Does Arabidopsis thaliana DREAM of cell cycle control?
Strict temporal control of cell cycle gene expression is essential for all eukaryotes including animals and plants. DREAM complexes have been identified in worm, fly, and mammals, linking several distinct transcription factors to coordinate gene expression throughout the cell cycle. In this issue of The EMBO Journal, Kobayashi et al (2015) identify distinct activator and repressor complexes for genes expressed during the G2 and M phases in Arabidopsis that can be temporarily separated during proliferating and post‐mitotic stages of development. The complexes incorporate specific activator and repressor MYB and E2F transcription factors and indicate the possibility of the existence of multiple DREAM complexes in plants.


Clinical Investigation of Chemotherapeutic Resistance and miRNA Expressions in Head and Neck Cancers: A Thorough PRISMA Compliant Systematic Review and Comprehensive Meta-Analysis.
Background: Chemoresistance is a significant barrier to combating head and neck cancer, and decoding this resistance can widen the therapeutic application of such chemotherapeutic drugs. This systematic review and meta-analysis explores the influence of microRNA (miRNA) expressions on chemoresistance in head and neck cancers (HNC). The objective is to evaluate the theragnostic effects of microRNA expressions on chemoresistance in HNC patients and investigate the utility of miRNAs as biomarkers and avenues for new therapeutic targets. Methods: We performed a comprehensive bibliographic search that included the SCOPUS, PubMed, and Science Direct bibliographic databases. These searches conformed to a predefined set of search strategies. Following the PRISMA guidelines, inclusion and exclusion criteria were framed upon completing the literature search. The data items extracted were tabulated and collated in MS Excel. This spreadsheet was used to determine the effect size estimation for the theragnostic effects of miRNA expressions on chemoresistance in HNC, the hazard ratio (HR), and 95% confidence intervals (95% CI). The comprehensive meta-analysis was performed using the random effects model. Heterogeneity among the data collected was assessed using the Q test, Tau2, I2, and Z measures. Publication bias of the included studies was checked using the Egger's bias indicator test, Orwin and classic fail-safe N test, Begg and Mazumdar rank collection test, and Duval and Tweedie's trim and fill methods. Results: After collating the data from 23 studies, dysregulation of 34 miRNAs was observed in 2189 people. These data were gathered from 23 studies. Out of the 34 miRNAs considered, 22 were up-regulated, while 12 were down-regulated. The TaqMan transcription kits were the most used miRNA profiling platform, and miR-200c was seen to have a mixed dysregulation. We measured the overall pooled effect estimate of HR to be 1.516 for the various analyzed miRNA at a 95% confidence interval of 1.303-1.765, with a significant p-value. The null hypothesis test's Z value was 5.377, and the p-value was correspondingly noted to be less than 0.0001. This outcome indicates that the risk of death is determined to be higher in up-regulated groups than in down-regulated groups. Among the 34 miRNAs that were investigated, seven miRNAs were associated with an improved prognosis, especially with the overexpression of these seven miRNAs (miR15b-5p, miR-548b, miR-519d, miR-1278, miR-145, miR-200c, Hsa- miR139-3p). Discussion: The findings reveal that intricate relationships between miRNAs' expression and chemotherapeutic resistance in HNC are more likely to exist and can be potential therapeutic targets. This review suggests the involvement of specific miRNAs as predictors of chemoresistance and sensitivity in HNC. The examination of the current study results illustrates the significance of miRNA expression as a theragnostic biomarker in medical oncology.


Large-conductance Ca2+- activated K+ channels:physiological role and pharmacology.
Large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels differ from most of other K(+) channels in that their activation is under dual control, i.e., activated by either increase in intracellular Ca(2+) or membrane depolarization. These channels, which are widely distributed in a variety of cells, can control Ca(2+) influx as well as a number of Ca(2+)-dependent physiological processes. In neurons or neuroendocrine cells, BK(Ca) channels are believed to play an important role in controlling hormonal secretion by altering the duration and frequency of action potentials. The activity of BK(Ca) channels functionally expressed in vascular endothelial cells can control K(+) efflux and affect intracellular Ca(2+) concentration. Experimental observations have revealed that a variety of compounds can directly modulate BK(Ca) channel activity. Epoxyeicosatrienoic acids, a metabolite of arachidonic acid, and the increase in intracellular cyclic GMP with vinpocetine or YC-1 can stimulate BK(Ca) channel activity. The increased activity of BK(Ca) channels thus serves as a negative feedback mechanism to limit Ca(2+) influx in excitable cells. Clotrimazole, an imidazole P-450 inhibitor used for the management of sickle cell anemia, can directly suppress BK(Ca) channel activity. Riluzole, a drug used for the treatment of amyotrophic lateral sclerosis, can directly enhance channel activity in neuroendocrine cells. This effect may explain its inhibitory action on excitatory neurotransmission. 2-Methoxyestradil, an endogenous metabolite of 17beta-estradiol, suppresses BK(Ca) channel activity, whereas resveratrol, a natural phytoalexin present in grapes and wine, directly stimulates BK(Ca) channel activity in vascular endothelial cells. These effects may be responsible for their actions on functional activities of endothelial cells. The fenamates, a family of nonsteroidal anti-inflammatory drugs, are also openers of BK(Ca) channels. Therefore, the modulation of BK(Ca) channel activity in excitable and non-excitable cells can be important for therapeutic interventions.


Formulations and toxicologic in vivo studies of aqueous cyclosporin A eye drops with cyclodextrin nanoparticles.
Cyclosporin A (CyA) is an immunosuppressive drug used topically to treat ocular inflammatory disorder such as dry eye disease (DES). It is a lipophilic cyclic peptide with molecular weight of 1202.6Da. The aim of this study was to develop surfactant free aqueous 0.2% (w/v) CyA eye drops where the drug is present in an aqueous vehicle containing CyA/cyclodextrin (CyA/CD) nanoparticles and then do three-month toxicological testing in rabbits. Five formulations of different CD concentrations were studied, all of them contained 12.5% (w/v) of α-cyclodextrin (αCD) and various amounts of γ-cyclodextrin (γCD) (ranging from 0 to 12.5% w/v). αCD was used to solubilize the drug and γCD to promote formation of complex aggregates. CyA/CD complex aggregates were formed in all the formulations tested. However, the formulation containing 12.5% (w/v) αCD and 12.5% (w/v) γCD created more CyA/CD nanoparticles of suitable size and was therefore tested in vivo. The eye drops did not cause ocular irritation or toxic side effects upon topical administration to rabbits once or twice a day for three months.


Chromogenic Limulus amebocyte lysate assay as an aid in the diagnosis of meningitis.
Cerebrospinal fluids (CSFs) from 146 patients with suspected meningitis were screened by a recently introduced, rapid and sensitive chromogenic Limulus amebocyte lysate (CLAL) assay for endotoxin. Fifty-eight of these CSFs were screened as well for bacterial antigens by CIE, latex and/or coagglutination techniques. A total of 68 CSFs were positive by either culture and/or at least one of the antigen screens. The overall sensitivity of the CLAL assay was 93% with a specificity of 100%. However, the assay's sensitivity for community - acquired meningitis due to Haemophilus influenzae type b and Neisseria meningitidis was 100%. In this group the assay's sensitivity was better than those of direct gram stain (62%), culture (80%), and commercially available, rapid antigen detection methods (89%). Used judiciously, the CLAL assay is a cost-effective, helpful adjunct test for the diagnosis of gram-negative meningitis.


Impact of age on mortality and transfer to long-term care in patients in an intensive care unit.
In the global trend of population aging, age is one of the significant factors to be considered in critically ill patients. However, the impact of age on clinical outcomes and long-term prognosis in this population varies across different studies. We conducted a retrospective cohort analysis for patients admitted to the medical intensive care unit (ICU) (30 beds) between January 2017 and December 2020 at the tertiary referral hospital in Korea. Patients were classified into three groups according to age: <65 years, old age (65-79 years), and very old age (≥ 80 years). Subsequently, enrolled patients were analyzed for acute mortality and long-term prognosis. Among the 1584 patients, the median age was 67.0 (57.0-76.0) years, and 65.2% were male. Median ICU length of stay (LOS) (8, 9, and 10 days in < 65, 65-79, and ≥ 80 years, respectively; p = 0.006) and the proportion of patients who were transferred to long-term care hospital at the time of discharge (12.9% vs. 28.3% vs. 39.4%, respectively; p < 0.001) increased with age. Multivariable logistic analysis showed no significant difference in the 28-day mortality in the old age (adjusted odds ratio [aOR] 0.88; 95% confidence interval [CI] 0.65-1.17) and very old age (aOR 1.05; 95% CI 0.71-1.55) groups compared to that in patients with age < 65 years. However, the relevance of the proportion of ICU LOS ≥ 7 days and transfers to other hospitals after discharge increased with age. Age did not affect acute mortality in critical illness patients. However, surviving older age groups required more long-term care facilities compared to patients younger than 65 years after acute management. These results indicate that in an aging society, the importance of not only acute management but also long-term care facilities may increase for critical illness patients.


Epidemiologic considerations of ethylene glycol intoxication in small animals.
Using necropsy records and a practitioner survey, data for certain epidemiologic parameters on EG intoxication in dogs and cats were collected and analyzed. The practices surveyed reported diagnosing 150 cases/year in the 7-county metropolitan area of Minneapolis/St Paul, MN, compared with 32 cases reported in a nationwide survey done a decade earlier. Analysis of necropsy records showed that the annual number of post mortem cases had quintupled over the past decade, with the majority of cases occurring the colder months of the year. Cases involving dogs were twice as common as those involving cats, and males appeared twice as often as females in both species. Young male dogs, under 24 months of age, were the most frequently represented, with female dogs less than 12 months old the next most frequent group.


Methylation of the estrogen receptor CpG island in lung tumors is related to the specific type of carcinogen exposure.
Promoter methylation has recently been shown to be an alternative to mutation in inactivating tumor suppressor genes in human neoplasia. Although specific carcinogen exposures have been associated with characteristic mutation patterns in genes, the factors that lead to promoter hypermethylation remain unknown. One gene target for inactivation through promoter methylation is the estrogen receptor (ER). The purpose of this investigation was to determine the methylation status of this gene in lung tumors from smokers and those who never smoked and in rodents exposed to specific environmental carcinogens. Promoter methylation at the ER locus was detected in 4 of 11 tumors from never-smokers (36.4%) and 7 of 35 tumors from smokers (20%, P < 0.001). Lung tumors induced by the tobacco-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone also had a low incidence (16.7%) of ER methylation. In marked contrast, spontaneous and plutonium-induced tumors had a very high (81.8%) incidence of ER methylation. X-ray-induced tumors had an intermediate frequency of ER methylation (38.1%). The presence of ER methylation was associated with absent ER expression in rodent lung cancer cell lines. These results show for the first time that gene-specific promoter methylation can be modulated differentially depending on carcinogen exposure.


Manipulation of catalase levels produces altered photosynthesis in transgenic tobacco plants.
Constructs containing the cDNAs encoding the primary leaf catalase in Nicotiana or subunit 1 of cottonseed (Gossypium hirsutum) catalase were introduced in the sense and antisense orientation into the Nicotiana tabacum genome. The N. tabacum leaf cDNA specifically overexpressed CAT-1, the high catalatic [corrected] form, activity. Antisense constructs reduced leaf catalase specific activities from 0.20 to 0.75 times those of wild type (WT), and overexpression constructs increased catalase specific activities from 1.25 to more than 2.0 times those of WT. The NADH-hydroxypyruvate reductase specific activity in transgenic plants was similar to that in WT. The effect of antisense constructs on photorespiration was studied in transgenic plants by measuring the CO2 compensation point (gamma) at a leaf temperature of 38 degrees C. A significant linear increase was observed in gamma with decreasing catalase (at 50% lower catalase activity gamma increased 39%). There was a significant temperature-dependent linear decrease in gamma in transgenic leaves with elevated catalase compared with WT leaves (at 50% higher catalase gamma decreased 17%). At 29 degrees C, gamma also decreased with increasing catalase in transgenic leaves compared with WT leaves, but the trend was not statistically significant. Rates of dark respiration were the same in WT and transgenic leaves. Thus, photorespiratory losses of CO2 were significantly reduced with increasing catalase activities at 38 degrees C, indicating that the stoichiometry of photorespiratory CO2 formation per glycolate oxidized normally increases at higher temperatures because of enhanced peroxidation.


Bacteriology of expectorated sputum with quantitative culture and wash technique compared to transtracheal aspirates.
Techniques to improve the reliability of expectorated sputum culture were evaluated in 46 patients using a wash technique, quantitative culture, and a combination of washing and quantification. The wash procedure consisted of a jet of tap water over the specimen contained in a tea strainer. The true lower respiratory tract flora was determined by percutaneous transtracheal aspirates, which served as the basis for evaluating the methods of processing expectorated specimens. Either washing alone or quantification alone decreased the number of specimens with organisms that were not present in companion transtracheal aspirates; however, results that were sufficiently improved to be clearly advantageous for clinical interpretation were achieved only when washing and quantification were combined. Washed sputum specimens yielded oropharyngeal "contaminants" in concentrations exceeding 10(6) bacteria per ml in 12 of 46 specimens (26 per cent). Using this technique, only one specimen contained a misleading potential pathogen, and only one specimen failed to yield a potential pathogen that was recovered with the transtracheal aspirate. The wash procedure decreased the mean concentrations of contaminants approximately 100-fold for all specimens and 1,000-fold for purulent specimens.


Isolated growth hormone deficiency type II caused by a point mutation that alters both splice site strength and splicing enhancer function.
A heterozygous single base mutation in the human growth hormone (GH) gene (GH-1) was identified in a family presenting with isolated GH deficiency type II (IGHD II). Affected individuals have a guanine to adenine transition at the first nucleotide of exon 3 (E3+1 G-->A) that results in exon skipping and production of a dominant-negative 17.5-kDa isoform. We show that the mechanistic basis for exon skipping is due to the unique position of this mutation because it weakens the 3' splice site and simultaneously disrupts a splicing enhancer located within the first seven bases of exon 3. A G-->T mutation at this same position not only affects splicing but also results in a premature stop codon for those transcripts that include exon 3. Thus, mutations that alter the first nucleotide of exon 3 illustrate the various mechanisms by which changes in sequence can cause disease: splice site selection, splicing enhancer function, messenger RNA decay, missense mutations, and nonsense mutations. For IGHD II, only exon skipping leads to production of the dominant-negative isoform, with increasing skipping correlating with increasing disease severity.


Viral respiratory infection in schoolchildren: effects on middle ear pressure.
To evaluate the effect of uncomplicated viral respiratory infections (colds) on middle ear pressure in healthy school-aged children. Children (ages 2-12) with normal tympanograms before onset of illness had bilateral tympanometry daily except weekends for 2 weeks after the onset of a cold. Nasopharyngeal secretion obtained at onset of illness was cultured for bacterial pathogens of otitis media using selective agars and tested for rhinovirus, coronavirus, respiratory syncytial virus, influenza A and B, and parainfluenza 1-3 by reverse transcriptase polymerase chain reaction technology. Tympanometry was designated as abnormal with peak pressure of < or =-100 daPa or > or =50 daPa and/or a compliance peak of < 0.2 cm(3). Eighty-six colds were studied, 82 in schoolchildren (5-12 years old) and 4 in 2- to 3-year-olds. Abnormal negative middle ear pressure occurred at least once during the 2 weeks after onset in 57 (66%) of the 86 colds. Tympanometry was abnormal in the first week after onset in 50 (88%) of the 57 colds and was abnormal on a single day in 17 (30%) of the 57. The middle ear pressure abnormalities were intermittent and shifted from one ear to the other ear from day to day. Reverse transcriptase polymerase chain reaction was positive for a respiratory virus in 56 (65%) of the 86 illnesses. Rhinovirus was found in 48% and respiratory syncytial virus in 14%. Pathogenic bacteria (Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis) were detected in nasopharyngeal secretion in 29 (34%) of the 86 colds; the bacteria were in high titer (> or =10(3) cfu/mL) in 26 of the 29 positive specimens. None developed illness that required a visit to a physician. Age, detection of a respiratory virus, and presence of bacterial pathogen in the nasopharyngeal secretion had a negligible effect on the occurrence of abnormal tympanometry. Occurrence of negative middle ear pressure in winter-spring colds was significantly greater than in fall colds for unexplained reasons. Transient negative middle ear pressure occurred in two thirds of uncomplicated colds in healthy children. This negative pressure, which may facilitate secondary viral or bacterial otitis media, seems to result from viral infection of the nasopharynx and distal tube causing bilateral eustachian tube dysfunction. Tympanometry provides an objective measure of the potential beneficial effects of investigational treatments on the risk of eustachian tube dysfunction/otitis media.


A Cross-Sectional Survey on Older Adults' Community Mobility in an Indian Metropolis.
Community mobility supports occupational participation among older adults and promotes active ageing. This study aimed to explore community mobility of older adults within an urban Indian context in view of the limited available literature in this area. A cross-sectional survey was conducted on a convenience sample of 75 older adults residing in Chennai city using a questionnaire and a non-retrospective, open format, two-day time diary. Participants engaged in community mobility and activities outside home for 10% of time over two days. Activities and roles related to religious and spiritual activities and expression, social participation, leisure and informal personal education participation occupied most time and were engaged in most frequently. Walking was the most frequently used mode of transportation and participants reported numerous road-related hazards (lack of proper pavements, disobedience of traffic rules, difficulty crossing roads, crowded roads, and poor condition of roads). Participants used public transport less often. Public transport-related barriers (difficulty boarding and alighting buses/trains due to high steps/insufficient time, inadequate seat reservation for older adults, overcrowding and increased expense on auto rickshaws/taxis) were also expressed as concerns. Participants linked their ability to use public transport with independence and assigned relatively less value to driving. The findings emphasize the significance of community mobility to promote participation in older adults and recommend age-friendly environments in Indian cities.


Hyaluronic acid in cartilage and proteoglycan aggregation.
1. Dissociation of purified proteoglycan aggregates was shown to release an interacting component of buoyant density higher than that of the glycoprotein-link fraction of Hascall & Sajdera (1969). 2. This component, which produced an increase in hydrodynamic size of proteoglycans on gel chromatography, was isolated by ECTEOLA-cellulose ion-exchange chromatography and identified as hyaluronic acid. 3. The effect of pH of extraction showed that the proportion of proteoglycan aggregates isolated from cartilage was greatest at pH4.5. 4. The proportion of proteoglycans able to interact with hyaluronic acid decreased when extracted above or below pH4.5, whereas the amount of hyaluronic acid extracted appeared constant from pH3.0 to 8.5. 5. Sequential extraction of cartilage with 0.15m-NaCl at neutral pH followed by 4m-guanidinium chloride at pH4.5 was shown to yield predominantly non-aggregated and aggregated proteoglycans respectively. 6. Most of the hyaluronic acid in cartilage, representing about 0.7% of the total uronic acid, was associated with proteoglycan aggregates. 7. The non-aggregated proteoglycans were unable to interact with hyaluronic acid and were of smaller size, lower protein content and lower keratan sulphate content than the disaggregated proteoglycans. Together with differences in amino acid composition this suggested that each type of proteoglycan contained different protein cores.


Interspecific and environmentally induced variation in foliar dark respiration among eighteen southeastern deciduous tree species.
We measured variations in leaf dark respiration rate (Rd) and leaf nitrogen (N) across species, canopy light environment, and elevation for 18 co-occurring deciduous hardwood species in the southern Appalachian mountains of western North Carolina. Our overall objective was to estimate leaf respiration rates under typical conditions and to determine how they varied within and among species. Mean dark respiration rate at 20 degrees C (Rd,mass, micromol CO2 per kg leaf dry mass per s) for all 18 species was 7.31 micromol per kg per s. Mean Rd,mass of individual species varied from 5.17 micromol per kg per s for Quercus coccinea Muenchh. to 8.25 micromol per kg per s for Liriodendron tulipifera L. Dark respiration rate varied by leaf canopy position and was higher in leaves collected from high-light environments. When expressed on an area basis, dark respiration rate (Rd,area, micromol CO2 per kg leaf dry area per s) showed a strong linear relationship with the predictor variables leaf nitrogen (Narea, g N per square m leaf area) and leaf structure (LMA, g leaf dry mass per square m leaf area) (r squared = 0.62). This covariance was largely a result of changes in leaf structure with canopy position; smaller thicker leaves occur at upper canopy positions in high-light environments. Mass-based expression of leaf nitrogen and dark respiration rate showed that nitrogen concentration (Nmass, mg N per g leaf dry mass) was only moderately predictive of variation in Rd,mass for all leaves pooled (r squared = 0.11), within species, or among species. We found distinct elevational trends, with both Rd,mass and Nmass higher in trees originating from high-elevation, cooler growth environments. Consideration of interspecies differences, vertical gradients in canopy light environment, and elevation, may improve our ability to scale leaf respiration to the canopy in forest process models.


Increased identification of peptides by enhanced data processing of high-resolution MALDI TOF/TOF mass spectra prior to database searching.
This paper presents application of sequential enhanced data processing procedures to high-resolution tandem mass spectra for identification of peptides using the Mascot database search algorithm. A strategy for (1) selection of fragment ion peaks from MS/MS spectra, (2) utilization of improved mass accuracy of the precursor ions, and (3) wavelet denoising of the mass spectra prior to fragment ion selection have been developed. The number of peptide identifications obtained using the enhanced processing was then compared with that obtained using software provided by the instrument manufacturer. Approximately 9000 MS/MS spectra acquired by the Applied Biosystems 4700 TOF/TOF MS instrument were used as a model data set. After application of the new processing, an increase of 33% unique peptides and 22% protein identifications with at least two unique peptides were found. The influence of the processing on the percentage of false positives, estimated by searching against a randomized database, was estimated to increase false positive identifications from 2.7 to 3.9%, which was still below the 5% error rate specified in the Mascot search. These data processing approaches increase the amount of information that can be extracted from LC-MS analysis without the necessity of additional experiments.


Transcriptional targeting in the airway using novel gene regulatory elements.
The delivery of cystic fibrosis transmembrane conductance regulator (CFTR) to airway epithelia is a goal of many gene therapy strategies to treat cystic fibrosis. Because the native regulatory elements of the CFTR are not well characterized, the development of vectors with heterologous promoters of varying strengths and specificity would aid in our selection of optimal reagents for the appropriate expression of the vector-delivered CFTR gene. Here we contrasted the performance of several novel gene-regulatory elements. Based on airway expression analysis, we selected putative regulatory elements from BPIFA1 and WDR65 to investigate. In addition, we selected a human CFTR promoter region (∼ 2 kb upstream of the human CFTR transcription start site) to study. Using feline immunodeficiency virus vectors containing the candidate elements driving firefly luciferase, we transduced murine nasal epithelia in vivo. Luciferase expression persisted for 30 weeks, which was the duration of the experiment. Furthermore, when the nasal epithelium was ablated using the detergent polidocanol, the mice showed a transient loss of luciferase expression that returned 2 weeks after administration, suggesting that our vectors transduced a progenitor cell population. Importantly, the hWDR65 element drove sufficient CFTR expression to correct the anion transport defect in CFTR-null epithelia. These results will guide the development of optimal vectors for sufficient, sustained CFTR expression in airway epithelia.


[A case of Meigs' syndrome].
The described case of Meigs' [correction of Maigce] syndrome supports data on diversity of exudative pleurisies as some syndrome of manifestation of different pathological processes. Diagnosing and treatment by surgery technique of the female patient with Meigs' [correction of Magice] syndrome suggest expediency of examination by an obstetrician-gynecologist of all those women presenting with exudative pleurisy.


A quantitative magnetic resonance histology atlas of postnatal rat brain development with regional estimates of growth and variability.
There has been growing interest in the role of postnatal brain development in the etiology of several neurologic diseases. The rat has long been recognized as a powerful model system for studying neuropathology and the safety of pharmacologic treatments. However, the complex spatiotemporal changes that occur during rat neurodevelopment remain to be elucidated. This work establishes the first magnetic resonance histology (MRH) atlas of the developing rat brain, with an emphasis on quantitation. The atlas comprises five specimens at each of nine time points, imaged with eight distinct MR contrasts and segmented into 26 developmentally defined brain regions. The atlas was used to establish a timeline of morphometric changes and variability throughout neurodevelopment and represents a quantitative database of rat neurodevelopment for characterizing rat models of human neurologic disease.


Elevation of IgE in children with sickle cell disease is associated with doctor diagnosis of asthma and increased morbidity.
A doctor's diagnosis of asthma is associated with increased morbidity (pain and acute chest syndrome [ACS]) among children with sickle cell disease (SCD). An association between IgE levels and asthma and morbidity has not been investigated in children with SCD. We tested the hypothesis that elevated total and allergen-specific IgE levels are associated with asthma and SCD morbidity in children with SCD. A cross-sectional study of children with SCD who participated in the Silent Cerebral Infarct Trial was conducted. Logistic regression and negative binomial regression were used to investigate potential associations of total and allergen-specific IgE levels with asthma diagnosis and SCD morbidity, both confirmed by medical record review. Elevation of total IgE level was defined as age-adjusted and sex-adjusted IgE level exceeding the 90th percentile compared with a nonatopic reference population. IgE antibody positivity to Alternaria alternata (mold), Blattellagermanica (cockroach), and Dermatophagoides pteronyssinus (dust mite) was assessed by ImmunoCAP analysis. Children with SCD (140 with asthma; 381 without asthma) were evaluated. Elevations in total IgE level (P = .04) and IgE antibody specific for Alternaria alternata (P = .0003), Blattella germanica (P = .008), and Dermatophagoides pteronyssinus (P = .01) were associated with asthma. ACS (P = .048) but not pain (P = .20) was associated with total IgE level, but neither was associated with specific IgE levels. Significantly increased levels of total and allergen-specific IgE levels are associated with asthma in SCD. High IgE levels are a risk factor for ACS but not pain rates.


Structural basis for broad specificity in alpha-lytic protease mutants.
Binding pocket mutants of alpha-lytic protease (Met 192----Ala and Met 213----Ala) have been constructed recently in an effort to create a protease specific for Met just prior to the scissile bond. Instead, mutation resulted in proteases with extraordinarily broad specificity profiles and high activity [Bone, R., Silen, J. L., & Agard, D. A. (1989) Nature 339, 191-195]. To understand the structural basis for the unexpected specificity profiles of these mutants, high-resolution X-ray crystal structures have been determined for complexes of each mutant with a series of systematically varying peptidylboronic acids. These inhibitory analogues of high-energy reaction intermediates provide models for how substrates with different side chains interact with the enzyme during the transition state. Fifteen structures have been analyzed qualitatively and quantitatively with respect to enzyme-inhibitor hydrogen-bond lengths, buried hydrophobic surface area, unfilled cavity volume, and the magnitude of inhibitor accommodating conformational adjustments (particularly in the region of another binding pocket residue, Val 217A). Comparison of these four parameters with the Ki of each inhibitor and the kcat and Km of the analogous substrates indicates that while no single structural parameter consistently correlates with activity or inhibition, the observed data can be understood as a combination of effects. Furthermore, the relative contribution of each term differs for the three enzymes, reflecting the altered conformational energetics of each mutant. From the extensive structural analysis, it is clear that enzyme flexibility, especially in the region of Val 217A, is primarily responsible for the exceptionally broad specificity observed in either mutant. Taken together, the observed patterns of substrate specificity can be understood to arise directly from interactions between the substrate and the residues lining the specificity pocket and indirectly from interactions between peripheral regions of the protein and the active-site region that serve to modulate active-site flexibility.


Reviewing the Effectiveness of Music Interventions in Treating Depression.
Depression is a very common mood disorder, resulting in a loss of social function, reduced quality of life and increased mortality. Music interventions have been shown to be a potential alternative for depression therapy but the number of up-to-date research literature is quite limited. We present a review of original research trials which utilize music or music therapy as intervention to treat participants with depressive symptoms. Our goal was to differentiate the impact of certain therapeutic uses of music used in the various experiments. Randomized controlled study designs were preferred but also longitudinal studies were chosen to be included. 28 studies with a total number of 1,810 participants met our inclusion criteria and were finally selected. We distinguished between passive listening to music (record from a CD or live music) (79%), and active singing, playing, or improvising with instruments (46%). Within certain boundaries of variance an analysis of similar studies was attempted. Critical parameters were for example length of trial, number of sessions, participants' age, kind of music, active or passive participation and single- or group setting. In 26 studies, a statistically significant reduction in depression levels was found over time in the experimental (music intervention) group compared to a control (n = 25) or comparison group (n = 2). In particular, elderly participants showed impressive improvements when they listened to music or participated in music therapy projects. Researchers used group settings more often than individual sessions and our results indicated a slightly better outcome for those cases. Additional questionnaires about participants confidence, self-esteem or motivation, confirmed further improvements after music treatment. Consequently, the present review offers an extensive set of comparable data, observations about the range of treatment options these papers addressed, and thus might represent a valuable aid for future projects for the use of music-based interventions to improve symptoms of depression.


Dry powder versus intravenous and nebulized gentamicin in cystic fibrosis and bronchiectasis. A pilot study.
Aminoglycosides are a mainstay of therapy for patients with cystic fibrosis (CF) or non-CF bronchiectasis who are infected with Pseudomonas aeruginosa (Psa). Traditionally, aerosolized antibiotics are delivered by liquid nebulization. The objective of this study was to determine whether a gentamicin dry powder inhaler (DPI) is as microbiologically active and potentially safe as gentamicin inhaled via a small-volume nebulizer (SVN) or given intravenously. The study was done according to a randomized, single-dose, and triple crossover protocol. Ten patients with CF or non-CF bronchiectasis and chronically infected with Psa were recruited. Patients received a single dose of either gentamicin 160 mg via DPI or SVN, or gentamicin at 5 mg/kg by intravenous infusion. In seven of the 10 patients, the minimum inhibitory concentration (MIC) was achieved in sputum after DPI and SVN, with mean (95% confidence interval) gentamicin concentrations at 2 h after administration of 13.1 microgram/g sputum (range: 2.2 to 23.9 microgram/g) and 97.2 microgram/g sputum (range: 0.3 to 194.2 microgram/g), respectively, whereas gentamicin levels in the sputum after intravenous administration failed to reach the MIC. Gentamicin given by DPI and SVN significantly decreased the sputum Psa density (p < 0.05), by almost one order of magnitude. No significant decline in bacterial counts was observed after intravenous gentamicin. When gentamicin was inhaled, blood concentrations were minimal, and were below concentrations known to cause systemic toxicity. For treatment of Psa infections susceptible to gentamicin, gentamicin administration by DPI appeared to be as efficient as by SVN, despite the delivery of a 7-fold lower dose to the airways.


[Immunohistochemical diagnosis of occult breast cancer].
The techniques associated with immunohistochemistry are of major interest in modern tumour diagnosis. Their simple application provides a wider scope for diagnosis by increasing the possibilities of characterising tumour cells. In particular, the combination of various tumour markers has led to a better understanding of tumour histogenesis. If the primary tumour is unknown and only metastases are available for diagnosis, further important information can be gained allowing a correlation with the origin of the metastases. In three own cases an occult carcinoma of the female breast could be diagnosed pre-operatively via immunohistochemistry techniques. Since no marker is available that reacts specifically with cells of metastasizing mammary cancer, lymph node metastases have been examined with several different markers. For that purpose, the epithelial membrane antigen (EMA), Thomsen-Friedenreich-antigen (T-Ag) and alpha-lactalbumin (ALA) have been used to point out several pathways of cell metabolism. It could be demonstrated that the prospective use of the three markers is of the highest value to make diagnosis easier and safer than by interpreting the morphological appearance. The diagnostic value of tumour markers is an important step forward, especially in the interpretation of tumour cell embolism, macrometastases and micrometastases in regional lymph nodes.


Defective ribonucleoside diphosphate reductase impairs replication fork progression in Escherichia coli.
The observed lengthening of the C period in the presence of a defective ribonucleoside diphosphate reductase has been assumed to be due solely to the low deoxyribonucleotide supply in the nrdA101 mutant strain. We show here that the nrdA101 mutation induces DNA double-strand breaks at the permissive temperature in a recB-deficient background, suggesting an increase in the number of stalled replication forks that could account for the slowing of replication fork progression observed in the nrdA101 strain in a Rec(+) context. These DNA double-strand breaks require the presence of the Holliday junction resolvase RuvABC, indicating that they have been generated from stalled replication forks that were processed by the specific reaction named "replication fork reversal." Viability results supported the occurrence of this process, as specific lethality was observed in the nrdA101 recB double mutant and was suppressed by the additional inactivation of ruvABC. None of these effects seem to be due to the limitation of the deoxyribonucleotide supply in the nrdA101 strain even at the permissive temperature, as we found the same level of DNA double-strand breaks in the nrdA(+) strain growing under limited (2-microg/ml) or under optimal (5-microg/ml) thymidine concentrations. We propose that the presence of an altered NDP reductase, as a component of the replication machinery, impairs the progression of the replication fork, contributing to the lengthening of the C period in the nrdA101 mutant at the permissive temperature.


The ubiquitin-associated domain of cellular inhibitor of apoptosis proteins facilitates ubiquitylation.
The cellular inhibitor of apoptosis (cIAP) proteins are essential RING E3 ubiquitin ligases that regulate apoptosis and inflammatory responses. cIAPs contain a ubiquitin-associated (UBA) domain that binds ubiquitin and is implicated in the regulation of cell survival and proteasomal degradation. Here we show that mutation of the MGF and LL motifs in the UBA domain of cIAP1 caused unfolding and increased cIAP1 multimonoubiquitylation. By developing a UBA mutant that disrupted ubiquitin binding but not the structure of the UBA domain, we found that the UBA domain enhances cIAP1 and cIAP2 ubiquitylation. We demonstrate that the UBA domain binds to the UbcH5b∼Ub conjugate, and this promotes RING domain-dependent monoubiquitylation. This study establishes ubiquitin-binding modules, such as the UBA domain, as important regulatory modules that can fine tune the activity of E3 ligases.


Rapid determination of amino acid incorporation by stable isotope labeling with amino acids in cell culture (SILAC).
Stable isotope labeling with amino acids in cell culture (SILAC) has evolved to be a major technique for quantitative proteomics using cell cultures. We developed a rapid method to follow and determine the incorporation of arginine and lysine. Analysis of the heavy state is required to avoid quantification errors. Moreover, the mixture of light and heavy states can be exploited to normalize the protein amount for subsequent relative quantification experiments. Therefore, peptides from different cell lines were extracted with 0.1% trifluoroacetic acid and analyzed by matrix-assisted laser desorption/ionization tandem time-of-flight (MALDI-TOF/TOF) mass spectrometry (MS). This analysis was highly reproducible and was performed in less than 2 h, significantly faster than other methods for the same purpose. Similar peptide mass profiles were obtained for human EBV-transformed B, Jurkat T, and HeLa cells as well as for mouse embryonic fibroblasts. Proteolytic fragments of 27 human proteins were identified with 56 peptides by MALDI-MS/MS and can be used as a database for these kinds of experiments. Sequencing revealed that the peptides were predominantly amino- and carboxy-terminal protein fragments displaying a specificity characteristic of the acidic proteases cathepsin D and E. Many of the identified peptides contained arginine and/or lysine, allowing determination of the incorporation rate of these amino acids. Furthermore, the rate of conversion of arginine into proline could be monitored easily.


A new exon in the 5' untranslated region of the connexin32 gene.
The cloning and sequencing of two bovine connexin32 cDNAs are reported. Comparative analysis with known corresponding mammalian cDNA and protein sequences, besides confirming a high degree of similarity among these proteins, allowed us to identify some specific features of the bovine connexin32 gene. The latter include: the presence of a novel exon in the 5' UTR which is alternatively spliced, giving rise to a new mRNA species; the presence of two potential hairpin loops in the 5' and 3' UTR; and the presence of an additional amino acid, glycine235, in the C-terminal domain of the 284 residue protein. Among the common features, the presence of polypyrimidine clusters within the 3' UTR, containing a consensus sequence for a cis-acting element, is noteworthy. Expression of connexin32 mRNAs was analysed in 16 bovine tissues. Transcript analysis suggests the presence, in cattle, of an alternative downstream promoter.


Neural correlates of mindful emotion regulation in high and low ruminators.
Depressive rumination is considered a prominent risk factor for the occurrence, severity, and duration of depressive episodes. A variety of treatment options have been developed to treat depressive rumination of which mindfulness based programs are especially promising. In the current study, we investigated the neural underpinnings of a short mindfulness intervention and mindful emotion regulation in high and low trait ruminators in an ecologically valid environment using functional near-infrared spectroscopy (fNIRS). Participants were randomly assigned to a mindfulness instruction (MT) group or an instructed thinking (IT) group. Participants in the MT group were trained to either focus their attention mindfully on their breath or their emotions, while the IT group focused their attention on the past or future. Afterwards, all participants underwent an emotion regulation paradigm in which they either watched negative or neutral movie clips. During both paradigms cortical hemodynamic changes were assessed by means of fNIRS. Participants in the MT group showed lower activity in the cognitive control network (CCN) during the focus on breath condition in comparison to the focus on emotion condition. Additionally, oxygenated hemoglobin in the MT group tended to be lower than in the IT group. Further, self-reports of emotional distress during the instruction paradigm were reduced in the MT group. During the emotion regulation paradigm, we observed reduced emotional reactivity in terms of emotional distress and avoidance in the MT group in comparison to the IT group. Furthermore, on a neural level, we observed higher CCN activity in the MT group in comparison to the IT group. We did not find any effect of rumination, neither on the intervention nor on the emotion regulation task. The results of this pilot study are discussed in light of the present literature on the neural correlates of mindfulness based interventions in rumination and emphasize the use of fNIRS to track neural changes in situ over the course of therapy.


Preoperative chemoradiation and extended pelvic lymphadenectomy for rectal cancer: Two distinct principles.
Extended pelvic lymphadenectomy (EPL) with total mesorectal excision (TME) has been reported to provide oncological benefit in lower rectal cancer in Japan. In Western countries EPL is not widely accepted because of frequent morbidity but instead preoperative chemoradiation (CRT) followed by TME has been established as a standard treatment for decreasing local recurrence. Recently, several studies have focused on the comparison between these two distinct therapeutic approaches in Western countries and Japan. A study comparing Dutch trial data and Japanese data revealed that EPL and RT are almost equivalent in decreasing local recurrence in lower rectal cancer as compared with TME alone. Considering that almost 45% survival can be achieved by EPL even in the presence of metastatic lateral lymph nodes (LLNs), EPL performed by experienced surgeons definitely contributes to decrease local recurrence. On the other hand, a randomized controlled trial in Japan that compared EPL with conventional TME following preoperative RT revealed that EPL is associated with a higher frequency of sexual and urinary dysfunction without oncological benefits in the presence of preoperative RT. On this point, preoperative CRT followed by conventional TME without EPL would be a better therapeutic approach in patients without evident metastatic LLNs. For future treatment, it would be desirable to have a narrower indication for EPL using full advantage of recent improvement in image diagnosis. Although objective comparison of these two principles between Japan and the West is difficult due to differences in patient groups, further studies would lead to the next great step towards future improvement in treating lower rectal cancer.


The new CCP4 Coordinate Library as a toolkit for the design of coordinate-related applications in protein crystallography.
The new CCP4 Coordinate Library is a development aiming to provide a common layer of coordinate-related functionality to the existing applications in the CCP4 suite, as well as a variety of tools that can simplify the design of new applications where they relate to atomic coordinates. The Library comprises a wide spectrum of useful functions, ranging from parsing coordinate formats and elementary editing operations on the coordinate hierarchy of biomolecules, to high-level functionality such as calculation of secondary structure, interatomic bonds, atomic contacts, symmetry transformations, structure superposition and many others. Most of the functions are available in a C++ object interface; however, a Fortran interface is provided for compatibility with older CCP4 applications. The paper describes the general principles of the Library design and the most important functionality. The Library, together with documentation, is available under the LGPL license from the CCP4 suite version 5.0 and higher.


From Diverse Origins to Specific Targets: Role of Microorganisms in Indirect Pest Biological Control.
Integrated pest management (IPM) is today a widely accepted pest management strategy to select and use the most efficient control tactics and at the same time reduce over-dependence on chemical insecticides and their potentially negative environmental effects. One of the main pillars of IPM is biological control. While biological control programs of pest insects commonly rely on natural enemies such as predatory insects, parasitoids and microbial pathogens, there is increasing evidence that plant, soil and insect microbiomes can also be exploited to enhance plant defense against herbivores. In this mini-review, we illustrate how microorganisms from diverse origins can contribute to plant fitness, functional traits and indirect defense responses against pest insects, and therefore be indirectly used to improve biological pest control practices. Microorganisms in the rhizosphere, phyllosphere and endosphere have not only been shown to enhance plant growth and plant strength, but also promote plant defense against herbivores both above- and belowground by providing feeding deterrence or antibiosis. Also, herbivore associated molecular patterns may be induced by microorganisms that come from oral phytophagous insect secretions and elicit plant-specific responses to herbivore attacks. Furthermore, microorganisms that inhabit floral nectar and insect honeydew produce volatile organic compounds that attract beneficial insects like natural enemies, thereby providing indirect pest control. Given the multiple benefits of microorganisms to plants, we argue that future IPMs should consider and exploit the whole range of possibilities that microorganisms offer to enhance plant defense and increase attraction, fecundity and performance of natural enemies.


[Significance of epidermal cytokines within the scope of wound healing].
Wound healing involves inflammation as well as repair of injured tissue. A variety of soluble mediators is involved in the regulation of the different phases of wound healing. Recently it has been shown that in addition to inflammatory cells, keratinocytes are able to produce distinct immunomodulating cytokines. Injurious stimuli significantly enhance mediator production and enable keratinocytes to activate various inflammatory cells such as granulocytes, lymphocytes, monocytes, natural killer cells and fibroblasts. Thus, cytokines released by keratinocytes may play an important regulatory role in inflammation, as well as within the framework of repair of damaged tissue.


A comparative evaluation of radiation-induced DNA damage using real-time PCR: influence of base composition.
To study the radiosensitivity of DNA segments at the open reading frame (gene) level, real-time PCR was used to analyze DNA damages induced by ionizing radiation. After irradiation (1, 3 and 5 kGy) of genomic DNA purified from Salmonella typhimurium, real-time PCR based on SYBR Green fluorescence and melting temperature was performed using various primer sets targeting the rfbJ, rfaJ, rfaB, hilD, ssrB, pipB, sopD, pduQ, eutG, oadB, ccmB and ccmA genes. The ccmA and ccmB genes, which existed as two copies on the chromosome and had a high GC content ( approximately 70%), showed much lower radiosensitivities than the other genes tested, particularly at 5 kGy; this distinctive feature was seen only when the genes were located on the chromosome, regardless of copy number. Our results reinforce the concept that gene sensitivity to ionizing radiation depends on the base composition and/or the spatial localization of the gene on the chromosome.


Fast Removal of Residual Water in Proton Spectra.
Quantification of metabolites in 1H spectra is difficult because of the presence of an unwanted water signal. Preprocessing, or removing the water contribution of a 1H spectrum, in the time domain is usually done using the state-space approach HSVD. HSVD removes the residual water and its side lobes, thereby reducing the baseline for the metabolites of interest and allowing subsequent data analysis using more sophisticated nonlinear least squares algorithms. However, the HSVD algorithm is computationally expensive because it estimates the signal subspace using the singular value decomposition (SVD). We show here that replacing the SVD by a low-rank revealing decomposition speeds up the computations without affecting the accuracy of the wanted parameter estimates. Copyright 1998 Academic Press.


A sensitive method for measuring protein turnover based on the measurement of 2-3H-labelled amino acids in protein.
A method for measuring the rate of protein degradation is described. The method measures the change in 2-3H content of protein with time by racemization of the protein hydrolysate with acetic anhydride. The 3H on C-2 of amino acids is stable in proteins but becomes labile, owing to the action of transaminases, once the amino acids are released by proteolysis. The specific measurement of 2-3H in amino acids largely overcomes problems due to compartmentation and isotope recycling and evidence to support this claim is presented. Values for the half-life of Lemna minor (duckweed) protein determined by the new method are compared with values obtained by other methods.


Effect of isocaloric fat or glucose on albumin synthesis and nitrogen balance in patients receiving amino acid infusion.
Twelve patients who had undergone colon operations were randomized prospectively in the postoperative recovery room. Seven received a hypocaloric intravenous solution consisting of 3.5% amino acids plus 2.5% glucose and five received 3.5% amino acids plus 10% fat. Nitrogen balance data indicated that isocaloric amounts of glucose and fat seem equally effective when combined with amino acids. Although the albumin synthesis rates (measured by the 14C technique on the fourth postoperative day) were not significantly different between the two groups, when the results were included with pooled data from previous similar studies, there was a statistically significant difference which indicated a higher rate of albumin synthesis in patients who received the combination of amino acids and fat compared with those who received amino acids and glucose P < 0.05). In this clinical setting, fat may favor the uptake and synthesis of amino acids into visceral proteins, while glucose may have a more direct role in the synthesis of skeletal muscle protein.


Advances in supportive care of myelodysplastic syndromes.
The myelodysplastic syndromes (MDS) are a heterogenous family of hematologic disorders characterized by ineffective hematopoiesis. Because of the variability between patients regarding prognosis and morbidity related to the disease, consensus regarding the management of these patients has been difficult. Over the past several years, new prognostic scoring systems such as the International Prognostic Scoring System (IPSS) have attempted to provide a projection for long-term stability of the percentage of patients who have "low-grade" or indolent MDS. Unfortunately, its lack of prospective use in clinical trials and other settings has thus far failed to validate it as a functional decision-making tool. Thus, investigators have hypothesized that separating patients based on more simplistic treatment-oriented guidelines may be more efficient. For the majority of patients with MDS, no curative option exists. Patients who are young enough and have an available matched sibling or matched unrelated donor may undergo an allogeneic bone marrow transplant (BMT) with a potential cure rate of 30% to 50%. The major issue regarding this approach is the relatively high morbidity and the risk that the patient's lives may be shortened, that their quality of life will be worsened, or that no overall benefit will occur (relapse). Compounding the issue of selection and timing for BMT is the fact that the best results in terms of relapse-free survival appear to be in the subset of patients with early or low-grade MDS, characterized by refractory anemia with or without ringed sideroblasts. For these patients, lacking a donor for BMT, the major issue has become the consideration of induction chemotherapy. While dose-intensive chemotherapy may improve outcome in a small percentage of patients, the majority of elderly patients with MDS are not optimal candidates for such an approach. As a result, supportive care has a major role for patients with MDS and depending on the French-American-British (FAB) presentation and comorbid illnesses may be the preferred approach. Erythropoietin, a growth factor, is perhaps the most commonly used supportive care after transfusion. The use of colony-stimulating growth factors to support leukopenia is currently under investigation. The use of thrombopoietic agents has lagged behind in the management of MDS patients. Investigation of interleukin-6 (IL-6), a thrombopoietic cytokine, showed some ability to increase platelets through significant toxicity. Investigation of IL-11, an approved thrombopoietic growth factor, is preparing to start and should aid in determining its role in this setting.


Growth kinetics of preexposed and naive populations of Tetrahymena pyriformis to 2-decanone and acetone.
The growth kinetics of preexposed and naive Tetrahymena pyriformis grown in the presence of one hydrophilic and one hydrophobic nonpolar narcotic (acetone and 2-decanone, respectively) have been evaluated. The response of naive Tetrahymena exposed to nonpolar narcotics varied from a change in generation time upon exposure to hydrophilic chemical to a change in lag phase with similar generation time compared to control upon exposure to hydrophobic compounds. Tetrahymena grown in the presence of low concentrations of 2-decanone and then transferred to higher concentrations acclimated to the presence of the toxicant. Acclimation was demonstrated by reduced lag phases compared to naive cells. Results of population growth studies of Tetrahymena grown in the presence of low concentrations of acetone and then transferred to higher concentrations of acetone exhibit the same pattern, an increased generation time with increasing concentration with no lag time, as naive populations. Additionally, the observed generation times in acetone were cumulative relative to the transfer concentration as well as the acclimation concentration. The most feasible explanation for this phenomenon is the interaction of the toxicants with the plasma membrane.


Increased self-awareness in the process of returning to work.
A group of employees on sick leave, living in the Oslo area, Norway, was offered participation in a counselling programme, based on Gestalt theory, mindfulness and phenomenological understanding of the body. To explore the participants' processes of change related to their increased ability to work. METHOD DESIGN: This qualitative study is based on modified grounded theory. A total of 12 female employees, all who had increased work ability 1 year after the programme, participated in open focus-group interviews at the end of the programme. The participants' experiences from processes of change are described through the following categories: becoming more aware of one's own thoughts, emotions and bodily reactions; taking oneself seriously and accepting oneself; being secure enough to face being challenged; realizing new possibilities and choices and trying out new ways of acting. The participants further described what had been helpful in these processes. Experience of a secure setting and open-minded listening seemed important for getting the courage to open up to all reactions. Then, they could explore new ways of thinking, communicating and behaving. Discussing existential issues such as their core values was important. This, together with being allowed to take their own emotions seriously and being challenged by the counsellors, had encouraged the processes of change. The women described how experiences of increased awareness contributed to reconstruction of their self-understanding and opened up for new possibilities. This seemed to have provided them with new ways of communicating and acting, which enhanced participation in work. The context of the learning programme, the existential issues and counselling challenges appeared as essential in these processes of change. The findings give insights into aspects that may be important when designing rehabilitation programmes.


Use of the Humeral Head as a Reference Point to Prevent Axillary Nerve Damage during Proximal Fixation of Humeral Fractures: An Anatomical and Radiographic Study.
Treatment of proximal humeral fractures with plate osteosynthesis or intramedullary nail fixation in humeral shaft fractures with a proximal locking bolt carries the risk of iatrogenic injury of the axillary nerve. The purpose of this anatomical study is to define a more reliable safe zone to prevent iatrogenic axillary nerve injury using the humeral head instead of the acromion as a (radiographic) reference point during operative treatment. Anatomical dissection and labeling of the axillary nerve and branches was performed on 10 specially embalmed human specimens. Standard AP and straight lateral radiographs were made. The distances were measured indirectly from the cranial tip of the humerus to the axillary nerve on radiographs. The median distance from the cranial tip of the humerus to the axillary nerve was 52 mm. The mean number of axillary nerve branches was 3. The distances from the cranial tip of the humerus to the nerve (branch) varied from 23 to 78 mm. The median distance from the proximal (anterior) branch was 36 mm, to the second branch 47 mm, 54 mm to the third branch and 73 mm to the fourth branch. The axillary nerve moves along with the humerus in cranial and caudal direction when the subacromial space varies. This study shows that the position of the axillary nerve can be better determent using the cranial tip of the humerus as a reference point instead of the acromion. Furthermore, it is unsafe to place the proximal locking bolts in the zone between 24 mm and 78 mm from the cranial tip of the humerus. The greatest chance to cause a lesion of the main branch of the axillary nerve is in the zone between 48 mm and 58 mm caudal from the tip of the humeral head. Theeuwes HP, Potters JW, Bessems JHJM, et al. Use of the Humeral Head as a Reference Point to Prevent Axillary Nerve Damage during Proximal Fixation of Humeral Fractures: An Anatomical and Radiographic Study. Strategies Trauma Limb Reconstr 2020;15(2):63-68.


A combination of metabolomics and metallomics studies of urine and serum from hypercholesterolaemic rats after berberine injection.
Berberine, long used as a remedy in China and India for intestinal infections, has been discovered in recent years in western countries and is now being used to treat ailments ranging from urinary tract infections to diabetes and obesity. In order to study the effect of berberine more deeply, a combined metabolomic and metallomic approach was developed in this study using the hypercholesterolaemic rat model, which involved the use of proton nuclear magnetic resonance for the analysis of rat urine to achieve metabolic fingerprinting and inductively coupled plasma mass spectrometry for the analysis of rat blood serum to achieve metallomic fingerprinting. The results obtained indicated that major metabolic processes like Krebs cycle, cholesterol metabolism and osmoregulation in hypercholesterolaemic rats are perturbed upon berberine injection. In addition, the changes of some elements, such as V, Mn, Na and K, revealed in the metallomic study may contribute to the search of new biomarkers for hypercholesterolaemic disease. We concluded that both the metabolomic and metallomic profiles of berberine-treated hypercholesterolaemic rats were different from those of the control group and that the selected metabolites and elements could probably be applied as potential biomarkers for the understanding of the effect of berberine on biochemical process in the animal model. Such a multi-analytical approach will potentially provide an information-rich platform for the elucidation of effects of xenobiotics and drug efficacy studies.


[The Expression Level and Diagnostic Value of Serum Free Light Chain in B-Cell Non-Hodgkin Lymphoma].
To investigate the expression level and the diagnostic value of serum free light chain in B-cell non-Hodgkin's lymphoma (B-NHL). We retrospectively analyzed the results of serum free light chain (sFLC) of 394 newly treated B-NHL patients in our hospital from January 2014 to December 2021 and compared the secretion levels of sFLC among different subtypes of B-NHL. The value of sFLC secretion levels in the diagnosis of WM was evaluated using ROC. Increased proportion of sFLC, abnormal ratio of sFLC (κ / λ) and the secretion levels of sFLC (κ+λ) were different in different B-NHL subtypes, Waldenstrom's macroglobulinemia (WM) had the highest proportion of elevated sFLC(82.68%) and abnormal sFLC(κ/ λ)(87.0%), the proportion of FL(18.0%) and DLBCL patients(12.8%) with elevated sFLC was lower (P<0.05). The expression levels of sFLC can helpful in the diagnosis of WM (AUC=0.874,P<0.001, 95% CI: 0.779-0.970). At the same time, higher sFLC levels and sFLC cloning patterns predicted the possibility of bone marrow infiltration of lymphoma. The serum free light chains is common in patients with B-NHL. The elevated level and type of free light chain are associated with the type of lymphoma, and the patients with bone marrow infiltration have higher sFLC(κ+ λ) expression level.


Cigarette smoking and thinning of the brain's cortex.
Cigarette smoking is associated with cognitive decline and dementia, but the extent of the association between smoking and structural brain changes remains unclear. Importantly, it is unknown whether smoking-related brain changes are reversible after smoking cessation. We analyzed data on 504 subjects with recall of lifetime smoking data and a structural brain magnetic resonance imaging at age 73 years from which measures of cortical thickness were extracted. Multiple regression analyses were performed controlling for gender and exact age at scanning. To determine dose-response relationships, the association between smoking pack-years and cortical thickness was tested and then repeated, while controlling for a comprehensive list of covariates including, among others, cognitive ability before starting smoking. Further, we tested associations between cortical thickness and number of years since last cigarette, while controlling for lifetime smoking. There was a diffuse dose-dependent negative association between smoking and cortical thickness. Some negative dose-dependent cortical associations persisted after controlling for all covariates. Accounting for total amount of lifetime smoking, the cortex of subjects who stopped smoking seems to have partially recovered for each year without smoking. However, it took ~25 years for complete cortical recovery in affected areas for those at the mean pack-years value in this sample. As the cortex thins with normal aging, our data suggest that smoking is associated with diffuse accelerated cortical thinning, a biomarker of cognitive decline in adults. Although partial recovery appears possible, it can be a long process.


Cardiovascular effects of nitric oxide and adenosine in the nucleus tractus solitarii of rats.
It has been shown that nitric oxide (NO) is synthesized in the central nervous system as well as in vascular endothelial cells. We recently reported that NO was involved in central cardiovascular regulation, modulated the baroreflex, and was involved in a reciprocal release with excitatory amino acids in the nucleus tractus solitarii (NTS) of rats. We also reported previously that adenosine increased the release of glutamate in the NTS. The purpose of the present study was to investigate the possible interaction of NO and adenosine in the NTS. Male Sprague-Dawley rats were anesthetized with urethane, and blood pressure was monitored intra-arterially. Unilateral microinjection of L-arginine (3.3 nmol/60 nL) into the NTS produced decreases in blood pressure and heart rate. Microinjection of adenosine (2.3 nmol/60 nL) also produced depressive and bradycardic effects. These cardiovascular effects were attenuated by prior administration of the specific adenosine receptor antagonist DPSPX (0.92 nmol). Similarly, prior administration of NO synthase inhibitor NG-monomethyl-L-arginine or NG-nitro-L-arginine methyl ester significantly attenuated the depressive and bradycardic effects of adenosine. These results demonstrate a reciprocal attenuation of adenosine receptor antagonist and NO synthase inhibitor on L-arginine and adenosine responses, respectively, in the NTS and implicate an interaction between NO and adenosine in central cardiovascular regulation.


Decay of cystalline order and equilibration during the solid-to-plasma transition induced by 20-fs microfocused 92-eV free-electron-laser pulses.
We have studied a solid-to-plasma transition by irradiating Al foils with the FLASH free electron laser at intensities up to 10(16) W/cm(2). Intense XUV self-emission shows spectral features that are consistent with emission from regions of high density, which go beyond single inner-shell photoionization of solids. Characteristic features of intrashell transitions allowed us to identify Auger heating of the electrons in the conduction band occurring immediately after the absorption of the XUV laser energy as the dominant mechanism. A simple model of a multicharge state inverse Auger effect is proposed to explain the target emission when the conduction band at solid density becomes more atomiclike as energy is transferred from the electrons to the ions. This allows one to determine, independent of plasma simulations, the electron temperature and density just after the decay of crystalline order and to characterize the early time evolution.


Moderate alcohol consumption and atherosclerosis : Meta-analysis of effects on lipids and inflammation.
Alcohol consumption plays an important role in the risk of major cardiovascular diseases. We conducted a meta-analysis to summarize the association between moderate alcohol consumption and atherosclerosis. In this study four databases and reference lists of retrieved articles were searched to identify eligible studies. A meta-analysis was carried out of all interventional studies that assessed the effects of moderate alcohol consumption on concentrations of low density lipoprotein cholesterol, high density lipoprotein cholesterol, triglycerides, apolipoprotein A I, interleukin 6, plasminogen activator inhibitor 1, fibrinogen, and other biomarkers previously found to be associated with risk of atherosclerosis. A total of 31 studies met the eligibility criteria. In response to moderate alcohol consumption, low density lipoprotein cholesterol decreased by 0.08 mmol/l (P = 0.05), and high density lipoprotein cholesterol increased by 0.08 mmol/l (P < 0.00001), whereas total cholesterol and triglyceride remained the same. Moreover, interleukin 6 decreased by 0.43 pg/ml (P = 0.03), whereas C‑reactive protein and tumor necrosis factor a remained the same. Several hemostatic factors and adiponectin were modestly affected by alcohol consumption. Moderate alcohol consumption is causally related to lower risk of atherosclerosis through changes in lipid profiles and inflammation.


Regression of cutaneous invasive squamous cell carcinoma in a patient with chronic cutaneous graft versus host disease.
Numerous complications can be observed in the post-transplant period among recipients of hematopoietic stem cells including graft-versus-host disease (GVHD), which is associated with significant morbidity and mortality. On the other hand, graft versus tumor (GVT) effect is a well-described phenomenon in patients with hematologic malignancies and has also been reported in renal cell cancer, ovarian cancer, breast carcinoma, and melanoma. We describe spontaneous regression of a cutaneous invasive squamous cell carcinoma and multifocal atypical intraepidermal proliferations in a patient with chronic graft-versus-host disease following initiation of extracorporeal photopheresis (ECP). This observation raises questions regarding the GVT in cutaneous neoplasms and potential immunomodulatory effects of ECP.


Frequency of persistent tooth pain after root canal therapy: a systematic review and meta-analysis.
Little is known about the frequency of persistent pain after endodontic procedures even though pain is a core patient-oriented outcome. We estimated the frequency of persistent pain, regardless of etiology, after endodontic treatment. Persistent tooth pain was defined as pain present > or = 6 months after endodontic treatment. Endodontic procedures included in the review were pulpectomy, nonsurgical root canal treatment, surgical root canal treatment, and retreatment. Four databases were searched electronically complemented by hand searching. Two independent reviewers determined eligibility, abstracted data, and assessed study quality. A summary estimate of persistent all-cause tooth pain frequency was established by using a random-effects meta-analysis. Using subgroup analyses, we explored the influence of treatment approach (surgical/nonsurgical), longitudinal study design (prospective/retrospective), follow-up rate, follow-up duration, initial treatment versus retreatment, and quality of reporting (Strengthening the Reporting of Observational Studies in Epidemiology rankings) on the pain frequency estimate. Of 770 articles retrieved and reviewed, 26 met inclusion criteria. A total of 5,777 teeth were enrolled, and 2,996 had follow-up information regarding pain status. We identified 168 teeth with pain and derived a frequency of 5.3% (95% confidence interval, 3.5%-7.2%, p < 0.001) for persistent all-cause tooth pain. High and statistically significant heterogeneity among studies (I2 = 80%) was present. In subgroup analysis, prospective studies had a higher pain frequency (7.6%) than retrospectives studies did (0.9%). Quality of study reporting was identified as the most influential reason for study heterogeneity. The frequency of all-cause persistent tooth pain after endodontic procedures was estimated to be 5.3%, with higher report quality studies suggesting >7%.


Use of desmopressin acetate in severe hyponatremia in the intensive care unit.
Excessive correction of chronic and profound hyponatremia may result in central pontine myelinolysis and cause permanent brain damage. In the case of foreseeable or established hyponatremia overcorrection, slowing down the correction rate of sodium plasma levels (PNa) or reinducing mild hyponatremia may prevent this neurologic complication. This retrospective and observational study was performed with 20 consecutive patients admitted to two intensive care units for severe hyponatremia, defined by PNa <120 mmol/L and/or neurologic complications ascribable to hyponatremia and subsequently treated by desmopressin acetate (DDAVP) during correction of hyponatremia when the rate of correction was overtly or predictably excessive. The primary endpoint was the effectiveness of DDAVP on PNa control. DDAVP dramatically decreased the rate of PNa correction (median 0.81 mmol/L per hour [interquartile range, 0.46, 1.48] versus -0.02 mmol/L per hour [-0.16, 0.22] before and after DDAVP, respectively; P<0.001) along with a concurrent decrease in urine output (650 ml/h [214, 1200] versus 93.5 ml/h [43, 143]; P=0.003), and a rise in urine osmolarity (86 mmol/L [66, 180] versus 209 mmol/L [149, 318]; P=0.002). The maximal magnitude of PNa variations was also markedly reduced after DDAVP administration (11.5 mmol/L [8.25, 14.5] versus 5 mmol/L [4, 6.75]; P<0.001). No patient developed seizures after DDAVP or after subsequent relowering of PNa that occurred in 11 patients. Desmopressin acetate is effective in curbing the rise of PNa in patients admitted in the intensive care unit for severe hyponatremia, when the initial rate of correction is excessive.


Listeria monocytogenes. Macroabscesses of placenta.
Macroabscesses of placenta caused by Listeria monocytogenes were observed in a 37-year-old febrile primigravida. She was prematurely delivered of a depressed 2310-g infant, who was resuscitated and promptly treated with antibiotics. Mother and child are well at 10-year followup. Although perinatal listeriosis with placentitis is not rare, its presentation as macroabscesses of the placenta has until now gone unreported in the English language literature.


Study designs for dependent happenings.
In 1916, Sir Ronald Ross defined "dependent happenings" as events where the number affected in a unit of time depends on the number already affected. That is, the incidence depends on the prevalence, a characteristic of many infectious diseases. Because of this dependence, interventions against infectious diseases can have not only direct protective effects for the person receiving an intervention, but also indirect effects resulting from changes in the intensity of transmission in the population. This paper develops the conceptual framework for four types of study designs that differentiate and account for direct and indirect effects of intervention programs in dependent happenings.


Effectiveness of postoperative irradiation in stage IIIA non-small cell lung cancer according to regression tree analyses of recurrence risks.
In the setting of grossly resected stage IIIA (N2 involvement) non-small cell lung carcinoma, the role of adjuvant postoperative thoracic radiation therapy (TRT) remains controversial. This study was initiated to subcategorize these patients into high-, intermediate-, and low-risk groups with respect to local recurrence and survival rates, and to determine whether there were certain subgroups of patients who were particularly likely or unlikely to benefit from postoperative TRT. Two hundred twenty-four patients were studied. A regression tree analysis was used to separate patients who had undergone operation alone into groups that had a high, intermediate, or low risk of local recurrence and death. The effect of adjuvant postoperative TRT then was examined in each of these groups. The use of adjuvant postoperative TRT (compared with operation alone) was associated with an improvement in freedom from local recurrence and survival for patients who had an intermediate or high risk of local recurrence and death. However, the greatest level of improvement in freedom from local recurrence (p < 0.0001) and survival (p = 0.0002) associated with the use of adjuvant postoperative TRT was in the high-risk group. Similarly, but of lesser magnitude, the intermediate-risk group had improved freedom from local recurrence and survival rates with the use of adjuvant post-operative TRT (p = 0.002 and p = 0.01, respectively). For the low-risk group, the freedom from local recurrence and survival rates were not statistically different between the patients who received adjuvant postoperative TRT and those who underwent observation. Patients with non-small cell lung carcinoma involving ipsilateral mediastinal lymph nodes (stage IIIA) who undergo gross resection and who are at either high or intermediate risk for local recurrence and death are likely to benefit from adjuvant postoperative irradiation. The role of radiation therapy in low-risk patients is unclear. Prospective confirmation of these observations is warranted.


Cerebral small vessel disease, cognitive impairment and vascular dementia.
In recent years, accumulating evidence has suggested that vascular risk factors (especially hypertension, and also diabetes, high level of cholesterol and smoking) contribute to Alzheimer disease. Vascular dementia had been traditionally considered secondary to stroke and vascular disease. However it appears that there is a continuous spectrum of disease, composed of a gradient of features of both types of dementia. The brain is an early target for organ damage due to high blood pressure. Hypertension is the major modifiable risk factor for stroke and small vessel disease and is known to be the most-important factor for macrovascular cerebral complications such as atherotrombotic stroke and, consequently, vascular dementia. Hypertension may also predispose to more subtle cerebral processes based on arteriolar narrowing or microvascular pathological changes. The term cerebral small vessel disease refers to a group of pathological processes with various etiologies that affect the small arteries, arterioles, venules, and capillaries of the brain. Age-related and hypertension-related small vessel diseases and cerebral amyloid angiopathy are the most common forms. It has been suggested that cerebral microvascular disease contributes to vascular cognitive impairment. The mechanisms underlying hypertension-related cognitive changes are complex and not yet fully understood. Both high and, especially in the elderly, low blood pressure have been linked to cognitive decline and dementia. There is some evidence that antihypertensive drug treatment could play a role in the prevention of cognitive impairment or vascular dementia through BP control. The BP levels that should be targeted to achieve optimal perfusion while preventing cognitive decline are still under debate.


Analysis of erythrocyte and platelet membrane proteins in various forms of beta-thalassemia.
Major membrane proteins have been quantitatively analyzed in erythrocytes and platelets from patients with homozygous (splenectomized and non-splenectomized) and heterozygous forms of beta-thalassemia depending on severity of clinical manifestation of this disease. Quantitative analysis of erythrocyte membrane proteins revealed increase in alpha- and beta-spectrin. (In non-splenectomized patients with homozygous beta-thalassemia the amount of this protein was lower than in corresponding controls.) Besides spectrin, the increase of 2.1-2.3 fractions of ankyrin, and the decrease of band 3 protein (anion-transport protein), 4.1, palladin, and glyceraldehyde-3-phosphate dehydrogenase were also found. Analysis of major platelet membrane proteins revealed significant increase in gelsolin. This increase was found in all forms of beta-thalassemia irrespective of gender. Significant changes in platelet membrane protein fractions were found in patients (especially non-splenectomized) with homozygous beta-thalassemia. These included significant decrease in myosin, profilin, and gamma-actin and increase in actin-binding protein in both male and female patients. The content of other protein fractions (alpha-actinin, tubulin, tropomyosin) remained unchanged. Changes in protein fractions of erythrocytes and platelets correlated with severity of clinical manifestation of the disease.


Current Models for Development of Disease-Modifying Osteoarthritis Drugs.
Osteoarthritis (OA) is a painful and disabling disease that affects millions of people worldwide. Symptom-alleviating treatments exist, although none with long-term efficacy. Furthermore, there are currently no disease-modifying OA drugs (DMOADs) with demonstrated efficacy in OA patients, which is, in part, attributed to a lack of full understanding of the pathogenesis of OA. The inability to translate findings from basic research to clinical applications also highlights the deficiencies in the available OA models at simulating the clinically relevant pathologies and responses to treatments in humans. In this review, the current status in the development of DMOADs will be first presented, with special attention to those in Phase II-IV clinical trials. Next, current in vitro, ex vivo, and in vivo OA models are summarized and the respective advantages and disadvantages of each are highlighted. Of note, the development and application of microphysiological or tissue-on-a-chip systems for modeling OA in humans are presented and the issues that need to be addressed in the future are discussed. Microphysiological systems should be given serious consideration for their inclusion in the DMOAD development pipeline, both for their ability to predict drug safety and efficacy in human clinical trials at present, as well as for their potential to serve as a test platform for personalized medicine. Impact statement At present, no disease-modifying osteoarthritis (OA) drugs (DMOADs) have been approved for widespread clinical use by regulatory bodies. The failure of developing effective DMOADs is likely owing to multiple factors, not the least of which are the intrinsic differences between the intact human knee joint and the preclinical models. This work summarizes the current OA models for the development of DMOADs, discusses the advantages/disadvantages of each, and then proposes future model development to aid in the discovery of effective and personalized DMOADs. The review also highlights the microphysiological systems, which are emerging as a new platform for drug development.


Quantifying treatment selection bias effect on survival in comparative effectiveness research: findings from low-risk prostate cancer patients.
Comparative effectiveness research (CER) using national registries influences cancer clinical trial design, treatment guidelines, and patient management. However, the extent to which treatment selection bias (TSB) affects overall survival (OS) in cancer CER remains poorly defined. We sought to quantify the TSB effect on OS in the setting of low-risk prostate cancer, where 10-year prostate cancer-specific survival (PCSS) approaches 100% regardless of treatment modality. The Surveillance, Epidemiology, and End Results database was queried for patients with low-risk prostate cancer (cT1-T2a, PSA < 10, and Gleason 6) who received radical prostatectomy (RP), brachytherapy (BT), or external beam radiotherapy (EBRT) from 2005 to 2015. The TSB effect was defined as the unadjusted 10-year OS difference between modalities that was not due to differences in PCSS. Propensity score matching was used to estimate the TSB effect on OS due to measured confounders (variables present in the database and associated with OS) and unmeasured confounders. A total of 50,804 patients were included (8845 RP; 18,252 BT; 23,707 EBRT) with a median follow-up of 7.4 years. The 10-year PCSS for the entire cohort was 99%. The 10-year OS was 92.9% for RP, 83.6% for BT, and 76.9% for EBRT (p < 0.001). OS differences persisted after propensity score matching of RP vs. EBRT (7.4%), RP vs. BT (4.6%), and BT vs. EBRT (3.7%) (all p < 0.001). The TSB effect on 10-year OS was estimated to be 15.0% for RP vs. EBRT (8.6% measured, 6.4% unmeasured), 8.5% for RP vs. BT (4.8% measured, 3.7% unmeasured), and 6.5% for BT vs. EBRT (3.1% measured, 3.4% unmeasured). Patients with low-risk prostate cancer selected for RP exhibited large OS differences despite similar PCSS compared to radiotherapy, suggesting OS differences are almost entirely driven by TSB. The quantities of these effects are important to consider when interpreting prostate cancer CER using national registries.


Using lateral radiographs to determine umbilical venous catheter tip position in neonates.
We aimed to assess the difference in measurement of the distance of the UVC tip from the diaphragm between (Anteroposterior) AP and lateral radiographs and to determine the reliability of the measurement of UVC tip distance from the diaphragm between the two views. A retrospective review of paired AP and lateral radiographs taken to assess UVC tip position was carried out in 25 infants was conducted and reliability analysis was carried out. There was a significant difference in the mean (SD) distance of the UVC catheter above the diaphragm between the AP and lateral radiographs: 8.7 (7.8) mm versus 11.6 (7.3) mm (p = 0.003) respectively. Measurements using lateral radiographs were more reliable (Intraclass correlation coefficient: 0.99 vs. 0.93). Inter-observer reliability analysis yielded similar results. Lateral radiographs are more reliable in measurement of UVC tip position and should be performed in conjunction with AP films to aid in determining UVC position.


The effect of ICP monitoring in severe traumatic brain injury: a propensity score-weighted and adjusted regression approach.
The use of intracranial pressure (ICP) monitoring has been postulated to be beneficial in patients with severe traumatic brain injury (TBI), although studies investigating this hypothesis have reported conflicting results. The objective of this study was to evaluate the effect of inserting an ICP monitor on survival in patients with severe TBI. The Oslo University Hospital trauma registry was searched for the records of all patients admitted between January 1, 2002, and December 31, 2013, who fulfilled the Brain Trauma Foundation criteria for intracranial hypertension and who survived at least 24 hours after admission. The impact of ICP monitoring was investigated using both a logistic regression model and a multiple imputed, propensity score-weighted logistic regression analysis. The study involved 1327 patients, in which 757 patients had an ICP monitor implanted. The use of ICP monitors significantly increased in the study period (p < 0.01). The 30-day overall mortality was 24.3% (322 patients), divided into 35.1% (200 patients, 95% confidence interval [CI] 31.3%-39.1%) in the group without an ICP monitor and 16.1% (122 patients, 95% CI 13.6%-18.9%) in the group with an ICP monitor. The impact of ICP monitors on 30-day mortality was found to be beneficial both in the complete case analysis logistic regression model (odds ratio [OR] 0.23, 95% CI 0.16-0.33) and in the adjusted, aggregated, propensity score-weighted imputed data sets (OR 0.22, 95% CI 0.15-0.35; both p < 0.001). The sensitivity analysis indicated that the findings are robust to unmeasured confounders. The authors found that the use of an ICP monitor is significantly associated with improved survival in patients with severe head injury.


Trends in Healthcare Expenditures Among US Adults With Hypertension: National Estimates, 2003-2014.
One in 3 US adults has high blood pressure, or hypertension. As prior projections suggest hypertension is the costliest of all cardiovascular diseases, it is important to define the current state of healthcare expenditures related to hypertension. We used a nationally representative database, the Medical Expenditure Panel Survey, to calculate the estimated annual healthcare expenditure for patients with hypertension and to measure trends in expenditure longitudinally over a 12-year period. A 2-part model was used to estimate adjusted incremental expenditures for individuals with hypertension versus those without hypertension. Sex, race/ethnicity, education, insurance status, census region, income, marital status, Charlson Comorbidity Index, and year category were included as covariates. The 2003-2014 pooled data include a total sample of 224 920 adults, of whom 36.9% had hypertension. Unadjusted mean annual medical expenditure attributable to patients with hypertension was $9089. Relative to individuals without hypertension, individuals with hypertension had $1920 higher annual adjusted incremental expenditure, 2.5 times the inpatient cost, almost double the outpatient cost, and nearly triple the prescription medication expenditure. Based on the prevalence of hypertension in the United States, the estimated adjusted annual incremental cost is $131 billion per year higher for the hypertensive adult population compared with the nonhypertensive population. Individuals with hypertension are estimated to face nearly $2000 higher annual healthcare expenditure compared with their nonhypertensive peers. This trend has been relatively stable over 12 years. Healthcare costs associated with hypertension account for about $131 billion. This warrants intense effort toward hypertension prevention and management.


A comparison of the interaction of glucagon, human parathyroid hormone-(1-34)-peptide and calcitonin with dimyristoylphosphatidylglycerol and with dimyristoylphosphatidylcholine.
The interaction of glucagon, human parathyroid hormone-(1-34)-peptide and salmon calcitonin with dimyristoylphosphatidylglycerol (DMPG) and with dimyristoylphosphatidylcholine (DMPC) was studied as a function of pH and temperature. The effect of lipid on the secondary structure of the peptide was assessed by circular dichroism and the effect of the peptide on the phase transition properties of the lipid was studied using differential scanning calorimetry. Some peptides interact more strongly with anionic than with zwitterionic phospholipids. This does not require an overall positive charge on the peptide. Increased thermal stability is observed in complexes formed between cationic peptides and anionic lipids. Particularly marked effects of glucagon and human parathyroid hormone-(1-34)-peptide on the phase transition properties of DMPG at pH 5 have been observed. The transition temperature is raised over 10 degrees C at a lipid/peptide molar ratio of less than 30:1 and the transition enthalpy is increased over 2-fold. These effects do not occur with any basic peptide and were not observed with metorphinamide, molluscan cardioexcitatory neuropeptide or myelin basic protein. The results demonstrate that certain peptides can affect the phase transition properties of lipids in a manner similar to divalent cations. The overall hydrophobicities of these peptides can be evaluated by their partitioning between aqueous and organic solvents. None of the above three peptide hormones partition into the organic phase. However, a closely related peptide, human calcitonin, does exhibit substantial partitioning into the organic phase. Nevertheless, human calcitonin has a weaker interaction with both DMPC and DMPG than does salmon calcitonin. The effects of human calcitonin on the phase transition of DMPC are qualitatively different from those of salmon calcitonin in that the human form more readily eliminates the pretransition but causes less change in the main transition. Like overall charge, overall hydrophobicity is not an overwhelming factor in determining the ability of peptides to interact with phospholipids but rather more specific interactions are required for strong complexes to form.


Management of carbon monoxide poisoning using oxygen therapy.
The management of carbon monoxide poisoning requires an accurate assessment of the extent of blood oxygenation. Measuring the fractional oxyhaemoglobin content by using co-oximetry gives a true picture of the oxygen-carrying capacity of blood in the presence of carboxyhaemoglobin. The use of readings from pulse oximetry or a standard blood gas analyser is insufficient and can be misleading. We report on a case of carbon monoxide poisoning to illustrate this potential pitfall.


Efficacy of boron neutron capture therapy on liver metastases of colon adenocarcinoma: optical and ultrastructural study in the rat.
The effect of neutron boron capture therapy (BNCT) was studied in rat tumor liver cells after induction of the liver metastases by splenic inoculation of cells from DHA/K12/TRb line. Ten days following the treatment, the BPA was injected into rats and therefore the animals were sacrificed, the liver was exposed to neutron irradiation and processed. In some experiments the liver was reimplanted (after irradiation) in syngenic animals and studied 3 days later, following sacrifice. Samples of tissue obtained from metastasised and non-metastasised areas of the liver parenchyma, before and after the neutron irradiation, were examined in light microscopy and electron microscopy. The analysis pointed out damages induced by the neutron treatment in single tumor cells mostly localised in the synusoidal blood stream. Debris and apoptotic cells were sometimes observed in the neoplastic nodules before treatment, while the tumor cell death (apoptosis) increased in the tumor cells following BNCT treatment. An intense scavenger activity of Kupffer cells after irradiation was accompanied by a strong acid phosphatase reaction detectable in wide cytoplasmic areas. In the liver parenchyma of reimplanted animals, the presence of large collagen bundles spread among the hepatocytes was observed at electron microscopy.


Intakes of vitamins A, C, and E and use of multiple vitamin supplements and risk of colon cancer: a pooled analysis of prospective cohort studies.
To evaluate the associations between intakes of vitamins A, C, and E and risk of colon cancer. Using the primary data from 13 cohort studies, we estimated study- and sex-specific relative risks (RR) with Cox proportional hazards models and subsequently pooled RRs using a random effects model. Among 676,141 men and women, 5,454 colon cancer cases were identified (7-20 years of follow-up across studies). Vitamin A, C, and E intakes from food only were not associated with colon cancer risk. For intakes from food and supplements (total), the pooled multivariate RRs (95% CI) were 0.88 (0.76-1.02, >4,000 vs. ≤ 1,000 μg/day) for vitamin A, 0.81 (0.71-0.92, >600 vs. ≤ 100 mg/day) for vitamin C, and 0.78 (0.66-0.92, > 200 vs. ≤ 6 mg/day) for vitamin E. Adjustment for total folate intake attenuated these associations, but the inverse associations with vitamins C and E remained significant. Multivitamin use was significantly inversely associated with colon cancer risk (RR = 0.88, 95% CI: 0.81-0.96). Modest inverse associations with vitamin C and E intakes may be due to high correlations with folate intake, which had a similar inverse association with colon cancer. An inverse association with multivitamin use, a major source of folate and other vitamins, deserves further study.