Effect of sarcolemmal rupture on myocardial electrical impedance during oxygen deprivation.
Plasma membrane disruption is a characteristic feature of cell death induced by hypoxia or ischemia. Here, we investigated whether analysis of tissue electrical impedance allows detection of ongoing cell membrane rupture and necrotic cell death in hypoxic or ischemic myocardium. Twenty-eight isolated rat hearts were submitted to 5 h of ischemia (n = 8) or hypoxia (n = 20). Myocardial electrical impedance and lactate dehydrogenase (LDH) release were monitored. The time course of hypoxia-induced cell death was modified by altering pH (pH 7.4 or 6.4, 5 h) or by adding 3 or 10 mM glycine. Ischemia and hypoxia induced an increase in electrical impedance, followed by a plateau, and later a reduction. During hypoxia, LDH release started after a prolonged lapse of time (80.00 +/- 8.37 min at pH 7.4 and 122.50 +/- 11.82 min at pH 6.4). The onset of LDH release was followed by the onset of the late reduction in electrical impedance, and both were delayed by acidic pH (P < 0.05) and by glycine (P < 0.05). The times of onset of LDH release and of late electrical changes were significantly correlated (r = 0.752, P < 0.001). In separate experiments, induction of sarcolemmal rupture with Triton X-100 (n = 6) mimicked the late effects of ischemia or hypoxia on tissue impedance. The protective effects of glycine and acidosis on membrane disruption were confirmed (propidium iodide) in energy-deprived HL-1 cardiomyocytes. These results describe for the first time a late fall in electrical impedance in myocardium submitted to prolonged oxygen deprivation and demonstrate that this fall allows detection of ongoing cell necrosis.


Tracer clearance in radionuclide cisternography in patients with spontaneous intracranial hypotension.
We semiquantitatively analysed radionuclide cisternography in three patients with spontaneous cerebrospinal fluid (CSF) leakage diagnosed by typical symptoms and magnetic resonance imaging findings before and several months after treatment with epidural blood patch. Radioactivity in the whole CSF space was measured immediately after and at 1, 5, 7 and 24 h after intrathecal injection of (111)In-diethylenetriaminepentaacetic acid (DTPA). Initial findings included the vague appearance of leakage in the thoracic spine in two patients, early bladder filling at 1 h in one and a lack of tracer filling into the high cranial convexity in all three. The radioactivity count rapidly decreased within several hours after injection and reached 20% of the initial value at 24 h. In contrast, no rapid decrease was observed after treatment and more than 50% of tracer remained at 24 h after injection. Semiquantitative analysis of tracer clearance may provide additional information in the diagnosis of CSF leakage, especially with no obvious qualitative findings.


Steroid determination in fish plasma using capillary electrophoresis.
A capillary separation method that incorporates pH-mediated stacking is employed for the simultaneous determination of circulating steroid hormones in plasma from Perca flavescens (yellow perch) collected from natural aquatic environments. The method can be applied to separate eight steroid standards: progesterone, 17alpha,20beta-dihydroxypregn-4-en-3-one, 17alpha-hydroxyprogesterone, testosterone, estrone, 11-ketotestosterone, ethynyl estradiol, and 17beta-estradiol. Based on screening of plasma, the performance of the analytical method was determined for 17alpha,20beta-dihydroxypregn-4-en-3-one, testosterone, 11-ketotestosterone, and 17beta-estradiol. The within-day reproducibility in migration time for these four steroids in aqueous samples was < or =2%. Steroid quantification was accomplished using a calibration curve obtained with external standards. Plasma samples from fish collected from the Choptank and Severn Rivers, Maryland, USA, stored for up to one year were extracted with ethyl acetate and then further processed with anion exchange and hydrophobic solid phase extraction cartridges. The recovery of testosterone and 17beta-estradiol from yellow perch plasma was 84 and 85%, respectively. Endogenous levels of testosterone ranged from 0.9 to 44 ng/ml, and when detected 17alpha,20beta-dihydroxypregn-4-en-3-one ranged from 5 to 34 ng/ml. The reported values for testosterone correlated well with the immunoassay technique. Endogenous concentrations of 17beta-estradiol were < or =1.7 ng/ml. 11-Ketotestosterone was not quantified because of a suspected interferant. Higher levels of 17alpha,20beta-dihydroxypregn-4-en-3-one were found in male and female fish in which 17beta-estradiol was not detected. Monitoring multiple steroids can provide insight into hormonal fluctuations in fish.


Comorbidities: a key issue in patients with disorders of consciousness.
The aim of this study was to identify the impact of comorbidities on outcomes of patients with vegetative state (VS) or minimally conscious state (MCS). All patients in VS or MCS consecutively admitted to two postacute care units within a 1-year period were evaluated at baseline and at 6 months through the Coma Recovery Scale-Revised Version and the Disability Rating Scale (DRS). Comorbidities were also recorded for each patient along the same period. Six-month outcomes included death, full recovery of consciousness, and functional improvement. One hundred and thirty-nine patients (88 male and 51 female; median age, 59 years) were included. Ninety-seven patients were in VS (70%) and 42 in MCS (30%). At 6 months, 33 patients were dead (24%), 39 had a full recovery of consciousness (28%), and 67 remained in VS or MCS (48%). According to DRS scores, 40% of patients (n=55) showed a functional improvement in the level of disability. One hundred and thirty patients (94%) showed at least one comorbidity. Severity of comorbidities (hazard ratio [HR]=2.8; 95% confidence interval [CI], 1.71-4.68; p<0.001) and the presence of ischemic or organic heart diseases (HR=2.6; 95% CI, 1.21-5.43; p=0.014) were the strongest predictors of death, together with increasing age (HR=1.0; 95% CI, 1.0-1.06; p=0.033). Respiratory diseases and arrhythmias without organic heart diseases were negative predictors of full recovery of consciousness (odds ratio [OR]=0.3; 95% CI, 0.12-0.7; p=0.006; OR=0.2; 95% CI, 0.07-0.43; p<0.001) and functional improvement (OR=0.4; 95% CI, 0.15-0.85, p=0.020; OR=0.2; 95% CI, 0.08-0.45; p<0.001). Our data show that comorbidities are common in these patients and some of them influence recovery of consciousness and outcomes.


Tuning the Optical and Electrical Properties of Few-Layer Black Phosphorus via Physisorption of Small Solvent Molecules.
Black phosphorus (BP) is recently becoming more and more popular among semiconducting 2D materials for (opto)electronic applications. The controlled physisorption of molecules on the BP surface is a viable approach to modulate its optical and electronic properties. Solvents consisting of small molecules are often used for washing 2D materials or as liquid media for their chemical functionalization with larger molecules, disregarding their ability to change the opto-electronic properties of BP. Herein, it is shown that the opto-electronic properties of mechanically exfoliated few-layer BP are altered when physically interacting with common solvents. Significantly, charge transport analysis in field-effect transistors reveals that physisorbed solvent molecules induce a modulation of the charge carrier density which can be as high as 1012 cm-2 in BP, i.e., comparable to common dopants such as F4 -TCNQ and MoO3 . By combining experimental evidences with density functional theory calculations, it is confirmed that BP doping by solvent molecules not only depends on charge transfer, but is also influenced by molecular dipole. The results clearly demonstrate how an exquisite tuning of the opto-electronic properties of few-layer BP can be achieved through physisorption of small solvent molecules. Such findings are of interest both for fundamental studies and more technological applications in opto-electronics.


Acute medical complications in 277 general dental practices.
Due to the aging of the population on one hand and both medical and dental innovations on the other, the number of medical complications which occur during dental treatment is expected to rise. In order to prevent such complications, dental practitioners have used a medical risk-related history which includes risk determination and preventive measures (together the MRRH system). In this study, the medical complications which occurred in their practice have been compared with those recorded by a control group. First, a tested registration form was used. In addition, the group using the MRRH system had previously attended a 1-day introductory course de voted to the MRRH system. Furthermore, a power analysis was used to determine the group sizes. The registration period was set at 1 year, during which the dentists sent in monthly reports. Only patients over the age of 18 were included, after having given their oral consent. An independent diagnosis was given of all registered medical complications by two different internists. A total of 208 medical complications were reported: 45 complications were reported by the 62 dentists who used the MRRH system (reference group) and 163 by the 215 dentists of the control group. First, it should be noted that some reports did not register vital signs; this is reflected in categories such as "no diagnosis," "collapse eci," and "others." Second, the study has revealed that the reference group has registered the heart rate and the frequency of breathing of patients more frequently than the control group. Also, a relatively lower percentage of complications was recorded within the reference group due to the intravenous injection of local anesthetics. The number of medical complications recorded in the two groups shows little variation. There is a considerable difference, however, in the nature of these complications.


Up-regulation of Mcl-1 is critical for survival of human melanoma cells upon endoplasmic reticulum stress.
We have previously shown that most melanoma cell lines are insensitive to endoplasmic reticulum (ER) stress-induced apoptosis, and this involves activation of the mitogen-activated protein/extracellular signal-regulated kinase (MEK)/ERK signaling pathway and expression of the apoptosis repressor with caspase recruitment domain (ARC) protein in the cells. In the present study, we show that up-regulation of the antiapoptotic Bcl-2 family member Mcl-1 is another mechanism critical for protection of melanoma cells against ER stress-induced apoptosis. Inhibition of Mcl-1 by small interference RNA (siRNA) rendered melanoma cells sensitive to apoptosis induced by the ER stress inducers thapsigargin and tunicamycin, but this sensitization was partially reversed by siRNA knockdown of PUMA or Noxa, as shown in Mcl-1-deficient melanoma cells. Both PUMA and Noxa were increased by ER stress through transcriptional up-regulation, but only up-regulation of Noxa was dependent on p53, whereas up-regulation of PUMA seemed to be mediated by a p53-independent mechanism(s). Up-regulation of Mcl-1 was also due to increased transcription that involved the IRE1alpha and activating transcription factor 6 signaling pathways of the unfolded protein response. In addition, activation of the MEK/ERK signaling pathway seemed to be necessary for optimal up-regulation of Mcl-1. Taken together, these results reveal the mechanisms of resistance of melanoma cells to apoptosis induction mediated by BH3-only proteins upon ER stress, and identify Mcl-1 as a target for the treatment of melanoma in combination with therapeutics that induce ER stress.


Alpha-adrenergic receptors in human myometrium during pregnancy.
The distribution and mechanisms of alpha-adrenergic receptors have been studied in myometrial preparations from women delivered by cesarean section at term. With the use of the radioligand tritiated dihydroergocryptine, the number of alpha-adrenergic receptors was 210 fmol/mg of protein in the uterine fundus and 195 fmol/mg of protein in the lower uterine segment. Competition experiments showed that 60% of the alpha-adrenergic receptors had properties as alpha 1-adrenergic receptors and 40% as alpha 2-adrenergic receptors. In vitro tension studies verified the existence of physiologically active alpha 1- and alpha 2-adrenergic receptors in the myometrial preparations. alpha 2-Adrenergic receptor stimulation resulted in lowered levels of intracellular cyclic adenosine monophosphate. The intracellular cyclic adenosine monophosphate was further reduced by additional alpha 1-adrenergic receptor stimulation, probably secondary to an activation of calcium-calmodulin-dependent phosphodiesterase.


Sulfur availability regulates plant growth via glucose-TOR signaling.
Growth of eukaryotic cells is regulated by the target of rapamycin (TOR). The strongest activator of TOR in metazoa is amino acid availability. The established transducers of amino acid sensing to TOR in metazoa are absent in plants. Hence, a fundamental question is how amino acid sensing is achieved in photo-autotrophic organisms. Here we demonstrate that the plant Arabidopsis does not sense the sulfur-containing amino acid cysteine itself, but its biosynthetic precursors. We identify the kinase GCN2 as a sensor of the carbon/nitrogen precursor availability, whereas limitation of the sulfur precursor is transduced to TOR by downregulation of glucose metabolism. The downregulated TOR activity caused decreased translation, lowered meristematic activity, and elevated autophagy. Our results uncover a plant-specific adaptation of TOR function. In concert with GCN2, TOR allows photo-autotrophic eukaryotes to coordinate the fluxes of carbon, nitrogen, and sulfur for efficient cysteine biosynthesis under varying external nutrient supply.


Characterization and sequence analyses of antibody-selected antigenic variants of herpes simplex virus show a conformationally complex epitope on glycoprotein H.
Thirteen antigenic variants of herpes simplex virus which were resistant to neutralization by monoclonal antibody 52S or LP11 were isolated and characterized. The antibodies in the absence of complement potently neutralize infectivity of wild-type virus as well as inhibit the transfer of virus from infected to uninfected cells ("plaque inhibition") and decrease virus-induced cell fusion by syncytial strains. The first variant isolated arose in vivo. Of 66 type 1 isolates analyzed from typing studies of 100 clinical isolates, one was identified as resistant to neutralization by LP11 antibody. The glycoprotein H (gH) sequence was derived and compared with those of wild-type and syncytial laboratory strains SC16, strain 17, and HFEM. The sequences were highly conserved in contrast to the diversity observed between gH sequences from herpesviruses of different subgroups. Only four coding changes were present in any of the comparisons, and only one unique coding change was observed between the laboratory strains and the clinical isolate (Asp-168 to Gly). These sequences were compared with those of antigenic variants selected by antibody in tissue culture. Twelve variants were independently selected with antibody LP11 or 52S from parent strain SC16 or HFEM. For each variant, the gH nucleotide sequence was derived and a point mutation was identified giving rise to a single amino acid substitution. The LP11-resistant viruses encoded gH sequences with amino acid substitutions at sites distributed over one-half of the gH external domain, Glu-86, Asp-168, or Arg-329, while the 52S-resistant mutant viruses had substitutions at adjacent positions Ser-536 and Ala-537. One LP11 mutant virus had a point mutation in the gH gene that was identical to that of the clinical isolate, giving rise to a substitution of Asp-168 with Gly. Both LP11 and 52S appeared to recognize distinct gH epitopes as mutant virus resistant to neutralization and immunoprecipitation with LP11 remained sensitive to 52S and the converse was shown for the 52S-resistant mutant virus. This is consistent with previous studies which showed that while the 52S epitope could be formed in the absence of other virus products, virus gene expression was required for stable presentation of the LP11 epitope, and for transport of gH to the cell surface (Gompels and Minson, J. Virol. 63:4744-4755, 1989). All mutant viruses produced numbers of infectious particles that were similar to those produced by the wild-type virus, with the exception of one variant which produced lower yields.(ABSTRACT TRUNCATED AT 400 WORDS)


Diffractive optical elements with continuous relief fabricated by focused ion beam for monomode fiber coupling.
The design, microfabrication and testing of diffractive optical elements (DOE's) with continuous relief used for fiber coupling are discussed in detail. DOE's with diameters as small as 50 mm are fabricated by means of focused ion beam (FIB) technology. A focused Ga+ ion beam is used to mill a continuous relief microstructure at a 50 kV acceleration voltage. The optical performance of DOE's made in this way was compared with that of DOE's fabricated by other methods. The focusing performance of DOE's fabricated with three and six annulus by FIB milling was investigated. Testing of the system which has a coupling efficiency of -1.25 dB (75%) shows that the design meets the application's requirement for fiber coupling, and that DOE's manufactured by our FIB technology are practicable. Compared with a conventional fiber coupling system that uses a plano - convex lens, our system has the advantages of simplicity, short focal length, low cost for the lens and high coupling efficiency.


Utilizing three monoclonal antibodies in the development of an immunochromatographic assay for simultaneous detection of sulfamethazine, sulfadiazine, and sulfaquinoxaline residues in egg and chicken muscle.
A rapid and sensitive immunochromatographic assay (ICA) based on competitive format was developed and validated for simultaneous detection of sulfamethazine (SM(2)), sulfadiazine (SDZ), and sulfaquinoxaline (SQX) in chicken breast muscle and egg samples. For this purpose, three monoclonal antibodies raised against those three sulfonamides were conjugated to colloidal gold particles and applied to the conjugate pads of the test strip. The competitors of the sulfonamides (SM(2)/SDZ/SQX-bovine serum albumin conjugates) were immobilized onto a nitrocellulose membrane at three detection zones to form T(1), T(2), and T(3), respectively. With this method, the cutoff values for the three test lines were achieved at 80 μg/kg, which is lower than the maximum residue levels (MRLs) established for sulfonamides. The recoveries in negative samples spiked at concentrations of 10, 50, and 100 μg/kg ranged from 75% to 82% for egg samples and from 78% to 81% for chicken samples. The method was compared with the HPLC method by testing 180 eggs and chicken breast samples from local markets, and an agreement rate of 99.7% was obtained between the two methods.


Alcohol Use Patterns and DSM-5 Alcohol Use Disorder on Both Sides of the U.S.-Mexico Border.
Alcohol consumption patterns on the U.S.-Mexico border and their relationships with DSM-5 alcohol use disorders (AUD) have been understudied. Yet, the effects of drinking by Mexican-origin individuals may differ between cities on versus off the border both in the United States and in Mexico. We characterize prior 12-month drinking patterns and examine their relationships with AUD, in border and off-border cities of Texas and adjacent Mexican states. Data come from the U.S.-Mexico Study of Alcohol and Related Conditions involving 2,336 Mexican Americans in Texas and 2,460 Mexicans in bordering states of Nuevo Leon and Tamaulipas in Mexico. Drinking pattern was defined as an interaction between volume and maximum amount, or intensity (never vs. ever 5+/4+ [men/women], 8+, and 12+ drinks in a day). DSM-5 AUD was assessed using an adaptation of the Alcohol Section of the World Health Organization Composite International Diagnostic Interview core. Separately by gender, 5 logistic regressions models controlling for age were estimated predicting symptoms in 2 or more AUD criteria domains from volume, heavy pattern and, successively, effects of country, and (by country) residing on vs. off the border, or in each of 3 cities/country. A segmentation analysis for Texas males based on rate of experiencing AUD generated several distinct volume groups, each partitioned by an empirically selected maximum, and helped identify a drinking-pattern typology. In gender-stratified models of AUD rates using this typology, adjusting for age, significant volume and intensity effects were seen, more strongly in the United States. Border versus interior differences implied more AUD for given patterns at the border in the United States and the reverse in Mexico, with some city differences also evident. Drinking-pattern analyses confirm that border proximity may affect drinking problems but in opposite directions in the United States and Mexico, possibly related to economic and psychological stresses specific to respective communities.


Thyroid nodules and its association with vitamin D in centenarians.
Thyroid Nodules (TNs) and hypovitaminosis D are common conditions in old people. Our objective was to determine the prevalence of benign and malignant thyroid nodules in centenarians and to examine their associations with serum vitamin D levels. A population-based survey of 875 centenarians in Hainan, China was conducted. The thyroid glands and neck areas were scanned by board-certified sonographers using standard procedures. The prevalence of thyroid nodules (TN) was 74.2%, with 58.9% in group of possibly benign thyroid nodules (TIRADS 2, 3) and 15.5% in group of possibly malignant thyroid nodules (TIRADS 4A, 4B, 4C, 5). An analysis of logistic regression revealed that serum vitamin D levels were independently associated with increased thyroid nodule prevalence. We observed an inverse dose-effect relationship between TNs and serum vitamin D status with full adjustments (P for trend = 0.025%). For the severely vitamin D deficient group, the deficient group, and the insufficient group, respectively, odds ratios and 95% confidence intervals (OR: CI) for possibly malignant TNs were 3.46 (1.26-9.51), 2.15 (1.08-4.28), and 1.41 (0.72-2.75), compared to the optimal vitamin D status group. The multivariable OR with a 5 ng/mL decrease in serum vitamin D levels was 1.16 (95% CI: 1.01-1.33), for possibly malignant TNs in centenarians. Nearly three-quarters of centenarians were found to have thyroid nodules. Most of these nodules were benign and did not possess any suspicious ultrasound findings. Vitamin D deficiency was associated with thyroid nodules as suggestive characteristics of malignancy in this population.


A rare case report showing direct association between hepatitis B and bulbar palsy.
Bulbar Palsy is B/L impairment of function of cranial N. 9, 10, 11, 12 at lower motor neuron level either at nuclear or fascicular level in medulla or B/L lesion of lower cranial N. outside brainstem. We present case of viral hepatitis who initially presented with classical signs and symptoms of hepatitis B followed by characteristic features of bulbar palsy in form of difficulty in swallowing and slurring of speech reduced gag reflex, weak palatal movement. Other causes for bulbar palsy were excluded and indirect laryngoscopy confirmed presence of bulbar palsy. Patient had no previous neurological abnormality, there are many studies in the past for association of hepatitis B and bulbar palsy but no one confirmed about a direct association between hepatitis B and bulbar palsy. To best of knowledge this is the first case report which shows direct association between hepatitis B and bulbar palsy.


The Transformation of Achilles in The Iliad: A Reading from the Views of Sibling Narratives and Nonlinear Growth.
I wish to showcase the importance of plasticity of narrative in fantasy formations, as exemplified in Achilles' psychological trajectory in The Iliad. Applying conceptual formulations concerning the psychoanalytic developmental process to Achilles' growth piques my reflections about the sibling experience and its unique position in the mental life of children and adolescents. With developmental advance and the capacity for measured fluidity of self and other structures, the original sibling experience--whether it be tilted toward aggressiveness or toward loving concern or a place in between--may acquire new meanings. By locating it within this contextual framework, Achilles' story line can be seen as a metaphorical description of the continuous and discontinuous patterns in growth. This poses intriguing questions: What contexts are useful in pondering Achilles' psychological shifts? Might the domain of disposition prove useful? Is birth order another? Is his gradual empathic concern for the enemy a demonstration of an elasticity of imaginative capacity that reassembles murderous potential? Child and adult analysts alike may find a rich trove in Homer's masterpiece for contemplating potential sources within their patients that spur forward movement.


Data on the occurrence of a Brass texture and elastic anisotropy in laser blown powder processed superalloy IN718.
The additive manufacturing (AM) of components through laser-blown-powder directed-energy-deposition (LBP-DED) is highly applicable to the repair of aerospace components. Fabrication of superalloys with this technique, as with other AM methods, often encounters complications that include the formation of undesired phases, irregular microstructure and texture leading to anisotropic elastic properties. Heat treatments and other post-processing techniques can be used to mitigate these issues. The collected data demonstrates the effects of different heat treatment protocols on the microstructure, elastic properties, and hardness of LBP-DED IN718. In this study eight different heat treatment were used to investigate the effects of treatment time and temperature. The microstructure was investigated through SEM, with XRD and EDX used for phase analysis. The texture was characterised using SEM coupled with EBSD and the elastic properties were determined from resonant ultrasound spectroscopy.


Barnacle allergy: allergen characterization and cross-reactivity with mites.
Barnacles are a type of seafood with worldwide distribution and abundant along the shores of temperate seas. They are particularly appreciated and regularly consumed in Portugal as well as in Spain, France and South America, but barnacle allergy is a rare condition of which there is only one reference in the indexed literature. The molecular allergens and possible cross-reactivity phenomena implicated (namely with mites) have not been established. To demonstrate the IgE-mediated allergy to barnacle and to identify the proteins implicated as well as possible cross-reactivity phenomena with mites. We report the clinical and laboratory data of five patients with documented IgE-mediated allergy to barnacle. The diagnosis was based on a suggestive clinical history combined with positive skin prick tests (SPT) to barnacle--prick to prick method. Two barnacle extracts were prepared (raw and cooked barnacle) and sodium dodecylsulphate polyacrylamide gel electrophoresis (SDS-PAGE) and IgE-immunoblotting were performed. An immunoblotting inhibition assay with Dermatophagoides pteronyssinus was also done in order to evaluate cross-reactivity. All patients had mite-related asthma and the allergic rhinoconjunctivitis; they all experienced mucocutaneous symptoms. All of them had positive SPT to barnacle, and the immunoblotting showed several allergenic fractions with a wide molecular weight range (19 - 94 kDa). The D. pteronyssinus extract inhibited several IgE-binding protein fractions in the barnacle extract. We describe five patients with IgE-mediated barnacle allergy. We also describe a group of IgE-binding+proteins between 30 and 75 kDa as the allergenic fractions of this type of Crustacea. Cross-reactivity with D. pteronyssinus was demonstrated in two cases.


Methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus epidermidis infections in the cornea.
To describe the incidence and clinical management of corneal infections with methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant Staphylococcus epidermidis (MRSE). The incidence of methicillin-resistant Staphylococcus (MRS) at the Department of Ophthalmology, Kyoto Prefectural University of Medicine, was reviewed during the 5-year period from January 1996 to December 2000. Clinical aspects of MRS colonization or infection in the eye were investigated. Methicillin-resistant S. aureus or MRSE was detected from 30 eyes with ocular diseases; post-keratoplasty (11 eyes), ocular surface disorders without operation (9 eyes), and others (10 eyes). Among the 30 eyes, 12 manifested keratitis. Eight cases (8 eyes) occurred after keratoplasty, including four postoperative cases in patients with Stevens-Johnson syndrome, and two bilateral cases (4 eyes) in patients with acute-phase Stevens-Johnson syndrome. The degree of MRS keratitis was classified into 4 groups: asymptomatic carrier or conjunctivitis, intraepithelial infiltrations, superficial keratitis, and severe keratitis leading to corneal perforation. All cases of keratitis were treated successfully with topical ofloxacin (OFLX), vancomycin (VCM), or arbekacin (ABK). Factors associated with ocular MRS colonization were long-term use of antibiotics and/or steroids, and hospitalization. Patients who had undergone keratoplasty or who had Stevens-Johnson syndrome were at increased risk of MRS keratitis. Superficial stromal infiltrations, minimal melting, and minimal stromal scarring are characteristic of MRS keratitis. Therapy for MRS keratitis is summarized. Ofloxacin, VCM, and ABK are effective in the treatment of MRS keratitis. Vancomycin eye ointment is effective as the final choice in serious cases.


[Evaluation of cardiac load by measuring brain natriuretic peptide after thoracic esophagectomy and gastric tube in place].
A small dose of dopamine has been routinely infused for hemodynamic stabilization and diuresis in patients undergoing esophagectomy and gastric tube in place until the seventh postoperative day in our hospital. The timing of discontinuing infusion of dopamine was determined by our experience. However, there was no rationale to determine the timing of discontinuing it. Therefore, eight patients with ASA physical status I or II, undergoing esophagectomy and gastric tube in place were studied to evaluate postoperative cardiac load using brain natriuretic peptide, which is a biochemical detector of left ventricular dysfunction. There were no hemodynamic and cardiac events including myocardial ischemia and infarction in any patients. The postoperative course was uneventful in all patients. Serum BNP increased gradually and significantly until the third postoperative day with increasing urine volume. Serum BNP returned to the baseline level on the fourth postoperative day. However, serum BNP was still high in 3 patients on the sixth postoperative day in spite of dopamine. We conclude that cardiac overload was recognized until the third postoperative day.


Resolution No. G-960, 12 January 1988.
This Resolution restructures the Venezuelan Permanent Commission of Primary Health Attention. Among the departments of the Commission is a directorate for maternal-child care and family planning. Among the functions of the Commission are the following: 1) to coordinate primary health attention activities of the bureau and/or of other institutions in the Health sector of the country; 2) to give technical advice to those responsible for the practice or strategy of primary health attention at the national level, with an emphasis on health districts; 3) to designate working subcommissions, in conformity with the technical necessities of primary health attention; 4) to continue revising rules and procedures essential to those activities tied to primary health attention; and 5) to supervise and evaluate periodically the development of primary health attention.


Transient elastography with controlled attenuation parameter versus two-dimensional shear wave elastography with attenuation imaging for the evaluation of hepatic steatosis and fibrosis in NAFLD.
This study compared the controlled attenuation parameter (CAP) to attenuation imaging (ATI) in the diagnosis of steatosis and transient elastography (TE) to two-dimensional shear wave elastography (2D-SWE) for the diagnosis of fibrosis in a prospectively constructed nonalcoholic fatty liver disease (NAFLD) patient cohort. Participants who underwent TE with CAP were included from a previously constructed NAFLD cohort with multiparametric ultrasound data. The degree of hepatic steatosis and stage of liver fibrosis were assessed. Diagnostic performance was evaluated using the area under the receiver operating characteristic curve (AUROC) for the grades of steatosis (S1-3) and fibrosis (F0-F4). There were 105 participants. The distribution of hepatic steatosis grades (S0-S3) and liver fibrosis stages (F0-F4) was as follows: S0, n=34; S1, n=41; S2, n=22; S3, n=8; F0, n=63; F1, n=25; F2, n=5; F3, n=7; and F4, n=5. No significant difference was found between CAP and ATI in detecting ≥S1 (AUROC: 0.93 vs. 0.93, P=0.956) or ≥S2 (0.94 vs. 0.94, P=0.769). However, the AUROC of ATI in detecting ≥S3 was significantly higher than that of CAP (0.94 vs. 0.87, P=0.047). Regarding the detection of liver fibrosis, no significant difference was found between TE and 2D-SWE. The AUROCs of TE and 2D-SWE were as follows: ≥F1, 0.94 vs. 0.89 (P=0.107); ≥F2, 0.89 vs. 0.90 (P=0.644); ≥F3, 0.91 vs. 0.90 (P=0.703); and ≥F4, 0.88 vs. 0.92 (P=0.209). 2D-SWE and TE showed comparable diagnostic performance in assessing liver fibrosis, and ATI provided significantly better performance in detecting ≥S3 steatosis than CAP.


An m5C methylation regulator-associated signature predicts prognosis and therapy response in pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive digestive malignancy due to frequent late-stage diagnosis, rapid progression and resistance to therapy. With increasing PDAC incidence worldwide, there is an urgent need for new prognostic biomarkers and therapy targets. Recently, RNA methylation has emerged as a new tumorigenic mechanism in different cancers. 5-methylcytosine (m5C) is one of the most frequent RNA modifications and occurs on a variety of RNA species including mRNA, thereby regulating gene expression. Here we investigated the prognostic role of m5C-regulator-associated transcriptional signature in PDAC. We evaluated m5C-regulator status and expression in 239 PDAC samples from publicly available datasets. We used unsupervised consensus clustering analyses to classify PDACs based on m5C-regulator expression. From the resulting signature of differentially expressed genes (DEGs), we selected prognosis-relevant DEGs to stratify patients and build a scoring signature (m5C-score) through LASSO and multivariate Cox regression analyses. The m5C-score represented a highly significant independent prognostic marker. A high m5C-score correlated with poor prognosis in different PDAC cohorts, and was associated with the squamous/basal subtype as well as activated cancer-related pathways including Ras, MAPK and PI3K pathways. Furthermore, the m5C-score correlated with sensitivity to pathway-specific inhibitors of PARP, EGFR, AKT, HER2 and mTOR. Tumors with high m5C-score were characterized by overall immune exclusion, low CD8+ T-cell infiltration, and higher PD-L1 expression. Overall, the m5C-score represented a robust predictor of prognosis and therapy response in PDAC, which was associated with unfavorable molecular subtypes and immune microenvironment.


Children's judgements of psychological harm in normal and noncanonical situations.
This study investigated children's (3-, 5-, and 7-year-olds) and adults' (total N = 92) integration of information about intentions, acts, and outcomes in moral judgments of psychological harm. Behavioral and emotional predictions and judgments of act acceptability and punishment were made under normal and noncanonical causal conditions. Participants at all ages judged it wrong to inflict negative psychological reactions of fear or embarrassment on unwilling participants, even when these reactions were idiosyncratic or noncanonical. When assigning punishment, younger children tended to use an outcome rule, whereas older participants were more likely to use an intention rule or a conjunction rule (if outcome is negative and intention is negative, then punish). The results show that children as young as 3 years are able to take into account other people's idiosyncratic perspectives when making moral judgments of psychological harm.


Endoscopic Resection Without Subsequent Ablation Therapy for Early Barrett's Neoplasia: Endoscopic Findings and Long-Term Mortality.
After endoscopic resection (ER) of neoplasia in Barrett's esophagus (BE), it is recommended to ablate the remaining BE to minimize the risk for metachronous disease. However, we report long-term outcomes for a nationwide cohort of all patients who did not undergo ablation of the remaining BE after ER for early BE neoplasia, due to clinical reasons or performance status. Endoscopic therapy for BE neoplasia in the Netherlands is centralized in 8 expert centers with specifically trained endoscopists and pathologists. Uniformity is ensured by a joint protocol and regular group meetings. We report all patients who underwent ER for a neoplastic lesion between 2008 and 2018, without further ablation therapy. Outcomes include progression during endoscopic FU and all-cause mortality. Ninety-four patients were included with mean age 74 (± 10) years. ER was performed for low-grade dysplasia (LGD) (10%), high-grade dysplasia (HGD) (25%), or low-risk esophageal adenocarcinoma (EAC) (65%). No additional ablation was performed for several reasons; in 73 patients (78%), the main argument was expected limited life expectancy. Median C2M5 BE persisted after ER, and during median 21 months (IQR 11-51) with 4 endoscopies per patient, no patient progressed to advanced cancer. Seventeen patients (18%) developed HGD/EAC: all were curatively treated endoscopically. In total, 29/73 patients (40%) with expected limited life expectancy died due to unrelated causes during FU, none of EAC. In selected patients, ER monotherapy with endoscopic surveillance of the residual BE is a valid alternative to eradication therapy with ablation.


Epidemiology of Staphylococcus aureus bacteraemia at a tertiary children's hospital in Cape Town, South Africa.
Staphylococcus aureus is an important pathogen in paediatric patients with bloodstream infections. The epidemiology of S. aureus bacteraemia, however, has not been well documented in children in South Africa. A retrospective study was conducted at a children's hospital in Cape Town, South Africa, to investigate the epidemiology of S. aureus bacteraemia from 2007-2011. The incidence, clinical presentation, risk factors, management and outcomes of methicillin sensitive S. aureus (MSSA) and methicillin resistant S. aureus (MRSA) bacteraemia were compared. Over the five year study period, 365 episodes of S. aureus bacteraemia were identified. The annual incidence was 3.28 cases per 1000 hospital admissions. MRSA was responsible for 26% of S. aureus bacteraemia and 72% of nosocomial infections. Only six possible cases of community-acquired MRSA infections were described. MSSA bacteraemia was more likely to present as pulmonary and bone or joint infections, while bacteraemia without a source was the most common presentation with MRSA. Infants, children with malnutrition, and residents of long-term care facilities were at highest risk for MRSA bacteraemia. The overall case fatality rate for S. aureus bacteraemia was 8.8% over five years, with MRSA being the only significant risk factor for mortality. The incidence of S. aureus bacteraemia and MRSA bacteraemia in children has remained stable over the past five years. MRSA is a predominantly nosocomial pathogen in children with S. aureus bacteraemia in Cape Town, South Africa.


Frequent misdiagnosis of adult polyglucosan body disease.
Adult polyglucosan body disease (APBD) is a rare glycogenosis manifesting progressive spastic paraparesis, sensorimotor polyneuropathy and neurogenic bladder. Misdiagnosis of APBD may lead to unnecessary investigations and to potentially harmful therapeutic interventions. To examine the frequency of misdiagnosis of APBD, we retrospectively reviewed the clinical data of 30 patients diagnosed between 1991 and 2013. Diagnosis was based on the combination of typical clinical and imaging findings, reduced glycogen branching enzyme activity, and the presence of p.Y326S GBE1 mutation. Initial symptoms started in the 5th-6th decade with bladder dysfunction (47 %), gait problems (33 %) or both. Diagnosis of APBD was delayed by 6.8 (±4.8) years. Consistent signs at diagnosis were spasticity in the legs (93 %), decreased or absent ankle reflexes (100 %), bilateral extensor plantar response (100 %) and distal sensory deficit (80 %). Nerve conduction study showed invariable sensorimotor polyneuropathy, and MRI demonstrated cervical spinal cord atrophy (100 %) and leukoencephalopathy (97 %). All 30 patients were initially misdiagnosed. Common misdiagnoses included cerebral small vessel disease (27 %), multiple sclerosis (17 %), amyotrophic lateral sclerosis (17 %) and peripheral neuropathies (20 %). Consequently, 27 % received inappropriate therapy. In addition, lower urinary tract symptoms in 60 % of men were attributed solely to prostatic disorders but did not respond to medical treatment or prostatectomy. These findings suggest that despite limited clinical variability, APBD is invariably misdiagnosed and patients are often mistreated. Physicians' unfamiliarity with the typical clinical and imaging features of APBD appears as the main reason for misdiagnosis.


Peripheral vascular responses during stimulation of the low pressure receptors in man.
Several studies have been devoted to the cardiovascular responses to stimulation of low pressure receptors in animals. Yet, in man, the vascular participation in this reflex response is not fully documented. In the present work, the response of forearm and finger blood vessels was studied in a group of healthy subjects during stimulation of the low pressure receptors, using lower body negative pressure (LBNP) at -10, -20 and -40 mmHg. Blood flow was measured simultaneously at the forearm and the finger with an electrocardiogram (ECG)-triggered venous occlusion plethysmograph. Blood pressure remained unchanged at LBNP -10 and -20 mmHg, while there was a significant decrease of systolic and mean arterial blood pressure at LBNP -40 mmHg. Heart rate significantly increased at LBNP -20 and -40 mmHg, while no change in heart rate was seen at LBNP -10 mmHg. There was a significant decrease of blood flow at the forearm and a significant increase of the vascular resistance at LBNP -10, -20 and -40 mmHg. There were no changes in finger circulation. Thus, peripheral circulation is only partially involved in the cardiovascular response to stimulation of the low pressure receptors in men. There is a significant vasoconstriction of forearm blood vessels, occurring before any change in blood pressure and heart rate, while finger blood vessels do not participate in this reflex.


The effects of gadolinium, a stretch-sensitive channel blocker, on diaphragm muscle.
Stretch-activated channels (SAC) have been identified in many cell types including striated muscles. In diaphragm muscle, the influence of SAC on the length-active tension relationship remains unknown. Patch clamp experiments were performed on single fibres (n = 10). In isolated diaphragm muscle from adult hamsters, the effects of gadolinium (Gd3+), the most potent inhibitor of SAC blocker, on tension response to stretch at baseline were studied (n = 10), after pretreatment of the muscle with 1 nmol isoproterenol (n = 10), 0.5 micromol forskolin (n = 6), or 0.1 mmol dibutyryl cyclic adenosine monophosphate (cAMP) (n = 10). Results were compared to those obtained in low [Na+]e (n = 10), Ca2+-free medium (n = 6) or after 5 micromol nifedipine (n = 8). Gd3+ reduced active tension measured over a range of initial muscle lengths in a concentration-dependent manner (10 and 50 micromol). In isolated fibres, mechanical stretch generated a membrane current that was sensitive to Gd3+. In muscles, lowering [Na+]e mimicked the effects of Gd3+, while no change in the length-tension relationship was observed in Ca2+-free medium or after nifedipine. Drugs which increase cAMP prevented the effects of Gd3+ on active tension. In the diaphragm, gadolinium-sensitive channels are activated during physiological changes in length and influence tension development. Moreover, cyclic adenosine monophosphate content modulates the effects of gadolinium on stretch-activated channels.


Prevalence of filariasis in rural areas of Shahjahanpur district (Uttar Pradesh).
Night blood survey was carried out during May, 1990 to December, 1991 in 18 villages of 5 Primary Health Centres of district Shahjahanpur (UP), to find out the prevalence of filariasis in the area. Out of 2141 individuals surveyed randomly, 217 were found positive for microfilariae of Wuchereria bancrofti. The microfilaria rate, filarial disease rate and filarial endemicity rates were 10.1, 11.4 and 18.8 per cent respectively. An entomological survey revealed Culex quinquefasciatus as the vector. The average man hour density was 25.8. It is clear from the results that filariasis is more endemic in rural areas than urban area of Shahjahanpur as observed by local filariasis control unit.


[Perceptions of students and teachers about clinical medicine learning].
The transition to the clinical courses represents a major challenge for medical students who are expected to become experiential learners, able to integrate theory and practice in the context of patient care. There are questions about how students face this challenge. To understand and compare the perceptions of students and clinical tutors on how medical students learn during the transition to the clinical levels of the curriculum. We performed eight focus group discussions with 54 students enrolled in years three to seven and we interviewed eight clinical tutors. Both students' focus group discussions and tutors' interviews were audio recorded, transcribed and analyzed according to the Grounded Theory. Nine main themes emerged from the analysis of students' opinions and six from the tutors' views. The following themes were common to both students and educators: educational activities, actors, clinical settings, learning strategies, transition markers and tutor's role. Educators emphasized the importance of curricular courses' design and students, that of emotions, adaptation and self-care strategies, and threats to learning. There is a common core of students' and clinical tutors' perceptions about the relevance of practical activities, social interactions and context in the development of students' learning and adaptation strategies during the transition to the clinical levels of the curriculum. These results are related to social and cultural theories of learning. Thus we propose a model for early clinical learning that might help to stimulate the reflection of students and medical educators regarding clinical learning and contribute to the development of interventions that improve the clinical learning and teaching practices.


Triple recognition of B-DNA by a neomycin-Hoechst 33258-pyrene conjugate.
Recent developments have indicated that aminoglycoside binding is not limited to RNA, but to nucleic acids that, like RNA, adopt conformations similar to its A-form. We further sought to expand the utility of aminoglycoside binding to B-DNA structures by conjugating neomycin, an aminoglycoside antibiotic, with the B-DNA minor groove binding ligand Hoechst 33258. Envisioning a dual groove binding mode, we have extended the potential recognition process to include a third, intercalative moiety. Similar conjugates, which vary in the number of binding moieties but maintain identical linkages to allow direct comparisons to be made, have also been prepared. We report herein novel neomycin- and Hoechst 33258-based conjugates developed in our laboratories for exploring the recognition potential with B-DNA. Spectroscopic studies such as UV melting, differential scanning calorimetry, isothermal fluorescence titrations, and circular dichroism together illustrate the triple recognition of the novel conjugate containing neomycin, Hoechst 33258, and pyrene. This study represents the first example of DNA molecular recognition capable of minor versus major groove recognition in conjunction with intercalation.


The marketing concept applied to an education program.
Dietetic education programs seeking to maintain their enrollment levels may find it necessary to adopt more sophisticated marketing strategies. This article describes the application of the marketing process to an extended degree dietetic program that serves a national audience. It also presents a strategy for initiating a marketing study and marketing orientation by analyzing its internal program data. The article discusses the specific market characteristics of the program's primary market segments, and it presents further implications for dietitians at work in health care facilities, in businesses, or in private practice.


Delayed diagnosis of a pediatric airway foreign body: case report and review of the literature.
Foreign body aspiration is a common pediatric problem that affects children of all ages, including those who are well into their adolescence. We describe the case of a 9-year old boy with an airway foreign body that had gone unrecognized for 3 months. We also review the literature on pediatric airway foreign bodies, with a focus on delayed diagnosis. A diagnosis of foreign body aspiration should be considered whenever a previously healthy child suddenly exhibits unexplained symptoms that are refractory to medical treatment and are consistent with airway obstruction.


Activators of the Anticipatory Unfolded Protein Response with Enhanced Selectivity for Estrogen Receptor Positive Breast Cancer.
Approximately 75% of breast cancers are estrogen receptor alpha-positive (ERα+), and targeting ERα directly with ERα antagonists/degraders or indirectly with aromatase inhibitors is a successful therapeutic strategy. However, such treatments are rarely curative and development of resistance is universal. We recently reported ErSO, a compound that induces ERα-dependent cancer cell death through a mechanism distinct from clinically approved ERα drugs, via hyperactivation of the anticipatory unfolded protein response. ErSO has remarkable tumor-eradicative activity in multiple ERα+ tumor models. While ErSO has promise as a new drug, it has effects on ERα-negative (ERα-) cells in certain contexts. Herein, we construct modified versions of ErSO and identify variants with enhanced differential activity between ERα+ and ERα- cells. We report ErSO-DFP, a compound that maintains antitumor efficacy, has enhanced selectivity for ERα+ cancer cells, and is well tolerated in rodents. ErSO-DFP and related compounds represent an intriguing new class for the treatment of ERα+ cancers.


[Application of enhanced recovery after surgery in perioperative management of patients with gallbladder carcinoma].
Objective: To investigate the efficacy and safety of enhanced recovery after surgery (ERAS) in perioperative management of patients with gallbladder carcinoma. Methods: The data of the patients with gallbladder carcinoma admitted at Peking Union Medical College Hospital between January 2017 and December 2021 were analyzed retrospectively. There were 69 males(42.1%) and 95 females(57.9%),with age of (64.0±10.3) years(range:37 to 89 years). Patients were divided into ERAS group(n=53) and normal group(n=111) according to whether they were treated with ERAS measures during the perioperative period.The basic characteristics of the two groups were matched by propensity score matching,and then the perioperative information was compared between the two groups. Categorical variables were presented as absolute numbers or frequencies. Differences between study groups were analyzed using χ2 test, Fisher's exact test, t-test, or Mann-Whitney U test, as appropriate. Results: Each group had 45 patients after propensity score matching with well-balanced basic characteristics. There was no difference in basic characteristics, operation time,bleeding,complication,and hospitalization expenses between two groups(all P>0.05). Compared with the normal group,time of ambulation (M(IQR)) (1(1) day vs. 2(2) days;Z=-3.839,P<0.01),postoperative anal exhaust time (2(1) days vs. 3(1) days;Z=-3.013,P=0.003),feeding time(2(1) days vs. 2(1) days;Z=-3.647,P<0.01),postoperative (5(2) days vs. 7(4) days;Z=-3.984,P<0.01) and total(8(4) days vs. 13(6) days;Z=-3.605,P<0.01) hospitalization time were shorter in ERAS group. Postoperative complications occurred in 12 patients. According to the Clavien-Dindo classification,6,4,and 2 patients were classified as grade Ⅰ,Ⅱ,and Ⅲa,respectively. Conclusion: The ERAS measures is safe and effective for perioperative management of patients with gallbladder carcinoma, enhancing patient recovery and shortening hospitalization time without increasing complication or hospitalization cost.


Laryngograph: speech pattern element tools for therapy, training and assessment.
The clinically based, real-time analysis of speech into physically definable elements, which are of direct perceptual and productive importance, has become more readily possible in recent years as the result of microprocessor developments. The combination of the acoustic signal of speech derived from a microphone together with the accompanying Laryngograph signal provides the basis for a highly reliable set of facilities. The paper describes methods and results for the analysis of voice, frication and timbre for both quantitative analysis and teaching and therapy using interactive visual displays. A brief discussion is given of links to work in stroboscopy, electropalatography and the associated use of additional sensors. Finally reference is made to a complete clinical work station combining these different facilities together with the quantitative analytical procedures of the speech pattern audiometer.


Healthcare and Health Problems from the Perspective of Indigenous Population of the Peruvian Amazon: A Qualitative Study.
Indigenous communities usually experience higher levels of mortality and poorer access to healthcare services compared to non-indigenous communities. This study aims to understand the most prevalent health problems and their treatment in the Asháninka indigenous communities of the Peruvian Amazon. We conducted an ethnographic study in order to explore the perceived health problems, the use of traditional medicine and the resources offered by the official Peruvian healthcare system. Field notes and semi-structured interviews were used. A total of 16 indigenous and four non-indigenous people were interviewed, and interpretative analysis was used to identify themes. The Asháninka community is an overlooked population, which, due to distance restrictions, misconceptions and ethnical disparities, is far away from an appropriate healthcare system and is subjected to acute medical conditions such as infections and gastrointestinal problems. This group tends to seek traditional medicine, mostly herbal medications and traditional healers. The use of a health professional is seen as a last resort. Although the official Peruvian health system incorporates community participation strategies to improve the healthcare of indigenous people, the shortage of material, human resources and cultural sensitivity makes this difficult. Healthcare strategies should be devised and implemented in order to minimize health inequality in this population.


Systematic Review on Late Cochlear Implantation in Early-Deafened Adults and Adolescents: Predictors of Performance.
Early-deafened, late-implanted adolescents and adults constitute a unique group of cochlear implant (CI) users, showing a large variability in outcomes. The current systematic review aimed to determine which preimplantation factors are relevant in predicting postoperative outcomes in this patient group. A systematic search for studies published between 2000 and September 2017 was performed in five electronic databases (PubMed, Embase, the Cochrane library, CINAHL, and PsycInfo). Prognostic studies that assessed the relation between patient-related factors and CI outcomes in early-deafened but late-implanted adolescent and adult CI users were included. Study quality was assessed with the Quality In Prognosis Studies (QUIPS) tool. The systematic search and subsequent full-text evaluation identified 13 studies that had a clear prognostic study goal. Eight out of these 13 studies had a high risk of bias for at least one of the five QUIPS domains. Analysis of the outcomes identified that communication mode (in childhood), preoperative speech intelligibility, and preoperative speech recognition scores were significantly related to speech perception outcomes for this group of CI users. A number of additional factors considered worth for further investigation were also identified. The analysis of the studies assessing the effect of a number of patient-related factors on outcome with CI in early-deafened adolescents and adults identified three potential prognostic factors and a number of additional factors to be incorporated in future research. More high-quality prognosis studies in the investigated patient population are still needed.


Biochemical analysis of myelin proteins in a novel neurological mutant: the taiep rat.
Hemispheres, spinal cords, and sciatic nerves were taken from taiep, carrier, and control rats at ages ranging from 1 day to 16 months. Absolute myelin yields from CNS taiep tissues peaked at approximately 2 months and then decreased until they reached a low but stable level. Myelin yield from the affected hemispheres expressed as a percentage of age-matched controls decreased continuously from 2 weeks until it reached a stable level of approximately 10-15%. The same was true for the spinal cords, but here the myelin yield reached a plateau at a slightly higher percentage of 20-25%. In comparison with control rats, isolated CNS myelin fractions from the affected rats had a greater content of high molecular weight proteins. Western blot analyses of CNS homogenates revealed that myelin basic protein (MBP), proteolipid protein, and 2',3'-cyclic nucleotide 3'-phosphodiesterase were all present but decreased to levels generally consistent with the deficiencies of myelin. However myelin-associated glycoprotein (MAG) levels always were reduced much more than those of the other three myelin proteins, and at younger ages the apparent molecular weight for MAG was increased in the mutants. Western blot analyses of sciatic nerve homogenates showed that the levels of MBP, MAG, and P0 were not significantly different in control and mutant animals. These results suggested an early hypomyelination of the CNS, with peak levels of myelin at 2 months, followed by a prolonged period of myelin loss, until a very low but stable myelin level was reached. The consistently greater loss of MAG, in comparison with other CNS myelin proteins, is different from most other hypomyelinating mutants in which MAG is relatively preserved in comparison with the proteins of compact myelin. This might be due to microtubular abnormalities in the taiep mutant interfering with transport of myelin proteins and having the greatest effect on MAG because of its most distal location in the periaxonal oligodendroglial membranes.


Spirituality and holistic care.
National and international professional health and nursing guidelines recommend that attention should be given to the spiritual and religious needs of patients. This suggests that spiritual care is an important aspect of holistic patient care that needs to be considered and supported, if relevant, in a healthcare context.


Medication Costs and Use of Older Americans in Assisted Living Settings: a Nationally Representative Cross-Sectional Study.
Assisted-living (AL) settings are an important residential care option for old and disabled Americans, but there are no national data characterizing medication use in AL. To investigate medication costs and use of older adults living in the AL settings compared to those in the community, independent living, and nursing home settings. 2015 National Health and Aging Trends Study; nationally representative cross-sectional study. Respondents ≥ 65 years with Medicare Part D prescription drug coverage (n = 5980, representing 32.34 million older adults). Total Part D medication costs; number of 30-day prescription fills; binary indicators for overall polypharmacy (≥ 5 and ≥ 10 concurrent medications), prescription fills of opioid and psychotropic medications including antipsychotics, benzodiazepines, gabapentinoids, antidepressants, and central nervous system-active (CNS-active) polypharmacy. Adjusting for demographics, the annual medication costs among AL residents, at $3890, were twice as high as those of their community-dwelling counterparts ($1932; p < .01). All medication outcomes except opioids were higher for older adults in AL compared to community settings. While the adjusted number of 30-day prescription fills among AL residents was slightly lower than that of nursing home residents (89.5 vs. 106.2; p < .05), AL residents experienced equivalent rates of overall polypharmacy ≥ 10 medications (30.2% vs. 23.5%), antipsychotics (30.8% vs. 27.8%), benzodiazepines (30.7% vs. 32.6%), gabapentinoids (21.2% vs. 16.1%), and CNS-active polypharmacy (26.0% vs. 36.9%; p > .05 for all). Patterns of use across settings were consistent when limited to older adults with dementia. Older Americans in AL experience a prescription medication burden similar to those in nursing homes. AL settings have an important opportunity to ensure their medication-related clinical services and supports match the needs of their residents.


Association of the CHA2D(S2)-VASc Score and Its Components With Overt and Silent Ischemic Brain Lesions in Patients With Atrial Fibrillation.
Background: Silent and overt ischemic brain lesions are common and associated with adverse outcome. Whether the CHA2DS2-VASc score and its components predict magnetic resonance imaging (MRI)-detected ischemic silent and overt brain lesions in patients with atrial fibrillation (AF) is unclear. Methods: In this cross-sectional analysis, patients with AF were enrolled in a multicenter cohort study in Switzerland. Outcomes were clinically overt, silent [in the absence of a history of stroke/transient ischemic attack (TIA)] and any MRI-detected ischemic brain lesions. Logistic regression analyses were performed to assess the relationship of the CHA2DS2-VASc score and its components with ischemic brain lesions. An adapted CHA2D-VASc score (excluding history of stroke/TIA) for the analyses of clinically overt and silent ischemic brain lesions was used. Results: Overall, 1,741 patients were included in the analysis (age 73 ± 8 years, 27.4% female). At least one ischemic brain lesion was observed in 36.8% (clinically overt: 10.5%; silent: 22.9%; transient ischemic attack: 3.4%). The CHA2D-VASc score was strongly associated with clinically overt and silent ischemic brain lesions {odds ratio (OR) [95% confidence interval (CI)] 1.32 (1.17-1.49), p < 0.001 and 1.20 (1.10-1.30), p < 0.001, respectively}. Age 65-74 years (OR 2.58; 95%CI 1.29-5.90; p = 0.013), age ≥75 years (4.13; 2.07-9.43; p < 0.001), hypertension (1.90; 1.28-2.88; p = 0.002) and diabetes (1.48; 1.00-2.18; p = 0.047) were associated with clinically overt brain lesions, whereas age 65-74 years (1.95; 1.26-3.10; p = 0.004), age ≥75 years (3.06; 1.98-4.89; p < 0.001) and vascular disease (1.39; 1.07-1.79; p = 0.012) were associated with silent ischemic brain lesions. Conclusions: A higher CHA2D-VASc score was associated with a higher risk of both overt and silent ischemic brain lesions. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02105844.


[CADASIL with clinical manifestations of lumbago, hunchback and Parkinson's syndrome].
To report a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) manifesting as lumbago, hunchback and Parkinson's syndrome. A 49-years-old male CADASIL patient was reported. Results of clinical examination, neuroimaging and genetic testing were analyzed. His family members were also subjected to genetic testing. Related literature was reviewed. The patient had no typical symptoms of CADASIL such as headache, repeated stroke, dementia and emotional disorders, but progressive Parkinson's syndrome, late onset lumbago, hunchback, dysphagia, and diplopia. Brain MRI showed left basal ganglia and external capsule lacunar infarction. Genetic testing revealed a point mutation c.1630C>T (p.R544C) in exon 11 of the NOTCH3 gene. A heterozygous mutation was detected in the same gene in his mother, elder sister and younger brother, all of whom showed different clinical phenotypes. The clinical features of CADASIL are heterogeneous. Lumbago, humpback, and Parkinson's syndrome may be a rare clinical phenotype of CADASIL.


Simulation Analysis and Process Evaluation of Cooling Hole Forming Precision in Mask Assisted Electrochemical Machining Based on GH4169.
Good heat dissipation performance of aero-engine an effectively improve the service performance and service life of aero-engine. Therefore, this paper studies the machining method of cooling holes of high-temperature existent material GH 4169 for aero-engine innovatively puts forward the mask electrochemical machining method of cooling holes and explores the entrance morphology and taper formation law of the hole structure of high-temperature resistant material GH 4169. The mathematical model of anode dissolution of cooling holes in ECM is established, and the influence of voltage and electrolyte flow rate on cooling holes in ECM is analyzed. Compared with the mask-less electrochemical machining, the inlet radius of cooling holes in mask electrochemical machining is reduced by about 16.0% and the taper is reduced by 52.8% under the same machining parameters, which indicates that the electrochemical machining efficiency of mask is higher and the machining accuracy is better. Experiments show that the diameter of the mask structure improves the accuracy of the inlet profile of the cooling hole in the ECM. The diameter of the mask increases from 2 mm to 2.8 mm, and the inlet radius of the cooling hole increased from 1.257 mm to 1.451 mm When the diameter of the mask is 2.2 mm, the taper of the cooling hole decreased by 53.4%. The improvement effect is best, and the thickness of the mask has little influence on the forming accuracy of the cooling hole.


Iron Activates cGAS-STING Signaling and Promotes Hepatic Inflammation.
Iron deposition and chronic inflammation are associated with chronic liver diseases, such as alcoholic liver disease, nonalcoholic fatty liver disease, and chronic hepatitis B and C. However, the relationship between iron deposition and chronic inflammation in these diseases is still unclear. In the current study, we aimed to investigate the effect of iron on chronic inflammation in HepG2 cells and mice liver. We demonstrated that iron treatment enhanced the expression of cGAS, STING, and their downstream targets, including TBK1, IRF-3, and NF-κB in HepG2 cells and mice liver. We also found that treatment of HepG2 cells and mice with ferric ammonium citrate increased the expression of inflammatory cytokines, such as IFN-β. Finally, we found that genes involved in iron metabolism and the STING signaling pathway were up-regulated in liver cancer tissues, and the survival time of patients with high expression of these genes in tumor tissues was significantly shortened. These results suggest that iron overload may promote the progress of the chronic liver disease by activating cGAS-STING-mediated chronic inflammation, which provides a new idea for the development of drugs for the treatment of the chronic liver disease.


Genetic variants in the fibroblast growth factor pathway as potential markers of ovarian cancer risk, therapeutic response, and clinical outcome.
The fibroblast growth factor (FGF) and FGF receptor (FGFR) axis plays a critical role in tumorigenesis, but little is known of its influence in ovarian cancer. We sought to determine the association of genetic variants in the FGF pathway with risk, therapeutic response, and survival of patients with ovarian cancer. We matched 339 non-Hispanic white ovarian cancer cases with 349 healthy controls and genotyped them for 183 single-nucleotide polymorphisms (SNPs) from 24 FGF (fibroblast growth factor) and FGFR (fibroblast growth factor receptor) genes. Genetic associations for the main effect, gene-gene interactions, and the cumulative effect were determined. Multiple SNPs in the FGF-FGFR axis were associated with an increased risk of ovarian cancer. In particular, FGF1 [fibroblast growth factor 1 (acidic)] SNP rs7727832 showed the most significant association with ovarian cancer (odds ratio, 2.27; 95% CI, 1.31-3.95). Ten SNPs were associated with a reduced risk of ovarian cancer. FGF18 (fibroblast growth factor 18) SNP rs3806929, FGF7 (fibroblast growth factor 7) SNP rs9920722, FGF23 (fibroblast growth factor 23) SNP rs12812339, and FGF5 (fibroblast growth factor 5) SNP rs3733336 were significantly associated with a favorable treatment response, with a reduction of risk of nonresponse of 40% to 60%. Eleven SNPs were significantly associated with overall survival. Of these SNPs, FGF23 rs7961824 was the most significantly associated with improved prognosis (hazard ratio, 0.55; 95% CI, 0.39-0.78) and was associated with significantly longer survival durations, compared with individuals with the common genotype at this locus (58.1 months vs. 38.0 months, P = 0.005). Survival tree analysis revealed FGF2 rs167428 as the primary factor contributing to overall survival. Significant associations of genetic variants in the FGF pathway were associated with ovarian cancer risk, therapeutic response, and survival. The discovery of multiple SNPs in the FGF-FGFR pathway provides a molecular approach for risk assessment, monitoring therapeutic response, and prognosis.


[Inflammatory response mediators in newborns and infants with congenital heart diseases during surgical treatment under extracorporeal circulation].
Surgical treatment of complex congenital heart disease under extracorporeal circulation is accompanied by a systemic inflammatory reaction occurring in neonatal infants and babies. There were drastic increases in the concentration of tumor necrosis factor, interleukin-8, neutrophilic elastase and a predominance of a proinflammatory response over an inflammatory one at the warming stages and after administration of protamine sulfate. The rate of an inflammatory response depended on the duration of extracorporeal circulation. Modified ultrafiltration could remove cytokines; however, their concentration in the body remains high. A relationship was found between the course of a postoperative period and the rate of a developing reaction to extracorporeal circulation in the surgical treatment of congenital heart diseases.


Host IQGAP1 and Ebola virus VP40 interactions facilitate virus-like particle egress.
We have identified host IQGAP1 as an interacting partner for Ebola virus (EBOV) VP40, and its expression is required for EBOV VP40 virus-like particle (VLP) budding. IQGAP1 is involved in actin cytoskeletal remodeling during cell migration and formation of filopodia. The physical interaction and the functional requirement for IQGAP1 in EBOV VP40 VLP egress link virus budding to the cytoskeletal remodeling machinery. Consequently, this interaction represents a novel target for development of therapeutics to block budding and transmission of filoviruses.


Long-term transgene expression in mice infected with a herpes simplex virus type 1 mutant severely impaired for immediate-early gene expression.
The role of viral immediate-early (IE) gene expression in herpes simplex virus type 1 (HSV-1) latency was investigated. The HSV-1 multiple mutant in1312, defective for the expression of the virion transactivator VP16 and the IE proteins ICP0 and ICP4, was used as the parent for these studies. The coding sequences of the Escherichia coli lacZ gene, preceded by the encephalomyocarditis virus internal ribosome entry site, were inserted into the region of in1312 that encodes the latency-associated transcripts (LATs) such that transcription of the transgene was controlled by the LAT promoter. This insert has previously been shown to direct long-term latent-phase expression of beta-galactosidase in a wild-type HSV-1 genome (R. H. Lachmann and S. Efstathiou, J. Virol. 71, 3197-3207, 1997). The resulting recombinant, in1388, was apathogenic after inoculation into mice via the footpad and did not detectably replicate in dorsal root ganglia (DRG) or footpads. Mutant in1388 established latency in DRG, and beta-galactosidase was expressed in increasing numbers of neurons over the first 25 days of infection. During latency, more than 1% of neurons in ganglia that innervate the footpad expressed beta-galactosidase, with the number of positive cells remaining constant for at least 5 months. Rescue of the VP16, ICP0, or ICP4 mutations of in1388 did not affect the number of beta-galactosidase-expressing neurons detected during latency. The results demonstrate that HSV-1 mutants severely impaired for IE gene expression are capable of establishing latency and efficiently expressing a foreign gene product under control of the LAT promoter.


Online Rumor Diffusion Model Based on Variation and Silence Phenomenon in the Context of COVID-19.
In the era of mobile internet, information dissemination has made a new leap in speed and in breadth. With the outbreak of the coronavirus disease 2019 (COVID-19), the COVID-19 rumor diffusion that is not limited by time and by space often becomes extremely complex and fickle. It is also normal that a piece of unsubstantiated news about COVID-19 could develop to many versions. We focus on the stagnant role and information variants in the process of rumor diffusion about COVID-19, and through the study of variability and silence in the dissemination, which combines the effects of stagnation phenomenon and information variation on the whole communication system in the circulation of rumors about COVID-19, based on the classic rumor SIR (Susceptible Infected Recovered) model, we introduce a new concept of "variation" and "oyster". The stability of the new model is analyzed by the mean field equation, and the threshold of COVID-19 rumor propagation is obtained later. According to the results of the simulation experiment, whether in the small world network or in the scale-free network, the increase of the immure and the silent probability of the variation can effectively reduce the speed of rumor diffusion about COVID-19 and is conducive to the dissemination of the truth in the whole population. Studies have also shown that increasing the silence rate of variation can reduce COVID-19 rumor transmission more quickly than the immunization rate. The interesting discovery is that at the same time, a higher rumor infection rate can bring more rumors about COVID-19 but does not always maintain a high number of the variation which could reduce variant tendency of rumors. The more information diffuses in the social group, the more consistent the version and content of the information will be, which proves that the more adequate each individual information is, the slower and less likely rumors about COVID-19 spread. This consequence tells us that the government needs to guide the public to the truth. Announcing the true information publicly could instantly contain the COVID-19 rumor diffusion well rather than making them hidden or voiceless.


Deep learning via LSTM models for COVID-19 infection forecasting in India.
The COVID-19 pandemic continues to have major impact to health and medical infrastructure, economy, and agriculture. Prominent computational and mathematical models have been unreliable due to the complexity of the spread of infections. Moreover, lack of data collection and reporting makes modelling attempts difficult and unreliable. Hence, we need to re-look at the situation with reliable data sources and innovative forecasting models. Deep learning models such as recurrent neural networks are well suited for modelling spatiotemporal sequences. In this paper, we apply recurrent neural networks such as long short term memory (LSTM), bidirectional LSTM, and encoder-decoder LSTM models for multi-step (short-term) COVID-19 infection forecasting. We select Indian states with COVID-19 hotpots and capture the first (2020) and second (2021) wave of infections and provide two months ahead forecast. Our model predicts that the likelihood of another wave of infections in October and November 2021 is low; however, the authorities need to be vigilant given emerging variants of the virus. The accuracy of the predictions motivate the application of the method in other countries and regions. Nevertheless, the challenges in modelling remain due to the reliability of data and difficulties in capturing factors such as population density, logistics, and social aspects such as culture and lifestyle.


TOF-SIMS imaging reveals tumor heterogeneity and inflammatory response markers in the microenvironment of basal cell carcinoma.
Basal cell carcinoma (BCC) is the most common skin malignancy. In fact, it is as common as the sum of all other skin malignancies combined and the incidence is rising. In this focused and histology-guided study, tissue from a patient diagnosed with aggressive BCC was analyzed by imaging mass spectrometry in order to probe the chemistry of the complex tumor environment. Time-of-flight secondary ion mass spectrometry using a (CO2)6 k + gas cluster ion beam allowed a wide range of lipid species to be detected. Their distributions were then imaged in the tissue that contained small tumor islands that were histologically classified as more/less aggressive. Maximum autocorrelation factor (MAF) analysis highlighted chemical differences between the tumors and the surrounding stroma. A closer inspection of the distribution of individual ions, selected based on the MAF loadings, showed heterogeneity in signal between different microtumors, suggesting the potential of chemically grading the aggressiveness of each individual tumor island. Sphingomyelin lipids were found to be located in stroma containing inflammatory cells.


Complexity of human postural control in young and older adults during prolonged standing.
Aging is known to have a degrading influence on many structures and functions of the human sensorimotor system. The present work assessed aging-related changes in postural sway using fractal and complexity measures of the center of pressure (COP) dynamics with the hypothesis that complexity and fractality decreases in the older individuals. Older subjects (68 +/- 4 years) and young adult subjects (28 +/- 7 years) performed a quiet stance task (60 s) and a prolonged standing task (30 min) where subjects were allowed to move freely. Long-range correlations (fractality) of the data were estimated by the detrended fluctuation analysis (DFA); changes in entropy were estimated by the multi-scale entropy (MSE) measure. The DFA results showed that the fractal dimension was lower for the older subjects in comparison to the young adults but the fractal dimensions of both groups were not different from a 1/f noise, for time intervals between 10 and 600 s. The MSE analysis performed with the typically applied adjustment to the criterion distance showed a higher degree of complexity in the older subjects, which is inconsistent with the hypothesis that complexity in the human physiological system decreases with aging. The same MSE analysis performed without adjustment showed no differences between the groups. Taken all results together, the decrease in total postural sway and long-range correlations in older individuals are signs of an adaptation process reflecting the diminishing ability to generate adequate responses on a longer time scale.


HIV/AIDS and aging.
Average life expectancy in developed countries has rapidly increased in the middle of the 20th century and the geriatric problems have become an increasingly important issue. Many diseases in the elderly are more frequent and more severe in comparison to the younger population. This is certainly true for the infectious diseases which are in the elderly associated with poor outcome, moreover they have often the distinct features with respect to clinical presentation, laboratory and imaging test results, microbial epidemiology, and methods of treatment. The most important reasons why the diseases in the elderly are more frequent and more severe these are: typical for advanced age immunosenescence, malnutrition, large number of age-associated social, psychological, economical, moreover physiological and anatomical alterations. The older HIV positive adults, have lower CD4 counts at moment of diagnosis, faster progression to AIDS, more opportunistic infections, shorter survival rate than younger adults--regardless of when they were first diagnosed with HIV.


Gender Differences in Genetic Associations of RAB38 with Urinary Protein-to-Creatinine Ratio (UPCR) Levels in Diabetic Nephropathy Patients.
Renal dysfunction is common in patients with diabetes mellitus (DM). Previous findings from a meta-analysis of GWAS indicated that the variation of RAB38/CTSC is highly associated with the urinary albumin-to-creatinine ratio (UACR) in European populations. In addition, RAB38 knockout rats showed an increase in urinary albumins. Although the prevalence of chronic kidney disease is high in Taiwan, the role of genetic variants in diabetic renal function is still unclear. In the current study, 275 diabetic nephropathy (DN) patients were recruited to perform a genetic association study. Our results indicated that rs1027027, rs302647, and rs302646 in RAB38 were significantly associated with urinary protein-to-creatinine ratio (UPCR) levels in DN patients. Importantly, after analysis stratified by gender, a significant genetic influence on UPCR levels was observed in the male population. The findings confirmed the roles of gender and variants of RAB38 in the risk of UPCR in Diabetic Nephropathy patients.


Pregnancy and lactation are associated with diminished concentrations of choline and its metabolites in rat liver.
Choline is an important nutrient that is actively transported from mother to fetus across the placenta and from mother to infant across the mammary gland. Thus, pregnancy and lactation are times when dietary requirements for choline may be increased. Pregnant rats eating AIN-76A diet (with and without choline) for 6 d (d 12-18 gestation) were compared with nonmated female and male rats eating the same diets. Similarly, lactating rats were compared with nonmated female rats, both groups eating these same diets for 25 d (gestation d 12-postpartum d 15). We measured choline and choline metabolites in livers on the last day of feeding. Nonmated female rats, eating the control diet, had higher hepatic choline metabolites concentrations than did male rats (choline, 98%; betaine, 96%; and phosphorylcholine, 55% higher), pregnant rats (phosphorylcholine, 47%; and betaine, 42% higher) or lactating rats (phosphorylcholine, 49%; phosphatidylcholine, 37%; and betaine, 273% higher). We found that nonmated females eating a choline deficient diet had only a modest diminution (33%) of the labile choline metabolite PCho in liver, compared with similar rats eating a control diet. When compared with similar rats fed a choline-adequate diet, pregnant rats fed a choline-deficient diet had significantly great diminution of hepatic phosphorylcholine (83% lower) than did nonmated females. Liver phosphorylcholine was only 12% lower than in controls in nonmated females fed the deficient diet for the same 25-d period. Lactating rats were the most sensitive to choline deficiency, with liver phosphorylcholine 88% lower than in similar rats fed control diet.(ABSTRACT TRUNCATED AT 250 WORDS)


Rasagiline and safinamide as a dopamine-sparing therapy for Parkinson's disease.
To evaluate whether the prescription of monoamine oxidase B inhibitors (MAOB-I), rasagiline and safinamide, contributes to the reduction of levodopa and/or dopamine agonists (DA) dose in order to minimize adverse effects. A total of 724 patients with Parkinson's disease (PD) have been prospectively included in our database since the year 2000, representing a total of 5124 visits. For each patient and visit, antiparkinsonian treatment was recorded. In the presence of rasagiline and safinamide, we analysed the evolution of levodopa equivalent dose (LED) and LED for DA (LED-DA). The data obtained from the 1664 visits between 2006 and 2010 (321 patients) and the 1709 visits between 2014 and 2018 (403 patients) were analysed in order to assess the impact of the introduction of rasagiline and safinamide, respectively. The annual mean LED remained stable without statistically significant differences. In the first period (impact of rasagiline), the annual mean LED-DA in 2010 was significantly higher than in 2006 (P = 0.001). In the second period (impact of safinamide), the annual mean LED-DA in 2018 was significantly lower than in 2014 (P = 0.002). A repeated-measure analyses of LED-DA including only patients who had taken safinamide showed a statistically significant decrease in LED-DA (P = 0.027). The introduction of MAOB-I in the overall treatment of PD as part of routine clinical practice has not helped to reduce annual mean LED. However, safinamide reduces annual mean LED-DA and may be linked to a reduction in dose-dependent adverse effects in the long term.


What do palliative staff think about audit?
Forty-one of 68 palliative care clinicians responded to an anonymous questionnaire assessing the attitudinal, training, management, and support needs for introducing audit. Most respondents (88%) felt it was a good idea; reservations concerned the increase in work load. Although 66% of respondents had received audit training, only 39% were currently involved in audit. Respondents identified a need for more information and feedback, experienced assistance, and support. These concerns have to be addressed by health care managers if audit is to be successfully maintained. Current training sessions do not adequately meet staff needs; palliative care staff require an advanced audit training that includes staff motivation, analysis of results, and the provision of feedback.


Late corneal perforation with topical diclofenac sodium use after radiotherapy.
To report a case of spontaneous corneal perforation after radiotherapy connected with long-term use of topical 0.1% diclofenac sodium. A 31-year-old man presented with corneal melting and spontaneous corneal perforation. From his medical history, it was learned that he underwent radiotherapy for his nasopharyngeal carcinoma 25 months ago. He has been on artificial tears and topical 0.1% diclofenac sodium for 1 month for his dry eye. Diclofenac sodium was discontinued, and the corneal perforation site was sutured along with a bandage contact lens application. Melting area disappeared, and stromal opacity was detected at the site of corneal perforation. Use of long-term diclofenac sodium for dry eye after radiotherapy was possibly responsible for the spontaneous corneal perforation in our patient. It should always be borne in mind that topical diclofenac sodium should be used with caution in patients with compromised ocular surface.


Conserved proline residue at position 189 in cone visual pigments as a determinant of molecular properties different from rhodopsins.
To identify the amino acid residue(s) responsible for the difference in the molecular properties between rod and cone pigments, we have prepared chicken green mutants where each of the residues (Val77, Gly144, and Pro189) completely conserved in the cone pigments was replaced with the residue in the rod pigment rhodopsin. Among the mutants, the P189I mutant showed an expression level in cultured HEK293 cells and a thermal stability higher than did the wild-type chicken green. The mutation caused a reduced decay rate of the meta II intermediate, while the mutation of the wild-type chicken rhodopsin at position 189 (I189P) resulted in an increased decay rate. The additional mutation at position 122, the previously reported site where the amino acid residue is one of the determinants of the meta II decay rate, converted the meta II decay rate into that observed in the wild-type chicken rhodopsin. These results suggest that the difference in the meta II decay rate between the chicken green and rhodopsin is due to the difference in the amino acid residues at positions 189 and 122. The completely conserved nature of proline at position 189 could provide a clue to the molecular evolution of the pigments.


Pulmonary gas exchange responses to histamine and methacholine challenges in mild asthma.
Histamine (HIST) produces greater changes in bronchial and pulmonary vasculature, and so may produce more gas exchange abnormalities, than methacholine (MTH) after inhalational challenge. The goals of this study were to compare the effects of HIST and MTH challenge on pulmonary gas exchange in patients with mild asthma at an equivalent degree of bronchoconstriction. Eleven patients were studied (mean+/-SEM age, 22+/-1 yr; forced expiratory volume in one second (FEV1), 91+/-5% pred) using a randomized, double-blind cross-over design. Respiratory system resistance (Rrs), arterial blood gases, and ventilation-perfusion distributions were measured before and after HIST/MTH challenges when cumulative doses caused a 30% fall in FEV1. Compared with baseline, HIST and MTH provoked similar moderate to severe increases in Rrs (p<0.005 each), and mild to moderate decreases in arterial oxygen tension (Pa,O2) due to ventilation-perfusion abnormalities (dispersion of pulmonary blood flow -log SDQ-, 0.40+/-0.03-0.71+/-0.08 and 0.47+/-0.04-0.89+/-0.06; normal values <0.60-0.65), respectively, similar to those shown in mild to moderate acute asthma, without differences between them. For the same degree of airflow obstruction, both histamine and methacholine bronchoprovocations induce, in patients with mild asthma, very similar disturbances in ventilation-perfusion distribution and respiratory system resistance, suggesting similar mechanisms of airway narrowing.


Genetic effects and sexual dimorphism in tyrosine hydroxylase activity in two mouse strains and their reciprocal F1 hybrids.
This study further analyzed the environmental and genetic mechanisms underlying the previously reported strain differences in tyrosine hydroxylase (TH) activity in the nigrostriatal and hypothalamic dopamine system of the BALB/cJ (B) and CBA/J (C) inbred mouse strains and related behavioral processes using parental and reciprocal F1 hybrid generations. Significant strain differences were found in both sexes in all the measured characters. Comparing males and females, sexual dimorphisms were found in TH activity of substantia nigra (SN), corpus striatum (CS) and hypothalamus (H), and in exploratory behavior (IE). Presence of sexual dimorphism was genotype dependent, with the exception of TH activity in H. Major components of strain differences, maternal effects and additive gene effects, were separated by biometrical genetic methods. The analysis indicated that significant maternal effects were present in TH activity of TH and CS with a trend towards this phenomenon in the SN. Additive gene effects were significant in all characters and various degrees of dominance were expressed in the hybrids in TH activity of SN and CS, as well as in behavioral traits, IE and spontaneous locomotion (SL). All the biochemical and behavioral parameters were expressed at lower levels in CBA/J than in BALB/cJ mice and reciprocal F1 hybrids took intermediate positions between the two parental strains for all phenotypes examined, with the exception of IE, where complete dominance was found in (CXB)F1 females. These results are consistent with the hypothesis that some of the genes affecting TH activity in brain dopamine systems contribute to the expression of dopamine mediated behaviors. Our analysis also indicates the possibility that the maternal effects on TH activity in CS and SN are the consequences of X-chromosome linked gene effects. We suggest that the influence of the X-chromosome linked gene(s) is dependent upon the action of gonadal steroids during the critical period of ontogenesis, and X-chromosome linked gene(s) play a major role in the genotype dependent expression of sexual dimorphism in TH activity.


Optogenetic Application to Investigating Cell Behavior and Neurological Disease.
Cells reside in a dynamic microenvironment that presents them with regulatory signals that vary in time, space, and amplitude. The cell, in turn, interprets these signals and accordingly initiates downstream processes including cell proliferation, differentiation, migration, and self-organization. Conventional approaches to perturb and investigate signaling pathways (e.g., agonist/antagonist addition, overexpression, silencing, knockouts) are often binary perturbations that do not offer precise control over signaling levels, and/or provide limited spatial or temporal control. In contrast, optogenetics leverages light-sensitive proteins to control cellular signaling dynamics and target gene expression and, by virtue of precise hardware control over illumination, offers the capacity to interrogate how spatiotemporally varying signals modulate gene regulatory networks and cellular behaviors. Recent studies have employed various optogenetic systems in stem cell, embryonic, and somatic cell patterning studies, which have addressed fundamental questions of how cell-cell communication, subcellular protein localization, and signal integration affect cell fate. Other efforts have explored how alteration of signaling dynamics may contribute to neurological diseases and have in the process created physiologically relevant models that could inform new therapeutic strategies. In this review, we focus on emerging applications within the expanding field of optogenetics to study gene regulation, cell signaling, neurodevelopment, and neurological disorders, and we comment on current limitations and future directions for the growth of the field.


The macrophage mannose receptor induces IL-17 in response to Candida albicans.
The cytokine IL-17 controls neutrophil-mediated inflammatory responses. The pattern recognition receptor(s) that induce Th17 responses during infection, in the absence of artificial mitogenic stimulation with anti-CD3/anti-CD28 antibodies, remain obscure. We investigated the innate immune receptors and pathogen-associated molecular patterns involved in triggering Th17 responses during pathogen-specific host defense. The prototypic fungal pathogen Candida albicans was found to induce IL-17 more potently than Gram-negative bacteria. Candida mannan, but not zymosan, beta-glucans, Toll-like receptor (TLR) agonists, or the NOD2 ligand MDP, induced IL-17 production in the absence of anti-CD3/anti-CD28 antibodies. Candida-induced IL-17 response was dependent on antigen-presenting cells and the macrophage mannose receptor (MR), demonstrating that Candida mannan is not simply a mitogenic stimulus. The TLR2/dectin-1 pathway, but not TLR4 or NOD2, amplified MR-induced IL-17 production. This study identifies the specific pattern recognition receptors that trigger the Th17 response induced by a human pathogen in the absence of mitogenic stimulation.


Neighborhood, neighborliness, and family and child well-being.
Although neighborhood context is a well-recognized factor in the well-being of children and families, little systematic research exists to guide inquiries into the intersection of neighborhood social processes and child and family well-being. Moreover, despite the increased popularity of neighborhood effects research over the last several decades, crucial questions around the debate on how to align research findings with tangible experiences for children and families remain open. This article reviews selected studies that linked neighborhood factors to specific domains of child and family well-being: parenting, safety, health, and educational outcomes. By focusing on neighborliness, a particular form of neighboring, the study aims to shift the focus from macrolevel indicators of neighborhood context, to a more dynamic set of attributes that characterize neighborhood life, with the hope of inspiring others to build upon the findings and begin to translate the conclusions to meaningful policies and programs. (PsycInfo Database Record (c) 2021 APA, all rights reserved).