Bioanalytical Measurements Enabled by Surface-Enhanced Raman Scattering (SERS) Probes.
Since its discovery in 1974, surface-enhanced Raman scattering (SERS) has gained momentum as an important tool in analytical chemistry. SERS is used widely for analysis of biological samples, ranging from in vitro cell culture models, to ex vivo tissue and blood samples, and direct in vivo application. New insights have been gained into biochemistry, with an emphasis on biomolecule detection, from small molecules such as glucose and amino acids to larger biomolecules such as DNA, proteins, and lipids. These measurements have increased our understanding of biological systems, and significantly, they have improved diagnostic capabilities. SERS probes display unique advantages in their detection sensitivity and multiplexing capability. We highlight key considerations that are required when performing bioanalytical SERS measurements, including sample preparation, probe selection, instrumental configuration, and data analysis. Some of the key bioanalytical measurements enabled by SERS probes with application to in vitro, ex vivo, and in vivo biological environments are discussed.


Parental views of in-home services: what predicts satisfaction with child welfare workers?
Evidence on client satisfaction deserves consideration in the design of child welfare policies, programs, and practices. Data in this study come from the National Survey of Child and Adolescent Well-Being. Clients receiving in-home services reported moderate levels of satisfaction with their child welfare workers. Caregiver reports of having less than two child welfare workers, having more recent contact, and receiving timely, responsive services were associated with higher perceived quality of relationships with child welfare workers. The child welfare workers' reports of cooperativeness by the caregiver were also associated with higher caregiver-reported relationship quality.


Prospective carbon footprint comparison of hydrogen options.
The Life Cycle Assessment methodology is often used to evaluate the environmental performance of hydrogen energy systems. However, even though hydrogen is usually seen as a strategic energy carrier for the future energy sector, there is a lack of case studies assessing its prospective life-cycle performance. In order to contribute to filling this gap, this work addresses a carbon footprint comparison of hydrogen options from a prospective standpoint. Four relevant hydrogen production pathways (steam methane reforming, grid-powered alkaline electrolysis, wind-powered alkaline electrolysis, and biomass gasification) under three time scenarios (reference, year 2030, and year 2050) are assessed, taking into account the expected evolution of key technical parameters such as efficiencies, lifespans, and the grid electricity mix. The results show a favourable carbon footprint of renewable hydrogen from biomass gasification and wind electrolysis, with a relatively steady near-zero carbon footprint. Despite the unfavourable carbon footprint results of conventional hydrogen from steam methane reforming and hydrogen from grid electrolysis, the latter is associated with a rapid trend towards a suitable long-term carbon footprint.


Polycomb domain formation depends on short and long distance regulatory cues.
Polycomb group (PcG) proteins dynamically define cellular identities through the epigenetic repression of key developmental genes. In Drosophila, cis-regulatory regions termed PcG response elements (PREs) act as nucleation sites for PcG proteins to create large repressive PcG domains that are marked by trimethylation of lysine 27 on histone H3 (H3K27me3). In addition to an action in cis, PREs can interact over long distances, thereby enhancing PcG dependent silencing. How PcG domains are established, which factors limit their propagation in cis, and how long range interactions of PREs in trans affect the chromatin structure is largely unknown. We demonstrate that the insertion of a PRE-containing transgene in the Drosophila genome generates an artificial PcG domain and we analyze its organization by quantitative ChIP and ChIP-on-chip experiments. Intriguingly, a boundary element and known insulator proteins do not necessarily interfere with spreading of H3K27me3. Instead, domain borders correlate with the presence of promoter regions bound by RNA Polymerase II and active chromatin marks. In contrast, genes that are silent during early fly development get included within the PcG domain and this incorporation interferes with gene activation at later developmental stages. Moreover, trans-interaction of the transgenic PRE with its homologous endogenous PRE results in increased PcG binding, correlating with reinforced silencing of genes within the domain borders. Our results suggest that higher-order organization of PcG-bound chromatin can stabilize gene silencing within PcG domains. Further we propose that multi-protein complexes associated with active promoters are able to define the limits of PcG domains. Future work aimed to pinpoint the factors providing this barrier function will be required to understand the precise molecular mechanism by which active promoter regions can act as boundaries to stop spreading of H3K27me3.


National Longitudinal Comparison of Patients Undergoing Surgical Management of Craniosynostosis.
Limited cross-institutional studies compare strip craniectomy versus cranial vault remodeling (CVR) for craniosynostosis management. Given competing surgical preferences, the authors conducted a large-scale analysis of socioeconomic differences, costs, and complications between treatment options. Nonsyndromic craniosynostosis patients receiving strip craniectomies or CVR were identified in the Kids' Inpatient Database for years 2000 to 2009. Demographics, socioeconomic background, hospital characteristics, charge, and outcomes were tabulated. Univariate and multivariate analyses were performed for comparison. Two hundred fifty-one strip craniectomies and 1811 CVR patients were captured. Significantly more strip craniectomy patients were White while more CVR patients were Hispanic or Black (P < 0.0001). Strip craniectomy patients more often had private insurance and CVR patients had Medicaid (P < 0.0001). Over time, CVR trended toward treating a higher proportion of Hispanic and Medicaid patients (P = 0.036). Peri-operative charges associated with CVR were $27,962 more than strip craniectomies, and $11,001 after controlling for patient payer, income, bedsize, and length of stay (P < 0.0001). Strip craniectomies were performed more frequently in the West and Midwest, while CVR were more common in the South (P = 0.001). Length of stay was not significant. Postsurgical complications were largely equivocal; CVR was associated with increased accidental puncture (P = 0.025) and serum transfusion (P = 0.002). Our national longitudinal comparison demonstrates widening socioeconomic disparities between strip craniectomy and CVR patients. Cranial vault remodeling is more commonly performed in underrepresented minorities and patients with Medicaid, while strip craniectomy is common in the White population and patients with private insurance. While hospital charges and complications were higher among CVR, differences were smaller than expected.


Selective interactions between diverse STEs organize the ANT-C Hox cluster.
The three-dimensional organization of the eukaryotic genome is important for its structure and function. Recent studies indicate that hierarchies of chromatin loops underlie important aspects of both genomic organization and gene regulation. Looping between insulator or boundary elements interferes with enhancer-promoter communications and limits the spread active or repressive organized chromatin. We have used the SF1 insulator in the Drosophila Antennapedia homeotic gene complex (ANT-C) as a model to study the mechanism and regulation of chromatin looping events. We reported previously that SF1 tethers a transient chromatin loop in the early embryo that insulates the Hox gene Sex comb reduce from the neighbor non-Hox gene fushi tarazu for their independent regulation. To further probe the functional range and connectivity of SF1, we used high-resolution chromosomal conformation capture (3C) to search for SF1 looping partners across ANT-C. We report here the identification of three distal SF1 Tether Elements (STEs) located in the labial, Deformed and Antennapedia Hox gene regions, extending the range of SF1 looping network to the entire complex. These novel STEs are bound by four different combinations of insulator proteins and exhibit distinct behaviors in enhancer block, enhancer-bypass and boundary functions. Significantly, the six STEs we identified so far map to all but one of the major boundaries between repressive and active histone domains, underlining the functional relevance of these long-range chromatin loops in organizing the Hox complex. Importantly, SF1 selectively captured with only 5 STEs out of ~20 sites that display similar insulator binding profiles, indicating that presence of insulator proteins alone is not sufficient to determine looping events. These findings suggest that selective interaction among diverse STE insulators organize the Drosophila Hox genes in the 3D nuclear space.


Effect of Perioperative Stroke on Survival After Carotid Intervention.
Perioperative stroke is the most dreaded complication of carotid artery interventions and can severely affect patients' quality of life. This study evaluated the impact of this event on mortality for patients undergoing interventional treatment of carotid artery stenosis with three different modalities. Patients undergoing carotid revascularization at participating Memorial Hermann Health System facilities were captured from 2003-2022. These patients were treated with either carotid endarterectomy (CEA), transfemoral carotid stenting (TF-CAS), or transcarotid artery revascularization (TCAR). Perioperative outcomes, including stroke and mortality, as well as follow-up survival data at 6-month intervals, were analyzed and stratified per treatment modality. Of the 1681 carotid revascularization patients identified, 992 underwent CEA (59.0%), 524 underwent TCAR (31.2%), and 165 underwent TF-CAS (9.8%). The incidence of stroke was 2.1% (CEA 2.1%, TCAR 1.7%, and TF-CAS 3.6%; P = .326). The perioperative (30-day) death rate was 2.1% (n = 36). The perioperative death rate was higher in patients who suffered from an intraoperative stroke than in those who did not (8.3% vs 1.9%, P = .007). Perioperative death was also different between CEA, TCAR, and TF-CAS for patients who had an intraoperative stroke (.0% vs 33.3% vs .0%, P = .05). TCAR patients were likely to be older (P < .001), have a higher body mass index (P < .001), and have diabetes mellitus (P < .001). Patients who suffered from an intraoperative stroke were more likely to have a symptomatic carotid lesion (58.3% vs 28.8%, P < .001). The TCAR group had a significantly lower survival at 6 months and 12 months when compared to the other two groups (64.9% vs 100% P = .007). Perioperative stroke during carotid interventions significantly impacts early patient survival with otherwise no apparent change in mid-term outcomes at 5 years. This difference appears to be even more significant in patients undergoing TCAR, possibly due to their baseline higher-risk profile and lower functional reserve.


Efficacy of neoadjuvant cisplatin and oral capecitabine in triple-negative breast cancers: a pilot study.
Due to the lack of molecular targets, triple-negative breast cancers (TNBCs) typically represent a worse prognosis compared to their hormone-positive counterparts. While neoadjuvant chemotherapy has been used for breast cancers for a long time, there is no standard chemotherapy regimen for TNBCs. Cisplatin has generally been regarded as an effective chemotherapy agent against TNBCs. However, here we present a pilot study involving the use of cisplatin in combination with oral capecitabine in the neoadjuvant setting in 16 patients with TNBC. Twelve patients were African American and 4 patients were white. Six patients completed all 4 cycles of chemotherapy, 6 patients completed 3 cycles, and 4 patients completed 2 cycles. A complete clinical response was observed in 2 patients, and 10 patients achieved partial clinical response. One patient had progressive disease, and 3 patients were lost to follow-up or taken off study. Following chemotherapy, 12 patients underwent surgery (7 patients had breast conservation, and 5 patients had a mastectomy). Ten of the 12 patients who had surgery achieved a partial pathologic response and the other 2 patients had complete pathologic response. Grade 3 nausea, vomiting, and diarrhea occurred in 7 patients; 1 patient experienced dehydration and renal failure; and 5 patients had grade 1/2 hand-foot syndrome. There were no grade 4 or 5 toxicities. The response to cisplatin-capecitabine combination chemotherapy in the neoadjuvant setting was suboptimal compared to that with single-agent cisplatin in prior studies. The toxicity profile with this combination was also worse than that of cisplatin alone. Based on our findings, we do not recommend this combination regimen in the neoadjuvant setting for TNBCs. However, future studies analyzing the use of cisplatin with other combinations are warranted.


The Degree of Nesting between Spindles and Slow Oscillations Modulates Neural Synchrony.
Spindles and slow oscillations (SOs) both appear to play an important role in memory consolidation. Spindle and SO "nesting," or the temporal overlap between the two events, is believed to modulate consolidation. However, the neurophysiological processes modified by nesting remain poorly understood. We thus recorded activity from the primary motor cortex of 4 male sleeping rats to investigate how SO and spindles interact to modulate the correlation structure of neural firing. During spindles, primary motor cortex neurons fired at a preferred phase, with neural pairs demonstrating greater neural synchrony, or correlated firing, during spindle peaks. We found a direct relationship between the temporal proximity between SO and spindles, and changes to the distribution of neural correlations; nesting was associated with narrowing of the distribution, with a reduction in low- and high-correlation pairs. Such narrowing may be consistent with greater exploration of neural states. Interestingly, after animals practiced a novel motor task, pairwise correlations increased during nested spindles, consistent with targeted strengthening of functional interactions. These findings may be key mechanisms through which spindle nesting supports memory consolidation.SIGNIFICANCE STATEMENT Our analysis revealed changes in cortical spiking structure that followed the waxing and waning of spindles; firing rates increased, spikes were more phase-locked to spindle-band local field potential, and synchrony across units peaked during spindles. Moreover, we showed that the degree of nesting between spindles and slow oscillations modified the correlation structure across units by narrowing the distribution of pairwise correlations. Finally, we demonstrated that engaging in a novel motor task increased pairwise correlations during nested spindles. These phenomena suggest key mechanisms through which the interaction of spindles and slow oscillations may support sensorimotor learning. More broadly, this work helps link large-scale measures of population activity to changes in spiking structure, a critical step in understanding neuroplasticity across multiple scales.


Dopaminergic neuronal death via necroptosis in Parkinson's disease: A review of the literature.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive dysfunction and loss of dopaminergic neurons of the substantia nigra pars compacta (SNc). Several pathways of programmed cell death are likely to play a role in dopaminergic neuron death, such as apoptosis, necrosis, pyroptosis and ferroptosis, as well as cell death associated with proteasomal and mitochondrial dysfunction. A better understanding of the molecular mechanisms underlying dopaminergic neuron death could inform the design of drugs that promote neuron survival. Necroptosis is a recently characterized regulated cell death mechanism that exhibits morphological features common to both apoptosis and necrosis. It requires activation of an intracellular pathway involving receptor-interacting protein 1 kinase (RIP1 kinase, RIPK1), receptor-interacting protein 3 kinase (RIP3 kinase, RIPK3) and mixed lineage kinase domain-like pseudokinase (MLKL). The potential involvement of this programmed cell death pathway in the pathogenesis of PD has been studied by analysing biomarkers for necroptosis, such as the levels and oligomerization of phosphorylated RIPK3 (pRIPK3) and phosphorylated MLKL (pMLKL), in several PD preclinical models and in PD human tissue. Although there is evidence that other types of cell death also have a role in DA neuron death, most studies support the hypothesis that this cell death mechanism is activated in PD tissues. Drugs that prevent or reduce necroptosis may provide neuroprotection for PD. In this review, we summarize the findings from these studies. We also discuss how manipulating necroptosis might open a novel therapeutic approach to reduce neuronal degeneration in PD.


[Long-term results following breast augmentation].
One hundred late results of augmentation mammaplasty for the following conditions are reported: aplasia, hypoplasia, asymmetry and deformities after total and partial mastectomy. Our criteria for assessment were shape, consistency and quality of scars. The objective assessments were compared with the patients subjective assessments. The most unsatisfactory results were in augmentation after subcutaneous mastectomy and the best were in hypoplasias when small implants were used. Two types of implant were compared: gel filled and inflatable. Results were slightly better with gel filled implants. Better results were obtained if the implant was placed subpectorally and postoperative massage was carried out. Special note is made of the high rate of fibrous capsule contraction.


Human mononuclear cell factors suppress contractility of isolated mouse soleus muscle.
Weakness in polymyositis-dermatomyositis is often greater than would be suggested by histologic evidence of fiber degeneration or necrosis. Mononuclear cell infiltration is the key pathologic feature of polymyositis-dermatomyositis, and previous studies suggest a role for cellular immunity. In this study, the effect of supernatants from mitogen-stimulated human blood mononuclear cells on contractility of isolated mouse normal soleus muscle was examined. Mononuclear cell factor-rich supernatants were generated in 5-day cultures by phytohemagglutinin P stimulation of mononuclear cells from normal volunteers. Mouse soleus muscle was mounted isometrically in a muscle bath filled with oxygenated Ringer's solution or RPMI-1640 and was stimulated electrically. In 10 individual experiments, all muscles exposed to mononuclear cell factor-rich supernatants showed a rapid and progressive decline in active force of isometric contraction; a 40% decrease in active force was observed 5 to 13 minutes (average, 8 minutes) after the addition of supernatant. The inhibitory effect was reversible on removal of mononuclear cell factor-rich supernatants. Control culture medium and supernatants from unstimulated cell cultures showed no appreciable effect on active force. The factor(s) producing suppression of muscle contractility was dialyzable and stable through several cycles of freezing and thawing. Gel chromatography (Sephadex G-25 fine) showed one active fraction corresponding to an apparent molecular weight of approximately 2000. These data indicate that factor(s) released by human mononuclear cells can directly suppress the contraction of normal skeletal muscle.


A long-term survey of tooth loss in 600 treated periodontal patients.
1. Six hundred patients in a private periodontal practice were reexamined an average of 22 years after their active treatment and the patterns of tooth loss were observed. 2. During the post-treatment period, 300 patients had lost no teeth from periodontal disease, 199 had lost one to three teeth, 76 had lost 4 to 9 teeth and 25 had lost 10 to 23 teeth. 3. Of 2,139 teeth that originally had been considered of questionable prognosis, 666 were lost. Of these, 394 were lost by one sixth of the patients and only 272 by the other five-sixths. 4. Of 1,464 teeth which originally had furcation involvements, 460 were lost, 240 of them by one-sixth of the patients who deteriorated most. 5. The mortality of teeth which were treated with periodontal surgery was compared with that of teeth which did not have surgery. Tooth retention seemed more closely related to the case type than the surgery performed. 6. In general, periodontal disease is bilaterally symmetrical and there is a predictable order of likelihood of tooth loss according to position in the arch.


Iodipamide kinetics: capacity-limited biliary excretion with simultaneous pseudo-first-order renal excretion.
Iodipamide was infused into three dogs with bile fistulas to achieve various steady-state blood levels. When using ultracentrifugation techniques, iodipamide was found to be highly bound to plasma protein. The total blood clearance was low relative to hepatic blood flow. For either the whole blood concentration or the unbound concentration of iodipamide, the biliary excretion was shown to be capacity limited with a transport maximum, Tm, of approximately 1.0mumole/kg/min. The steady-state renal excretion rate, plotted against the whole blood concentration of iodipamide, resulted in a concave ascending curve, which could lead to the false conclusion that iodipamide was undergoing active renal tubular reabsorption. However, when corrected for plasma protein binding, a linear relationship was obtained, suggesting that the renal excretion of iodipamide is a pseudo-first-order process. The Michaelis-Menten parameters for the extrarenal elimination, when calculated using the whole blood concentration of iodipamide, led to a similar discrepancy compared to the parameter estimates obtained from biliary excretion rate data. This discrepancy can be eliminated when one uses the unbound concentration of iodipamide in the parameter estimates.


Searching for G: A New Evaluation of SPM-LS Dimensionality.
There has been increased interest in assessing the quality and usefulness of short versions of the Raven's Progressive Matrices. A recent proposal, composed of the last twelve matrices of the Standard Progressive Matrices (SPM-LS), has been depicted as a valid measure of g. Nonetheless, the results provided in the initial validation questioned the assumption of essential unidimensionality for SPM-LS scores. We tested this hypothesis through two different statistical techniques. Firstly, we applied exploratory graph analysis to assess SPM-LS dimensionality. Secondly, exploratory bi-factor modelling was employed to understand the extent that potential specific factors represent significant sources of variance after a general factor has been considered. Results evidenced that if modelled appropriately, SPM-LS scores are essentially unidimensional, and that constitute a reliable measure of g. However, an additional specific factor was systematically identified for the last six items of the test. The implications of such findings for future work on the SPM-LS are discussed.


The relationship of symptom dimensions with premorbid adjustment and cognitive characteristics at first episode psychosis: Findings from the EU-GEI study.
Premorbid functioning and cognitive measures may reflect gradients of developmental impairment across diagnostic categories in psychosis. In this study, we sought to examine the associations of current cognition and premorbid adjustment with symptom dimensions in a large first episode psychosis (FEP) sample. We used data from the international EU-GEI study. Bifactor modelling of the Operational Criteria in Studies of Psychotic Illness (OPCRIT) ratings provided general and specific symptom dimension scores. Premorbid Adjustment Scale estimated premorbid social (PSF) and academic adjustment (PAF), and WAIS-brief version measured IQ. A MANCOVA model examined the relationship between symptom dimensions and PSF, PAF, and IQ, having age, sex, country, self-ascribed ethnicity and frequency of cannabis use as confounders. In 785 patients, better PSF was associated with fewer negative (B = -0.12, 95% C.I. -0.18, -0.06, p < 0.001) and depressive (B = -0.09, 95% C.I. -0.15, -0.03, p = 0.032), and more manic (B = 0.07, 95% C.I. 0.01, 0.14, p = 0.023) symptoms. Patients with a lower IQ presented with slightly more negative and positive, and fewer manic, symptoms. Secondary analysis on IQ subdomains revealed associations between better perceptual reasoning and fewer negative (B = -0.09, 95% C.I. -0.17, -0.01, p = 0.023) and more manic (B = 0.10, 95% C.I. 0.02, 0.18, p = 0.014) symptoms. Fewer positive symptoms were associated with better processing speed (B = -0.12, 95% C.I. -0.02, -0.004, p = 0.003) and working memory (B = -0.10, 95% C.I. -0.18, -0.01, p = 0.024). These findings suggest that the negative and manic symptom dimensions may serve as clinical proxies of different neurodevelopmental predisposition in psychosis.


An unusual position of retromandibular vein: a surgical challenge in parotid surgeries.
A 44-year-old man presented with swelling in the left parotid region. The swelling was firm and Fine Needle Aspiration Cytology report proved pleomorphic adenoma. In the CT scan, the tumour was confined to the superficial lobe of parotid. So, left superficial parotidectomy was planned. Modified Wilson Blair's incision was used. On course of identifying the facial nerve, a large calibre vein was identified running vertically through the parotid substance. Assuming it as retromandibular vein, further dissection was carried out more meticulously. Marginal mandibularbranch of facial nerve was identified near the angle of mandible and retrograde dissection showed the cervicofacial division running medial to retromandibular vein with the main facial nerve trunk lying unusually medial and posterior to it. Adding to it, the temporofacial division was found 'forked' between the branches of retromandibular vein. These variations in head and neck venous channels are not that rare as we believe. All these variations have an embryological basis. Therefore, knowledge and understanding of this complex anatomy will help us preventing devastating complications like bleeding and facial nerve injury in such cases.


[Inpatient social psychiatric crisis intervention exemplified by the crisis intervention center of the Social Psychiatric University Clinic of Bern].
With a case-history of a puerperic psychosis we describe the crisis-interventions-technique in six steps used in our 16-bed, socio-psychiatric ward in the city of Berne at a general hospital. Out of more than 5 years of work we illustrate one year with client-data, working-methods and statistical results. With such a ward in the community, embedded in a complete net of socio-psychiatric institutions, we can treat quite serious psychosocial crisis adequately and in relatively short time.


Vitamin D receptor Fok1 polymorphism and blood lead concentration in children.
Variation in blood lead concentration is caused by a complex interaction of environmental, social, nutritional, and genetic factors. We evaluated the association between blood lead concentration and a vitamin D receptor (VDR) gene polymorphism. Environmental samples and blood were analyzed for lead, nutritional and behavioral factors were assessed, and VDR -Fok1 genotype was determined in 245 children. We found a significant interaction between floor dust lead and genotype on blood lead concentration. For every 1 microg/ft(2) increase in floor dust, children with VDR -FF genotype had a 1.1% increase in blood lead [95% confidence interval (CI), 0.69-1.5], VDR -Ff, 0.53% increase (95% CI, 0.1-0.92), and VDR -ff, 3.8% increase (95% CI, 1.2-6.3); however, at floor dust levels < 10 microg/ft(2), children with VDR -ff had the lowest blood lead concentrations. These data suggest that VDR -Fok1 is an effect modifier of the relationship of floor dust lead exposure and blood lead concentration.


Transient complex peroxisomal interactions: A new facet of peroxisome dynamics in mammalian cells.
Mitochondria and peroxisomes are ubiquitous subcellular organelles that fulfill essential metabolic functions, rendering them indispensable for human development and health. Both are highly dynamic organelles that can undergo remarkable changes in morphology and number to accomplish cellular needs. While mitochondrial dynamics are also regulated by frequent fusion events, the fusion of mature peroxisomes in mammalian cells remained a matter of debate. In our recent study, we clarified systematically that there is no complete fusion of mature peroxisomes analogous to mitochondria. Moreover, in contrast to key division components such as DLP1, Fis1 or Mff, mitochondrial fusion proteins were not localized to peroxisomes. However, we discovered and characterized novel transient, complex interactions between individual peroxisomes which may contribute to the homogenization of the often heterogeneous peroxisomal compartment, e.g., by distribution of metabolites, signals or other "molecular information" via interperoxisomal contact sites.


Skeletal Muscle Mass Change During Chemotherapy: A Systematic Review and Meta-analysis.
Skeletal muscle mass loss is an emerging concern in oncology. Our systematic review and meta-analysis identified the mean difference in skeletal muscle index pre- to post-chemotherapy and synthesized potential key factors. We searched primary original research published through October 2019 in four databases: MEDLINE via PubMed, Scopus, CINAHL, and Embase. Fifteen studies were included, 60% published in the past 2 years (2018-2019). Advanced non-small cell lung cancer was the most frequently reported cancer, and overall survival the most often identified key related factor. Mean difference in skeletal muscle index during chemotherapy was 2.72 (95%CI=1.77-3.67, p=0.00), with muscle loss in males (4.52, 95%CI=3.34-5.71, p=0.00) about 1.6 times higher than that in females (2.86, 95%CI=0.81-4.92, p=0.01). Oncologists should recognize sex-specific differences in skeletal muscle mass loss during chemotherapy and consider adjusting treatment accordingly.


Apoptosis pathways and osteoporosis: An approach to genomic analysis.
Osteoporosis is a disease of the bone system that causes a decrease in skeletal density and degrades skeletal tissue. Decreased bone quality, so that bones are easily broken, damaged and fractured, is an important public health problem. Previous studies have shown that the maintenance of adult bone mass is not only due to changes in bone marrow and bone cells. By regulating apoptosis, they change the lifespan of each individual. This study influences understanding of the function of apoptosis in the pathogenesis of osteoporosis and the importance of controlling the mechanisms of osteoporosis. On the National Institute of Biotechnology Information website, Gene Expression Omnibus (GEO) microarray data and GSE551495 GEO profiles were collected. The gene set enrichment analysis tool was used to confirm the enrichment of genetic sets in relation to the gene set. The collection of C2 gene sets is compiled from the KEGG (https://www.gsea-msigdb.org/gsea/msigdb/human/search.jsp and https://www.kegg.jp/kegg/) online database and REACTOME (https://www.gsea-msigdb.org/gsea/msigdb/human/search.jsp and https://reactome.org/) pathway analysis. The Search Tool for the Retrieval of Interaction Genes (STRING) website was used to construct and select proteins and genes. The comparative toxicological genomic database (CTD) tools can be used to predict the relationship between apoptosis, osteoporosis-related genes and interactions between central genes and osteoporosis. These results generally expand our understanding of the path of apoptosis in osteoporosis. We have discovered genes CASP9, CASP8, CASP3, BAX and TP53 associated with osteoporosis. In activation of KEGG apoptosis and REACTOME, caspase activation through the extrinsic apoptotic signaling pathway is characterized by the identification of a subcollection of C2. Other STRINGs show the formation of protein networks and central gene selection, and CTD can accurately predict the relationship between these apoptosis pathways and central genes. Our research has highlighted the importance of the osteoporosis pathway associated with osteoporosis apoptosis with several analytical approaches. These results have broadened our understanding of the pathways of osteoporosis apoptosis. It is particularly possible to predict the sensitivity and vulnerability to osteoporosis.


Prognostic importance of sodium level trajectory in acute heart failure.
Low sodium levels are strongly associated with poor prognosis in acute heart failure (AHF); however, the prognostic impact of the sodium level trajectory overtime has not been determined. A secondary analysis of the AQUAMARINE study in which patients with AHF and renal impairment were randomized to receive either tolvaptan or conventional treatment was performed. Sodium levels were evaluated at the baseline and at 6, 12, 24, and 48 h. We defined 'sodium dipping' as sodium level falling below the baseline level at any time point. The primary endpoint was the combined event of all-cause death and heart failure rehospitalization during follow-up. The analysis included 184 patients with a median follow-up of 21.1 months. Sodium levels more steeply increased during the 48 h in patients without events as compared to sodium levels in patients with events (P = 0.018 in linear-mixed effect model). The sodium dipping group (n = 100; 54.3%) demonstrated significantly less urine output, less body weight reduction, and poorer diuretic response within 48 h compared to the non-dipping group. The sodium dipping group was also significantly associated with a low combined-event-free survival after adjustment for other prognostic factors (HR 1.97; 95% CI 1.06-3.38; P = 0.033). The trajectory of sodium levels during the acute phase is associated with the prognosis of patients with AHF independently of the baseline sodium level.


Morphogenesis and ultrastructure of Geotrichum candidum septa.
The ultrastructure and mode of formation of septa of Geotrichum candidum were investigated by light and electron microscopy. The invaginations of the lateral membrane and wall appear to initiate at multiple points around the circumference of the cell; the immature septum subsequently assumes a cart-wheel shape, with branched spokes radiating from the center of the septum. Each face of the septum is covered with a membrane possessing hitherto undescribed structural differentiation; the membrane substructures are comprised of two central subunits encircled by 12 identical subunits. The diameter of the entire 12 plus 2 structure is 24 to 25 nm, and the diameter of each individual subunit is approximately 4 nm. The maturation of the septum appears to occur by further deposition of material along the branched skeletal regions. Numerous small openings (micropores), formed as a result of incomplete deposition, ultimately give rise to plasmodesmata. During arthrospore formation, the plasmodesmal canals and associated micropores are occluded by electron-dense materials, rendering each segment of the hyphae completely independent of the rest of the hyphae.


Acetylcholinesterase and butyrylcholinesterase expression in adult rabbit tissues and during development.
A large cDNA fragment covering the complete sequence of the mature catalytic subunit of rabbit acetylcholinesterase (AChE) has been cloned and sequenced. This sequence was compared to that of rabbit butyrylcholinesterase [BChE; Jbilo, O. & Chatonnet, A. (1990) Nucleic Acids Res. 18, 3990]. Amino acid sequences of AChE and BChE have 51% identity. They both possessed a choline-binding site W84, a catalytic triad S200-H440-E327 and six cysteine residues (positions 67-94, 254-265, 402-521) in conserved sequence positions to those that form three intrachain disulfide bonds in all cholinesterases (by convention, numbering of amino acids is that used for Torpedo AChE). Rabbit AChE had a larger number of aromatic residues lining the active-site gorge than rabbit BChE (14 compared to 8, respectively) and a smaller number of potential N-glycosylation sites (3 compared to 8, respectively). Both catalytic subunits have a hydrophilic C-terminus (catalytic subunits of type T). Expression of acetylcholinesterase and butyrylcholinesterase genes (ACHE and BCHE) was studied in rabbit tissues and during development by a correlation of Northern-blot analysis and enzymic activities. This correlation was rendered difficult by the presence of an eserine-resistant esterase active on butyrylthiocholine in serum, liver and lung. When the contribution of this carboxylesterase was taken into account, brain was found as the richest source of BChE followed by lung and heart. Rabbit liver had a very low content of BChE that correlated with the low BChE activity in plasma. During development, BCHE transcripts were detected as early as day 10 post coitum, whereas ACHE transcripts appeared only on day 12.


Transition-Metal Dichalcogenide Artificial Antibodies with Multivalent Polymeric Recognition Phases for Rapid Detection and Inactivation of Pathogens.
Antibodies are recognition molecules that can bind to diverse targets ranging from pathogens to small analytes with high binding affinity and specificity, making them widely employed for sensing and therapy. However, antibodies have limitations of low stability, long production time, short shelf life, and high cost. Here, we report a facile approach for the design of luminescent artificial antibodies with nonbiological polymeric recognition phases for the sensitive detection, rapid identification, and effective inactivation of pathogenic bacteria. Transition-metal dichalcogenide (TMD) nanosheets with a neutral dextran phase at the interfaces selectively recognized S. aureus, whereas the nanosheets bearing a carboxymethylated dextran phase selectively recognized E. coli O157:H7 with high binding affinity. The bacterial binding sites recognized by the artificial antibodies were thoroughly identified by experiments and molecular dynamics simulations, revealing the significance of their multivalent interactions with the bacterial membrane components for selective recognition. The luminescent WS2 artificial antibodies could rapidly detect the bacteria at a single copy from human serum without any purification and amplification. Moreover, the MoSe2 artificial antibodies selectively killed the pathogenic bacteria in the wounds of infected mice under light irradiation, leading to effective wound healing. This work demonstrates the potential of TMD artificial antibodies as an alternative to antibodies for sensing and therapy.


A nuclear-localized HSP70 confers thermoprotective activity and drought-stress tolerance on plants.
To investigate the function of nuclear-localized plant HSP70, we used NtHSP70-1 isolated from Nicotiana tabacum. The subcellular localization of NtHSP70-1 was identified by fluorescence microscopy for NtHSP70-1/GFP or smGFP fusion proteins in onion epidermal cells, obtained using particle gun bombardment. To analyze the drought-stress tolerance and thermoprotective role of NtHSP70-1, we obtained transgenic tobacco plants that constitutively expressed elevated levels of NtHSP70-1 as well as transgenic plants containing either the vector alone or else having NtHSP70-1 in the antisense orientation. From analysis for genomic DNA in transgenic seedlings after heat stress, NtHSP70-1 helps to prevent the fragmentation and degradation of nuclear DNA during heat stress. In addition, seedlings constitutively overexpressing NtHSP70-1 grew to be healthy plants, whereas transgenic vector or antisense seedlings resulted in death after heat-/drought-stress.


Biomarkers in Moderate to Severe Pediatric Traumatic Brain Injury: A Review of the Literature.
Despite decades of research, outcomes in pediatric traumatic brain injury (pTBI) remain highly variable. Brain biofluid-specific biomarkers from pTBI patients may allow us to diagnose and prognosticate earlier and with a greater degree of accuracy than conventional methods. This manuscript reviews the evidence surrounding current brain-specific biomarkers in pTBI and assesses the temporal relationship between the natural history of the traumatic brain injury (TBI) and measured biomarker levels. A literature search was conducted in the Ovid, PubMed, MEDLINE, and Cochrane databases seeking relevant publications. The study selection and screening process were documented in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram. Extraction forms included developmental stages of patients, type and biofluid source of biomarkers, brain injury type, and other relevant data. The search strategy identified 443 articles, of which 150 examining the biomarkers of our interest were included. The references retrieved were examined thoroughly and discussed at length with a pediatric neurocritical care intensivist specializing in pTBI and a Ph.D. scientist with a high degree of involvement in TBI biomarker research, authoring a vast amount of literature in this field. TBI biomarkers might serve as valuable tools in the diagnosis and prognosis of pTBI. However, while each biomarker has its advantages, they are not without limitations, and therefore, further research is critical in pTBI biomarkers.


A Lipid-Nanosphere-Small MyoD Activating RNA-Bladder Acellular Matrix Graft Scaffold [NP(saMyoD)/BAMG] Facilitates Rat Injured Bladder Muscle Repair and Regeneration [NP(saMyoD)/BAMG].
Bladder tissue engineering is an excellent alternative to conventional gastrointestinal bladder enlargement in the treatment of various acquired and congenital bladder abnormalities. We constructed a nanosphere-small MyoD activating RNA-bladder acellular matrix graft scaffold NP(saMyoD)/BAMG inoculated with adipose-derived stem cells (ADSC) to explore its effect on smooth muscle regeneration and bladder repair function in a rat augmentation model. We performed many biotechniques, such as reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot, MTT assay, HE staining, masson staining, and immunohistochemistry in our study. Lipid nanospheres were transfected into rat ADSCs after encapsulate saRNA-MyoD as an introduction vector. Lipid nanospheres encapsulated with saRNA-MyoD were transfected into rat ADSCs. The functional transfected rat ADSCs were called ADSC-NP(saMyoD). Then, Rat models were divided into four groups: sham group, ADSC-BAMG group, ADSC-NP(saMyoD)/BAMG group, and ADSC-NP(saMyoD)/SF(VEGF)/BAMG group. Finally, we compared the bladder function of different models by detecting the bladder histology, bladder capacity, smooth muscle function in each group. RT-PCR and Western blot results showed that ADSCs transfected with NP(saMyoD) could induce high expression of α-SMA, SM22α, and Desmin. At the same time, MTT analysis showed that NP(saMyoD) did not affect the activity of ADSC cells, suggesting little toxicity. HE staining and immunohistochemistry indicated that the rat bladder repair effect (smooth muscle function, bladder capacities) was better in the ADSC-NP(saMyoD)/BAMG group, ADSC-NP(saMyoD)/SF(VEGF)/BAMG group than in the control group. Taken together, our results demonstrate that the NP(saMyoD)/SF(VEGF)/BAMG scaffold seeded with ADSCs could promote bladder morphological regeneration and improved bladder urinary function. This strategy of ADSC-NP(saMyoD)/SF(VEGF)/BAMG may has a potential to repair bladder defects in the future.


Self-supervised Natural Image Reconstruction and Large-scale Semantic Classification from Brain Activity.
Reconstructing natural images and decoding their semantic category from fMRI brain recordings is challenging. Acquiring sufficient pairs of images and their corresponding fMRI responses, which span the huge space of natural images, is prohibitive. We present a novel self-supervised approach that goes well beyond the scarce paired data, for achieving both: (i) state-of-the art fMRI-to-image reconstruction, and (ii) first-ever large-scale semantic classification from fMRI responses. By imposing cycle consistency between a pair of deep neural networks (from image-to-fMRI & from fMRI-to-image), we train our image reconstruction network on a large number of "unpaired" natural images (images without fMRI recordings) from many novel semantic categories. This enables to adapt our reconstruction network to a very rich semantic coverage without requiring any explicit semantic supervision. Specifically, we find that combining our self-supervised training with high-level perceptual losses, gives rise to new reconstruction & classification capabilities. In particular, this perceptual training enables to classify well fMRIs of never-before-seen semantic classes, without requiring any class labels during training. This gives rise to: (i) Unprecedented image-reconstruction from fMRI of never-before-seen images (evaluated by image metrics and human testing), and (ii) Large-scale semantic classification of categories that were never-before-seen during network training. Such large-scale (1000-way) semantic classification from fMRI recordings has never been demonstrated before. Finally, we provide evidence for the biological consistency of our learned model.


Proteome Analysis of Temporomandibular Joint with Disc Displacement.
Disc displacement without reduction is a common disorder of the temporomandibular joint, causing clinical symptoms and sometimes condylar degeneration. In some cases, bone regeneration is detected following disc-repositioning procedures. Until now, however, systems-wide knowledge of the protein levels for condylar outcome with disc position is still lacking. Here, we performed comprehensive expression profiling of synovial fluid from 109 patients with disc displacement without reduction using high-resolution data-independent acquisition mass spectrometry and characterized differences in 1,714 proteins. Based on magnetic resonance imaging, samples were divided into groups with versus without condylar absorption and subgroups with versus without new bone. For the proteomic analysis, 32 proteins in groups presented with statistical significance (>2-fold, P < 0.05). Pathways such as response to inorganic substances, blood coagulation, and estrogen signaling were significantly expressed in the group with bone absorption as compared with pathways such as regulation of body fluid levels, vesicle-mediated transport, and focal adhesion, which were enriched in the group without bone absorption. In subgroup analysis, 45 proteins of significant importance (>2-fold, P < 0.05) were associated with pathways including would healing, glycolysis and gluconeogenesis, and amino acid metabolism. Combined with clinical examination, molecules such as acetyl-CoA carboxylase beta (ACACB) and transforming growth factor beta 1 (TGFB1) were related to features such as visual analog scale and maximum interincisal opening (P < 0.05). In addition, 7 proteins were examined by Western blotting, including progesterone immunomodulatory binding factor 1 (PIBF1), histidine-rich glycoprotein (HRG), and protein kinase C and casein kinase substrate in neurons 2 (PACSIN2). In conclusion, this study provides the first proteome analysis of condylar absorption at disc displacement without reduction and postoperative new bone formation after disc reposition. Integrated with clinical data, this analysis provides an important insight into the proteomics of condylar modification at disc position.


Utilization of intracellular acylcarnitine pools by mononuclear phagocytes.
Carnitine is essential for the metabolism of long-chain fatty acids and has both direct and indirect roles in the metabolism of short-chain and medium-chain acyl-CoAs. The purpose of this study was to quantitate and identify the individual acylcarnitines that occur in human mononuclear phagocytes (MNP) after activating them with phorbol-12-myristate 13-acetate (PMA). Mononuclear phagocytes were isolated from healthy adults and the levels of free carnitine and individual acylcarnitines were determined in unactivated and activated cells. The degree of activation of MNP was assessed by following hydrogen peroxide production. In unactivated cells, acetyl-L-carnitine represented more than 80% of the total acylcarnitine pool. Small amounts of 3-carbon and 4-carbon acylcarnitines were present, with less than 10% of the carnitine pool being long-chain acylcarnitine. Free carnitine in unactivated cells represented 7% of the total carnitine pool, which remained essentially unchanged in unactivated cells when monitored for a period of 60 min. However, free carnitine rose to more than 50% of the total pool in PMA-activated cells. Similarly, after 1 h of activation, the acetylcarnitine level in activated cells decreased by more than 50%. These data suggest that acetylcarnitine plays a key metabolic role as MNP initiate an immune response. It was further shown that MNP contain both carnitine acetyltransferase and malonyl-CoA-sensitive carnitine palmitoyltransferase in mitochondrial-enriched fractions, as well as in post-mitochondrial supernatant fractions.


Increased serum levels of interleukin-9 correlate to negative prognostic factors in Hodgkin's lymphoma.
Hodgkin's lymphoma (HL) is characterised by an unbalanced cytokine secretion. Many of these cytokines have been implicated in the regulation of malignant and infiltrating cells. Interleukin-9 (IL-9) has been described to act in an autocrine fashion in HL, stimulating proliferation of the malignant cells. To investigate the potential clinical implication of this observation, a novel ELISA method was used to examine the serum levels of IL-9 in lymphoma patients. High levels of IL-9 were found in the sera from patients with HL (18/44), but not in the sera from non-Hodgkin's lymphoma patients (3/21) or healthy controls. The highest serum IL-9 levels, up to 3350 pg/ml, were observed in the nodular sclerosis subtype, and there was a correlation between IL-9 levels and the negative prognostic factors advanced stage, B-symptoms, low blood Hb and high erythrocyte sedimentation rate. Furthermore, there was no correlation between serum levels of IL-9 and IL-13, a cytokine where serum levels have been speculated to be of clinical importance. This is the first report showing that IL-9 can be measured in serum samples. A novel correlation between increased serum IL-9 levels, HL and clinical features is shown, suggesting that IL-9 is a candidate factor contributing to the development of HL.


Ensembles of Deep Learning Architectures for the Early Diagnosis of the Alzheimer's Disease.
Computer Aided Diagnosis (CAD) constitutes an important tool for the early diagnosis of Alzheimer's Disease (AD), which, in turn, allows the application of treatments that can be simpler and more likely to be effective. This paper explores the construction of classification methods based on deep learning architectures applied on brain regions defined by the Automated Anatomical Labeling (AAL). Gray Matter (GM) images from each brain area have been split into 3D patches according to the regions defined by the AAL atlas and these patches are used to train different deep belief networks. An ensemble of deep belief networks is then composed where the final prediction is determined by a voting scheme. Two deep learning based structures and four different voting schemes are implemented and compared, giving as a result a potent classification architecture where discriminative features are computed in an unsupervised fashion. The resulting method has been evaluated using a large dataset from the Alzheimer's disease Neuroimaging Initiative (ADNI). Classification results assessed by cross-validation prove that the proposed method is not only valid for differentiate between controls (NC) and AD images, but it also provides good performances when tested for the more challenging case of classifying Mild Cognitive Impairment (MCI) Subjects. In particular, the classification architecture provides accuracy values up to 0.90 and AUC of 0.95 for NC/AD classification, 0.84 and AUC of 0.91 for stable MCI/AD classification and 0.83 and AUC of 0.95 for NC/MCI converters classification.


Duration and extent of antianginal effects of a sustained-release formulation of nifedipine in angina.
Twenty-four patients with chronic stable exertional angina pectoris were randomized in a double-blind, placebo-controlled, crossover trial to assess the efficacy and durability of a newly developed, sustained-release formulation of nifedipine (nifedipine CC) in a single 40-mg oral dose. Symptom-limited graded treadmill exercise tests were performed just before, and at 4, 7, and 24 h after a single administration of the drug or the placebo was given. Exercise tolerance at 4, 7, and 24 h after the drug were compared with the corresponding placebo values. Data could be analysed for 19 patients. Maximal exercise time, time to the onset of angina, and time to 1 mm ST segment placebo. The average maximal exercise time was significantly increased by 72, 76, and 37 s at 4, 7, and 24 h. Rate-pressure product at rest and at peak exercise showed significant changes only at 24 h compared with placebo (both P < 0.05). The maximal increase in exercise tolerance was most marked at 7 h nifedipine CC, at which time plasma drug concentration was 99.4 +/- 14.0 ng.ml-1. Thus, in patients with chronic stable exertional angina pectoris, nifedipine CC showed a prolonged improvement in exercise tolerance up to 24 h after a single oral administration.


Treating calcific aortic stenosis: an evolving science.
Calcific aortic stenosis is a common valvular disease, but its pathophysiology remains undetermined and important considerations exist for treatment. Pathophysiology, treatment by the advanced practice nurse, and literature review are discussed in the context of a case study.


A case report of COVID-19-associated acute hand ischaemia in a young professional volleyball player.
Several coronavirus disease-19 (COVID-19)-associated complications are being increasingly reported, including arterial and venous thrombo-embolic events that may lead to amputation of the affected limbs. So far, acute upper limb ischaemia (ULI) has been reported only in critically ill patients. Herein, we aimed to present a case of a 29-year-old, otherwise healthy male volleyball player, with acute ischaemic signs in the upper extremity who was diagnosed with COVID-19 1 month before the ischaemic event. It has been shown that volleyball players experience repetitive stress that involves their hands and, in particular, their fingers. Repetitive trauma can lead to local vascular abnormalities, such as reduced capillarization and lower resting blood flow that can lead to pain and cold digits, but never acute ULI. To our knowledge, this is the first case of such a hypercoagulable synergistic mechanism that leads to a high thrombus burden. Intra-arterial local thrombolysis and percutaneous transluminal angioplasty failed to succeed, and percutaneous large-bore embolectomy with the Indigo Aspiration System (Penumbra Inc., CA, USA) was deemed necessary.


Evaluation of the most current and effective methods in the analysis of chlorinated dioxins in ground beef.
Chlorinated dioxins are the group of environmental pollutants consisting of 210 chlorinated dibenzo-p-dioxins and dibenzofurans. They are highly toxic and persistent. They are lipophilic and can easily biomagnify in the food chain, hence posing a serious threat to human health. The daily consumption of low-level contaminated food, mainly of animal origin, leads to the accumulation of dioxins in the human body. The exposures of the general human population to dioxins and the specific issues of a risk assessment of dioxin pose serious concerns in public environmental and nutritional health. This paper reviews the analysis of chlorinated dioxins in ground beef. The sources of contamination of chlorinated dioxins in ground beef are first reviewed to form a basis for a clear understanding of the health implications of chlorinated dioxins in the human food chain and why it is necessary to monitor the level of dioxins in animal food products, especially ground beef. The methods of collection, sampling, and processing of ground beef, and the methods of sample clean up prior to the analysis, are reviewed. Emphasis is laid on the new techniques that are available and that might be effective in the analysis of chlorinated dioxins in ground beef. Among these new methods and techniques are: the synergistic combination of ELISA/GC/MS, direct sample introduction to /GC/MS-MS, automated clean-up method, and the supercritical fluid extraction methods. The possible treatments of results from each method and technique are discussed and their respective efficiencies are compared. Finally, quality control and quality assurance parameters are evaluated for levels of accuracy, reproducibility, and precision.


Prognostic value of positron emission tomography/computed tomography for adjuvant chemotherapy of colon cancer.
To assess the prognostic value of preoperative 18 F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with high-risk stage II or stage III colon cancer who underwent FOLFOX chemotherapy. The study included 166 patients with high-risk stage II or stage III colon cancer who received FOLFOX4 chemotherapy. Retrospective patient data were analysed including pathological stage, histology, disease-free survival (DFS) and the maximum standardized uptake value (SUVmax ) of the primary tumour on 18 F-fluorodeoxyglucose positron emission tomography/computed tomography. The primary end point was DFS. There were recurrences in 29 of the 166 patients (17.4%). Measuring the area under the receiver operating characteristic curve, the cut-off value of SUVmax with maximum sensitivity and specificity was 10.95. Using the Kaplan-Meier method, the DFS of the patients categorized by SUVmax tended to differ (P = 0.055). In univariate analyses, the risk factors for DFS were age over 70 years, higher N stage and neural invasion. SUVmax ≤ 10.95 showed a tendency, but was not significant (P = 0.0604). In multivariate analyses, the risk factors for DFS were age over 70 and neural invasion. The results of this study suggest that high fluorodeoxyglucose uptake of the primary mass in high-risk stage II and stage III colon cancer does not significantly correlate with DFS.


Perceived Fatigability, Fatigue, and Mortality in Mid-to-Late Life in the Baltimore Longitudinal Study of Aging.
Fatigue is an established prognostic indicator of mortality risk. It remains unknown whether fatigability anchored to a physical task is a more sensitive prognostic indicator and whether sensitivity differs by prevalent chronic conditions. 1,076 physically well-functioning participants aged ≥50 years in the Baltimore Longitudinal Study of Aging self-reported fatigue (unusual tiredness or low energy) and had perceived fatigability assessed after a standardized treadmill walk. All-cause mortality was ascertained by proxy contact and National Death Index linkage. Cox proportional hazards models estimated associations of perceived fatigability and fatigue with all-cause mortality, adjusting for demographic and clinical covariates. Interactions by chronic conditions were also examined. ResultsEach one-standard deviation higher in perceived fatigability, unusual tiredness, or low energy was associated with a higher relative hazard of all-cause mortality after covariate adjustment (fatigability: HR = 1.18, 95% CI: 1.03-1.36; unusual tiredness: HR = 1.25, 95% CI: 1.08-1.44; low energy: HR = 1.27, 95% CI: 1.10-1.46). Models had similar discrimination (p > 0.14 for all). Perceived fatigability was associated with mortality risk among participants free of arthritis or osteoarthritis who otherwise appeared healthy (no arthritis: HR = 1.45, 95% CI: 1.15-1.84; arthritis: HR = 1.09, 95% CI: 0.92-1.30; p-interaction = 0.031). Unusual tiredness was associated with mortality among those with a history of diabetes (no diabetes: HR = 1.16, 95% CI: 0.97-1.38; diabetes: HR = 1.65, 95% CI: 1.22-2.23; p-interaction = 0.045) or pulmonary disease (no pulmonary disease: HR = 1.22, 95% CI: 1.05-1.43; pulmonary disease: HR = 2.15, 95% CI: 1.15-4.03; p-interaction = 0.034). Higher perceived fatigability and fatigue symptoms were similarly associated with higher all-cause mortality, but utility differed by chronic condition. Perceived fatigability might be useful for health screening and long-term mortality risk assessment for well-functioning adults. Alternatively, self-reported fatigue appears more disease-specific with regards to mortality risk.


Guidelines for internal validation of the HLA-DQ alpha DNA typing system.
Validation experiments were performed to evaluate the HLA-DQ alpha DNA typing system for forensic casework. Temperature profiles for two Perkin Elmer TC-1 Thermal Cyclers were measured, and the efficiency of the instruments was tested by amplifying a control sample (DQ alpha 1.2,4) susceptible to allelic drop-out. DNA extraction using chelex was compared to non-organic extraction, and the amplification and hybridization procedures were evaluated at extremes of time and temperature. With the protocol in place, samples exposed to stresses commonly encountered in forensic casework were typed to determine the flexibility of the system. Mixed samples of two different bloods and blood mixed with saliva were typed to determine the threshold at which mixtures could be resolved using the reverse dot blot method. Different storage conditions were evaluated using a set of control bloodstrains, and a set of 12 postmortem blood samples was typed repeatedly over the course of 5 months to determine the effects of natural degradation on the DQ alpha results. Finally, casework stains on a variety of substrates were typed. These experiments demonstrate the flexibility of the HLA-DQ alpha system. Based upon these results, a comprehensive quality assurance program was developed to ensure the integrity of typing results for casework.


Imipramine-Induced Cutaneous and Iris Hyperpigmentation: A Case Report and Literature Review.
Objective: To describe a novel case of imipramine-induced hyperpigmentation and characterize the literature pertaining to imipramine-induced hyperpigmentation to this point. Data Sources: PubMed and Google Scholar were searched through July 2021 utilizing various combinations of imipramine, discoloration, and hyperpigmentation. The references of initial articles were searched for more case reports and imipramine-related literature. Also, articles that cited the references identified in the literature search were reviewed using Google Scholar. Only articles published in English were included. Study Selection: A total of 19 cases of imipramine-induced hyperpigmentation were found in 15 publications to date. All cases were included to determine the variation in clinical presentations of this rare condition. Data Extraction: The case reports were reviewed in their entirety for information concerning patient demographic, clinical presentation, histologic findings on biopsy, and treatment options for imipramine-induced hyperpigmentation. Results: This presentation, to our knowledge, represents the third case of imipramine-induced iris hyperpigmentation, the first case of iris hyperpigmentation occurring in a blue-eyed individual, and the first report to include pictures of the hyperpigmented irides. A novel proposed pathophysiologic mechanism is also provided. Conclusions: Imipramine is a tricyclic antidepressant with a rare side effect of cutaneous and iris hyperpigmentation. Granular dermal deposits in microscopy appear to be the cause of this discoloration. Treatment primarily focuses on discontinuing imipramine or laser therapy.


Getting around the gut: a unique management challenge of thyroid storm precipitated by amphetamine-associated duodenal ischaemia leading to compromised enteric absorption.
Thyroid storm is a rare, life-threatening endocrine emergency with a high mortality rate of up to 30%. We present a unique management challenge of a critically ill patient who developed thyroid storm in the setting of a duodenal perforation from amphetamine-associated non-occlusive mesenteric ischaemia. The diagnosis of 'thyroid storm' was made based on clinical criteria and a Burch-Wartofsky score of 100. During emergent exploratory laparotomy, a 1 cm duodenal perforation with surrounding friable tissue was found and repaired. Intraoperatively, a nasogastric tube was guided distal to the area of perforation to allow for enteric administration of medications, which was critical in the setting of thyroid storm. Therapeutic plasma exchange achieved biochemical control of our patient's thyroid storm but ultimately did not prevent in-hospital mortality.


Body composition as a predictor of blood pressure in three communities in Guangdong province, China.
The aim of this study was to compare mean blood pressure (BP), anthropometric and body compositional measurements in three Chinese communities and to examine relationships between BP and body composition in these communities. A total of 935 adult (aged >= 25 years) men and women were randomly sampled from three communities (Chauzhou County speaking Teochew, Meixian County speaking Hakka, and Xinhui speaking Cantonese) in Guangdong Province, China. Self-administered questionnaires about food habits, lifestyle and health status were completed. Body weight, stature, waist and hip circumferences and systolic and diastolic blood pressures were measured. Body mass index, waist to hip ratio, fat free mass, total body fat mass and the percentage body fat were calculated to assess body composition. No significant differences were found in stature, body mass index, umbilical circumference, hip circumference, fat free mass, percentage body fat and defined hypertension between the three communities. However, the waist to hip ratio was lower in Chauzhou men than Meixian women. The mean BPs were different between the communities and mean blood pressure was the highest in the Chauzhou community. Intra-community non-parametric relations between BP and body composition were found mostly in men with increased total and abdominal fatness positively related to BP. The relationships of the aggregate communities with blood pressure were found consistent with those for intra-community analyses, although the body fatness-blood pressure relationship was then evident without exception. Anthropometrically assessed body composition predicts BP in Chinese men, but to a lesser extent, in Chinese women in Guangdong Province, China.


An assessment of two amplitude-compression hearing aid systems, especially in high ambient noise.
A critical test of the suitability of amplitude compression in hearing aid design must look at the performance of such devices with high levels of background noise. A series of tests was carried out, using both normal and hearing-impaired subjects and word-list test material. The results favour some forms of amplitude compression, even under these critical conditions. However, nonlinear compression ('Carrier Clipping') can reduce the signal-to-noise ratio to unity under adverse conditions. Under these circumstances, such compression impairs performance, though in most situations, it is beneficial.


Intrauterine growth retarded infants. Correlation of gestational age with maternal factors, mode of delivery, and perinatal survival.
Fifty-eight infants of 3332 deliveries (1.7%) were found to be growth retarded (IGR) at birth. For purposes of analysis, the infants were divided into 2 groups according to gestational age at delivery: Group I infants were delivered between 38 and 43 weeks' gestation, and Group II infants were delivered between 28 and 37 weeks'. The infants at greatest risk are those who manifest chronic intrauterine fetal distress associated with prematurity. Asphyxia was evident in 9 of 19 infants (47%) in Group II as compared to 9 of 36 infants (25%) in Group I. The premature IGR infants delivered by low forceps and cesarean section had higher 1- and 5-minute Apgar scores than those delivered spontaneously. There was a five-fold increase of intrauterine demise and a two-fold increase of neonatal deaths in Group II IGR infants as compared to the non-IGR premature infants. In the management of IGR, a combined obstetric-pediatric approach is important. A higher index of suspicion, appropriate evaluation, earlier diagnosis, and expedient delivery are essential if the prognosis for an IGR infant is to be improved.


Pathophysiology of disseminated intravascular coagulation in saline-induced abortion.
Our previous studies suggested that disseminated intravascular coagulation (DIC) may be a sequel to saline-induced abortion. A hypothetical mechanism for the DIC is that hypertonic saline produces cellular disruption in the products of conception with the release of thromboplastic substances into the amniotic fluid. These substances, in turn, diffuse through the damaged membranes into the maternal circulation. To examine this hypothesis we obtained samples of amniotic fluid (AF) from 5 patients just prior to and at 1 hour, 6 hours, and 24 hours after intraamniotic instillation of hypertonic saline. The procoagulant and thromboplastic properties of the various AF specimens were quantitated using the prothrombin time (PT), partial thromboplastin time (PTT), and activated clotting time (ACT) as in vitro test systems. The results indicate that a change in the procoagulant and/or thromboplastic activity of AF following saline instillation is not afactor in the pathophysiology of DIC associated with saline abortion.


Searching for the optimal data partitioning strategy in mitochondrial phylogenomics: a phylogeny of Acridoidea (Insecta: Orthoptera: Caelifera) as a case study.
One of the main challenges in analyzing multi-locus phylogenomic data is to find an optimal data partitioning strategy to account for variable evolutionary histories of different loci for any given dataset. Although a number of studies have addressed the issue of data partitioning in a Bayesian phylogenetic framework, such studies in a maximum likelihood framework are comparatively lacking. Furthermore, a rigorous statistical exploration of possible data partitioning schemes has not been applied to mitochondrial genome (mtgenome) data, which provide a complex, but manageable platform for addressing various challenges in analyzing phylogenomic data. In this study, we investigate the issue of data partitioning in the maximum likelihood framework in the context of the mitochondrial phylogenomics of an orthopteran superfamily Acridoidea (Orthoptera: Caelifera). The present study analyzes 34 terminals representing all 8 superfamilies within Caelifera, which includes newly sequenced partial or complete mtgenomes for 11 families. Using a new partition-selection method implemented in the software PartitionFinder, we compare a large number of data partitioning schemes in an attempt to identify the most effective method of analyzing the mtgenome data. We find that the best-fit partitioning scheme selected by PartitionFinder is superior to any a priori schemes commonly utilized in mitochondrial phylogenomics. We also show that over-partitioning is often detrimental to phylogenetic reconstruction. A comparative analysis of mtgenome structures finds that the tRNA gene rearrangement between cytochrome c oxidase subunit II and ATP synthase protein 8 does not occur in the most basal caeliferan lineage Tridactyloidea, suggesting that this gene rearrangement must have evolved at least in the common ancestor of Tetrigoidea and Acridomorpha. We find that mtgenome data contain sufficient phylogenetic information to broadly resolve the relationships across Acridomorpha and Acridoidea.


Clinical utility of current NNRTIs and perspectives of new agents in this class under development.
Highly active antiretroviral therapy (HAART) has significantly reduced the number of deaths caused by AIDS. However, the antiviral efficacy of HAART comprising protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) is frequently accompanied by a decrease in patients' quality of life. PI-based therapies often fail due to poor adherence caused by heavy pill burden, complex dosing schedules and undesirable side effects. The current trend is to switch from PI-based to PI-sparing regimens consisting of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and NRTIs. Despite some encouraging results from NNRTI-containing therapies, two major concerns in using the currently available NNRTIs remain: 1) low genetic barrier to the emergence of resistance and 2) cross-resistance due to single mutations that often render the whole class of NNRTIs ineffective. Clearly, new and improved NNRTIs are needed to address these concerns.


Surgical treatment of tumours of the eyelids.
Sixty-five patients, in whom eyelid cysts and tumours were surgically excised and examined histopathologically, were followed up. The general principles of treatment are outlined. The procedures used in the reconstruction of the eyelids, which depended upon the extent of lid-loss; the results obtained; and the complications encountered, are described.Surgical excision with subsequent repair is preferred to radiation therapy in view of the unique accessibility, general low malignancy and infrequent metastases of these tumours. Such excision and repair produces a better cosmetic and functional result.


Treatment of Alec: "History does not have to repeat itself".
Treatment of patients with pathological narcissism presents several challenges and there is paucity of published case reports that document meaningful and durable change in patients suffering from this condition. Using descriptive and atheoretical language, this paper presents a treatment of a young man in his transition from young adulthood to middle adulthood while he was negotiating complex residues of his experiences of growing up along with developmental challenges related to work and love. Against the backdrop of these transitions, the patient was working through various aspects of functioning related to pathological narcissism. Initially, given academic pressures and past romantic disappointments, he was confronting issues related to perfectionism, self-criticism, and avoidance. While he was able to move past some of these dynamics and function academically, later challenges related to becoming an independent adult led to a retreat into an avoidant state of futility and pessimism. Working through painful family dynamics related to not being seen and controlled, along with a deepening attachment in therapy as well as confrontation with realities of his life, led him to take steps toward greater independence. Thereafter, his treatment focused on learning from life experiences such as a newly developed career and romantic life, accepting the complexity of self and others, and tolerating disillusionments.


Agricultural change and population growth: a brief survey on the case of China in historical perspective.
A historical review of the relationship between agricultural change and population growth in China is presented. "This paper will try to discuss four aspects of agricultural change that are related to population growth. They are: (1) expansion of agricultural frontier, (2) changes in cultivation methods and land use, (3) improvements in agricultural technology, and (4) irrigation and water-control. Each of these aspects [is] treated briefly with temporal and spatial perspectives...." The relevance of the Boserup theory that population pressure leads to agricultural development is considered in the Chinese context. It is found that some evidence supports the theory. (summary in CHI)


Translational Informatics for Natural Products as Antidepressant Agents.
Depression, a neurological disorder, is a universally common and debilitating illness where social and economic issues could also become one of its etiologic factors. From a global perspective, it is the fourth leading cause of long-term disability in human beings. For centuries, natural products have proven their true potential to combat various diseases and disorders, including depression and its associated ailments. Translational informatics applies informatics models at molecular, imaging, individual, and population levels to promote the translation of basic research to clinical applications. The present review summarizes natural-antidepressant-based translational informatics studies and addresses challenges and opportunities for future research in the field.


Tuberculous Dactylitis with Concomitant Thyroid Involvement: A Rare Presentation of Childhood Tuberculosis.
Extrapulmonary tuberculosis rarely presents as thyroid involvement along with other manifestations, and poses a diagnostic challenge on account of paucibacillary nature of disease. In general, the diagnosis of tuberculosis is based on epidemiological risk factors, clinical features, imaging studies, in addition to a positive skin testing or Interferon Gamma Release Assay (IGRA). A 14-year boy presented with history of fever and weight loss for one year. On examination, he had painful swelling of fingers and toes along with a painless thyroid nodule and squint. Hand X-ray showed lytic-sclerotic lesions in phalanges. MRI of brian showed multiple ring enhancing lesions and radionuclide thyroid scan showed multinodular goitre. Histology showed epithelioid cell granulomas (thyroid and bone) and tuberculomas of brain confirmed tuberculosis. He responded well to four-drug anti-tuberculous therapy and his fever, squint, thyroid nodule, and dactylitis disappeared. Tuberculosis of thyroid, a rare phenomenon, can be diagnosed and treated well; if clinical index of suspicion is kept high, particularly in tuberculosis prevalent areas.


2-D assembly of supramolecular nanoarchitectures on Mg(0001).
In this work, a Mg(0001) single crystal is used as a novel template to grow 2D supramolecular nano-architectures. By using scanning tunnelling microscopy (STM) and high-resolution X-ray photoemission spectroscopy (HR-XPS), the formation of either a homo-molecular or metal-organic network is reported for carboxylic or amino functionalized molecules, respectively.


Nutritional status of centenarians assessed by activity and anthropometric, hematological and biochemical characteristics.
For the maintenance of good health of very old people such as centenarians, nutrition is very important. However, the information on their nutritional status is very limited. In this study, we evaluated the nutritional status of centenarians by comparison with elderly in their 70 s and young adults. Volunteer subjects were comprised of 71 centenarians (51 females, 20 males) who were not bed ridden, 84 elderly in their 70 s (51 females, 33 males) who had no specific health problems and 27 healthy young adults in their 20 s (17 females, 10 males). We compared 11 items of the activities of daily living (ADL), height, weight, hematological (hemoglobin, hematocrit and red blood cell count) and biochemical [total protein, albumin, total-, HDL-, LDL- and VLDL-cholesterols, triglycerides, glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT) and creatinine] variables among the three age groups. Since the atrophy of muscle is more severe than the atrophies of other tissues in the elderly, we studied the muscle protein breakdown using plasma 3-methylhistidine (3-MH) as a marker. The results of all indices except serum lipids, GOT and GPT, were lower in the centenarians than in the subjects in their 20 s (p < 0.05) and were lower than the lower reference limits. Most of the results of the elderly in their 70s were within the reference intervals. However, as compared to the young subjects, they had: 1) normal ADL; 2) shorter height; 3) heavier weight in females and lighter weight in males; 4) lower total protein and albumin levels and albumin/globulin (A/G) ratios; and 5) higher total- and LDL-cholesterol levels in females and HDL-cholesterol levels in males (p < 0.05). The plasma 3-MH concentration was higher in the centenarian group than in the young and elderly groups (p < 0.05). However, serum creatinine concentrations also tended to be high in the group, suggesting that a high 3-MH concentration did not indicate accelerated muscle protein breakdown but rather poor kidney functions. The results of this study show that the centenarians had shrunken stature, low hematological values and poor protein nutrition but rather normal lipid nutrition, however the elderly subjects in their 70s could still maintain most nutritional parameters in relatively normal condition.


Iseganan (IntraBiotics pharmaceuticals).
Iseganan (IB-367) is a protegrin under development by IntraBiotics, as part of a larger protegrin program, for the potential treatment of oral mucositis, a frequent side effect of anticancer therapies. The company is developing three formulations of the drug: A rinse for the potential treatment of mucositis, an aerosolized liquid for the potential treatment of respiratory infection and a gel formulation for the potential treatment of pneumonia [376325]. Iseganan kills a broad-spectrum of bacteria and fungi, including those resistant to conventional antimicrobial drugs, by attaching to and destroying the integrity of the lipid cell membrane [241594]. Until August 1999, Pharmacia & Upjohn was a codeveloper of iseganan. IntraBiotics re-acquired the global rights to iseganan in December 1999, and both companies agreed to terminate the collaboration [335766]. In May 2000, analysts at SG Cowen predicted the drug's potential market at US $100 to US $200 million [376325].


Regulation of tissue transglutaminase by prolonged increase of intracellular Ca2+, but not by initial peak of transient Ca2+ increase.
Tissue transglutaminase (tTGase) is a member of calcium-dependent transamidation enzyme family, but a detailed regulation mechanism of tTGase by intracellular Ca(2+) is not clearly understood. Arachidonic acid (AA) and maitotoxin (MTX) activated tTGase in a dose- and time-dependent manner. Transfection of tTGase siRNA largely inhibited tTGase expression and tTGase activation by MTX. AA induced an initial increase of intracellular Ca(2+) followed by a prolonged increase. Removal of extracellular Ca(2+) with EGTA blocked the prolonged Ca(2+) increase in response to AA, although the initial Ca(2+) increase remained. In contrast, EGTA completely blocked the increase of intracellular Ca(2+) by MTX. The activation of tTGase by AA or MTX was significantly inhibited by EGTA. Moreover, EGTA prevented the prolonged increase of intracellular Ca(2+) and tTGase activation by lysophosphatidic acid, but had no effect on the initial Ca(2+) increase. These results suggested that tTGase is regulated by the prolonged increase of intracellular Ca(2+) originated from Ca(2+) influx, rather than by the initial peak of transient Ca(2+) increase.


Plant-animal interactions in larkspur poisoning in cattle.
Larkspur (Delphinium spp.) toxicity in cattle seriously impedes the efficient use of productive mountain rangelands. Larkspurs contain complex diterpenoid alkaloids that cause acute intoxication and death from respiratory paralysis. Alkaloids and their concentrations vary among larkspur species, plant parts and phenological growth stages, thus causing great variability in toxicity. Ingestion rate of larkspur by the cow, alkaloid toxicity and concentration in the plant and the kinetics of absorption and excretion interact to determine whether a cow is poisoned. Plant and animal factors influencing consumption and subsequent intoxication must be further elucidated to devise management strategies to reduce liverstock losses.


Computational insight into hydrogen persulfide and a new additive model for chemical and biological simulations.
S-Sulfhydration of cysteine to the Cys-SSH persulfide is an oxidative post-translational modification that plays an important regulatory role in many physiological systems. Though hydrogen persulfide (H2S2) has recently been established as a signaling and cellular sulfhydration reagent, the chemistry and chemical biology of persulfides remain poorly explored. We first report an extensive high-level ab initio quantum chemical investigation of (H2S2)n, (H2S2)m·H2O, and (H2O)m·H2S2 clusters (n = 1-3 and m = 1, 2) and of H2S2 complexes with 19 compounds that model the side chains of naturally-occurring amino acids. The high polarizability of S necessitates the use of large, very diffuse, basis sets for proper description of H2S2 and its complexes. H2S2 possesses a skewed equilibrium geometry, with nonpolar trans and more polar cis conformers 6 and 8 kcal mol-1 higher in energy, respectively; the skewed conformation is preserved in all neutral and cationic complexes while a cis geometry prevails in some anionic complexes. H2S2 is found to be a better H-bond donor and a poorer acceptor than H2S, and that in complexes with H2O, alcohols and amines, H2S2 is a better H-bond donor. Radical delocalization on both S atoms stabilizes the perthiyl (HSS˙) over the thiyl (HS˙) radical and results in a ∼20 kcal mol-1 lower S-H homolytic bond dissociation in H2S2, making it a potential antioxidant. A simple additive model is optimized for H2S2 and used together with the TIP3P model and the CHARMM36 all-atom force field (FF) to investigate the structure and thermodynamic properties of liquid H2S2 and the solubility of H2S2 in water, and to model H2S2-protein interactions (for which new FF parameters are further developed). Very weak H-bonding characterizes liquid H2S2 and it is found immiscible in liquid water with a trend in H-bonding strengths between H2S2 and H2O in the order O-HO ≫ S-HO > O-HS. This work does not only provide a thorough description of the structure and energetics of H2S2 and its various complexes, but also yields a reliable FF for investigating H2S2 in chemistry and biology.


Automated HLA-B27 testing using the FACSPrep/FACScan system.
Tissue typing can help in the diagnosis of the seronegative arthropathy ankylosing spondylitis. Using an automatic sample preparation system and flow cytometry (FACSPrep/FACScan) we have developed a test for HLA-B27 screening using whole blood which is both rapid, reproducible, and permits simultaneous screening of large numbers of samples. We have used both indirect (248 cases) and direct (126 cases) monoclonal antibody staining techniques. Results were assessed using median channel shift (CS) from the negative control and relative fluorescence intensity. There is known cross-reactivity between HLA-B27 and HLA-B7 with the monoclonal antibody (MoAb) HLA-ABC-m3. Using this antibody and indirect staining, HLA-B7 samples had a significantly lower CS value than HLA-B27 samples. In 60% of these cases there was a clear distinction between HLA-B27 and HLA-B7. All HLA-B27 and HLA-B7 negative samples had a CS of 0 (P < 0.001). Using direct dual staining with CD3 and HLA-B27, all HLA-B27 and HLA-B7 negative samples had a low CS value (15 maximum), HLA-B7 samples had an intermediate CS value (20-85), and HLA-B27 samples had the highest CS values (70 upward). This system permits large scale rapid negative screening of samples with the elimination of over 60% as negatives (CS < 15). Limitations as a definitive test for HLA-B27 are due to MoAb cross-reactivity with HLA-B7 which necessitates other confirmatory techniques. The substitution of the HLA-ABC-m3 with the recently available HLA-B27 specific MoAb FD705 would substantially increase the value of this technique for routine HLA-B27 typing.


Asbestos and cancer: human natural killer cell activity is suppressed by asbestos fibers but can be restored by recombinant interleukin-2.
Inhalation of asbestos fibers is associated with a marked increase in the risk of developing pulmonary malignancy, particularly bronchogenic carcinoma. As natural killer (NK) cells are specialized lymphocytes that are considered to have an important in vivo role in the recognition and destruction of malignant cells, we examined the capacity of asbestos fibers (chrysotile, amosite, and crocidolite) to interfere with the NK activity of nylon wool-nonadherent, human blood lymphocytes (51Cr-release assay, K562 target cells, 14 h effector-to-target ratio = 50:1). Final asbestos concentrations used were 1 to 1,000 micrograms/ml. None of the fibers altered spontaneous target cell lysis or lymphocyte viability. All types of asbestos suppressed NK activity in a dose-dependent fashion. This effect was most marked with chrysotile, which exerted a profound inhibitory effect on blood NK cell activity; at 100 micrograms/ml, NK activity was inhibited 84 +/- 2% (p less than 0.001). The suppressive effects of asbestos were exerted directly on the NK cells (large granular lymphocytes, 91 +/- 2% inhibition at 100 micrograms/ml; p less than 0.001). Exposure of lymphocytes to recombinant interleukin-2 (IL-2, 150 units/ml) for 24 h prior to exposure to asbestos restored the level of activity to 99 +/- 6% of the original value (p less than 0.001), and lung lymphocytes that were exposed to IL-2 in vivo (active sarcoidosis) were resistant to suppression by asbestos. Similar results were observed in a group of patients with asbestosis. This suppression of NK activity may contribute to the increased susceptibility of asbestos-exposed persons to the development of pulmonary malignancy.


An incremental approach to a Web-based computerized medical record.
Acceptance of an electronic medical record within physician practices is a challenge that the Everett Clinic and the Wenatchee Valley Clinic in Washington State have chosen to approach incrementally. These two independent clinics, with 180 physicians each, joined forces in 1995 to form an information service organization, CliniTech Information Resources, to consolidate operation of their practice management and lab systems. With that done, in 1997 they asked CliniTech to come up with a solution to give physicians online access to clinical data in a way that didn't interrupt their work-flow or decrease their productivity--not a small order. The first HTML application was On Line Transcription, for viewing chart notes and radiology reports. Next, the On Line Patient Profile was developed to replace the face sheet. On Line Lab Results followed as a way to view results from the clinics' internal and reference lab systems. A single user interface was created in 2000 to link these components to the physician's schedule and clinical references. The new computerized medical record (CMR) has been embraced by the clinics' physicians (currently at 70 percent usage) and will continue to grow with additional results and images. Electronic signature capabilities for transcription and results are also slated for 2001 and will be the first change to how the physician practices.


Effect of Hospital Volume on Prosthesis Use and Mortality in Aortic Valve Operations in the Elderly.
This study was designed to examine the effect of hospital procedural volume on outcomes in aortic valve replacement (AVR) in the elderly. The study included 277,928 Medicare beneficiaries who underwent AVR from 2000 through 2009 at one of 1,255 participating hospitals. Operative mortality and the use of mechanical prostheses were analyzed according to hospital annual procedural volume. Annual AVR volume was divided into 5 different categories: the smallest volume group with less than 10 AVRs per year to the largest group averaging more than 70 AVRs per year. The overall observed operative mortality rate was 7.3%; for isolated AVR it was 5.5%. Lower-volume hospitals exhibited increased adjusted operative mortality: 10 cases or fewer per year--odds ratio (OR), 1.55; 95% confidence interval (CI), 1.39 to 1.72; 11 to 20 cases per year--OR, 1.35; 95% CI, 1.23 to 1.47; 21 to 40 cases per year--OR, 1.15; 95% CI, 1.06 to 1.25; 41 to 70 cases per year--OR, 1.10; 95% CI, 1.01 to 1.20 relative to those hospitals performing more than 70 cases per year. The discrepancy in operative mortality between low- and high-volume hospitals diverged during the study. Mechanical valve use decreased with increasing hospital volume (p = 0.0001). Mechanical valves were used in 64.5% of AVRs in hospitals with an annual AVR volume less than 10 in contrast to only 25.4% in hospitals with an annual AVR volume more than 70. After adjustment, the use of mechanical valves was independently associated with increased operative mortality (OR, 1.15; 95% CI, 1.11-1.19). Low-volume centers were characterized by increased adjusted operative mortality and greater use of mechanical prostheses, a trend that persisted during the 10-year course of the study. These data would support the center-of-excellence concept for AVR and may be particularly relevant in the elderly population.


Chronic hyperbaric exposure activates proinflammatory mediators in humans.
Decompression illness (DCI) is an illness affecting divers subjected to reductions in ambient pressure. Besides a mechanical explanation to DCI, an inflammatory mechanism has been suggested. In this study, levels of interleukin (IL)-8, IL-6, IL-1 receptor antagonist (IL-1ra), secretory leukocyte protease inhibitor (SLPI), and neutrophil gelatinase-associated lipocalcin (NGAL) were measured in divers before and after a 2-mo period of daily diving. The divers were military conscripts and completed their diving period with no clinical symptoms of DCI. We found no change in IL-6 and IL1-ra but did find an increase in IL-8 and NGAL together with a decrease in SLPI levels. The findings suggest an inflammatory activation. This activation is not severe because no changes in IL-6 or IL-1ra were found. The increase in NGAL and IL-8 levels were interpreted as a sign of leukocyte activation. The decreased SLPI levels suggest an influence on the inflammatory defense mechanism. All in all, the findings of this study show a compensated activation of the inflammatory defense mechanism without loss of homeostasis of the inflammatory system.


Quantification of endogenous metabolites by the postcolumn infused-internal standard method combined with matrix normalization factor in liquid chromatography-electrospray ionization tandem mass spectrometry.
Quantification of endogenous metabolites has enabled the discovery of biomarkers for diagnosis and provided for an understanding of disease etiology. The standard addition and stable isotope labeled-internal standard (SIL-IS) methods are currently the most widely used approaches to quantifying endogenous metabolites, but both have some limitations for clinical measurement. In this study, we developed a new approach for endogenous metabolite quantification by the postcolumn infused-internal standard (PCI-IS) method combined with the matrix normalization factor (MNF) method. MNF was used to correct the difference in MEs between standard solution and biofluids, and PCI-IS additionally tailored the correction of the MEs for individual samples. Androstenedione and testosterone were selected as test articles to verify this new approach to quantifying metabolites in plasma. The repeatability (n=4 runs) and intermediate precision (n=3 days) in terms of the peak area of androstenedione and testosterone at all tested concentrations were all less than 11% relative standard deviation (RSD). The accuracy test revealed that the recoveries were between 95.72% and 113.46%. The concentrations of androstenedione and testosterone in fifty plasma samples obtained from healthy volunteers were quantified by the PCI-IS combined with the MNF method, and the quantification results were compared with the results of the SIL-IS method. The Pearson correlation test showed that the correlation coefficient was 0.98 for both androstenedione and testosterone. We demonstrated that the PCI-IS combined with the MNF method is an effective and accurate method for quantifying endogenous metabolites.


The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity.
The ubiquitin-proteasome pathway is critically involved in the pathology of neurodegenerative diseases characterized by protein misfolding and aggregation. Data in the present study suggest that the polyglutamine neurodegenerative disease protein, ataxin-3 (AT3), functions in the ubiquitin-proteasome pathway. AT3 contains an ubiquitin interaction motif (UIM) domain that binds polyubiquitylated proteins with a strong preference for chains containing four or more ubiquitins. Mutating the conserved leucine in the first UIM (L229A) almost totally eliminates binding to polyubiquitin chains while a similar mutation in the second UIM (L249A) also inhibits binding to polyubiquitin chains but to a lesser extent. Both wild-type and pathological AT3 increase cellular levels of a short-lived GFP that is degraded by the ubiquitin-proteasome pathway. AT3 has several properties characteristic of ubiquitin proteases including decreasing polyubiquitylation of 125I-lysozyme by removing ubiquitin from polyubiquitin chains, cleaving a ubiquitin protease substrate, and binding the specific ubiquitin protease inhibitor, ubiquitin-aldehyde. Mutating the predicted catalytic cysteine in AT3 inhibits each of these ubiquitin protease activities. The ability to bind and cleave ubiquitylated proteins is consistent with AT3 playing a role in the ubiquitin-proteasome system. This raises the possibility that pathological AT3, which tends to misfold and aggregate, may be exposed to aggregate-prone misfolded/denatured proteins as part of its normal function.