Influence of prior hyperventilation duration on respiratory chemosensitivity and cerebrovascular reactivity during modified hyperoxic rebreathing.
What is the central question of this study? We characterized and compared the cardiorespiratory and cerebrovascular responses to the 'Duffin' modified hyperoxic CO2 rebreathing test by randomly altering the prior hyperventilation duration. What is the main finding and its importance? Our main finding was that prior hyperventilation duration (1, 3 or 5 min) had no effect on cardiorespiratory and cerebrovascular responses to the hyperoxic rebreathing test, within individuals. These findings suggest that the standard 5 min prior hyperventilation duration used to clear body CO2 stores is unnecessary and can reasonably be shortened to 1 min, reducing protocol times and improving participant comfort. The 'Duffin' modified hyperoxic rebreathing test allows investigators to characterize and quantify the ventilatory and cerebrovascular responses to CO2 across a large physiological range, allowing quantification of basal ventilation and the ventilatory recruitment threshold (VRT). Although the standard protocol includes 5 min of prior hyperventilation to clear body CO2 stores, there is no experimental evidence that a full 5 min is required. We hypothesized that there would be no within-individual differences in the cardiorespiratory or cerebrovascular responses to rebreathing with shortened hyperventilation duration prior to hyperoxic rebreathing. Using a rebreathing apparatus, transcranial Doppler ultrasound and beat-to-beat blood pressure monitoring, we tested 19 participants in the supine position using three randomly assigned hyperoxic rebreathing tests with 1, 3 or 5 min of prior hyperventilation. We measured VRT (in Torr CO2 ), time to VRT (in seconds), central respiratory chemoreflex (breathing frequency, tidal volume and minute ventilation), cerebrovascular (middle and posterior cerebral artery velocity) and cardiovascular (heart rate and mean arterial pressure) responses to CO2 during hyperoxic rebreathing. Using linear regression and repeated-measures ANOVAs, we found no differences in any of the cardiorespiratory or cerebrovascular response magnitudes between trials (P > 0.05). The only difference observed was in the time to VRT (in seconds), whereby 1 min prior hyperventilation duration was shorter (135.4 ± 19.7 s) than with 3 or 5 min prior hyperventilation (176.3 ± 15.1 and 187.2 ± 11.6 s, respectively; P < 0.001). Our findings indicate that 5 min of prior hyperventilation is unnecessary during modified rebreathing when using it to quantify respiratory or cerebrovascular responses and can be reasonably shortened to 1 min, reducing protocol times and improving participant comfort.


Analysis of compassionate use itraconazole therapy for invasive aspergillosis by the NIAID Mycoses Study Group criteria.
Successful therapy of invasive aspergillosis is difficult, and the place of new drugs is evolving. Earlier studies, with fewer patients, suggest itraconazole, an oral azole, is effective for some patients. Compassionate use data were analyzed by criteria applied previously in a multicenter trial as a reference point. The course of 125 patients was evaluated and their clinical settings and responses were categorized. Overall, 34 (27%) had a complete response, 45 (36%) improved, 20 (16%) were unchanged, and 26 (21%) worsened. The subset receiving less than 2 weeks of itraconazole therapy had a worse outcome than the remainder of the group as did patients with sinus, central nervous system, or widely disseminated disease. Prior therapy, age, underlying disease, other sites of aspergillosis, dose, or Aspergillus species did not correlate closely with outcome. In patients who responded, a period of months was commonly required before objective improvement was documented. Patients who underwent bone marrow transplantation fared better than in previous reports. Itraconazole is effective in many patients with aspergillosis. This large series supports earlier conclusions that response rates are similar to those reported for amphotericin B.


Epidemiology of tobacco use and dependence in adults in a poor peri-urban community in Lima, Peru.
Tobacco smoking is an important public health concern worldwide leading to both chronic disease and early death. In Latin America, smoking prevalence is estimated at approximately 30% and prior studies suggest that the prevalence in Peru is 22% to 38%. We sought to determine the prevalence of daily smoking in a poor peri-urban community in Lima, Peru. We conducted a cross-sectional survey in a random sample of adults ≥40 years of age living in Pampas de San Juan de Miraflores, Lima, Peru. We asked participants to respond to a survey that included questions on sociodemographics, tobacco use and dependence. We enrolled 316 participants. Average monthly household income was ≤ 400 USD and nearly all homes had running water, sewage, and electricity. Most individuals had not completed high school. Smoking prevalence was 16% overall, yet daily smoking prevalence was 1.9%. Former daily smokers comprised 3.8% of current nonsmokers and 9.1% current occasional smokers. Average scores for the Fagerstrom Test for Nicotine Dependence for daily smokers and occasional smokers were 1.5 and 0, respectively. Daily use of tobacco is uncommon among adults in peri-urban communities of Lima, Peru, unlike their counterparts in Lima and other Latin American capital cities. Tobacco dependence is also low. Hence, efforts aimed at primary prevention are of utmost importance in these communities. This study provides an accurate baseline using an internationally recognized assessment tool (Global Adult Tobacco Survey), allowing for accurate assessment of tobacco control interventions over time.


Outcomes in Black and White Patients With Metastatic Renal Cell Carcinoma Treated With First-Line Tyrosine Kinase Inhibitors: Insights From Two Large Cohorts.
To investigate whether black race is an independent predictor of overall survival (OS) in metastatic renal cell carcinoma (mRCC). We performed a retrospective 2-cohort (International Metastatic Renal Cell Carcinoma Database Consortium [IMDC] and trial-database) study of patients with mRCC treated with first-line tyrosine kinase inhibitors (TKIs). Unmatched (UM) and matched (M) analyses accounting for imbalances in region, year of treatment, age, and sex between races were performed. Cox models adjusting for histology, number of metastatic sites, nephrectomy, and IMDC risk compared time to treatment failure (TTF; IMDC cohort), progression-free survival (PFS; trial-database cohort), and OS. The IMDC cohort included 73 black versus 3,381 (UM) and 1,236 (M) white patients. The trial-database cohort included 21 black versus 1,040 (UM) and 431 (M) white patients. Median OS for black versus white patients was 18.5 versus 25.8 months in the IMDC group and 21.0 versus 25.6 months in the trial-database group. Differences in OS were not significant in multivariable analysis in the IMDC group (hazard ratio [HR]M, 1.0; 95% CI, 0.7 to 1.5; HRUM, 1.1; 95% CI, 0.8 to 1.4) and trial-database (HRM, 1.5; 95% CI, 0.8 to 2.7; HRUM, 1.4; 95% CI, 0.8 to 2.6) cohorts. TTF for black patients was shorter in the UM IMDC cohort (HRUM, 1.4; 95% CI, 1.1 to 1.8; P = .003), but not in the M analysis. PFS was shorter for black patients in both analyses in the trial-database cohort (HRM, 2.3; 95% CI, 1.4 to 3.9; P = .002; HRUM, 2.3; 95% CI, 1.4 to 3.9; P = .002). Black patients had more IMDC risk factors and worse outcomes with TKIs versus white patients. Race was not an independent predictor of OS. Strategies to understand biologic determinants of outcomes for minority patients are needed to optimize care.


Widespread occurrence of intranuclear atrophin-1 accumulation in the central nervous system neurons of patients with dentatorubral-pallidoluysian atrophy.
Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion. In the present study of DRPLA, we have demonstrated immunohistochemically that diffuse accumulation of mutant atrophin-1 in the neuronal nuclei, rather than the formation of neuronal intranuclear inclusions (NIIs), was the predominant pathologic condition and involved a wide range of central nervous system regions far beyond the systems previously reported to be affected. In the neuronal nuclei harboring NIIs, promyelocytic leukemia protein (PML) nuclear bodies were redistributed into a single NII, and the CREB (cAMP-responsive element-binding protein)-binding protein was also recruited into NIIs. The results suggest that the novel lesion distribution revealed by the diffuse nuclear labeling may be responsible for a variety of clinical features, such as dementia and epilepsy in DRPLA, and that certain transcriptional abnormalities may be induced secondarily in neuronal nuclei with the formation of NIIs.


Optimal Culture Conditions for Mycelial Growth of Lignosus rhinocerus.
Lignosus rhinocerus is a macrofungus that belongs to Polyporaceae and is native to tropical regions. This highly priced mushroom has been used as folk medicine to treat diseases by indigenous people. As a preliminary study to develop a culture method for edible mushrooms, the cultural characteristics of L. rhinocerus were investigated in a range of culture media under different environmental conditions. Mycelial growth of this mushroom was compared on culture media composed of various carbon and nitrogen sources in addition to C/N ratios. The optimal conditions for mycelial growth were 30℃ at pH 6 and 7. Rapid mycelial growth of L. rhinocerus was observed on glucose-peptone and yeast extract peptone dextrose media. Carbon and nitrogen sources promoting mycelial growth of L. rhinocerus were glucose and potassium nitrate, respectively. The optimum C/N ratio was approximately 10 : 1 using 2% glucose supplemented as a carbon source in the basal media.


Reactive oxygen and nitrogen species regulate mitochondrial Ca2+ homeostasis and respiration.
The reduction of molecular oxygen to water provides most of the biologically useful energy. However, oxygen reduction is a mixed blessing because incompletely reduced oxygen species such as superoxide or peroxides are quite reactive and can, when out of control, cause damage. In mitochondria, where most of the oxygen utilized by eukaryotic cells is reduced, the dichotomy of oxygen shows itself best. Thus, reactive oxygen is a threat to them, as is evident from oxidative damage to mitochondrial lipids, proteins, and nucleic acids. Reactive oxygen, in the form of peroxides, also serves useful functions in mitochondria. This is exemplified by the control of mitochondrial and cellular calcium homeostasis, whose understanding has improved greatly during the last few years. An exciting new aspect is the discovery that nitric oxide and congeners have an enormous impact on mitochondria. Physiological concentrations of nitrogen monoxide (NO) at physiological cellular oxygen pressure inhibit cytochrome oxidase and thereby respiration. A transient inhibition of cytochrome oxidase by NO appears to be used in at least some forms of cell signalling. Peroxynitrite, the product of the reaction between superoxide and NO, can stimulate the specific calcium release pathway from mitochondria by oxidizing some vicinal thiols in mitochondria. There is evidence mounting that mitochondrial calcium handling and its modulation by reactive oxygen and nitrogen species is important for necrotic and apoptotic cell death.


Comparison of Saccadic Eye Movements Among the High-tension Glaucoma, Primary Angle-closure Glaucoma, and Normal-tension Glaucoma.
Saccadic eye movements were compared between high-tension glaucoma (HTG), normal-tension glaucoma (NTG), and primary angle-closure glaucoma (PACG). Saccades were differently affected between the subtypes of primary glaucoma. The aim of the study was to compare saccadic eye movements in eyes with HTG, PACG, and NTG. Saccadic eye movements were recorded using the eye tracker Eyelink-1000 in 52 participants: 15 HTG, 14 PACG, 8 NTG, and 15 normal controls. All participants underwent a complete ophthalmic and visual field examination. Prosaccades were measured using the gap paradigm. Prosaccades were measured at 3 target eccentricities (5-, 7-, and 10-degree eccentricity). All prosaccade targets were projected outside the area of visual field defect. Saccade latency, average and peak velocity, and amplitude difference of the saccades were compared between glaucoma subtypes. The mean±SD age was lesser in controls compared with glaucoma (P=0.02). The mean age in all the glaucoma subtypes was comparable (P=0.92). The average mean deviation in PACG (-16.66±6.69 dB) was worse (P=0.01) than in HTG (-11.56±6.08 dB) and NTG (-9.55±3.96 dB). The latencies were delayed, average and peak velocities were reduced, and saccades were hypometric in glaucoma compared with controls (P<0.01). Between subtypes, the differences in latency (P<0.01), peak velocity (P=0.02), and amplitude (P=0.02) were significant. Saccadic eye movements were significantly different in NTG compared with other glaucoma subtypes (post hoc analysis; latency (HTG vs. NTG; P<0.01, HTG vs. PACG; P=0.01), peak velocity (HTG vs. NTG; P=0.02) and amplitude difference (HTG vs. NTG; P=0.02). Saccadic eye movement parameters were differently affected among the glaucoma subtypes. Saccadic parameters were more affected in NTG.


A three-dimensionally preserved lobopodian from the Herefordshire (Silurian) Lagerstätte, UK.
The Herefordshire (Silurian) Lagerstätte (approx. 430 Myr BP) has yielded, among many exceptionally preserved invertebrates, a wide range of new genera belonging to crown-group Panarthropoda. Here, we increase this panarthropod diversity with the lobopodian Thanahita distos, a new total-group panarthropod genus and species. This new lobopodian preserves at least nine paired, long, slender appendages, the anterior two in the head region and the posterior seven representing trunk lobopods. The body ends in a short post-appendicular extension. Some of the trunk lobopods bear two claws, others a single claw. The body is covered by paired, tuft-like papillae. Thanahita distos joins only seven other known three-dimensionally preserved lobopodian or onychophoran (velvet worm) fossil specimens and is the first lobopodian to be formally described from the Silurian. Phylogenetic analysis recovered it, together with all described Hallucigenia species, in a sister-clade to crown-group panarthropods. Its placement in a redefined Hallucigeniidae, an iconic Cambrian clade, indicates the survival of this clade to Silurian times.


Comparative reactivity of hamster cheek pouch microvessels to arginine vasopressin and angiotensin II.
Experiments were carried out to determine the relative sensitivity of hamster cheek pouch vessels to arginine vasopressin (AVP) and angiotensin II (AII). Hamsters were anesthetized with pentobarbital sodium (6 mg/100 g, ip), a plastic chamber inserted into the cheek pouch and the membrane exposed. The membrane was suffused continuously with bicarbonate-buffered Ringer's solution at 36 degrees C while constantly monitoring blood pressure. After stabilization (30 min) of the membrane, arterioles (30-80 microM diam) were selected for application of AVP or AII in a random fashion. The peptides were applied to the vessels through a micropipette (10-15 mM tip diam) over two minutes using a pump. Total volume delivered was always 20 microliters irrespective of the total amount of peptide (10(0)-10(-4) ng) applied. Vessel diameter was monitored continuously with a shearing device before, during and after the administration of the peptide. The following results were obtained tachyphylaxis was noted to AII but to AVP; the dose response curve for AVP was shifted to the left of that for AII with the threshold dose for AII one hundred times more than that of AVP and AVP had little effect on venules whereas AII produced venoconstriction. These results indicate that AVP is a more potent vasoconstrictor than AII, whereas AII is a more potent venoconstrictor.


Short-term and long-term health impacts of air pollution reductions from COVID-19 lockdowns in China and Europe: a modelling study.
Exposure to poor air quality leads to increased premature mortality from cardiovascular and respiratory diseases. Among the far-reaching implications of the ongoing COVID-19 pandemic, a substantial improvement in air quality was observed worldwide after the lockdowns imposed by many countries. We aimed to assess the implications of different lockdown measures on air pollution levels in Europe and China, as well as the short-term and long-term health impact. For this modelling study, observations of fine particulate matter (PM2·5) concentrations from more than 2500 stations in Europe and China during 2016-20 were integrated with chemical transport model simulations to reconstruct PM2·5 fields at high spatiotemporal resolution. The health benefits, expressed as short-term and long-term avoided mortality from PM2·5 exposure associated with the interventions imposed to control the COVID-19 pandemic, were quantified on the basis of the latest epidemiological studies. To explore the long-term variability in air quality and associated premature mortality, we built different scenarios of economic recovery (immediate or gradual resumption of activities, a second outbreak in autumn, and permanent lockdown for the whole of 2020). The lockdown interventions led to a reduction in population-weighted PM2·5 of 14·5 μg m-3 across China (-29·7%) and 2·2 μg m-3 across Europe (-17·1%), with unprecedented reductions of 40 μg m-3 in bimonthly mean PM2·5 in the areas most affected by COVID-19 in China. In the short term, an estimated 24 200 (95% CI 22 380-26 010) premature deaths were averted throughout China between Feb 1 and March 31, and an estimated 2190 (1960-2420) deaths were averted in Europe between Feb 21 and May 17. We also estimated a positive number of long-term avoided premature fatalities due to reduced PM2·5 concentrations, ranging from 76 400 (95% CI 62 600-86 900) to 287 000 (233 700-328 300) for China, and from 13 600 (11 900-15 300) to 29 500 (25 800-33 300) for Europe, depending on the future scenarios of economic recovery adopted. These results indicate that lockdown interventions led to substantial reductions in PM2·5 concentrations in China and Europe. We estimated that tens of thousands of premature deaths from air pollution were avoided, although with significant differences observed in Europe and China. Our findings suggest that considerable improvements in air quality are achievable in both China and Europe when stringent emission control policies are adopted. None.


Metformin Promotes Apoptosis but Suppresses Autophagy in Glucose-Deprived H4IIE Hepatocellular Carcinoma Cells.
Metformin, a well-known anti-diabetic drug, has gained interest due to its association with the reduction of the prevalence of cancer in patients with type 2 diabetes and the anti-proliferative effect of metformin in several cancer cells. Here, we investigated the anti-proliferative effect of metformin with respect to apoptosis and autophagy in H4IIE hepatocellular carcinoma cells. H4IIE rat cells were treated with metformin in glucose-free medium for 24 hours and were then subjected to experiments examining the onset of apoptosis and/or autophagy as well as the related signaling pathways. When H4IIE cells were incubated in glucose-free media for 24 hours, metformin and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) reduced the viability of cells. Inhibition of AMP-activated protein kinase (AMPK) by compound C significantly blocked cell death induced by metformin or AICAR. Pro-apoptotic events (nuclear condensation, hydrolysis of intact poly ADP ribose polymerase and caspase-3) were stimulated by metformin and then suppressed by compound C. Interestingly, the formation of acidic intracellular vesicles, a marker of autophagy, was stimulated by compound C. Although the deprivation of amino acids in culture media also induced apoptosis, neither metformin nor compound C affected cell viability. The expression levels of all of the autophagy-related proteins examined decreased with metformin, and two proteins (light chain 3 and beclin-1) were sensitive to compound C. Among the tested inhibitors against MAP kinases and phosphatidylinositol-3-kinase/mammalian target of rapamycin, SB202190 (against p38MAP kinase) significantly interrupted the effects of metformin. Our data suggest that metformin induces apoptosis, but suppresses autophagy, in hepatocellular carcinoma cells via signaling pathways, including AMPK and p38 mitogen-activated protein kinase.


Interactions of the Kaposi's Sarcoma-associated herpesvirus nuclear egress complex: ORF69 is a potent factor for remodeling cellular membranes.
All herpesviruses encode a complex of two proteins, referred to as the nuclear egress complex (NEC), which together facilitate the exit of assembled capsids from the nucleus. Previously, we showed that the Kaposi's sarcoma-associated herpesvirus (KSHV) NEC specified by the ORF67 and ORF69 genes when expressed in insect cells using baculoviruses for protein expression forms a complex at the nuclear membrane and remodels these membranes to generate nuclear membrane-derived vesicles. In this study, we have analyzed the functional domains of the KSHV NEC proteins and their interactions. Site-directed mutagenesis of gammaherpesvirus conserved residues revealed functional domains of these two proteins, which in many cases abolish the formation of the NEC and remodeling of nuclear membranes. Small in-frame deletions within ORF67 in all cases result in loss of the ability of the mutant protein to induce cellular membrane proliferation as well as to interact with ORF69. Truncation of the C terminus of ORF67 that resides in the perinuclear space does not impair the functions of ORF67; however, deletion of the transmembrane domain of ORF67 produces a protein that cannot induce membrane proliferation but can still interact with ORF69 in the nucleus and can be tethered to the nuclear membrane by virtue of its interaction with the wild-type-membrane-anchored ORF67. In-frame deletions in ORF69 have varied effects on NEC formation, but all abolish remodeling of nuclear membranes into circular structures. One mutant interacts with ORF67 as well as the wild-type protein but cannot function in membrane curvature and fission events that generate circular vesicles. These studies genetically confirm that ORF67 is required for cellular membrane proliferation and that ORF69 is the factor required to remodel these duplicated membranes into circular-virion-size vesicles. Furthermore, we also investigated the NEC encoded by Epstein-Barr virus (EBV). The EBV complex comprised of BFRF1 and BFLF2 was visualized at the nuclear membrane using autofluorescent protein fusions. BFRF1 is a potent inducer of membrane proliferation; however, BFLF2 cannot remodel these membranes into circular structures. What was evident is the superior remodeling activity of ORF69, which could convert the host membrane proliferations induced by BFRF1 into circular structures.


No evidence for an ethnic influence on basal metabolism: an examination of data from India and Australia.
A lower BMR of Indians, when compared with Westerners matched for age, sex and either surface area or body weight, has often been reported in the literature and has been interpreted to reflect an ethnic influence on BMR. To determine the contribution of body composition to these observed differences in BMR, we analysed the data on ninety-six Indians and eighty-one Caucasian Australians of both sexes, aged 18-30 years, studied in Bangalore, India and Melbourne, Australia. Absolute BMR and BMR adjusted for body weight were significantly lower in Indians when compared with Australians of the corresponding sex. However, BMR adjusted for fat-free mass (FFM) in men, and BMR adjusted for FFM and fat mass (FM) in women, were not significantly different between the two groups. Stepwise regression of FFM, FM, sex (0 = women; 1 = men) and ethnicity (0 = Indian; 1 = Australian) on BMR, resulted in the following relationship for the combined data on all subjects: BMR = 88.7 x FFM (kg) + 1713 (n 177; r 0.92; r2 0.85; SEE 425 kJ). The Indian equations of Hayter & Henry (1994), based on body weight, resulted in a significant bias (measured-predicted BMR) of 318 (SE 54) kJ/d in Indian men and -409 (SE 70) kJ/d in Indian women. The equation of Cunningham (1991), based on FFM, accurately predicted the BMR of Indian men, Indian women and Australian men. The small but significant bias of 185 (SE 61) kJ/d in Australian women, may be explained by the significant contribution of FM to BMR in this group. The present study does not provide any evidence for an ethnic influence on basal metabolism. The results strongly support the use of FFM, rather than body weight, for the prediction of BMR in population groups of varying body size and composition. This would allow an accurate estimation of BMR and hence energy requirements in population groups worldwide.


[Differences in differential diagnosis between acute mesenterial lymphadenitis and appendicitis in children].
The thermal streams intensity (THSI) from definite points of anterior abdominal wall in children with an acute mesenterial lymphadenitis (AML) and an acute appendicitis (AA) were determined. It was established, that in right inguinal region THSI in AA was in 4.06 times higher than in AML, in paraumbilical region--THSI was in 2.78 times, in the left subcostal region--in 1.76 times higher in AML than in AA. In the right subcostal region THSI was higher in an AA. Differential algorithm for AML and AA was determined. In children with an AML the circulating immune complexes level in the blood plasma was by 26.4% higher than such in children with an AA, presenting possible additional differential-diagnostical criterion.


A zero-voltage switching technique for minimizing the current-source power of implanted stimulators.
The current-source power of an implanted stimulator is reduced almost to the theoretical minimum by driving the electrodes directly from the secondary port of the inductive link with a dedicated zero-voltage switching power supply. A feedback loop confined to the secondary of the inductive link adjusts the timing and conduction angle of switching to provide just the right amount of supply voltage needed for keeping the current-source voltage constant at or slightly above the compliance limit. Since drive is based on current rather than voltage, and supply-voltage update is near real-time, the quality of the current pulses is high regardless of how the electrode impedance evolves during stimulation. By scaling the switching frequency according to power demand, the technique further improves overall power consumption of the stimulator. The technique is implemented with a very simple control circuitry comprising a comparator, a Schmitt trigger and a logic gate of seven devices in addition to an on-chip switch and an off-chip capacitor. The power consumed by the proposed supply circuit itself is no larger than what the linear regulator of a conventional supply typically consumes for the same stimulation current. Still, the sum of supply and current-source power is typically between 20% and 75% of the conventional source power alone. Functionality of the proposed driver is verified experimentally on a proof-of-concept prototype built with 3.3 V devices in a 0.18 μm CMOS technology.


A scoping review of the psychological responses to interval exercise: is interval exercise a viable alternative to traditional exercise?
While considerable evidence suggests that interval exercise confers numerous physiological adaptations linked to improved health, its psychological consequences and behavioural implications are less clear and the subject of intense debate. The purpose of this scoping review was to catalogue studies investigating the psychological responses to interval exercise in order to identify what psychological outcomes have been assessed, the research methods used, and the results. A secondary objective was to identify research issues and gaps. Forty-two published articles met the review inclusion/exclusion criteria. These studies involved 1258 participants drawn from various active/inactive and healthy/unhealthy populations, and 55 interval exercise protocols (69% high-intensity interval training [HIIT], 27% sprint interval training [SIT], and 4% body-weight interval training [BWIT]). Affect and enjoyment were the most frequently studied psychological outcomes. Post-exercise assessments indicate that overall, enjoyment of, and preferences for interval exercise are equal or greater than for continuous exercise, and participants can hold relatively positive social cognitions regarding interval exercise. Although several methodological issues (e.g., inconsistent use of terminology, measures and protocols) and gaps (e.g., data on adherence and real-world protocols) require attention, from a psychological perspective, the emerging data support the viability of interval exercise as an alternative to continuous exercise.


Identification of an 85 kDa phosphoprotein as an immunodominant protein specific for human herpesvirus 7-infected cells.
The reactivity of human cord blood sera was directed most frequently in Western blot assays to a protein with an apparent molecular mass of 85 kDa that belongs to the p85 complex, a family of antigenically related proteins identified previously in our laboratory with the aid of two MAbs. We show that the 85 kDa protein is phosphorylated. As antibodies present in the human sera were directed in part to proteins carrying cross-reactive epitopes between human herpesvirus 6 (HHV-6) and 7 (HHV-7), it is remarkable that reactivity to the 85 kDa phosphoprotein was maintained after preabsorption of the sera with HHV-6 antigen, but abolished after preabsorption with HHV-7 antigen. Therefore, the 85 kDa phosphoprotein may be considered a major determinant of the human immune response to HHV-7, discriminating HHV-6 from HHV-7 infection.


Sanger and Next-Generation Sequencing data for characterization of CTL epitopes in archived HIV-1 proviral DNA.
One of the strategies for curing viral HIV-1 is a therapeutic vaccine involving the stimulation of cytotoxic CD8-positive T cells (CTL) that are Human Leucocyte Antigen (HLA)-restricted. The lack of efficiency of previous vaccination strategies may have been due to the immunogenic peptides used, which could be different from a patient's virus epitopes and lead to a poor CTL response. To counteract this lack of specificity, conserved epitopes must be targeted. One alternative is to gather as many data as possible from a large number of patients on their HIV-1 proviral archived epitope variants, taking into account their genetic background to select the best presented CTL epitopes. In order to process big data generated by Next-Generation Sequencing (NGS) of the DNA of HIV-infected patients, we have developed a software package called TutuGenetics. This tool combines an alignment derived either from Sanger or NGS files, HLA typing, target gene and a CTL epitope list as input files. It allows automatic translation after correction of the alignment obtained between the HxB2 reference and the reads, followed by automatic calculation of the MHC IC50 value for each epitope variant and the HLA allele of the patient by using NetMHCpan 3.0, resulting in a csv file as output result. We validated this new tool by comparing Sanger and NGS (454, Roche) sequences obtained from the proviral DNA of patients at success of ART included in the Provir Latitude 45 study and showed a 90% correlation between the quantitative results of NGS and Sanger. This automated analysis combined with complementary samples should yield more data regarding the archived CTL epitopes according to the patients' HLA alleles and will be useful for screening epitopes that in theory are presented efficiently to the HLA groove, thus constituting promising immunogenic peptides for a therapeutic vaccine.


Risk of Unsuccessful Noninvasive Ventilation for Acute Respiratory Failure in Heterogeneous Neuromuscular Diseases: A Retrospective Study.
If invasive ventilation can be avoided by performing noninvasive mechanical ventilation (NIV) in patients with acute respiratory failure (ARF), the disease can be effectively managed. It is important to clarify the characteristics of patients with neuromuscular diseases in whom initial NIV is likely to be unsuccessful. We studied 27 patients in stable neuromuscular condition who initially received NIV to manage fatal ARF to identify differences in factors immediately before the onset of ARF among patients who receive continuous NIV support, patients who are switched from NIV to invasive ventilation, and patients in whom NIV is discontinued. Endpoints were evaluated 24 and 72 hours after the initiation of NIV. After 24 hours, all but 1 patient with amyotrophic lateral sclerosis (ALS) received continuous NIV support. 72 hours later, 5 patients were switched from NIV to invasive ventilation, and 5 patients continued to receive NIV support. 72 hours after the initiation of NIV, the proportion of patients with a diagnosis of ALS differed significantly among the three groups (P=0.039). NIV may be attempted to manage acute fatal respiratory failure associated with neuromuscular diseases, but clinicians should carefully manage the clinical course in patients with ALS.


In vivo localized 1H NMR spectroscopy: an experimental characterization of the PRESS technique.
The aim of this study was the experimental characterization of the PRESS technique for image-guided in vivo 1H NMR spectroscopy, as implemented on a commercially available 1.5 T NMR whole-body system. Three characterization parameters were defined and evaluated in test object measurements: selection efficiency, suppression efficiency and contamination. The characterization parameters were evaluated in different experimental conditions. The profile of signal intensity across the volume of interest (VOI) was investigated. Our results show that the characterization parameters are slightly affected by the echo time, while they are not affected by changes in the repetition time. When the VOI is co-extensive with the inner cube of the test object the suppression efficiency is good but the selection efficiency is not very high. Contamination is affected by the synthesizer frequency offset, while the selection efficiency is quite stable. Contamination effects become significant in case of 90 degrees pulse maladjustment.


Crystal packing effects on protein loops.
The effects of crystal packing on protein loop structures are examined by (1) a comparison of loops in proteins that have been crystallized in alternate packing arrangements, and (2) theoretical prediction of loops both with and without the inclusion of the crystal environment. Results show that in a minority of cases, loop geometries are dependent on crystal packing effects. Explicit representation of the crystal environment in a loop prediction algorithm can be used to model these effects and to reconstruct the structures, and relative energies, of a loop in alternative packing environments. By comparing prediction results with and without the inclusion of the crystal environment, the loop prediction algorithm can further be used to identify cases in which a crystal structure does not represent the most stable state of a loop in solution. We anticipate that this capability has implications for structural biology.


Oligopin® Supplementation Mitigates Oxidative Stress in Postmenopausal Women with Osteopenia: A Randomized, Double-blind, Placebo-Controlled Trial.
Evidence indicates a close association between oxidative stress and the etiopathogenesis of osteopenia. In vitro and animal studies report that Oligopin®, an extract of French maritime pine bark extract, has beneficial effects on oxidative stress. Here, we aimed to determine whether supplementation with Oligopin® affects bone turnover markers, antioxidant enzymes, and oxidative stress markers in these patients. Forty-three postmenopausal women with osteopenia were randomized in a placebo-controlled, double-blind clinical trial to receive either 150 mg/day Oligopin® (n = 22) or placebo (n = 21) for 12 weeks. Plasma levels of bone turnover markers; osteocalcin (OC), type I collagen cross-linked C-telopeptide (CTX-1), OC/CTX1 ratio along with total antioxidant capacity(TAC), malondialdehyde (MDA) concentration, protein carbonyl, and total thiol contents in plasma, activities of manganese superoxide dismutase (MnSOD) and catalase in both peripheral blood mononuclear cells (PBMCs) and plasma as well as mRNA expression of MnSOD, catalase, and Nrf2 in PBMCs were measured at the baseline and the end of the intervention. Oligopin® supplementation significantly increased OC levels and the ratio of OC to CTX1 in women with osteopenia compared to placebo intervention after 12 weeks. Oligopin® significantly decreased plasma protein carbonyl content in postmenopausal women compared with the after placebo treatment. Moreover, Oligopin® intervention significantly increased plasma total thiol content, TAC, plasma activity of both MnSOD and catalase, and the transcript level of Nrf2, MnSOD, and catalase in comparison with the placebo group. Supplementation with 150 mg/day Oligopin® for 12 weeks exerts beneficial effects in postmenopausal osteopenia through improving the antioxidant defense system in the plasma and PBMCs that was accompanied by an increase in indicators of bone turnover.


Advocacy for active transport: advocate and city council perspectives.
Effective advocacy is an important part of efforts to increase population participation in physical activity. Research about effective health advocacy is scarce, however, the health sector can learn from the experiences and knowledge of community advocates and those who are on the receiving end of this advocacy. The aim of this study is to explore advocacy for active transport from the perspectives of community advocates and representatives from City councils. Cycling and walking advocates were identified from the local contact list of Cycling Advocates Network and Living Streets Aotearoa. Semi-structured telephone interviews were conducted with cycle and walking advocates from throughout New Zealand. Advocates also nominated a suitable council officer at their local City council to be interviewed. Interviews were recorded and transcribed and categories of responses for each of the questions created. Several processes were used by advocates to engage with council staff, including formal council submissions, meetings, stakeholder forums and partnership in running community events promoting active transport. Several other agencies were identified as being influential for active transport, some as potential coalition partners and others as potential adversaries. Barriers to improving conditions for active transport included a lack of funding, a lack of will-power among either council staff or councillors, limited council staff capacity (time or training) and a culture of providing infrastructure for motor vehicles instead of people. Several suggestions were made about how the health sector could contribute to advocacy efforts, including encouraging political commitment, engaging the media, communicating the potential health benefits of active transport to the general public and being role models in terms of personal travel mode choice and having workplaces that support participation in active transport. There is potential for the health sector to make an important contribution to advocacy for active transport in New Zealand. While there are many barriers to achieving supportive environments for cycling and walking, a range of advocacy strategies were identified which could help ensure that health perspectives are considered in decisions relevant to active transport.


[Parathormone and calcitonin in men suffering from ischemic heart disease].
It has been shown that in men with coronary heart disease (CHD), the basal concentrations of parathyroid hormone (PTH) and calcitonin (CT) in blood serum were increased both during an angina pectoris attack and the interparoxysmal period. During an angina pectoris attack, the highest CT concentration was detected in CHD patients with angina pectoris of effort on the day of the anginal attack. In acute myocardial infarction (AMI), the basal PTH level in the patients' blood serum was increased, particularly during the subacute disease stage. The blood serum CT content during AMI depended on the disease onset: in patients with a sudden disease onset, the parameter under study was increased, whereas in AMI patients with a history of angina pectoris, the CT concentration remained within normal. The authors discuss the pathogenetic role of the shifts in the function of the parathyroid glands and C cells of the thyroid during CHD and the possibility of the use of calcium antagonists and CT in the treatment of myocardial infarction.


Favorable survival observed after carboplatin, paclitaxel, and concurrent accelerated hyperfractionated radiotherapy for treatment of locally advanced head and neck carcinoma.
Several trials have demonstrated the superiority of simultaneous chemoradiotherapy compared with radiation alone for patients with locally advanced head and neck cancers. However, the optimal regimen remains to be defined. This study assessed the safety and activity of combined carboplatin (C), paclitaxel (P), and twice-daily radiotherapy (RT) in a community based, multicenter, phase II trial. Eligible patients (N = 52) had ECOG PS 0-2 and previously untreated, stage III or IV (M0), unresectable, squamous cell cancers of the head and neck. Treatment consisted of 6 weekly courses of C (AUC = 1), P (40 mg/m(2)/1-h) and twice-daily radiation (120 cGy BID; total dose of 6,960 cGy). Subsequently, patients with N2/N3 disease were permitted neck dissection. Median follow-up was 61 months. Sixty-seven percent (67%) of patients had stage IV (M0) disease at baseline. Fifty-five percent (55%) of treated patients experienced NCI Grade 3-4 dysphagia, stomatitis, or mucositis; 80% had > or = Grade 3 toxicity of any organ system. Median weight loss was 7.1 lbs; 35% of patients experienced 10% or more weight loss. Of 43 patients evaluable for response, responses were: 29 CR (67%), 7 PR (16%), 1 MR (2%), 4 SD (9%), and 2 PD (5%); the overall response rate (CR+PR) was 84%. For the entire cohort of 52 patients, the estimated overall survival at 36 months was 60%; progression-free survival was 50%. We conclude that weekly C + P and concurrent twice-daily hyperfractionated radiotherapy is tolerated and highly active in patients with unresectable, locally advanced squamous cell carcinoma of the head and neck.


Food Allergen Epitope Mapping.
With the increased global awareness and rise in food allergies, a multifold interest in food allergens is evident. The presence of undeclared food allergens results in expensive food recalls and increased risks of anaphylaxis for the sensitive individuals. Regardless of the allergenic food, the immunogen needs to be identified and detected before making any efforts to inactivate/eliminate it. In type I food allergies, protein immunogen cross-links immunoglobulin E, leading to basophil/mast cell degranulation, resulting in the symptoms that range from mild irritation to anaphylaxis. A portion/part of the protein, known as the epitope, can interact with either antibodies to elicit allergic reactions or T-cell receptors to initiate allergic sensitization. Antibody-recognized epitopes can be either a linear sequence of amino acids (linear epitope) or a three-dimensional motif (conformational epitope), while T-cell-receptor-recognized epitopes are exclusively linear peptides. Identifying and characterizing human-allergy-relevant epitopes are important for allergy diagnosis/prognosis, immunotherapy, and developing food processing methods that can reduce/eliminate immunogencity/immunoreactivity of the allergen.


Association of thyroid hormones and white matter hyperintensity in patients without intracranial arterial stenosis.
Thyroid hormones play important roles in most organs, including the brain. This study aimed to explore the association between thyroid hormones and the severity of white matter hyperintensities (WMH) in patients without intracranial arterial stenosis, which is a common manifestation in the brain. This retrospective study included 304 patients at the Department of Neurology in Nantong First People's Hospital between June 2018 and June 2020. Thyroid hormone levels and other laboratory data were collected on the day after admission. The patients were divided into two WMH burden groups based on Fazekas scores as follows: ''mild-moderate group'' and ''severe group.' The severe WMH group had higher ages (P=0.000), higher serum concentration of fibrinogen (P=0.040), higher concentration of creatinine (P=0.040), lower concentration of low-density lipoprotein (P=0.013), and higher concentration of free thyroxine (FT4) (P=0.003). The prevalence of cerebral microbleeds (CMBs) increased with increasing quartiles (P=0.023). Multivariable logistic regression and ordinal regression analysis showed that higher concentrations of FT4, age, and CMBs were also independent risk factors for severe WMH. The concentrations of FT4 were grouped according quartiles. The results showed that the prevalence of severe WMH increased with higher quartiles. This correlation persisted after adjusting for risk factors such as sex, age, history of hypertension, diabetes, drinking history, and smoking history. Our results support the hypothesis that FT4 is associated with the severity of WMH in patients without intracranial arterial stenosis. In addition, age and CMBs are independently related to the severity of WMH.


Nonfluoroscopic localization of an amagnetic stimulation catheter by multichannel magnetocardiography.
This study was performed to: (1) evaluate the accuracy of noninvasive magnetocardiographic (MCG) localization of an amagnetic stimulation catheter; (2) validate the feasibility of this multipurpose catheter; and (3) study the characteristics of cardiac evoked fields. A stimulation catheter specially designed to produce no magnetic disturbances was inserted into the heart of five patients after routine electrophysiological studies. The catheter position was documented on biplane cine x-ray images. MCG signals were then recorded in a magnetically shielded room during cardiac pacing. Noninvasive localization of the catheter's tip and stimulated depolarization was computed from measured MCG data using a moving equivalent current-dipole source in patient-specific boundary element torso models. In all five patients, the MCG localizations were anatomically in good agreement with the catheter positions defined from the x-ray images. The mean distance between the position of the tip of the catheter defined from x-ray fluoroscopy and the MCG localization was 11 +/- 4 mm. The mean three-dimensional difference between the MCG localization at the peak stimulus and the MCG localization, during the ventricular evoked response about 3 ms later, was 4 +/- 1 mm calculated from signal-averaged data. The 95% confidence interval of beat-to-beat localization of the tip of the stimulation catheter from ten consecutive beats in the patients was 4 +/- 2 mm. The propagation velocity of the equivalent current dipole between 5 and 10 ms after the peak stimulus was 0.9 +/- 0.2 m/s. The results show that the use of the amagnetic catheter is technically feasible and reliable in clinical studies. The accurate three-dimensional localization of this multipurpose catheter by multichannel MCG suggests that the method could be developed toward a useful clinical tool during electrophysiological studies.


Dietary rescue of lipotoxicity-induced mitochondrial damage in Peroxin19 mutants.
Mutations in peroxin (PEX) genes lead to loss of peroxisomes, resulting in the formation of peroxisomal biogenesis disorders (PBDs) and early lethality. Studying PBDs and their animal models has greatly contributed to our current knowledge about peroxisomal functions. Very-long-chain fatty acid (VLCFA) accumulation has long been suggested as a major disease-mediating factor, although the exact pathological consequences are unclear. Here, we show that a Drosophila Pex19 mutant is lethal due to a deficit in medium-chain fatty acids (MCFAs). Increased lipolysis mediated by Lipase 3 (Lip3) leads to accumulation of free fatty acids and lipotoxicity. Administration of MCFAs prevents lipolysis and decreases the free fatty acid load. This drastically increases the survival rate of Pex19 mutants without reducing VLCFA accumulation. We identified a mediator of MCFA-induced lipolysis repression, the ceramide synthase Schlank, which reacts to MCFA supplementation by increasing its repressive action on lip3. This shifts our understanding of the key defects in peroxisome-deficient cells away from elevated VLCFA levels toward elevated lipolysis and shows that loss of this important organelle can be compensated by a dietary adjustment.


Public-health education at Kansas State University.
What are veterinary medical and public-health professionals doing to remedy the immediate and impending shortages of veterinarians in population health and public practice? This question was addressed at the joint symposium of the Association of American Veterinary Medical Colleges and the Association of Schools of Public Health, held in April 2007. Thinking locally, faculty and students at Kansas State University (KSU) asked similar questions after attending the symposium: What are we doing within the College of Veterinary Medicine to tackle this problem? What can we do better with new collaborators? Both the professional veterinary curriculum and the Master of Public Health (MPH) at KSU provide exceptional opportunities to address these questions. Students are exposed to public health as a possible career choice early in veterinary school, and this exposure is repeated several times in different venues throughout their professional education. Students also have opportunities to pursue interests in population medicine and public health through certificate programs, summer research programs, study abroad, and collaborations with contributing organizations unique to KSU, such as its Food Science Institute, National Agricultural Biosecurity Center, and Biosecurity Research Institute. Moreover, students may take advantage of the interdisciplinary nature of public-health education at KSU, where collaborations with several different colleges and departments within the university have been established. We are pleased to be able to offer these opportunities to our students and hope that our experience may be instructive for the development of similar programs at other institutions, to the eventual benefit of the profession at large.


Structure-activity relationships of methoxychalcones as inducers of heme oxygenase-1.
Chalcones are naturally occurring flavonoids composed of two aromatic rings connected by a three-carbon unit forming an alpha-beta unsaturated carbonyl group. They are pharmacologically relevant because of their ability to exert anticarcinogenic, antimicrobial, and anti-inflammatory activities. Recent evidence indicates that the bioactivity of hydroxy-chalcones is correlated with their intrinsic property to induce the antioxidant and cytoprotective enzyme heme oxygenase-1 (HO-1). In the present study, we assessed how the methoxy substituents positioned on the two aromatic rings affect the anti-inflammatory action of different chalcones in relation to their ability to increase heme oxygenase in RAW246.7 macrophages. Structure-activity relationships of methoxychlacones were qualitatively and quantitatively examined and correlated with inhibition of endotoxin-mediated nitrite production and cytotoxic effects. Our data indicate that (i) a progressive increase in heme oxygenase activity is obtained by sequentially increasing the number of methoxy substituents in the 3,4,5- and 3',4',5'-positions of the aromatic rings; (ii) methoxy substituents placed either in the 2,4,6-positions or alone in the 4- or 4'-position are ineffective; (iii) increased heme oxygenase activity by chalcones is lost when the alpha-beta double bond and the carbonyl group are reduced or protected; (iv) the anti-inflammatory activity and cytotoxicity profiles of the chalcones examined correlate with their potency as HO-1 inducers; and (v) chalcone-mediated HO-1 induction is reduced by thiols or inhibitors of phosphatidylinositol-3 kinase (PI3K) pathway. This study provides additional information on the structural features that methoxychalcones and natural antioxidants need to possess to be considered as therapeutic agents for maximizing HO-1 expression and activity.


The Role of Simulation in Surgical Education.
The current healthcare environment demands optimization of patient outcomes in addition to maximal cost efficiency. Restrictions on resident work hours have placed limitations on the amount of time that trainee physicians can spend on patient care. For the surgery resident, the consequence is less time spent in the operating room under the supervision of a senior surgeon, the cornerstone of Halsted's approach to resident surgeon education. The use of simulation in graduate medical education has gained significant traction as a way to provide trainees with exposure to various techniques and procedures before use on the general patient population. This article describes simulation-based education with particular attention to surgical education. It proceeds to address competency-based education and mastery learning (ML) as key features of effective surgery education programs. A case study of ML in surgery is presented along with examples of translational medical education science from other medical specialties. The report concludes with a brief discussion about simulation-based surgical education today and prospects for the future.


Quantitative determination of DRF-1042 in human plasma by HPLC: validation and application in clinical pharmacokinetics.
A simple and sensitive high-performance liquid chromatography (HPLC) method has been developed and validated for the determination of DRF-1042, a novel orally active camptothecin (CPT) analog, in human plasma. The sample preparation was a simple deproteinization with acidified methanol yielding almost 100% recovery of DRF-1042. An isocratic reverse-phase HPLC separation was developed on a Supelcosil-LC318 column (250 x 4.6 mm, 5 microm) with mobile phase consisting of 1% v/v triethylamine acetate, pH 5.5 and acetonitrile (80:20, v/v) at a fl ow rate of 1.0 mL/min. The eluate was monitored with a fluorescence detector set at excitation and emission wavelengths of 370 and 430 nm, respectively. The standard curves were linear (r(2) > 0.999) in the concentration ranges 5.0-2004 ng/mL. The lower limit of quantification (LLQ) of the assay was 5 ng/mL. The mean measured quality control (QC) concentrations (range 5 ng/mL to 40 microg/mL) deviated from the nominal concentrations in the range of -10.5-0.08 and -14.5-7.97%, inter- and intra-day, respectively. The inter- and intra-day precisions in the measurement of QC samples at four tested concentrations, were in the range 0.64-5.89% relative standard deviation (RSD) and 0.33-14.7% RSD, respectively. The method was found to be suitable for measurement of plasma concentrations above the calibration curve after serial dilutions. Stability of DRF-1042 was confirmed in a battery of studies, viz., on bench-top, in the auto-sampler, in the stock solutions, after four quick freeze-thaw cycles, up to one month at -20 degree C in human plasma and up to 2 months in the ex vivo samples. The method is simple, sensitive and reliable and has been successfully implemented to investigate the clinical pharmacokinetics of DRF-1042 in cancer patients in a phase I clinical trial.


Ulcerative colitis impairs the acylethanolamide-based anti-inflammatory system reversal by 5-aminosalicylic acid and glucocorticoids.
Studies in animal models and humans suggest anti-inflammatory roles on the N-acylethanolamide (NAE)-peroxisome proliferators activated receptor alpha (PPARα) system in inflammatory bowel diseases. However, the presence and function of NAE-PPARα signaling system in the ulcerative colitis (UC) of humans remain unknown as well as its response to active anti-inflammatory therapies such as 5-aminosalicylic acid (5-ASA) and glucocorticoids. Expression of PPARα receptor and PPARα ligands-biosynthetic (NAPE-PLD) and -degrading (FAAH and NAAA) enzymes were analyzed in untreated active and 5-ASA/glucocorticoids/immunomodulators-treated quiescent UC patients compared to healthy human colonic tissue by RT-PCR and immunohistochemical analyses. PPARα, NAAA, NAPE-PLD and FAAH showed differential distributions in the colonic epithelium, lamina propria, smooth muscle and enteric plexus. Gene expression analysis indicated a decrease of PPARα, PPARγ and NAAA, and an increase of FAAH and iNOS in the active colitis mucosa. Immunohistochemical expression in active colitis epithelium confirmed a PPARα decrease, but showed a sharp NAAA increase and a NAPE-PLD decrease, which were partially restored to control levels after treatment. We also characterized the immune cells of the UC mucosa infiltrate. We detected a decreased number of NAAA-positive and an increased number of FAAH-positive immune cells in active UC, which were partially restored to control levels after treatment. NAE-PPARα signaling system is impaired during active UC and 5-ASA/glucocorticoids treatment restored its normal expression. Since 5-ASA actions may work through PPARα and glucocorticoids through NAE-producing/degrading enzymes, the use of PPARα agonists or FAAH/NAAA blockers that increases endogenous PPARα ligands may yield similar therapeutics advantages.


Proton magnetic resonance spectroscopy (1H-MRS) of the cerebrum in two young infants with Zellweger syndrome.
Cerebral metabolic abnormalities have been previously detected by 1H-MRS in infants with the Zellweger syndrome as young as 3 months. We hypothesized that metabolic abnormalities could also be found shortly after birth. Two fullterm infants with Zellweger syndrome were studied at 12 days and two months of age, respectively, using single voxel 1H-MRS. In the first case 1H-MRS was performed using PRESS with variable TE (31, 136, 272 ms); in the second, STEAM and PRESS sequences were used with different TE (STEAM at 30 and 144 ms; PRESS at 270 ms). In both cases a significant decrease of N-acetylaspartate (NAA) and an abnormal signal at 1.33 and 0.9 ppm, consisting of lactate (Lac) and lipids (Lip) were found. The reported MRS abnormalities, although not specific for peroxisomal dysfunctions, may support the suspicion of Zellweger syndrome and may indicate direct referral to the specific laboratory and molecular studies necessary to establish the diagnosis and prognosis of this syndrome.


Prevalence and incidence of primary hyperparathyroidism in Bahrain: A retrospective study from one medical center.
Primary hyperparathyroidism (PHPT) is considered the third endocrine disorder worldwide. However, the incidence of PHPT is variable in different populations. Since there are no studies on PHPT performed in Bahrain or the surrounding Arab Middle Eastern countries, this study aimed to determine the prevalence and incidence of PHPT and its variants in Bahrain. A retrospective study was conducted over a 3-year period (2018-2020) at the Bahrain Defense Force Military Hospital. Patients' data with normal kidney function, age 14 years and older, and had related laboratory results (calcium, PTH, phosphorus, and vitamin D) were retrieved and analyzed for prevalence and incidence of hypercalcemia and PHPT according to age and sex. Out of 9650 patients, 417 patients had corrected hypercalcemia. Of these, 240, 125, and 88 patients per 100,000 had classic, non-classic, or early/normocalcemic PHPT, respectively. These numbers resulted in a prevalence of PHPT of 274 per 100,000 in Bahrain. The age-adjusted incidence of all types of PHPT was 179 per 100,000/year. Overall, PHPT incidence, whether classic or not, significantly increased in the 50 years age group and above (OR 1.023 with 95% CI 1.013-1.033). Furthermore, hypercalcemia and non-classic PHPT were predominant in females than males. Lastly, vitamin D level was significantly less in classic PHPT than the non-classic variant. The high prevalence and incidence of PHPT should alarm physicians and clinical practices in Bahrain and the Middle East region to investigate routinely for classic and non-classic PHPT to control and manage the complications that arise from PHPT. However, more epidemiological studies in the Middle East region are warranted to investigate the reasons behind the high incidence of PHPT.


Pregnancy complications and obstetric care in women with inherited bleeding disorders.
Women with inherited bleeding disorders (IBD) require the input of a multidisciplinary team to improve outcomes of pregnancy. The role of the haemophilia nurse within the multidisciplinary team is to provide educational and emotional support to the women and to facilitate and co-ordinate patient-centred care. Prenatal diagnosis in cases of haemophilia is an integral part of the management of early pregnancy with a recent drive towards non-invasive prenatal diagnostic techniques. There is a current lack of data on the risk of miscarriage and bleeding complications during pregnancy. A clear association has only been established in women with fibrinogen and factor XIII deficiency. In the affected neonate with severe bleeding disorders such as haemophilia, the risk of head bleeding is significant, and appropriate management of labour and delivery has an important impact on reducing the risk. Women with IBD are at risk of both primary and secondary postpartum haemorrhage. Appropriate risk assessment and advance planning for haemostatic cover can reduce the bleeding risk.


A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer and other neuroendocrine tumors.
Small cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer with high mortality. We used a systematic drug repositioning bioinformatics approach querying a large compendium of gene expression profiles to identify candidate U.S. Food and Drug Administration (FDA)-approved drugs to treat SCLC. We found that tricyclic antidepressants and related molecules potently induce apoptosis in both chemonaïve and chemoresistant SCLC cells in culture, in mouse and human SCLC tumors transplanted into immunocompromised mice, and in endogenous tumors from a mouse model for human SCLC. The candidate drugs activate stress pathways and induce cell death in SCLC cells, at least in part by disrupting autocrine survival signals involving neurotransmitters and their G protein-coupled receptors. The candidate drugs inhibit the growth of other neuroendocrine tumors, including pancreatic neuroendocrine tumors and Merkel cell carcinoma. These experiments identify novel targeted strategies that can be rapidly evaluated in patients with neuroendocrine tumors through the repurposing of approved drugs. Our work shows the power of bioinformatics-based drug approaches to rapidly repurpose FDA-approved drugs and identifies a novel class of molecules to treat patients with SCLC, a cancer for which no effective novel systemic treatments have been identified in several decades. In addition, our experiments highlight the importance of novel autocrine mechanisms in promoting the growth of neuroendocrine tumor cells.


[The effect of lead on cells cultivated in vitro. I. Acute effects (author's transl)].
Static suspension cultures of L-A cells, a subline of L929 mouse fibroblasts, were exposed to inorganic lead salts. Lead caused a growth inhibition which was independent of the anion used and which could be prevented by the addition of Ca-EDTA. The LD50 was approximately 1 mM when exposing the cells for 2 days and 2 X 10(-4) M when treating them for 7 days. The minimal growth inhibiting dose was in the range of 2 to 4 X 10(-5) M. Concomitant with the dose-dependent inhibition of proliferation the fraction of cells synthesizing DNA and the mitotic rate were lowered, suggesting a block in the G1 phase of the cell cycle. Energy metabolism appeared affected as evidenced by a rise in lactate production. Lactate dehydrogenase release was in the control range. Lead induced an increase in cell size and, at higher concentrations, cellular vacuolations.


Circadian rhythmicity of active GSK3 isoforms modulates molecular clock gene rhythms in the suprachiasmatic nucleus.
The suprachiasmatic nucleus (SCN) drives and synchronizes daily rhythms at the cellular level via transcriptional-translational feedback loops comprising clock genes such as Bmal1 and Period (Per). Glycogen synthase kinase 3 (GSK3), a serine/threonine kinase, phosphorylates at least 5 core clock proteins and shows diurnal variation in phosphorylation state (inactivation) of the GSK3β isoform. Whether phosphorylation of the other primary isoform (GSK3α) varies across the subjective day-night cycle is unknown. The purpose of this study was to determine if the endogenous rhythm of GSK3 (α and β) phosphorylation is critical for rhythmic BMAL1 expression and normal amplitude and periodicity of the molecular clock in the SCN. Significant circadian rhythmicity of phosphorylated GSK3 (α and β) was observed in the SCN from wild-type mice housed in constant darkness for 2 weeks. Importantly, chronic activation of both GSK3 isoforms impaired rhythmicity of the GSK3 target BMAL1. Furthermore, chronic pharmacological inhibition of GSK3 with 20 µM CHIR-99021 enhanced the amplitude and shortened the period of PER2::luciferase rhythms in organotypic SCN slice cultures. These results support the model that GSK3 activity status is regulated by the circadian clock and that GSK3 feeds back to regulate the molecular clock amplitude in the SCN.


Myopic foveoschisis: a clinical review.
To review the literature on epidemiology, clinical features, diagnostic imaging, natural history, management, therapeutic approaches, and prognosis of myopic foveoschisis. A systematic Pubmed search was conducted using search terms: myopia, myopic, staphyloma, foveoschisis, and myopic foveoschisis. The evidence base for each section was organised and reviewed. Where possible an authors' interpretation or conclusion is provided for each section. The term myopic foveoschisis was first coined in 1999. It is associated with posterior staphyloma in high myopia, and is often asymptomatic initially but progresses slowly, leading to loss of central vision from foveal detachment or macular hole formation. Optical coherence tomography is used to diagnose the splitting of the neural retina into a thicker inner layer and a thinner outer layer, but compound variants of the splits have been identified. Vitrectomy with an internal limiting membrane peel and gas tamponade is the preferred approach for eyes with vision decline. There has been a surge of new information on myopic foveoschisis. Advances in optical coherence tomography will continually improve our understanding of the pathogenesis of retinal splitting, and the mechanisms that lead to macular damage and visual loss. Currently, there is a good level of consensus that surgical intervention should be considered when there is progressive visual decline from myopic foveoschisis.


Direct polymerase chain reaction detection of Campylobacter jejuni and Campylobacter coli in raw milk and dairy products.
A polymerase chain reaction (PCR) method designed to sensitively detect and identify Campylobacter jejuni and Campylobacter coli without the need for isolating and culturing strains is described. The intergenic sequence between the flagellin genes flaA and flaB was amplified and characterized with a triple primer or seminested primer approach. A total of 50 bacterial strains, 27 of C. jejuni and C. coli and 23 of other species, were tested, giving no false-positive or false-negative results. The detection limit as determined by ethidium bromide staining of amplification products on agarose gels was 10 bacteria or less in artificially contaminated water, milk, and soft cheese samples with the seminested primer PCR assay. As an application of the PCR system, a set of 93 samples of milk and other dairy products was screened for the presence of C. jejuni and C. coli. We identified six positive samples (6.5%), while none were found with a conventional culture method.


Early exposure to intermediate-frequency magnetic fields alters brain biomarkers without histopathological changes in adult mice.
Recently we have reported that intermediate-frequency magnetic field (IF-MF) exposure transiently altered the mRNA expression levels of memory function-related genes in the hippocampi of adult male mice. However, the effects of IF-MF exposure during brain development on neurological biomarkers have not yet been clarified. In the present study, we investigated the effect of IF-MF exposure during development on neurological and immunological markers in the mouse hippocampus in 3- and 7-week-old male mice. Pregnant C57BL/6J mice were exposed to IF-MF (21 kHz, 3.8 mT) for one hour per day from organogenesis period day 7 to 17. At adolescence, some IF-MF-exposed mice were further divided into exposure, recovery, and sham-exposure groups. The adolescent-exposure groups were exposed again to IF-MF from postnatal day 27 to 48. The expression of mRNA in the hippocampi was examined using a real-time RT-PCR method, and microglia activation was examined by immunohistochemical analysis. The expression levels of NR1 and NR2B as well as transcription factors (CaMKIV, CREB1), inflammatory mediators (COX2, IL-1 b,TNF-α), and the oxidative stress marker heme-oxygenase (HO)-1 were significantly increased in the IF-MF-exposed mice, compared with the control group, in the 7-week-old mice, but not in the 3-week-old mice. Microglia activation was not different between the control and other groups. This study provides the first evidence that early exposure to IF-MF reversibly affects the NMDA receptor, its related signaling pathways, and inflammatory mediators in the hippocampus of young adult mice; these changes are transient and recover after termination of exposure without histopathological changes.


Ascites in chronic leukemia: a case report and review of the literature.
Ascites is a common manifestation of solid tumors, but is unusual secondary to reticuloendothelial and lymphoproliferative malignancies. This report describes a case of chronic lymphocytic leukemia whose relapse was heralded by splenomegaly with massive ascites. A 2,750 g spleen was removed which showed extensive infiltration with lymphocytes. The portal areas of the liver were similarly infiltrated. This hepatic and splenic involvement most likely produced portal hypertension which resulted in ascites. The formation of ascites in such patients heralds a short survival, since it is probably one of the manifestations of the accelerated form of the disease.


Health Is not always written in bone: using a modern comorbidity index to assess disease load in paleopathology.
Paleopathology has revealed much about disease in the past but is usually limited to conditions with osteological manifestations; this often excludes acute soft tissue infections and causes of death for most individuals in the past and present. Our understanding of the evolution of disease is essential for contextualizing and predicting the epidemiological shifts that are happening in modern society, as high rates of infectious disease coexist alongside high rates of chronic disease in rates unlike those observed previously in human history. Moreover, many physiological states not previously classified as "disease" (obesity) have become pathologized, influencing our conception of disease and what defines health. By using the Galler Collection, a pre-antibiotic and pre-chemotherapeutic osteological series with modern autopsy records, our research quantifies disease burden of the past using the Charlson Index (CI), a modern comorbidity index of disease severity. Galler Collection remains and autopsy records were scored with the Charlson Index to correlate bone findings with soft tissue findings, and statistical analysis was performed for cumulative scores and absolute diagnosis counts, with patients stratified by sex and cause of death (pneumonia or cancer). Osteological diagnosis counts were more predictive of soft-tissue autopsy disease counts than were associated cumulative CI scores. Diagnosis counts and CI scores for osteological data were more closely related to associated soft tissue data for cancer patients than for pneumonia patients. This research indicates how interdisciplinary paleopathological analysis assists in making more reliable assessments of health and mortality in the past, with implications for trending and predicting future epidemiological shifts.


Resolution of recalcitrant molluscum contagiosum virus lesions in human immunodeficiency virus-infected patients treated with cidofovir.
Molluscum contagiosum virus (MCV) causes cutaneous skin growths that mainly affect children, sexually active adults, and immunocompromised individuals. Lesions of MCV in patients infected with human immunodeficiency virus can be large and numerous, and response to available treatments is often unsatisfactory. We describe 3 men infected with human immunodeficiency virus who presented with extensive MCV lesions that were not responsive to various treatments. Patient 1 demonstrated dramatic clearing of his MCV lesions when intravenous cidofovir therapy was started for his treatment-resistant bilateral CMV retinitis and because of cidofovir's possible activity against MCV. In case 2, cidofovir was compounded as a 3% cream in a combination vehicle (Dermovan) for extensive facial involvement, and complete resolution of MCV was seen after 1 month of therapy. In case 3, intravenous cidofovir therapy was started both for CMV retinitis and in an attempt to clear 90% facial MCV involvement; after 1 month of treatment, all clinical evidence of MCV had resolved. All 3 patients remain clear of recurrence. Cidofovir, a nucleotide analog of deoxycytidine monophosphate, appears to have contributed to clearing of advanced MCV lesions in these 3 patients, thus providing suggestive evidence of clinical activity against MCV. Controlled trials of cidofovir therapy for MCV in persons infected with human immunodeficiency virus are warranted.


Buchwald Hartwig diversification of unprotected halotryptophans, halotryptophan containing tripeptides and the natural product barettin in aqueous conditions.
Blending synthetic biology and synthetic chemistry represents a powerful approach to diversity complex molecules. To further enable this, compatible synthetic tools are needed. We report the first Buchwald Hartwig amination reactions with unprotected halotryptophans under aqueous conditions and demonstrate this methodology is applicable also to the modification of unprotected tripeptides and the natural product barettin.


Two threonine residues in the M2 segment of the alpha 1 beta 1 GABAA receptor are critical for ion channel function.
The role of three threonine residues in the M2 hydrophobic region of the GABAA receptor has been investigated by replacing these polar residues with alanine at the 6', 10' and 13' positions of M2 in the GABAA alpha 1, and beta 1 subunits and co-expressing the mutated subunits in the baculovirus Sf9 insect cell system. GABA did not elicit a current in cells expressing either the 6' or 13' threonine to the alanine mutants. The mutant subunits formed intact heteromeric GABAA receptors as judged by the binding of [3H] muscimol or the relative level of alpha 1 protein present in the plasma membrane. In contrast, a chloride current was generated by GABA in cells expressing the 10' mutant receptor. However, the current decayed more rapidly to baseline in the continued presence of GABA in the 10' mutant receptor than in the wild type receptor. The results are discussed in terms of the possible roles of the threonine residues in the ion conduction pathway.


Development, anatomy, histology, lymphatic drainage, clinical features, and cell differentiation markers of canine mammary gland neoplasms.
Mammary neoplasms are the most common neoplasm in female dogs. This article describes the embryologic development, normal anatomy, and histology of the canine mammary gland from the onset of first estrous and the changes that occur in the mammary gland during the estrus cycle. The clinical features of canine mammary gland tumors and their relation to prognosis are discussed, including age, hormones, breed, diet, and obesity. Additional clinical prognostic factors including clinical presentation, tumor size, and lymph node status at the time of presentation are discussed in relation to diagnosis and tumor staging. Immunohistochemical evaluation of the cell differentiation markers of the normal and neoplastic canine mammary gland is described and compared with similar studies in humans; the ways these markers may be used to assist with the prognosis of canine mammary neoplasms are discussed.


Regulation of fructose uptake and catabolism by succinate in Azospirillum brasilense.
Fructose uptake and catabolism in Azospirillum brasilense is dependent on three fructose-inducible enzymes (fru-enzymes): (i) enzyme I and (ii) enzyme II of the phosphoenolpyruvate:fructose phosphotransferase system and (iii) 1-phosphofructokinase. In minimal medium containing 3.7 mM succinate and 22 mM fructose as sources of carbon, growth of A. brasilense was diauxic, succinate being utilized in the first phase of growth and fructose in the second phase with a lag period between the two growth phases. None of the fru-enzymes could be detected in cells grown with succinate as the sole source of carbon, but they were detectable toward the end of the first phase of diauxie. All the fru-enzymes were coinduced by fructose and coordinately repressed by succinate. Studies on the effect of succinate on differential rates of syntheses of the fru-enzymes revealed that their induced syntheses in fructose minimal medium were subject to transient as well as permanent (catabolite) repression by succinate. Succinate also caused a similar pattern of transient and permanent repression of the fructose transport system in A. brasilense. However, no inducer (fructose) exclusionlike effect was observed as there was no inhibition of fructose uptake in the presence of succinate with fructose-grown cells even when they were fully induced for succinate uptake activity.


Clinical Significance of Totally Laparoscopic Distal Gastrectomy: A Comparison of Short-term Outcomes Relative to Open and Laparoscopic-assisted Distal Gastrectomy.
Laparoscopic distal gastrectomy has become an established minimally invasive treatment for gastric cancer since it was first reported in 1994. We retrospectively assessed the clinical outcomes of 248 patients who had undergone open distal gastrectomy (ODG), laparoscopic-assisted distal gastrectomy (LADG), and totally laparoscopic distal gastrectomy (TLDG) for gastric cancer. TLDG showed superiority in terms of blood loss, reconstruction options, and postoperative recovery compared with ODG and LADG. Especially, the mean operating time in the TLDG group was significantly shorter than that of the LADG group (P=0.003). Book-binding technique used in TLDG was one of the reasons of this result. The only inferior aspect of TLDG was the longer operating time compared with ODG; TLDG had no disadvantages compared with LADG. Although the operating time and long-term outcome remain problems, we suggest that TLDG has the potential to serve as an optimal operative method.


Effects of Multi-Point Contacts during Object Contour Scanning Using a Biologically-Inspired Tactile Sensor.
Vibrissae are an important tactile sense organ of many mammals, in particular rodents like rats and mice. For instance, these animals use them in order to detect different object features, e.g., object-distances and -shapes. In engineering, vibrissae have long been established as a natural paragon for developing tactile sensors. So far, having object shape scanning and reconstruction in mind, almost all mechanical vibrissa models are restricted to contact scenarios with a single discrete contact force. Here, we deal with the effect of multi-point contacts in a specific scanning scenario, where an artificial vibrissa is swept along partly concave object contours. The vibrissa is modeled as a cylindrical, one-sided clamped Euler-Bernoulli bending rod undergoing large deflections. The elasticae and the support reactions during scanning are theoretically calculated and measured in experiments, using a spring steel wire, attached to a force/torque-sensor. The experiments validate the simulation results and show that the assumption of a quasi-static scanning displacement is a satisfying approach. Beyond single- and two-point contacts, a distinction is made between tip and tangential contacts. It is shown that, in theory, these contact phases can be identified solely based on the support reactions, what is new in literature. In this way, multipoint contacts are reliably detected and filtered in order to discard incorrectly reconstructed contact points.


Which renal transplant patients should receive cytomegalovirus immune globulin? A cost-effectiveness analysis.
Our study objective was to determine the cost-effectiveness of prophylaxis with cytomegalovirus immune globulin for preventing CMV-associated disease in renal transplant patients. We used a decision analytic model applied to 5 groups of renal transplant recipients at varying risks of developing CMV-associated disease. We obtained the rates of developing CMV-associated disease, graft rejection, and mortality, and the effectiveness of CMV-IG from the published literature. We used actual variable costs of CMV-IG, hospitalization, dialysis, and outpatient follow-up. The incremental cost of administering CMV-IG compared with withholding it ranged from $29,800 per life saved for the highest risk group, CMV-seronegative recipients of kidneys from CMV-seropositive cadaveric donors, to $1.68 million per additional life saved for the lowest risk group, CMV-seronegative recipients of grafts from CMV-seronegative donors. The outcome was somewhat sensitive to the effectiveness of CMV-IG in preventing CMV-associated disease but not sensitive to wide variations in CMV-IG costs, dialysis costs, outpatient costs, and the probability of graft rejection. Our conclusion is that prophylaxis with CMV-IG is very worthwhile for renal transplant recipients at high risk of CMV-associated disease and is possibly worthwhile for some patients at lower risk. The cost-effectiveness of other strategies for preventing CMV-associated disease, such as prophylaxis with acyclovir, CMV vaccine, or unselected immune globulin, should be compared with CMV-IG.


Menopausal hormones and breast cancer in a biracial population.
This study examined the association between menopausal hormones and breast cancer in a biracial population. Logistic regression was used to calculate odds ratios for breast cancer associated with hormone use among 397 cases and 425 controls, all menopausal women. Odds ratios for ever use of hormones were 0.8 (95% confidence interval [CI] = 0.5, 1.2) for White women and 0.7 (95% CI = 0.4, 1.2) for Black women. Risk was not increased with longer duration of use or more recent use. Breast cancer risk was not increased among White or Black women who used menopausal hormones, despite patterns of use varying considerably between races.


Metal-Organic Frameworks Mediate Cu Coordination for Selective CO2 Electroreduction.
The electrochemical carbon dioxide reduction reaction (CO2RR) produces diverse chemical species. Cu clusters with a judiciously controlled surface coordination number (CN) provide active sites that simultaneously optimize selectivity, activity, and efficiency for CO2RR. Here we report a strategy involving metal-organic framework (MOF)-regulated Cu cluster formation that shifts CO2 electroreduction toward multiple-carbon product generation. Specifically, we promoted undercoordinated sites during the formation of Cu clusters by controlling the structure of the Cu dimer, the precursor for Cu clusters. We distorted the symmetric paddle-wheel Cu dimer secondary building block of HKUST-1 to an asymmetric motif by separating adjacent benzene tricarboxylate moieties using thermal treatment. By varying materials processing conditions, we modulated the asymmetric local atomic structure, oxidation state and bonding strain of Cu dimers. Using electron paramagnetic resonance (EPR) and in situ X-ray absorption spectroscopy (XAS) experiments, we observed the formation of Cu clusters with low CN from distorted Cu dimers in HKUST-1 during CO2 electroreduction. These exhibited 45% C2H4 faradaic efficiency (FE), a record for MOF-derived Cu cluster catalysts. A structure-activity relationship was established wherein the tuning of the Cu-Cu CN in Cu clusters determines the CO2RR selectivity.


Genome-Wide Association Study of Pericardial Fat Area in 28 161 UK Biobank Participants.
BACKGROUND Pericardial adipose tissue (PAT) is the visceral adipose tissue compartment surrounding the heart. Experimental and observational research has suggested that greater PAT deposition might mediate cardiovascular disease, independent of general or subcutaneous adiposity. We characterize the genetic architecture of adiposity-adjusted PAT and identify causal associations between PAT and adverse cardiac magnetic resonance imaging measures of cardiac structure and function in 28 161 UK Biobank participants. METHODS AND RESULTS The PAT phenotype was extracted from cardiac magnetic resonance images using an automated image analysis tool previously developed and validated in this cohort. A genome-wide association study was performed with PAT area set as the phenotype, adjusting for age, sex, and other measures of obesity. Functional mapping and Bayesian colocalization were used to understand the biologic role of identified variants. Mendelian randomization analysis was used to examine potential causal links between genetically determined PAT and cardiac magnetic resonance-derived measures of left ventricular structure and function. We discovered 12 genome-wide significant variants, with 2 independent sentinel variants (rs6428792, P=4.20×10-9 and rs11992444, P=1.30×10-12) at 2 distinct genomic loci, that were mapped to 3 potentially causal genes: T-box transcription factor 15 (TBX15), tryptophanyl tRNA synthetase 2, mitochondrial (WARS2) and early B-cell factor-2 (EBF2) through functional annotation. Bayesian colocalization additionally suggested a role of RP4-712E4.1. Genetically predicted differences in adiposity-adjusted PAT were causally associated with adverse left ventricular remodeling. CONCLUSIONS This study provides insights into the genetic architecture determining differential PAT deposition, identifies causal links with left structural and functional parameters, and provides novel data about the pathophysiological importance of adiposity distribution.


[Possible role of tRNA1Lys in the splicing of mitochondrial transcripts in yeasts].
Probably the only RNA molecule to be imported into yeast mitochondria is tRNA1Lys. The tRNA is not aminoacylated in mitochondria and its function remains unclear. I have noted that after partial unwinding the tRNA1Lys (more of less in the position, where reverse transcriptase unwinds primer tRNAs) it is possible to fit the donor regions of seven different mitochondrial mosaic genes introns to the unwound part of tRNA. The exact splice site is in all cases found according to the following rule: base pair, cross, locate first m2G X U, cut, base pair. Possible exception is the 5th intron of cob-box where the boundary indicated is not the one accepted in literature, nevertheless the boundary suggested here seems possible. The complementarity suggested permits accurate prediction of 4 (5 if b15 counts) "uncanonical" donor boundaries. The four remaining introns are fitted by the author into looped structures held by unwound tRNA1Lys. The two groups of introns suggested coincide exactly with the Dujonian classes I and II, his classification being based on inner clusters of homology rather than intron/exon boundaries used here. A quite impressive fit was found also between tRNA1Lys and box 9, a sequence needed for splicing of a 1st class intron b14 RNA. The sequences playing probably a crucial role in splicing of 2nd class introns: GGGGG and GGCUC are both complementary to a 3'-CCCCC--GAG-5'-sequence in the GT psi C loop+arm of tRNA1Lys. Used or not in splicing tRNA1Lys curiously enough looks like a compendium of nucleotide sequences needed to handle the mitochondrial mosaic genes RNAs.(ABSTRACT TRUNCATED AT 250 WORDS)


Expression and localization of p53 and bcl-2 in healing wounds in diabetic and nondiabetic mice.
In a healing wound, inflammatory cells undergo apoptosis immediately beneath the leading edge of migrating epithelium. A potential mediator of this apoptosis pattern is p53, a protein with antiproliferative effects. Another protein, bcl-2, is antagonistic to p53 and prevents apoptosis. The purpose of this study was to determine the expression and location of p53 and bcl-2 mRNA and protein in healing wounds of normal and genetically diabetic mice. At various time points, full-thickness skin wounds from nondiabetic and diabetic mice were evaluated for p53 and bcl-2 by immunohistochemistry and in situ hybridization. Apoptosis patterns were also determined using the TUNEL method. Messenger RNA for p53 and bcl-2 were quantitated by competitive reverse transcriptase-polymerase chain reaction. Protein and mRNA for p53 were expressed in the leading edge of migrating epithelium, with apoptosis patterns closely following those of p53 production. p53 mRNA levels decreased soon after wounding, but after a few days, levels increased to greater than baseline. bcl-2 was localized to the wound epithelium, but relative amounts tended to oppose levels of p53, i.e, when p53 increased, bcl-2 decreased and vice versa. Wounds in diabetic animals showed a delayed onset of p53 mRNA expression but had persistently greater levels for longer periods of time. bcl-2 mRNA expression was further delayed in diabetic mice and did not develop to levels as high as p53. Production of both proteins was delayed, consistent with the mRNA expression. Our data show that immediately after wounding, bcl-2 increases and p53 decreases to allow for the cellular proliferation that is required for tissue repair. Over time, bcl-2 levels decrease while p53 levels increase to shut down the inflammatory process and down-regulate the proliferative response. Diabetic animals appear to lose the indirect relationship between p53 and bcl-2. This loss may contribute to the altered apoptosis patterns observed in diabetic healing.


Etiology and diagnosis of tooth wear: a literature review and presentation of selected cases.
This article presents an overview of etiologies associated with tooth wear. Specific types of wear based on clinical findings and patient history are described. The occurrence and pattern of tooth wear are related to cultural, dietary, occupational, and geographic factors. Examples of tooth wear related to these factors with regional specificity are presented. The dental practitioner should recognize the characteristic signs of tooth wear, as they may be the first to discuss the problem with the patient. Management should be based on accurate diagnosis.


Volume Transitions of Isolated Cell Nuclei Induced by Rapid Temperature Increase.
Understanding the physical mechanisms governing nuclear mechanics is important as it can impact gene expression and development. However, how cell nuclei respond to external cues such as heat is not well understood. Here, we studied the material properties of isolated nuclei in suspension using an optical stretcher. We demonstrate that isolated nuclei regulate their volume in a highly temperature-sensitive manner. At constant temperature, isolated nuclei behaved like passive, elastic and incompressible objects, whose volume depended on the pH and ionic conditions. When the temperature was increased suddenly by even a few degrees Kelvin, nuclei displayed a repeatable and reversible temperature-induced volume transition, whose sign depended on the valency of the solvent. Such phenomenon is not observed for nuclei subjected to slow heating. The transition temperature could be shifted by adiabatic changes of the ambient temperature, and the magnitude of temperature-induced volume transition could be modulated by modifying the chromatin compaction state and remodeling processes. Our findings reveal that the cell nucleus can be viewed as a highly charged polymer gel with intriguing thermoresponsive properties, which might play a role in nuclear volume regulation and thermosensing in living cells.


Methotrexate for primary biliary cirrhosis.
Methotrexate, a folic acid antagonist with immunosuppressive properties, has been used to treat patients with primary biliary cirrhosis. The therapeutic responses to methotrexate in randomised clinical trials have been heterogeneous. To assess the beneficial and harmful effects of methotrexate for patients with primary biliary cirrhosis. Relevant randomised clinical trials were identified by searching The Cochrane Hepato-Biliary Group Controlled Trials Register (June 2004), The Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 2, 2004), MEDLINE (January 1966 to August 2004), EMBASE (January 1980 to August 2004), and manual searches of bibliographies. We contacted authors of trials and pharmaceutical companies. Randomised clinical trials comparing methotrexate with placebo, no intervention, or another drug were included irrespective of blinding, language, year of publication, and publication status. Our primary outcomes were mortality and mortality or liver transplantation. Dichotomous outcomes were reported as relative risk (RR) and hazard ratio (HR) if applicable. Continuous outcomes were reported as weighted mean difference (WMD). We examined intervention effects by using both a random-effects model and a fixed-effect model. Heterogeneity was investigated by subgroup analyses and sensitivity analyses. We identified four trials (370 patients) that compared methotrexate with placebo with or without ursodeoxycholic acid as co-intervention. One additional trial (87 patients) compared methotrexate with colchicine without and later with ursodeoxycholic acid as co-intervention. The methodological quality of the trials was low. We did not find significant effects of methotrexate on pruritus, fatigue, liver complications, liver biochemistry, liver histology, or adverse events. The pruritus score (WMD - 0.68, 95% CI - 1.11 to - 0.25), the levels of serum alkaline phosphatases (WMD - 0.41, 95% CI - 0.70 to - 0.12) and plasma immunoglobulin M (WMD - 0.47, 95% CI - 0.74 to - 0.20) were significantly lower in the patients receiving methotrexate. Methotrexate increased mortality in patients with primary biliary cirrhosis. We do not recommend methotrexate for patients with primary biliary cirrhosis outside randomised trials.


Retrospective confidence judgments: Meta-analysis of functional magnetic resonance imaging studies.
Confidence in our retrieved memories, that is, retrospective confidence, is a metamemory process we perform daily. There is an abundance of applied research focusing on the metamemory judgments and very diverse studies including a wide range of clinical populations. However, the neural correlates that support its functioning are not well defined impeding the implementation of noninvasive neuromodulatory clinical interventions. To address the neural basis of metamemory judgments, we ran a meta-analysis, where we used the activation likelihood estimation method on the 19 eligible functional magnetic resonance imaging studies. The main analysis of retrospective confidence revealed concordant bilateral activation in the parahippocampal gyrus, left middle frontal gyrus, and right amygdala. We also run an analysis between the two extreme levels of confidence, namely, high and low. This additional analysis was exploratory, since the minimum amount of articles reporting these two levels was not reached. Activations for the exploratory high > low confidence subtraction analysis were the same as observed in the main analysis on retrospective confidence, whereas the exploratory low > high subtraction showed distinctive activations of the right precuneus. The involvement of the right precuneus emphasizes its role in the evaluation of low confidence memories, as suggested by previous studies. Overall, our study contributes to a better understanding of the specific brain structures involved in confidence evaluations. Better understanding of the neural basis of metamemory might eventually lead to designing more precise neuromodulatory interventions, significantly improving treatment of patients suffering from metamemory problems.