Docosahexaenoic acid and human brain development: evidence that a dietary supply is needed for optimal development.
Humans evolved a uniquely large brain among terrestrial mammals. Brain and nervous tissue is rich in the omega-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA). Docosahexaenoic acid is required for lower and high order functions in humans because of understood and emerging molecular mechanisms. Among brain components that depend on dietary components, DHA is limiting because its synthesis from terrestrial plant food precursors is low but its utilization when consumed in diet is very efficient. Negligible DHA is found in terrestrial plants, but in contrast, DHA is plentiful at the shoreline where it is made by single-celled organisms and plants, and in the seas supports development of very large marine mammal brains. Modern human brains accumulate DHA up to age 18, most aggressively from about half-way through gestation to about two years of age. Studies in modern humans and non-human primates show that modern infants consuming infant formulas that include only DHA precursors have lower DHA levels than for those with a source of preformed DHA. Functional measures show that infants consuming preformed DHA have improved visual and cognitive function. Dietary preformed DHA in the breast milk of modern mothers supports many-fold greater breast milk DHA than is found in the breast milk of vegans, a phenomenon linked to consumption of shore-based foods. Most current evidence suggests that the DHA-rich human brain required an ample and sustained source of dietary DHA to reach its full potential.


Study of the regulatory effect of acupuncture on rotation-induced gastric dysrhythmia in rabbits.
A model of experimental gastric dysrhythmia in rabbits was set up to evaluate the effect of different acupoints on regulating gastric dysrhythmia in rabbits so as to promote acupuncture treatment for this kind of disease. A model of gastric dysrhythmia in rabbits was established by the rotation method using the basic electrical rhythm (BER) as an objective index. After puncturing at the points of Zusanli (ST36), Neiguan (PC6), Tiaokou (ST38) and Tianquan (PC2) in the four groups of experimental gastric dysrhythmia rabbits, the difference in regulatory effects on the disturbance and frequency of the gastric electric slow wave was observed. Before needling at the specific acupoints Zusanli and Neiguan, the percentage of disturbance electric slow wave for the Zusanli and Neiguan groups was 57.0785 ± 10.644 and 55.5173 ± 6.0500, respectively; after such needling, the percentage was 43.7823 ± 10.1518 and 43.5147 ± 6.8983 for the Zusanli and Neiguan groups, respectively, while the frequency of electric slow wave for the Zusanli and Neiguan groups was 2.2870 ± 0.3800 and 2.4020 ± 0.3536, respectively, before needling and after needling, the frequency was 2.7090 ± 0.5865 and 2.9220 ± 0.4923 for the Zusanli and Neiguan groups, respectively. Comparing the percentage and frequency for the Zusanli and Neiguan groups before and after needling, the result shows that both groups have a significant difference statistically (P < 0.05) but between the Zusanli and Neiguan groups, there was no significant difference. Before and after needling the nonspecific acupoints of Tiaokou and Tianquan, there was no difference between the Tiaokou and Tianquan groups. Between the Zusanli and Tiaokou groups and the Neiguan and Tianquan groups, there are significant differences in regulating gastric dysrhythmia. This model is suitable for the observation of gastric dysrhythmia. The specific acupoints of Zusanli and Neiguan have good effects on the treatment of gastric dysrhythmia.


Effects of target structure on the performance of laser time-of-flight velocimeter systems.
The consequences of partially developed speckle and the effects giving rise to bias errors in velocity determination are discussed with respect to robustness of a classical laser time-of-flight velocimetry (LTV) system. It is demonstrated that surface regimes exist that define the degree of partially developed speckle. These regimes are explored both theoretically and experimentally; surface models are developed to predict the resulting cross covariance from which velocity estimations can be obtained. The surface models describe the behavior of the cross covariance caused by reflection structures and with disparate lateral-roughness scales. In particular, it is shown that it is possible to obtain a twin-Gaussian cross covariance as a result of the presence of partially developed speckle. All models described are compared with experimental observations of the cross covariance for differing surface regimes. The objects are solid targets having lateral spatial correlations in reflection amplitude, height, or both, generally giving rise to partially developed speckle. In almost all cases good agreement with the corresponding theoretical predictions are found. Decorrelation caused by velocity misalignment is shown to shift the peak of the cross covariance significantly, giving a velocity bias. A corresponding theoretical model is developed and verified experimentally. Cross-talk measurements have been performed and compared with a theory developed herein. Both measurements and theory indicate that only spot sizes comparable with or larger than their corresponding separation will lead to a measurable peak shift of the time lag for the maximum of the cross covariance. We conclude that LTV systems will provide accurate velocity estimates under a wide variety of practical conditions.


Prospective Evaluation of High Titer Autoantibodies and Fetal Home Monitoring in the Detection of Atrioventricular Block Among Anti-SSA/Ro Pregnancies.
This prospective study of pregnant patients, Surveillance To Prevent AV Block Likely to Occur Quickly (STOP BLOQ), addresses the impact of anti-SSA/Ro titers and utility of ambulatory monitoring in the detection of fetal second-degree atrioventricular block (AVB). Women with anti-SSA/Ro autoantibodies by commercial testing were stratified into high and low anti-52-kD and/or 60-kD SSA/Ro titers applying at-risk thresholds defined by previous evaluation of AVB pregnancies. The high-titer group performed fetal heart rate and rhythm monitoring (FHRM) thrice daily and weekly/biweekly echocardiography from 17-26 weeks. Abnormal FHRM prompted urgent echocardiography to identify AVB. Anti-52-kD and/or 60-kD SSA/Ro met thresholds for monitoring in 261 of 413 participants (63%); for those, AVB frequency was 3.8%. No cases occurred with low titers. The incidence of AVB increased with higher levels, reaching 7.7% for those in the top quartile for anti-60-kD SSA/Ro, which increased to 27.3% in those with a previous child who had AVB. Based on levels from 15 participants with paired samples from both an AVB and a non-AVB pregnancy, healthy pregnancies were not explained by decreased titers. FHRM was considered abnormal in 45 of 30,920 recordings, 10 confirmed AVB by urgent echocardiogram, 7 being second-degree AVB, all <12 hours from normal FHRM and within another 0.75 to 4 hours to echocardiogram. The one participant with second/third-degree and two participants with third-degree AVB were diagnosed by urgent echocardiogram >17 to 72 hours from an FHRM. Surveillance echocardiograms detected no AVB when the preceding interval FHRM recordings were normal. High-titer antibodies are associated with an increased incidence of AVB. Anti-SSA/Ro titers remain stable over time and do not explain the discordant recurrence rates, suggesting that other factors are required. Fetal heart rate and rhythm (FHRM) with results confirmed by a pediatric cardiologist reliably detects conduction abnormalities, which may reduce the need for serial echocardiograms.


In vivo 1H NMR measurement of glycine in rat brain at 9.4 T at short echo time.
Glycine is an amino acid present in mammalian brain, where it acts as an inhibitory and excitatory neurotransmitter. The two detectable protons of glycine give rise to a singlet at 3.55 ppm that overlaps with the more intense myo-inositol resonances, and its measurement has traditionally required specific editing efforts. The aim of the current study was to reduce the signal intensity of myo-inositol relative to that of glycine by exploiting the fast signal J-evolution of the myo-inositol spin system when using a single spin-echo localization method we recently introduced. Glycine was detected at TE = 20 ms with an average Cramér-Rao lower bound (CRLB) of 8.6% +/- 1.5% in rat brain (N = 5), at 9.4 T. The concentration of glycine was determined using LCModel analysis at 1.1 +/- 0.1 mM, in good agreement with biochemical measurements previously reported. We conclude that at high magnetic fields, glycine can be measured at a relatively short echo time (TE) without additional editing efforts.


Predicting phosphorescence energies and inferring wavefunction localization with machine learning.
Phosphorescence is commonly utilized for applications including light-emitting diodes and photovoltaics. Machine learning (ML) approaches trained on ab initio datasets of singlet-triplet energy gaps may expedite the discovery of phosphorescent compounds with the desired emission energies. However, we show that standard ML approaches for modeling potential energy surfaces inaccurately predict singlet-triplet energy gaps due to the failure to account for spatial localities of spin transitions. To solve this, we introduce localization layers in a neural network model that weight atomic contributions to the energy gap, thereby allowing the model to isolate the most determinative chemical environments. Trained on the singlet-triplet energy gaps of organic molecules, we apply our method to an out-of-sample test set of large phosphorescent compounds and demonstrate the substantial improvement that localization layers have on predicting their phosphorescence energies. Remarkably, the inferred localization weights have a strong relationship with the ab initio spin density of the singlet-triplet transition, and thus infer localities of the molecule that determine the spin transition, despite the fact that no direct electronic information was provided during training. The use of localization layers is expected to improve the modeling of many localized, non-extensive phenomena and could be implemented in any atom-centered neural network model.


Mycophenolic acid inhibits activation of inducible nitric oxide synthase in rodent fibroblasts.
Mycophenolate mofetil (MMF) is an immunosuppressive drug that acts as a selective inhibitor of inosine monophosphate dehydrogenase (IMPDH). MMF has recently been shown to inhibit the enzymatic activity of inducible NO synthase (iNOS) and subsequent production of the cytotoxic free radical nitric oxide (NO) in endothelial cells. We here investigated the effect of bioactive MMF compound mycophenolic acid (MPA) on iNOS-mediated NO synthesis in fibroblasts, which are important source of NO in rheumatoid arthritis and during rejection of solid organ transplants. MPA exerted dose-dependent inhibition of NO synthesis, measured as nitrite accumulation, in IFN-gamma + LPS-stimulated L929 mouse fibroblast cell line and rat primary fibroblasts. The effect of MPA was not mediated through interference with IMPDH-dependent synthesis of iNOS co-factor BH4 and subsequent suppression of iNOS enzymatic activity, as direct BH4 precursor sepiapterin failed to block the action of the drug. MPA suppressed the IFN-gamma + LPS-induced expression of fibroblast iNOS protein, as well as mRNA for iNOS and its transcription factor IRF-1, as assessed by cell-based ELISA and semiquantitative RT-PCR, respectively. MPA suppression of fibroblast NO release, iNOS, and IRF-1 activation, was efficiently prevented by exogenous guanosine, indicating that the drug acted through reduction of IMPDH-dependent synthesis of guanosine nucleotides. These results suggest that MPA inhibits NO production in fibroblasts by blocking guanosine nucleotide-dependent expression of iNOS gene, through mechanisms that might involve the interference with the induction of iNOS transcription factor IRF-1.


Gliomatosis cerebri.
Gliomatosis cerebri is a rare diffusely infiltrating glial tumor involving two or more lobes and is frequently is bilateral. Infiltrative extent of tumor is out of proportion to histological and clinical features. We present a case in which finally the diagnosis of gliomatosis cerebri was made. In this case, computed tomography showed that midline structures were insignificantly shifted to the left, there was a mild dilatation of lateral ventricles more expressed on the right, and no pathologic changes of brain tissue density were found. On magnetic resonance tomography, T2W/SE and T2W/FLAIR images revealed zones of hyperintense signal, spreading with time, through several lobes of the brain with no enhancement on T1W images. Diagnosis of gliomatosis cerebri was suspected, stereotaxic biopsy was performed, and pathological examination revealed changes typical of diffuse glial tumor. In this article, changes typical of gliomatosis cerebri seen in other radiological methods such as computed tomography, magnetic resonance spectroscopy, dynamic contrast-enhanced T2*-weighted magnetic resonance, and positron emission tomography also are discussed.


Reductive activation of ricin and ricin A-chain immunotoxins by protein disulfide isomerase and thioredoxin reductase.
Intracellular activation of ricin and of the ricin A-chain (RTA) immunotoxins requires reduction of their intersubunit disulfide(s). This crucial event is likely to be catalyzed by disulfide oxidoreductases and precedes dislocation of the toxic subunit to the cytosol. We investigated the role of protein disulfide isomerase (EC 22.214.171.124, PDI), thioredoxin (Trx), and thioredoxin reductase (EC 18.104.22.168, TrxR) in the reduction of ricin and of a ricin A-chain immunotoxin by combining enzymatic assays, SDS-PAGE separation and immunoblotting. We found that, whereas PDI, Trx, and TrxR used separately were unable to directly reduce ricin and the immunotoxin, PDI and Trx in the presence of TrxR and NADPH could reduce both ricin and immunotoxin in vitro. PDI functioned only after pre-incubation with TrxR and the reductive activation of ricin was more efficient in the presence of glutathione. Similar results were obtained with microsomal membranes or crude cell extracts. Pre-incubation with the gold(I) compound auranofin, which irreversibly inactivates TrxR, resulted in a dose-dependent inhibition of ricin and immunotoxin reduction. Reductive activation of ricin and immunotoxin decreased or was abolished in microsomes depleted of TrxR and in cell extracts depleted of both PDI and Trx. Pre-incubation of U-937, Molt-3, Jurkat, and DU145 cells with auranofin significantly decreased ricin cytotoxicity with respect to mock-treated controls (P<0.05). Conversely, auranofin failed to protect cells from the toxicity of pre-reduced ricin which does not require intracellular reduction of disulfide between the two ricin subunits. We conclude that TrxR, by activating disulfide reductase activity of PDI, can ultimately lead to reduction/activation of ricin and immunotoxin in the cell.


3-(2-Bromoacetamido)-N-(9-ethyl-9H)-carbazol fluorescent probe and its application for the determination of thiophenols in rubber products by HPLC with fluorescence detection and atmospheric chemical ionization mass spectrometry identification.
A rapid, sensitive, and selective precolumn derivatization method for the simultaneous determination of eight thiophenols using 3-(2-bromoacetamido)-N-(9-ethyl-9H)-carbazol as a labeling reagent by high-performance liquid chromatography with fluorescence detection has been developed. The labeling reagent reacted with thiophenols at 50°C for 50 min in aqueous acetonitrile in the presence of borate buffer (0.10 mol/L, pH 11.2) to give high yields of thiophenol derivatives. The derivatives were identified by online postcolumn mass spectrometry. The collision-induced dissociation spectra for thiophenol derivatives gave the corresponding specific fragment ions at m/z 251.3, 223.3, 210.9, 195.8, and 181.9. At the same time, derivatives exhibited intense fluorescence with an excitation maximum at λex = 276 nm and an emission maximum at λem = 385 nm. Excellent linear responses were observed for all analytes over the range of 0.033-6.66 μmol/L with correlation coefficients of more than 0.9997. Detection limits were in the range of 0.94-5.77 μg/L with relative standard deviations of less than 4.54%. The feasibility of derivatization allowed the development of a rapid and highly sensitive method for the quantitative analysis of trace levels of thiophenols from some rubber products. The average recoveries (n = 3) were in the range of 87.21-101.12%.


Quantitative relationships between suckling-induced teat stimulation and the release of prolactin, gastrin, somatostatin, insulin, glucagon and vasoactive intestinal polypeptide in sows.
The pituitary hormones prolactin and oxytocin play important roles in the production and ejection of milk. In addition, some gastrointestinal peptides are released in response to suckling. During suckling, the piglets massage the udder of the sow both before and after let-down and the duration of suckling is correlated to the amount of milk produced by the sow. The aim of this study was to investigate whether there is a quantitative relation between the release of prolactin, gastrin, somatostatin, insulin, glucagon and vasoactive intestinal polypeptide (VIP) and the amount of stimulation of the sow's teats by the piglets. Repeated blood samples were drawn from three Swedish Landrace sows during three consecutive nursings by each sow on days 1, 3, 7 and 14 after parturition. The duration of massage by the piglets was noted, as was the number of piglets massaging. Hormone levels were quantified by radioimmunoassay. The release of prolactin, somatostatin, insulin, glucagon and VIP but not of gastrin were found to be significantly related to the amount of teat massage performed by the piglets during the first 2 weeks of lactation. The release was related to the duration of piglet massage or to the combined effect of duration and the number of piglets massaging but not to the number of piglets massaging per se. The basal level of prolactin was found to decrease during this time.


The synergistic effects of oxaliplatin and piperlongumine on colorectal cancer are mediated by oxidative stress.
Oxaliplatin-based chemotherapy is recommended as the first-line therapeutic regimen for metastatic colorectal cancer. However, long-term and repeated oxaliplatin therapy leads to drug resistance and severe adverse events, which hamper its clinical application. Thus, chemosensitizers are urgently required for overcoming oxaliplatin resistance and toxicity. Here, the anticancer effects of oxaliplatin combined with piperlongumine (PL), a molecule promoting reactive oxygen species (ROS) generation, in colorectal cancer, were assessed. We demonstrated that oxaliplatin elevated cellular ROS amounts and showed synergistic anticancer effects with PL in colorectal cancer cells. These anticancer effects were mediated by mitochondrial dysfunction and endoplasmic reticulum (ER) stress apoptotic-associated networks. Meanwhile, blockage of ROS production prevented apoptosis and fully reversed mitochondrial dysfunction and ER stress associated with the oxaliplatin/PL combination. Moreover, xenograft assays in mouse models highly corroborated in vitro data. In conclusion, this study provides a novel combination therapy for colorectal cancer, and reveals that manipulating ROS production might constitute an effective tool for developing novel treatments in colorectal cancer.


Implications of accounting for management intensity on carbon and nitrogen balances of European grasslands.
European managed grasslands are amongst the most productive in the world. Besides temperature and the amount and timing of precipitation, grass production is also highly controlled by applications of nitrogen fertilizers and land management to sustain a high productivity. Since management characteristics of pastures vary greatly across Europe, land-use intensity and their projections are critical input variables in earth system modeling when examining and predicting the effects of increasingly intensified agricultural and livestock systems on the environment. In this study, we aim to improve the representation of pastures in the dynamic global vegetation model LPJ-GUESS. This is done by incorporating daily carbon allocation for grasses as a foundation to further implement daily land management routines and land-use intensity data into the model to discriminate between intensively and extensively used regions. We further compare our new simulations with leaf area index observations, reported regional grassland productivity, and simulations conducted with the vegetation model ORCHIDEE-GM. Additionally, we analyze the implications of including pasture fertilization and daily management compared to the standard version of LPJ-GUESS. Our results demonstrate that grassland productivity cannot be adequately captured without including land-use intensity data in form of nitrogen applications. Using this type of information improved spatial patterns of grassland productivity significantly compared to standard LPJ-GUESS. In general, simulations for net primary productivity, net ecosystem carbon balance and nitrogen leaching were considerably increased in the extended version. Finally, the adapted version of LPJ-GUESS, driven with projections of climate and land-use intensity, simulated an increase in potential grassland productivity until 2050 for several agro-climatic regions, most notably for the Mediterranean North, the Mediterranean South, the Atlantic Central and the Atlantic South.


A novel activation mechanism of avian influenza virus H9N2 by furin.
Avian influenza virus H9N2 is prevalent in waterfowl and has become endemic in poultry in Asia and the Middle East. H9N2 influenza viruses have served as a reservoir of internal genes for other avian influenza viruses that infect humans, and several cases of human infection by H9N2 influenza viruses have indicated its pandemic potential. Fortunately, an extensive surveillance program enables close monitoring of H9N2 influenza viruses worldwide and has generated a large repository of virus sequences and phylogenetic information. Despite the large quantity of sequences in different databases, very little is known about specific virus isolates and their pathogenesis. Here, we characterize a low-pathogenicity avian influenza virus, A/chicken/Israel/810/2001 (H9N2) (Israel810), which is representative of influenza virus strains that have caused severe morbidity and mortality in poultry farms. We show that under certain circumstances the Israel810 hemagglutinin (HA) can be activated by furin, a hallmark of highly pathogenic avian influenza virus. We demonstrate that Israel810 HA can be cleaved in cells with high levels of furin expression and that a mutation that eliminates a glycosylation site in HA(1) allows the Israel810 HA to gain universal cleavage in cell culture. Pseudoparticles generated from Israel810 HA, or the glycosylation mutant, transduce cells efficiently. In contrast, introduction of a polybasic cleavage site into Israel810 HA leads to pseudoviruses that are compromised for transduction. Our data indicate a mechanism for an H9N2 evolutionary pathway that may allow it to gain virulence in a distinct manner from H5 and H7 influenza viruses.


The potential for tumor suppressor gene therapy in head and neck cancer.
Head and neck squamous cell carcinoma remains a highly morbid and fatal disease. Importantly, genomic sequencing of head and neck cancers has identified frequent mutations in tumor suppressor genes. While targeted therapeutics increasingly are being investigated in head and neck cancer, the majority of these agents are against overactive/overexpressed oncogenes. Therapy to restore lost tumor suppressor gene function remains a key and under-addressed niche in trials for head and neck cancer. Recent advances in gene editing have captured the interest of both the scientific community and the public. As our technology for gene editing and gene expression modulation improves, addressing lost tumor suppressor gene function in head and neck cancers is becoming a reality. This review will summarize new techniques, challenges to implementation, future directions, and ethical ramifications of gene therapy in head and neck cancer.


The PHH-1V HIPRA vaccine: a new tool in the vaccination strategy against COVID-19.
Vaccination against SARS-CoV-2 is essential to mitigate the personal, social and global impact of the coronavirus disease (COVID-19) as we move from a pandemic to an endemic phase. Vaccines are now required that offer broad, long-lasting immunological protection from infection in addition to protection from severe illness and hospitalisation. Here we present a review of the evidence base for a new COVID-19 vaccine, PHH-1V (Bimervax®; HIPRA HUMAN HEALTH S.L.U), and the results of an expert consensus. The expert committee consisted of Spanish experts in medicine, family medicine, paediatrics, immunology, microbiology, nursing, and veterinary medicine. Consensus was achieved using a 4-phase process consisting of a face-to-face meeting during which the scientific evidence base was reviewed, an online questionnaire to elicit opinions on the value of PHH-1V, a second face-to-face update meeting to discuss the evolution of the epidemiological situation, vaccine programmes and the scientific evidence for PHH-1V and a final face-to-face meeting at which consensus was achieved. The experts agreed that PHH-1V constitutes a valuable novel vaccine for the development of vaccination programmes aimed towards protecting the population from SARS-CoV-2 infection and disease. Consensus was based on evidence of broad-spectrum efficacy against established and emerging SARS-CoV-2 variants, a potent immunological response, and a good safety profile. The physicochemical properties of the PHH-1V formulation facilitate handling and storage appropriate for global uptake. The physicochemical properties, formulation, immunogenicity and low reactogenic profile of PHH-1V confirm the appropriateness of this new COVID-19 vaccine.


Does Preoperative Weight Loss Affect Outcomes After Major Liver Resection? Analysis of a National Database.
Introduction: The association between unintentional weight loss (WL) and outcomes after major hepatectomy for malignancy remains unclear.Methods: This retrospective cohort study reviewed the 2014-2019 NSQIP database of all patients who underwent major liver resections. The patients were categorized into two groups based on their history of weight loss. The primary outcome measure was the 30-day mortality. The secondary outcome was 30-day in-hospital complications.Results: In total, 384 patients had a history of preoperative weight loss. Preoperative WL was an independent predictor of septic shock (OR, 2.44; CI: 1.61, 3.69), bile leak (OR: 1.96; CI: 1.51, 2.55), and grade C liver failure (OR: 2.57; CI: 1.64, 4.01). However, preoperative WL was not a significant predictor of perioperative mortality (OR: 1.38; CI: 0.82, 2.32).Conclusion: The study found higher morbidity rates in patients undergoing liver resection with a history of weight loss. Further validation with prospective weight monitoring is needed to validate as a prognostic marker in patients undergoing hepatectomy. In addition, weight changes can help guide multidisciplinary decision-making in treating patients undergoing hepatectomy.


Characteristics of a new system for monitoring the leakage factor during regional hyperthermic isolated limb perfusion.
A new system is presented and evaluated for real-time monitoring of blood leakage during hyperthermic isolated limb perfusion (HILP) surgery, the Veenstra HILP system. This system incorporates two software models to determine blood leakage: a single-nuclide algorithm and a newly developed dual-nuclide algorithm. The latter algorithm has the advantage that, in principle, it is independent of system sensitivity and thus independent of changes in geometrical efficiency. A physical description of the system is given, together with the required hardware and software specifications. In-vitro measurements, corresponding to the intended clinical use, are presented to investigate the relevant performance characteristics of the system: count rate linearity, measurement uncertainty, response time, and accuracy. As the Veenstra HILP system provides the opportunity to use different filter settings and averaging time, the influence of these settings on the time response and measurement uncertainty is described. Count rate linearity was better than 1% for the count rate domain typically observed during HILP procedures. The response time of the system degrades with increasing total averaging time. In contrast, measurement uncertainty in the blood leakage factor improves with increasing radiotracer count rates and increasing total averaging time. For both blood leakage algorithms, measurement accuracy is better than 1.0 and 1.5%, respectively. Measurements have shown that the system is well suited for the real-time monitoring of blood leakage during HILP surgery. Furthermore, a good agreement was observed between the theoretical and measured response time and measurement uncertainty.


Basal cell carcinoma: an updated epidemiological and therapeutically profile of an urban population.
To describe the epidemiological profile of basal cell carcinoma patients at a private hospital in São Paulo and to evaluate the treatment adopted. A prospective study of 202 patients, on which 253 lesions were diagnosed for histopathological exam as basal cell carcinoma within the period of January 2001 to September 2003, in the Plastic Surgery Residency Program at the Hospital Jaraguá. The susceptibility factor of the host, the environment variables, the characteristics of the lesions and the efficacy of the treatment were examined. The data were statistically evaluated. The incidence of basal cell carcinoma was 126 cases per 100,000 patients in a period of 32 months (36 cases per 100,000 patients/year). The patients were evenly distributed in terms of sex: 48% male and 52% female. The greater incidence was in patients between the ages of 60 and 80 years and the average was 64 years. The survey revealed susceptibility factors such as white race and phototypes I and II in 95.5% of the patients. Exposition to ultraviolet radiation was reported by 77% of the patients and the most frequent location of tumors was on the face (71.2% of the cases). Actinic keratosis and a history of skin cancer were reported in 43.6% and in 25% of the cases, respectively. The adopted treatment was surgery in 99.4% of the cases and only one patient was treated with radiotherapy. Twenty lesions (8%) had incomplete excision. The recurrence rate was 2% (5 cases). There were no cases with metastasis or fatal outcome. The factors related to the development of basal cell cancer which were significantly present in the population surveyed were: older age, white individuals, phototypes I and II, presence of actinic keratosis, previous history of non-melanoma skin cancer and exposure to ultra-violet rays both in recreational and in occupational form. The surgical treatment employed was effective with a rate of incomplete excision and recurrence similar to those found in the literature.


Two novel missense mutations in the connexin 26 gene in Turkish patients with nonsyndromic hearing loss.
Most nonsyndromic hearing losses are caused by mutations in the GJB2 gene, and studies have revealed that the forms and frequencies of these mutations are largely dependent on ethnic origin. In the present study, we aimed to characterize the mutation profiles of 151 patients with hearing loss in Turkey. The entire coding region of the GJB2 was directly sequenced in all patients. We found 35 (23.2%) individuals carrying GJB2 mutations. Seven different mutations were identified, five of which were previously known (35delG, delE120, R184P, M163V, L90P), the remaining two being novel variants (M34V, L205V). The most common mutation was 35delG followed by delE120. The 35delG mutation was homozygous in 22 cases (14.5%) and heterozygous in 4 cases (2.6%). Compound heterozygosity for 35delG was also observed. The delE120 mutation was found in three patients in homozygous form. A homozygous L90P and heterozygous mutations M163V and M34V were found in single cases.


Methylation analysis of circadian clock gene promoters in forensic autopsy specimens.
DNA methylation in gene promoter regions influences gene expression. Circadian clock genes play an important role in the formation of a biological clock and aberrant methylation of these genes contributes to several disorders. In this study, we examined forensic autopsy specimens to determine whether DNA methylation status in the promoter regions of nine circadian clock genes (Per1, Per2, Per3, Cry1, Cry2, Bmal1, Clock, Tim, and Ck1e) is related to a change in acquired diathesis and/or causes of death. Methylation-specific PCR and direct sequencing methods revealed that the promoters of Per1, Cry2, Bmal1, Clock, and Ck1e were unmethylated in all the forensic autopsy specimens, while the promoters of Per2, Per3, Cry1, and Tim were partially methylated. Methylation status varied between individuals and between tissues in the same patient. A detailed analysis of methylation patterns in the Cry1 promoter region revealed that the patterns also varied between individuals and the Cry1 promoter had highly methylated patterns in two cases that had been exposed to methamphetamine. These results suggest that the methylation status of clock gene promoters varies between individuals. Methamphetamine use may influence methylation in the Cry1 gene promoter region and disturb circadian rhythmicity.


An update on enzalutamide in the treatment of prostate cancer.
Enzalutamide is an oral androgen receptor inhibitor that targets multiple steps in the androgen receptor signaling pathway. In the randomized phase III AFFIRM study, significant improvements in survival versus placebo were observed when enzalutamide was used as a treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) following prior treatment with docetaxel. Additional benefits included significant delay in time to first skeletal-related event, and improvement in several measures of pain and health-related quality of life. Treatment effects were consistent across all prespecified subgroups. The phase III PREVAIL study evaluated enzalutamide versus placebo in patients with mCRPC who had not received chemotherapy. Enzalutamide significantly decreased the risk of radiographic progression and death. There were also significant improvements in all secondary and prespecified exploratory endpoints, including delayed initiation of chemotherapy, reduction in risk of first skeletal-related event and a high percentage of patients with objective response compared with placebo. Enzalutamide was also studied in hormone naïve patients (as monotherapy) in a small, open-label phase II study in patients with prostate cancer who were eligible for androgen-deprivation therapy. A prostate-specific antigen (PSA) response, defined as ⩾80% decline in PSA level from baseline at week 25, was achieved in 92.5% of patients. Long-term follow up is ongoing. Despite differences between these three trials, enzalutamide displayed a favorable safety profile in all three patient populations. Similar rates of adverse events between the enzalutamide and placebo groups were observed in AFFIRM and PREVAIL, with fatigue, diarrhea, back pain and hot flashes being more common with enzalutamide than with placebo. Hypertension was reported at a higher rate in the enzalutamide group than in the placebo group in PREVAIL. Breast-related disorders associated with enzalutamide treatment were also reported in the Monotherapy trial. Few seizures were reported in any trial. Enzalutamide is being studied in several early disease state populations.


Mechanisms of nanoscale zero-valent iron mediating aerobic denitrification in Pseudomonas stutzeri by promoting electron transfer and gene expression.
Aerobic denitrification and its mechanism by P. stutzeri was investigated in the presence of nanoscale zero-valent iron (nZVI). The removal of nitrate and ammonia was accelerated and the nitrite nitrogen accumulation was reduced by nZVI. The particle size and dosage of nZVI were key factors for enhancing aerobic denitrification. nZVI reduced the negative effects of low carbon/nitrogen, heavy metals, surfactants and salts to aerobic denitrification. nZVI and its dissolved irons were adsorbed into the bacteria cells, enhancing the transfer of electrons from nicotinamide adenine dinucleotide (NADH) to nitrate reductase. Moreover, the activities of NADH-ubiquinone reductase involved in the respiratory system, and the denitrifying enzymes were increased. The expression of denitrifying enzyme genes napA and nirS, as well as the iron metabolism gene fur, were promoted in the presence of nZVI. This work provides a strategy for enhancing the biological denitrification of wastewater using the bio-stimulation of nanomaterials.


A Deep Learning Framework for Image-Based Screening of Kawasaki Disease.
Kawasaki disease (KD) is a leading cause of acquired heart disease in children and is characterized by the presence of a combination of five clinical signs assessed during the physical examination. Timely treatment of intravenous immunoglobin is needed to prevent coronary artery aneurysm formation, but KD is usually diagnosed when pediatric patients are evaluated by a clinician in the emergency department days after onset. One or more of the five clinical signs usually manifests in pediatric patients prior to ED admission, presenting an opportunity for earlier intervention if families receive guidance to seek medical care as soon as clinical signs are observed along with a fever for at least five days. We present a deep learning framework for a novel screening tool to calculate the relative risk of KD by analyzing images of the five clinical signs. The framework consists of convolutional neural networks to separately calculate the risk for each clinical sign, and a new algorithm to determine what clinical sign is in an image. We achieved a mean accuracy of 90% during 10-fold cross-validation and 88% during external validation for the new algorithm. These results demonstrate the algorithms in the proposed screening tool can be utilized by families to determine if their child should be evaluated by a clinician based on the number of clinical signs consistent with KD.Clinical Relevance- This screening framework has the potential for earlier clinical evaluation and detection of KD to reduce the risk of coronary artery complications.


Restoration of BMI1 levels after the administration of early harvest extra virgin olive oil as a therapeutic strategy against Alzheimer's disease.
Even though Alzheimer's disease (AD) is the most common cause of dementia, the mechanisms governing the establishment and progression of the disease remain largely unknown. Here, we investigated the implication of the neuroprotective protein BMI1 (B lymphoma Mo-MLV insertion region 1 homolog) in AD and the possibility to reverse the onset of the disease through the administration of extra virgin olive oil (EVOO) in Mild Cognitive Impairment (MCI) patients. For this purpose, we utilized a wide bank of MCI patient samples to examine the potential effects of EVOO. We found that while EVOO treatment increases BMI1 levels, p53 levels drop in MCI patient serum after EVOO treatment for 12 months. Additionally, AD-related biomarkers (p-tau, Aβ1-42 and Aβ1-42/Aβ-40 ratio) return to normal levels after administration of EVOO in MCI patients for 12 months. Moreover, we show that upon EVOO administration, BMI1-upregulation correlates with reduction of oxidative stress and inflammatory responses. In conclusion, we provide clinical trial evidence to confirm that restoration of BMI1 activity through EVOO administration in MCI patients constitutes a potential therapeutic approach against neurodegeneration leading to AD.


[Antiaggregant and antioxidant activity of estradiol and tamoxifen].
Tamoxifen did not influence the human platelet aggregation in vitro, while estradiol at a concentration of 10(-6) M inhibited the aggregation of human thrombocytes induced by ADP, serotonin + adrenaline, and adrenaline (epinephrine) by 14.7, 12.5, and 16.6%, respectively. Estradiol introduced in the range of effective concentrations from 10(-8) to 10(-4) M inhibited lipid peroxidation, while tamoxifen produced this effect only at a concentration of 10(-4) M. There was a correlation between the antiaggregant activity and antioxidant properties of estradiol.


Citation Network Study on the Use of New Technologies in Neurorehabilitation.
New technologies in neurorehabilitation is a wide concept that intends to find solutions for individual and collective needs through technical systems. Analysis through citation networks is used to search scientific literature related to a specific topic. On the one hand, the main countries, institutions, and authors researching this topic have been identified, as well as their evolution over time. On the other hand, the links between the authors, the countries, and the topics under research have been analyzed. The publications analysis was performed through the Web of Science database using the search terms "new technolog*," "neurorehabilitation," "physical therapy*," and "occupational therapy*." The selected interval of publication was from 1992 to December 2020. The results were analyzed using CitNetExplorer software. After a Web of Science search, a total of 454 publications and 135 citation networks were found, 1992 being the first year of publication. An exponential increase was detected from the year 2009. The largest number was detected in 2020. The main areas are rehabilitation and neurosciences and neurology. The most cited article was from Perry et al. in 2007, with a citation index of 460. The analysis of the top 20 most cited articles shows that most approach the use of robotic devices and brain-computer interface systems. In conclusion, the main theme was found to be the use of robotic devices to address neuromuscular rehabilitation goals and brain-computer interfaces and their applications in neurorehabilitation.


Nasal administration of IgA to individuals with hypogammaglobulinemia.
Many immunodeficient patients constantly carry non-typable Hemophilus influenzae (NTHI) in the nasopharynx, despite seemingly adequate antibiotic therapy. We have studied the effect of nasal administration of IgA on nasopharyngeal colonization in 5 patients with hypogammaglobulinemia, with a productive cough, especially in the mornings, who were constant carriers of NTHI in the nasopharynx, and had IgA, 1 ml 6 times/day, given nasally for 14 days. Nasopharyngeal cultures were obtained on days 0, 7, 14 and 28. Two of the patients became culture-negative during the treatment, and the cough was alleviated in all patients.


Does computerized tomography change the treatment decision in pediatric medial epicondyle fractures?
The amount of displacement in medial epicondylar fracture is one of the most important criteria for treatment decision. The displacement of medial epicondyle fractures of the humerus may be underestimated by standard AP and lateral views of elbow. The aim of the current study is to show the clinical relavance of computerized tomography (CT) for medial epicondyle fractures. A retrospective analysis on patients with medial epicondyle fracture was performed. Measurements were performed by 9 reviewer, there were 12 cases available for review with both radiographs and CT. The difference between measurement of AP Xray versus frontal and axial CT scans was found to be statistically significant for 1st and 2nd assessments (p=0.001). The decision for operative treatment was higher after evaluation with CT for both first and second assessment and this was statistically significant (p=0,0001). CT is found to be superior to determine the real amount of the fracture displacement and was relavant for treatment decision of pediatric medial epicondylar fractures. We also found a better interobserver agreement for axial CT scans relative to treatment decision. Level of evidence : IV.


Metabolic and miRNA profiling of TMV infected plants reveals biphasic temporal changes.
Plant viral infections induce changes including gene expression and metabolic components. Identification of metabolites and microRNAs (miRNAs) differing in abundance along infection may provide a broad view of the pathways involved in signaling and defense that orchestrate and execute the response in plant-pathogen interactions. We used a systemic approach by applying both liquid and gas chromatography coupled to mass spectrometry to determine the relative level of metabolites across the viral infection, together with a miRs profiling using a micro-array based procedure. Systemic changes in metabolites were characterized by a biphasic response after infection. The first phase, detected at one dpi, evidenced the action of a systemic signal since no virus was detected systemically. Several of the metabolites increased at this stage were hormone-related. miRs profiling after infection also revealed a biphasic alteration, showing miRs alteration at 5 dpi where no virus was detected systemically and a late phase correlating with virus accumulation. Correlation analyses revealed a massive increase in the density of correlation networks after infection indicating a complex reprogramming of the regulatory pathways, either in response to the plant defense mechanism or to the virus infection itself. Our data propose the involvement of a systemic signaling on early miRs alteration.


Correction of hyperleucinemia in MSUD patients on leucine-free dietary therapy.
Maple Syrup Urine Disease (MSUD) is a rare disorder of branched-chain amino acid catabolism associated with encephalopathy from accumulation of leucine. Leucine is closely monitored during normal growth and particularly during acute illness. As most hospitals do not have access to rapid plasma amino acid quantification, the initial management is often empirical. A model describing the reduction of plasma leucine in hyperleucinemic patients on leucine-free formula would help to guide management and optimize testing frequency. We retrospectively reviewed charts from 15 MSUD patients comprising 29 episodes of hyperleucinemia that were managed with leucine-free formula. Episodes were categorized by clinical presentation. Upon leucine restriction, plasma leucine concentrations fell exponentially at a rate proportional to approximately 50% of the starting value over each 24-hour period. Recovery appears to be sensitive to clinical status and triggering event of the hyperleucinemic episode. Patients with upper respiratory infections generally recovered slowly, while cases of dietary non-adherence resolved more quickly. This general model may help anticipate leucine levels during clinical management of MSUD patients when using nutritional support and leucine-free formula. The response of individual patients may vary depending on clinical status and triggering factors.


Polycyclic aromatic hydrocarbon degradation by a new marine bacterium, Neptunomonas naphthovorans gen. nov., sp. nov.
Two strains of bacteria were isolated from creosote-contaminated Puget Sound sediment based on their ability to utilize naphthalene as a sole carbon and energy source. When incubated with a polycyclic aromatic hydrocarbon (PAH) compound in artificial seawater, each strain also degraded 2-methylnaphthalene and 1-methylnaphthalene; in addition, one strain, NAG-2N-113, degraded 2,6-dimethylnaphthalene and phenanthrene. Acenaphthene was not degraded when it was used as a sole carbon source but was degraded by both strains when it was incubated with a mixture of seven other PAHs. Degenerate primers and the PCR were used to isolate a portion of a naphthalene dioxygenase iron-sulfur protein (ISP) gene from each of the strains. A phylogenetic analysis of PAH dioxygenase ISP deduced amino acid sequences showed that the genes isolated in this study were distantly related to the genes encoding naphthalene dioxygenases of Pseudomonas and Burkholderia strains. Despite the differences in PAH degradation phenotype between the new strains, the dioxygenase ISP deduced amino acid fragments of these organisms were 97.6% identical. 16S ribosomal DNA-based phylogenetic analysis placed these bacteria in the gamma-3 subgroup of the Proteobacteria, most closely related to members of the genus Oceanospirillum. However, morphologic, physiologic, and genotypic differences between the new strains and the oceanospirilla justify the creation of a novel genus and species, Neptunomonas naphthovorans. The type strain of N. naphthovorans is strain NAG-2N-126.


Injection Drug Use and Hepatitis C as Risk Factors for Mortality in HIV-Infected Individuals: The Antiretroviral Therapy Cohort Collaboration.
HIV-infected individuals with a history of transmission through injection drug use (IDU) have poorer survival than other risk groups. The extent to which higher rates of hepatitis C (HCV) infection in IDU explain survival differences is unclear. Adults who started antiretroviral therapy between 2000 and 2009 in 16 European and North American cohorts with >70% complete data on HCV status were followed for 3 years. We estimated unadjusted and adjusted (for age, sex, baseline CD4 count and HIV-1 RNA, AIDS diagnosis before antiretroviral therapy, and stratified by cohort) mortality hazard ratios for IDU (versus non-IDU) and for HCV-infected (versus HCV uninfected). Of 32,703 patients, 3374 (10%) were IDU; 4630 (14%) were HCV+; 1116 (3.4%) died. Mortality was higher in IDU compared with non-IDU [adjusted HR 2.71; 95% confidence interval (CI): 2.32 to 3.16] and in HCV+ compared with HCV- (adjusted HR 2.65; 95% CI: 2.31 to 3.04). The effect of IDU was substantially attenuated (adjusted HR 1.57; 95% CI: 1.27 to 1.94) after adjustment for HCV, while attenuation of the effect of HCV was less substantial (adjusted HR 2.04; 95% CI: 1.68 to 2.47) after adjustment for IDU. Both IDU and HCV were strongly associated with liver-related mortality (adjusted HR 10.89; 95% CI: 6.47 to 18.3 for IDU and adjusted HR 14.0; 95% CI: 8.05 to 24.5 for HCV) with greater attenuation of the effect of IDU (adjusted HR 2.43; 95% CI: 1.24 to 4.78) than for HCV (adjusted HR 7.97; 95% CI: 3.83 to 16.6). Rates of CNS, respiratory and violent deaths remained elevated in IDU after adjustment for HCV. A substantial proportion of the excess mortality in HIV-infected IDU is explained by HCV coinfection. These findings underscore the potential impact on mortality of new treatments for HCV in HIV-infected people.


Gender-related clinical differences in older patients with schizophrenia.
Gender differences in the clinical presentation of young patients with schizophrenia have been well-documented, yet few studies have investigated gender-related clinical differences in older patients. Furthermore, the symptoms of late-onset schizophrenia have been described, but the interaction between gender and age at onset has not been examined. In an older (46-85 years of age) outpatient sample, we assessed clinical characteristics of women and men with early-onset schizophrenia (N = 90) and late-onset schizophrenia (N = 34). Subjects did not differ with respect to age, education, ethnicity, severity of depression, daily neuroleptic dosage, subtype of schizophrenia, total score on the Mini-Mental State Examination, or severity of overall psychopathology. Diagnosis was made using the Structured Clinical Interview for the DSM-III-R or DSM-IV. A significantly greater proportion of women had late-onset schizophrenia (41% vs. 20%), and women overall had more severe positive psychotic symptoms. Although there was no overall gender difference in severity of negative psychotic symptoms, women with late onset had significantly less severe negative symptoms than men with early onset, men with late onset, and women with early onset. Furthermore, age at onset of schizophrenia was inversely correlated with severity of negative symptoms for women, but not for men. These results indicate that women overall may develop more severe positive symptoms than men, and that when women develop schizophrenia after age 45, they may suffer less severe negative symptoms than men or than women with earlier onset. Our results suggest that some of the clinical differences between late-onset and early-onset schizophrenia may relate to gender effects, and that there may be inherent differences in the clinical presentation of schizophrenia that are related to gender and gender by age at onset interactions. These differences may reflect the influence of sex hormones and menopause on the clinical presentation of schizophrenia or the possible existence of an "estrogen-related" form of schizophrenia in women with late-onset schizophrenia.


Molecular recognition of bio-active flavonoids quercetin and rutin by bovine hemoglobin: an overview of the binding mechanism, thermodynamics and structural aspects through multi-spectroscopic and molecular dynamics simulation studies.
The binding of two bio-active flavonoids, quercetin and rutin, with bovine hemoglobin (BHb) was investigated by multi-spectroscopic and computational (molecular docking and molecular dynamics simulation) studies. The two flavonoids were found to quench the intrinsic fluorescence of BHb through a static quenching mechanism. The binding constants at 288 K were observed to be (14.023 ± 0.73) × 104 M-1 and (7.848 ± 0.20) × 104 M-1, respectively for quercetin and rutin binding with BHb. Both rutin and quercetin were observed to increase the polarity around the Trp residues of BHb as indicated by synchronous and 3D spectral studies. No significant alterations in the secondary structural components of the protein were caused during the binding of the flavonoids as studied by CD and FTIR studies. The negative molar Gibbs free energies indicated the spontaneity of the interaction processes while the binding processes were characterized by a negative enthalpy change (ΔH) and a positive entropy change (ΔS). The possibility of energy transfer from the donor (BHb) to the acceptor molecules (flavonoids) was indicated by the FRET studies. According to the fluorescence studies, the flavonoids interact near to the β2-Trp37 residue of BHb. Excellent correlations with the experimental studies were observed from the molecular docking and molecular dynamics (MD) simulation studies. Further investigations established that these flavonoids are efficient in the inhibition of glucose mediated glycation of BHb.


Exploring the application of mesenchymal stem cells in bone repair and regeneration.
Failure of bone repair is a challenging problem in the management of fractures. There is a limited supply of autologous bone grafts for treating nonunions, with associated morbidity after harvesting. There is need for a better source of cells for repair. Mesenchymal stem cells (MSCs) hold promise for healing of bone because of their capacity to differentiate into osteoblasts and their availability from a wide variety of sources. Our review aims to evaluate the available clinical evidence and recent progress in strategies which attempt to use autologous and heterologous MSCs in clinical practice, including genetically-modified MSCs and those grown on scaffolds. We have compared various procedures for isolating and expanding a sufficient number of MSCs for use in a clinical setting. There are now a number of clinical studies which have shown that implantation of MSCs is an effective, safe and durable method for aiding the repair and regeneration of bone.


Pemphigus in Pakistan, a study of 108 cases [corrected].
Pemphigus has an average age of onset in the fifth and sixth decades of life, with a mean age of onset of about 50 to 60 years. In this study of 108 patients conducted in Karachi, Pakistan, 82 had pemphigus vulgaris, 24 pemphigus foliaceus and 2 pemphigus vegetans. Other types of pemphigus were not seen. Seventy cases were under 41 years with the mean age at the time of diagnosis being 33.8 years, which is considerably low compared to that mentioned in standard western literature. Considerable variation in the age incidence of the disease exists in different geographic locations.


Prediction models for insulin resistance.
A prediction model for estimating insulin resistance in hypertensive patients is presented. Body-mass index, serum triglyceride concentrations and liver enzyme activity in plasma correlate to insulin resistance determined with the euglycaemic, hyperinsulinaemic clamp technique. Prediction models using body-mass index and either triglycerides or serum alanine-amino transferase were equally good in predicting insulin resistance and gave results that were as reliable as those obtained in a model using fasting-insulin concentrations. The hyperinsulinaemic clamp had a reproducibility error of 14%, and body-mass index and serum triglycerides had a multiple correlation of 0.57 to the insulin-sensitivity results. The model predicts insulin resistance with acceptable statistical power, whereas the power to predict high values of insulin sensitivity is less good.


Potential impacts of anthropogenic nutrient enrichment on coral reefs in the South China Sea: evidence from nutrient and chlorophyll a levels in seawater.
Anthropogenic nutrient enrichment is considered to be one of the causes resulting in coral reef decline. In order to better understand the trophic status and to further explore the potential impacts of nutrients on the coral reef decline in the South China Sea (SCS), we investigated the nutrient and chlorophyll a (chl a) distributions in the surface water of reef areas across latitudes from 9-22° of the SCS. The results showed that nutrient and chl a concentrations in coastal reefs were obviously higher than those in the central and southern basin. Meanwhile, the investigation of two long-distance transects revealed an inshore-offshore nutrient decreasing trend. However, some offshore coral reefs, such as Yongxing Island, Huaguang Reef and Huangyan Island, were exceptions with relatively higher concentrations than in the surrounding reefs because of the ever-increasing human activity. Compared to other coral reefs worldwide, the nutrient concentration in reef regions of the northern and central SCS was obviously higher than that in healthy coral reefs, approaching that in unhealthy reef areas, which suggested that the present nutrient concentration may reach a risky level. Field survey showed a high ratio of macroalgal cover and coral cover in these reefs, and the significant correlation between the nutrient level and macroalgal cover indicated that elevated nutrients resulted in the phase shift from coral-dominated to macroalgal-dominated reef areas. On the other hand, a significant positive correlation between chl a in lagoons and the volume of lagoons indicated that the structural properties of large lagoons could enhance retention of nutrients and promote the growth of macroalgae, and human disturbance may aggravate the macroalgal overgrowth. Overall, anthropogenic nutrient enrichment has caused negative impacts on coral reefs of the SCS, such as regional macroalgal blooms in coastal reefs and disturbed remote reefs.


[Renal artery stenosis in the transplant patient].
To present our experience in the diagnosis and treatment of renal artery stenosis in kidney transplants. A review of 601 renal transplants performed in adults showed 32 cases of renal artery stenosis. The diagnostic techniques utilized were arteriography in 18 patients, DIVAS in 15, echo-Doppler in 11 patients and MAG with captopril test on two occasions. Arterial hypertension was the most common symptom (92.8%), alone (53.1%) or in association with impaired renal function (43.7%). 46.8% of the cases could be managed by drug therapy. Percutaneous transluminal angioplasty was performed in 14 patients. Surgery was required on two occasions. The incidence of renal artery stenosis in our series of renal transplants in adults up to 1997 was 5.3%. Arterial hypertension with or without impairment of renal function was the most common symptom. Currently, echo-doppler and MAG with captopril test are the most widely utilized diagnostic techniques. Percutaneous transluminal angioplasty is the treatment of choice in renal artery stenosis when arterial hypertension is refractory to drug therapy. Good results are achieved in 57%, although it is not free from complications. In case of failure, revascularization surgery is the alternative approach.


CaMKIIδC Drives Early Adaptive Ca2+ Change and Late Eccentric Cardiac Hypertrophy.
CaMKII (Ca2+-Calmodulin dependent protein kinase) δC activation is implicated in pathological progression of heart failure (HF) and CaMKIIδC transgenic mice rapidly develop HF and arrhythmias. However, little is known about early spatio-temporal Ca2+ handling and CaMKII activation in hypertrophy and HF. To measure time- and location-dependent activation of CaMKIIδC signaling in adult ventricular cardiomyocytes, during transaortic constriction (TAC) and in CaMKIIδC transgenic mice. We used human tissue from nonfailing and HF hearts, 4 mouse lines: wild-type, KO (CaMKIIδ-knockout), CaMKIIδC transgenic in wild-type (TG), or KO background, and wild-type mice exposed to TAC. Confocal imaging and biochemistry revealed disproportional CaMKIIδC activation and accumulation in nuclear and perinuclear versus cytosolic regions at 5 days post-TAC. This CaMKIIδ activation caused a compensatory increase in sarcoplasmic reticulum Ca2+ content, Ca2+ transient amplitude, and [Ca2+] decline rates, with reduced phospholamban expression, all of which were most prominent near and in the nucleus. These early adaptive effects in TAC were entirely mimicked in young CaMKIIδ TG mice (6-8 weeks) where no overt cardiac dysfunction was present. The (peri)nuclear CaMKII accumulation also correlated with enhanced HDAC4 (histone deacetylase) nuclear export, creating a microdomain for transcriptional regulation. At longer times both TAC and TG mice progressed to overt HF (at 45 days and 11-13 weeks, respectively), during which time the compensatory Ca2+ transient effects reversed, but further increases in nuclear and time-averaged [Ca2+] and CaMKII activation occurred. CaMKIIδ TG mice lacking δB exhibited more severe HF, eccentric myocyte growth, and nuclear changes. Patient HF samples also showed greatly increased CaMKIIδ expression, especially for CaMKIIδC in nuclear fractions. We conclude that in early TAC perinuclear CaMKIIδC activation promotes adaptive increases in myocyte Ca2+ transients and nuclear transcriptional responses but that chronic progression of this nuclear Ca2+-CaMKIIδC axis contributes to eccentric hypertrophy and HF.


Evolution of Klk4 and enamel maturation in eutherians.
Kallikrein-related peptidase 4 (KLK4) is a secreted serine protease that degrades residual enamel proteins to facilitate their removal by ameloblasts, which increases mineralization and hardens the enamel. Mutations in human KLK4 cause hypomaturation amelogenesis imperfecta. Enamel formed by Klk4 null mice is normal in thickness and prism structure, but the enamel layer retains proteins, is hypomineralized, and undergoes rapid attrition following tooth eruption. We searched multiple databases, retrieved Klk4 and Klk5 from various mammalian genomes, and identified Klk4 in 46 boreoeutherian genomes. In non-Boreoeutheria, Klk4 was detected in only one afrotherian genome (as a pseudogene), and not in the other six afrotherian, two xenarthran, or three marsupial genomes. In contrast, Klk5 was detected in both marsupial and eutherian mammals. Our phylogenetic and mutation rate analyses support the hypothesis that Klk4 arose from Klk5 by gene duplication near the divergence of Afrotheria, Xenarthra and Boreoeutheria, and that functionally-differentiated Klk4 survived only in Boreoeutheria. Afrotherian mammals share the feature of delayed dental eruption relative to boreoeutherian mammals. KLK4 shortens the time required for enamel maturation and could have alleviated negative selection following mutations that resulted in thicker enamel or earlier tooth eruption, without reducing enamel hardness or causing dental attrition.


Collateral Consequences of Juvenile Sex Offender Registration and Notification: Results From a Survey of Treatment Providers.
Among many in the research, policy, and practice communities, the application of sex offender registration and notification (SORN) to juveniles who sexually offend (JSO) has raised ongoing concerns regarding the potential collateral impacts on youths' social, mental health, and academic adjustment. To date, however, no published research has systematically examined these types of collateral consequences of juvenile SORN. Based on a survey of a national sample of treatment providers in the United States, this study investigates the perceived impact of registration and notification on JSO across five key domains: mental health, harassment and unfair treatment, school problems, living instability, and risk of reoffending. Results indicate that treatment providers overwhelmingly perceive negative consequences associated with registration with an incremental effect of notification indicating even greater concern across all five domains. Providers' demographics, treatment modalities, and client profile did not influence their perceptions of the collateral consequences suggesting that provider concern about the potential harm of SORN applied to juveniles is robust. Policy implications are discussed.


Mammalian cells preferentially internalize hydrogel nanodiscs over nanorods and use shape-specific uptake mechanisms.
Size, surface charge, and material compositions are known to influence cell uptake of nanoparticles. However, the effect of particle geometry, i.e., the interplay between nanoscale shape and size, is less understood. Here we show that when shape is decoupled from volume, charge, and material composition, under typical in vitro conditions, mammalian epithelial and immune cells preferentially internalize disc-shaped, negatively charged hydrophilic nanoparticles of high aspect ratios compared with nanorods and lower aspect-ratio nanodiscs. Endothelial cells also prefer nanodiscs, however those of intermediate aspect ratio. Interestingly, unlike nanospheres, larger-sized hydrogel nanodiscs and nanorods are internalized more efficiently than their smallest counterparts. Kinetics, efficiency, and mechanisms of uptake are all shape-dependent and cell type-specific. Although macropinocytosis is used by both epithelial and endothelial cells, epithelial cells uniquely internalize these nanoparticles using the caveolae-mediated pathway. Human umbilical vein endothelial cells, on the other hand, use clathrin-mediated uptake for all shapes and show significantly higher uptake efficiency compared with epithelial cells. Using results from both upright and inverted cultures, we propose that nanoparticle internalization is a complex manifestation of three shape- and size-dependent parameters: particle surface-to-cell membrane contact area, i.e., particle-cell adhesion, strain energy for membrane deformation, and sedimentation or local particle concentration at the cell membrane. These studies provide a fundamental understanding on how nanoparticle uptake in different mammalian cells is influenced by the nanoscale geometry and is critical for designing improved nanocarriers and predicting nanomaterial toxicity.


The allergenic acarofauna of house dust from dwellings, hospitals, libraries and institutes in Upper Silesia (Poland).
A survey of dust samples from dwellings, hospitals and some public utilities (libraries, institutes) in several Upper Silesian towns was undertaken to determine the prevalence, number and species of mites. Total seasonal dynamics of dust mite species of the family Pyroglyphidae in dust from beds, floors/carpets and upholstery furniture in dwellings was analysed. Over a 4-years period, 402 dust samples were studied: 238 samples from dwellings, 122 samples from hospitals, 14 from libraries and 28 from institutes. Mites were present in 51.3%, 50.0%, 21.3% and 17.9% of dust samples from dwellings, libraries, hospitals and institutes, respectively. Generally, they were found in 160 samples (39.8%) out of 402 examined. The majority of mites (96.0%) were found in samples from the dwellings, especially in dust from upholstery furniture, couches, sofas and beds. More than 30 mite species were found of which the most abundant and common were pyroglyphids, especially Dermatophagoides pteronyssinus and D. farinae. The pyroglyphid mites constituted 89.2%, 78.9% and 57.5% of a total count of mites collected from dwellings, libraries and hospitals, respectively, and were not found in institutes. D. pteronyssinus was the dominant, especially in libraries and hospitals, however, in dwellings D. farinae was more abundant per 1 gram of dust as the former species. Another pyroglyphid mite, Euroglyphus maynei, occurred in very small numbers. The highest mite densities per gram of dust were noted in dwellings and libraries. A mean number of mites per 1 gram of dust from dwellings was 73.7 +/- 182.9 (range 1.0 - 1560.0), whereas mean values of indoor relative humidity and temperature were 64.5% RH and 22.7 degrees C, respectively. The low mean indoor relative humidity of ambient air, resulted in the relatively low mite frequency (only about 51.3% of samples were positive for mites) and density detected in the dwellings.


Clinical characteristics of children referred to a child development center for evaluation of speech, language, and communication disorders.
Speech, language, and communication disorders are prominent reasons for referrals to a child development center. From 1984 to 1988, 1,090 preschool children were referred to our child development center, which serves the Tel Aviv metropolitan area. Of all referrals, 432 (41%) were primarily due to speech, language, and communication problems. After exclusion of those with IQ < 50 and those with non-language-related disabilities, 323 children remained. The children were classified into different subtypes of developmental language disorders and autistic spectrum disorders. The main developmental language disorder subtypes were combined expressive-receptive (49%) and expressive (44%). Central processing deficits were less common, occurring in 20 (7%) of the children. Parents of children with developmental language disorders had educational levels similar to those of parents of children referred to the child development center for other causes. However, parents of children with infantile autism had higher educational levels than parents of children with developmental language disorder or parents of children referred for other causes (P < .001). Our results reflect the distribution of language and related problems in an unselected population of preschool children referred to a child development center.


Math = male, me = female, therefore math not = me.
College students, especially women, demonstrated negativity toward math and science relative to arts and language on implicit measures. Group membership (being female), group identity (self = female), and gender stereotypes (math = male) were related to attitudes and identification with mathematics. Stronger implicit math = male stereotypes corresponded with more negative implicit and explicit math attitudes for women but more positive attitudes for men. Associating the self with female and math with male made it difficult for women, even women who had selected math-intensive majors, to associate math with the self. These results point to the opportunities and constraints on personal preferences that derive from membership in social groups.


Exploring Attitudes to Conception in Partners and Young Women with Gynecologic Cancers Treated by Fertility Sparing Surgery.
Approximately 20% of women with gynecologic cancers are under age 40 and with delayed childbearing, women may be diagnosed before their first pregnancy. Although fertility preservation is a priority for many women, attitudes to conception have not previously been investigated in these patients or their partners. We explored attitudes to conception in partners and young women, following fertility preserving treatment for gynecologic cancers. A total of 16 telephone interviews were conducted with a purposive sample of patients who had had an early stage gynecologic cancer or borderline ovarian tumor treated by fertility sparing surgery in Western Australia between January 1st, 2005 to December 31st, 2016. The interviews were audio recorded, transcribed and thematic analysis was conducted. Four main themes were identified: (i) Emotions at diagnosis and perception of information given; (ii) Discussions of fertility and factors affecting childbearing; (iii) Role of partners in decision making and relationship pressures; (iv) Decision for treatment and postoperative regrets. Regret and relationship breakdown were commonly reported. Women need appropriate support including inviting their partners to attend clinic appointments and may need several appointments before treatment. Regret was commonly reported by women who opted for completion surgery.<br />.


Production of recombinant nonstructural 1 protein in Escherichia coli for early detection of Japanese encephalitis virus infection.
Japanese encephalitis is a major public health problem in South-East Asia and Western Pacific countries. The recombinant nonstructural 1 (rNS1) protein of Japanese encephalitis virus is a potential diagnostic as well as vaccine candidate. Developments of cost-effective and simple culture media as well as appropriate culture conditions are generally favourable for large-scale production of recombinant proteins. The effects of medium composition and cultivation conditions on the production of rNS1 protein were investigated in shake flask culture as well as batch cultivation of Escherichia coli. Further, the fed-batch process was also carried out for high cell density cultivation (HCDC) of E. coli expressing rNS1 protein. Isopropyl-β-d-thiogalactopyranoside (IPTG) was used to induce the expression of rNS1 protein at ∼ 13 g dry cell weight per litre of culture. The final dry cell weight after fed-batch cultivation was ∼ 17 g l(-1) . The Inclusion bodies were isolated and purified through affinity chromatography to give a final product yield of ∼ 142 mg l(-1) . The reactivity of purified protein was confirmed by Western blotting and Enzyme linked immunosorbent assay. These results show that rNS1 protein may be used as a diagnostic reagent or for further prophylactic studies. This approach of producing rNS1 protein in E. coli with high yield may also offer promising method for production of other viral recombinant proteins.


The PRO: essential partner in health care quality improvement.
The health care profession has undergone radical changes and shifts that no one associated with the medical field in New Jersey would have predicted only a decade ago. As cost containment, managed care, mergers, and downsizing dominate New Jersey's health care agenda, the concept of quality-how to define it, how to measure it, and how to improve it-often takes a back seat to these issues.


[Microbiological and parasitological contamination of lettuce (Lactuca sativa) from self service restaurants of Niterói city, RJ].
Thirty samples of lettuces from self service restaurants of Niterói were analyzed to detect bacteriological and parasitological contamination. Sixteen samples presented fecal coliform, 16 mesophilic aerobic microorganisms greater than 10(7) UFC/g and 3 cysts of Entamoeba coli. These data suggest the need of better orientation for food handlers regarding the hygiene of processed vegetables.


Predicting Flory-Huggins χ from Simulations.
We introduce a method, based on a novel thermodynamic integration scheme, to extract the Flory-Huggins χ parameter as small as 10^{-3}kT for polymer blends from molecular dynamics (MD) simulations. We obtain χ for the archetypical coarse-grained model of nonpolar polymer blends: flexible bead-spring chains with different Lennard-Jones interactions between A and B monomers. Using these χ values and a lattice version of self-consistent field theory (SCFT), we predict the shape of planar interfaces for phase-separated binary blends. Our SCFT results agree with MD simulations, validating both the predicted χ values and our thermodynamic integration method. Combined with atomistic simulations, our method can be applied to predict χ for new polymers from their chemical structures.


The risk of ectopic pregnancy following GnRH agonist triggering compared with hCG triggering in GnRH antagonist IVF cycles.
The aim of this study was to compare the incidence of ectopic pregnancy in GnRH agonist triggered IVF cycles with intensive luteal support versus hCG triggered IVF cycles. This study was conducted as a retrospective cohort analysis of women who underwent IVF treatment employing GnRH agonist or recombinant hCG (rhCG) triggers during 2-year period. The medical charts of women who achieved pregnancies were reviewed and their demographic characteristics, infertility reasons and IVF data were recorded. A multiple logistic regression analysis was performed to estimate the association between the triggering medication used to stimulate final oocyte maturation (GnRHa or rhCG) and EP, with adjustment for important confounders: the day of embryo transfer (ETD), the etiology of infertility and estrogen level at the time of triggering. The number of metaphase II oocytes, fertilized oocytes and good quality embryos were significantly higher in the GnRH agonist triggered group compared with the hCG triggered group (p < 0.001 for all). The clinical pregnancy and implantation rates in the hCG triggered cycles were 38.6 and 31.1 %, respectively and 24.7 and 22 %, respectively in the triptorelin triggered cycles. The ectopic pregnancy rates were 5.3 % in the triptorelin triggered group and 1.4 % in the hCG triggered group. The trigger medication and the day of embryo transfer were found to have a significant effect on the probability of developing ectopic pregnancy (p = 0.028, p = 0.046 respectively). However, the estrogen level was not found to have a significant effect on the probability of developing ectopic pregnancy (p = 0.447). The reasons for higher ectopic pregnancy rates in GnRH agonist triggered cycles relative to hCG triggered cycles may be the decreased receptivity of the endometrium due to insufficient luteal support and higher implantation potential of embryos in correlation with a higher number of good quality embryos obtained in these cycles.


Does aberrant membrane transport contribute to poor outcome in adult acute myeloid leukemia?
Acute myeloid leukemia in adults is a highly heterogeneous disease. Gene expression profiling performed using unsupervised algorithms can be used to distinguish specific groups of patients within a large patient cohort. The identified gene expression signatures can offer insights into underlying physiological mechanisms of disease pathogenesis. Here, the analysis of several related gene expression clusters associated with poor outcome, worst overall survival and highest rates of resistant disease and obtained from the patients at the time of diagnosis or from previously untreated individuals is presented. Surprisingly, these gene clusters appear to be enriched for genes corresponding to proteins involved in transport across membranes (transporters, carriers and channels). Several ideas describing the possible relationship of membrane transport activity and leukemic cell biology, including the "Warburg effect," the specific role of chloride ion transport, direct "import" of metabolic energy through uptake of creatine phosphate, and modification of the bone marrow niche microenvironment are discussed.


Central nervous system complications in human herpesvirus-6 infection.
Human herpesvirus-6 (HHV-6) is the causative agent of the common childhood infectious disease, exanthem subitum. After the virus was recently isolated from humans, it was found to be closely related to human cytomegalovirus (CMV), and was thus classified within the beta subgroup of human herpesviruses. HHV-6 possesses neurotropism in vitro, and it has been suggested that primary infection can cause complications of the central nervous system (CNS), including febrile seizures and encephalitis/encephalopathy. There is also speculation that the direct invasion of the virus into the CNS may play an important role in causing these neurological complications. Moreover, there are several reports which have suggested an association between HHV-6 and a variety of neurological disorders in adults. This paper will briefly review our virological understanding of the virus, and summarize recent findings regarding HHV-6 as an etiologic agent for CNS infection.


NF-M trans-activates the human DNA topoisomerase II alpha promoter independently of c-Myb in HL-60 cells.
Identifying transcriptional regulators of DNA topoisomerase II alpha (topo II alpha) is essential to decipher the mechanisms underlying leukemia cell resistance to topo II-directed antitumor drugs. We have previously reported that the proto-oncogene transcription factor c-Myb transactivates the topo II alpha promoter in several hematopoietic cell lines. Currently, we investigate whether NF-M, a C/EBP beta family member, cooperates with c-Myb in activating topo II alpha transcription. Although NF-M is the most efficacious trans-activator of topo II alpha that we have examined (approximately 38-fold over basal), NF-M does not appear to be involved in the endogenous transcriptional regulation of topo II alpha. Interestingly, we report that the sodium butyrate-dependent induction of the topo II alpha promoter observed previously appears to be mediated by c-Myb, independent of NF-M.


Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis.
Cholangiocarcinoma (CCA) is a dreaded complication of primary sclerosing cholangitis (PSC); however, marked variability in the incidence of CCA in PSC is reported. Furthermore, limited information exists on risk factors for the development of CCA in PSC. The aim of this study was to determine the incidence of CCA in patients with PSC and to evaluate baseline risk factors for the later development of CCA. From a previous study of the natural history of PSC, we identified 161 patients with PSC who did not have CCA at study entry. Patients were followed until a diagnosis of CCA was established, liver transplantation was performed, or death occurred. Patients were followed for a median of 11.5 yr (interquartile range 4.0-16.1 yr). Fifty-nine patients (36.6%) died, 50 patients (31.1%) underwent liver transplantation, and 11 patients (6.8%) developed CCA. The rate of CCA developing was approximately 0.6% per year. Compared to the incidence rates of CCA in the general population, the relative risk of CCA in PSC was significantly increased (RR = 1,560; 95%CI = 780, 2,793; p < 0.0001). On univariate analysis, a history of variceal bleeding (p < 0.001), proctocolectomy (p= 0.01), and lack of symptoms (p= 0.02) were significant risk factors for CCA with the Mayo Risk Score being marginally significant (p= 0.051). Multivariate analysis determined only variceal bleeding to be a significant risk factor for CCA (RR 24.2; 95%CI: 3.3-67.1). No association was found between the duration of PSC and the incidence of CCA. In conclusion, approximately 7% of PSC patients later developed CCA over a mean follow-up of 11.5 yr, which is dramatically higher than the rates in the general population. Variceal bleeding is a major risk factor for the later development of CCA.


Differing contributions of inferior prefrontal and anterior temporal cortex to concrete and abstract conceptual knowledge.
Semantic cognition is underpinned by regions involved in representing conceptual knowledge and executive control areas that provide regulation of this information according to current task requirements. Using distortion-corrected fMRI, we investigated the contributions of these two systems to abstract and concrete word comprehension. We contrasted semantic decisions made either with coherent contextual support, which encouraged retrieval of a rich conceptual representation, or with irrelevant contextual information, which instead maximised demands on control processes. Inferior prefrontal cortex was activated more when decisions were made in the presence of irrelevant context, suggesting that this region is crucial for the semantic control functions required to select appropriate aspects of meaning in the face of competing information. It also exhibited greater activation for abstract words, which reflects the fact that abstract words tend to have variable, context-dependent meanings that place higher demands on control processes. In contrast, anterior temporal regions (ATL) were most active when decisions were made with the benefit of a coherent context, suggesting a representational role. There was a graded shift in concreteness effects in this region, with dorsolateral areas particularly active for abstract words and ventromedial areas preferentially activated by concrete words. This supports the idea that concrete concepts are closely associated with visual experience and abstract concepts with auditory-verbal information; and that sub-regions of the ATL display graded specialisation for these two types of knowledge. Between these two extremes, we identified significant activations for both word types in ventrolateral ATL. This area is known to be involved in representing knowledge for concrete concepts; here we established that it is also activated by abstract concepts. These results converge with data from rTMS and neuropsychological investigations in demonstrating that representational content and task demands influence recruitment of different areas in the semantic network.


Low intakes of dietary fiber and magnesium are associated with insulin resistance and hyperandrogenism in polycystic ovary syndrome: A cohort study.
Women with polycystic ovary syndrome (PCOS) often have insulin resistance (IR) which may be worsened by obesity. The roles of dietary intake and activity are unclear. Our objectives were to determine whether (a) high caloric intake or inactivity explains obesity in PCOS, and (b) dietary composition is associated with PCOS phenotypes. Eighty-seven women with PCOS and 50 women without PCOS participated in this cohort study at a reproductive medicine center. Data collected included 3-day food and physical activity records, anthropometrics, and metabolic and hormonal assays. Women with PCOS had increased body mass index (BMI) but similar caloric intake and activity to women without PCOS. There were no differences in protein, carbohydrates, fat, or glycemic load consumption, but women with PCOS consumed less fiber (medians: 19.6 vs. 24.7 g) and less magnesium (medians: 238.9 vs. 273.9 mg). In women with PCOS, those with IR consumed less fiber, less magnesium, and greater glycemic load than those without IR (medians: 18.2 vs. 22.1 g, 208.4 vs. 264.5 mg, 89.6 vs. 83.5). Fiber intake of women with PCOS was negatively correlated with IR, fasting insulin, glucose tolerance, testosterone, and dehydroepiandrosterone sulfate. Magnesium intake was negatively correlated with IR, C-reactive protein, and testosterone, but positively correlated with HDL cholesterol. Fiber intake and BMI accounted for 54.0% of the variance observed in IR. Obesity in women with PCOS could not be explained by overeating or inactivity. Increasing dietary fiber and magnesium intakes may assist in reducing IR and hyperandrogenemia in women with PCOS.


An error-weighted regularization algorithm for image motion-field estimation.
Local motion measurement errors are used to guide the global smoothing process in order to preserve motion-field discontinuities. A field-smoothing algorithm based on matching-error weighting is proposed. The added computation is minimal, since it uses byproducts of the local measurement process. The error-weighting functional provides significantly improved motion field estimates, as measured by motion-compensated interpolation performance. However, the mean-square reconstruction error is somewhat higher than that obtained by performing the much more computationally expensive stochastic optimization.


Autopneumonectomy with compensatory lung growth.
A 23-year-old female immigrant from Ethiopia presented with a history of hemoptysis and an abnormal chest x-ray. A computed tomography scan showed that her left lung was greatly shrunken and her right lung was very large but structurally normal. She had a history of multiple respiratory infections as a young child but had been well since the age of five years. Her lung function was within normal limits except for an increased residual volume. It is very likely that her left lung was destroyed early in childhood and that her right lung underwent compensatory growth. She did not show airways obstruction, which is usually seen when compensatory lung growth occurs after surgical removal of lung tissue; this may indicate that, in those cases, the surgery compromised airway function.


Genetic control of endotoxic responses in mice.
A number of altered immunologic responses to lipopolysaccharide (LPS) in C3H/HeJ mice result from the expression in B lymphocytes of a defective genetic locus, termed Lps. Lps has been mapped to chromosome 4 between two loci, Mup-1 and Ps. As it is difficult to type individual mice for LPS responsiveness in more than one type of assay, we have utilized Mup-1 as a genetic marker to correlate LPS responses in mice to the expression of the Lps locus. Three nonlymphoid responses to LPS have been examined in 12 recombinant inbred strains of mice and in a backcross linkage analysis, and are all regulated by the expression of the Lps locus. These responses are hypothermal changes in body temperature, and the elevation in serum levels of a colony stimulating factor and the precursor of the secondary amyloid protein AA. Therefore, the initiation of LPS responses in different cell types in mice involve the expression of a common locus. These linkage studies provide a means for analyzing the genetic control of many of the diverse reactions of the endotoxic response to LPS.


Hearing sensitivity and amplitude coding in bats are differentially shaped by echolocation calls and social calls.
Differences in auditory perception between species are influenced by phylogenetic origin and the perceptual challenges imposed by the natural environment, such as detecting prey- or predator-generated sounds and communication signals. Bats are well suited for comparative studies on auditory perception since they predominantly rely on echolocation to perceive the world, while their social calls and most environmental sounds have low frequencies. We tested if hearing sensitivity and stimulus level coding in bats differ between high and low-frequency ranges by measuring auditory brainstem responses (ABRs) of 86 bats belonging to 11 species. In most species, auditory sensitivity was equally good at both high- and low-frequency ranges, while amplitude was more finely coded for higher frequency ranges. Additionally, we conducted a phylogenetic comparative analysis by combining our ABR data with published data on 27 species. Species-specific peaks in hearing sensitivity correlated with peak frequencies of echolocation calls and pup isolation calls, suggesting that changes in hearing sensitivity evolved in response to frequency changes of echolocation and social calls. Overall, our study provides the most comprehensive comparative assessment of bat hearing capacities to date and highlights the evolutionary pressures acting on their sensory perception.


The pivotal role of nitric oxide for vascular health.
The endothelium is a single cell layer that lines all blood vessels. This tissue produces an impressive array of paracrine factors that maintain vascular homeostasis. One of these factors is the potent vasodilator endothelium-derived nitric oxide (NO). Impairment in the synthesis or bioactivity of NO, as manifested by reduced endothelium-dependent vasodilation, has been shown to be an independent risk factor for major adverse cardiovascular events. The linkage between endothelium-derived NO and cardiovascular health is likely due to the pleiotropic effects of NO on the vessel wall. NO inhibits the proliferation of vascular smooth muscle cells, the aggregation of platelets, and the adherence and infiltration of inflammatory cells. Thus, an impairment of NO bioactivity or synthesis will reduce its braking effect on processes involved in atherogenesis. New insights have been made regarding the mechanisms by which NO bioactivity becomes impaired. Cardiovascular risk factors induce vascular oxidative stress, which accelerates the degradation of NO. In addition, oxidative stress causes the accumulation of asymmetric dimethylarginine (ADMA). ADMA is an endogenous inhibitor of NO synthesis. Elevation of ADMA appears to be a common mediator by which cardiovascular risk factors impair NO synthesis. Elevation of plasma ADMA has been linked to impaired endothelium-dependent vasodilation, carotid intimal thickening and adverse cardiovascular events. A number of modern therapies directed against atherosclerosis also improve the function of the NO synthase pathway. New agents that specifically target the NO synthase pathway have been developed, and represent a new front on the war against heart disease.


Proinsulin Secretion Is a Persistent Feature of Type 1 Diabetes.
Abnormally elevated proinsulin secretion has been reported in type 2 and early type 1 diabetes when significant C-peptide is present. We questioned whether individuals with long-standing type 1 diabetes and low or absent C-peptide secretory capacity retained the ability to make proinsulin. C-peptide and proinsulin were measured in fasting and stimulated sera from 319 subjects with long-standing type 1 diabetes (≥3 years) and 12 control subjects without diabetes. We considered three categories of stimulated C-peptide: 1) C-peptide positive, with high stimulated values ≥0.2 nmol/L; 2) C-peptide positive, with low stimulated values ≥0.017 but <0.2 nmol/L; and 3) C-peptide <0.017 nmol/L. Longitudinal samples were analyzed from C-peptide-positive subjects with diabetes after 1, 2, and 4 years. Of individuals with long-standing type 1 diabetes, 95.9% had detectable serum proinsulin (>3.1 pmol/L), while 89.9% of participants with stimulated C-peptide values below the limit of detection (<0.017 nmol/L; n = 99) had measurable proinsulin. Proinsulin levels remained stable over 4 years of follow-up, while C-peptide decreased slowly during longitudinal analysis. Correlations between proinsulin with C-peptide and mixed-meal stimulation of proinsulin were found only in subjects with high stimulated C-peptide values (≥0.2 nmol/L). Specifically, increases in proinsulin with mixed-meal stimulation were present only in the group with high stimulated C-peptide values, with no increases observed among subjects with low or undetectable (<0.017 nmol/L) residual C-peptide. In individuals with long-duration type 1 diabetes, the ability to secrete proinsulin persists, even in those with undetectable serum C-peptide.


Insights into next generation sequencing guided antibody selection strategies.
Therapeutic antibody discovery often relies on in-vitro display methods to identify lead candidates. Assessing selected output diversity traditionally involves random colony picking and Sanger sequencing, which has limitations. Next-generation sequencing (NGS) offers a cost-effective solution with increased read depth, allowing a comprehensive understanding of diversity. Our study establishes NGS guidelines for antibody drug discovery, demonstrating its advantages in expanding the number of unique HCDR3 clusters, broadening the number of high affinity antibodies, expanding the total number of antibodies recognizing different epitopes, and improving lead prioritization. Surprisingly, our investigation into the correlation between NGS-derived frequencies of CDRs and affinity revealed a lack of association, although this limitation could be moderately mitigated by leveraging NGS clustering, enrichment and/or relative abundance across different regions to enhance lead prioritization. This study highlights NGS benefits, offering insights, recommendations, and the most effective approach to leverage NGS in therapeutic antibody discovery.