Temperature dependent Raman and X-ray diffraction studies of anhydrous milk fat.
Raman spectroscopy was used to characterize the polymorphs and liquid state of anhydrous milk fat, with emphasis placed on the thermal evolution of the ester carbonyl stretching modes (1800-1700cm-1) and the comparative study of the Raman-active CC (1660cm-1) and CH (3000-2700cm-1) vibrational modes. Specific Raman signatures in the crystalline phase were found and attributed to the coexistence of two groups of triglycerides. This was confirmed using differential scanning calorimetry and X-ray diffraction methods. In the ester carbonyl band, the effect of changing temperature on both the number of modes and new defined intensity ratios was studied and enabled polymorph discrimination. CH stretching signals increased with polymorph stability, indicating the dominance of antisymmetric CH methylene vibrations as the anhydrous milk fats crystal lattice became more ordered. The change in intensity of the CH stretching bands as a function of temperature was used to probe the order-disorder transition.


The UTE Disc Sign on MRI: A Novel Imaging Biomarker Associated With Degenerative Spine Changes, Low Back Pain, and Disability.
Cross-sectional. To assess the distribution of the ultra-short time-to-echo (UTE) disc sign (UDS) and its association with disc degeneration, other magnetic resonance imaging (MRI) phenotypes, pain, and disability profiles. Disc degeneration has been conventionally assessed by T2-weighted (T2W) signal intensity on MRI; however, its clinical utility has been questionable. UTE MRI assesses short T2 components. The authors have identified a new imaging biomarker on UTE-the UDS. One hundred eight subjects were recruited. T2W MRI assessed disc degeneration and other phenotypes, and T1-rho MRI values represented quantitative proteoglycan disc profiles of L1-S1. UDS was detected on UTE (i.e., hyper-/hypointense disc band). A UDS score (cumulative number of UDS levels) and T2W summated lumbar degenerated scores (cumulative disc degeneration score) were assessed. Subject demographics, chronic low back pain (LBP), and disability profiles (Oswestry Disability Index: ODI) were obtained. UDS was noted in 39.8% subjects, 61.4% occurred at the lower lumbar spine and 39.5% had multilevel UDS. UDS subjects had significantly greater severity and extent of disc degeneration, and Modic changes (P < 0.05). By disc levels, a higher prevalence of disc degeneration/displacement, Modic changes, and spondylolisthesis were noted in UDS discs than non-UDS discs (P < 0.05). T1-rho values were also lower in UDS discs (P = 0.022). The majority of UDS could not be detected on T2W. The UDS score significantly correlated with worse ODI scores (r = 0.311; P = 0.001), whereas T2W cumulative disc degeneration score did not (r = 0.13; P = 0.19). LBP subjects exhibited more multilevel UDS (P < 0.015) but not on T2W MRI (P = 0.53). The UDS score was significantly related to LBP (P = 0.009), whereas T2W cumulative disc degeneration score was not (P = 0.127). This is the first study to report "UDS" in humans. UDS is a novel imaging biomarker that is highly associated with degenerative spine changes, chronic LBP, and disability than conventional T2W MRI. 2.


Bidirectional relationship between nonalcoholic fatty liver disease and serum creatinine-to-body weight ratio as a proxy for skeletal muscle mass index.
Although an association between skeletal muscle mass index and nonalcoholic fatty liver disease (NAFLD) has previously been demonstrated, the causal direction remains unclear. Herein, we investigated the directional association between NAFLD and the serum creatinine-to-body weight ratio (sCr/bw), a surrogate marker of the muscle mass index, using longitudinal data. We recruited 9662 participants in 2017 and performed follow-up over 4 years. We evaluated whether sCr/bw was related to NAFLD development (Analysis I) and whether NAFLD was associated with a low sCr/bw incidence (Analysis II) using logistic regression models. Furthermore, a random intercept cross-lagged panel model was applied to evaluate the bidirectional association between sCr/bw ratio and NAFLD (Analysis III). Analysis I demonstrated an association between sCr/bw and incident NAFLD (odds ratio [OR] = 0.160, 95% confidence interval [CI]:0.107-0.232). Analysis II indicated a relationship between NAFLD and subsequent low sCr/bw ratio (OR = 1.524, 95% CI: 1.258-1.846). Analysis III indicated that the standard regression coefficient from sCr/bw to subsequent hepatic steatosis (HS) was -0.053 for βsCr/bw2017 → HS2019 and -0.060 for βsCr/bw2019 → HS2021 and the coefficient from HS to subsequent sCr/bw was -0.093 for βHS2017 → sCr/bw2019 and -0.112 for βHS2019 → sCr/bw2021 (all P < 0.05). This study indicated mutual causality between sCr/bw and NAFLD. Considering that sCr/bw is a surrogate marker of muscle mass index, the findings emphasize that NAFLD and low muscle mass form a vicious cycle, which should be taken seriously in clinical practice.


Advances in neuroimaging for HIV-1 associated neurological dysfunction: clues to the diagnosis, pathogenesis and therapeutic monitoring.
Persons with advanced human immunodeficiency virus type one (HIV-1) infection seek medical advice for a wide range of neurological disorders including, but not limited to, peripheral neuropathy, toxoplasmosis, cryptococcal meningitis, cytomegalovirus retinitis progressive multifocal leukoencephalopathy, lymphoma and dementia. The diagnosis of HIV-1-associated dementia (HAD) induced as a direct consequence of HIV infection of the brain comes commonly by exclusion. Diagnostic decisions can often be clouded by concomitant depression, motor impairments, and lethargy that follow debilitating immune suppression and weight loss. Indeed, cognitive, motor and behavior abnormalities underlie a variety of neurological dysfunctions associated with advanced HIV-1 infection. Thus, even combinations of clinical, laboratory and neuroimaging tests [for example, magnetic resonance imaging (MRI), computed tomography (CT), single photon emission computed tomography (SPECT) and positron emission tomography (PET)] often fail to provide conclusive diagnostic information. Nonetheless, the recent development of quantitative MR spectroscopic imaging has improved diagnostic possibilities for HAD. We are pleased to discuss these developments as well as taking a forward look into what will soon be made available to improve neuroimaging diagnostic precision. New MR and SPECT testing are being developed in our laboratories and elsewhere both for animal model systems and in humans with HIV-1 disease. Such tests can facilitate dynamic measures of HIV-1 neuropathogenesis providing information for disease events that even 2 years ago were unattainable.


Submassive Pulmonary Embolism Complicating Small Bowel Obstruction.
The evaluation of patients with pulmonary embolism (PE) requires a comprehensive approach that assesses physical and laboratory exam findings, interprets varying imaging modalities, and selects appropriate treatment strategies. Comorbidities can complicate treatment and influence physicians to make difficult management decisions. In this case report, we present a patient with a small bowel obstruction complicated by submassive intermediate high-risk PE. Stratifying risk in PE patients is crucial to gauge when to use invasive interventions. There is limited clinical data to identify the optimal timing of surgery in patients with concurrent PE. We describe a challenging case where a patient requires multiple life-saving interventions; however, each treatment method carries a risk of bleeding or further complicating surgical candidacy. The patient in question first undergoes treatment of PE to improve hemodynamics and lower the clot burden prior to proceeding with resection of the small bowel. This report emphasizes the utility of the Pulmonary Embolism Response Team to facilitate care when surgical comorbidities require immediate attention as well.


Increased muscle proteasome activities in rats fed a polyunsaturated fatty acid supplemented diet.
Changes in the proteasome system, a dominant actor in protein degradation in eukaryotic cells, have been documented in a large number of physiological and pathological conditions. We investigated the influence of monounsaturated or polyunsaturated fatty acids (PUFAs) supplemented diets on the proteasome system, in rat skeletal muscles. Thirty rats were randomly assigned to three groups. The control group received only a standard diet. The monounsaturated fatty acid (MUFA) enriched diet group was fed with 3% sunflower oil in addition to standard food, and the polyunsaturated fatty acid supplemented diet group received 9% Maxepa) in addition to the standard diet. We analyzed muscle proteasome activities and content. Monounsaturated or PUFAs supplemented diets given for 8 weeks induced a significant increase in proteasome activities. With the polyunsaturated fatty acid enriched diet, the chymotrypsin-like and peptidylglutamylpeptide hydrolase activities increased by 45% in soleus and extensor digitorum longus (EDL), and by 90% in the gastrocnemius medialis (GM) muscle. Trypsin-like activity of the proteasome increased by 250% in soleus, EDL and GM. This increase in proteasome activities was associated with a concomitant enhancement in the muscle content of proteasome. Proteasome activities and level were less stimulated with a monounsaturated fatty acid supplemented diet. This study provides evidence that a monounsaturated or polyunsaturated fatty acid supplemented diet may regulate muscle proteasomes. Unsaturated fatty acids are particularly prone to free radical attack. Thus, we suggest that alterations in muscle proteasome may result from monounsaturated and polyunsaturated fatty acid-induced peroxidation, in order to eliminate damaged proteins.


A review of audiovisual telemedicine utilization and satisfaction assessment during the COVID-19 pandemic.
The use of telemedicine has broadened as technology that both restores continuity of care during disruptions in healthcare delivery and routinely provides primary care alone or in combination with in-person care. During the Covid-19 outbreak, the use of telemedicine as a routine care modality further accelerated. A review of scientific studies that used telemedicine to provide care from December 2019 to December 2020 is presented. From an initial set of 2,191 articles, 36 studies are analyzed. Evidence is organized and evaluated according to the country of study, the clinical specialty, the technology platform used, and satisfaction and utilization outcomes. Thirty-one studies reported high patient satisfaction scores. Eight studies reported satisfaction from both providers and patients with no uniformly accepted assessment instrument. Eight studies conducted a descriptive analysis of telemedicine use and patient adoption patterns. Less than one-third of studies were controlled before/after studies. Most studies were conducted in the USA followed by Europe. Reported satisfaction rates are high, consistent with previously documented research, whereas utilization rates increased significantly compared with the prepandemic period. Future work in developing standardized uniform assessment instruments, embedded with each telemedicine system, would increase versatility and agility in the assessment, boosting statistical power and the interpretation of results.


GABA immunoreactivity in the retina.
Presumed GABA neurons were studied in chick, guinea pig, and rabbit retinae with an immunohistochemical procedure aimed at direct demonstration of the endogenous GABA. In all species, a subset of amacrine cells was immunoreactive, as well as numerous fibers in the inner plexiform layer. In the chick, immunoreactivity was also demonstrated in horizontal cells, and single cell processes could be distinguished in both plexiform layers. The study indicates that the endogenous stores of GABA in GABAergic neurons can be visualized with immunohistochemical techniques. This direct approach thus gives additional information and probably is less subject to nonspecific staining than the demonstration of enzymes linked to GABA synthesis and metabolism. It also gives superior resolution in comparison with the autoradiographic techniques currently used for demonstrating GABA neurons. Invest Ophthalmol Vis Sci 27:674-678, 1986.


A Role of Endogenous Progesterone in Stroke Cerebroprotection Revealed by the Neural-Specific Deletion of Its Intracellular Receptors.
Treatment with progesterone protects the male and female brain against damage after middle cerebral artery occlusion (MCAO). However, in both sexes, the brain contains significant amounts of endogenous progesterone. It is not known whether endogenously produced progesterone enhances the resistance of the brain to ischemic insult. Here, we used steroid profiling by gas chromatography-tandem mass spectrometry (GC-MS/MS) for exploring adaptive and sex-specific changes in brain levels of progesterone and its metabolites after MCAO. We show that, in the male mouse brain, progesterone is mainly metabolized via 5α-reduction leading to 5α-dihydroprogesterone (5α-DHP), also a progesterone receptor (PR) agonist ligand in neural cells, then to 3α,5α-tetrahydroprogesterone (3α,5α-THP). In the female mouse brain, levels of 5α-DHP and 3α,5α-THP are lower and levels of 20α-DHP are higher than in males. After MCAO, levels of progesterone and 5α-DHP are upregulated rapidly to pregnancy-like levels in the male but not in the female brain. To assess whether endogenous progesterone and 5α-DHP contribute to the resistance of neural cells to ischemic damage, we inactivated PR selectively in the CNS. Deletion of PR in the brain reduced its resistance to MCAO, resulting in increased infarct volumes and neurological deficits in both sexes. Importantly, endogenous PR ligands continue to protect the brain of aging mice. These results uncover the unexpected importance of endogenous progesterone and its metabolites in cerebroprotection. They also reveal that the female reproductive hormone progesterone is an endogenous cerebroprotective neurosteroid in both sexes.SIGNIFICANCE STATEMENT The brain responds to injury with protective signaling and has a remarkable capacity to protect itself. We show here that, in response to ischemic stroke, levels of progesterone and its neuroactive metabolite 5α-dihydroprogesterone are upregulated rapidly in the male mouse brain but not in the female brain. An important role of endogenous progesterone in cerebroprotection was demonstrated by the conditional inactivation of its receptor in neural cells. These results show the importance of endogenous progesterone, its metabolites, and neural progesterone receptors in acute cerebroprotection after stroke. This new concept could be exploited therapeutically by taking into account the progesterone status of patients and by supplementing and reinforcing endogenous progesterone signaling for attaining its full cerebroprotective potential.


Combining 3D single molecule localization strategies for reproducible bioimaging.
Here, we present a 3D localization-based super-resolution technique providing a slowly varying localization precision over a 1 μm range with precisions down to 15 nm. The axial localization is performed through a combination of point spread function (PSF) shaping and supercritical angle fluorescence (SAF), which yields absolute axial information. Using a dual-view scheme, the axial detection is decoupled from the lateral detection and optimized independently to provide a weakly anisotropic 3D resolution over the imaging range. This method can be readily implemented on most homemade PSF shaping setups and provides drift-free, tilt-insensitive and achromatic results. Its insensitivity to these unavoidable experimental biases is especially adapted for multicolor 3D super-resolution microscopy, as we demonstrate by imaging cell cytoskeleton, living bacteria membranes and axon periodic submembrane scaffolds. We further illustrate the interest of the technique for biological multicolor imaging over a several-μm range by direct merging of multiple acquisitions at different depths.


MiR-221 Exacerbate Cell Proliferation and Invasion by Targeting TIMP3 in Papillary Thyroid Carcinoma.
MiR-221 is frequently upregulated in papillary thyroid cancer (PTC) tissues and cell lines, and this study was designed to validate the association of miR-221 with PTC proliferation, apoptosis, and migration. We observed that miR-221 suppressed TIMP3 expression by binding to 3' untranslated region of TIMP3 mRNA, and TIMP3 expression was increased with the presence of miR-221 inhibitors; TIMP3 siRNA could reverse the effects of miR-221 inhibitors on PTC cells. The results indicated that miR-221 exacerbated PTC by downregulating the expression of TIMP3. The effects of miR-221 and TIMP3 in vivo were also confirmed by human PTC-bearing mice models which suggest consistent results with those in vitro studies. In summary, miR-221 could aggravate cell proliferation and invasion of PTC by targeting TIMP3.


Delta sleep ratio. A biological correlate of early recurrence in unipolar affective disorder.
Slow wave sleep abnormalities have long been described in depression but were considered to be nonspecific indicators of psychopathology. Computerized techniques, including amplitude frequency measures and spectral analyses, are permitting new approaches to the examination of delta sleep. Early studies suggested that many depressed patients demonstrate lower delta wave intensity during the first non-rapid eye movement period than the second one. This finding, prominent in middle-aged depressed patients, has led to an examination of the ratio between the first and second non-rapid eye movement periods. This delta sleep measure seems to be a more robust predictor of recurrence than rapid eye movement latency. Analysis of data on 74 patients in a long-term maintenance treatment study for a minimum of 24 months demonstrates that the delta sleep ratio can predict survival time following discontinuation of drug treatment. Individuals with a high delta sleep ratio remain clinically remitted five times longer than those with a low delta sleep ratio.


Serotonin pharmacodynamics in hypothalamic tissues from young and old female rats.
The purpose of this study was to determine the effects of aging on serotonin (5-HT) pharmacodynamics in rostral hypothalamic tissue of female rats. Monoamine oxidase (MAO) activity was greater in old (19 months old) than in young (3 months old) animals. This difference resulted from a higher Vmax for hypothalamic MAO from old rats, whereas Km's were comparable in both age groups. These enzymatic changes were accompanied by altered uptake and release of [3H]5-HT. Although [3H]5-HT uptake was not different at equilibrium between groups, the equilibrium state was achieved more slowly by hypothalamic tissue from old rats. Basal and potassium-stimulated efflux of [3H]5-HT was significantly greater in old rats compared with young ones and these differences remained during multiple depolarizations. The findings of this study suggest that synaptic levels of hypothalamic 5-HT increase with age. Since pharmacological simulation of this condition in young rats produces physiologic dysfunction, the spontaneous changes that occur in hypothalamic 5-HT pharmacodynamics during aging have the potential to promote senescence.


Generation of an induced pluripotent stem cell line (ZJUi013-A) from a Familial cortical myoclonic tremor with epilepsy type 1 patient carrying (TTTCA)n insertion in the SAMD12 gene.
FCMTE1 is an autosomal dominant inherited neurodegenerative disorder characterized by myoclonic tremors and epilepsy. The cause of FCMTE1 is an abnormal (TTTCA)n insertion in intron 4 of SAMD12 gene. Fibroblasts obtained from a FCMTE1 patient were successfully transformed into induced pluripotent stem cells (iPSCs) (ZJUi013-A) using the Sendai virus. Our approach provided a resource for further pathogenesis study and drug screening of FCMTE1.


A knowledge-based approach to intelligent alarms in anesthesia.
The combination and aggregation of separate information sources to generate more ;intelligent' alarms using a knowledge-based approach is described. The approach gas developed as part of the knowledge-based anesthesia decision support system, AES-2, which monitors the patient's physiological state during anesthesia and eventually suggests therapeutic actions. Integration of the alarm system into a conventional information system is discussed. The state variable model used and the modeling of uncertainty are examined. The tools that support knowledge acquisition, design of knowledge-base prototypes. and test of the knowledge base of the AES-2 are described. A simulation example is given.


Epitope discovery for a synthetic polymer nanoparticle: a new strategy for developing a peptide tag.
We describe a novel epitope discovery strategy for creating an affinity agent/peptide tag pair. A synthetic polymer nanoparticle (NP) was used as the "bait" to catch an affinity peptide tag. Biotinylated peptide tag candidates of varied sequence and length were attached to an avidin platform and screened for affinity against the polymer NP. NP affinity for the avidin/peptide tag complexes was used to provide insight into factors that contribute NP/tag binding. The identified epitope sequence with an optimized length (tMel-tag) was fused to two recombinant proteins. The tagged proteins exhibited higher NP affinity than proteins without tags. The results establish that a fusion peptide tag consisting of optimized 15 amino acid residues can provide strong affinity to an abiotic polymer NP. The affinity and selectivity of NP/tMel-tag interactions were exploited for protein purification in conjunction with immobilized metal ion/His6-tag interactions to prepare highly purified recombinant proteins. This strategy makes available inexpensive, abiotic synthetic polymers as affinity agents for peptide tags and provides alternatives for important applications where more costly affinity agents are used.


Species interactions limit the occurrence of urban-adapted birds in cities.
Urbanization represents an extreme transformation of more natural systems. Populations of most species decline or disappear with urbanization, and yet some species persist and even thrive in cities. What determines which species persist or thrive in urban habitats? Direct competitive interactions among species can influence their distributions and resource use, particularly along gradients of environmental challenge. Given the challenges of urbanization, similar interactions may be important for determining which species persist or thrive in cities; however, their role remains poorly understood. Here, we use a global dataset to test among three alternative hypotheses for how direct competitive interactions and behavioral dominance may influence the breeding occurrence of birds in cities. We find evidence to support the competitive interference hypothesis: behaviorally dominant species were more widespread in urban habitats than closely related subordinate species, but only in taxa that thrive in urban environments (hereafter, urban adapted), and only when dominant and subordinate species overlapped their geographic ranges. This result was evident across diverse phylogenetic groups but varied significantly with a country's level of economic development. Urban-adapted, dominant species were more widespread than closely related subordinate species in cities in developed, but not developing, countries; countries in economic transition showed an intermediate pattern. Our results provide evidence that competitive interactions broadly influence species responses to urbanization, and that these interactions have asymmetric effects on subordinate species that otherwise could be widespread in urban environments. Results further suggest that economic development might accentuate the consequences of competitive interactions, thereby reducing local diversity in cities.


Discharge of patients to long-term care from a large acute hospital over a 12-year period.
Several factors may be important in determining the discharge of patients to long-term care from the acute hospital. We aimed to look at factors associated with discharge to long-term care from St. James's Hospital, Dublin between 1997 and 2008. Data obtained from a long-term care database within the geriatric service were analysed. This service is responsible for assessing and listing all patients for long-term care within the hospital. 3,107 patients were listed and 2,520 discharged to long-term care during the period. Mean age was 81.7±7.3 years and 64.1% were female. The number listed increased since 1997, but there was no change in age or gender. Median time to discharge was 52 days, but varied by year and was longer for public versus private facilities (mean difference=18 days, P=0.006). Mortality of those awaiting long-term care was 17.0%, but varied significantly by year and ranged form 9.3-29.0%. Mortality was higher in males, in those of older age and during the winter months. Variation in the time to discharge appears to be associated with changes in the provision of publicly funded private nursing home beds.


Nonketotic hyperglycemia appearing as choreoathetosis or ballism.
A number of focal neurologic abnormalities may accompany severe, nonketotic hyperglycemia, but extrapyramidal movement disorders have not previously been described. We evaluated the conditions of three patients with marked hyperglycemia in whom hemichorea or ballism developed that resolved completely with normalization of the blood glucose level. Potential pathogenetic mechanisms include relative dopaminergic hypersensitivity, impaired synthesis of acetylcholine or gamma-aminobutyric acid, or an undefined effect of hyperosmolarity, perhaps unmasking a previously subclinical lesion of the basal ganglia. Serum glucose level should be determined in anyone with the new onset of choreoathetosis or ballism, as hyperglycemia is a rapidly reversible cause of these conditions.


Prodigiosin rescues deficient p53 signaling and antitumor effects via upregulating p73 and disrupting its interaction with mutant p53.
p53 reactivation offers a broad-based strategy for cancer therapy. In this study, we report the identification of prodigiosin that can reactivate p53 family-dependent transcriptional activity in p53-deficient human colon cancer cells. Prodigiosin and its structural analogue (compound R) induced the expression of p53 target genes accompanied by cell-cycle arrest and apoptosis in p53-deficient cancer cells. Prodigiosin restored p53 signaling in cancer cells harboring hotspot TP53 mutations, with little to no detectable cytotoxicity in normal human fibroblasts and with no genotoxicity. Prodigiosin induced the expression of p73 and disrupted its interaction with mutant p53, thereby rescuing p53 pathway deficiency and promoting antitumor effects. The disruption of mutant p53/p73 interaction was specific to prodigiosin and not related to mTOR inhibition. Our findings suggest that mutant p53 needs to be targeted in the context of p73 stimulation to allow efficient restoration of the p53 pathway. In exhibiting this capability, prodigiosin and its analogue provide lead compounds to rescue deficiencies in the p53 pathway in cancer cells by upregulating p73 and targeting mutant p53/p73 interaction there.


Cancer incidence in Estonian migrants to Sweden.
Cancer incidence in Estonians who took refuge in Sweden in 1944-1945 has been compared with that in the total Swedish population and that among Estonians in Estonia in 1974-1985 using data from the Swedish and the Estonian countrywide population-based cancer registries. The vast majority of the Estonian immigrants studied had been living in Sweden for 30 years when the follow-up with respect to cancer incidence started in this investigation. In spite of the long residence in Sweden, differences in cancer incidence could be observed between these immigrants and the total Swedish population. The age-standardized incidence of stomach cancer was higher in the Estonian migrants than in the total Swedish population (SIR = 1.6 and 2.1 for males and females, respectively). Breast cancer incidence was lower in the migrant women (SIR = 0.75) and lung cancer incidence higher in migrant men (SIR = 1.5). An increased incidence of colorectal cancer was also found for both sexes in the migrant population (SIR = 1.4 for both males and females). A comparison between Estonians in Estonia and the total Swedish population revealed that the cancer incidence for the Estonians was lower than expected at age 70 and over. Male lung cancer and stomach cancer showed a higher incidence in the Estonian population than in the Swedish and in the migrant populations. The migrant population showed an intermediate incidence relative to Estonians in Estonia and the entire Swedish population. The colon-cancer risk in Estonian migrants to Sweden was higher than the risk for Estonians in Estonia and for the Swedish population. This contrasts with most findings in the present and other studies on intermediate risks of migrants compared to the risks in the country of origin and in the new country of residence.


Cells in fluidic environments are sensitive to flow frequency.
Virtually all cells accommodate to their mechanical environment. In particular, cells subject to flow respond to rapid changes in fluid shear stress (SS), cyclic stretch (CS), and pressure. Recent studies have focused on the effect of pulsatility on cellular behavior. Since cells of many different tissue beds are constantly exposed to fluid flows over a narrow range of frequencies, we hypothesized that an intrinsic flow frequency that is optimal for determining cell phenotype exists. We report here that cells from various tissue beds (bovine aortic endothelial cells (BAEC), rat small intestine epithelial cells (RSIEC), and rat lung epithelial cells (RLEC)) proliferate maximally when cultured in a perfusion bioreactor under pulsatile conditions at a specific frequency, independent of the applied SS. Vascular endothelial and pulmonary epithelial cell proliferation peaked under 1 Hz pulsatile flow. In contrast, proliferation of gastrointestinal cells, which in their physiological context are subject to no flow or higher wavelength signal, was maximum at 0.125 Hz or under no flow. Moreover, exposure of BAEC to pulsatile flow of varying frequency influenced their nitric oxide synthase activity and prostacyclin production, which reached maximum values at 1 Hz. Notably, the "optimal" frequencies for the cell types examined correspond to the physiologic operating range of the organs from where they were initially derived. These findings suggest that frequency, independent of shear, is an essential determinant of cell response in pulsatile environments.


Meat intake, cooking methods, dietary carcinogens, and colorectal cancer risk: findings from the Colorectal Cancer Family Registry.
Diets high in red meat and processed meats are established colorectal cancer (CRC) risk factors. However, it is still not well understood what explains this association. We conducted comprehensive analyses of CRC risk and red meat and poultry intakes, taking into account cooking methods, level of doneness, estimated intakes of heterocyclic amines (HCAs) that accumulate during meat cooking, tumor location, and tumor mismatch repair proficiency (MMR) status. We analyzed food frequency and portion size data including a meat cooking module for 3364 CRC cases, 1806 unaffected siblings, 136 unaffected spouses, and 1620 unaffected population-based controls, recruited into the CRC Family Registry. Odds ratios (OR) and 95% confidence intervals (CI) for nutrient density variables were estimated using generalized estimating equations. We found no evidence of an association between total nonprocessed red meat or total processed meat and CRC risk. Our main finding was a positive association with CRC for pan-fried beefsteak (P(trend) < 0.001), which was stronger among MMR deficient cases (heterogeneity P = 0.059). Other worth noting associations, of borderline statistical significance after multiple testing correction, were a positive association between diets high in oven-broiled short ribs or spareribs and CRC risk (P(trend) = 0.002), which was also stronger among MMR-deficient cases, and an inverse association with grilled hamburgers (P(trend) = 0.002). Our results support the role of specific meat types and cooking practices as possible sources of human carcinogens relevant for CRC risk.


Posterior vitreous mobility delineated by tracking of optical coherence tomography images in eyes with idiopathic macular holes.
To demonstrate the posterior vitreous mobility following eye movements in patients forming macular holes, using an optical coherence tomography (OCT) eye-tracking system. Prospective consecutive interventional case series. Twenty-four eyes of 17 consecutive patients with idiopathic macular hole and the remaining fellow eyes were recruited. Following acquisition of baseline fundus scans, all patients were instructed to perform sets of standardized full-excursion vertical and horizontal eye movements. Immediately after each set of movements an OCT scan registered to the baseline fundus image was obtained using the eye-tracking system. Three images were then overlaid using picture-editing software, thereby documenting the changing configuration of the posterior vitreous as well as its position relative to the static retinal structures. In patients with macular hole, 22 of 24 eyes (92%) had duplication of the posterior cortical vitreous in overlaid images. The extent of duplication (indicating mobility) was increased with increasing vitreous separation and as the stage of macular hole increased (75% in stage 0; 80% in stage 1; 100% in both stage 2 and stage 3). In all eyes in which there was a wavy configuration to the vitreous face, or in which there was a greater angle of vitreous insertion into the peripheral retina, vitreous mobility was evident on overlaid images (P = 2.7 × 10(-17) and P = 1.7 × 10(-13), respectively). By dynamically evaluating patients, we offer potential mechanistic insights that may further implicate mobile vitreous and associated fluid currents in the pathogenesis and progression of macular holes.


Maternal body composition, offspring blood pressure and the hypothalamic-pituitary-adrenal axis.
We tested the hypothesis that women who are thin or have poor pregnancy weight gain have offspring with higher blood pressure and examined whether this link is mediated by increased secretion of cortisol. We studied a cohort of 388 children born in Kingston, Jamaica. From hospital records we obtained information about their mother's body mass index (BMI) and weight gain during pregnancy. At age 8.5 years we measured the children's fasting plasma cortisol concentrations and blood pressure and assessed their mother's anthropometry. There were no relationships between the mother's BMI or weight gain during pregnancy and offspring blood pressure. However, mothers with a greater subscapular to triceps skinfold thickness ratio (SSTR) had offspring with higher blood pressure (5.6 mmHg systolic and 3.7 mmHg diastolic increase per unit change in SSTR, P = 0.002 and P = 0.008 respectively). Fasting plasma cortisol concentrations correlated with the children's systolic (r = 0.33, P < 0.0001) and diastolic pressures (r = 0.12, P = 0.02) independently of age, gender, weight or socio-economic status and were also predicted by the mother's SSTR. These findings suggest that maternal truncal obesity rather than thinness is associated with raised blood pressure in the offspring, and that this link may be mediated by increased cortisol secretion.


Do Not Cut Off Your Tail: A Mega-Analysis of Responses to Auditory Perturbation Experiments.
The practice of removing "following" responses from speech perturbation analyses is increasingly common, despite no clear evidence as to whether these responses represent a unique response type. This study aimed to determine if the distribution of responses to auditory perturbation paradigms represents a bimodal distribution, consisting of two distinct response types, or a unimodal distribution. This mega-analysis pooled data from 22 previous studies to examine the distribution and magnitude of responses to auditory perturbations across four tasks: adaptive pitch, adaptive formant, reflexive pitch, and reflexive formant. Data included at least 150 unique participants for each task, with studies comprising younger adult, older adult, and Parkinson's disease populations. A Silverman's unimodality test followed by a smoothed bootstrap resampling technique was performed for each task to evaluate the number of modes in each distribution. Wilcoxon signed-ranks tests were also performed for each distribution to confirm significant compensation in response to the perturbation. Modality analyses were not significant (p > .05) for any group or task, indicating unimodal distributions. Our analyses also confirmed compensatory reflexive responses to pitch and formant perturbations across all groups, as well as adaptive responses to sustained formant perturbations. However, analyses of sustained pitch perturbations only revealed evidence of adaptation in studies with younger adults. The demonstration of a clear unimodal distribution across all tasks suggests that following responses do not represent a distinct response pattern, but rather the tail of a unimodal distribution. https://doi.org/10.23641/asha.24282676.


Microvolume, kinetic-dependent enzyme-linked immunosorbent assay for amoeba antibodies.
We describe a microvolume enzyme-linked immunosorbent assay based on enzyme rate kinetics. Antigens from Entamoeba histolytica were adsorbed in wells of disposable polystyrene strips containing 12 flat-bottom wells. After exposure to the serum of a patient and peroxidase-labeled anti-human immunoglobulin G, the rate of color change in specific substrate was determined by eight sequential readings of individual wells over a 2-min period with a microcomputer-controlled model MR-600 automated plate reader. The changes in absorbance readings were converted to slope values for each well by the microcomputer. Thus, 12 samples were read, and results were printed in ca. 3.5 min. Assay conditions are described and data are presented to show that this assay is quantitative for antibody and antigen concentration with a single-tube (well) dilution.


Preference for place-of-death among terminally ill cancer patients in Denmark.
Achieving home death is often seen as an important endpoint in palliative care, but no studies of the preferred place-of-death have yet been conducted in Scandinavia. Furthermore, we do not know if professionals' report on deceased patients' preference of place-of-death is a valid information. The aim of this study was to describe where terminally ill Danish cancer patients prefer to die and to determine if their preference changed during the palliative period, as reported retrospectively by bereaved relatives, general practitioners (GPs) and community nurses (CNs) and to assess the agreement of their accounts. The study was a population-based, cross-sectional combined register and questionnaire study in Aarhus County, Denmark. The population comprised 599 deceased adult cancer patients who had died from 1 March to 30 November 2006 and were identified through merging of health registers. Relatives returned 198 questionnaires about patients' preferred place-of-death, GPs 333 and CNs 201. The study showed that most terminally ill cancer patients preferred home death (up to 80.7%). The reported preference for home death weakened as death approached (down to 64.4%). A better congruence was seen between relatives' and GPs' accounts of preference for place of death at the end of the palliative period (κ 0.71) than between relatives' and CNs' accounts (κ 0.37). In conclusion, bereaved relatives (and GPs and CNs) report retrospectively that most terminally ill cancer patients wish to die at home. The preference weakened significantly as death approached. The agreement between relatives' and GPs' accounts on patients' preferences at the end of the palliative period was 'substantial', whereas the agreement between relatives' and CNs' accounts at the same time was significantly less outspoken. This indicates that CNs may be facing a problem in assessing their patients' wishes retrospectively.


Novel integrase-defective lentiviral episomal vectors for gene transfer.
High levels of circular viral extrachromosomal DNA (E-DNA) are normally produced after infection with integration-competent and -incompetent lentiviruses. Although E-DNA has been shown to be transcriptionally active, it lasts for only a short time in replicating cells. Here, we report an integrase (IN)-defective lentiviral episomal vector in which insertion of the simian virus 40 (SV40) promoter, containing the origin of replication (ori), is associated with long-term expression and persistence of E-DNA in the presence of SV40 large T antigen (TAg) from 293T cells. 293 and 293T cell lines transduced with IN-competent lentiviral vectors expressing green fluorescent protein (GFP) or luciferase from the cytomegalovirus (CMV) or SV40 promoter gave similar levels of transduction and expression. In contrast, only transient reporter expression occurred when using the CMV IN-defective control vector in both 293 and 293T cells. However, reporter gene expression was maintained for more than 8 weeks in 293T, but not 293, cells transduced with the IN-defective lentiviral vector containing the SV40-ori promoter. Polymerase chain reaction for two-long terminal repeat (2LTR) extrachromosomal circular forms, a marker of lentiviral E-DNA, and fluorescence in situ hybridization analysis confirmed the persistence and episomal nature of circular E-DNA up to 60 days after transduction. Taken together, these results indicate that insertion of the SV40-ori promoter in a lentiviral vector contributes to long-term expression by promoting episomal replication when TAg is provided in trans. Lentiviral episomal vectors may serve as specific tools for therapeutic approaches to diseases, particularly those associated with episomal replication of DNA viruses including papillomaviruses, polyomaviruses, and herpesviruses.


Effects of submicrometer particle compositions on cytokine production and lipid peroxidation of human bronchial epithelial cells.
To identify the size and components related to toxicity of ambient particles, we used a trichotomous impactor to collect 17 sets of particles in three size ranges--submicrometer (diameters < 1 microm; PM1.0, fine (diameters between 1 and 2.5 microm; PM1.0-2.5, and coarse (diameters between 2.5 and 10 microm; PM2.5-10--at stations monitoring background, urban, traffic, and industrial air in Taiwan. Elemental contents, carbon contents, soluble ions, and endotoxin content of particles were determined by X-ray fluorescence spectrometry, thermal analysis, ion chromatography, and the Limulus amebocyte lysate assay, respectively. Human bronchial epithelial BEAS-2B cells were exposed to particle extracts at 100 micro g/mL for 8 hr, and interleukin-8 (IL-8) concentrations in the medium and lipid peroxidation products were measured. Particle-induced tumor necrosis factor-alpha (TNF-alpha) production by mouse macrophage RAW 264.7 cells was also measured. PM1.0 stimulation resulted in significantly higher IL-8 production and lipid peroxidation than PM2.5-10, whereas the responses elicited by PM1.0-2.5 were not significantly higher than blank filters. Untreated and polymyxin B-pretreated PM1.0 also stimulated more TNF-alpha production by RAW 264.7 cells than PM2.5-10 and PM1.0-2.5. Cytokine production was significantly associated with metal contents of PM1.0: IL-8 correlated with Cr and Mn, and TNF-alpha correlated with Fe and Cr. Lipid peroxidation in BEAS-2B cells correlated with elemental and organic carbon contents. Our study found that size and composition of ambient particles were both important factors in inducing cytokine production and lipid peroxidation.


Thyroid status and adenosine content of adipose tissue.
Fat-cells from hypothyroid rats lack the normal lipolytic response to catecholamines. We have suggested that this is due to increased sensitivity to the inhibitory actions of endogenous adenosine. In this paper we present evidence that thyroid hormones increase adipose-tissue adenosine contents and suggest that the increased sensitivity to adenosine in hypothyroidism is due to relief from desensitization by endogenous adenosine.


Recent advances in the management of difficult constipation.
Constipation is a highly prevalent disorder. Some patients suffer from acute, intermittent episodes of constipation. Others, however, suffer from chronic constipation, a term that refers to those patients with symptoms of constipation for more than 6 months. In clinical practice, chronic constipation is often used interchangeably with the term functional constipation, which is currently defined using the Rome III criteria. Symptoms can be burdensome, leading to a reduction in patients' quality of life. In addition, chronic constipation is important because it imposes a significant economic impact to the health care system. Some patients with chronic constipation have persistent symptoms despite implementing lifestyle changes and using either over-the-counter agents or prescription medications. These patients may be categorized as having difficult constipation. This report will focus on recent advances in the management of difficult constipation, and include a discussion of new and upcoming medications as well as new diagnostic tests and procedures.


[Menstrual blood and human milk. Reflections and new proposals on breast-feeding in ancient Greece].
Within a larger study on breast-feeding in ancient Greece, we dwelt on four subjects (the superstitions concerning menstrual blood, milk and dairy products consumption by the Athenians, different kinds of milk and beliefs related to the transmission of hereditary characteristics through human milk, the connection between milk, breast and madness) on which we have identified a certain number of neglected sources. Starting from these, we can gain not only some mosaic tiles of the overall fragmentary view on habits and beliefs about breast-feeding, but also, more generally, helpful hints on some aspects of the Greek world and mentality that we barely know. In attempting to reach some general conclusions, we have also considered the iconographic sources, trying to explain, in part at least, the reason for the almost complete absence of scenes of breast-feeding in the archaic and classical art.


COVID-19 induced haemobilia: a novel entity.
Hemobilia which is firstly described in 1948 is a rare cause of gastrointestinal bleeding. Since its main clinic takes time to occur and may cause mortality, early diagnosis and management have a great importance. Almost for 3 years, the world has been facing with an unknown viral infection called COVID-19 whose clinic changes from asymptomatic respiratory infection to symptoms associated with multiple system involvement. The clinical presentation of Covid-19 infection varies tremendously depending on the severity of the illness. In this report, we present the first two cases of severe COVID-19 induced hemobilia.


Stereotactic radiosurgery at a low marginal dose for the treatment of pediatric arteriovenous malformations: obliteration, complications, and functional outcomes.
OBJECT.: Stereotactic radiosurgery (SRS) is an established treatment modality for brain arteriovenous malformations (AVMs) in children, but the optimal treatment parameters and associated treatment-related complications are not fully understood. The authors present their single-institution experience of using SRS, at a relatively low marginal dose, to treat AVMs in children for nearly 20 years; they report angiographic outcomes, posttreatment hemorrhage rates, adverse treatment-related events, and functional outcomes. The authors conducted a retrospective review of 2 cohorts of children (18 years of age or younger) with AVMs treated from 1991 to 1998 and from 2000 to 2010. A total of 80 patients with follow-up data after SRS were identified. Mean age at SRS was 12.7 years, and 56% of patients had hemorrhage at the time of presentation. Median target volume was 3.1 cm(3) (range 0.09-62.3 cm(3)), and median prescription marginal dose used was 17.5 Gy (range 12-20 Gy). Angiograms acquired 3 years after treatment were available for 47% of patients; AVM obliteration was achieved in 52% of patients who received a dose of 18-20 Gy and in 16% who received less than 18 Gy. At 5 years after SRS, the cumulative incidence of hemorrhage was 25% (95% CI 16%-37%). No permanent neurological deficits occurred in patients who did not experience posttreatment hemorrhage. Overall, good functional outcomes (modified Rankin Scale Scores 0-2) were observed for 78% of patients; for 66% of patients, functional status improved or remained the same as before treatment. A low marginal dose minimizes SRS-related neurological deficits but leads to low rates of obliteration and high rates of hemorrhage. To maximize AVM obliteration and minimize posttreatment hemorrhage, the authors recommend a prescription marginal dose of 18 Gy or more. In addition, SRS-related symptoms such as headache and seizures should be considered when discussing risks and benefits of SRS for treating AVMs in children.


Circumcision: postoperative complications that required reoperation.
Objective To evaluate post-operative complications of circumcision requiring surgical reintervention. Methods Retrospective analysis of medical records of patients submitted to circumcision from May 1st, 2015 to May 31st, 2016. Results A total of 2,441 circumcisions were performed; in that, 1,940 using Plastibell and 501 by the classic technique. Complications requiring surgical reintervention were found in 3.27% of patients. When separated by surgical technique, 3.4% of circumcisions using Plastibell device required reoperation, as compared to 3% of conventional technique (p=0.79). Preputial stenosis was most frequently found in classic circumcision, with statistical significance (p<0.001). Bleeding was more frequent when using Plastibell device, but the difference was not statistically different (p=0.37). Patients' age was also evaluated to investigate if this variable influenced on the postoperative outcome, but no significant difference was found. Conclusion There was no statistically significant difference when comparing complications between the different techniques performed at this hospital. Preputial stenosis was most frequently found in the classic circumcision, while bleeding was more prevalent when using Plastibell device. Patients' age did not influence in complications.


Rapid identification of urinary tract infection bacteria using hyperspectral whole-organism fingerprinting and artificial neural networks.
Three rapid spectroscopic approaches for whole-organism fingerprinting-pyrolysis mass spectrometry (PyMS), Fourier transform infra-red spectroscopy (FT-IR) and dispersive Raman microscopy--were used to analyse a group of 59 clinical bacterial isolates associated with urinary tract infection. Direct visual analysis of these spectra was not possible, highlighting the need to use methods to reduce the dimensionality of these hyperspectral data. The unsupervised methods of discriminant function and hierarchical cluster analyses were employed to group these organisms based on their spectral fingerprints, but none produced wholly satisfactory groupings which were characteristic for each of the five bacterial types. In contrast, for PyMS and FT-IR, the artificial neural network (ANN) approaches exploiting multi-layer perceptrons or radial basis functions could be trained with representative spectra of the five bacterial groups so that isolates from clinical bacteriuria in an independent unseen test set could be correctly identified. Comparable ANNs trained with Raman spectra correctly identified some 80% of the same test set. PyMS and FT-IR have often been exploited within microbial systematics, but these are believed to be the first published data showing the ability of dispersive Raman microscopy to discriminate clinically significant intact bacterial species. These results demonstrate that modern analytical spectroscopies of high intrinsic dimensionality can provide rapid accurate microbial characterization techniques, but only when combined with appropriate chemometrics.


Isolation and characterization of polyoma uncoating intermediates from the nuclei of infected mouse cells.
A method was developed which enabled the efficient recovery of polyoma uncoating intermediates from the nuclei of infected cells at early times after infection (15 min to 12 h). Cells were infected with radiolabeled virus and lysed with the detergent Nonidet P-40. The nuclei were then collected and sonicated, and the products were analyzed on sucrose gradients. The uncoating intermediate sedimented at 190S and was a viral DNA-protein complex closely associated with a structure of host origin. The host material associated with the 190S uncoating intermediate was determined by polyacrylamide gel electrophoresis and visualized by electron microscopy. The amount of 190S uncoating intermediate found in the nucleus increased with time after infection. The viral DNA was predominantly for I. All of the viral proteins were present in the 190S uncoating intermediate in amounts similar to those found in viral DNA-protein complex cores.


Sintering-Based In-Situ Synthesis and Characterization by TEM of Noble Metal Nanoparticles for Ceramic Glaze Color Control.
Gold and silver salt mixtures are incorporated in ceramic glazes for in situ development of mixtures of gold and silver nanoparticles (NPs) that subsequently allow for a wide spectrum of low metal loading color control within ceramic materials. Prior work has shown that gold NPs can be used to create vibrant, color-rich red pigments in high-temperature ceramic and glass applications, though the achievable diameter of the gold NP ultimately limits the available range of color. The current study significantly expands color control from traditional gold nanoparticle red through silver nanoparticle green via the alteration of gold-to-silver salt ratios incorporated in the glaze formulations prior to sintering. Nanoparticle-based coloring systems are tested in both oxidative and reductive firing atmospheres. While the oxidation environment is found to be prohibitive for silver NP stability, the reductive atmosphere is able to form and sustain mixtures of gold and silver NPs across a wide color spectrum. All glazes are analyzed via reflectance spectrometry for color performance and samples are characterized via TEM and EDS for composition and sizing trends. This study creates new groundwork for a color-controlled NP system based on noble metal ratio blends that are both nontoxic and achieved with radically lower metal pigment loading than traditional glazes.


Improving the Context Supporting Quality Improvement in a Neonatal Intensive Care Unit Quality Collaborative: An Exploratory Field Study.
Successful quality improvement (QI) requires a supportive context. The goal was to determine whether a structured curriculum could help QI teams improve the context supporting their QI work. An exploratory field study was conducted of 43 teams participating in a neonatal intensive care unit QI collaborative. Using a curriculum based on the Model for Understanding Success in Quality, teams identified gaps in their context and tested interventions to modify context. Surveys and self-reflective journals were analyzed to understand how teams developed changes to modify context. More than half (55%) targeted contextual improvements within the microsystem, focusing on motivation and culture. "Information sharing" interventions to communicate information about the project as a strategy to engage more staff were the most common interventions tested. Further study is needed to determine if efforts to modify context consistently lead to greater outcome improvements.


[Disease of the aortic arch and its branches from clinical neurological aspect (author's transl)].
The various disease of the aortic arch and its branches are dealt with and the individual parts of the diagnostic equipment critically examined from the point of view of the clinical neurologist. Peculiarities of differential diagnosis and questions of risk are presented and discussed. Possibly misleading vascular sounds were found in an angioma in the occipital region. The neurologist views with scepticism cervical ribs and gaps in the scalenus as pathogenic factors. Early diagnosis is important in carotid stenosis. The increased angiographical risk in vascular diseases requires informed willingness for operation on the part of the patient. Finally, the expected extent of clinical success of the operation must be weighed against the purely "vascular cosmetic" success.


Commodification of human tissue: implications for feminist and development ethics.
One effect of late capitalism--the commodification of practically everything--is to knock down the Chinese walls between the natural and productive realms, to use a Marxist framework. Women's labour in egg extraction and 'surrogate' motherhood might then be seen as what it is, labour which produces something of value. But this does not necessarily mean that women will benefit from the commodification of practically everything, in either North or South. In the newly developing biotechnologies involving stem cells, the reverse is more likely, particular given the the shortage in the North of the egg donors who will be increasingly necessary to therapeutic cloning. Although most of the ethical debate has focused on the status of the embryo, this is to define ethics with no reference to global or gender justice. There has been little or no debate about possible exploitation of women, particularly of ovum donors from the South. Countries of the South without national ethics committees or guidelines may be particularly vulnerable: although there is increasing awareness of the susceptibility of poorer countries to abuses in research ethics, very little has been written about how they might be affected by the enormously profitable new technologies exploiting human tissue. Even in the UK, although the new Medical Research Council guidelines make a good deal of the 'gift relationship', what they are actually about is commodification. If donors believe they are demonstrating altruism, but biotechnology firms and researchers use the discourse of commodity and profit, we have not 'incomplete commodification' but complete commodification with a plausibly human face.


Laparoscopic excision of subdiaphragmatic bronchogenic cyst occurring in the retroperitoneum: report of a case.
Although bronchogenic cysts (BCs) are benign congenital malformations usually occur in thoracic cavity, retroperitoneal location is extremely uncommon. We reported a case of BC occurred in the retroperitoneum, which was excised laparoscopically. A 64-year-old Japanese woman was admitted to the hospital because of submucosal tumor in the upper part of the stomach. An upper gastrointestinal endoscopy revealed a submucosal tumor located just distal to the esophagogastric junction. The abdominal computed tomography scan revealed a cystic mass located in contact with lesser curvature of the stomach and the dorsal surface of the liver. As the cystic mass was well-circumscribed and showed no positive findings suggestive of malignancy, the laparoscopic excision of the cystic mass was performed. The cystic tumor was completely excised with a laparoscopic procedure. The histologic findings indicated that the cyst was surfaced by the ciliated pseudostratified epithelium without the presence of the cartilage, which was compatible with the BC of the retroperitoneum. This case highlights the safety and the feasibility of complete laparoscopic excision of retroperitoneal BC. Laparoscopic excision of retroperitoneal BC definitely provides all advantages of minimally invasive procedure, which improves postoperative patient discomfort and pain and shortens hospital stay. Laparoscopic procedure may definitely be a standard approach for the excision of retroperitoneal BC.


ZNF70 regulates IL-1β secretion of macrophages to promote the proliferation of HCT116 cells via activation of NLRP3 inflammasome and STAT3 pathway in colitis-associated colorectal cancer.
Chronic inflammation is a key driver for colitis-associated colorectal cancer (CAC). It has been reported that inflammatory cytokines, such as IL-1β, could promote CAC. Zinc finger protein 70 (ZNF70) is involved in multiple biological processes. Here, we identified a previously unknown role for ZNF70 regulates macrophages IL-1β secretion to promote HCT116 proliferation in CAC, and investigated its underlying mechanism. We showed ZNF70 is much higher expressed in CAC tumor tissues compared with adjacent normal tissues in clinical CAC samples. Further experiments showed ZNF70 promoted macrophages IL-1β secretion and HCT116 proliferation. In LPS/ATP-stimulated THP-1 cells, we found ZNF70 activated NLRP3 inflammasome, resulting in robust IL-1β secretion. Interestingly, we discovered the ZnF domain of ZNF70 could interact with NLRP3 and decrease the K48-linked ubiquitination of NLRP3. Moreover, ZNF70 could activate STAT3, thereby promoting IL-1β synthesis. Noteworthy, ZNF70 enhanced proliferation by upregulating STAT3 activation in HCT116 cells cultured in the conditioned medium of THP-1 macrophages treated with LPS/ATP. Finally, the vivo observations were confirmed using AAV-mediated ZNF70 knockdown, which improved colitis-associated colorectal cancer in the AOM/DSS model. The correlation between ZNF70 expression and overall survival/IL-1β expression in colorectal cancer was verified by TCGA database. Taken together, ZNF70 regulates macrophages IL-1β secretion to promote the HCT116 cells proliferation via activation of NLRP3 inflammasome and STAT3 pathway, suggesting that ZNF70 may be a promising preventive target for treating in CAC.


Enhanced production of vascular endothelial growth factor by human monocytic cells stimulated with endotoxin through transcription factor SP-1.
The effect of endotoxin on the regulation of vascular endothelial growth factor (VEGF) mRNA expression in human monocytic (THP-1) cells was examined. Endotoxic lipopolysaccharide (LPS) from Escherichia coli and synthetic E. coli-type lipid A (LA-15-PP) enhanced VEGF mRNA expression. LPS-induced VEGF mRNA accumulation was regulated, at least in part, at the transcriptional level. Enhancement of VEGF gene expression by LPS was shown by gel shift analysis and use of transcription factor inhibitors to be mediated via the activation of SP-1.


[Toxic effect of hydroxylated ions of heavy metals on the cytoplasmic membrane of bacterial cells].
The influence of nickel, copper, cadmium, and lead ions at concentrations of 50 to 100 microM on the barrier properties of the plasma membrane (PM) and the electrophoretic mobility (EPM) of Pseudomonas fluorescens 71, Escherichia coli K-12, and Mycobacterium phlei B-1291 VKM cells was studied at pH values from 5 to 9 by electro-orientational (EO) spectroscopy and microelectrophoresis of cells. According to the data of EO spectroscopy, the increase in the toxicity of heavy metal cations to cells corresponded to transition of cations to monovalent hydroxylated forms. Hydroxylated ions were found to more easily adsorb on, or penetrate across, the PM and to bind to competent proteins. During the treatment of all three investigated microorganisms with Cu and Pb ions, and gram-negative bacteria also with Ni ions, the EPM of cells changed in a pH range corresponding to the transition of bivalent metal ions to their monovalent hydroxylated forms. Changes in the EPM induced by increasing pH correlated well with the enhanced toxicity of these metals to the PM, as evidenced by the EO spectroscopy data. At the same time, this correlation was less pronounced for cadmium sulfate toxicity to all of the microorganisms studied and for nickel chloride toxicity to M. phlei cells.


Serum levels of beta-2 microglobulin in oral tumor patients.
Beta-2 microglobulin (beta-MG) is a low molecular weight protein of 100 amino-acids. It is the light chain of HLA-A, -B or -C antigens which on the surface of nearly all nucleated cells. Clinically, the serum levels of beta-MG are increased in patients with renal failure, immune disorders, and various malignant diseases. In this study, the serum levels of beta-MG were measured clinically for a total of 114 cases. Diverse conditions were ensured by biopsy except for 10 control cases, and the following eight groups were diversified: (1) control group, 10 cases; (2) oral carcinoma, 36 cases; (3) mixed tumor, 7 cases; (4) pyogenic granuloma, 12 cases; (5) leukoplakia, 18 cases; (6) mucocele, 15 cases; (7) ameloblastoma, 7 cases; (8) fibroma, 9 cases. The serum levels of beta-MG in oral cancer and leukoplakia patients were found to be significantly higher compared with that of the control group and patients with benign oral tumors. Further study to unravel the correlations between the clinical stages, the treatment of oral cancer, and beta-MG is now in progress.


Myofibrillar muscle protein synthesis rates subsequent to a meal in response to increasing doses of whey protein at rest and after resistance exercise.
The intake of whey, compared with casein and soy protein intakes, stimulates a greater acute response of muscle protein synthesis (MPS) to protein ingestion in rested and exercised muscle. We characterized the dose-response relation of postabsorptive rates of myofibrillar MPS to increasing amounts of whey protein at rest and after exercise in resistance-trained, young men. Volunteers (n = 48) consumed a standardized, high-protein (0.54 g/kg body mass) breakfast. Three hours later, a bout of unilateral exercise (8 × 10 leg presses and leg extensions; 80% one-repetition maximum) was performed. Volunteers ingested 0, 10, 20, or 40 g whey protein isolate immediately (~10 min) after exercise. Postabsorptive rates of myofibrillar MPS and whole-body rates of phenylalanine oxidation and urea production were measured over a 4-h postdrink period by continuous tracer infusion of labeled [(13)C6] phenylalanine and [(15)N2] urea. Myofibrillar MPS (mean ± SD) increased (P < 0.05) above 0 g whey protein (0.041 ± 0.015%/h) by 49% and 56% with the ingestion of 20 and 40 g whey protein, respectively, whereas no additional stimulation was observed with 10 g whey protein (P > 0.05). Rates of phenylalanine oxidation and urea production increased with the ingestion of 40 g whey protein. A 20-g dose of whey protein is sufficient for the maximal stimulation of postabsorptive rates of myofibrillar MPS in rested and exercised muscle of ~80-kg resistance-trained, young men. A dose of whey protein >20 g stimulates amino acid oxidation and ureagenesis. This trial was registered at http://www.isrctn.org/ as ISRCTN92528122.


Activation of human VPS4A by ESCRT-III proteins reveals ability of substrates to relieve enzyme autoinhibition.
VPS4 proteins are AAA(+) ATPases required to form multivesicular bodies, release viral particles, and complete cytokinesis. They act by disassembling ESCRT-III heteropolymers during or after their proposed function in membrane scission. Here we show that purified human VPS4A is essentially inactive but can be stimulated to hydrolyze ATP by ESCRT-III proteins in a reaction that requires both their previously defined MIT interacting motifs and ∼50 amino acids of the adjacent sequence. Importantly, C-terminal fragments of all ESCRT-III proteins tested, including CHMP2A, CHMP1B, CHMP3, CHMP4A, CHMP6, and CHMP5, activated VPS4A suggesting that it disassembles ESCRT-III heteropolymers by affecting each component protein. VPS4A is thought to act as a ring-shaped cylindrical oligomer like other AAA(+) ATPases, but this has been difficult to directly demonstrate. We found that concentrating His(6)-VPS4A on liposomes containing Ni(2+)-nitrilotriacetic acid-tagged lipid increased ATP hydrolysis, confirming the importance of inter-subunit interactions for activity. We also found that mutating pore loops expected to line the center of a cylindrical oligomer changed the response of VPS4A to ESCRT-III proteins. Based on these data, we propose that ESCRT-III proteins facilitate assembly of functional but transient VPS4A oligomers and interact with sequences inside the pore of the assembled enzyme. Deleting the N-terminal MIT domain and adjacent linker from VPS4A increased both basal and liposome-enhanced ATPase activity, indicating that these elements play a role in autoinhibiting VPS4A until it encounters ESCRT-III proteins. These findings reveal new ways in which VPS4 activity is regulated and specifically directed to ESCRT-III polymers.


A scanning electron microscopy study of Taxus leaves as related to taxonomy.
Scanning electron microscopy, when applied to the surfaces of the needles of Taxus spp. (yew) revealed features that appear useful in the taxonomy of this tree species which yields the important anticancer drug, taxol. For instance, all of the four North American species have 3-5 rows of stomata on one-half of the abaxial leaf surface, whereas all of the others, including those from Europe and Asia, have 7-10 rows of stomata. The appearance of individual or fused papilliform epidermal cells and their arrangement on the leaf surface also is a feature that varies between species. Patterns of wax formation appeared on all species of yew examined but none could characteristically be assigned to a given species. Wax pattern variation was dependent upon age, environment, and probably to some extent, species differences. This study may provide some additional useful and reliable indicators in Taxus taxonomy.


Genome-wide screening for cis-regulatory variation using a classical diallel crossing scheme.
Large-scale screening studies carried out to date for genetic variants that affect gene regulation are generally limited to descriptions of differences in allele-specific expression (ASE) detected in vivo. Allele-specific differences in gene expression provide evidence for a model whereby cis-acting genetic variation results in differential expression between alleles. Such gene surveys for regulatory variation are a first step in identifying the specific nucleotide changes that govern gene expression differences, but they leave the underlying mechanisms unexplored. Here, we propose a quantitative genetics approach to perform a genome-wide analysis of ASE differences (GASED). The GASED approach is based on a diallel design that is often used in plant breeding programs to estimate general combining abilities (GCA) of specific inbred lines and to identify high-yielding hybrid combinations of parents based on their specific combining abilities (SCAs). In a context of gene expression, the values of GCA and SCA parameters allow cis- and trans-regulatory changes to be distinguished and imbalances in gene expression to be ascribed to cis-regulatory variation. With this approach, a total of 715 genes could be identified that are likely to carry allelic polymorphisms responsible for at least a 1.5-fold allelic expression difference in a total of 10 diploid Arabidopsis thaliana hybrids. The major strength of the GASED approach, compared to other ASE detection methods, is that it is not restricted to genes with allelic transcript variants. Although a false-positive rate of 9/41 was observed, the GASED approach is a valuable pre-screening method that can accelerate systematic surveys of naturally occurring cis-regulatory variation among inbred lines for laboratory species, such as Arabidopsis, mouse, rat and fruitfly, and economically important crop species, such as corn.


Preparation of metal-organic framework @molecularly imprinted polymers for extracting N-nitrosamines in salted vegetables.
In this paper, the novel metal-organic framework @molecularly imprinted polymers were prepared and applied in extracting N-nitrosamines from salted vegetables. The imprinted polymers were coated on the surface of MIL-101 using multi-dummy template molecules (5-nonanol, benzhydrol and N-formylpyrrolidine). The characterization and adsorbing experiments showed that the hybrid imprinted polymers presented spherical particles with typically core-shell structure, and exhibited high adsorption capacity (maximum capacity: 46.85 mg/g) and fast equilibrium rate (only 5 min) for N-nitrosamines. Various parameters (sample loading solvent, pH, washing solvent, elution solvent and elution volume) affecting solid-phase extraction were optimized. Under the optimum conditions, the solid-phase extraction process based on the hybrid polymers combined with high performance liquid chromatography-ultraviolet detection method was established and applied to analyze N-nitrosamines in different salted vegetables. The results showed that the developed method produced the linear relationship between the peak areas versus the N-nitrosamines concentrations of 0.2-10 µg/g with limit of detections from 20.6 to 76.1 ng/g. The spiked recovery of N-nitrosamines in the salted vegetable samples was in the range of 66-100.5 % with relative standard deviation from 0.1 to 3.4 %. Those results demonstrated that the established method was sensitive and efficient for directly enriching and analyzing trace N-nitrosamines in salted vegetables.


[Kinetics of radioactive thallium chloride (201TlCl3) transport from the blood to myocardial tissue normally and in cardiac ischemia].
Extraction of 201TlCl3 diffusing into the heart tissue under conditions of its normal functioning and in the presence of ischemia was appraised on a model with isolated coronary perfusion of the myocardium by the dual-tracer method. From analysis of the discharge curve of the tracers used it is concluded whether or not microcirculation of the perfused area of the heart is uniform or heterogeneous. It was established that in myocardial ischemia, 201TlCl3 does not accumulate in the interstitium, which makes it possible to evaluate the zones with diminished inclusion of 201TlCl3 encountered in scanning of the heart as corresponding to diminished blood supply.


The safety of olanzapine compared with other antipsychotic drugs: results of an observational prospective study in patients with schizophrenia (EFESO Study). Pharmacoepidemiologic Study of Olanzapine in Schizophrenia.
Results of controlled clinical trials should be confirmed through safety and effectiveness studies in nonselected patient cohorts treated according to routine clinical practice. Outpatients with schizophrenia (ICD-10 criteria) entered this prospective, naturalistic study when they received a new prescription for an antipsychotic drug. Treatment assignment was based on purely clinical criteria, as the study did not include any experimental intervention. Safety was evaluated through the collection of spontaneous adverse events and a specific questionnaire for extrapyramidal symptoms. Global clinical status was measured through the Clinical Global Impressions-Severity (CGI-S) and the Global Assessment of Functioning (GAF) scales. From the 2967 patients included, 2128 patients were treated with olanzapine as monotherapy or combined with other drugs (olanzapine group), and 821 were treated with other antipsychotic drugs as monotherapy or combined with other drugs (control group). There were no statistical differences between treatment groups at baseline regarding age, gender, disease duration, or severity of symptoms. Olanzapine was well tolerated and effective in this study. Overall incidence of adverse events was significantly lower in the olanzapine group compared with the control group (p < .001). Somnolence and weight gain were significantly more frequent in the olanzapine group, and akathisia, dystonia, extrapyramidal syndrome, hypertonia, hypokinesia, and tremor were significantly higher in the control group. Clinical improvement at endpoint, measured through the mean change in the CGI-S and the GAF, was significantly higher in the olanzapine group compared with the control group (p = .004). These results show that olanzapine is safe and effective in nonselected schizophrenic outpatients and are consistent with the efficacy and safety profile that olanzapine has shown in previous controlled clinical trials.


Sensitive SERS assay for glyphosate based on the prevention of l-cysteine inhibition of a Au-Pt nanozyme.
Herein, an indirect SERS sensing assay was developed for the determination of glyphosate (Gly) in tap water. The mechanism of detection was based on relieving the inhibitory effect of l-cysteine (l-cys) on a Au-Pt nanozyme by combining Gly with l-cys through divalent copper ions (Cu2+). In this method, a novel nano-chain-like Au-Ag composite with good repeatability was successfully fabricated to detect SERS signals of oxTMB without disturbing TMB Raman signals. Under optimal conditions, the SERS signal intensity of oxTMB (at 1605 cm-1) was proportional to the concentration of Gly. The results showed a good linear response over the concentration ranges of 10 μg L-1 to 1000 mg L-1. The limit of detection and limit of quantitation of Gly were found to be 5 μg L-1 and 10 μg L-1, respectively. In addition, good anti-interference ability against interfering cations and structural analogues deserves to be mentioned. This SERS assay can be used for detection of Gly in tap water that can meet the needs of practical detection.


Remembering verbally-presented items as pictures: Brain activity underlying visual mental images in schizophrenia patients with visual hallucinations.
Previous research suggests that visual hallucinations in schizophrenia consist of mental images mistaken for percepts due to failure of the reality-monitoring processes. However, the neural substrates that underpin such dysfunction are currently unknown. We conducted a brain imaging study to investigate the role of visual mental imagery in visual hallucinations. Twenty-three patients with schizophrenia and 26 healthy participants were administered a reality-monitoring task whilst undergoing an fMRI protocol. At the encoding phase, a mixture of pictures of common items and labels designating common items were presented. On the memory test, participants were requested to remember whether a picture of the item had been presented or merely its label. Visual hallucination scores were associated with a liberal response bias reflecting propensity to erroneously remember pictures of the items that had in fact been presented as words. At encoding, patients with visual hallucinations differentially activated the right fusiform gyrus when processing the words they later remembered as pictures, which suggests the formation of visual mental images. On the memory test, the whole patient group activated the anterior cingulate and medial superior frontal gyrus when falsely remembering pictures. However, no differential activation was observed in patients with visual hallucinations, whereas in the healthy sample, the production of visual mental images at encoding led to greater activation of a fronto-parietal decisional network on the memory test. Visual hallucinations are associated with enhanced visual imagery and possibly with a failure of the reality-monitoring processes that enable discrimination between imagined and perceived events.


Dual promoters of mouse mu-opioid receptor gene.
Two transcriptional initiation sites, distal and proximal, located at approximately 500 bp apart in mouse mu-opioid receptor gene were identified recently. Using deletional and transfection analyses, the distal or proximal promoter alone displayed similar activity in neuronal cells constitutively expressing mu-opioid receptors (SH-SY-5Y). The presence of both promoters did not result in an increase in activity. However, when distal promoter linked with 3'-downstream sequences without the proximal promoter region, the distal promoter activity was abolished. Transfection analysis using various cell lines further suggested that only the proximal promoter preferentially directed the neuronal subtype expression. To verify the physiological importance of each promoter, the ratio of mu-receptor transcripts initiated by either promoter was examined by quantitative RT-PCR using mouse adult brain mRNA. We found that receptor mRNA was predominantly initiated by the proximal promoter. These studies suggested that the proximal promoter was the major functional promoter.


Coping strategies for chronically ill children and adolescents facing the COVID-19 pandemic.
to understand the experiences and coping strategies of children and adolescents with chronic illnesses during the COVID-19 pandemic. a descriptive study, with a qualitative approach, carried out with six children and adolescents at the reception of an outpatient clinic of a pediatric hospital in the state of Ceará. Data collection took place from April to September 2021, using story-drawing, analyzed in light of Coutinho's criteria. two thematic categories emerged: Situations experienced by children and adolescents in times of COVID-19; Coping strategies for children and adolescents in their chronic illness process during the COVID-19 pandemic. understanding the experiences and coping strategies of children and adolescents with chronic illness demonstrated the expression of creative imagination, incorporated by subjective components, which brings to light an approximation with the reality perceived and interpreted in a context of the COVID-19 pandemic.


Efficacy of electrohydraulic lithotripsy in the ureter.
Since January of 1983, 62 patients with ureteral calculi had their stones fragmented with electrohydraulic lithotripsy via an antegrade approach percutaneously or retrograde approach ureteroscopically. Success was achieved in 97% of these cases, with insignificant ureteral perforations noted in eight. Follow-up via intravenous pyelograms obtained in 60 patients revealed no significant persistent hydronephrosis. It appears, therefore, that the use of electrohydraulic lithotripsy in the ureter utilized with direct vision endoscopes is safe, efficacious and relatively inexpensive.


Onboard acoustic recording from diving northern elephant seals.
This study was the first phase in a long-term investigation of the importance of low-frequency sound in the aquatic life of northern elephant seals, Mirounga angustirostris. By attaching acoustic recording packages to the backs of six translocated juveniles, the aim was to determine the predominant frequencies and sound levels impinging on them, and whether they actively vocalize underwater on their return to their rookery at Ano Nuevo, California, from deep water in Monterey Bay. All packages contained a Sony digital audio tape recorder encased in an aluminum housing with an external hydrophone. Flow noise was minimized by potting the hydrophone in resin to the housing and orienting it posteriorly. The diving pattern of four seals was recorded with a separate time-depth recorder or a time-depth-velocity recorder. Good acoustic records were obtained from three seals. Flow noise was positively correlated with swim speed, but not so high as to mask most low-frequency sounds in the environment. Dominant frequencies of noise impinging on the seals were in the range 20-200 Hz. Transient signals recorded from the seals included snapping shrimp, cetacean vocalizations. boat noise, small explosive charges, and seal swim strokes, but no seal vocalizations were detected. During quiet intervals at the surface between dives, the acoustic record was dominated by respiration and signals that appeared to be heartbeats. This study demonstrates the feasibility of recording sounds from instruments attached to free-ranging seals, and in doing so, studying their behavioral and physiological response to fluctuations in ambient sounds.


Assessment of Ketamine Binding of the Serotonin Transporter in Humans with Positron Emission Tomography.
Comprehensive description of ketamine's molecular binding profile becomes increasingly pressing as use in real-life patient cohorts widens. Animal studies attribute a significant role in the substance's antidepressant effects to the serotonergic system. The serotonin transporter is a highly relevant target in this context, because it is central to depressive pathophysiology and treatment. This is, to our knowledge, the first study investigating ketamine's serotonin transporter binding in vivo in humans. Twelve healthy subjects were assessed twice using [11C]DASB positron emission tomography. A total of 0.50 mg/kg bodyweight ketamine was administered once i.v. prior to the second positron emission tomography scan. Ketamine plasma levels were determined during positron emission tomography. Serotonin transporter nondisplaceable binding potential was computed using a reference region model, and occupancy was calculated for 4 serotonin transporter-rich regions (caudate, putamen, thalamus, midbrain) and a whole-brain region of interest. After administration of the routine antidepressant dose, ketamine showed <10% occupancy of the serotonin transporter, which is within the test-retest variability of [11C]DASB. A positive correlation between ketamine plasma levels and occupancy was shown. Measurable occupancy of the serotonin transporter was not detectable after administration of an antidepressant dose of ketamine. This might suggest that ketamine binding of the serotonin transporter is unlikely to be a primary antidepressant mechanism at routine antidepressant doses, as substances that facilitate antidepressant effects via serotonin transporter binding (e.g., selective serotonin reuptake inhibitors) show 70% to 80% occupancy. Administration of high-dose ketamine is widening. Based on the positive relationship we find between ketamine plasma levels and occupancy, there is a need for investigation of ketamine's serotonin transporter binding at higher doses.


Pathway of propionate oxidation by a syntrophic culture of Smithella propionica and Methanospirillum hungatei.
The pathway of propionate conversion in a syntrophic coculture of Smithella propionica and Methanospirillum hungatei JF1 was investigated by (13)C-NMR spectroscopy. Cocultures produced acetate and butyrate from propionate. [3-(13)C]propionate was converted to [2-(13)C]acetate, with no [1-(13)C]acetate formed. Butyrate from [3-(13)C]propionate was labeled at the C2 and C4 positions in a ratio of about 1:1.5. Double-labeled propionate (2,3-(13)C) yielded not only double-labeled acetate but also single-labeled acetate at the C1 or C2 position. Most butyrate formed from [2,3-(13)C]propionate was also double labeled in either the C1 and C2 atoms or the C3 and C4 atoms in a ratio of about 1:1.5. Smaller amounts of single-labeled butyrate and other combinations were also produced. 1-(13)C-labeled propionate yielded both [1-(13)C]acetate and [2-(13)C]acetate. When (13)C-labeled bicarbonate was present, label was not incorporated into acetate, propionate, or butyrate. In each of the incubations described above, (13)C was never recovered in bicarbonate or methane. These results indicate that S. propionica does not degrade propionate via the methyl-malonyl-coenzyme A (CoA) pathway or any other of the known pathways, such as the acryloyl-CoA pathway or the reductive carboxylation pathway. Our results strongly suggest that propionate is dismutated to acetate and butyrate via a six-carbon intermediate.


Regional facial asymmetries in unilateral orofacial clefts.
Assess facial asymmetry in subjects with unilateral cleft lip (UCL), unilateral cleft lip and alveolus (UCLA), and unilateral cleft lip, alveolus, and palate (UCLP), and to evaluate which area of the face is most asymmetrical. Standardized three-dimensional facial images of 58 patients (9 UCL, 21 UCLA, and 28 UCLP; age range: 8.6-12.3 years) and 121 controls (age range 9-12 years) were mirrored and distance maps were created. Absolute mean asymmetry values were calculated for the whole face, cheek, nose, lips, and chin. One-way analysis of variance, Kruskal-Wallis, and t-test were used to assess the differences between clefts and controls for the whole face and separate areas. Clefts and controls differ significantly for the whole face as well as in all areas. Asymmetry is distributed differently over the face for all groups. In UCLA, the nose was significantly more asymmetric compared with chin and cheek (P = 0.038 and 0.024, respectively). For UCL, significant differences in asymmetry between nose and chin and chin and cheek were present (P = 0.038 and 0.046, respectively). In the control group, the chin was the most asymmetric area compared to lip and nose (P = 0.002 and P = 0.001, respectively) followed by the nose (P = 0.004). In UCLP, the nose, followed by the lips, was the most asymmetric area compared to chin, cheek (P < 0.001 and P = 0.016, respectively). Despite division into regional areas, the method may still exclude or underrate smaller local areas in the face, which are better visualized in a facial colour coded distance map than quantified by distance numbers. The UCL subsample is small. Each type of cleft has its own distinct asymmetry pattern. Children with unilateral clefts show more facial asymmetry than children without clefts.


Safety of Endovascular Thrombectomy for Acute Ischaemic Stroke in Anticoagulated Patients Ineligible for Intravenous Thrombolysis.
Endovascular thrombectomy may be performed in anticoagulated patients taking vitamin-K antagonists (VKA) or direct-acting oral anticoagulants (DOAC) in whom the use of intravenous tissue plasminogen activator (tPA) is contraindicated. We aimed to investigate the efficacy and safety of mechanical thrombectomy specifically in anticoagulated patients ineligible for thrombolysis. We performed a retrospective analysis of a prospectively collected database of consecutive ischaemic stroke patients undergoing mechanical thrombectomy from January 2008 to June 2017. Patients receiving any dose of intravenous or intra-arterial thrombolysis were excluded. Patients taking oral anticoagulants (VKAs or DOACs) were compared with non-anticoagulated patients. Outcomes compared between groups included the rate of intracerebral haemorrhage (ICH) on follow-up imaging (ICHany), symptomatic ICH, functional independence at 90 days (modified Rankin scale score, 0-2), mortality, and post-treatment recanalization (Thrombolysis in Cerebral Infarction score ≥2b). In all, 102 patients undergoing mechanical thrombectomy without prior thrombolysis were included in the study. Sixty-six (64.7%) patients were not anticoagulated, 23 (22.5%) patients were taking VKAs, and 13 (12.7%) patients were taking DOACs. There were no significant differences in the rate of ICHany (11.1 vs. 13.6%, p = 0.93) or sICH (2.8 vs. 1.5%, p = 0.14) in anticoagulated patients compared to non-anticoagulated patients. No cases of sICH were observed among patients taking DOACs. After 90 days of follow-up, the rates of functional independence (50.0 vs. 43.1%) and mortality (27.8 vs. 25.8%) were also similar between the anticoagulation and the non-anticoagulation groups. Mechanical thrombectomy appears to be safe and effective in anticoagulated patients ineligible for thrombolysis, with observed haemorrhage rates similar to those of patients not on anticoagulant therapy. However, further multicentre prospective studies are needed, due to the rising number of patients on warfarin and DOACs worldwide.


Therapeutic Implications of Targeting AKT Signaling in Melanoma.
Identification of key enzymes regulating melanoma progression and drug resistance has the potential to lead to the development of novel, more effective targeted agents for inhibiting this deadly form of skin cancer. The Akt3, also known as protein kinase B gamma, pathway enzymes regulate diverse cellular processes including proliferation, survival, and invasion thereby promoting the development of melanoma. Accumulating preclinical evidence demonstrates that therapeutic agents targeting these kinases alone or in combination with other pathway members could be effective for the long-term treatment of advanced-stage disease. However, currently, no selective and effective therapeutic agent targeting these kinases has been identified for clinical use. This paper provides an overview of the key enzymes of the PI3K pathway with emphasis placed on Akt3 and the negative regulator of this kinase called PTEN (phosphatase and tensin homolog deleted on chromosome 10). Mechanisms regulating these enzymes, their substrates and therapeutic implications of targeting these proteins to treat melanoma are also discussed. Finally, key issues that remain to be answered and future directions for interested researchers pertaining to this signaling cascade are highlighted.


Local Electron Correlation Treatment in Extended Multireference Calculations: Effect of Acceptor-Donor Substituents on the Biradical Character of the Polycyclic Aromatic Hydrocarbon Heptazethrene.
The implementation of a local correlation (LC) treatment of multireference (MR) configuration interaction approaches within the COLUMBUS program system is reported. The LC treatment is based on the weak pairs approximation of Sæbø and Pulay (Ann. Rev. Phys. Chem. 1993, 44, 213) and a geometrical analysis of Walter et al. (Chem. Phys. Lett. 2001, 346, 177). The removal of simultaneous single excitations out of the weak pairs is based on the reference doubly occupied space only, leading to a straightforward program implementation and a conceptual simplicity in terms of well-defined localized orbitals. Reductions of up to an order of magnitude in the configuration space expansion and in computer time for the Davidson diagonalization step are found. The selection of the active and the virtual orbital spaces is not affected by this procedure. This treatment is successfully applied to the singlet biradical heptazethrene and its different acceptor-donor substituents: 4,12-dicyanoheptazethrene, 4,12-diaminoheptazethrene, and 4-amino-12-cyanoheptazethrene. Simultaneous insertion of pairs of donor and acceptor groups increases the biradical character; for push-pull substitution, this effect is significantly smaller. In addition, results obtained from spin-corrected unrestricted density functional theory calculations are supported by our MR calculations.


Chronic post-traumatic volar plate avulsions of the finger proximal interphalangeal joint: A literature review of different surgical techniques.
Avulsions of the volar plate of the finger proximal interphalangeal joint (PIPJ) following sprains are often undiagnosed in the acute setting. Therefore, the chronic outcomes of this injury are most frequently the object of study and treatment. Different techniques for volar plate chronic avulsion repair are described in the literature. The most used among these are mainly two: the direct suturing with or without the use of bone anchors and the tenodesis techniques with flexor digitalis superficialis (FDS). The aim of this systematic review is to determine outcomes and complications associated with these surgical treatments of post-traumatic volar plate avulsions without phalangeal fractures. An electronic literature research was carried out and pertinent articles were selected. Surgical techniques details, outcomes and complications for direct sutures and tenodesis technique are discussed. Outcomes (Range of motion and pain) seem to be comparable, whereas authors that use the direct suture technique describe more frequently PIPJ flexion contracture complication. From this review of the literature, authors believe that both techniques are available for the repair of chronic injuries of the volar plate of the PIPJ, although direct suturing can be considered as less reproducible.


Reframing human trafficking awareness campaigns in the United States: goals, audience, and content.
Human trafficking (HT) awareness campaigns can educate the public and specific professional figures about this crime and ways to prevent it. However, there currently remains a gap in terms of how to best frame such campaigns without stigmatizing groups of individuals or portraying victims in unrealistic ways. We conducted four focus groups with 22 experts in HT to explore their perspectives and opinions on current challenges in the framing of HT awareness campaigns in the United States. Focus groups were conducted via Zoom and transcribed verbatim. Two independent reviewers analyzed the transcripts to identify themes using an inductive approach. The results of the focus groups analysis were used to structure the guiding questions of a brainstorming technique named Nominal Group Technique (NGT). Fifteen of 22 experts that participated in the focus groups joined the in-person NGT with the intent of generating ideas and achieving consensus on target audiences, goals, and content of human trafficking awareness campaigns. At the end of the NGT participants ranked priority for actions in the development of HT awareness efforts in the United States. During the NGT the experts provided a number of recommendations to improve HT awareness and to empower victims to reach for help. They pointed to the need for: awareness efforts that describe HT on a spectrum of human abuse and exploitation; training for professional figures about trauma-informed care and communication; and efforts that empower trafficked victims to seek support. They also pointed to the need to develop awareness efforts tailored to local needs in close collaborations with the community-based organizations that can champion their dissemination and be the primary point of access for victims seeking help.