Biophysics of the inhibition of the growth of maize roots by lowered temperature.
Roots of hydroponically grown maize (Zea mays cv LG11) have a greatly reduced growth rate at 5 degrees C (0.02 millimeters per hour) compared with those at 20 degrees C (1.2 millimeters per hour). Various physical parameters of roots growing at each temperature were compared. Turgor pressure of cells in the elongation zone increased from 0.59 +/- 0.05 megapascal at 20 degrees C to 0.82 +/- 0.04 megapascal after 70 hours at 5 degrees C; thus, growth rate was not limited by decreased pressure. On cooling, tissue plasticity (measured by Instron/tensiometer) decreased slowly over 70 hours. On rewarming to 20 degrees C from 5 degrees C, growth rate, turgor pressure, and tissue plasticity all returned concertedly to their original values over a period of days. However, immediately following cooling growth rate dropped rapidly from 1.8 to 0.12 millimeters per hour in 30 minutes but turgor pressure and tissue Instron plasticity remained unchanged. A plot of turgor pressure against growth rate indicated that, following cooling from 30 to 15 degrees C, the in vivo wall extensibility of the tissue was reduced by 75%. Yield threshold was unchanged. Cells whose expansion was arrested in the long-term cold treatment do not resume growth. Root growth recovers by the expansion of cells newly produced by the meristem. Cessation of extension growth is an effect on the individual expanding cell. Growth recovery is not a reverse of this effect but requires the generation of fresh cells.


Gene Expression Analysis of Potato (Solanum tuberosum L.) Lipoxygenase Cascade and Oxylipin Signature under Abiotic Stress.
The metabolism of polyunsaturated fatty acids through the lipoxygenase-catalyzed step and subsequent reactions is referred to as the lipoxygenase (LOX) pathway. The components of this system, such as jasmonates, are involved in growth, development and defense reactions of plants. In this report, we focus on dynamics of expression of different LOX pathway genes and activities of target enzymes with three abiotic stress factors: darkness, salinity and herbicide toxicity. To obtain a more complete picture, the expression profiles of marker genes for salicylic acid, abscisic acid, ethylene, auxin and gibberellin-dependent signaling systems under the same stresses were also analyzed. The gene expression in Solanum tuberosum plants was analyzed using qRT-PCR, and we found that the LOX-cascade-related genes responded to darkness, salinity and herbicide toxicity in different ways. We detected activation of a number of 9-LOX pathway genes; however, in contrast to studies associated with biotic stress (infection), the 9-divinyl ether synthase branch of the LOX cascade was inhibited under all three stresses. GC-MS analysis of the oxylipin profiles also showed the main activity of the 9-LOX-cascade-related enzymes after treatment with herbicide and darkness.


Hsp72 mediates TAp73α anti-apoptotic effects in small cell lung carcinoma cells.
The transcription factor p73, a member of the p53 family of proteins, is involved in the regulation of cell cycle progression and apoptosis. Due to alternative promoters and carboxy-terminal splicing, the P73 gene gives rise to a range of different isoforms. Interestingly, a particular increase in expression of the TAp73α isoform has been reported in various tumours. In addition, TAp73α has been shown to inhibit Bax activation and mitochondrial dysfunctions and thereby to confer small cell lung carcinoma (SCLC) cells resistance to drug-induced apoptosis. However, the precise mechanism by which TAp73α exerts its pro-survival effect is yet unclear. Here we report that TAp73α, but not TAp73β, regulates the expression of inducible Hsp72/HSPA1A. Hsp72 proved to be required for the survival effects of TAp73α as antisense knockdown of Hsp72 resulted in an abolishment of the anti-apoptotic effect of TAp73α in SCLC cells upon Etoposide treatment. Importantly, depletion of Hsp72 allowed activation of Bax, loss of mitochondrial membrane potential and lysosomal membrane permeabilization in SCLC cells even in the presence of TAp73α. Finally, we revealed that TAp73β counteracts the anti-apoptotic effect of TAp73α by preventing Hsp72 induction. Our results thus provide additional evidence for the potential oncogenic role of TAp73α, and extend the understanding of the mechanism for its anti-apoptotic effect.


Geographic region, weather, pilot age, and air carrier crashes: a case-control study.
Information about risk factors of aviation crashes is crucial for developing effective intervention programs. Previous studies assessing factors associated with crash risk were conducted primarily in general aviation, air taxis, and commuter air carriers. A matched case-control design was used to examine the associations of geographic region, basic weather condition, and pilot age with the risk of air carrier (14 CFR Part 121) crash involvement. Cases (N = 373) were air carrier crashes involving aircraft made by Boeing, McDonnell Douglas, and Airbus recorded in the National Transportation Safety Board's aviation crash database during 1983 through 2002, and controls (N = 746) were air carrier incidents involving aircraft of the same three makes selected at random from the Federal Aviation Administration's aviation incident database. Each case was matched with two controls on the calendar year when the index crash occurred. Conditional logistic regression was used for statistical analysis. With adjustment for basic weather condition, pilot age, and total flight time, the risk of air carrier crashes in Alaska was more than three times the risk for other regions ladjusted odds ratio (OR) 3.18, 95% confidence interval (CI) 1.35-7.49]. Instrument meteorological conditions were associated with an increased risk for air carrier crashes involving pilot error (adjusted OR 2.26, 95% CI 1.15-4.44) and a decreased risk for air carrier crashes without pilot error (adjusted OR 0.60, 95% CI 0.37-0.96). Neither pilot age nor total flight time were significantly associated with the risk of air carrier crashes. The excess risk of air carrier crashes in Alaska and the effect of adverse weather on pilot-error crashes underscore the importance of environmental hazards in flight safety.


Prostate-specific antigen evolution after photoselective vaporization of the prostate.
Prostate-specific antigen (PSA) variations after photoselective vaporization of the prostate are an unsolved question. We included prospectively 323 patients who underwent GreenLight® prostate vaporization for prostatic hyperplasia between 2005 and 2013. We excluded patients with prostate cancer and those with concomitant prostate biopsies. Serum PSA levels were measured before and after the procedure at 1, 6, 12, 24, 36, and 48 months. The median preoperative PSA level was 4.50 ng/mL; it decreased to 2.41 ng/mL at 1 month (47% reduction), 2.17 ng/mL at 6 months (52% reduction), 2.30 ng/mL at 1 year (49% reduction), 2.40 ng/mL at 2 years (47% reduction), 2.31 ng/mL at 3 years (49% reduction), and 2.54 ng/mL at 4 years (44% reduction) (P values were all <0.0001). The median PSA nadir at 6 months was significantly different from the median PSA level at 1, 2, 3, and 4 years (respectively P=0.0046, P=0.0017, P=0.0006, and P=0.01). Patients who received ≤3000 J/cc had a significant trend to a PSA reascension after 6 months. Patients who received ≥4000 J/cc did not show any significant PSA reascension during the 4 years after procedure. Energy was correlated with the PSA reascension in univariate and multivariate analysis. The PSA level significantly decreased by half 1 month after the procedure, reached its nadir at 6 months, and showed a slight progressive reascension during the 4 following years. Applying an energy rate ≥4000 J/cc of prostate induced PSA stability over time whereas energy ≤3000 J/cc induced a reascension of the PSA level after 6 months.


Cervical cancer incidence in British Columbia: Predicting effects of changes from Pap to human papillomavirus screening and of changes in screening participation.
Objectives To estimate the impact of increased participation in screening, and of the proposed change from Pap to human papillomavirus screening on the incidence of cervical cancer in British Columbia. Methods For invasive cervical cancer cases diagnosed in British Columbia between 2002 and 2011, data were extracted on age and cancer morphology from the British Columbia Cancer Registry, and Pap screening history was obtained from the British Columbia Cervical Cancer Screening Program database. Only screening performed two to seven years prior to diagnosis was assumed to reduce subsequent risk of cancer. Results from randomized trials of human papillomavirus versus cytology screening and population based estimates of cytology screening were used to estimate the effect of a change in screening test and increases in participation. Results Between 2002 and 2011, there were 1663 cases of cervical cancer reported; 660 (367 squamous and 293 non-squamous) were eligible and screened two to seven years prior to diagnosis. The predicted reduction by changing to human papillomavirus screening was 363 (95% confidence interval = 124-496) representing 22% of all cases. If 50% of subjects not screened two to seven years prior had undergone Pap screening, it is projected that a further 268 cases (16%) could have been prevented; if they had undergone human papillomavirus screening, a further 365 cases (22%) could have been prevented. Conclusions For many women who develop cervical cancer, primary human papillomavirus testing could have substantially reduced their cancer risk. Human papillomavirus rather than Pap testing would further increase the gains from any increases in population screening participation.


Medical providers' dental information needs: a baseline survey.
Articulation of medical and dental practices has been strongly called for based on the many oral-systemic connections. With the rapid development and adoption of electronic health records, the feasibility of integrating medical and dental patient data should be strongly considered. The objective of this study was to develop an initial understanding of the medical providers' core dental information needs and opinion of integrated medical-dental electronic health record (iEHR) environment in their workflow. This was achieved by administering a 13 question survey to a group of 1,197 medical care providers employed by Marshfield Clinic in Wisconsin, United States. The survey received a response rate of 35%. The responses were analyzed based on provider 'Role' and 'Specialty'. The majority of the respondents felt the need for patient's dental information to coordinate or provide effective medical care. An integrated electronic health record environment could facilitate this holistic patient care approach.


A study of various tests to detect asymptomatic urinary tract infections in an obstetric population.
To compare rapid screening techniques for detecting asymptomatic urinary tract infections (AUTIs) in pregnant women. Comparison of results of the screening tests of urinalysis, urine dipstick, and Gram's staining with the results of standard urine culture at an initial prenatal visit. In follow-up visits, urine dipstick testing was compared with urinalysis. Departments of Family Medicine and Obstetrics and Gynecology, Mayo Clinic, Rochester, Minn. Pregnant women (1047) from the local community were screened for AUTI on initial and follow-up visits. Initial prenatal urine was tested by using urine dipstick testing, urinalysis, Gram's staining, and urine culture. At each follow-up visit, urine specimens were tested by using urine dipstick and urinalysis. Sensitivity and specificity, incremental patient costs, and clinical outcomes were used to assess the effectiveness of the techniques. On initial visits, rapid screening tests for AUTI in pregnant women revealed the following: Gram's staining identified 22 of 24 patients with AUTI (sensitivity, 91.7%; specificity, 89.2%); urine dipstick, 12 of 24 (sensitivity, 50.0%; specificity, 96.9%); and urinalysis with presence of leukocytes, six of 24 (sensitivity, 25.0%; specificity, 99.0%). In follow-up visits, urine dipstick tests detected 19 infections and urinalysis, three (positive predictive value, 5% compared with 3%). Urine dipstick testing for nitrites identified half of all patients with urinary tract infections and was superior to urinalysis on follow-up visits. Although Gram's staining is more expensive, it was more accurate for AUTI than urinalysis or urine dipstick test for nitrites. Urinalysis was never the test of choice because it was more expensive and detected fewer positive cultures. Leukocyte measurement correlated poorly with AUTI.


Intestinal microcirculatory dysfunction and neonatal necrotizing enterocolitis.
Based on the observation that coagulation necrosis occurs in the majority of neonatal necrotizing enterocolitis (NEC) patients, it is clear that intestinal ischemia is a contributing factor to the pathogenesis of NEC. However, the published studies regarding the role of intestinal ischemia in NEC are controversial. The aim of this paper is to review the current studies regarding intestinal microcirculatory dysfunction and NEC, and try to elucidate the exact role of intestinal microcirculatory dysfunction in NEC. The studies cited in this review were mainly obtained from articles listed in Medline and PubMed. The search terms used were "intestinal microcirculatory dysfunction" and "neonatal necrotizing enterocolitis". Mainly original milestone articles and critical reviews written by major pioneer investigators in the field were selected. Immature regulatory control of mesentery circulation makes the neonatal intestinal microvasculature vulnerable. When neonates are subjected to stress, endothelial cell dysfunction occurs and results in vasoconstriction of arterioles, inflammatory cell infiltration and activation in venules, and endothelial barrier disruption in capillaries. The compromised vasculature increases circulation resistance and therefore decreases intestinal perfusion, and may eventually progress to intestinal necrosis. Intestinal ischemia plays an important role through the whole course of NEC. New therapeutic agents targeting intestinal ischemia, like HB-EGF, are promising therapeutic agents for the treatment of NEC.


Diagnostic capability of biological markers in assessment of obstructive sleep apnea: a systematic review and meta-analysis.
The purpose of this systematic review is to evaluate the diagnostic value of biological markers (exhaled breath condensate, blood, salivary and urinary) in the diagnosis of OSA in comparison to the gold standard of nocturnal PSG. Studies that differentiated OSA from controls based on PSG results, without age restriction, were eligible for inclusion. The sample of selected studies could include studies in obese patients and with known cardiac disease. A detailed individual search strategy for each of the following bibliographic databases was developed: Cochrane, EMBASE, MEDLINE, PubMed, and LILACS. The references cited in these articles were also crosschecked and a partial grey literature search was undertaken using Google Scholar. The methodology of selected studies was evaluated using the 14-item Quality Assessment Tool for Diagnostic Accuracy Studies. After a two-step selection process, nine articles were identified and subjected to qualitative and quantitative analyses. Among them, only one study conducted in children and one in adults found biomarkers that exhibit sufficiently satisfactory diagnostic accuracy that enables application as a diagnostic method for OSA. Kallikrein-1, uromodulin, urocotin-3, and orosomucoid-1 when combined have enough accuracy to be an OSA diagnostic test in children. IL-6 and IL-10 plasma levels have potential to be good biomarkers in identifying or excluding the presence of OSA in adults.


Internuclear synapse in the amygdala is not facilitated in fear conditioning.
The amygdala is essential for fear learning and memory. Synaptic transmission is enhanced in two pathways in the amygdala in fear conditioning. In this study we examined whether lateral (LA) to basolateral (BLA) amygdala synapses are potentiated and participate in intra-amygdala plasticity during the maintenance of fear memory. Our data showed that synaptic strength from the LA (ventrolateral) to the BLA (parvicellular) pathway was not increased after fear conditioning and suggests that this pathway does not integrate information relevant to the coding of memories in auditory fear learning.


Inhibition of Scavenger Receptor A Expression Treated with PMA by the Inhibitor of Tyrosine Protein Kinase Genistein.
In order to investigate the relationship between scavenger receptor type A and cell signal transduction, human U937 macrophages were treated with tyrosine protein kinase inhibitor genistein, then the cells were incubated with [(125)I]ox-LDL or ox-LDL, and the cellular degradation of [(125)I]ox-LDL or binding were measured separately. Then the effect of the drug on cell surface expression of SR-A were measured by means of autoradiography, it was found that genistein could reduce cellular SR-A mRNA transcription by RT-PCR. The results indicated that genistein could reduce U937 macrophages to bind lipids and reduce SR-A expression by suppression of transcription, and could reduce degradation of lipids by U937 macrophage and accumulation of cholesterol within the cells. It suggests that the function of scavenger receptors may be correlated with cell tyrosine protein kinase, the mechanism is transcriptional and it also suggests that SR-A may participate in the signal transduction directly.


Treatment outcomes among patients admitted to hospital with antiretroviral and/or antituberculosis drug-induced liver injury.
South Africa (SA) has among the highest rates of HIV and tuberculosis (TB) in the world. Antituberculosis and antiretroviral treatment (ART) can cause drug-induced liver injury (DILI), consequences of which are disease relapse, treatment failure and drug resistance. To: (i) determine the demographics of patients with DILI and the proportion of patients on antituberculosis drugs v. antiretroviral therapy or both; (ii) determine the median time to DILI after starting medication, and patterns of clinical presentation; (iii) determine the numbers of patients successfully re-challenged to initial therapy as inpatients; and (iv) determine the in-hospital mortality rate and predictors of all-cause mortality. This was a retrospective record review of adult patients with DILI admitted to a tertiary hospital in Johannesburg, SA, between October 2015 and February 2017. Data on drug history, biochemical investigations and relevant imaging were collected. The total sample was 129 records: 79 (61.2%) were males, 46 (35.7%) had TB DILI, 29 (22.5%) had ART DILI, and 54 (41.9%) had mixed TB/ART DILI. Only 7.4% (2/27) of those with ART DILI and 30.6% (11/36) with TB DILI were re-challenged to their original regimen by discharge. Patients were followed from admission until the earlier of death (10 with TB DILI, 2 with ART DILI and 9 with mixed DILI) or discharge (after a median (interquartile range) of 14.0 (9 - 23) days). In adjusted analysis, severe DILI at admission predicted all-cause mortality (adjusted hazard ratio 8.58; 95% confidence interval 1.13 - 65.4). This study is one of only a few analyses of hospitalised patients with DILI in SA. Among those with severe DILI, outcomes are poor, the majority cannot tolerate standard regimens, and mortality is high.


Signaling pathways controlling second heart field development.
Insight into the mechanisms underlying congenital heart defects and the use of stem cells for cardiac repair are major research goals in cardiovascular biology. In the early embryo, progenitor cells in pharyngeal mesoderm contribute to the rapid growth of the heart tube during looping morphogenesis. These progenitor cells constitute the second heart field (SHF) and were first identified in 2001. Direct or indirect perturbation of SHF addition to the heart results in congenital heart defects, including arterial pole alignment defects. Over the last 3 years, a number of studies have identified key intercellular signaling pathways that control the proliferation and deployment of SHF progenitor cells. Here, we review data concerning Wnt, fibroblast growth factor, bone morphogenetic protein, Hedgehog, and retinoic acid signaling that have begun to identify the ligand sources and responding cell types controlling SHF development. These studies have revealed the importance of signals from pharyngeal mesoderm itself, as well as critical inputs from adjacent pharyngeal epithelia and neural crest cells. Proliferation is emerging as a central checkpoint in the regulation of SHF development. Together, these studies contribute to defining the niche of cardiac progenitor cells in the early embryo, and we discuss the implications of these findings for the regulation of resident stem cell populations in the fetal and postnatal heart. Characterization of signals that maintain, expand, and regulate the differentiation of cardiac progenitor cells is essential for understanding both the etiology of congenital heart defects and the biomedical application of stem cell populations for cardiac repair.


How personal is the political? Democratic revolution and fertility decline.
Existing theory has identified the capacity of political revolutions to effect change in a variety of social institutions, although relationships between revolution and many institutions remain unexplored. Using historical data from twenty-two European and four diaspora countries, the author examines the temporal relationship between timing of revolution and onset of fertility decline. The author hypothesizes that specific kinds of revolutionary events affect fertility by engendering ideological changes in popular understandings of the individual's relationship to society and ultimately the legitimacy of couples' authority over their reproductive capacities. Results demonstrate that popular democratic revolutions -- but not institutionalized democratic structures -- predict the timing of the onset of fertility decline.


miR-6883 Family miRNAs Target CDK4/6 to Induce G1 Phase Cell-Cycle Arrest in Colon Cancer Cells.
CDK4/6 targeting is a promising therapeutic strategy under development for various tumor types. In this study, we used computational methods and The Cancer Genome Atlas dataset analysis to identify novel miRNAs that target CDK4/6 and exhibit potential for therapeutic development in colorectal cancer. The 3'UTR of CDK4/6 mRNAs are targeted by a family of miRNAs, which includes miR-6883-5p, miR-149*, miR-6785-5p, and miR-4728-5p. Ectopic expression of miR-6883-5p or miR-149* downregulated CDK4 and CDK6 levels in human colorectal cancer cells. RNA-seq analysis revealed an inverse relationship between the expression of CDK4/6 and miR-149* and intronic miRNA-6883-5p encoding the clock gene PER1 in colorectal cancer patient samples. Restoring expression of miR-6883-5p and miR-149* blocked cell growth leading to G0-G1 phase cell-cycle arrest and apoptosis in colorectal cancer cells. CDK4/6 targeting by miR-6883-5p and miR-149* could only partially explain the observed antiproliferative effects. Notably, both miRNAs synergized with the frontline colorectal cancer chemotherapy drug irinotecan. Further, they resensitized mutant p53-expressing cell lines resistant to 5-fluorouracil. Taken together, our results established the foundations of a candidate miRNA-based theranostic strategy to improve colorectal cancer management. Cancer Res; 77(24); 6902-13. ©2017 AACR.


Gut Bacteroides species in health and disease.
The functional diversity of the mammalian intestinal microbiome far exceeds that of the host organism, and microbial genes contribute substantially to the well-being of the host. However, beneficial gut organisms can also be pathogenic when present in the gut or other locations in the body. Among dominant beneficial bacteria are several species of Bacteroides, which metabolize polysaccharides and oligosaccharides, providing nutrition and vitamins to the host and other intestinal microbial residents. These topics and the specific organismal and molecular interactions that are known to be responsible for the beneficial and detrimental effects of Bacteroides species in humans comprise the focus of this review. The complexity of these interactions will be revealed.


Constraints of Tones, Vowels and Consonants on Lexical Selection in Mandarin Chinese.
Previous studies have shown that when speakers of European languages are asked to turn nonwords into words by altering either a vowel or consonant, they tend to treat vowels as more mutable than consonants. These results inspired the universal vowel mutability hypothesis: listeners learn to cope with vowel variability because vowel information constrains lexical selection less tightly and allows for more potential candidates than does consonant information. The present study extends the word reconstruction paradigm to Mandarin Chinese--a Sino-Tibetan language, which makes use of lexically contrastive tone. Native speakers listened to word-like nonwords (e.g., su3) and were asked to change them into words by manipulating a single consonant (e.g., tu3), vowel (e.g., si3), or tone (e.g., su4). Additionally, items were presented in a fourth condition in which participants could change any part. The participants' reaction times and responses were recorded. Results revealed that participants responded faster and more accurately in both the free response and the tonal change conditions. Unlike previous reconstruction studies on European languages, where vowels were changed faster and more often than consonants, these results demonstrate that, in Mandarin, changes to vowels and consonants were both overshadowed by changes to tone, which was the preferred modification to the stimulus nonwords, while changes to vowels were the slowest and least accurate. Our findings show that the universal vowel mutability hypothesis is not consistent with a tonal language, that Mandarin tonal information is lower-priority than consonants and vowels and that vowel information most tightly constrains Mandarin lexical access.


Treating nicotine dependence during pregnancy and postpartum: understanding clinician knowledge and performance.
This study investigated the relationship of clinicians' knowledge of treatments for nicotine dependence during pregnancy and postpartum and explored what provider characteristics are associated with knowledge levels. Survey data from community health center (CHC)-based prenatal, pediatric (PED), and WIC program (Special Supplemental Nutrition Program for Women, Infants, and Children) providers participating in a randomized clinical study were used. Providers reported low awareness of the health risks of smoking to the developing fetus/child of pregnant and postpartum women and of the effectiveness of nicotine replacement therapy (NRT) for doubling quit rates. Obstetric (OB) and WIC providers were more aware than PED providers that provider-delivered interventions are effective. Confidence in using counseling steps was significantly associated with general and NRT-related knowledge. NRT-related knowledge, but not general knowledge, was associated with higher performance of intervention steps. Educational programs targeting OB, WIC, and PED providers' knowledge about effective smoking cessation counseling strategies and their confidence in being effective with patients are needed.


Isolated Dislocation of Fourth Carpometacarpal Joint: Case Report.
We present a case of dislocation of the fourth carpometacarpal joint without associated fractures. This is the first case to be reported in the literature. Carpal injuries are uncommon; it is even rare for isolated carpometacarpal dislocation to occur without associated fractures. The injury is difficult to diagnose because of the swelling of the hand and may be missed on several occasions. A lateral radiograph of the wrist has been found to be mandatory to its precise diagnosis if suspected. Early recognition and anatomical reduction are essential in achieving good long-term outcomes.


Optically pure calix[6]tris-ammoniums: syntheses and host-guest properties toward neutral guests.
[reaction: see text] Optically pure calix[6]arenes bearing chiral amino arms 4, 7, and 10 have been synthesized in high yields from the known symmetrically 1,3,5-trismethylated calix[6]arene. For both compounds 7 and 10, the key step consists of an efficient selective alkylation on the narrow rim of the calix[6]arene with Ba(OH)2 as the base. All of these chiral calix[6]tris-amines possess a similar flattened cone conformation with the cavity occupied by the methoxy groups. In contrast to 4 and 7, upon protonation, the enantiopure calix[6]arene 10 can switch to the opposite flattened cone conformation through self-assembly of its ammonium arms in an ion-paired cap which closes the cavity. As shown by NMR host-guest studies and an X-ray structure, the obtained polarized host (10 x 3H+) behaves as a remarkable endo-receptor for small polar neutral molecules. Thanks to the tris-cationic chiral binding site of 10 x 3H+, it was shown that the guests experience a chiral environment upon inclusion. Finally, the first example of enantioselective molecular recognition inside the cavity of a calix[6]arene has been evidenced with a racemic 1,2-diol guest.


[Angiotensin-converting enzyme and 1,25-dihydroxyvitamin D3 in hypercalcemia of unknown origin].
Sarcoidosis of the kidneys and liver without radiologically demonstrable lung involvement in a 44-year-old woman was shown to be the cause of a hypercalcaemia syndrome. The hypercalcaemia was presumably due to an increased production of 1,25-(OH)2-vitamin D3 which--like the increased angiotensin converting enzyme--is produced in the epithelioid and giant cells. Corticoid treatment normalized serum calcium and ACE levels and improved renal function. These observations demonstrate that measurement of ACE and 1,25-(OH)2-vitamin D3 levels is helpful in the differential diagnosis of hypercalcaemia, in view of the possibility of sarcoidosis, and should be among the diagnostic tests.


Aprotinin increases mortality as compared with tranexamic acid in cardiac surgery: a meta-analysis of randomized head-to-head trials.
To determine whether aprotinin increases mortality as compared with tranexamic acid in cardiac surgery, we performed a meta-analysis of randomized head-to-head trials. All prospective randomized head-to-head trials of aprotinin vs. tranexamic acid enrolling patients undergoing cardiac surgery were identified using a web-based search engine (PubMed). For each study, data regarding mortality in both the aprotinin and tranexamic acid groups were used to generate risk ratios (RRs) and 95% confidence intervals (CIs). Study-specific estimates were combined using inverse variance-weighted averages of logarithmic RRs in random-effects models. Our search identified nine trials (eight trials included in the previous meta-analysis and the blood conservation using antifibrinolytics in a randomized trial [BART] study). Seven trials were composed of low-risk patients (n=1291) and two trials consisted of low-risk patients (n=1628). Pooled analysis of the nine trials demonstrated a statistically significant 45% increase in mortality with aprotinin relative to tranexamic acid therapy (RR, 1.45; 95% CI, 1.00 [1.0002]-2.11; P=0.05 [0.0499]). The present meta-analysis of updated all randomized head-to-head trials, the best evidence, demonstrated a statistically significant increase in mortality with aprotinin relative to tranexamic acid therapy in cardiac surgery.


Preferential Infiltration of Unique Vγ9Jγ2-Vδ2 T Cells Into Glioblastoma Multiforme.
Glioblastoma multiforme (GBM) is clinically highly aggressive as a result of evolutionary dynamics induced by cross-talk between cancer cells and a heterogeneous group of immune cells in tumor microenvironment. The brain harbors limited numbers of immune cells with few lymphocytes and macrophages; thus, innate-like lymphocytes, such as γδ T cells, have important roles in antitumor immunity. Here, we characterized GBM-infiltrating γδ T cells, which may have roles in regulating the GBM tumor microenvironment and cancer cell gene expression. V(D)J repertoires of tumor-infiltrating and blood-circulating γδ T cells from four patients were analyzed by next-generation sequencing-based T-cell receptor (TCR) sequencing in addition to mutation and immune profiles in four GBM cases. In all tumor tissues, abundant innate and effector/memory lymphocytes were detected, accompanied by large numbers of tumor-associated macrophages and closely located tumor-infiltrating γδ T cells, which appear to have anti-tumor activity. The immune-related gene expression analysis using the TCGA database showed that the signature gene expression extent of γδ T cells were more associated with those of cytotoxic T and Th1 cells and M1 macrophages than those of Th2 cells and M2 macrophages. Although the most abundant γδ T cells were Vγ9Vδ2 T cells in both tumor tissues and blood, the repertoire of intratumoral Vγ9Vδ2 T cells was distinct from that of peripheral blood Vγ9Vδ2 T cells and was dominated by Vγ9Jγ2 sequences, not by canonical Vγ9JγP sequences that are mostly commonly found in blood γδ T cells. Collectively, unique GBM-specific TCR clonotypes were identified by comparing TCR repertoires of peripheral blood and intra-tumoral γδ T cells. These findings will be helpful for the elucidation of tumor-specific antigens and development of anticancer immunotherapies using tumor-infiltrating γδ T cells.


Evolution and critical appraisal of anastomotic technique following resection of esophageal adenocarcinoma.
The aim of this study was to critically evaluate acute and long-term complications of hand-sewn and semimechanical cervical esophagogastric anastomosis following resection of primary esophageal adenocarcinoma. Between February 1991 and 2001, 91 consecutive patients underwent subtotal esophagectomy (transthoracic, n=49; transhiatal, n=42), transposing a gastric tube based on the right gastroepiploic artery. All esophagogastric anastomoses were performed in the left neck using a hand-sewn technique (n=53) and, from September 1997, a side-to-side semimechanical technique (n=38). Outcomes evaluated were anastomotic leak rates, length of stay, and development of strictures. Postoperative mortality was 4.4% (all cardiopulmonary causes). Fifty-eight patients (63.7%) had an uncomplicated postoperative course, with a median postoperative length of stay of 10 days (vs. 20 days with associated morbidity; P </= 0.001). Anastomotic leaks were the leading cause of postoperative morbidity (16.5%, 15/91), and were classified into four types based on severity. The semimechanical anastomotic technique was associated with a reduced leak rate compared with the hand-sewn technique (7.9%, 3/38 vs. 22.6%, 12/53; P=0.08), although different patterns of anastomotic failure were seen following semimechanical anastomoses, with increased mediastinal and pleural sepsis. Anastomotic strictures developed in nine (17.0%) hand-sewn and three (7.9%) semimechanical anastomoses. Our conclusion was that a semimechanical technique for cervical esophagogastrostomy is associated with reduced anastomotic leak rates compared with hand-sewn anastomoses, resulting in a shorter postoperative stay. Patterns of anastomotic failure varied between each technique, possibly as a consequence of a longer cervical esophageal segment required for construction of a semimechanical anastomosis. The association between anastomotic technique and stricture development was not clear from this study.


The social impact of HIV/AIDS in India.
This paper is based on the last public lecture given by Dr Solomon at the 7th World Workshop on Oral Health & Disease in HIV/AIDS, held in Hyderabad, India, in November 2014. It examines the social impact of HIV in India and the founding of the Y.R. Gaitonde Center for AIDS Research and Education (YRG CARE) clinic in Chennai, India, by Dr Suniti Solomon and her colleagues. This is a story of prejudice and ignorance throughout the various social levels in India. Reports of India's first AIDS case surfaced in 1986, when female sex workers were found to be HIV positive. The first voluntary counseling and testing center, part of a sexually transmitted diseases (STD) clinic, was set up to increase awareness about the epidemic. To address the rapid spread of HIV infection in Tamil Nadu and the existing stigma in society and hospitals, Dr Solomon established YRG CARE in 1993. She recognized that fear and panic about HIV led to widespread social prejudice against HIV-positive patients, even within hospitals. By the end of 2014, over 34 000 patients had accessed these services and 20 000 HIV+ patients had been registered, nearly 40% of whom were females. The team embarked on a statewide awareness program on HIV and sexuality, covering over two hundred schools and colleges educating them about prevention strategies and combating the social stigma attached. The grass-root work of YRG CARE in the management of HIV infections revealed a widespread prejudice, due largely to the lack of awareness about the subject. It is estimated that even in 2015, as little as 40% of HIV-infected people are formally diagnosed and have access to care. In a country as socially and culturally diverse as India, there is much more to be carried out to build on the pioneering work of Dr Solomon.


Current tools for norovirus drug discovery.
Rapid transmission of norovirus often occurs due to its low infectious dosage, high genetic diversity and its short incubation time. The viruses cause acute gastroenteritis and may lead to death. Presently, no effective vaccine or selective drugs accepted by the United States Food and Drug Administration (FDA) are available for the treatment of norovirus. Advances in the development of norovirus replicon cell lines, GII.4-Sydney HuNoV strain human B cells, and murine and gnotobiotic pig norovirus models have facilitated the discovery of effective small molecule inhibitors in vitro and in vivo. This review gives a brief discussion of the biology and replication of norovirus before highlighting the discovery of anti-norovirus molecules. The article coverage includes: an overview of the current state of norovirus drug discovery, the targeting of the norovirus life cycle, the inhibition of structural and nonstructural proteins of norovirus such as proteases and polymerase, and the blockage of virus entry into host cells. Finally, anti-norovirus drugs in the clinical development stage are described. The current approach for the counteraction of norovirus focuses on the inhibition of viral RNA polymerase, norovirus 3C-like protease and the structural proteins VP1 as well as the blockade of norovirus entry. Broad-spectrum anti-norovirus molecules, based on the inhibition of 3C-like protease, have been developed. Other host factors and ways to overcome the development of resistance through mutation are also being examined. A dual approach in targeting viral and host factors may lead to an effective counteraction of norovirus infection. Current successes in developing norovirus replicon harboring cells and norovirus infected human cells, as well as murine norovirus models and other animal models such as piglets have facilitated the discovery of effective drugs and helped our understanding of its mechanism of action.


Mesenchymal stem cell-based treatment in autoimmune liver diseases: underlying roles, advantages and challenges.
Autoimmune liver disease (AILD) is a series of chronic liver diseases with abnormal immune responses, including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). The treatment options for AILD remain limited, and the adverse side effects of the drugs that are typically used for treatment frequently lead to a low quality of life for AILD patients. Moreover, AILD patients may have a poor prognosis, especially those with an incomplete response to first-line treatment. Mesenchymal stem cells (MSCs) are pluripotent stem cells with low immunogenicity and can be conveniently harvested. MSC-based therapy is emerging as a promising approach for treating liver diseases based on their advantageous characteristics of immunomodulation, anti-fibrosis effects, and differentiation to hepatocytes, and accumulating evidence has revealed the positive effects of MSC therapy in AILD. In this review, we first summarize the mechanisms, safety, and efficacy of MSC treatment for AILD based on work in animal and clinical studies. We also discuss the challenges of MSC therapy in clinical applications. In summary, although promising data from preclinical studies are now available, MSC therapy is currently far for being applied in clinical practice, thus developing MSC therapy in AILD is still challenging and warrants further research.


Ulinastatin, an elastase inhibitor, inhibits the increased mRNA expression of prostaglandin H2 synthase-type 2 in Kawasaki disease.
Kawasaki disease is an inflammatory disease of unknown cause that causes panvasculitis, including coronary arteritis. Polymorphonucleocytosis in the early stage of the illness suggests the implication of neutrophils in the pathogenesis of the disease. In the acute phase of Kawasaki disease, mRNA expression of prostaglandin H2 synthase (PHS)-2, as determined by reverse transcription-polymerase chain reaction, was markedly enhanced, and thromboxane A2 (TXA2)-synthesizing activity was increased in polymorphonuclear leukocytes (PMNL). This up-regulation of PHS-2 was suppressed by ulinastatin (a neutrophil-elastase inhibitor) treatment. Lipopolysaccharide-induced enhancement of PHS-2 mRNA was also inhibited by therapeutic doses of ulinastatin in vitro by use of PMNL from healthy volunteers. Thus, ulinastatin inhibits arachidonate PHS metabolism by inhibiting new induction of PHS-2 at the mRNA level, which is a novel pharmacologic action of this substance. Ulinastatin treatment is possibly an additional therapeutic approach to Kawasaki disease.


Quality of life after gestational trophoblastic disease.
To describe the quality of life (QoL) and long-term psychosocial sequelae in women diagnosed with gestational trophoblastic tumor (GTT) 5-10 years earlier. Utilizing a cross-sectional descriptive design, 111 survivors completed a comprehensive QoL interview. Participants were predominantly married and non-Hispanic white, with a mean age at diagnosis of 30 years and a current mean age of 37 years. This disease-free sample enjoys a good QoL, with physical, social and emotional functioning comparable to or better than comparative norms. However, certain psychological survivorship sequelae persist. Additionally, a sizable number of survivors currently experience significant reproductive concerns. Participants reporting good QoL were less likely to report ongoing coping efforts related to having had this illness, more likely to report greater social support (P < .0001), greater sexual pleasure (P = .0063), and less GTT-specific distress (P < .0001). Fifty-one percent of respondents expressed that they would likely participate in a counseling program today to discuss psychosocial issues raised by having had GTT, and 74% stated that they would have attended a support group program during the initial treatment if it had been offered. This information provides insight into the complex survivorship relationships between QoL and sequelae of GTT.


Influence of Child Abuse and Neglect on Histrionic Personality Pathology.
Histrionic personality pathology is among the most common forms of personality pathology, although little is known about its potential risk factors. One possible factor that may influence histrionic personality pathology is childhood trauma, most notably sexual abuse and physical/emotional neglect. However, there is little research on how these and other forms of childhood trauma may influence histrionic personality pathology relative to each other. To address this, in this study we examined the relative effects of different forms of child abuse and neglect on histrionic personality pathology in a sample of women and men from Amazon's Mechanical Turk (N = 399) using a Bayesian approach to structural equation modeling. Results suggest that child sexual abuse is the strongest predictor of histrionic personality pathology in adulthood. However, this differs between women and men such that physical neglect also predicts histrionic personality pathology for women, whereas physical and emotional abuse as well as emotional neglect predict histrionic personality pathology for men. These findings provide insight into the developmental precursors to histrionic personality pathology and have implications for research on and clinical intervention with people exhibiting histrionic personality pathology.


Effect of Nitrogen Partial Pressure on Structure, Mechanical Property, and Corrosion Behavior of ZrNx Films Prepared by Reactive DC Magnetron Sputtering.
ZrNx films were deposited by DC magnetron sputtering with pure Zr target in different nitrogen partial pressure atmospheres (r = N2/[Ar + N2]). The structure and composition of the thin films were characterized as a function of r using scanning electron microscope, glancing angle X-ray diffraction, and X-ray photoelectron spectroscopy. The hardness, adhesive strength, and corrosion behavior of the coatings were measured by nanoindentation, microscratch, and potentiodynamic measurements in 3.5 wt% NaCl solution. The results show that the structure of the ZrNx films changes from a nearly stoichiometric ZrN with a typical columnar structure to mixed phases composited of ZrN and α-ZrNx with a dense glass structure as r increases from 12% to 50%. The mechanical properties including hardness, elastic modulus, and adhesion decrease with increasing r due to nonstoichiometric compound and glass phase structure of the coatings, while the dense glass structure significantly improves the corrosion inhibition.


Ethnicity as a factor in reproductive health care utilization among males attending family planning clinics.
Health care utilization of reproductive health care services among males is an emerging issue. This study examined ethnicity as a factor in reproductive health care utilization among 1,606 African American and Hispanic young males attending family planning clinics. Seventy percent were African American and 30% were Hispanic. Across groups, the most received service was treatment for a sexually transmitted infection (STI). African American males were more likely than Hispanic males to have health insurance, report a prior visit to a family planning/STI clinic, and have a history of an STI. Hispanic males had higher rates of employment. The most common source of referral for family planning services for both groups was either a current girlfriend or female friend. Hispanic males were more likely to use family as a referral source than African American males. Differences were also noted in regard to interest in health topics with African American males most interested in STI prevention and getting a job and Hispanic males in services related to working-out/eating well, controlling anger, feeling depressed, and getting along with family. Young males' perceptions of what they consider to be important health care needs should be assessed carefully in order to maintain their interest in returning to the clinics.


Evidence-Informed Milestones for Developmental Surveillance Tools.
The Centers for Disease Control and Prevention's (CDC) Learn the Signs. Act Early. program, funded the American Academy of Pediatrics (AAP) to convene an expert working group to revise its developmental surveillance checklists. The goals of the group were to identify evidence-informed milestones to include in CDC checklists, clarify when most children can be expected to reach a milestone (to discourage a wait-and-see approach), and support clinical judgment regarding screening between recommended ages. Subject matter experts identified by the AAP established 11 criteria for CDC milestone checklists, including using milestones most children (≥75%) would be expected to achieve by specific health supervision visit ages and those that are easily observed in natural settings. A database of normative data for individual milestones, common screening and evaluation tools, and published clinical opinion was created to inform revisions. Application of the criteria established by the AAP working group and adding milestones for the 15- and 30-month health supervision visits resulted in a 26.4% reduction and 40.9% replacement of previous CDC milestones. One third of the retained milestones were transferred to different ages; 67.7% of those transferred were moved to older ages. Approximately 80% of the final milestones had normative data from ≥1 sources. Social-emotional and cognitive milestones had the least normative data. These criteria and revised checklists can be used to support developmental surveillance, clinical judgment regarding additional developmental screening, and research in developmental surveillance processes. Gaps in developmental data were identified particularly for social-emotional and cognitive milestones.


High sensitivity of tropical precipitation to local sea surface temperature.
Precipitation and atmospheric circulation are the coupled processes through which tropical ocean surface temperatures drive global weather and climate1-5. Local sea surface warming tends to increase precipitation, but this local control is difficult to disentangle from remote effects of conditions elsewhere. As an example of such a remote effect, El Niño Southern Oscillation (ENSO) events in the equatorial Pacific Ocean alter precipitation across the tropics. Atmospheric circulations associated with tropical precipitation are predominantly deep, extending up to the tropopause. Shallow atmospheric circulations6-8 affecting the lower troposphere also occur, but the importance of their interaction with precipitation is unclear. Uncertainty in precipitation observations9,10 and limited observations of shallow circulations11 further obstruct our understanding of the ocean's influence on weather and climate. Despite decades of research, persistent biases remain in many numerical model simulations12-18, including excessively wide tropical rainbands14,18, the 'double-intertropical convergence zone problem'12,16,17 and too-weak responses to ENSO15. These biases demonstrate gaps in our understanding, reducing confidence in forecasts and projections. Here we use observations to show that seasonal tropical precipitation has a high sensitivity to local sea surface temperature. Our best observational estimate is an 80 per cent change in precipitation for every gram per kilogram change in the saturation specific humidity (itself a function of the sea surface temperature). This observed sensitivity is higher than in 43 of the 47 climate models studied, and is associated with strong shallow circulations. Models with more realistic (closer to 80%) sensitivity have smaller biases across a wide range of metrics. Our results apply to both temporal and spatial variation, over regions where climatological precipitation is about one millimetre per day or more. Our analyses of multiple independent observations, physical constraints and model data underpin these findings. The spread in model behaviour is further linked to differences in shallow convection, thus providing a focus for accelerated research to improve seasonal forecasts through multidecadal climate projections.


Distance-Dependent Fluorescence Resonance Energy Transfer Enhancement on Nanoporous Gold.
Fluorescence resonance energy transfers (FRET) between cyan fluorescent protein (CFP) and yellow fluorescent protein (YFP) on nanoporous gold (NPG) are systematically investigated by controlling the distance between NPG and fluorescent proteins with polyelectrolyte multilayers. The FRET between CFP and YFP is significantly enhanced by NPG, and the maximum enhancement is related to both ligament size of NPG and the distance between NPG and proteins. With the optimized distance, 18-fold FRET enhancement was obtained on NPG compared to that on glass, and the conversion efficiency is about 90%. The potential to tune the characteristic energy transfer distance has implications for applications in nanophotonic devices and provides a possible way to design sensors and light energy converters.


[Theoretical considerations of dose-rate effect for clinical application: a study of pulsed brachytherapy].
Pulsed brachytherapy is starting to be used for patients with various kinds of carcinoma, in the expectation of fair treatment results without increasing the late radiation-induced damage. We calculated the early and late biologically effective dose (BED) of this modality to predict early and late radiation damage based on the linear-quadratic model (L-Q model). The way to set the values of alpha/beta and mu (factor of repair) in the L-Q model remains controversial. The value of alpha/beta has been fixed at 3Gy for the late effect and 10Gy for the early effect in recent studies. In this study, we applied these alpha/beta values to calculate the BED, however, the effects of its alteration ranged from 0.5Gy through 15Gy on BED were also analysed. We assumed mu = 0.5 (T1/2 = 1-2 hours) in this study, but we also tried to examine the effects of its variation. Our results indicate that pulsed brachytherapy is a safe treatment procedure even if the dose-rate ranges from 1Gy/hr through 100Gy/hr, but the fractionation number should be increased when using a very high dose rate. Pulsed brachytherapy should be applied cautiously for tissues with a small mu value, such as the spinal cord, because an extremely high late BED would be expected in such cases.


Identification of proximate regions in a complex of retinal guanylyl cyclase 1 and guanylyl cyclase-activating protein-1 by a novel mass spectrometry-based method.
A key challenge in studying protein/protein interactions is to accurately identify contact surfaces, i.e. regions of two proteins that are in direct physical contact. Aside from x-ray crystallography and NMR spectroscopy few methods are available that address this problem. Although x-ray crystallography often provides detailed information about contact surfaces, it is limited to situations when a co-crystal of proteins is available. NMR circumvents this requirement but is limited to small protein complexes. Other methods, for instance protection from proteolysis, are less direct and therefore less informative. Here we describe a new method that identifies candidate contact surfaces in protein complexes. The complexes are first stabilized by cross-linking. They are then digested with a protease, and the cross-linked fragments are analyzed by mass spectrometry. We applied this method, referred to as COSUMAS (contact surfaces by mass spectrometry), to two proteins, retinal guanylyl cyclase 1 (RetGC1) and guanylyl cyclase-activating protein-1 (GCAP-1), that regulate cGMP synthesis in photoreceptors. Two regions in GCAP-1 and three in RetGC1 were identified as possible contact sites. The two regions of RetGC1 that are in the vicinities of Cys(741) and Cys(780) map to a kinase homology domain in RetGC1. Their identities as contact sites were independently evaluated by peptide inhibition analysis. Peptides with sequences from these regions block GCAP-1-mediated regulation of guanylyl cyclase at both high and low Ca2+ concentrations. The two regions of GCAP-1 cross-linked to these peptides were in the vicinities of Cys(17) and Cys(105) of GCAP-1. Peptides with sequences derived from these regions inhibit guanylyl cyclase activity directly. These results support a model in which GCAP-1 binds constitutively to RetGC1 and regulates cyclase activity by structural changes caused by the binding or dissociation of Ca2+.


Radiotherapy: long-term effects on gastrointestinal function.
Radiotherapy frequently results in persistent effects on gastrointestinal function adversely impacting on the quality of life of patients cured of their malignant disease. Long-term effects on gastrointestinal function remain prevalent despite the advent of three-dimensional techniques of radiotherapy because higher radiation doses and more combined modality treatments are prescribed to improve cure rates. Chronic elevation of cytokine levels and implication of the cyclooxygenase-2 pathway in radiation bowel injury in animals, and the involvement of the Rho/Rho kinase pathway in the fibrogenic differentiation of smooth muscle cells of patients with late radiation enteritis, suggest a role for inhibition of these pathways. The importance of limiting acute gastrointestinal toxicity by dietary, pharmacological and physical interventions and of optimizing radiotherapy techniques and prescriptions is underscored by increasing evidence that a component of the long-term effects of radiotherapy on gastrointestinal function is a consequence of acute damage. Strategies to control acute toxicity are important in reducing the impact of long-term effects of radiotherapy on gastrointestinal function. Further research into genetic profiling to characterize individual risk of radiation bowel damage and the pathways implicated in fibrogenic differentiation is needed to reduce and prevent bowel complications.


Blood Cadmium Levels and Oxygen Desaturation during the 6-Minute Walk Test in Patients with Chronic Obstructive Pulmonary Disease.
Background and Objectives: chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and a history of exposure to noxious stimuli. Cigarette smoking is the most important causal factor for developing COPD. Cadmium, a minor metallic element, is one of the main inorganic components in tobacco smoke. Inhaled cadmium was associated with a decline in lung function, gas exchange impairment, and the development of obstructive lung disease. Patients with COPD who had oxygen desaturation during the 6-min walk test (6MWT) had a significantly worse prognosis than non-desaturation in COPD patients. Nonetheless, few studies have addressed the influence of blood cadmium levels on exercise-induced oxygen desaturation in COPD patients. Our objective was to assess the potential impact of blood cadmium levels on oxygen desaturation during the 6MWT among COPD patients. Materials and Methods: we performed a retrospective analysis of patients with COPD who were examined for blood cadmium levels in a tertiary care referral center in Taiwan, between March 2020 and May 2021. The 6-min walk test was performed. Normal control subjects who had no evidence of COPD were also enrolled. Results: a total of 73 COPD patients were analyzed and stratified into the high-blood cadmium group (13 patients) and low-blood cadmium group (60 patients). A total of 50 normal control subjects without a diagnosis of COPD were enrolled. The high-blood cadmium group had a significantly higher extent of desaturation than the low-blood cadmium group. The frequency of desaturation during 6MWT revealed a stepwise-increasing trend with an increase in blood cadmium levels. A multivariable logistic regression model revealed that blood cadmium levels were independently associated with desaturation during the 6MWT (odds ratio 12.849 [95% CI 1.168-141.329]; p = 0.037). Conclusions: our findings indicate that blood cadmium levels, within the normal range, were significantly associated with desaturation during 6MWT in patients with COPD.


Thermostable feruloyl esterase for the bioproduction of ferulic acid from triticale bran.
A putative alpha/beta hydrolase fold-encoding gene (locus tag TTE1809) from the genome of Thermoanaerobacter tengcongensis was cloned and expressed in Escherichia coli as a possible source of thermostable feruloyl esterase (FAE) for the production of antioxidant phenolic acids from biomass. Designated as TtFAE, the 33-kDa protein was purified to apparent homogeneity. The lipase-like sequence characteristics of TtFAE and its substrate specificity towards methyl ferulate, methyl sinapate, and methyl p-coumarate classify it as a new member of the type A FAEs. At 75 degrees C, the enzyme retained at least 95% of its original activity for over 80 min; at 80 degrees C, its half-life was found to be 50 min, rendering TtFAE a highly thermostable protein. Under different hydrolytic conditions, ferulic acid (FA) was shown to be released from feruloylated oligosaccharides prepared from triticale bran. An estimated recovery of 68 mg FA/100 g triticale bran was demonstrated by a 30% release of the total FA from triticale bran within a 5-h incubation period. Both the oxygen radical absorbing capacity values of the feruloylated oligosaccharides and free FA were also determined. Overall, this work introduces a new bacterial member to the growing family of plant cell wall degrading FAEs that at present is largely of fungal origin, and it benchmarks the bioproduction of FA from triticale bran.


Uniform-intensity, visible light source for in situ imaging.
A flexible, low-cost, high-brightness light source for biological and biomedical imaging is presented. The illuminating device consists of a custom-size square plastic pouch 10 to 20 mm on a side and 1 to 3 mm thick that can be inserted fully or partially into both in situ or in vitro specimens to be imaged. The pouch contains a silicone-based gel medium embedded with silica particles that scatters light and provides a reasonably uniform, planar light source. Light is delivered to the pouch using a multimode optical fiber and a high-intensity tungsten lamp. Pouch size and geometry can be readily altered as needed for a particular application. Benefits of the device include reasonably uniform light intensity, low temperature rise (<2 degrees C), a nearly white light spectrum, and a thin (<2 mm thick) flexible form factor. The design, fabrication, and preliminary results from the device are presented using hamster cheek pouch tissue, with comparisons to standard intravital microscopy, along with suggestions for further improvement and potential uses.


Actions of gibberellic Acid and phytochrome on the germination of grand rapids lettuce seeds.
Red light and gibberellic acid were about equally effective in promoting germination of Grand Rapids lettuce (Lactuca sativa L.) seeds. With initial far red light treatment more than 80% remained dormant in subsequent dark storage. After 2 days of dark storage, red light effectively promoted germination, while gibberellic acid action was weak. With between 2 and 10 days of dark storage, gibberellic acid had little effect, while promotion by red light decreased slowly and finally disappeared. After 10 days of dark storage, both gibberellic acid and red light were required for germination. The dark storage treatment interferes with phytochrome-independent germination processes and cannot be overcome by added gibberellic acid. However, storage may also decrease the effectiveness of endogenous gibberellins. Phytochrome-dependent germination seems to require only low levels of endogenous gibberellin activity or the addition of gibberellic acid. Gibberellins and red light appear to act on germination by regulation of sequential sites of a branched-looped pathway.


A critical comparison of platelet preparation methods.
Platelet concentrates may be prepared from whole blood or by plateletpheresis. Currently, the non-evidence-based preponderance of apheresis units in the United States and the 50: 50 ratio in Europe may not optimize the gifts of whole-blood donors or minimize healthcare costs. Post-storage pooled, whole-blood-derived platelets, on the other hand, do not provide the convenience of or an equivalent level of safety as apheresis platelets. Some data suggest that different methods of manufacture of whole-blood-derived platelets (platelet-rich plasma or buffy coat intermediate steps) result in differing degrees of platelet activation, which may impact on the quality of stored concentrates. Recent studies have observed superior radiolabel recovery and post-transfusion increments for platelets derived from apheresis compared with platelet-rich plasma whole-blood-derived platelets. A pre-storage pooling system for whole-blood-derived platelets has just been licensed in the USA, and may eventually combine the benefits of apheresis-derived and whole-blood-derived platelets. The advantages of the European method of manufacture of buffy coat whole-blood-derived platelet concentrate have convinced the Canadian Blood Services to abandon platelet-rich-plasma-derived concentrates. We present a literature-based review of the relative merits of apheresis-derived and whole-blood-derived platelets. Additional studies are needed in order to define the optimal proportion of the platelet supply from apheresis collections and the choice of whole-blood-derived production method for US blood providers.


[Effect of prenatal lead exposure on the expression of POU-domain proteins in different brain regions of rat offsprings].
To study the role of POU-domain proteins in the neurotoxic mechanism of lead. Methods The pregnant rats were randomly divided into 4 groups, which were provided with distilled water, 0.5g/L, 1.0 g/L and 2.0 g/L lead actate solution via drinking water, respectively, the lead-exposure period for exposure groups was limited from the 15th day after pregnancy to the 21st day when the offspring began to weaned, the expression of Oct-2 and Brn-3a proteins in neural cells from cerebral cortex, hippocampus and cerebellum were measured by immunohistochemistry methods. The immununohistochemistry results showed that Oct-2 increased significantly and Brn-3a decreased significantly in lead poisoning groups compared with that of the control group (P < 0.05 or P < 0.01). The results indicateded that POU-domain proteins, as a transcription regular factor, may participate in the neurological toxicity damaging the learning and memory ability induced by lead. The study provided experimental basis for revealing the molecular neurotoxic mechanism of lead.


Growing-cube isosurface extraction algorithm for medical volume data.
In medical applications, three-dimensional volume data such as CT and MRI are gathered from medical-imaging devices. Marching cube (MC) algorithm is a common routine to extract isosurfaces from volume data. The MC algorithm generates the massive number of triangles to represent an isosurface. It is difficult to render this amount of triangles in real-time on general workstations. In this paper, we present a growing-cube algorithm to reduce the number of triangles generated by the MC algorithm. Growing-cube algorithm uses a surface tracker to avoid exhaustive searching isosurfaces cell-by-cell and, therefore, it saves computation time. During surface tracking, the growing-cube algorithm adaptively merges surfaces contained in the tracked cells to reduce the number of triangles. Surfaces are merged as long as the error is within user-specified error thresholds. Therefore, the proposed algorithm can generate a variable resolution of isosurfaces according to these error parameters.


Transport of infectious reovirus into bile: class II major histocompatibility antigen-bearing cells determine reovirus transport.
We have previously demonstrated that mammalian reovirus type 1 enters the bile and gut lumen after systemic administration. In the present study, we showed that Kupffer cell uptake is essential for the transport of reovirus into the bile. Furthermore, class II major histocompatibility antigen (I-A)-bearing cells are a major determinant for the transit of reovirus from the hepatic environment, as well as from the intestine, during the course of systemic infection. These findings may provide an approach to the control of viral pathogens that cause systemic disease by selective utilization or modification of I-A-bearing cells.


Assessment of Seasonal Radon Concentration in Dwellings and Soils in Selected Areas in Ga East, Greater Accra Region of Ghana.
Seasonal radon levels have been studied in dwellings and soils in selected areas in Ga East, Greater Accra Region of Ghana using LR-115-type II (SSNTDs). This study was conducted to determine the seasonal correlation between soil and dwelling radon concentrations. Detectors were exposed from January to March and April to June, for dry and wet seasons, respectively. Overall, indoor radon was 133.4 ± 6.7 Bqm-3 and 72.1 ± 3.6 Bqm -3 for wet and dry seasons. The estimated annual effective dose to the lung received by the occupants at Paraku Estate, Dome, and Kwabenya was 6.9 ± 0.4, 7.2 ± 0.5, and 9.8 ± 0.8 mSvy-1 for the wet season and 3.8 ± 0.2, 4.3 ± 0.2, and 4.6 ± 0.3 mSvy-1 for the dry season. On average, the soil radon concentration was found to be 0.96 ± 0.07 kBqm-3 and 2.24 ± 0.01 kBqm-3 for wet and dry seasons. To determine the correlation between soil and dwelling radon, a positive Pearson correlation coefficient value R = (0.74) and R = (0.66) was obtained representing the dry and wet seasons. To test the statistical significance between soil and dwelling radon, P < 0.05 was obtained, indicating a statically significant relationship between the two.


Electrocardiogram in the ambulatory clinic in older patients with cardiac disease: an assessment of the contribution to management.
To assess the value of the routine electrocardiogram (EKG) in the management of older (> 65 years) patients with cardiac disease during return visits to the ambulatory clinic. Retrospective chart analysis. Seventy-one patients older than 65 years of age, with cardiac diagnoses, presenting for follow-up visits. Chart notes from 254 encounters with 71 patients in a cardiology clinic were analyzed. Excluded were new patients as well as patients followed in special arrhythmia clinics for pacemakers or significant arrhythmias. All patients underwent an EKG during each clinic visit, irrespective of their clinical status, according to the clinic's protocol. The frequency and nature of therapeutic decisions made in the clinic, the contribution of the EKG to the decision-making process, the appropriateness of the EKG, and the physician response to the EKG were assessed. Therapeutic decisions, the most common of which (28%) was medication changes, were made in 78 (31%) patients. The routine EKG was considered inappropriate in 60%. Unexpected diagnostic information not obtained from history or examination was not present in any encounter. EKG findings were not addressed by physicians in 22%. Most older patients seen in the cardiology clinic for return visits with stable symptoms do not benefit from EKGs. Unexpected diagnostic information from the EKG leading to major therapeutic decisions is rare in older people with stable symptoms.


Association of glycated hemoglobin with hemoglobin levels in elderly nondiabetic subjects.
Glycated hemoglobin (HgbA1C) is being increasingly used for the diagnosis of diabetes mellitus due to its high availability and reproducibility. Several studies have shown that HgbA1C levels may be affected by levels of hemoglobin and nutritional factors associated with anemia, such as vitamin B12 and iron deficiency. However, none included elderly subjects. The aim of the present study was to investigate these effects in the older nondiabetic population. A retrospective cohort study design was used. The computerized database of a large health management organization was reviewed for all subjects without diabetes mellitus who underwent at least one measurement of HgbA1C and other hemoglobin parameters in 2002 at age≥65years. HgbA1C levels were correlated with hemoglobin, hematocrit, ferritin, iron, transferrin, vitamin B12, and folic acid levels. A total of 11,352 subjects met the study criteria. Those with HgbA1C levels in the highest quintile (6.21-6.49%, 44.4-47.7mmol/mol) had significantly lower levels of hemoglobin, hematocrit, and iron than patients with HgbA1C levels in the lowest quintile (<5.4%, 36mmol/mol), but no linear correlation was found. There was no correlation of HgbA1C level with levels of ferritin, vitamin B12, and folic acid. In elderly nondiabetic subjects, HgbA1C levels are not correlated with hemoglobin level or nutritional factors associated with anemia and may be interpreted without consideration of these factors.


Rho kinase and Ca2+ entry mediate increased pulmonary and systemic vascular resistance in L-NAME-treated rats.
The small GTP-binding protein and its downstream effector Rho kinase play an important role in the regulation of vasoconstrictor tone. Rho kinase activation maintains increased pulmonary vascular tone and mediates the vasoconstrictor response to nitric oxide (NO) synthesis inhibition in chronically hypoxic rats and in the ovine fetal lung. However, the role of Rho kinase in mediating pulmonary vasoconstriction after NO synthesis inhibition has not been examined in the intact rat. To address this question, cardiovascular responses to the Rho kinase inhibitor fasudil were studied at baseline and after administration of an NO synthesis inhibitor. In the intact rat, intravenous injections of fasudil cause dose-dependent decreases in systemic arterial pressure, small decreases in pulmonary arterial pressure, and increases in cardiac output. L-NAME caused a significant increase in pulmonary and systemic arterial pressures and a decrease in cardiac output. The intravenous injections of fasudil after L-NAME caused dose-dependent decreases in pulmonary and systemic arterial pressure and increases in cardiac output, and the percent decreases in pulmonary arterial pressure in response to the lower doses of fasudil were greater than decreases in systemic arterial pressure. The Ca(++) entry blocker isradipine also decreased pulmonary and systemic arterial pressure in L-NAME-treated rats. Infusion of sodium nitroprusside restored pulmonary arterial pressure to baseline values after administration of L-NAME. These data provide evidence in support of the hypothesis that increases in pulmonary and systemic vascular resistance following L-NAME treatment are mediated by Rho kinase and Ca(++) entry through L-type channels, and that responses to L-NAME can be reversed by an NO donor.


[Contemporary views on treatment of cruciate ligament injuries].
It is commonly assumed that the anterior crucial ligament is injured most often from all ligaments of the knee. Complexity of the structure and function of the whole capsular-ligamentous system of the knee makes the operative treatment extremely difficult. In the light of the contemporary views the problems concerning the treatment of the failure of the anterior crucial ligament belong to the main orthopedic problems requiring solution.


Hearing Loss and Sixth Cranial Nerve Paresis after COVID-19.
An 80-year-old patient was admitted to the internal medicine department for binocular diplopia and hearing loss with sudden onset. The patient had presented with SARS-CoV-2 infection 3 weeks previously and had been admitted to hospital. Complete work-up including autoimmunity, serum and LCR viral serology and MRI did not allow a diagnosis to be established. The hypothesis of a microvascular origin or the previous SARS-CoV-2 infection was considered. The latter was retained in light of the temporal relationship, the absence of other pathologies after exhaustive work-up, and the clinical evolution. A temporal relationship between SARS-CoV-2 infection and symptoms in the absence of other pathologies is important for diagnosis.Mid or long-term follow-up is necessary in patients with unexplained symptoms after SARS-CoV-2 infection.


Accurate reactions open up the way for more cooperative societies.
We consider a prisoner's dilemma model where the interaction neighborhood is defined by a square lattice. Players are equipped with basic cognitive abilities such as being able to distinguish their partners, remember their actions, and react to their strategy. By means of their short-term memory, they can remember not only the last action of their partner but the way they reacted to it themselves. This additional accuracy in the memory enables the handling of different interaction patterns in a more appropriate way and this results in a cooperative community with a strikingly high cooperation level for any temptation value. However, the more developed cognitive abilities can only be effective if the copying process of the strategies is accurate enough. The excessive extent of faulty decisions can deal a fatal blow to the possibility of stable cooperative relations.


Reduced expression of the vca0421 gene of Vibrio cholerae O1 results in innate resistance to ciprofloxacin.
A mini-Tn5 insertion into a ciprofloxacin (CIP)-resistant mutant of Vibrio cholerae O1 revealed that overexpression of the vca0421 gene, which encodes a hypothetical protein, in the CIP-resistant mutant carrying a mutation in the quinolone resistance-determining region (QRDR) of the gyrA gene causes sensitization to CIP. We propose a new intrinsic mechanism of resistance to fluoroquinolones due to the inherently reduced expression of the vca0421 gene in V. cholerae O1.


Atrial fibrillation down-regulates renal neutral endopeptidase expression and induces profibrotic pathways in the kidney.
Recent studies suggest that atrial fibrillation (AF) substantially influences microvascular flow in ventricular myocardium. This process may contribute to the occurrence of heart failure in AF. In general, development of heart failure and renal dysfunction go hand-in-hand causing systemic fluid overload and oedema. So far, it is unknown whether AF itself influences renal function. The aim of the present study was to determine the impact of AF on renal gene expression in a closed chest rapid atrial pacing model. A total of 14 pigs were studied. In five pigs, rapid atrial pacing (AT) was performed for 7 h (600 bpm); in five additional animals, rapid atrial pacing was performed in the presence of irbesartan infusion (irbesartan group). Four pigs were instrumented without interventions (sham). After the pacing period, renal expression of collagen I alpha 1 and I alpha 3, transforming growth factor-beta (TGF-beta), neutral endopeptidase (NEP; the main enzyme involved in natriuretic protein metabolism), and atrial natriuretic peptide (ANP) were determined by RT-PCR and immunoblot analysis. Functional in vitro experiments were performed using HEK-293 kidney cells. Renal mRNA expression of NEP was substantially down-regulated during AT (AT: 12.7 +/- 9.3% vs. sham: 100 +/- 43.4%; P < 0.01). Results at the mRNA level were confirmed at the protein level. Irbesartan therapy did not prevent down-regulation of NEP. In contrast, TGF-beta1 mRNA expression was up-regulated (AT: 208.5 +/- 79.3% vs. sham: 100 +/- 34.6% P< 0.05). Collagen and angiotensin II type 1 receptor (AT1R) expression were not significantly altered by AT. HEK-293 cells were used to determine the potential humoral factors involved in down-regulation of NEP. Application of aldosterone, ANP, asymmetric dimethylarginine, and angiotensin peptides failed to cause down-regulation of renal NEP expression in vitro. AT reduces NEP expression and stimulates TGF-beta1 signalling in the kidneys. Thus, even brief episodes of AT affect renal gene expression, which may account for structural renal changes and alterations of renal function in the long term.


Oxaliplatin for metastatic colon cancer in a patient with renal failure.
Oxaliplatin, a key part of the standard regimen for colorectal cancer in Western countries, has become available in Japan. In a hemodialysis patient with cecal cancer, we investigated the efficacy, safety, pharmacokinetics, and dialysability of oxaliplatin. A 65-year-old man who had cecal cancer was treated with oxaliplatin (40 mg/m(2)) and l-leucovorin(l-LV) (200 mg/m(2)), which were administered simultaneously over 120 min via the side and main arms of a Y-tube, respectively. Then 5-FU (400 mg/m(2)) was administered rapidly via the side tube, followed by 5-FU (2,000 mg/m(2)) over 46 hours via the main tube. The patient had chronic renal failure due to diabetic nephropathy and hemodialysis was performed 3 times a week. Blood samples were collected from the dialyzer before and after each hemodialysis session to examine platinum clearance. The patient received 3 courses of oxaliplatin before he died of cancer. During hemodialysis, the platinum level fell from 0.32 μg/mL to 0.15 μg/mL. Since patients with renal failure have various associated disorders and oxaliplatin has a long half-life, it is necessary to obtain more pharmacokinetic data to investigate its accumulation and dialysability during long-term treatment. Such data will assist in treating the rapidly increasing number of hemodialysis patients with colorectal cancer.


[Hyperlysinemia and hyperammonemia].
A quite important increase of plasma lysine was often reported in different cases of hyperammonemia. This retrospective study of patients with different types of hyperammonemia shows that hyperlysinemia is not automatically associated to hyperammonemia (lysinemia is expressed as the percent of total aminoacidemia). Hyperlysinemia was observed with neonatal propionic and methylmalonic acidurias. Reye's syndrome and to a less extent with ornithine transcarbamylase deficiency.


Missing the Mark: The State of Health Care Literacy in Plastic Surgery.
The Institute of Medicine defines health literacy as the degree to which individuals have the capacity to obtain, process, and understand basic health information. Low health literacy is at a crisis level in the United States. Health literacy is a stronger predictor of a person's health than age, income, employment status, education level, and race. In the plastic surgery literature to date, there is no study that evaluates health communication between plastic surgery patients and providers. This study also aims to establish the readability of the American Society of Plastic Surgeons informed consent forms. A survey instrument was designed to assess health literacy of plastic surgery patient and health communication competencies of providers. The Readability Calculator and Hemingway Editor were used to determine the readability of a sample of the American Society of Plastic Surgeons informed consent forms. Twenty-one percent of patients did not complete high school. Fifty-one percent of patients agreed that better communication with their provider would improve their health. Seventy-six percent of providers agreed that they have difficulty communicating with patients with different cultural backgrounds; 29% of providers stated that they offered patients low-literacy educational material. The average readability of the informed consents distributed to plastic surgery patients is above 12th grade. This study identifies the gap in communication between plastic surgery patients and providers in a county hospital setting. Failure to take appropriate actions toward eliminating inherent barriers in health communication is costly to both the hospital and the patients. These findings also raise concern about the understanding of informed consent in plastic surgery patients.


Analysis of damage to human ciliated nasopharyngeal epithelium by Neisseria meningitidis.
We used an in vitro model of human nasopharyngeal tissue in organ culture to evaluate the effects of Neisseria meningitidis on human cilia and ciliary function. Encapsulated, viable meningococci damaged ciliated epithelium of nasopharyngeal organ cultures, whereas Neisseria subflava, a commensal species, did not. Meningococcus-induced ciliary damage was due to loss of ciliated cells to which meningococci were not attached. Damage was seen with piliated and nonpiliated meningococci and did not appear to require the presence of other specific meningococcal surface proteins. Meningococcal viability was a requirement for both ciliary damage and interactions of meningococci with microvilli of nonciliated epithelial cells. That is, filter-sterilized supernatants from meningococcus-infected organ cultures, heat-killed meningococci at high inoculum, and purified meningococcal or gonococcal lipopolysaccharide at concentrations of 100 micrograms/ml did not damage ciliary activity of nasopharyngeal organ cultures. In contrast, meningococcal lipopolysaccharide at 10 micrograms/ml markedly damaged ciliary activity of human fallopian tube organ cultures, suggesting a selective toxicity of lipopolysaccharide for specific human ciliated cells. Damage to nasopharyngeal ciliated epithelium by N. meningitidis may be an important first step in meningococcal colonization of the human nasopharynx, but meningococcal lipopolysaccharide does not appear to be directly responsible for this toxicity.


Evaluation of the combination of bead technology with SELDI-TOF-MS and 2-D DIGE for detection of plasma proteins.
Today biomarker discovery is one of the most active aspects of proteomic investigations. However, the wide dynamic range of plasma proteins makes the analysis very challenging because high abundance proteins tend to mask those of lower abundance. Using a large bead-based library of combinatorial peptide ligands (Equalizer beads or ProteoMiner), the dynamic range of the protein concentration is compressed, the high abundance proteins present in the sample are reduced and the low abundance proteins are enriched, while retaining representatives of all proteins within the sample. In the present study, the combination of beads with surface enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF-MS) and two-dimensional differential gel electrophoresis (2-D DIGE) technology were evaluated considering efficiency, reproducibility, sensitivity, and compatibility. The bead technology is easily compatible with both SELDI-TOF-MS and 2-D DIGE and the samples can be analyzed directly without any processing of the sample. The use of the beads prior SELDI-TOF-MS and 2-D DIGE enabled detection of many new protein spots/peaks and increased resolution and improved intensity of low abundance proteins in a reproducible fashion compared with the depletion technique. Several proteins have been identified by the combination of beads, 2-D DIGE and MS for example different kinds of complement factors and cytoskeletal proteins. Our data suggest that integration of the bead technology with our current proteomic technologies will enhance the possibility to deliver new peptide/protein biomarker candidates in our projects.


Economic valuations in global health.
This paper deals with three issues concerning economic valuation in global health. First, we argue that the economic value of health delivery in resource-limited settings is not fully captured through the adding up of successive assessments of individual interventions. Second, we suggest that economic valuations can be used to identify social barriers to the success of health technologies in resource-limited settings. Third, we briefly discuss new directions for research on economic valuations given the interdependency between poor health and economic impoverishment.


Crystal growth, structure, and physical properties of LnCu2(Al,Si)5 (Ln = La and Ce).
LnCu(2)(Al,Si)(5) (Ln = La and Ce) were synthesized and characterized. These compounds adopt the SrAu(2)Ga(5) structure type and crystallize in the tetragonal space group P4/mmm with unit cell dimensions of a ≈ 4.2 Å and c ≈ 7.9 Å. Herein, we report the structure as obtained from single crystal X-ray diffraction. Additionally, we report the magnetic susceptibility, magnetization, resistivity, and specific heat capacity data obtained for polycrystalline samples of LnCu(2)(Al,Si)(5) (Ln = La and Ce).


Physiological Characterization of a Single-Gene Mutant of Pisum sativum Exhibiting Excess Iron Accumulation: I. Root Iron Reduction and Iron Uptake.
Root systems of mutant (E107) and parental (cv ;Sparkle') Pisum sativum genotypes were studied to determine the basis for excess Fe accumulation in E107. Plants were grown with (+Fe-treated) or without (-Fe-treated) added Fe(III)-N,N'-ethylenebis[2-(2-hydroxyphenyl)glycine] in aerated nutrient solutions. Daily measurements of Fe(III) reduction indicated a four-to seven-fold higher reduction rate in +Fe- or -Fe-treated E107, and -Fe-treated Sparkle, when compared with +Fe-treated Sparkle. An agarose-based staining technique used to localize Fe(III) reduction, revealed Fe(III) reduction over most of the length of the roots (but not at the root apices) in both E107 treatments and -Fe-treated Sparkle. In +Fe-treated Sparkle, Fe(III) reduction was either nonexistent or localized to central regions of the roots. Measurements of short-term Fe influx (with 0.1 millimolar (59)Fe(III)-ethylenediaminetetraacetic acid) was also enhanced (threefold) in +Fe- or -Fe-treated E107 and -Fe-treated Sparkle, relative to +Fe-treated Sparkle. The physiological characteristics of E107 root systems, which are similar to those seen in Fe-deficient Sparkle, have led us to conclude that the mutation causes E107 to act functionally as an Fe-deficient plant, and appears to explain the excess Fe accumulation in E107.


Selection of Oral Antifungals for Initial Maintenance Therapy in Chronic Pulmonary Aspergillosis: A Longitudinal Analysis.
There are limited data for direct comparisons of the efficacy of oral itraconazole (ITCZ) and oral voriconazole (VRCZ) therapy in the treatment of chronic pulmonary aspergillosis (CPA). We conducted a retrospective, follow-up, observational study of CPA patients enrolled in 2 previous multicenter trials. Of the 273 CPA patients, 59 and 101 patients started maintenance therapy with oral ITCZ and oral VRCZ, respectively, just after the end of acute intravenous therapy in each trial. At the end of the observation period in this follow-up study (median observation period, 731 days), the percentage of patients who showed improvement was lower in the ITCZ group than in the VRCZ group (18.2% vs 40.0%). However, after including stable patients, the percentages were 50.9% and 52.6%, respectively, in the ITCZ and VRCZ groups, which were not significantly different (P = .652). Multivariable Cox regression analysis showed no significant influence of the choice of initial maintenance treatment (ITCZ or VRCZ) on overall mortality as well as CPA-associated mortality. Multivariable logistic regression showed that oral ITCZ selection for initial maintenance therapy was an independent risk factor for hospital readmission and switching to other antifungal agents (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.3-7.5 and OR, 5.7; 95% CI, 2.0-15.7, respectively). Oral VRCZ for initial maintenance therapy showed better effectiveness than oral ITCZ for clinical improvement in CPA patients. There was no difference in crude mortality between initial maintenance therapy with VRCZ and ITCZ, especially in elderly CPA patients. UMIN000007055.


[Pathology and pathogenesis of pituitary corticotroph adenoma].
Corticotroph adenoma is a benign tumor composed of adenohypophyseal cells; carcinoma with metastasis and ectopic adenoma have also been reported. In our pathological series, the frequency of this type of adenoma is 13% (250/1863 tumors removed between 1970 and 2001). Usually, corticotroph adenomas synthesize peptides derived from POMC maturation: ACTH, ss-endorphine, and ssLPH. In the great majority of cases, ACTH induces hypercorticism with clinical and biological signs of Cushing's disease. However, some tumors the pathologist identifies as corticotroph adenomas are not associated with clinical signs of hypercorticism (20% of the corticotroph adenomas in our series). Corticotroph adenoma is a basophilic or chromophobe tumor composed of cells which remain regulated by cortisol. This may explain the small size of this type of adenoma in 80% of the cases. In contrast, "silent" adenomas or macroadenonas which synthesize high-weight POMC are aggressive invasive tumors. Neurosurgery is indicated for the treatment of corticotroph adenoma. Recurrence is explained by incomplete removeal of the tumor. Peroperative studies may be necessary to find microadenomas. In some cases, the whole pituitary must be removed and cut in serial sections to find a tumor measuring<2 mm. In our opinion, the existence of corticotroph hyperplasia inducing Cushing's disease remains to be proven (we have never observed one). The pituitary origin of the tumor is based on its monoclonality. The general mechanism of tumorigenesis is known, but the specific factors involved and markers of aggressiveness remain to be discovered.


Synthesis, Crystal Structure, and Biological Evaluation of Novel 5-Hydroxymethylpyrimidines.
Pyrimidine displays a wide array of bioactivities, and thence, it is still considered a potent unit of new drug research. Its derivative, 5-hydroxymethylpyrimidine, can be found as a scaffold of nontypical nitrogen bases in DNA and as a core of some natural bioactive compounds. In this study, we obtained a series of 5-hydroxymethylpyrimidines that vary in the 4-position by the reduction of proper esters. All compounds were characterized by spectroscopic analysis, and single-crystal X-ray diffraction was performed for some of them. Biological investigations estimated cytotoxic properties against normal (RPTEC) and cancer (HeLa, HepaRG, Caco-2, AGS, A172) cell lines. It was found that the derivatives with an aliphatic amino group at the 4-position are generally less toxic to normal cells than those with a benzylsulfanyl group. Moreover, compounds with bulky constituents exhibit better anticancer properties, though at a moderate level. The specific compounds were chosen due to their most promising IC50 concentration for in silico study. Furthermore, antimicrobial activity tests were performed against six strains of bacteria and one fungus. They demonstrated that only derivatives with at least three carbon chain amino groups at the 4-position have weak antibacterial properties, and only the derivative with 4-benzylsulfanyl constituent exhibits any antifungal action.


Acute myocardial infarction in a 24 year-old man possibly associated with sibutramine use.
Sibutramine is an anti-obesity drug, which acts by inhibiting neuronal re-uptake of noradrenaline and serotonin. Although the most frequently seen effect of sibutramine on cardiovascular system is an increase in blood pressure and pulse rate, rare but severe side effects such as sibutramine-induced ventricular arrhythmias, heart failure and cardiovascular disease-related death are also reported. We describe a 24 year-old man with low atherosclerotic risk profile who had acute myocardial infarction possibly associated with sibutramine use.


Does a history of cardiovascular disease or cancer affect mortality after SARS-CoV-2 infection?
Cardiovascular disease and cancer have been described as possible risk factors for COVID-19 mortality. The purpose of this study was to investigate whether a history of cardiovascular disease or cancer affects the risk of dying after a COVID-19 diagnosis in Norway. Data were compiled from the Norwegian Surveillance System for Communicable Diseases, the Norwegian Cardiovascular Disease Registry and the Cancer Registry of Norway. Univariable and multivariable regression models were used to calculate both relative and absolute risk. In the first half of 2020, 8 809 people tested positive for SARS-CoV-2 and 260 COVID-19-associated deaths were registered. Increasing age, male sex (relative risk (RR): 1.5; confidence interval (CI): 1.2-2.0), prior stroke (RR: 1.5; CI: 1.0-2.1) and cancer with distant metastasis at the time of diagnosis (RR: 3.0; CI: 1.1-8.2) were independent risk factors for death after a diagnosis of COVID-19. After adjusting for age and sex, myocardial infarction, atrial fibrillation, heart failure, hypertension, and non-metastatic cancer were no longer statistically significant risk factors for death. The leading risk factor for death among individuals who tested positive for SARS-CoV-2 was age. Male sex, and a previous diagnosis of stroke or cancer with distant metastasis were also associated with an increased risk of death after a COVID-19 diagnosis.


Comparison of bone morphogenetic protein-2 delivery systems to induce supracrestal bone guided by titanium implants in the rabbit mandible.
To compare the ability of three non-glycosylated/rhBMP-2 (BMP-2) delivery systems to induce supracrestal bone. Thirty-six custom SLActive dental implants were partially embedded in transverse orientation into the posterior mandibles of 18 adult rabbits with the head of the implant located 3 mm supracrestal. Delivery of BMP-2 (30 μg) from the following materials was studied: (1) Ti implant + BMP-2 with hydroxyapatite (HA)-coated collagen (Col/HA) scaffold, (2) Ti implant with Col/HA infused with PEG hydrogel + BMP-2, or (3) Ti implant with HA/β-TCP/PEG hydrogel scaffold + BMP-2. Scaffolds were secured with a metal "umbrella." Non-BMP-2 contralateral controls were included. MicroCT imaging and histological analysis was performed after 10 weeks to assess new supracrestal bone formation. In vitro BMP-2 release studies were conducted. All treatment groups displayed new supracrestal bone formation. Ti + BMP-2 with Col/HA (3.0 ± 0.2 mm) and Ti with Col/HA/PEG hydrogel + BMP-2 (2.7 ± 0.4 mm) had significantly greater (P < 0.05) outcomes than without BMP-2. Maximum bone volume occurred in the Ti implant with HA/β-TCP/PEG hydrogel scaffold + BMP-2 group. The use of an implant system composed of a partially inserted Ti implant, adjacent scaffold and scaffold stabilizer resulted in the formation of new supracrestal bone across all test groups with and without BMP-2. Delivery of BMP-2 directly from the Ti implant increased bone height, BIC and bone volume as compared to no BMP-2 when a Col/HA was used, but did not improve performance of the HA/β-TCP/PEG scaffold.