Electron transfer pathways in a light, oxygen, voltage (LOV) protein devoid of the photoactive cysteine.
Blue-light absorption by the flavin chromophore in light, oxygen, voltage (LOV) photoreceptors triggers photochemical reactions that lead to the formation of a flavin-cysteine adduct. While it has long been assumed that adduct formation is essential for signaling, it was recently shown that LOV photoreceptor variants devoid of the photoactive cysteine can elicit a functional response and that flavin photoreduction to the neutral semiquinone radical is sufficient for signal transduction. Currently, the mechanistic basis of the underlying electron- (eT) and proton-transfer (pT) reactions is not well understood. We here reengineered pT into the naturally not photoreducible iLOV protein, a fluorescent reporter protein derived from the Arabidopsis thaliana phototropin-2 LOV2 domain. A single amino-acid substitution (Q489D) enabled efficient photoreduction, suggesting that an eT pathway is naturally present in the protein. By using a combination of site-directed mutagenesis, steady-state UV/Vis, transient absorption and electron paramagnetic resonance spectroscopy, we investigate the underlying eT and pT reactions. Our study provides strong evidence that several Tyr and Trp residues, highly conserved in all LOV proteins, constitute the eT pathway for flavin photoreduction, suggesting that the propensity for photoreduction is evolutionary imprinted in all LOV domains, while efficient pT is needed to stabilize the neutral semiquinone radical.


Method of detection of breast cancer in low-income women.
Breast cancer is the most common malignancy among women, and its timely diagnosis and treatment are of paramount importance, especially for vulnerable groups, such as low-income and uninsured women. Recent literature confirms that the method of breast cancer detection may be an important prognostic factor, but there are no studies that examine the method of breast cancer detection in low-income populations. We sought to analyze the determinants of method of detection (medical vs. self) in a cohort of low-income women with breast cancer receiving care through California's Breast and Cervical Cancer Treatment Program. This is a cross-sectional survey analysis of 921 low-income women interviewed within 6 months of definitive surgical treatment. The outcome analyzed was self vs. medical detection of breast cancer. The mean age of the women was 53 years, with nearly 88% reporting an income of <$30,000 per year; 64% of women self-detected their breast cancer. Logistic regression analyses revealed that older women, Latinas, and women having any health insurance before diagnosis had lower odds of self-detecting their lesions. Patient age, ethnicity, and regular source of care were associated with method of breast cancer detection in a low-income underserved population. The rate of self-detection in our population correlates with the literature, but we need to improve efforts to increase mammography screening to ensure early detection of disease in this vulnerable group.


Improving care for cardiac patients with heart arrhythmias.
Sue Armstrong, Advanced Clinical Practitioner, University Hospitals of Leicester NHS Trust (email@example.com), won a Bronze Award in the Cardiovascular Nurse of the Year Category in the BJN Awards 2023.


Response of cutaneous A- and C-fiber nociceptors in the monkey to controlled-force stimuli.
The goal of this study was to determine the capacity of primary afferent nociceptive fibers (nociceptors) to encode information about noxious mechanical stimuli in primates. Teased-fiber techniques were used to record from 14 A-fiber nociceptors and 18 C-fiber nociceptors that innervated the hairy skin. Stimulus-response functions were examined with an ascending series of force-controlled stimuli. Stimulus-interaction effects were examined with use of a series of paired stimuli in which the interval between the stimulus pairs was varied systematically. Both A-fiber and C-fiber nociceptors exhibited a slowly adapting response to the stepped force stimuli. The response of the A fibers increased monotonically with increasing force, whereas the response of the C fibers reached a plateau at low force levels. The slope of the stimulus-response function for the A fibers was significantly steeper than that for the C fibers, and the total response was greater. The A fibers also provided more discriminative information regarding stimulus intensity. The C fibers demonstrated a significant fatigue in response when the interstimulus interval between the paired stimuli was </=150 s, whereas the A fibers did not demonstrate a significant fatigue until the interstimulus interval was </=30 s. This fatigue in response was not due to changes in tissue compliance. These results suggest that A- and C-fiber nociceptors have different mechanical transduction mechanisms. A-fiber nociceptors exhibit steeper stimulus-response functions and less fatigue than C-fiber nociceptors.


Sulfomucins in the human body.
Mucins are widely distributed in mucous secretion fluids or are associated with plasma membranes. Up to now 9 genes of epithelial mucins have been identified, distributed over five chromosomes. Superposed on the genetic diversity, each type of mucin displays heterogeneity in oligosaccharide composition, including the terminal sugar residues. On top of that there is variation between individuals brought about by blood group antigens. Heterogeneity is further incited by the degree of sulfation. This tremendous structural heterogeneity endows mucin molecules with properties suggestive for a multifunctional role. The major biological function assigned to mucins is still the protection of tissues covered by the mucous gel. Current knowledge on the specific biological functions of the sulfate residues is fragmentary and periphrastic. Glycosylation including sulfation appears to be subject to modification under pathological conditions. There is evidence that sulfation rate-limits bacterial degradation of mucins. Moreover, accumulating data focus towards their involvement in recognition phenomena. Sulfate residues on blood group related structures provoke specific epitopes for selective interaction with microorganisms e.g. Helicobacter pylori. A distinct class of mucins acts as ligands for selectins, crucial in cellular recognition processes like cellular homing of lymphocytes. Whereas in earlier days mucins were only seen as water-binding molecules, protecting the underlying mucosa against harmful agents, the current picture of these molecules is characterized by the selective interaction with their environment, including epithelial-, and endothelial cells and microorganisms, thereby regulating a great number of biological processes. However, the specific role of sulfate remains to be further elucidated.


Robot-assisted laparoscopic pyeloplasty (RALP) in children with horseshoe kidneys: results of a multicentric study.
This multicentric study aimed to report our experience with robot-assisted laparoscopic pyeloplasty (RALP) in children with horseshoe kidney (HSK). The records of 14 patients (11 boys and 3 girls with an average age of 9 years), who underwent RALP for repair of pelvi-ureteric junction obstruction (PUJO) in HSK in five international pediatric urology units over a 5-year period, were retrospectively reviewed. A dismembered pyeloplasty with no division of isthmus was performed in all the cases. The average operative time including docking was 143.5 min (range 100-205). No conversions to laparoscopy or open surgery or intra-operative complications occurred. Patients were discharged on postoperative day 2 following catheter and drain removal. The JJ stent was removed at mean 33 days postoperatively. Overall success rate was 92.8%. As for postoperative complications, we recorded a urinary tract infection (UTI) and stent-related irritative symptoms, managed with medical therapy, in two patients (II Clavien) and an anastomotic stricture in one patient needing surgical revision with no further recurrence (IIIb Clavien). At follow-up, all the patients (one after redo-surgery) reported complete resolution of symptoms, improvement of hydronephrosis on ultrasound and no residual obstruction on diuretic renogram. Our experience suggested that RALP in HSK is safe, feasible and with good medium-term outcomes in expert hands. An accurate pre-operative planning associated with a standardized technique is key points to achieve good surgical and functional outcomes in these challenging cases. The da Vinci robot technology offers the advantages of MIS procedures and overcomes the technical challenges of laparoscopic approach.


Unicentric Castleman's disease associated with end stage renal disease caused by amyloidosis.
Castleman's disease (CD), also known as angiofolicular lymph node hyperplasia, is a rare heterogenous group of lymphoproliferative disorders. Histologically, it can be classified as hyaline vascular type, plasma cell type, or mixed type. Clinically two different subtypes of the CD are present: Unicentric and multicentric. Unicentric CD is generally asymptomatic and associated with hyaline vascular type, and its diagnoses depend on the localized lymphadenopathy on examination or imaging studies. However, multicentric CD presents with generalized lymphadenopathy and systemic symptoms including malaise, fever, night sweats, weight loss, and it is associated with the plasma cell type and mix type. Herein, we report a patient with unicentric CD of the plasma cell type without systemic symptoms, who developed end stage renal failure caused by amyloidosis 6 years after onset of CD.


Why is a verb like an inanimate object? Grammatical category and semantic category deficits.
Semantic category effects, such as difficulties in naming animate things relative to inanimate objects, have been explained in terms of the relative weightings of perceptual and functional features within the semantic representations of these concepts. We argue that grammatical category deficits, such as difficulties in naming nouns relative to verbs, can be explained within the same framework. We hypothesize that verb concepts are richer in functional than sensory features and present a model of the semantic representations of animate nouns, inanimate nouns, and verbs. The model demonstrates that sensory feature damage results in a deficit for naming living things but spares verb naming, and functional feature damage results in a deficit for naming inanimate objects and verbs. We then report the assessment results of two patient groups. In accordance with the model's predictions, the "verb spared" patients were consistently worse at naming living things than inanimate objects, and their definitions of both living and nonliving items were lacking in sensory information. We conclude that damage to sensory features in semantic representations causes difficulties in naming concrete nouns relative to action verbs, and within the grammatical category of nouns, animate items will be more severely affected. Imageability was shown to be a strong predictor of naming performance in the "verb deficit" patients, and when this variable was controlled no class effect remained. Production of definitions revealed no differential damage to sensory or functional features, and no consistent effect of animacy in naming was shown. While the model suggests that verb deficits might occur in patients for whom functional features are damaged relative to sensory features, we conclude that the "verb deficit" shown in our patients (and potentially in many previously reported cases) was an artifact of the lower imageability of verbs in confrontation naming tasks.


Conformation change of an isotactic poly (N-isopropylacrylamide) membrane: Molecular dynamics.
In this work, isotactic Poly (N-Isopropylacrylamide)-PNIPAM-in neat water and in electrolyte solutions is studied by means of molecular dynamics simulations. This is done for an infinitely diluted oligomer and for an assembly of several PNIPAM chains arranged into a planar membrane configuration with a core-shell morphology. We employed two different force fields, AMBER (assisted model building with energy refinement) and OPLS-AA (all atom - optimized potentials for liquid simulations) in combination with extended simple point charge water. Despite the more water insoluble character of isotactic oligomers, our results support the existence of a coil to globule transition for the isolated 30-mer. This may imply the existence of an oligomer rich phase of coil-like structures in equilibrium with a water rich phase for temperatures close but below the coil to globule transition temperature, TΘ. However, the obtained coil structure is much more compact than that corresponding to the syndiotactic chain. Our estimations of TΘ are (308±5) K and (303±5) K for AMBER and OPLS-AA, respectively. The membrane configuration allows one to include chain-chain interactions, to follow density profiles of water, polymer, and solutes, and accessing the membrane-water interface tension. Results show gradual shrinking and swelling of the membrane by switching temperature above and below TΘ, as well as the increase and decrease of the membrane-water interface tension. Finally, concentration profiles for 1M NaCl and 1M NaI electrolytes are shown, depicting a strong salting-out effect for NaCl and a much lighter effect for NaI, in good qualitative agreement with experiments.


Proximity effects and exchange bias in Co/MnF2(111) heterostructures studied by x-ray magnetic circular dichroism.
Cobalt nano-structured ultrathin films were grown on orthorhombic MnF(2) by molecular beam epitaxy on CaF(2) epitaxial layers deposited on Si(111) substrates. The Co film was grown at room temperature. It was found to be polycrystalline, forming nano-islands with height≈diameter≤10 nm. X-ray absorption evidences the chemical stability of the Co/MnF(2) interface. Remarkably, x-ray magnetic circular dichroism (XMCD) demonstrates that the Co induces a net magnetization on the Mn ions close to the interface. The magnetic moments of these Mn ions couple antiparallel to the Co and rotate upon field reversal following the magnetization of the Co both below and high above the Néel temperature of MnF(2) (T(N) = 67 K). The density of coupled Mn moments is found to be temperature dependent, with an equivalent thickness of ~1.5 MnF(2) monolayers at 20 K, decreasing to about ~0.5 ML as the temperature is raised to 300 K. Interestingly, the intensity of the Mn XMCD signal appears to be related to the coercivity of the Co layer. This behavior is interpreted in terms of the competition between thermal fluctuations, exchange coupling between Co and Mn at the interface and, at low temperature, the antiferromagnetic order in MnF(2).


Development of Dyslexia: The Delayed Neural Commitment Framework.
It is now evident that explanations of many developmental disorders need to include a network perspective. In earlier work, we proposed that developmental dyslexia (DD) is well-characterized in terms of impaired procedural learning within the language networks, with the cerebellum being the key structure involved. Here, we deepen the analysis to include the child's developmental process of constructing these networks. The "Delayed Neural Commitment (DNC)" framework proposes that, in addition to slower skill acquisition, dyslexic children take longer to build (and to rebuild) the neural networks that underpin the acquisition of reading. The framework provides an important link backwards in time to the development of executive function networks and the earlier development of networks for language and speech. It is consistent with many theories of dyslexia while providing fruitful suggestions for further research at the genetic, brain, cognitive and behavioral levels of explanation. It also has significant implications for assessment and teaching.


Pineal denervation by cervical sympathetic ganglionectomy suppresses the role of photoperiod on pregnancy or pseudopregnancy, body weight and moulting periods in the mink (Mustela vison).
In mink, termination of the delayed implantation period, following reactivation of the corpora lutea, and onset of the spring moult are associated with a rise in prolactin secretion triggered by increasing daylength, while decreasing daylength induces the autumn moult. To establish whether suppression of the function of the pineal rendered the mink unresponsive to daylength changes, the superior cervical ganglion was removed bilaterally 2-4 weeks before mating. Intact and operated females were then left outdoors or were put under a lighting regime of either 15 h light:9 h darkness (15L:9D) or 8L:16D. In July, at the end of the spring moult, the 15L:9D lighting regime was changed to one of 8L:16D. Under artificial photoperiods ganglionectomy suppressed the stimulatory role of long days and the inhibitory role of short days on prolactin secretion, and consequently on progesterone secretion and spring moult. Neither was the autumn moult, induced early in intact females by the change to a short photoperiod, advanced in ganglionectomized females, showing that the latter were unresponsive to the artificial modification of the photoperiod. However, in animals kept outdoors, prolactin and progesterone secretion and spring moult were not changed by ganglionectomy. Increase in body weight and autumn moult were only slightly delayed by the operation suggesting that other environmental factors had replaced the synchronizing effect of the daylength changes. Alternatively the desynchronization between intact females responsive to photoperiodism and those rendered unresponsive may be too slow to be observed soon after ganglionectomy.


Knowledge and acceptability of pap smears, self-sampling and HPV vaccination among adult women in Kenya.
Our study aimed to assess adult women's knowledge of human papillomavirus (HPV) and cervical cancer, and characterize their attitudes towards potential screening and prevention strategies. Women were participants of an HIV-discordant couples cohort in Nairobi, Kenya. An interviewer-administered questionnaire was used to obtain information on sociodemographic status, and sexual and medical history at baseline and on knowledge and attitudes towards Pap smears, self-sampling, and HPV vaccination at study exit. Only 14% of the 409 women (67% HIV-positive; median age 29 years) had ever had a Pap smear prior to study enrollment and very few women had ever heard of HPV (18%). Although most women knew that Pap smears detect cervical cancer (69%), very few knew that routine Pap screening is the main way to prevent ICC (18%). Most women reported a high level of cultural acceptability for Pap smear screening and a low level of physical discomfort during Pap smear collection. In addition, over 80% of women reported that they would feel comfortable using a self-sampling device (82%) and would prefer at-home sample collection (84%). Nearly all women (94%) reported willingness to be vaccinated to prevent cervical cancer if offered at no or low cost. These findings highlight the need to educate women on routine use of Pap smears in the prevention of cervical cancer and demonstrate that vaccination and self-sampling would be acceptable modalities for cervical cancer prevention and screening.


Matrix control of scarring.
Repair of wounds usually results in restoration of organ function, even if suboptimal. However, in a minority of situations, the healing process leads to significant scarring that hampers homeostasis and leaves the tissue compromised. This scar is characterized by an excess of matrix deposition that remains poorly organized and weakened. While we know much of the early stages of the repair process, the transition to wound resolution that limits scar formation is poorly understood. This is particularly true of the inducers of scar formation. Here, we present a hypothesis that it is the matrix itself that is a primary driver of scar, rather than being simply the result of other cellular dysregulations.


The Prevalence of Malnutrition and Effectiveness of STRONGkids Tool in the Identification of Malnutrition Risks among Pediatric Surgical Patients.
High prevalence of malnutrition along with the risk for the development of malnutrition in hospitalised children has been reported. However, this problem remains largely unrecognised by healthcare workers. To determine the prevalence of malnutrition and effectiveness of STRONGkids nutritional risk screening (NRS) tool in the identification of malnutrition risk among pediatric surgical patients. Cross-sectional study. A total of 494 pediatric surgical patients (median age 59 months, 75.8% males) were included in this prospective study conducted over 3 months. SD-scores <-2 for Body Mass Index (BMI) for age or weight-for-height (WFH) and height-for-age (HFA) were considered to indicate acute and chronic malnutrition, respectively. The STRONGkids NRS tool was used to determine risk for malnutrition. Malnutrition was detected in 13.4% in this group of pediatric surgical patients. Acute malnutrition was identified in 10.1% of patients and more commonly in patients aged ≤60 months than aged >60 months (13.4 vs. 6.6%, p=0.012). Chronic malnutrition was identified in 23 (4.6%) of patients with no significant difference between age groups. There were 7 (1.4%) children with coexistent acute and chronic malnutrition. The STRONGkids tool revealed that 35.7% of patients were either in the moderate or high risk group for malnutrition. Malnutrition, as revealed by anthropometric measurements, was more likely in the presence of gastrointestinal (26.9%, p=0.004) and inguinoscrotal/penile surgery (4.0%, p=0.031), co-morbidities affecting nutritional status (p<0.001) and inpatient admissions (p=0.014). Among patients categorized as low risk for malnutrition, there were more outpatients than inpatients (89.3 vs. 10.7%, p<0.001) and more elective surgery cases than emergency surgery cases (93.4 vs. 6.6%, p<0.001). Providing data on the prevalence of malnutrition and risk of malnutrition in a prospectively recruited group of hospitalised pediatric surgical patients, the data acquired in the present study emphasise the need to raise clinician's awareness about the importance of nutritional status assessment among hospitalised pediatric patients and the benefits of identifying patients at the risk of nutritional depletion before malnutrition occurs. Our findings support the use of the STRONGkids tool among pediatric surgical patients to identify patients at risk for malnutrition and to increase the physician's awareness of nutritional assessment among hospitalised patients upon admission.


Association between the XRCC1 polymorphisms and clinical outcomes of advanced NSCLC treated with platinum-based chemotherapy: a meta-analysis based on the PRISMA statement.
Base excision repair (BER) pathway is a DNA repair pathway that is important in carcinogenesis and in response to DNA-damaging chemotherapy. XRCC1 is one of important molecular markers for BER. So far, the role of XRCC1 polymorphisms with clinical outcomes of advanced NSCLC treated with platinum-based chemotherapy is inconclusive. To explore the relationship between XRCC1 polymorphisms and platinum-based chemotherapy in advanced NSCLC patients, we performed this meta-analysis. Crude odds ratios (ORs), Cox proportional hazard ratios (HRs) with the corresponding 95% confidence intervals (CIs) were adopted to assess the strength of association between XRCC1 polymorphisms and response rate, Overall survival (OS) and progression free survival (PFS) of advanced NSCLC treated with platinum-based chemotherapy. Q test and I 2 test were used for the assessment of heterogeneity. Subgroup analyses were conducted when heterogeneity exists. Begg's funnel plots and Egger's linear regression test were used to estimate publication bias. Sensitivity analysis was performed to evaluate the stability of the result. A total of 19 studies including 2815 individuals were eligible for the analysis, results showed XRCC1 194Arg allele was negatively associated with the objective response rate relative to 194Trp, and results of homozygous model, dominant model and heterozygous model suggested a gene dosage effect negative correlation between 194Arg allele and objective response rate(ArgArg vs TrpTrp: OR = 0.64(95%CI: 0.44-0.91); ArgArg + TrpArg vs TrpTrp: OR = 0.79(95%CI: 0.57-1.11); TrpArg vs TrpTrp: OR = 1.05(95%CI: 0.73-1.51)). XRCC1 399Gln may indicate favorable overall survival (GlnGln + GlnArg vs ArgArg: HR = 0.65(95%CI: 0.43-0.98)) and favorable PFS (GlnGln vs ArgArg: HR = 0.72(95%CI: 0.48-0.97)) in Asian patients; while in Caucasian patients, XRCC1 399Gln indicated poorer overall survival (GlnGln vs ArgArg: HR = 2.29(95%CI: 1.25-3.33)). Our results indicated that in NSCLC patients treated with platinum-based regimen, XRCC1 194Arg allele suggest poor objective response rate, the GlnGln genotype of XRCC1 399 suggest poorer overall survival in Caucasian patients, and longer PFS in Asian patients.


Metal-organic frameworks based on uranyl and phosphonate ligands.
Three new crystalline metal-organic frameworks have been prepared from the reaction of uranyl nitrate with nitrilotris(methylphosphonic acid) [H6nmp, N(CH2PO3H2)3], 1,4-phenylenebis(methylene)diphosphonic acid [H4pmd, C6H4(PO3H2)2], and (benzene-1,3,5-triyltris(methylene))triphosphonic acid [H6bmt, C6H3(PO3H2)3]. Compound [(UO2)2F(H3nmp)(H2O)]·4H2O (I) crystallizes in space group C2/c, showing two crystallographically independent uranyl centres with pentagonal bipyramidal coordination geometries. While one metal centre is composed of a {(UO2)O3(μ-F)}2 dimer, the other comprises an isolated {(UO2)O5} polyhedron. Compound [(UO2)(H2pmd)] (II) crystallizes in space group P21/c, showing a centrosymmetric uranyl centre with an octahedral {(UO2)O4} coordination geometry. Compound [(UO2)3(H3bmt)2(H2O)2]·14H2O (III) crystallizes in space group P\bar 1, showing two crystallographically independent uranyl centres. One uranyl centre is a {(UO2)O5} pentagonal bipyramid similar to that in (I), while the other is a {(UO2)O4} centrosymmetric octahedron similar to that in (II). Compounds (I) and (III) contain solvent-accessible volumes accounting for ca 23.6 and 26.9% of their unit-cell volume, respectively. In (I) the cavity has a columnar shape and is occupied by disordered water molecules, while in (III) the cavity is a two-dimensional layer with more ordered water molecules. All compounds have been studied in the solid state using FT-IR spectroscopy. Topological studies show that compounds (I) and (III) are trinodal, with 3,6,6- and 4,4,6-connected networks, respectively. Compound (II) is instead a 4-connected uninodal network of the type cds.


[Unique tissue differentiation in peripheral nervous system tumors (glandular neurofibroma)].
A rare observation of glandular differentiation in neurofibroma of the right orbit is described. Data on another 7 similar tumors reported in the literature are presented. The problems of histogenesis of such neoplasias and difficulties of their diagnosis are discussed. Glandular neurinomas and neurofibromas are characterized by a malignant course and trend for relapses favouring high lethality in this disease.


The multi-institutional validation of the new screening index for physical child abuse.
There is currently no evidence-based screening instrument to assist in the detection of physical child abuse patients. The screening index for physical child abuse (SIPCA) was previously developed as a potentially new tool for this need. It is a scale that assigns point values, on the basis of variable weights from logistic regression models, to age and patterns of injuries (including fracture of base or vault of skull, contusion of eye, rib fracture, intracranial bleeding, multiple burns), with higher scores indicating greater suspicion for abuse. The purpose of this study is to validate this new tool in another independent data set. A cross-sectional hospital discharge database from 1961 hospitals in 17 states is used (n = 58558). Children aged 14 years or younger with International Classification of Diseases, Ninth Revision, Clinical Modification codes 800 to 959 are included for analysis. Child abuse cases are identified by E codes and certain International Classification of Diseases, Ninth Revision, Clinical Modification codes in the 995.5x range. Screening index for physical child abuse performance is evaluated by discrimination (receiver operating characteristic) and goodness of fit (pseudo r2). A total of 447 abused patients (0.76%) was identified. The receiver operating characteristic of SIPCA in this data set is 0.89 as compared with 0.86 in the development data set. The pseudo r 2 of SIPCA in this data set is 0.26 as compared with 0.28 in the development data set. A SIPCA score of 3 has a sensitivity of 86.6% and a specificity of 80.5% for detecting physical abuse; raising the threshold to a score of 4 improves the specificity to 93.1% but at a loss of sensitivity to 71.8%. The validity of the new SIPCA instrument is supported by its performance in an independently derived data set. A score of 3 on SIPCA represents a balanced trade off in the sensitivity and specificity of the instrument in detecting physical abuse and is an optimal threshold above which to begin considering abuse in differential diagnosis. Application of the instrument could assist clinicians in detecting physical child abuse cases among pediatric trauma patients.


Conscious sedation with combined hypnotic agents for implantation of implantable cardioverter-defibrillators.
The objective of this study was to evaluate the feasibility, safety and efficacy of placing implantable cardioverter-defibrillators (ICDs) in the electrophysiology laboratory using conscious sedation with combined hypnotic agents and deep sedation with etomidate. Implantable cardioverter-defibrillators with transvenous leads permit the use of simplified implantation techniques similar to those used for the insertion of permanent pacemakers. However, implantation of ICDs without general anesthesia has thus far gained limited acceptance. In 162 patients, conscious sedation during ICD placement was achieved with combined intravenous midazolam, morphine and promethazine (Phenergan). Intravenous etomidate was administered to induce deep sedation for defibrillation threshold testing. First-time implantations were in the prepectoral position (n = 142), but some patients with preexisting devices received abdominal implants (n = 20). The results were compared with those of concurrent patients (n = 56) who received prepectoral implants under propofol anesthesia administered by an attending anesthesiologist. The anesthetic protocol was implemented without major intraoperative complications. During deep sedation with etomidate, episodes of apnea, hypoxia or arterial hypotension requiring therapeutic intervention did not occur. During a mean (+/-SD) follow-up period of 257 +/- 140 days (median 227, range 14 to 482), there were, among the 162 patients, a total of two nonsudden cardiac deaths-one 71 days and the other 157 days after the operation. There were two nonsudden deaths in the concurrent control subjects (n = 56)-one 13 days and the other 110 days after the operation. Implantation of ICDs under conscious sedation with combined hypnotic agents and deep sedation with etomidate is a safe and effective procedure with low perioperative morbidity and low long-term complication rates.


Identification of broad-based HIV-1 protease inhibitors from combinatorial libraries.
Clinically approved inhibitors of the HIV-1 protease function via a competitive mechanism. A particular vulnerability of competitive inhibitors is their sensitivity to increases in substrate concentration, as may occur during virion assembly, budding and processing into a mature infectious viral particle. Advances in chemical synthesis have led to the development of new high-diversity chemical libraries using rapid in-solution syntheses. These libraries have been shown previously to be effective at disrupting protein-protein and protein-nucleic acid interfaces. We have screened 44000 compounds from such a library to identify inhibitors of the HIV-1 protease. One compound was identified that inhibits wild-type protease, as well as a drug-resistant protease with six mutations. Moreover, analysis of this compound suggests an allosteric non-competitive mechanism of inhibition and may represent a starting point for an additional strategy for anti-retroviral therapy.


In vivo correlation of thermodilution cardiac output and videodensitometric indicator-dilution curves obtained from contrast two-dimensional echocardiograms.
In previous studies, indicator-dilution curves obtained by videodensitometry of contrast two-dimensional echocardiograms have shown close correlation with measurements of blood flow in vitro. In this study the technique was extended and contrast indicator-dilution curves obtained in vivo were correlated with simultaneous cardiac output measurements determined by thermodilution in eight dogs. Two-dimensional echocardiograms of the left ventricle were performed with the transducer on the myocardium during left atrial-pulmonary vein injection of 10 cc of a 1 X 10(-4) concentration of 30 mu diameter microballoons. A total of 148 injections were performed at 37 levels of cardiac output (1.70 to 7.90 liters/min) induced by alterations of left ventricular preload, isoproterenol and propranolol. Indicator-dilution curves were obtained from recordings of the analog signal of a linear videodensitometer focused on the left ventricle. Linear regression analysis between total area of the indicator-dilution curves and cardiac output yielded correlation coefficients (r) of 0.77 to 0.96 (mean 0.90) for individual dogs, and 0.65 for all cardiac output determinations in all dogs. Analysis of indicator-dilution curve area by the forward triangle-exponential decay method yielded enhanced individual coefficients of 0.90 to 0.97 (mean 0.94) with cardiac output and 0.61 for the group of animals. It is concluded that echographic indicator-dilution curves obtained from uniform size microballoons and videodensitometry may be obtained in vivo and correlate with cardiac output measurements.


Craniectomy position affects morris water maze performance and hippocampal cell loss after parasagittal fluid percussion.
Valid and reliable animal models are essential for mechanistic and therapeutic studies of traumatic brain injury (TBI). Therefore, model characterization is a continual and reciprocal process between the experimental laboratory and the clinic. Several excellent experimental models of TBI, including the lateral fluid percussion rat model, are currently in wide use in many neurotrauma laboratories. However, small differences in the position of lateral fluid percussion craniectomy are reported between labs. Additionally, differences in hippocampal cell death have also been reported. Therefore, we hypothesized that small changes in craniectomy position could affect commonly used outcome measures such as vestibulomotor function, Morris water maze (MWM) performance, hippocampal cell loss, and glial fibrillary acidic protein (GFAP) immunoreactivity. Four placements were systematically manipulated: rostral, caudal, medial, and lateral. The medial and caudal placements produced significantly greater impairments in the MWM acquisition task over the lateral and rostral placements. The rostral placement produced diffuse cortical damage but little hippocampal cell loss. In contrast, the medial, lateral, and caudal placements produced more mid-dorsally localized cortical damage and significant cell loss in the CA2/CA3 and hilus ipsilateral to the injury site. Furthermore, reactive astrocytosis was more pronounced in the medial, lateral, and caudal placements than in the rostral placement. All craniectomy position groups had similar durations of traumatic unconsciousness and similar impairment on motor tasks. We conclude that small alterations in craniectomy position produce differences in cognitive performance, hippocampal cell loss, and reactive astrocytosis but not in motor performance nor transient unconsciousness.


[The homosexual as a "molesting personality". Nikolaus Jensch and his psychiatric-genetic studies].
For the first time ever, this study presents facts on the biography of Nikolaus Jensch (1913 - 1964), who worked in Wroclav, Leipzig, Strasbourg and Bremen, and on his psychiatric-genetic studies on homosexuality during the Nazi regime. Jensch tried, under methodologically rather doubtful presuppositions, to separate "genuine" from so-called "pseudo-homosexuals", who for him were receptive to psychotherapeutic and educational intervention. Ultimately he aimed to establish an empiric prediction as to the heredity of homosexuality, although even that would not exculpate homosexuals from prosecution. In a different study he analysed the curing effects of castration for homosexuality and other sexual deviances. Although acknowledging the mutilating character of castration and its due to high recrudescence rates rather poor therapeutic outcome, he never pleaded to refrain from this intervention.


Neuropsychiatric Systemic Lupus Erythematosus: A Diagnostic Conundrum.
A 70-year-old man presented with complaints of rapid cognitive decline and new onset leukopenia. The patient had a 17-year history of refractory seizures. Detailed review of symptoms and investigations revealed the patient met American College of Rheumatology (ACR) diagnostic criteria for systemic lupus erythematosus (SLE). The patient had high titer ANA with a strongly positive dsDNA. Immunosuppressive therapy with hydroxychloroquine and mycophenolate mofetil led to significant improvement in cognition and seizures. Neuropsychiatric SLE should be considered a potential differential diagnosis for patients presenting with seizures or cognitive decline. Moreover, neuropsychiatric manifestations especially seizures are an early event in the disease course of SLE. Hence, we believe that early diagnosis of SLE by neuropsychiatric manifestations will not only lead to better control of CNS symptoms but early immunosuppressive therapy could control the progression of the underlying autoimmune disease.


Formulation development of SYN-004 (ribaxamase) oral solid dosage form, a β-lactamase to prevent intravenous antibiotic-associated dysbiosis of the colon.
SYN-004 (ribaxamase) delayed release drug product is a multi-particulate, hard capsule for oral delivery of a recombinant β-lactamase enzyme designed to degrade β-lactam antibiotics administered intravenously, and thus prevent colon dysbiosis. Here we describe the development of the SYN-004 enteric coated pellet formulation, which has been tested in multiple clinical trials. Since the SYN-004 drug substance is a buffered liquid, several binder excipients in different ratios were tested to facilitate binding of SYN-004 to sugar spheres. The binding systems were evaluated by droplet pre-evaluation and film casting tests. The most promising formulations were produced in small scale fluidized bed application runs and analyzed by dissolution tests and complementary analytical assays. Hydroxypropyl cellulose was selected as the preferred SYN-004 binding excipient. The formulation included a second, outer coat containing the enteric EUDRAGIT® L 30 D-55 polymer-based formulation to achieve gastric protection, and rapid SYN-004 release in the intestinal tract, when the pH rises above 5.5. Additional formulation improvements resulted in an increase in the SYN-004 load compared to a predecessor oral enzyme formulation (Ipsat P1A). Thus, a novel formulation and process for an orally administered enzyme was developed and used to manufacture drug product for clinical trials.


Human antiglobulin response to foreign antibodies: therapeutic benefit?
Immunotherapies for cancer offer attractive alternatives to conventional therapies although human anti-globulin antibody (HAGA) against the antibody (Ab) administered to the patient can be an obstacle to repeated treatment. Monoclonal antibodies (mAb), whether foreign or human in origin, have been used safely in patients for two decades. Adverse events have not proven to be significant clinical obstacles, although alterations of pharmacokinetic behavior of subsequently administered Ab can lead to less effective therapy. Not only is HAGA safe, but it can be associated with beneficial immunity in patients. Studies have shown that some patients have unexpectedly prolonged survival associated with HAGA. In our own non-Hodgkin's lymphoma (NHL) patients treated with mouse Lym-1 anti-lymphoma mAb, a high human anti-mouse Ab (HAMA) titer was associated with increased survival. The possible mechanisms linking HAMA responses to survival are likely related to Ab generated against the idiotopes of the administered Ab. An induced immune cascade in these patients, including anti-idiotypic Ab (Ab2) and cytotoxic Ab1' or Ab3 probably contributed to survival. In summary, HAGA should not a priori preclude the therapeutic use of Ab for cancer.


Deletion of alpha-, beta-, and omega-interferon genes in malignant cells from children with acute lymphocytic leukemia.
Scanning densitometry and restriction fragment length polymorphism analysis were used to study the alpha-, beta-, gamma-, and omega-interferon (IFN) genes in malignant cells from 11 children with acute lymphocytic leukemia and in one cell line of T-cell origin. In the malignant cells of one patient there was a complete loss of alpha-, beta-, and omega-IFN genes, whereas in another patient one of the alleles of these genes had been deleted. Cytogenetic analysis revealed a deletion of the short arm of chromosome 9, i.e., the region containing the alpha-, beta-, and omega-IFN genes, in the latter patient. The normal cells of the patients with IFN gene deletions had two alleles of the alpha-, beta-, and omega-IFN genes. In cells from none of the patients could deletions or rearrangements of the gamma-IFN genes be detected. We conclude that in 2 of 11 patients with acute lymphocytic leukemia the malignant transformation is accompanied by loss of material on one or both chromosomes 9 and that the alpha-, beta-, and omega-IFN genes are included in these deletions.


Clade classification of monolignol biosynthesis gene family members reveals target genes to decrease lignin in Lolium perenne.
In monocots, lignin content has a strong impact on the digestibility of the cell wall fraction. Engineering lignin biosynthesis requires a profound knowledge of the role of paralogues in the multigene families that constitute the monolignol biosynthesis pathway. We applied a bioinformatics approach for genome-wide identification of candidate genes in Lolium perenne that are likely to be involved in the biosynthesis of monolignols. More specifically, we performed functional subtyping of phylogenetic clades in four multigene families: 4CL, COMT, CAD and CCR. Essential residues were considered for functional clade delineation within these families. This classification was complemented with previously published experimental evidence on gene expression, gene function and enzymatic activity in closely related crops and model species. This allowed us to assign functions to novel identified L. perenne genes, and to assess functional redundancy among paralogues. We found that two 4CL paralogues, two COMT paralogues, three CCR paralogues and one CAD gene are prime targets for genetic studies to engineer developmentally regulated lignin in this species. Based on the delineation of sequence conservation between paralogues and a first analysis of allelic diversity, we discuss possibilities to further study the roles of these paralogues in lignin biosynthesis, including expression analysis, reverse genetics and forward genetics, such as association mapping. We propose criteria to prioritise paralogues within multigene families and certain SNPs within these genes for developing genotyping assays or increasing power in association mapping studies. Although L. perenne was the target of the analyses presented here, this functional subtyping of phylogenetic clades represents a valuable tool for studies investigating monolignol biosynthesis genes in other monocot species.


Effect of resection of localized pancreaticobiliary adenocarcinoma on angiogenic markers and tissue factor related pro-thrombotic and pro-angiogenic activity.
In this study, 52 patients were studied to elucidate the relative impact of resection of localized pancreaticobiliary adenocarcinoma (PBC) on circulating factors of tumour-associated angiogenesis e.g. tissue factor bearing microparticles (TFMP) and vascular endothelial growth factor (VEGF) and their clinicopathological significance to angiogenesis markers in cancer tissue from PBC patients. Angiogenesis array analysis on serum samples revealed that surgical resection of tumour lesion in PBC patients affects the levels of a panel of angiogenesis-related molecules, including VEGF that was verified by ELISA to significantly reduce (median & IQR: 1003(369-2000) vs. 457(159-834) pg/ml; p<0.05). Correspondingly, a significant decrease in the angiogenic activity (decreased capillary tube formation; p<0.05) of serum samples after the surgery was also found. Despite a decrease in number of circulating TFMP after surgery, this did not reach statistical significance; there was a significant reduction in pro-coagulant activity (prolonged prothrombin time, p<0.001) post-operatively. In addition, the activity of total microparticles (MP activity assay, p<0.05) was decreased significantly. Immunohistochemical staining of tumour tissue revealed a strong correlation between the microvessel density (MVD) and VEGF expression. Also, higher levels of circulating TFMP or TF related activity (prothrombin time) correlated significantly with TF expression and MVD on tumour tissues from PBC patients. These findings suggest that in pancreaticobiliary adenocarcinoma TF related angiogenesis drivers are equally significant to VEGF ones, raising the clinical question of whether the effectiveness of angiogenesis targeting studies could be improved through the 'dual' targeting of these pathways in PBC.


Open reduction and internal fixation of tibial pilon fractures.
Although it is evident that the fracture of the tibial plafond is a complex, often debilitating injury, its management is not clear. These injuries generally fall into one of two categories. The low-energy, rotational type of fracture has been shown to have excellent clinical and functional results with open reduction and internal fixation. The high-energy, compression type of fracture has had uniformly moderate results and historically high complication rates. Some authors think that bridging external fixation with or without limited internal fixation should be employed in high-energy fractures. Others believe that open reduction and internal fixation to avoid articular incongruence and development of axial malalignment is needed for good long-term outcome. The authors believe the latter. Staging the treatment of the patient can minimize development of soft tissue complications. The authors follow the recommendations of Patterson and Sirkin and believe that high-energy pilon fractures should be temporized with an external fixator with or without fibular plating to restore length. Any open would should be addressed at this time. Definitive fixation should be planned for between 10 and 14 days, by which time the soft tissue envelop is likely to be ready to accept the further insult of surgery. The surgical technique should be well planned for and include the use of meticulous soft tissue techniques and indirect reduction methods. With the proper attention to detail, long-term results will be maximized.


SOS2 modulates the threshold of EGFR signaling to regulate osimertinib efficacy and resistance in lung adenocarcinoma.
Son of sevenless 1 and 2 (SOS1 and SOS2) are RAS guanine nucleotide exchange factors (RasGEFs) that mediate physiologic and pathologic receptor tyrosine kinase (RTK)-dependent RAS activation. Here, we show that SOS2 modulates the threshold of epidermal growth factor receptor (EGFR) signaling to regulate the efficacy of and resistance to the EGFR tyrosine kinase inhibitor (EGFR-TKI) osimertinib in lung adenocarcinoma (LUAD). SOS2 deletion (SOS2KO ) sensitized EGFR-mutated cells to perturbations in EGFR signaling caused by reduced serum and/or osimertinib treatment to inhibit phosphatidylinositol 3-kinase (PI3K)/AKT pathway activation, oncogenic transformation, and survival. Bypassing RTK reactivation of PI3K/AKT signaling represents a common resistance mechanism to EGFR-TKIs; SOS2KO reduced PI3K/AKT reactivation to limit osimertinib resistance. In a forced HGF/MET-driven bypass model, SOS2KO inhibited hepatocyte growth factor (HGF)-stimulated PI3K signaling to block HGF-driven osimertinib resistance. Using a long-term in situ resistance assay, most osimertinib-resistant cultures exhibited a hybrid epithelial/mesenchymal phenotype associated with reactivated RTK/AKT signaling. In contrast, RTK/AKT-dependent osimertinib resistance was markedly reduced by SOS2 deletion; the few SOS2KO cultures that became osimertinib resistant primarily underwent non-RTK-dependent epithelial-mesenchymal transition (EMT). Since bypassing RTK reactivation and/or tertiary EGFR mutations represent most osimertinib-resistant cancers, these data suggest that targeting proximal RTK signaling, here exemplified by SOS2 deletion, has the potential to delay the development osimertinib resistance and enhance overall clinical responses for patients with EGFR-mutated LUAD.


[Comparative study of cyclic nucleotide phosphodiesterase activity in the rabbit and bovine heart].
Activities of cyclic nucleotide phosphodiesterases (PDE) were studied in partially purified preparations from bovine and rabbit heart tissues. The PDE activity from rabbit heart was not increased in the course of purification and remained distinctly lower as compared with the enzymatic activity from bovine heart. Specific chelating agent Ca2+-EGTA (5 X 10(-4)M) inhibited effectively the PDE activity from bovine heart both in the ammonium sulfate fraction and in the fractions obtained by means of gel filtration on Sepharose 6B, but affected only slightly the enzyme activity from rabbit heart. The enzyme from bovine heart appears to involve mainly the Ca2+-calmodulin -dependent form, while the enzyme from rabbit heart, isolated under similar conditions, was Ca2+-calmodulin -independent. Phenothiazine derivatives inhibited distinctly the PDE activity from bovine heart at 5 X 10(-5)M concentration, whereas they did not affect or affected only slightly the enzyme preparations from rabbit heart even at 1 X 10(-4)M concentration; the inhibition was of the calmodulin -unspecific type. Phenothiazine derivatives (inhibitors of the calmodulin activity) exhibited only slight effect on the Ca2+-calmodulin -independent PDE from rabbit heart. This enzyme could not be used in studies of drugs, the effect of which is realized via regulation of the enzymatic activity by means of Ca2+ and calmodulin.


Survival analysis with error-prone time-varying covariates: a risk set calibration approach.
Occupational, environmental, and nutritional epidemiologists are often interested in estimating the prospective effect of time-varying exposure variables such as cumulative exposure or cumulative updated average exposure, in relation to chronic disease endpoints such as cancer incidence and mortality. From exposure validation studies, it is apparent that many of the variables of interest are measured with moderate to substantial error. Although the ordinary regression calibration (ORC) approach is approximately valid and efficient for measurement error correction of relative risk estimates from the Cox model with time-independent point exposures when the disease is rare, it is not adaptable for use with time-varying exposures. By recalibrating the measurement error model within each risk set, a risk set regression calibration (RRC) method is proposed for this setting. An algorithm for a bias-corrected point estimate of the relative risk using an RRC approach is presented, followed by the derivation of an estimate of its variance, resulting in a sandwich estimator. Emphasis is on methods applicable to the main study/external validation study design, which arises in important applications. Simulation studies under several assumptions about the error model were carried out, which demonstrated the validity and efficiency of the method in finite samples. The method was applied to a study of diet and cancer from Harvard's Health Professionals Follow-up Study (HPFS).


[Diagnosis of neurocysticercosis by immunoenzymatic staining technique (IEST) with frozen sections of Cysticercus cellulosae].
This article deals with the sensitivity and specificity of IEST in neurocysticercosis with frozen sections of Cysticerus cellulosae as antigens. 55 out of 56 cases (98.2%) of neurocysticercosis showed positive reaction. All serum specimens from healthy human controls (50 cases), clonorchiasis (23 cases) and paragonimiasis (26 cases) were negative, but 18% (4/22) of serum specimens from echinococcosis revealed positive reactions. The results indicate that IEST is specific, sensitive, economical and easy to perform for the diagnosis of neurocysticercosis.


Case report: painful peripheral neuropathy following treatment with docetaxel for breast cancer.
Peripheral neuropathy is a common side effect of many chemotherapy agents. As many as 60% of patients receiving taxane therapy report symptoms such as numbness, tingling, burning, pain, and, in severe cases, weakness in a stocking and glove pattern. These symptoms are associated with problems in physical mobility and decreased quality of life, yet few articles in the literature discuss collaborative interdisciplinary assessment and treatment of this population. This article describes the care of a patient with diabetes and docetaxel-induced, painful peripheral neuropathy by a multidisciplinary team of nurses, physicians, and physical therapists. Because nurses are often the first clinicians to recognize symptoms of chemotherapy-induced peripheral neuropathy, they provide the essential coordination of care by appropriate medical and rehabilitative services. This case also raises important questions about the relationship between diabetes mellitus and persistent, painful peripheral neuropathy.


Multiplexed protein array platforms for analysis of autoimmune diseases.
Several proteomics platforms have emerged in the past decade that show great promise for filling in the many gaps that remain from earlier studies of the genome and from the sequencing of the human genome itself. This review describes applications of proteomics technologies to the study of autoimmune diseases. We focus largely on biased technology platforms that are capable of analyzing a large panel of known analytes, as opposed to techniques such as two-dimensional gel electrophoresis (2DIGE) or mass spectroscopy that represent unbiased approaches (as reviewed in 1). At present, the main analytes that can be systematically studied in autoimmunity include autoantibodies, cytokines and chemokines, components of signaling pathways, and cell-surface receptors. We review the most commonly used platforms for such studies, citing important discoveries and limitations that exist. We conclude by reviewing advances in biomedical informatics that will eventually allow the human proteome to be deciphered.


Zebularine-induced reduction in VEGF secretion by HIF-1α degradation in oral squamous cell carcinoma.
Vascular endothelial growth factor (VEGF) is a potent inducer of angiogenesis in oral squamous cell carcinoma (OSCC). In this study, we used the novel DNA methyltransferase inhibitor zebularine (Zeb) to investigate epigenetic influences on the secretion of VEGF-A in the OSCC cell line HSC-3. Under normoxic conditions, we found that Zeb inhibited secretion in a dose-dependent manner by reducing the activity of hypoxia-inducible factor-1α (HIF-1α). Treatment of the cells with the proteasome inhibitor MG132 protected the HIF-1α protein from Zeb-mediated epigenetic regulation. In addition, our study revealed that neither the PI3K/Akt nor the p53 signaling pathway is required for Zeb-induced HIF-1α degradation. In short, Zeb influenced the stability of the HIF-1α protein and the activity of its targets, such as VEGF, in HSC-3 cells in normoxic conditions. This study has laid the foundation for a novel anti-cancer approach, which may find applications in molecular staging.


[Calcified giant aneurysm of the middle cerebral artery].
A rare case of calcified giant aneurysm of the middle cerebral artery is presented. This is a 28-year-old female with seizures and right-sided hemiparesis in whom plain scull films and computed tomography revealed a large calcified lesion (measuring 7.5 x 5.5 x 4.5 cm) of the left cerebral hemisphere. The lesion was removed by the pterional transsylvian approach and found to be a calcified giant thrombotic aneurysm of the middle cerebral artery. The CT characteristics of these rare lesions and the success of surgery in this case are briefly discussed.


Epstein-Barr virus essential antigen EBNA3C attenuates H2AX expression.
Epstein-Barr virus (EBV) latent antigen EBNA3C is implicated in B-cell immortalization and linked to several B-cell malignancies. Deregulation of H2AX can induce genomic instability with increased chromosomal aberrations, which ultimately leads to tumorigenesis. Here we demonstrated that EBNA3C can attenuate H2AX expression at the transcript and protein levels. A reduction of total H2AX levels was clearly observed upon infection of primary B cells with wild-type EBV but not with EBNA3C knockout recombinant EBV. H2AX also interacted with EBNA3C through its N-terminal domain (residues 1 to 100). Furthermore, H2AX mutated at Ser139 failed to interact with EBNA3C. Luciferase-based reporter assays also revealed that the binding domain of EBNA3C is sufficient for transcriptional inhibition of the H2AX promoter. EBNA3C also facilitated H2AX degradation through recruitment of components of the ubiquitin proteasome pathway. We further demonstrated that knockdown of H2AX in lymphoblastoid cell lines (LCLs) led to the upregulation of the Bub1 oncoprotein and downregulated expression of p53. Overall, our study provides additional insights into EBV-associated B-cell lymphomas, which are linked to the regulation of the DNA damage response system in infected cells. The importance of these insights are as follows: (i) EBNA3C downregulates H2AX expression at the protein and transcript levels in epithelial cells, B cells, and EBV-transformed LCLs, (ii) EBNA3C binds with wild-type H2AX but not with the Ser139 mutant of H2AX, (iii) the N terminus (residues 1 to 100) of EBNA3C is critical for binding to H2AX, (iv) localization of H2AX is predominantly nuclear in the presence of EBNA3C, and (v) H2AX knocked down in LCLs led to enhanced expression of Bub1 and downregulation of the tumor suppressor p53, which are both important for driving the oncogenic process.


Corn mint (Mentha arvensis) extract diminishes acute Chlamydia pneumoniae infection in vitro and in vivo.
Corn mint ( Mentha arvensis ) provides a good source of natural phenols such as flavone glycosides and caffeic acid derivatives, which may have prophylactic properties against inflammations. This study investigated whether corn mint extract would be beneficial against a universal respiratory tract pathogen, Chlamydia pneumoniae , infection. The extract inhibited the growth of C. pneumoniae CWL-029 in vitro in a dose-dependent manner. The inhibition was confirmed against a clinical isolate K7. The phenolic composition of the extract was analyzed by UPLC-ESI/Q-TOF/MS, the main components being linarin and rosmarinic acid. These compounds were active in vitro against C. pneumoniae. Linarin completely inhibited the growth at 100 μM. Inbred C57BL/6J mice were inoculated with C. pneumoniae K7. M. arvensis extract was given intraperitoneally once daily for 3 days prior to inoculation and continued for 10 days postinfection. The extract was able to diminish the inflammatory parameters related to C. pneumoniae infection and significantly (p = 0.019) lowered the number of C. pneumoniae genome equivalents detected by PCR at biologically relevant amounts.


The short- and long-term fitness consequences of natal dispersal in a wild bird population.
Dispersal is a key process in population and evolutionary ecology. Individual decisions are affected by fitness consequences of dispersal, but these are difficult to measure in wild populations. A long-term dataset on a geographically closed bird population, the Mauritius kestrel, offers a rare opportunity to explore fitness consequences. Females dispersed further when the availability of local breeding sites was limited, whereas male dispersal correlated with phenotypic traits. Female but not male fitness was lower when they dispersed longer distances compared to settling close to home. These results suggest a cost of dispersal in females. We found evidence of both short- and long-term fitness consequences of natal dispersal in females, including reduced fecundity in early life and more rapid aging in later life. Taken together, our results indicate that dispersal in early life might shape life history strategies in wild populations.


Epstein-Barr Virus Reactivation-Induced Immunoglobulin Production: Significance on Autoimmunity.
Epstein-Barr virus (EBV) mainly persists in B cells, which differentiate into antibody-producing cells, and thus, EBV has been implicated in autoimmune diseases. We aimed to describe the EBV reactivation and its relevance to autoimmune disease, focusing on Graves' disease, which is an autoimmune hyperthyroidism caused by thyrotropin receptor antibodies. Circulating autoreactive B cells that have evaded from the selection have difficulties differentiating to produce antibodies. However, once EBV infects such B cells and reactivates, the B cells may become plasma cells and produce autoantibody. We herein proposed an EBV reactivation-induced Ig production system, which is a distinct pathway from the antibody production system through germinal centers and bone marrow and has the following characteristics: 1. IgM dominance, 2. ubiquitous Ig production, and 3. the rescue of autoreactive B cells, which skews Ig production toward autoantigens. IgM autoantibodies induced by EBV reactivation may activate the classical complement pathway and injure healthy tissue, which supply autoantigens for the production of affinity-matured IgG autoantibodies. Antibodies induced by EBV reactivation may play important roles in the development and exacerbation of autoimmune diseases.


Yellow fever vaccines and international travelers.
The growth of air travel has diminished the barriers to the spread of yellow fever, posing a threat to regions that have not previously been reached by the disease but are considered receptive, including the Middle East, coastal East Africa, the Indian subcontinent, Asia and Australia. For many decades, vaccination against yellow fever has been required for travelers entering many countries with receptive mosquito vectors in order to prevent the importation of yellow fever virus from a country that had ongoing transmission. Each year, approximately 9 million tourists travel to countries where yellow fever is endemic; the number of tourists who visit yellow fever-endemic regions within these countries may exceed 3 million. Risk estimates of yellow fever to travelers are extremely difficult to ascertain due to fluctuation of the disease by year and season, incomplete surveillance data, and lack of accurate data regarding vaccine coverage of the local population. The 17D live yellow fever vaccine has been widely acknowledged as one of the most effective and safe vaccines in use. Recently, however, reports of severe and previously unrecognized significant adverse events linked to the 17D vaccine have caused major concern. Some have called for the development of new inactivated yellow fever vaccines for travelers. A new approach for manufacturing the live 17D vaccine involves using a full-length cDNA clone of 17D-204 virus. This new method allows production in a cell culture system and potentially reduces the risk of adventitious viruses and selection of a subpopulation during replication, thereby increasing safety.


Attachment and antibiotic response of early-stage biofilms studied using resonant hyperspectral imaging.
Many bacterial species readily develop biofilms that act as a protective matrix against external challenge, e.g., from antimicrobial treatment. Therefore, biofilms are often responsible for persistent and recurring infections. Established methods for studying biofilms are either destructive or focus on the biofilm's surface. A non-destructive method that is sensitive to the underside of the biofilm is highly desirable, as it allows studying the penetration of antibiotics through the film. Here, we demonstrate that the high surface sensitivity of resonant hyperspectral imaging provides this capability. The method allows us to monitor the early stages of Escherichia coli biofilm formation, cell attachment and microcolony formation, in-situ and in real-time. We study the response of the biofilm to a number of different antibiotics and verify our observations using confocal microscopy. Based on this ability to closely monitor the surface-bound cells, resonant hyperspectral imaging gives new insights into the antimicrobial resistance of biofilms.


Recombinant adeno-associated virus serotypes 2- and 5-mediated gene transfer in the mammalian brain: quantitative analysis of heparin co-infusion.
Recombinant adeno-associated viruses (rAAVs) are among the most promising vectors for gene delivery into the CNS. However, a major hurdle for gene transfer to the mammalian brain is to achieve high transduction levels in target cells beyond the immediate injection site. Therefore, building upon the optimization of injection parameters on which we have recently reported, it is important to define additional methods to increase the volume of distribution. Here, we establish an optimal heparin concentration, and show that co-injection of heparin together with rAAV2 leads to a significantly higher and more homogeneous distribution of transduced cells. In contrast, the diffusion pattern of rAAV serotype 5 differs from that of rAAV2, in that its distribution is less homogeneous, more variable, and patchy. Furthermore, this study illustrates the influence of receptor binding on the expression pattern following injection of rAAV in the CNS. In addition to improvements in expression cassettes and viral titers and the use of very slow infusion rates, gene transfer studies in the CNS where the goal is to obtain widespread transduction should consider co-injecting the viral vector rAAV2 with heparin to maximize transduction efficiency and viral spread.


Inhibition of growth and alteration of host cell interactions of Pasteurella multocida with natural byproducts.
Pasteurella multocida is a leading cause of fowl cholera in both free-range pasture and conventional/commercially raised poultry. Its infection is a serious threat to poultry health and overall flock viability. Organic poultry is comparatively more vulnerable to this pathogen. It is a significant cause of production loss and price increase of poultry products, specifically organic poultry products. Some plant products are well documented as sources of natural antimicrobials such as polyphenols found in different berry pomaces and citrus oil. Pomace, a byproduct (primarily of seeds and skins) of fruits used for juice and wine production, and citrus oil, the byproduct of citrus juice production, show promising antimicrobial activity against various pathogens. Here, we showed for the first time that blackberry and blueberry pomace extracts and citrus oil inhibited P. multocida growth. Minimum bactericidal concentrations were determined as 0.3 and 0.4 mg/mL gallic acid equivalent for blackberry and blueberry pomace extracts, respectively. Similarly, only 0.05% citrus oil (vol/vol) completely inhibited P. multocida growth. Under shaking conditions, the antimicrobial activity of both pomace extracts and citrus oil was more intensive. Even citrus oil vapor also significantly reduced the growth of P. multocida. In addition, cell surface hydrophobicity of P. multocida was increased by 2- to 3-fold and its adherence to chicken fibroblast (DF1) and bovine mammary gland (MacT) cells was reduced significantly in the presence of pomace extracts only. This study indicates that these natural products might be good alternatives to conventional antimicrobial agents, and hence, may be used as feed or water supplements to control fowl cholera and reduce production loss caused by P. multocida.


Angel-closure glaucoma following scleral buckling operations.
We have observed 22 patients with angle-closure glaucoma following scleral buckling operations. These patients did not have narrow anterior chamber angles preoperatively, and several were aphakix with surgical iris colobomas. The angle-closure glaucoma was manifest by a hazy cornea, elevated intraocular pressure, closed angle, absence or iris bombé, and presence of choroidal detachments. Treatment with cycloplegics and corticosteroids was more effective than treatment with miotics. A likely pathogenic mechanism is congestion and swelling of the ciliary body due to a temporary interference by the scleral buckle with venous drainage. Episcleral implants accounted for a statistically significant higher incidence of angle-closure glaucoma as compared to intrascleral implants.


Digital image processing.
The image quality of a radiograph is determined by the local contrast, spatial resolution, latitude and the image noise. The goal of digital processing is to improve the visualisation of pathology by optimising these physical parameters. Processing parameters need to be chosen correctly in order to overcome the inverse relationship between contrast and latitude while producing images that retain a conventional appearance. Unsharp mask filtering (UMF) is a simple technique for improving image quality. This technique, however, suffers from serious drawbacks, such as the suppression of pathologic lesions or artifacts that may simulate pathology. Manufacturers have developed different approaches in order to overcome problems and artifacts derived from this technique.


Personal computer teleradiology interhospital image transmission of neonatal radiographs to facilitate tertiary neonatology telephone consultation and patient transfer.
Our purpose was to study the ability of personal computer teleradiology (PCT) to improve the quality of communication between physicians during newborn infant transfers and consultations. In the first part of the study 36 radiographs of neonatal intensive care unit patients were transmitted by PCT. The pediatrician reviewed the original films and three neonatologists reviewed the PCT images. Their interpretations were scored by use of criteria established by a neutral reader. In the second part chest x-ray films (CXR) of 31 newborns weighing > 2000 gm with respiratory distress were transmitted by PCT. A pediatrician and three neonatologists participated in an exercise to simulate a telephone neonatology consultation. Patient severity assessments as measured by assignments to receive intermediate or intensive care were compared before and after neonatologists viewed the PCT image of the CXR. In part 1 of the study neonatologists correctly identified 98%, 91%, and 98% of the x-ray interpretation scoring items, whereas at best the pediatrician identified 82% of the scoring items (p = 0.002). In part 2 neonatologists correctly assigned patient care levels an average of 73% after reviewing a standard clinical profile and a written description of the infant's CXR. After reviewing a PCT image of the infant's CXR, patient care level assignments were correctly assigned an average of 67%. The interpretation of the PCT CXR image was consistent with the radiologic report of record in 90 of 93 interpretations (31 cases read by three neonatologists). PCT represents an inexpensive means to accurately send a radiographic image over the phone as part of a telephone consultation. Neonatologists were able to interpret teleradiology images more accurately than a pediatrician reviewing the original film. Although this did not result in an improvement in the neonatologists' ability to determine patient severity on the basis of the model used in part 2, their identification of serious radiographic findings missed by the pediatrician can only suggest that teleradiology may be beneficial in certain instances. Although verbal communication can often suffice in a telephone consultation or transfer, there may be specific instances when visualizing a radiographic image such as an x-ray film or computed tomographic scan can provide important information that cannot be optimally described verbally. Rural hospitals can form interhospital image transmission links with tertiary center resources.


Antigenic and structural variation of the p28 core polypeptide of goat and sheep retroviruses.
The p28 core polypeptides of four isolates of caprine arthritis-encephalitis virus (CAEV) from goats was compared with those of visna virus (VV) and progressive pneumonia virus (PPV) from sheep. Monoclonal antibodies recognized p28 epitopes common to all six retrovirus isolates, a p28 epitope on four CAEV isolates, but not VV and PPV isolates, a p28 epitope on four CAEV isolates and VV, but not PPV and a p28 epitope unique to the CAEV isolate used for immunizing the mouse spleen donor. Comparison of two-dimensional maps of tyrosine containing tryptic peptides of p28 demonstrated that three CAEV isolates had similar maps while a fourth CAEV isolate, VV and PPV had several different from the three closely related CAEV p28s and from each other.


Nitric-oxide synthase mediates the ability of darbepoetin alfa to attenuate pre-existing spatial working memory deficits in rats subjected to transient global ischemia.
Erythropoietin has been reported to improve the behavioral performance of healthy mice in tests thought to depend on synaptic plasticity in the CA1 region of the hippocampus. We show here for the first time that a single injection of the erythropoietin analog darbepoetin alfa reverses pre-existing cognitive deficits in adult rats that had been subjected to transient global ischemia produced by four-vessel occlusion (4-VO). Quantification of neuronal density demonstrated that 12 min of 4-VO selectively killed more than 90% of CA1 neurons in the dorsal hippocampus. Rats that had sustained a bilateral loss of hippocampal CA1 neurons in this range (4-VO rats) displayed more errors and longer escape latencies in the Barnes maze compared with sham-operated controls. A single injection of darbepoetin alfa (5000 U/kg i.p.) 4 h before behavioral testing decreased deficits in escape latency for 4-VO rats but not sham-operated controls. This improvement in spatial working memory performance was correlated with increased levels of nitric-oxide metabolites in the ventral hippocampus. Systemic administration of the nitric-oxide synthase inhibitor N(G)-nitro-L-nitro-arginine methyl ester reversed the increase in nitric-oxide metabolites and improvements in spatial working memory produced by darbepoetin alfa (5000 U/kg, i.p.) at a dose (10 mg/kg, i.p.) that did not impair the spatial working memory performance of intact rats. Taken together, these findings suggest that darbepoetin alfa reverses pre-existing spatial working memory deficits resulting from transient global ischemia by increasing the activity of nitric-oxide synthase, an enzyme implicated in synaptic plasticity.


Metastatic spine tumors.
Cancer is the second leading cause of death in the United States, and vertebral body metastases often occur in systemic malignancy. Metastatic spinal tumors may present with pain or neurologic deficit, or may be detected during screening examinations in patients with known malignancy. Management of spinal metastases remains controversial. The role of surgery, especially decompressive laminectomy without stabilization, has been questioned. Recent series attest to the beneficial role of surgery, emphasizing anterior and combined decompression and stabilization procedures. We review the relevant literature on metastatic spinal tumors, assessing imaging strategies, adjuvant treatment, patient selection, and results and complications. Operative decompression and stabilization is an important tool in the management of spinal metastatic disease. Patient selection and appropriate use of anterior and/or posterior decompression and stabilization are necessary to optimize surgical results.


Partitioning the Relative Importance of Phylogeny and Environmental Conditions on Phytoplankton Fatty Acids.
Essential fatty acids (EFA), which are primarily generated by phytoplankton, limit growth and reproduction in diverse heterotrophs. The biochemical composition of phytoplankton is well-known to be governed both by phylogeny and environmental conditions. Nutrients, light, salinity, and temperature all affect both phytoplankton growth and fatty acid composition. However, the relative importance of taxonomy and environment on algal fatty acid content has yet to be comparatively quantified, thus inhibiting predictions of changes to phytoplankton food quality in response to global environmental change. We compiled 1145 published marine and freshwater phytoplankton fatty acid profiles, consisting of 208 species from six major taxonomic groups, cultured in a wide range of environmental conditions, and used a multivariate distance-based linear model to quantify the total variation explained by each variable. Our results show that taxonomic group accounts for 3-4 times more variation in phytoplankton fatty acids than the most important growth condition variables. The results underscore that environmental conditions clearly affect phytoplankton fatty acid profiles, but also show that conditions account for relatively low variation compared to phylogeny. This suggests that the underlying mechanism determining basal food quality in aquatic habitats is primarily phytoplankton community composition, and allows for prediction of environmental-scale EFA dynamics based on phytoplankton community data. We used the compiled dataset to calculate seasonal dynamics of long-chain EFA (LCEFA; ≥C20 ɷ-3 and ɷ-6 polyunsaturated fatty acid) concentrations and ɷ-3:ɷ-6 EFA ratios in Lake Washington using a multi-decadal phytoplankton community time series. These analyses quantify temporal dynamics of algal-derived LCEFA and food quality in a freshwater ecosystem that has undergone large community changes as a result of shifting resource management practices, highlighting diatoms, cryptophytes and dinoflagellates as key sources of LCEFA. Moreover, the analyses indicate that future shifts towards cyanobacteria-dominated communities will result in lower LCEFA content in aquatic ecosystems.


[Recent progresses in the treatment of dyslipidemia].
There is a linear relationship between LDLcholesterol plasma concentration and coronary events, both in patients with stable angina pectoris and after an acute event. All medications that affect the lipid profile do not have a favorable effect on cardiovascular events (i.e. niacin, inhibitors of the cholesteryl ester transfer protein). Statins increase slightly the risk of type II diabetes in subjects at risk. We have also learnt that statins activate a transcription factor that increases LDL-cholesterol receptors, as well as a protein named " PCSK9 ". This latter protein reduces the number of LDL-cholesterol receptors on the hepatocyte and hampers thereby the LDLcholesterol lowering effects of statins. Spontaneous mutations that render PCSK9 ineffective reduce the LDL-cholesterol, and prevent coronary heart disease. Similar observations have been reproduced with numerous mutations that affect LDL-cholesterol levels. If a monoclonal antibody against PSCK9 is provided in addition to statin therapy, LDLcholesterol plasma concentration falls at unprecedented low concentrations of 30 mg/dl. 4.4% of these patients present a myocardial infarction, as compared to 6.3% in the placebo group. This new class of medication seems therefore promising for the secondary prevention in patients at risk of recurrent ischemic events.


Investigating the effects of dietary folic acid on sperm count, DNA damage and mutation in Balb/c mice.
To date, fewer than 50 mutagens have been studied for their ability to cause heritable mutations. The majority of those studied are classical mutagens like radiation and anti-cancer drugs. Very little is known about the dietary variables influencing germline mutation rates. Folate is essential for DNA synthesis and methylation and can impact chromatin structure. We therefore determined the effects of folic acid-deficient (0mg/kg), control (2mg/kg) and supplemented (6mg/kg) diets in early development and during lactation or post-weaning on mutation rates and chromatin quality in sperm of adult male Balb/c mice. The sperm chromatin structure assay and mutation frequencies at expanded simple tandem repeats (ESTRs) were used to evaluate germline DNA integrity. Treatment of a subset of mice fed the control diet with the mutagen ethylnitrosourea (ENU) at 8 weeks of age was included as a positive control. ENU treated mice exhibited decreased cauda sperm counts, increased DNA fragmentation and increased ESTR mutation frequencies relative to non-ENU treated mice fed the control diet. Male mice weaned to the folic acid deficient diet had decreased cauda sperm numbers, increased DNA fragmentation index, and increased ESTR mutation frequency. Folic acid deficiency in early development did not lead to changes in sperm counts or chromatin integrity in adult mice. Folic acid supplementation in early development or post-weaning did not affect germ cell measures. Therefore, adequate folic acid intake in adulthood is important for preventing chromatin damage and mutation in the male germline. Folic acid supplementation at the level achieved in this study does not improve nor is it detrimental to male germline chromatin integrity.


Effect of dietary phosphatidylinositol on cholesterol metabolism in Zucker (fa/fa) rats.
Recent studies have shown that dietary phospholipids, especially phosphatidylcholine and phosphatidylserine, have various beneficial biological effects. However, there are not enough data concerning the physiological function of dietary phosphatidylinositol (PI). The metabolic syndrome, a cluster of metabolic abnormalities such as dyslipidemia, diabetes mellitus, and hypertension, is widespread and increasingly prevalent diseases in industrialized countries. In the present study, we evaluated that the effect of dietary PI on cholesterol metabolism in metabolic syndrome model Zucker (fa/fa) rats. For 4 weeks, rats were fed semisynthetic diets containing either 7% soybean oil or 5% soybean oil plus 2% PI. Dietary PI prevented the mild hypercholesterolemia and hepatic cholesterol accumulation in Zucker (fa/fa) rats. These effects were attributable to an increased fecal bile acid excretion and to the tendencies of decreased ACAT1 mRNA level and increased CYP7A1 mRNA level in the liver. Additionally, dietary PI markedly increased microsomal PI content in the liver of Zucker (fa/fa) rats. Our study suggests that dietary PI normalizes cholesterol metabolism through the enhancement of fecal bile acid excretion in the metabolic syndrome model rats.


Enzyme-linked immunosorbent assay for detection of antibodies to extractable nuclear antigens in systemic lupus erythematosus, with nylon as solid phase.
In this enzyme-linked immunosorbent assay (ELISA) for detection of antibodies against extractable nuclear antigens (ENA) in sera of patients with systemic lupus erythematosus (SLE), nylon is used as solid phase for antigen binding instead of the commonly used polystyrene surface. Optimal conditions for activation of the nylon beads, antigen coating, and other relevant factors have been investigated. We compared the incidence of anti-ENA antibodies in SLE, using chromogenic and fluorogenic enzyme substrates. Of SLE patients, 54% were positive for anti-ENA antibodies when chromogenic substrate was used as compared with 68% for fluorogenic substrate. Antibody activity against Sm and RNP antigens was distinguished on the basis of ribonuclease sensitivity of the RNP antigen. The method described offers advantages such as decreased background activity, increased surface area, facility for prolonged storage of antigen-coated solid phase, and miniaturization of the assay.


To evaluate the epidemiological, clinical, echocardiographic, microbiological characteristics and complications of patients with complicated infective endocarditis (IE) in a Peruvian refence hospital. A retrospective, descriptive study was carried out reviewing the medical records of patients diagnosed with IE treated at Instituto Nacional Cardiovascular-INCOR between years 2012 and 2016; collecting clinical, imaging and laboratory variables. 59 cases were included, predominantly males (66.1%) and the median age was 50 years (IQR 37-62). The most frequent comorbidities were congenital heart disease (42.3%) and the presence of a prosthetic valve (23.7%). The most frequent sign found in the physical examination was fever (69.49%) and the most common symptom was dyspnea (52.5%). The proportion of positive blood cultures was 55.9%, and in 51.5% of these the isolated pathogen was Staphylococcus spp. The most affected valve was the aortic (72.8%), the most frequent finding by echocardiography was the presence of vegetations (91.5%). The most common complications were atrioventricular block (28.8%) and heart failure (22%). Overall, in-hospital mortality was 20.3%. IE continues to be a challenging pathology, our clinical-epidemiological results are comparable to those found internationally, which reflect the change in the microbiology and in its epidemiology. However, despite advances in diagnosis and treatment, mortality remains unchanged.


An exact mapping from ReLU networks to spiking neural networks.
Deep spiking neural networks (SNNs) offer the promise of low-power artificial intelligence. However, training deep SNNs from scratch or converting deep artificial neural networks to SNNs without loss of performance has been a challenge. Here we propose an exact mapping from a network with Rectified Linear Units (ReLUs) to an SNN that fires exactly one spike per neuron. For our constructive proof, we assume that an arbitrary multi-layer ReLU network with or without convolutional layers, batch normalization and max pooling layers was trained to high performance on some training set. Furthermore, we assume that we have access to a representative example of input data used during training and to the exact parameters (weights and biases) of the trained ReLU network. The mapping from deep ReLU networks to SNNs causes zero percent drop in accuracy on CIFAR10, CIFAR100 and the ImageNet-like data sets Places365 and PASS. More generally our work shows that an arbitrary deep ReLU network can be replaced by an energy-efficient single-spike neural network without any loss of performance.


Higher Circulating Cortisol in the Follicular vs. Luteal Phase of the Menstrual Cycle: A Meta-Analysis.
Although results of animal research show that interactions between stress and sex hormones are implicated in the development of affective disorders in women, translation of these findings to patients has been scarce. As a basic step toward advancing this field of research, we analyzed findings of studies which reported circulating cortisol levels in healthy women in the follicular vs. luteal phase of the menstrual cycle. We deemed this analysis critical not only to advance our understanding of basic physiology, but also as an important contrast to the findings of future studies evaluating stress and sex hormones in women with affective disorders. We hypothesized that cortisol levels would be lower in the follicular phase based on the proposition that changes in levels of potent GABAergic neurosteroids, including allopregnanolone, during the menstrual cycle dynamically change in the opposite direction relative to cortisol levels. Implementing strict inclusion criteria, we compiled results of high-quality studies involving 778 study participants to derive a standardized mean difference between circulating cortisol levels in the follicular vs. luteal phase of the menstrual cycle. In line with our hypothesis, our meta-analysis found that women in the follicular phase had higher cortisol levels than women in the luteal phase, with an overall Hedges' g of 0.13 (p < 0.01) for the random effects model. No significant between-study difference was detected, with the level of heterogeneity in the small range. Furthermore, there was no evidence of publication bias. As cortisol regulation is a delicate process, we review some of the basic mechanisms by which progesterone, its potent metabolites, and estradiol regulate cortisol output and circulation to contribute to the net effect of higher cortisol in the follicular phase.


Transcriptional Alterations by Ischaemic Postconditioning in a Pig Infarction Model: Impact on Microvascular Protection.
Although the application of cardioprotective ischaemia/reperfusion (I/R) stimuli after myocardial infarction (MI) is a promising concept for salvaging the myocardium, translation to a clinical scenario has not fulfilled expectations. We have previously shown that in pigs, ischaemic postconditioning (IPostC) reduces myocardial oedema and microvascular obstruction (MVO), without influencing myocardial infarct size. In the present study, we analyzed the mechanisms underlying the IPostC-induced microvascular protection by transcriptomic analysis, followed by pathway analysis. Closed-chest reperfused MI was induced by 90 min percutaneous balloon occlusion of the left anterior descending coronary artery, followed by balloon deflation in anaesthetised pigs. Animals were randomised to IPostC (n = 8), MI (non-conditioned, n = 8), or Control (sham-operated, n = 4) groups. After three hours or three days follow-up, myocardial tissue samples were harvested and subjected to RNA-seq analysis. Although the transcriptome analysis revealed similar expression between IPostC and MI in transcripts involved in cardioprotective pathways, we identified gene expression changes responding to IPostC at the three days follow-up. Focal adhesion signaling, downregulated genes participating in cardiomyopathy and activation of blood cells may have critical consequences for microvascular protection. Specific analyses of the gene subsets enriched in the endothelium of the infarcted area, revealed strong deregulation of transcriptional functional clusters, DNA processing, replication and repair, cell proliferation, and focal adhesion, suggesting sustentative function in the endothelial cell layer protection and integrity. The spatial and time-dependent transcriptome analysis of porcine myocardium supports a protective effect of IPostC on coronary microvasculature post-MI.


The effect of displacement time on gingival crevice width.
The authors investigated the length of time medicated displacement cord should remain in the gingival crevice prior to impression making. A silk cord (Deknatel) was placed into the sulcus and was not removed during the study. Medicated cords (Hemodent on Ultrapak #1) were placed into the gingival sulcus for 2, 4, 6, and 8 minutes. Following cord removal, closure of the sulcus was recorded at intervals using a miniature video camera. Crevicular widths were measured at the midbuccal and transitional line angle areas. At both the midbuccal and transitional line angle areas, gingival crevices displaced for 2 minutes were significantly smaller at 20 seconds (P < .05) than crevices following displacement for 4, 6, and 8 minutes. No significant difference in crevicular width was found at any time period after cord removal for crevices displaced for 4, 6, and 8 minutes. At the transitional line angle, crevicular widths were significantly smaller than at the midbuccal at 20 seconds for all times and remained so up to 180 seconds. To achieve a crevicular width of 0.2 mm, cord should remain in the gingival crevice for an optimum time of 4 minutes prior to impression making when using the materials evaluated in this study.


Molecular regulation of sex change induced by methyltestosterone -feeding and methyltestosterone -feeding withdrawal in the protogynous orange-spotted grouper.
The sex identity of fish can be easily manipulated by exogenous hormones. Treatment with 17-methyltestosterone (MT) has been widely used to induce a male fate, but the molecular and cellular processes underlying sex changes induced by MT treatments and the withdrawal of MT are not well studied. In this study, we systematically investigated gonadal histology, gene expression profiles, sex steroid hormone levels, and cellular changes during sex changes induced by MT-feeding and MT-feeding withdrawal in the protogynous orange-spotted grouper, Epinephelus coioides. Based on gonadal histology, we demonstrated that MT-feeding-induced sex reversal can be divided into early and late phases: in the early phase, male and female germ cells coexist, and MT-feeding withdrawal leads to a female fate; in the late phase, only male germ cells are observed, and MT-feeding withdrawal does not reverse the process, leading to a male fate. In both the early and late phases, cytochrome P450 family19 subfamily A member 1 (cyp19a1a) gene expression increased in response to MT-feeding withdrawal. Finally, by tracing doublesex- and Mab-3-related transcription factor 1 (dmrt1)-expressing cells, we found that gonia-like cells in the germinal epithelium might be the major germ cell sources for developing testes during sex reversal. Collectively, our findings provide insights into the molecular and cellular mechanisms underlying sex changes induced by exogenous hormones.


Contemporary clinical updates on the prevention of future cardiovascular disease in women who experience adverse pregnancy outcomes.
Adverse pregnancy outcomes including hypertensive disorders of pregnancy and gestational diabetes are significant causes of maternal mortality. There is substantial evidence of an association between adverse events during pregnancy and long-term maternal cardiovascular risk. It is therefore important to understand the role of risk modification prior to, during, and after pregnancy to reduce adverse outcomes. These efforts include risk assessment, routine screening for cardiovascular risk factors, and potential pharmacotherapeutic risk reduction. In this manuscript, we aim to highlight the current evidence in the areas of cardiovascular risk assessment and risk modification, and the role for potential risk reduction therapies before, during, and after pregnancy.


Lipoamino bundle LNPs for efficient mRNA transfection of dendritic cells and macrophages show high spleen selectivity.
Messenger RNA (mRNA) is a powerful tool for nucleic acid-based therapies and vaccination, but efficient and specific delivery to target tissues remains a significant challenge. In this study, we demonstrate lipoamino xenopeptide carriers as components of highly efficient mRNA LNPs. These lipo-xenopeptides are defined as 2D sequences in different 3D topologies (bundles or different U-shapes). The polar artificial amino acid tetraethylene pentamino succinic acid (Stp) and various lipophilic tertiary lipoamino fatty acids (LAFs) act as ionizable amphiphilic units, connected in different ratios via bisamidated lysines as branching units. A series of more lipophilic LAF4-Stp1 carriers with bundle topology is especially well suited for efficient encapsulation of mRNA into LNPs, facilitated cellular uptake and strongly enhanced endosomal escape. These LNPs display improved, faster transfection kinetics compared to standard LNP formulations, with high potency in a variety of tumor cell lines (including N2a neuroblastoma, HepG2 and Huh7 hepatocellular, and HeLa cervical carcinoma cells), J774A.1 macrophages, and DC2.4 dendritic cells. High transfection levels were obtained even in the presence of serum at very low sub-microgram mRNA doses. Upon intravenous application of only 3 µg mRNA per mouse, in vivo mRNA expression is found with a high selectivity for dendritic cells and macrophages, resulting in a particularly high overall preferred expression in the spleen.


The management of snake and spider bites in the southeastern United States.
Of all snake bites reported in the United States of America each year, 75 per cent occur in the states that form the Southeastern Surgical Congress. Pit vipers, coral snakes, and exotic imported snakes are all found in that area. Deaths from those snake bites are rare, but morbidity is high and it is often due to overtreatment rather than undertreatment. Treatment in the field is rarely necessary for the victim who is less than 1 hour away from definitive care. The type and size of the snake and the age, size, and health of the patient are important guides to therapy. Envenomation may not occur. When envenomation occurs from pit viper bites, antivenom is not always necessary, and its inherent dangers (serum sickness and possible hypersensitivity) must be weighed against the severity of systemic and local manifestations. All coral snake bites resulting in envenomation must be treated vigorously with coral snake antivenom. The Oklahoma City Poison Control Center can guide the treatment of bites from exotic snakes. The most frequently encountered toxic spider bites in the Southeast are those of the black widow and brown recluse spiders. The symptoms of black widow envenomation are best controlled with calcium gluconate or a muscle relaxant. Antivenom should be reserved for severe reactions. Brown recluse necrotic lesions are best controlled with dapsone.