and tissue regions to build HierArchical Cell-to-Tissue (HACT) graph representations, and devise HACT-Net, a message passing graph neural network, to classify the HACT representations. As part of this work, we introduce the BReAst Carcinoma Subtyping (BRACS) dataset, a large cohort of Haematoxylin & Eosin stained breast tumor regions-of-interest, to evaluate and benchmark our proposed methodology against pathologists and state-of-the-art computer-aided diagnostic approaches. Through comparative assessment and ablation studies, our proposed method is demonstrated to yield superior classification results compared to alternative methods as well as individual pathologists. The code, data, and models can be accessed at https://github.com/histocartography/hact-net.


H2 S works synergistically with rhizobia to modify photosynthetic carbon assimilation and metabolism in nitrogen-deficient soybeans.
Hydrogen sulfide (H2 S) performs a crucial role in plant development and abiotic stress responses by interacting with other signalling molecules. However, the synergistic involvement of H2 S and rhizobia in photosynthetic carbon (C) metabolism in soybean (Glycine max) under nitrogen (N) deficiency has been largely overlooked. Therefore, we scrutinised how H2 S drives photosynthetic C fixation, utilisation, and accumulation in soybean-rhizobia symbiotic systems. When soybeans encountered N deficiency, organ growth, grain output, and nodule N-fixation performance were considerably improved owing to H2 S and rhizobia. Furthermore, H2 S collaborated with rhizobia to actively govern assimilation product generation and transport, modulating C allocation, utilisation, and accumulation. Additionally, H2 S and rhizobia profoundly affected critical enzyme activities and coding gene expressions implicated in C fixation, transport, and metabolism. Furthermore, we observed substantial effects of H2 S and rhizobia on primary metabolism and C-N coupled metabolic networks in essential organs via C metabolic regulation. Consequently, H2 S synergy with rhizobia inspired complex primary metabolism and C-N coupled metabolic pathways by directing the expression of key enzymes and related coding genes involved in C metabolism, stimulating effective C fixation, transport, and distribution, and ultimately improving N fixation, growth, and grain yield in soybeans.


Axenic Paramecium caudatum. III. Biochemical and physiological changes with culture age.
As Paramecium caudatum passes through the lag, log and stationary phases of the culture cycle, cellular protein content, polar (PL) and neutral (NL) lipid contents, marker enzyme activities, rate of digestive vacuole formation and cellular viability undergo characteristic changes. Maximal protein content (60 ng/cell) and enzyme activities ranging from 7 nmoles for catalase to 0.2 pmoles/cell/min for alkaline phosphatase were observed between days 2 and 4. This active metabolism paralleled the fine structure of 1 to 3 day-old cells which contained extensive foci of rough endoplasmic reticulum (RER) partially bordered by Golgi stacks and the rapid depletion of those lipid fields accumulated during day 1. Decrease in protein content and enzyme activities in late log phase indicated a slowing of cellular synthesis. The lipids in the medium were largely depleted and accounted for the low lipid uptake of 14 ng/cell on day 5 as compared with 615 ng/cell on day 1. Yet a vast amount of protein lysate was still available in the culture medium. During stationary phase, catalase activity remained constant, but activities of alkaline and acid phosphatases and 5'nucleotidase declined gradually to low levels, while those of Ca2+-ATPase and malate dehydrogenase declined precipitously. Only 25% of the maximal activities of the latter two enzymes remained by the end of stationary phase. A ten-fold increase in the cellular PL and NL content was already observed 24 h postinoculation. This accumulation was used for subsequent growth and cell divisions; PL declined exponentially and NL less steeply between days 1 and 6. PL remained level (5 ng/cell) throughout stationary phase while NL declined further to 1 ng/cell by day 11. The rate of digestive vacuole formation was constant (6.3 +/- 0.5 DV/5 min pulse) during the entire log phase, then declined from 4.4 on day 6 to 0.22 on day 11. When early to mid-stationary-phase cells were subcultured, some lag in growth was seen; a definite lag was observed when inoculating with late-stationary-phase cells. When early-death-phase cells were given fresh nutrients, many died; the surviving ones became fully rejuvenated after 48 h. The biochemical and physiological data from this study are correlated with the morphological study of the companion paper.


You Will Never Walk Alone: Codispersal of JC Polyomavirus with Human Populations.
JC polyomavirus (JCPyV) is one of the most prevalent human viruses. Findings based on the geographic distribution of viral subtypes suggested that JCPyV codiverged with human populations. This view was however challenged by data reporting a much more recent origin and expansion of JCPyV. We collected information on ∼1,100 worldwide strains and we show that their geographic distribution roughly corresponds to major human migratory routes. Bayesian phylogeographic analysis inferred a Subsaharan origin for JCPyV, although with low posterior probability. High confidence inference at internal nodes provided strong support for a long-standing association between the virus and human populations. In line with these data, pairwise FST values for JCPyV and human mtDNA sampled from the same areas showed a positive and significant correlation. Likewise, very strong relationships were found when node ages in the JCPyV phylogeny were correlated with human population genetic distances (nuclear-marker based FST). Reconciliation analysis detected a significant cophylogenetic signal for the human population and JCPyV trees. Notably, JCPyV also traced some relatively recent migration events such as the expansion of people from the Philippines/Taiwan area into Remote Oceania, the gene flow between North-Eastern Siberian and Ainus, and the Koryak contribution to Circum-Arctic Americans. Finally, different molecular dating approaches dated the origin of JCPyV in a time frame that precedes human out-of-Africa migration. Thus, JCPyV infected early human populations and accompanied our species during worldwide dispersal. JCPyV typing can provide reliable geographic information and the virus most likely adapted to the genetic background of human populations.


The role of coronary angioplasty in the management of coronary artery disease.
Coronary angioplasty is well established as a treatment modality for coronary artery disease. Clinical experience leaves no doubt that it can be very effective in relieving symptoms in patients with unstable angina and with chronic stable angina. There are, at present, no controlled trials to demonstrate its efficacy, though several are under way. In straightforward cases the initial success rate is about 90%, but for each lesion dilated, there is about a 30% chance of significant re-stenosis. Re-stenosis (which is the main chronic complication) usually occurs early--often within a few weeks of the procedure--and it rarely develops later than six months after the procedure. Acute closure of the dilated artery (usually within an hour or two of procedure) is the most feared acute complication and is the main factor contributing to the 0.2% acute mortality rate and to the 1-5% risk of emergency coronary artery bypass grafting. The procedural risk does not increase progressively with serial interventions (in contrast to coronary artery surgery). Furthermore, angioplasty is often undertaken following surgery when stenoses have developed within the grafts, at the graft-vessel anastomosis, in the native vessels distal to the graft insertion or in native ungrafted vessels. Angioplasty is less costly than coronary surgery, although the 30% re-stenosis rate implies a requirement for additional interventions as a result of which the cost differential is not as great it initially appears.


Energy consumption analysis of power grid distribution transformers based on an improved genetic algorithm.
With the promotion of energy transformation, the utilization ratio of electrical power is progressively rising. Since electrical power is challenging to store, real-time production and consumption become imperative, imposing significant demands on the dependability and operational efficiency of electrical power apparatus. Suppose the load distribution among multiple transformers within a transformer network exhibits inequality. In such instances, it will amplify the total energy consumption during the voltage conversion process, and local, long-term high-load transformer networks become more susceptible to failures. In this article, we scrutinize the matter of transformer energy utilization in the context of electricity transmission within grid systems. We propose a methodology grounded on genetic algorithms to optimize transformer energy usage by dynamically redistributing loads among diverse transformers based on their operational status monitoring. In our experimentation, we employed three distinct approaches to enhance energy efficiency. The experimental findings evince that this approach facilitates swifter attainment of the optimal power level and diminishes the overall energy consumption during transformer operation. Moreover, it exhibits a heightened responsiveness to fluctuations in power demand from the electrical grid. Experimental results manifest that this technique can truncate monitoring time by 27% and curtail the overall energy consumption of the distribution transformer network by 11.81%. Lastly, we deliberate upon the potential applications of genetic algorithms in the realm of power equipment management and energy optimization issues.


Variation in the precursor to the major merozoite surface antigens of Plasmodium falciparum.
The major antigens on the surface of Plasmodium falciparum merozoites are derived from a single high molecular weight polypeptide. The precursor to the major merozoite surface antigen (PMMSA) has conserved and variable antigenic determinants and varies in size in different isolates. Since the protein is a candidate for a malaria vaccine, it is important to understand the molecular basis of this variation. We present the complete sequence of the PMMSA of the Papua New Guinea isolate FC27 and the partial sequence of the West African isolate NF7. The gene consists of blocks of sequence which are either conserved or variable between different isolates. Variable sequences fall into two distinct types, indicating that the PMMSA is encoded by dimorphic alleles that undergo recombination within conserved blocks at the 5' end of the gene. Genetic exchange is not apparent within the other two-thirds of the gene in 12 isolates, suggesting strong selection against such recombinants. The most variable block located near the 5' end contains repeats that are different in independent cloned isolates. This variation presumably accounts for much of the size and antigenic variability.


Nasal epithelial gene expression and total IgE in children and adolescents with asthma.
Little is known about nasal epithelial gene expression and total IgE in youth. We aimed to identify genes whose nasal epithelial expression differs by total IgE in youth, and group them into modules that could be mapped to airway epithelial cell types. We conducted a transcriptome-wide association study of total IgE in 469 Puerto Ricans aged 9 to 20 years who participated in the Epigenetic Variation and Childhood Asthma in Puerto Ricans study, separately in all subjects and in those with asthma. We then attempted to replicate top findings for each analysis using data from 3 cohorts. Genes with a Benjamini-Hochberg-adjusted P value of less than .05 in the Epigenetic Variation and Childhood Asthma in Puerto Ricans study and a P value of less than .05 in the same direction of association in 1 or more replication cohort were considered differentially expressed genes (DEGs). DEGs for total IgE in subjects with asthma were further dissected into gene modules using coexpression analysis, and such modules were mapped to specific cell types in airway epithelia using public single-cell RNA-sequencing data. A higher number of DEGs for total IgE were identified in subjects with asthma (n = 1179 DEGs) than in all subjects (n = 631 DEGs). In subjects with asthma, DEGs were mapped to 11 gene modules. The top module for positive correlation with total IgE was mapped to myoepithelial and mucus secretory cells in lower airway epithelia and was regulated by IL-4, IL5, IL-13, and IL-33. Within this module, hub genes included CDH26, FETUB, NTRK2, CCBL1, CST1, and CST2. Furthermore, an enrichment analysis showed overrepresentation of genes in signaling pathways for synaptogenesis, IL-13, and ferroptosis, supporting interactions between interleukin- and acetylcholine-induced responses. Our findings for nasal epithelial gene expression support neuroimmune coregulation of total IgE in youth with asthma.


A general catalytic hydroamidation of 1,3-dienes: atom-efficient synthesis of N-allyl heterocycles, amides, and sulfonamides.
Transition-metal-catalyzed hydroamination reactions are sustainable and atom-economical CN bond-forming processes. Although remarkable progress has been made in the inter- and intramolecular amination of olefins and 1,3-dienes, related intermolecular reactions of amides are still much less known. Control of the regioselectivity without analogous telomerization is the particular challenge in the catalytic hydroamidation of alkenes and 1,3-dienes. Herein, we report a general protocol for the hydroamidation of electron-deficient N-heterocyclic amides and sulfonamides with 1,3-dienes and vinyl pyridines in the presence of a catalyst derived from [{Pd(π-cinnamyl)Cl}2 ] and ligand L7 or L10. The reactions proceeded in good to excellent yield with high regioselectivity. The practical utility of our method is demonstrated by the hydroamidation of functionalized biologically active substrates. The high regioselectivity for linear amide products makes the procedure useful for the synthesis of a variety of allylic amides.


Effect of prokinetics in children with recurrent nocturnal retrosternal pain.
Children rarely present with vague complaints of nocturnal recurrent retrosternal or upper-abdominal, epigastric, pain. Dysmotility of the upper gastrointestinal tract, including gastro-oesophageal reflux, might be at the origin of these manifestations. To evaluate the clinical effect of prokinetics (cisapride) in children with recurrent nocturnal retrosternal pain, and to measure the effect of cisapride with a combined oesophageal ambulatory 24 h pH and pressure monitoring. Twelve children, mean age 9.5 years (range 4.1-14.0 years), with nocturnal recurrent retrosternal pain for more than 6 months, occurring at least three times a week. Single-blinded prospective study, with two periods of 2-3 weeks during which cisapride was administered, alternated with two placebo periods of the same duration. Clinical evaluation, and assessment with oesophageal pH and pressure monitoring. Cisapride was related to a temporary relief of the symptoms in 10/12 children. The improvement was demonstrated through a normalization of pH monitoring, and an increase in amplitude and duration of the contractions in the lower oesophagus. Cisapride improves complaints of recurrent nocturnal retrosternal pain in children.


Symptomatic isolated internal carotid artery occlusion with initial medical management: a monocentric cohort.
Symptomatic isolated carotid artery occlusions (ICAO) can lead to disability, recurrent stroke, and mortality, but natural history and best therapeutic management remain poorly known. The objective of this study was to describe our cohort of ICAO patients with an initial medical management. We conducted a retrospective study including consecutive patients admitted to our Comprehensive Stroke Center for ICAO within 24 h after stroke onset between January 2016 and September 2018. Patients with immediate endovascular therapy (EVT) were excluded. Medical treatment was based on anticoagulation (delayed by 24 h if intravenous thrombolysis was performed). 'Rescue' EVT was considered if first-week neurological deterioration (FWND) occurred. Fifty-six patients were included, with a median National Institutes of Health Stroke Scale (NIHSS) of 3. Eleven patients (20%) had FWND during the first week, four benefited from rescue EVT. A mismatch volume > 40 cc on initial perfusion imaging and FLAIR vascular hyperintensities were associated with FWND (p = 0.007 and p = 0.009, respectively). Thirty-eight patients (69%) had a good outcome (modified Rankin Scale mRS 0-2) at 3 months, 36 (69%) had an excellent outcome (mRS 0-1). Seventeen patients (38%) had carotid patency on 3-month control imaging. Recurrences occurred in six (13%) of the survivors (mean follow-up: 13.6 months). Our results suggest that the prognosis of patients with acute ICAO was favorable with a medical strategy, albeit a substantial rate of FWND and recurrence. FWND was well predicted by a core-perfusion mismatch volume > 40 cc. Randomized controlled trials are necessary to assess the benefit of EVT in ICAO.


Technological Advancement in Tower-Based Canopy Reflectance Monitoring: The AMSPEC-III System.
Understanding plant photosynthesis, or Gross Primary Production (GPP), is a crucial aspect of quantifying the terrestrial carbon cycle. Remote sensing approaches, in particular multi-angular spectroscopy, have proven successful for studying relationships between canopy-reflectance and plant-physiology processes, thus providing a mechanism to scale up. However, many different instrumentation designs exist and few cross-comparisons have been undertaken. This paper discusses the design evolution of the Automated Multiangular SPectro-radiometer for Estimation of Canopy reflectance (AMSPEC) series of instruments. Specifically, we assess the performance of the PP-Systems Unispec-DC and Ocean Optics JAZ-COMBO spectro-radiometers installed on an updated, tower-based AMSPEC-III system. We demonstrate the interoperability of these spectro-radiometers, and the results obtained suggest that JAZ-COMBO can successfully be used to substitute more expensive measurement units for detecting and investigating photosynthesis and canopy spectra. We demonstrate close correlations between JAZ-COMBO and Unispec-DC measured canopy radiance (0.75 ≤ R² ≤ 0.85) and solar irradiance (0.95 ≤ R² ≤ 0.96) over a three month time span. We also demonstrate close agreement between the bi-directional distribution functions obtained from each instrument. We conclude that cost effective alternatives may allow a network of AMSPEC-III systems to simultaneously monitor various vegetation types in different ecosystems. This will allow to scale and improve our understanding of the interactions between vegetation physiology and spectral characteristics, calibrate broad-scale observations to stand-level measurements, and ultimately lead to improved understanding of changing vegetation spectral features from satellite.


Minimally invasive pancreatic surgery.
Pancreatic resection is a complex procedure that involves exposure of the retroperitoneal gland, dissection around major vascular structures, and management of an intricate organ, all of which results in a procedure associated with a high morbidity. The application of minimally invasive techniques to pancreatic resection have been studied only relatively recently. This analysis of the current concepts in minimally invasive pancreatic surgery focuses on a select look at currently published series or reviews from centers and groups that have the most experience with this procedure. We aim to present a comprehensive review gained from the experiences of those who are on the leading edge of the learning curve, with an emphasis on describing the similarities and differences between the minimally invasive and open pancreatic procedure. Minimally invasive distal pancreatectomy appears to be on the verge of widespread acceptance and shows clear benefits over its open counterpart. Minimally invasive proximal (right-sided) pancreatectomy, on the other hand, appears to be limited to select centers that have been able to demonstrate promising results despite its challenges. Additionally, minimally invasive central pancreatectomy and enucleation appear feasible as experience is gained in laparoscopic and robotic pancreatic resection.


[Is there currently a role for radical surgery of pain?].
Radical surgery of pain is destined for chronic and intolerable pain, resistant to causal treatment, and rebellious to the various medicinal therapeutics. Conventional neuro surgery by selective section of nociceptive fibers is very valuable for cancerous subjects with a limited life span. On the other hand, there has been skepticism concerning the real efficiency of neuro stimulation. The advance made in the knowledge of neurophysiologic and neurochemical mechanism of pain will allow a radical transformation as substitute for this invasive type surgery.


Rhomboencephalitis.
Rhomboencephalitis-inflammation of the brainstem and cerebellum-has myriad clinical presentations including encephalopathy, cranial neuropathies, long tract signs and cerebellar dysfunction and is associated with significant morbidity and mortality. There are a variety of potential underlying causes that respond variably to treatment, including infections, parainfective syndromes, inflammatory disorders including autoimmune encephalitis and paraneoplastic syndromes. Here, we review its clinical presentation and outline a practical approach to its investigation, aiming to facilitate prompt diagnosis and confirmation of the underlying cause, to start appropriate management early and optimise the clinical outcome.


Pulse Arrival Time as surrogate for systolic blood pressure changes during impending neurally mediated syncope.
Blood pressure regulation failures cause neurally mediated syncope often resulting in a fall. A warning device might help to make patients aware of an impending critical event or even trigger the patient to perform countermeasures such as lying down or isometric exercises. We previously demonstrated that the Pulse Arrival Time (PAT) methodology is a potential approach to enable early detection of impending faints. The aim of the present study was to evaluate whether PAT can be used as an easy to measure beat-to-beat surrogate for systolic blood pressure (SBP) changes during a passive standing exercise (head-up tilt table testing (HUTT)). A significant PAT increase of more than 10 % was accompanied with a critical SBP decrease in syncope patients. Although PAT is in general not considered as a good measure of absolute blood pressure we found strong correlations (R>0.89, P<0.01) of SBP and PAT after PAT began to increase. Therefore, our data suggest that the pulse arrival time is useful to monitor blood pressure changes in patients with neurally mediated syncope. This might open up new avenues to prevent falls in these patients.


Prognostic factors of whiplash-associated disorders: a systematic review of prospective cohort studies.
We present a systematic review of prospective cohort studies. Our aim was to assess prognostic factors associated with functional recovery of patients with whiplash injuries. The failure of some patients to recover following whiplash injury has been linked to a number of prognostic factors. However, there is some inconsistency in the literature and there have been no systematic attempts to analyze the level of evidence for prognostic factors in whiplash recovery. Studies were selected for inclusion following a comprehensive search of MEDLINE, EMBASE, CINAHL, the database of the Dutch Institute of Allied Health Professions up until April 2002 and hand searches of the reference lists of retrieved articles. Studies were selected if the objective was to assess prognostic factors associated with recovery; the design was a prospective cohort study; the study population included at least an identifiable subgroup of patients suffering from a whiplash injury; and the paper was a full report published in English, German, French or Dutch. The methodological quality was independently assessed by two reviewers. A study was considered to be of 'high quality' if it satisfied at least 50% of the maximum available quality score. Two independent reviewers extracted data and the association between prognostic factors and functional recovery was calculated in terms of risk estimates. Fifty papers reporting on twenty-nine cohorts were included in the review. Twelve cohorts were considered to be of 'high quality'. Because of the heterogeneity of patient selection, type of prognostic factors and outcome measures, no statistical pooling was able to be performed. Strong evidence was found for high initial pain intensity being an adverse prognostic factor. There was strong evidence that for older age, female gender, high acute psychological response, angular deformity of the neck, rear-end collision, and compensation not being associated with an adverse prognosis. Several physical (e.g. restricted range of motion, high number of complaints), psychosocial (previous psychological problems), neuropsychosocial factors (nervousness), crash related (e.g. accident on highway) and treatment related factors (need to resume physiotherapy) showed limited prognostic value for functional recovery. High initial pain intensity is an important predictor for delayed functional recovery for patients with whiplash injury. Often mentioned factors like age, gender and compensation do not seem to be of prognostic value. Scientific information about prognostic factors can guide physicians or other care providers to direct treatment and to probably prevent chronicity.


[The dilemma of effectiveness and economic value of alternative medicine].
Medical practice is today, and has always been, subject to a professional ethos that excludes unnecessary and dishonest methods. There is some concern about soundness and affordability of our health service if one sees that despite the financial worries that beset our health services, more and more alternative treatments are being proposed and used which are not equal to their money's worth. Political and legal decisions, as well as the activities of alternative healers, illustrate the onslaught on the supremacy of scientific teaching. These developments must be opposed vigorously for sake of protecting our patients.


Temporal decrease of body temperature in middle-aged C57BL/6J mice.
Colonic temperature of C57BL/6J mice of both sexes between 12 and 19 months was measured at normal ambient temperature in four independent studies. One study was cross-sectional and the others were longitudinal. In all samples, colonic temperature at about 14 months was always lower than temperature at earlier ages. Furthermore, temperature always returned to earlier levels within 2 weeks; however, it remained unstable up to the age of 18 months after which it returned to the pre-14-month level until finally it fell late in life (after 23 months). Additionally, parametric studies showed that there were differences in the reliability of temperature probes made by different manufacturers to measure absolute temperature. These differences, however, did not affect relative differences among temperatures. Further parametric studies showed that colonic temperature in restrained mice rises 1.2 degrees C within the first 5 min after restraint indicating that duration of restraint is an important factor in studies such as these.


Methanobacterium thermoautotrophicus sp. n., an anaerobic, autotrophic, extreme thermophile.
The isolation of a new methanogenic bacterium, Methanobacterium thermoautotrophicus sp. n., is described. Successful isolation required a medium containing inorganic salts, an atmosphere consisting of an 80:20 mixture of hydrogen-carbon dioxide, and incubation temperatures of 65 to 70 C. Isolates of M. thermoautotrophicus were gram-positive, nonmotile, irregularly curved rods which frequently formed long filaments. The organism was found to be an autotroph and a strict anaerobe, and to have a pH optimum of 7.2 to 7.6. The optimal temperature for growth was 65 to 70 C, the maximum being 75 C and the minimum about 40 C. The generation time at the optimum was about 5 hr. The deoxyribonucleic acid of M. thermoautotrophicus had a guanine plus cytosine (GC) content of 52 moles per cent, whereas Methanobacterium sp. strain M.O.H. had a GC content of 38%. When heated, intact ribosomes of Methanobacterium sp. strain M.O.H. were stable up to 55 C and had a T(m) of 73 C. In contrast, ribosomes of M. thermoautotrophicus were stable up to 75 C and had a T(m) of 82 C. Upon complete thermal denaturation, ribosomes of strain M.O.H. underwent a 59% hyperchromic shift, whereas those of the thermophile showed only a 20% increase in hyperchromicity. Methane formation in cell-free extracts of M. thermoautotrophicus was temperature-dependent and required hydrogen and carbon dioxide; methyl cobalamin served as a methyl donor, and addition of coenzyme M stimulated methanogenesis.


The Smoking Cessation and Reduction in Pregnancy Treatment (SCRIPT) Adoption Scale: evaluating the diffusion of a tobacco treatment innovation to a statewide prenatal care program and providers.
When a new patient education program is being considered for adoption by a public health agency, it is essential to determine provider perceptions of its acceptability for routine use. In 2007, the West Virginia Bureau of Public Health Perinatal Program, Right From The Start (RFTS), decided to adopt the Smoking Cessation and Reduction in Pregnancy Treatment (SCRIPT) Program. RFTS is a statewide perinatal home visitation initiative delivered by designated care coordinators (DCCs). The authors developed the SCRIPT Adoption Scale (SAS) in the absence of a valid instrument to assess the perceived attributes of a tobacco treatment innovation among the RFTS DCC population. They evaluated the validity of the five constructs of the Rogers' Diffusion of Innovations model in an organization (relative advantage, compatibility, complexity, observability, and trialability) to predict SCRIPT use. After reviewing the literature and developing draft SAS forms, 2 expert panel reviews established the face and content validity of a 43-item SAS. It was administered to 90% (85/90) of the RFTS DCC population. Psychometric analyses confirmed the validity and reliability of a 28-item scale. All 28 items had factor loadings greater than 0.40 (range = 0.43-0.81). All SAS subscales were strongly correlated, r = 0.51 to 0.97, supporting the convergent validity of a 5-factor SAS. There was a significant association between the DCC SAS score and DCC SCRIPT Program Implementation Index supporting the SAS convergent (construct) validity (r = 0.38). The SAS internal consistencyr = 0.93 and stabilityr = 0.76. Although 2 specific subscales need to be improved, the SAS can be adapted by prenatal care programs to measure the attributes of adoption of new, evidence-based patient education and counseling methods.


Tunnel expansion following anterior cruciate ligament reconstruction: a comparison of hamstring and patellar tendon autografts.
Thirty patients having had anterior cruciate ligament (ACL) reconstruction with bone-patellar tendon-bone (BPTB) autograft and thirty patients having had ACL reconstruction with hamstring (HS) autograft were enrolled. All procedures were performed using an endoscopic technique with identical postoperative rehabilitation, such that the only variable was the type of graft and its fixation. Lateral and 45 degrees posteroanterior (PA) weightbearing radiographs were performed in each patient at 6-12 (mean 9) months postoperatively in the HS group and 9-22 (mean 13) months postoperatively in the PT group. The sclerotic margins of the tunnel were measured at the widest dimension of the tunnel by a single observer and were compared with the initially drilled tunnel size after correction for radiographic magnification. For the BPTB group, all bone plugs appeared to be incorporated radiographically. On the femoral side, the bone plug was incorporated at the roof of the intercondylar notch, such that no tunnel measurement could be made. Well-defined sclerotic margins were always present at the tibial and femoral tunnels for the HS group and at the tibial tunnel for the BPTB group. The mean percentage increase in tunnel size in the PA view was 9.7%+/-14.7% for the BPTB tibial tunnel, 20.9%+/-13.4% for the HS tibial tunnel, and 30.2%+/-17.2% for the HS femoral tunnel. The mean percentage increase in tunnel size in the lateral view was 14.4%+/-16.1% for the BPTB tibial tunnel, 25.5%+/-16.7% for the HS tibial tunnel, and 28.1%+/-14.7% for the HS femoral tunnel. The difference in HS and BPTB tibial tunnel expansion on both the PA and lateral views was statistically significant (P = 0.003 and P = 0.01, respectively). Inter-observer variability was excellent with an intra-class correlation coefficient of 0.92. Tunnel expansion was significantly greater following ACL reconstruction using HS autografts than in those using BPTB autografts. The points of fixation for the HS grafts are at a greater distance from the normal insertion site and biomechanical point of action of the ACL than the points of fixation for BPTB grafts. We believe that this greater distance creates a potentially larger force moment during graft cycling which may lead to greater expansion of bone tunnels.


Planar polarization of node cells determines the rotational axis of node cilia.
Rotational movement of the node cilia generates a leftward fluid flow in the mouse embryo because the cilia are posteriorly tilted. However, it is not known how anterior-posterior information is translated into the posterior tilt of the node cilia. Here, we show that the basal body of node cilia is initially positioned centrally but then gradually shifts toward the posterior side of the node cells. Positioning of the basal body and unidirectional flow were found to be impaired in compound mutant mice lacking Dvl genes. Whereas the basal body was normally positioned in the node cells of Wnt3a(-/-) embryos, inhibition of Rac1, a component of the noncanonical Wnt signalling pathway, impaired the polarized localization of the basal body in wild-type embryos. Dvl2 and Dvl3 proteins were found to be localized to the apical side of the node cells, and their location was polarized to the posterior side of the cells before the posterior positioning of the basal body. These results suggest that posterior positioning of the basal body, which provides the posterior tilt to node cilia, is determined by planar polarization mediated by noncanonical Wnt signalling.


The Papillomavirus E2 protein binds to and synergizes with C/EBP factors involved in keratinocyte differentiation.
The papillomavirus life cycle is closely linked to the differentiation program of the host keratinocyte. Thus, late gene expression and viral maturation are restricted to terminally differentiated keratinocytes. A variety of cellular transcription factors including those of the C/EBP family are involved in the regulation of keratinocyte differentiation. In this study we show that the papillomavirus transcription factor E2 cooperates with C/EBPalpha and -beta in transcriptional activation. This synergism was independent of an E2 binding site. E2 and C/EBP factors synergistically transactivated a synthetic promoter construct containing classical C/EBPbeta sites and the C/EBPalpha-responsive proximal promoter of the involucrin gene, which is naturally expressed in differentiating keratinocytes. C/EBPalpha or -beta coprecipitated with E2 proteins derived from human papillomavirus type 8 (HPV8), HPV16, HPV18, and bovine papillomavirus type 1 in vitro and in vivo, indicating complex formation by the cellular and viral factors. The interaction domains could be mapped to the C terminus of E2 and amino acids 261 to 302 located within the bZIP motif of C/EBPbeta. Our data suggest that E2, via its interaction with C/EBP factors, may contribute to enhancing keratinocyte differentiation, which is suppressed by the viral oncoproteins E6 and E7 in HPV-induced lesions.


Empagliflozin Regulates the AdipoR1/p-AMPK/p-ACC Pathway to Alleviate Lipid Deposition in Diabetic Nephropathy.
Abnormal lipid deposition in the progress of diabetic nephropathy (DN) plays an important role in a number of studies that have shown that SGLT2 inhibitor (SGLT2i) empagliflozin plays an important role in lipid metabolism, but its mechanism is still unclear. We aimed to explore the effect of empagliflozin on lipid levels in kidney cancer patients with DN and postoperative patients without DN kidney carcinoma; the patients with DN showed ectopic lipid deposition. In type 2 diabetes model mice induced by streptozotocin (STZ) and a high-fat diet, combined AMPK plus empagliflozin or empagliflozin inhibitor plus compound C was applied, followed by analyses of the blood, urine and kidney indexes to observe the correlation between SGLT2i and AMPK and lipid metabolism in diabetic kidney disease. We determined whether DN in patients with renal tubular atrophy involved lipid metabolism. In clinical specimens, the adiponectin receptor AdipoR1 was reduced, and the phosphorylation acetyl-CoA carboxylase (p-ACC) was increased. In vitro and in vivo pathological immunofluorescence and Western blotting confirmed that, under the condition of high glucose, malpighian tubules displayed ectopic lipid deposition and expressed related lipid parameters accompanied by fibrosis. Empagliflozin intervention reduced lipid deposition fibrosis and renal tubular atrophy, and the addition of compound C promoted disease progression. Moreover, siAdipoR1 transfection proved that AdipoR1 affected P-AMPK and then p-ACC affected lipid metabolism in renal tubular cells. According to the above experimental results, empagliflozin could reduce lipid metabolism of DN through AdipoR1/P-AMPK/P-ACC pathway and delay DN progress.