Search for hemodynamic compromise at 11-14 weeks in monochorionic twin pregnancy: is abnormal flow in the ductus venosus predictive of twin-twin transfusion syndrome?
Twin-twin transfusion syndrome is a devastating complication of monochorionic twin pregnancies. The presence of increased nuchal translucency thickness (NT) in one of the monochorionic twins has been associated with an increased risk of developing this syndrome. One of the most plausible mechanisms for increased nuchal translucency is heart failure, indirectly manifested by abnormal blood flow in the ductus venosus. We aimed to clarify the pathophysiology of increased NT found more frequently in monochorionic twins prone to develop twin-twin transfusion syndrome. We present 50 cases of monochorionic twin pregnancies in which nuchal translucency thickness was measured and ductus venosus blood flow evaluation was performed at 11-14 weeks of gestation. Whenever the fetuses of a twin pregnancy were found to have discrepant nuchal translucency thickness measurements and abnormal flow in the ductus venosus was found in the fetus with increased nuchal translucency thickness, twin-twin transfusion syndrome eventually developed. Progression to twin-to-twin transfusion syndrome was not observed in the twins displaying no intertwin difference in nuchal translucency thickness measurements and it was not observed in those with discrepant nuchal translucency thickness but normal flow in the ductus venosus of both fetuses. In the two cases which developed twin-to-twin transfusion syndrome, fetoscopic laser coagulation of the vascular anastomoses was successfully carried out at 18 weeks and normalization of the venous return was recorded. Both increased nuchal translucency and abnormal flow in the ductus venosus in monochorionic twins may be early manifestations of haemodynamic imbalance between donor and recipient. The combined evaluation of both parameters in monochorionic twin pregnancies may constitute an effective method for identifying those at risk of developing twin-to-twin transfusion syndrome.


Semiconductive microporous hydrogen-bonded organophosphonic acid frameworks.
Herein, we report a semiconductive, proton-conductive, microporous hydrogen-bonded organic framework (HOF) derived from phenylphosphonic acid and 5,10,15,20-tetrakis[p-phenylphosphonic acid] porphyrin (GTUB5). The structure of GTUB5 was characterized using single crystal X-ray diffraction. A narrow band gap of 1.56 eV was extracted from a UV-Vis spectrum of pure GTUB5 crystals, in excellent agreement with the 1.65 eV band gap obtained from DFT calculations. The same band gap was also measured for GTUB5 in DMSO. The proton conductivity of GTUB5 was measured to be 3.00 × 10-6 S cm-1 at 75 °C and 75% relative humidity. The surface area was estimated to be 422 m2 g-1 from grand canonical Monte Carlo simulations. XRD showed that GTUB5 is thermally stable under relative humidities of up to 90% at 90 °C. These findings pave the way for a new family of organic, microporous, and semiconducting materials with high surface areas and high thermal stabilities.


Successful Percutaneous Closure of a Ruptured Saphenous Vein Graft Aneurysm.
A 68-year-old man with previous coronary artery bypass surgery presented with acute onset chest pain. After ruling out an acute coronary syndrome, a computed tomography scan demonstrated a giant aneurysm (10 cm × 8 cm) of the right coronary artery saphenous vein graft (SVG) with signs of rupture into the mediastinum. An Amplatzer Vascular Plug II was successfully deployed at the proximal anastomosis of the SVG, achieving complete exclusion. At 6-month follow-up the patient remained asymptomatic and a computed tomography scan confirmed adequate position of the device. Amplatzer Vascular Plug II is a reasonable alternative for SVG aneurysm closure, providing the vein graft supplies nonviable myocardium.


Role of Hyperhomocysteinemia and Hyperuricemia in Pathogenesis of Atherosclerosis.
The mechanisms of hyperhomocysteinemia (HHcy) and hyperuricemia (HUA) that promote atherosclerosis were seldom explored and always indefinite. Therefore, we will discuss some new reviews about the role of HHcy and HUA in the pathogenesis of atherosclerosis. This study was conducted by reading a lot of literature, including basic research and clinical application research. HHcy is known as an independent risk factor for atherosclerosis. Possible mechanisms for the association between homocysteine and atherosclerosis include stimulating smooth muscle cell growth, reducing endothelial cell growth and endothelial cell relaxation, and decreasing synthesis of high-density lipoprotein. HUA causes endothelial dysfunction and thereby increases oxidative stress, inducing vascular smooth muscle cell proliferation and reducing endothelial nitric oxide bioavailability. HUA plays a role in the development and pathogenesis of metabolic syndrome, hypertension, stroke, and atherosclerosis. Accelerated atherosclerosis may be a consequence of the combined effect of HHcy and HUA.


[HDL cholesterol in diabetes mellitus type II].
The results of a study conducted on 60 diabetics are reported. The HDL cholesterol levels of the diabetics and healthy controls of the same sex and age were compared and no statistically significant differences were found: 49.3 +/- 12 (diabetics) versus 47.6 +/- 9 (controls).


Adolph Seeligmüller's contribution to myotonia congenita Thomsen.
In 1876, two articles appeared in Germany in different medical journals under almost the same title "Tonische Krämpfe in willkürlich beweglichen Muskeln in Folge von ererbter psychischer Disposition (Ataxia muscularis?)1" by Julius Thomsen and "Tonische Krämpfe in willkürlich beweglichen Muskeln (Muskelhypertrophie?)2" by Adolph Seeligmüller). The first article was by Julius Thomsen (1815-1896) from Kappeln, the second by Adolph Seeligmüller (1837-1912) from Halle (Saale). Both articles dealt with a disease that has later been referred to as myotonia congenita by Adolf Strümpell (1853-1925) in 1881. Carl Westphal (1833-1890), however, ignored the contribution of Seeligmüller and proposed to name the disease Thomsen'sche Krankheit (Thomsen disease). Despite, the temporal priority of Thomsen, the pathogenesis of the disease was more accurately described by Seeligmüller. He recognized the origin of the myotonia in voluntary muscle whereas Thomsen postulated the myotonia as a result of inherited psychological disposition. Thus, Seeligmüller's contribution to myotonia congenita has to be recognized and honored.


Extraction of impacted mandibular third molars in close proximity to the inferior alveolar canal with coronectomy-miniscrew traction to avoid nerve injury.
Extraction of impacted mandibular third molars (IMTMs) is the most common surgery performed in the Department of Oral and Maxillofacial Surgery. Inferior alveolar nerve (IAN) injury is a rare but severe complication, and the risk is significantly higher in cases of IMTM near the inferior alveolar canal (IAC). The existing surgical method to extract such IMTMs is either not safe enough or is time-consuming. A better surgical design is needed. From August 2019 to June 2022, 23 patients underwent IMTM extraction by Dr. Zhao at Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, and were found to have IMTMs in close proximity to the IAC. Due to high IAN injury risk, these patients underwent coronectomy-miniscrew traction to extract their IMTMs. The time between coronectomy-miniscrew insertion and complete removal of the IMTM was 32.65 ± 2.110 days, which was significantly shorter than that of traditional orthodontic traction. Two-point discrimination testing revealed no IAN injury, and no injury was reported by patients during follow-up. Other complications, such as severe swelling, severe bleeding, dry socket, and limited mouth opening, were not observed. Postoperative pain levels were not significantly higher in the coronectomy-miniscrew traction group than in the traditional IMTM extraction group. For IMTMs that are in close proximity to the IAC and must be extracted, coronectomy-miniscrew traction is a novel approach to minimize the risk of IAN injury in a less time-consuming way with a lower possibility of complications.


Developmental changes in endothelium-dependent vasodilation and the influence of superoxide anions in perinatal rabbit pulmonary arteries.
ACh-induced vasodilation was investigated in pulmonary arteries from 8 and 2 day pre-term foetal, neonatal (0-12 h and 4 day old) and adult rabbits. The effects of superoxide anion generation [with hypoxanthine (HX, 0.1 mM)/xanthine oxidase (XO, 15 mu ml(-1))], endogenous superoxide dismutase (SOD) inhibition [with the Cu-Zn SOD inhibitor triethylenetetramine (TETA, 1 mM)], endogenous superoxide anion scavenging [by superoxide dismutase (SOD, 50 u ml(-1))] and inhibition of endothelial nitric oxide synthase (eNOS) [with, Nomega-nitro-L-arginine methylester (L-NAME, 0.1 mM)], on basal and ACh-induced NO activity were studied by examining phenylephrine-induced contraction and ACh-induced vasodilation respectively. L-NAME and endothelium removal abolished all ACh-induced vasodilation and 1 microM sodium nitroprusside fully dilated all vessels. ACh-induced vasodilation was absent in the 8 day pre-term foetus and 0-12 h neonate but present at all other ages. L-NAME itself contracted 2 day pre-term foetal vessels. At 0 12 h, SOD, but not the phosphodiesterase 5 inhibitor zaprinast (1 microM), uncovered ACh-induced vasodilation. At this age SOD reduced phenylephrine-induced contraction which was not influenced by TETA, L-NAME or HX/XO, and L-NAME itself did not cause contraction. This suggests both ACh-induced and basal NO activity are compromise in these vessels by endogenous superoxide anion production and deficiencies in endogenous SOD activity. In 4 day vessels, but not adult vessels, L-NAME, TETA and HX/XO augmented contractions to phenylephrine, and L-NAME itself induced vasoconstriction, suggesting that basal NO and SOD activities were present by 4 days but were not evident in the adult. ACh-induced NO activity, and the influence of endogenous SOD on this, were present in the adult (and 4 day) vessels as superoxide generation with HX/XO significantly reduced ACh-induced vasodilation and this effect was inhibited by SOD and augmented by TETA. Increased oxygen tensions > 500 mmHg attenuated ACh-induced vasodilation in the foetal but not neonatal rabbits. Raising the oxygen tension from approximately 20 to approximately 120 mmHg revealed ACh-induced vasodilation in the 8 day pre-term vessels. In summary, superoxide anion accumulation combined with deficiencies in SOD activity may transiently compromise basal and ACh-induced NO activity at birth. Experimental oxygen tensions markedly influence ACh-induced vasodilation in foetal rabbit pulmonary arteries.


Synergistic interactions of ethidium bromide and bleomycin on cellular DNA and growth inhibition.
Bleomycin is an anti-tumor agent whose cytotoxicity is related to the introduction of both single-stranded and double-stranded breaks in cellular DNA. In an assay using isolated nuclei, low levels of ethidium bromide substantially increased bleomycin induced release of nuclear chromatin. Treatment of mouse L1210 leukemia cells in vitro with low levels of ethidium bromide followed 1 hr later by bleomycin produced a synergistic effect that was 8 fold greater than that expected from the additive cytotoxicity of each drug alone. Interestingly, when the order of drug addition was reversed the drug synergism was much reduced (2 fold). The combination of DNA unwinding and strand scission agents may represent a novel and rational approach to the chemotherapy of cancer.


Chromosome disorders associated with epilepsy.
Epilepsy is a feature of several hundred chromosome abnormalities. However, there are relatively few conditions in which epilepsy is a consistent feature and even fewer in which the electroclinical phenotype is recognizable. Advances in cytogenetics and molecular genetics are leading to the detection of more complex and smaller chromosomal re-arrangements, duplications, and deletions using techniques such as comparative genome hybridization (CGH). This will provide new challenges for the epilepsy specialist who, in partnership with the geneticist, will have to judge the clinical relevance of these abnormalities. Most chromosome anomalies associated with epilepsy are individually rare therefore clinicians must continue to collaborate to describe novel electroclinical phenotypes. Cytogenetic studies should be requested in all individuals with refractory epilepsy and no clear underlying cause even in cases with no dysmorphic features, no learning disability, and an EEG suggestive of genetic generalized epilepsy. In syndromes where epilepsy is a consistent feature the seizure semiology and EEG features can suggest a specific diagnosis and guide the clinician to the appropriate cytogenetic investigation. An early correct diagnosis can save unnecessary investigations and guide prognosis. Children with chromosomal disorders frequently have learning disability, which can be further compromised by an epileptic encephalopathy. Medications should be targeted to specific seizure types.


Evaluation study of the California Expanded Food and Nutrition Education Program: 24-hour food recall data.
The California Expanded Food and Nutrition Education program (EFNEP) Evaluation Study evaluated the effectiveness of the California program. The eating habits of 683 persons were studied in a group receiving EFNEP instruction (355 participants) and a control group (328 participants) that received no instruction. The 24-hour food recall was used to assess eating habits using the Synectics method. At the beginning of the study, there were no differences in food recall scores between the EFNEP and the control groups. After 6 months of instruction in the EFNEP group, there was a significant increase in food recall score for that group and no change in the control group. The improvements observed in the EFNEP group resulted from increased intakes from the milk, protein, and fruit and vegetable food groups. The program characteristics that led to those changes were determined to be in the length of the EFNEP visit, the number of EFNEP visits, and the EFNEP instruction topics. These results show that the California EFNEP is effective in producing significant changes in the eating habits of the low-income individuals it serves.


Population Pharmacokinetics and Pharmacodynamics of Carfilzomib in Combination with Rituximab, Ifosfamide, Carboplatin, and Etoposide in Adult Patients with Relapsed/Refractory Diffuse Large B Cell Lymphoma.
In patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), salvage chemotherapy regimens (e.g., rituximab, ifosfamide, carboplatin, and etoposide, R-ICE) yield poor outcomes. Carfilzomib, an irreversible proteasome inhibitor, can overcome acquired rituximab-chemotherapy resistance and, when combined with R-ICE, improves outcomes in patients with R/R DLBCL. This analysis aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model for carfilzomib in R/R DLBCL patients. In a single-center, open-label, prospective phase 1 study, patients received carfilzomib (10, 15, or 20 mg/m2) on days 1, 2, 8, and 9, and standard doses of R-ICE on days 3-6 every 21 days (maximum of three cycles). Carfilzomib plasma concentrations up to 24 h postinfusion were measured by liquid chromatography coupled with tandem mass spectrometry. Proteasome activity (PD biomarker) in peripheral blood mononuclear cells was assessed on days 1-2 with sparse sampling. PK/PD models were developed using NONMEM v7.4.1 interfaced with Finch Studio v1.1.0 and PsN v4.7.0. Model selection was guided by objective function value, goodness-of-fit, and visual predictive checks. Stepwise covariate modeling was used for covariate selection. Twenty-eight patients were enrolled in the PK/PD analysis, from whom 217 PK samples and 127 PD samples were included. Carfilzomib PK was best described by a two-compartment model with linear disposition (typical total clearance of 133 L/h). Proteasome activity was best characterized using a turnover model with irreversible inactivation. All parameters were estimated with good precision. No statistically significant covariates were identified. A validated population-based PK/PD model of carfilzomib was developed successfully. Further research is needed to identify sources of variability in response to treatment with carfilzomib in combination with R-ICE. ClinicalTrials.gov identifier number NCT01959698.


Characteristics of outpatients with COPD in daily practice: The E4 Spanish project.
The objective of this 1-week cross-sectional survey was to assess the clinical features of outpatients with chronic obstructive pulmonary disease (COPD). A one-page questionnaire was used to collect demographic data, smoking status, and COPD-related variables. Ten or 20 consecutive patients were selected from Primary care or specialised setting during a week. Pulmonary function (FEV1) was measured using an electronic device (Piko-1). The study sample comprised 11,973 COPD patients (83% men) with a mean (sd) age of 67 (10.7) years. Thirty-five percent of patients were current smokers and smoked a mean of 17.4 (9.9) cigarettes daily. COPD severity according to GOLD stages was mild in 20% of patients, moderate in 38%, severe in 30%, and very severe in 12%. A higher percentage of men showed severe (33%) or very severe (14%) disease compared to women (16% and 6%, respectively) (P<0.005). Forty-two percent of patients had severe functional impairment and 35% continued smoking. Moreover, 11% of patients with very severe COPD smoked more than 20 cigarettes a day. The mean frequency of visits in the previous year was every 4.6 (4.1) months, with cough as the main reason for consultation. The most commonly used drugs were long-acting beta2-agonists (78%) and inhaled steroids (77%). Inhaled steroids were used by 84% of patients with very severe, 82% with severe disease, 73% with moderate disease, and 69% with mild disease (chi2 for trend, P<0.0001). This survey carried out in a real life setting shows that 42% of the patients who completed the questionnaire had severe COPD, 35% of them continued smoking, and 69% of patients with mild COPD used inhaled steroids.


Effectiveness of Acceptance and Commitment Therapy in treating depression and suicidal ideation in Veterans.
This paper examines the effects of Acceptance and Commitment Therapy for depression (ACT-D), and the specific effects of experiential acceptance and mindfulness, in reducing suicidal ideation (SI) and depression among Veterans. Patients included 981 Veterans, 76% male, mean age 50.5 years. Depression severity and SI were assessed using the BDI-II. Experiential acceptance and mindfulness were measured with the Acceptance and Action Questionnaire-II (AAQ-II) and the Five Facet Mindfulness Questionnaire, respectively. Of the 981 patients, 647 (66.0%) completed 10 or more sessions or finished early due to symptom relief. For Veterans with SI at baseline, mean BDI-II score decreased from 33.5 to 22.9. For Veterans with no SI at baseline, mean BDI-II score decreased from 26.3 to 15.9. Mixed models with repeated measurement indicated a significant reduction in depression severity from baseline to final assessment (b = -10.52, p < .001). After adjusting for experiential acceptance and mindfulness, patients with SI at baseline demonstrated significantly greater improvement in depression severity during ACT-D treatment, relative to patients with no SI at baseline (b = -2.81, p = .001). Furthermore, increases in experiential acceptance and mindfulness scores across time were associated with a reduction in depression severity across time (b = -0.44, p < .001 and b = -0.09, p < .001, respectfully), and the attenuating effect of mindfulness on depression severity increased across time (b = -0.05, p = .042). Increases in experiential acceptance scores across time were associated with lower odds of SI across time (odds ratio = 0.97, 95% CI [0.95, 0.99], p = .016) and the attenuating effect of experiential acceptance on SI increased across time (odds ratio = 0.96, 95% CI [0.92, 0.99], p = .023). Overall the number of patients with no SI increased from 44.5% at baseline to 65% at follow-up. Veterans receiving ACT-D demonstrated decreased depression severity and decreased odds of SI during treatment. Increases in experiential acceptance and mindfulness scores were associated with reduction in depression severity across time and increases in experiential acceptance scores were associated with reductions in SI across time.


X-ray powder diffraction patterns for certain beta-lactam, tetracycline and macrolide antibiotic drugs.
X-ray powder diffraction (XRD) data for eight beta-lactam viz., ampicillin sodium, ampicillin trihydrate, penicillin G procaine, benzathine penicillin, benzyl penicillin sodium, cefalexin, cefotaxime sodium and ceftriaxone sodium; three tetracyclines viz., doxycycline hydrochloride, oxytetracycline dihydrate and tetracycline hydrochloride; and two macrolide viz., azithromycin and erythromycin estolate antibiotic drugs were obtained using a powder diffractometer. The drugs were scanned from Bragg angles (2theta) of 10 degrees to 70 degrees. The obtained data were tabulated in terms of the lattice spacing (A) and relative line intensities (I/I(I)). This new information may be useful for identifying these drugs from confiscated materials, which has been frequently encountered in forensic laboratories.


An interactive mutation database for human coagulation factor IX provides novel insights into the phenotypes and genetics of hemophilia B.
Factor IX (FIX) is important in the coagulation cascade, being activated to FIXa on cleavage. Defects in the human F9 gene frequently lead to hemophilia B. To assess 1113 unique F9 mutations corresponding to 3721 patient entries in a new and up-to-date interactive web database alongside the FIXa protein structure. The mutations database was built using MySQL and structural analyses were based on a homology model for the human FIXa structure based on closely-related crystal structures. Mutations have been found in 336 (73%) out of 461 residues in FIX. There were 812 unique point mutations, 182 deletions, 54 polymorphisms, 39 insertions and 26 others that together comprise a total of 1113 unique variants. The 64 unique mild severity mutations in the mature protein with known circulating protein phenotypes include 15 (23%) quantitative type I mutations and 41 (64%) predominantly qualitative type II mutations. Inhibitors were described in 59 reports (1.6%) corresponding to 25 unique mutations. The interactive database provides insights into mechanisms of hemophilia B. Type II mutations are deduced to disrupt predominantly those structural regions involved with functional interactions. The interactive features of the database will assist in making judgments about patient management.


Ultrasonic localization for renal biopsy in infants and children.
The authors describe a simple method of sonographic localizaiton for renal biopsy in unanaesthetized pediatric patients. Adequate biopsies have been obtained in 6 of 7 patients who ranged from 2 months of 8 years in age.


A novel method of preparing totally alpha-deuterated amino acids for selective incorporation into proteins. Application to assignment of 1H resonances of valine residues in dihydrofolate reductase.
The pyridoxal/2H2O exchange reaction of the alpha-CH of amino acids is known to be accompanied by racemisation: Thus by using a D-amino acid as the starting material any L-amino acid formed in the reaction will be essentially fully deuterated at its alpha-position. We have used this method to prepare alpha-deuterated L-valine and incorporated this biosynthetically into L. casei dihydrofolate reductase. A comparison of the alpha CH-NH fingerprint regions of COSY spectra of deuterated and normal DHFR complexes allows one to identify cross-peaks from 15 of the 16 valine residues.


Separation of enantiomers of ephedrine by capillary electrophoresis using cyclodextrins as chiral selectors: comparative CE, NMR and high resolution MS studies.
The enantiomer migration order (EMO) of ephedrine was investigated in the presence of various CDs in CE. The molecular mechanisms of chiral recognition were followed for the ephedrine complexes with native α- and β-CD and heptakis(2,3-di-O-acetyl-6-O-sulfo)-β-CD (HDAS-β-CD) by CE, NMR spectroscopy and high-resolution MS. Minor structural differences were observed between the complexes of ephedrine with α- and β-CD although the migration order of enantiomers was opposite when these two CDs were applied as chiral selectors in CE. The EMO was also opposite between β-CD and HDAS-β-CD. Significant structural differences were observed between ephedrine complexes with the native CDs and HDAS-β-CD. The latter CD was advantageous as chiral CE selector not only due to its opposite electrophoretic mobility compared with that of the cationic chiral analyte, but also primarily due to its enhanced chiral recognition ability towards the enantiomers of ephedrine.


High concentrations of plastic hidden beneath the surface of the Atlantic Ocean.
Concern over plastic pollution of the marine environment is severe. The mass-imbalance between the plastic litter supplied to and observed in the ocean currently suggests a missing sink. However, here we show that the ocean interior conceals high loads of small-sized plastic debris which can balance and even exceed the estimated plastic inputs into the ocean since 1950. The combined mass of just the three most-littered plastics (polyethylene, polypropylene, and polystyrene) of 32-651 µm size-class suspended in the top 200 m of the Atlantic Ocean is 11.6-21.1 Million Tonnes. Considering that plastics of other sizes and polymer types will be found in the deeper ocean and in the sediments, our results indicate that both inputs and stocks of ocean plastics are much higher than determined previously. It is thus critical to assess these terms across all size categories and polymer groups to determine the fate and danger of plastic contamination.


Tailoring the Interface with a Multifunctional Ligand for Highly Efficient and Stable FAPbI3 Perovskite Solar Cells and Modules.
Perovskite solar cells (PeSCs) using FAPbI3 perovskite films often exhibit unfavorable phase transitions and defect-induced nonradiative interfacial recombination, resulting in considerable energy loss and impairing the performance of PeSCs in terms of efficiency, stability, and hysteresis. In this work, a facile interface engineering strategy to control the surface structure and energy-level alignment of perovskite films by tailoring the interface between the FAPbI3 film and hole-transporting layer using 4-hydroxypicolinic acid (4HPA) is reported. According to density functional theory studies, 4HPA has prominent electron delocalization distribution properties that enable it to anchor to the perovskite film surface and facilitate charge transfer at the interface. By enabling multiple bonding interactions with the perovskite layer, including hydrogen bonds, PbO, and PbN dative bonds, 4HPA passivation significantly reduces the trap density and efficiently suppresses nonradiative recombination. The obtained perovskite films exhibit superior optoelectronic properties with improved crystallinity, pure α-phase FAPbI3 , and favorable energy band bending. Following this strategy, 4HPA post-treatment PeSCs achieve a champion power conversion efficiency of 23.28% in 0.12 cm2 cells and 19.26% in 36 cm2 modules with excellent environmental and thermal stabilities.


Identification of novel acetylenic alcohols and a new dihydrothiopyranone from the tropical sponge Reniochalina sp.
Two new acetylenic alcohols (1-2) and a new dihydrothiopyranone (3) were isolated from the tropical sponge Reniochalina sp. Their structures were determined by spectroscopic and chemical methods to be (3R)-hydroxyoctatriacont-(4E)-en-1-yne (1), 5-hydroxyheptatriacont-(3Z)-en-1-yne (2) and 2-hexadecyl-2,3-dihydrothiopyran-4-one (3). The acetylenic alcohol (1) exhibited significant growth inhibitory effect against human tumor cell lines.


Sodium chlorate induces DNA damage and DNA-protein cross-linking in rat intestine: A dose dependent study.
Sodium chlorate (NaClO3) is widely used in paper and pulp industries and as a non-selective herbicide. It is also a major by-product generated upon disinfection of drinking water by chlorine dioxide. In this study, we have investigated the genotoxicity of NaClO3 on the small intestine of rats. Adult male rats were divided into 5 groups: one control and four NaClO3 treated groups. The NaClO3 treated groups were given a single acute oral dose of NaClO3 (100, 250, 500 and 750 mg/kg body weight) and sacrificed 24 h later. Administration of NaClO3 caused significant DNA damage in a dose dependent manner in the rat intestine. This was evident from the comet assay which showed DNA strand breaks and was further confirmed by agarose gel electrophoresis and release of free nucleotides. Increased DNA protein cross-linking in NaClO3 administered groups showed formation of a critical lesion which hampers activities of proteins/enzymes involved in DNA repair, transcription and replication. Thus, oral administration of NaClO3 induces DNA damage in the rat intestine, probably through chlorate induced production of reactive oxygen species.


Thermally induced irreversible conformational changes in collagen probed by optical second harmonic generation and laser-induced fluorescence.
Irreversible thermal conformational changes induced to collagen have been studied by optical methods. More specifically, second harmonic generation (SHG) from incident nanosecond Ng:YAG 1064 nm radiation and laser-induced fluorescence by 337 nm, pulsed nanosecond nitrogen laser excitation, at 405, 410 and 415 nm emission wavelengths were registered at eight temperatures (40 degrees, 50 degrees, 55 degrees, 60 degrees, 65 degrees, 70 degrees, 75 degrees and 80 degrees C) and normalised with respect to the corresponding values at the ambient temperature of 30 degrees C. The heating protocol used in this work, was selected to monitor only permanent changes reflecting in the optical properties of the samples under investigation. In this context, the SHG, directly related to the collagen fibril population in triple helix conformation, indicated on irreversible phase transition around 64 degrees C. On the other hand fluorescence related to the destruction of cross-linked chromophores in collagen, some of which are related to the triple helix tertiary structure, also indicated a permanent phase transition around 63 degrees C. These results are in agreement with previous results from studies with differential scanning calorimetry. However SHG and fluorescence, being non-invasive optical methods are expected to have a significant impact in the fields of laser ablative surgery and laser tissue welding.


Effects of BDNF-Transfected BMSCs on Neural Functional Recovery and Synaptophysin Expression in Rats with Cerebral Infarction.
The purpose of this study was to investigate the effects of brain-derived neurotrophic factor (BDNF)-transfected bone marrow mesenchymal stem cells (BMSCs) on neural functional recovery and synaptophysin expression in rats with cerebral infarction (CI). A total of 120 healthy Sprague Dawley rats were randomly divided into sham group, control group, and model group. Craniotomy was conducted and neurological function defect scoring was used to verify the model. BDNF containing recombinant plasmid was transfected into rat BMSCs, which was verified by flow cytometry and Western Blot. After injection of the transfected BMSCs, neural functional recovery of the CI rats and synaptophysin expression were measured. After the CI rat model was established, magnetic resonance (MR) imaging, 2, 3, 5- triphenyl tetrazolium chloride (TTC) staining, and the neurological function defect scoring determined the success of the model. CD34 (-), CD45 (-), CD29 (+), and CD90 (+) cells detected showed that the obtained BMSCs have high purity. BDNF protein was highly expressed in the BMSCs successfully transfected with the recombinant plasmid. Balance beam walking score, rotating bar walking score, and screen test score were significantly lower, while synaptophysin expression was higher in the BDNF model group than those in the non-BDNF model group and sham group with time extension. BDNF can increase synaptic plasticity and neurogenesis and have a promotional role in neural functional recovery and synaptophysin expression in rats with CI. BDNF-transfected BMSCs may therefore have better treatment efficacy for CI clinically.


Photoplethysmography in the assessment of venous insufficiency.
Photoplethysmography has been used simultaneously with ambulatory venous pressure measurements to study 32 patients. Of the 62 limbs studied, 24 were normal, 20 had primary varicose veins, and 18 had deep valvular incompetence. The results indicate that the photoplethysmographic refilling time can provide a good separation between the three groups when the test is performed in the standing, but not in the sitting, position. However, the test is qualitative because we found a lack of correlation between the short refilling times in limbs with deep venous insufficiency and the ambulatory venous pressure.


Non-micellar ganglioside GM1 induces an instantaneous conformational change in Aβ42 leading to the modulation of the peptide amyloid-fibril pathway.
Alzheimer's disease is a progressive degenerative condition that mainly affects cognition and memory. Recently, distinct clinical and neuropathological phenotypes have been identified in AD. Studies revealed that structural variation in Aβ fibrillar aggregates correlates with distinct disease phenotypes. Moreover, environmental surroundings, including other biomolecules such as proteins and lipids, have been shown to interact and modulate Aβ aggregation. Model membranes containing ganglioside (GM1) clusters are specifically known to promote Aβ fibrillogenesis. This study unravels the modulatory effect of non-micellar GM1, a glycosphingolipid frequently released from the damaged neuronal membranes, on Aβ42 amyloid fibril formation. Using far-UV circular dichroism experiments, we observed a change in the peptide secondary structure from random-coil to β-turn structures with subsequent generation of predominantly β-sheet-rich species upon interaction with GM1. Thioflavin-T (ThT) fluorescence assays further indicated that GM1 likely interacts with an amyloidogenic Aβ42 intermediate species leading to a possible formation of GM1-modified Aβ42 fibril. Statistically, no significant difference in toxicity to RA-differentiated SH-SY5Y cells was observed between Aβ42 fibrils and GM1-tweaked Aβ42 aggregates. Moreover, GM1-modified Aβ42 aggregates exhibited prion-like properties in catalyzing the amyloid fibril formation of both major isomers of Aβ, Aβ40, and Aβ42.


MR-guided stereotactic body radiation therapy for intracardiac and pericardial metastases.
To assess the safety and efficacy of MR-guided stereotactic body radiation therapy (MRgSBRT) for cardiac metastases. This single institution retrospective analysis evaluated our experience with MRgSBRT for cardiac metastases. Response rate was compared between pre-RT and post-RT imaging. Symptomatic changes were also tracked and documented. Between 4/2019 and 3/2020, five patients with cardiac metastases (4 intracardiac and 1 pericardial) were treated with MRgSBRT. Median age at treatment was 73 years (range 64-80) and two patients had pre-existing cardiac disease. Histologies included melanoma and breast adenocarcinoma. Median lesion diameter was 2 cm (range 1.96-5.8 cm). Three patients were symptomatic, one of whom had pulmonary hypertension and RV enlargement. Another patient had an asymptomatic arrythmia. Median PTV prescribed dose was 40 Gy (range 40-50 Gy) and delivered in five fractions on nonconsecutive days. Median PTV volume was 53.4 cc (range 8.7-116.6 cc) and median coverage was 95% (range 84.1-100%). A uniform 3 mm margin was used for real-time gating, allowing a median 7% (range 5-10%) pixel excursion tolerance. Median follow-up was 4.7 months (range 0.9-12.3). Two patients exhibited stable disease, two had a partial response and one exhibited a complete response. All symptomatic patients experienced some relief. There were no acute adverse events, however, one patient without prior cardiac disease developed atrial fibrillation 6 months after treatment. Two patients died of causes unrelated to cardiac MRgSBRT. In this largest known series of cardiac metastasis MRgSBRT, real-time image guidance enables safe treatment resulting in good response with improving presenting symptoms without acute adverse events.


The sialic acid and galactose concentrations in erythrocyte membranes in patients with myotonic dystrophy, limb-girdle and facioscapulohumeral dystrophy.
Sialic acid is an important constituent of membrane-bound glycoproteins and glycolipids. It occurs linked to galactose at the surface of the membrane and is involved in, e.g., cation exchange, receptor function, maintenance of membrane polarity and intercellular interactions. In myotonic dystrophy there is evidence of an as yet basically undefined plasma-membrane abnormality. Considering the importance of sialic acid in membrane function, sialic acid as well as galactose concentrations were measured in erythrocyte membranes from 17 patients with myotonic dystrophy and compared to 17 matched healthy controls. There was a highly significant (P less than 0.0005) reduction of the sialic acid concentration in the patients, while no significant difference in galactose concentration was found. In 16 patients with limb-girdle and facioscapulohumeral dystrophy, sialic acid and galactose concentrations did not differ from matched controls. The possible importance of a reduced concentration of membrane-bound sialic acid in myotonic dystrophy is discussed in relation to previously reported biochemical membrane abnormalities in this disease.


Radiation-induced hyperprolactinaemia in a treated acromegalic.
A 31-year-old acromegalic was normoprolactinaemic after partial removal of her pituitary tumour. The post-operative external pituitary irradiation lowered the mean growth hormone (GH) level from 75 mU/1 to less than 1 mU/1 within 2 years. However, at the same time hyperprolactinaemia developed. These changes in the GH and prolactin levels were confirmed 3 and 4 years after irradiation. The cause of the hyperprolactinaemia was radiation-induced hypothalamic damage. Therefore it is suggested that similar damage may occur in patients receiving external pituitary irradiation for 'prolactinomas' and that this mechanism may contribute to the persistent hyperprolactinaemia observed in such patients.


It's all about functionality: How can metaproteomics help us to discuss the attributes of ecological relevance in soil?
Soil metaproteomics has been recently developed in order to link the phylogeny and functionality of soil microorganisms. After the development of protein extraction and peptide analysis, the use of improved mass-spectrometric systems has allowed the description of the microbial composition and the identification of proteins in soils subjected to deforestation, restoration, contamination and different agricultural managements. In this letter, we encourage one step-forward for soil metaproteomics. We believe that proteomics can complement ecological attributes that control the dynamics of soil microbial populations. Among these attributes, we highlight the resistance, resilience and plasticity of microbial populations. Providing with functional basis to these attributes will extend our knowledge on the microbial-mediated mechanisms regulating the impacts of climate change and agricultural management in the near future.


Auditory cortex activity related to perceptual awareness versus masking of tone sequences.
Sequences of repeating tones can be masked by other tones of different frequency. When these tone sequences are perceived, nevertheless, a prominent neural response in the auditory cortex is evoked by each tone of the sequence. When the targets are detected based on their isochrony, participants know that they are listening to the target once they detected it. To explore if the neural activity is more closely related to this detection task or to perceptual awareness, this magnetoencephalography (MEG) study used targets that could only be identified with cues provided after or before the masked target. In experiment 1, multiple mono-tone streams with jittered inter-stimulus interval were used, and the tone frequency of the target was indicated by a cue. Results showed no differential auditory cortex activity between hit and miss trials with post-stimulus cues. A late negative response for hit trials was only observed for pre-stimulus cues, suggesting a task-related component. Since experiment 1 provided no evidence for a link of a difference response with tone awareness, experiment 2 was planned to probe if detection of tone streams was linked to a difference response in auditory cortex. Random-tone sequences were presented in the presence of a multi-tone masker, and the sequence was repeated without masker thereafter. Results showed a prominent difference wave for hit compared to miss trials in experiment 2 evoked by targets in the presence of the masker. These results suggest that perceptual awareness of tone streams is linked to neural activity in auditory cortex.


SSRI treatment modifies the effects of maternal inflammation on in utero physiology and offspring neurobiology.
Perturbations to the in utero environment can dramatically change the trajectory of offspring neurodevelopment. Insults commonly encountered in modern human life such as infection, toxins, high-fat diet, prescription medications, and others are increasingly linked to behavioral alterations in prenatally-exposed offspring. While appreciation is expanding for the potential consequence that these triggers can have on embryo development, there is a paucity of information concerning how the crucial maternal-fetal interface (MFI) responds to these various insults and how it may relate to changes in offspring neurodevelopment. Here, we found that the MFI responds both to an inflammatory state and altered serotonergic tone in pregnant mice. Maternal immune activation (MIA) triggered an acute inflammatory response in the MFI dominated by interferon signaling that came at the expense of ordinary development-related transcriptional programs. The major MFI compartments, the decidua and the placenta, each responded in distinct manners to MIA. MFIs exposed to MIA were also found to have disrupted sex-specific gene expression and heightened serotonin levels. We found that offspring exposed to MIA had sex-biased behavioral changes and that microglia were not transcriptionally impacted. Moreover, the combination of maternal inflammation in the presence of pharmacologic inhibition of serotonin reuptake further transformed MFI physiology and offspring neurobiology, impacting immune and serotonin signaling pathways alike. In all, these findings highlight the complexities of evaluating diverse environmental impacts on placental physiology and neurodevelopment.


The impact of maternal weight in pregnancy on glucose metabolism in non-diabetic offspring in late adulthood.
We aimed to examine the association between maternal adiposity and glucose metabolism in adult offspring without diabetes, simultaneous taking offspring own adiposity into account. This longitudinal birth cohort study (Helsinki Birth Cohort Study) included 1,440 non-diabetic subjects examined at a mean age of 62 years. Subjects were divided into quartiles according to maternal body mass index (BMI). The impact of maternal BMI on offspring body composition was also studied. There were no differences in fasting glucose between the groups. In men, maternal BMI was inversely associated with mean 2-hour glucose concentration after a 75 g oral glucose tolerance test (p < 0.001) and mean homeostatic model assessment of insulin resistance (HOMA-IR) (p = 0.049). According to the subjects' own BMI, high maternal BMI was associated with lower 2-hour glucose concentrations only in non-obese men and with lower HOMA-IR only in obese men. Maternal BMI was not associated with glucose concentrations nor with HOMA-IR in women. In addition, maternal BMI was positively associated with a higher offspring lean body mass in men. High maternal BMI was associated with lower 2-hour plasma glucose concentration, especially in non-obese men. Offspring lean body mass may be a mediating factor for the association.


Apolysis and the turnover of plasma membrane plaques during cuticle formation in an insect.
The apical plasma membranes of Calpodes epidermal cells have small fattened areas or plaques with an extra density upon their cytoplasmic face. The plaques are typically at the tips of microvilli. The are present during the deposition of fibrous cuticle and the cuticulin layer. Since the plaques are close (less than 15nm) to the sites where these kinds of cuticle first appear, they are presumed to have a role in their synthesis and/or deposition and orientation. When fifth stage larval cuticle deposition ceases prior to pupation, the plaques are lost as the area of the apical plasma membrane is reduced. The plaques pass from the surface into pinocytosis vesicles and multivesicular bodies where they are presumably digested. The loss of plaques occurs as the blood level of moulting hormone reaches a peak at the critical period after which the prothoracic glands are no longer needed for pupation. Apolysis or separation of the epidermis from the old cuticle is the stage when plaques are absent, the old ones have been lost but the new ones have yet to form. After the critical period, the epidermis prepared for pupation with a phase of elevated RNA synthesis at the end of which plaques and microvilli reform in time to secrete the new cuticulin layer and later the fibrous cuticle of the pharate pupa. There is a new generation of plaques for each moult and succeeding intermoult and each generation is involved in two kinds of cuticle deposition before involution and redifferentiation.


Nipple migration in a pig using the technique of serial excision.
Moving a misplaced nipple-areola complex (NAC) without causing additional scarring has proved to be difficult, especially if it is to be moved medially, laterally or inferiorly. This study investigated the possibility of migrating the NAC without leaving additional scarring by using the technique of serial excision. Two adult female pigs were used. Three pairs of pseudo-areolas of similar size were tattooed around a teat in each pig. Crescentic serial excisions of skin were undertaken at 2 weekly intervals on the upper and middle pairs of pseudo-areolas in each pig and the lower pairs were left as controls. The crescentic excision on the upper set of nipples consisted of skin only. The crescentic excision on the middle set of nipples consisted of 75% skin and 25% tattooed pseudo-areola. Results showed that nipple migration by serial excision is possible. However, each set of nipple pseudo-areola complex (NPAC) behaved differently. When skin only was excised, the NPAC's became distorted and enlarged but when skin and areola was excised, the NPAC maintained its dimensions. Taking our findings into account, an approach to moving a misplaced NAC using this technique in the clinical situation is described. Its use to move a misplaced NAC in two women is demonstrated.


Computerized tomography in the study of West's syndrome.
37 children presenting with West's syndrome were studied by computerized tomography scanning. An abnormality consisting of diffuse cerebral atrophy, predominating in the fronto-temporal region, was demonstrated in 30 cases. The abnormality was sometimes associated with calcification (tuberous sclerosis) or malformation (agenesis of the corpus callosum). The aetiology of the atrophy and its relationship to clinical and electroencephalographic signs is discussed. Computerized tomography scanning is recommended for children with West's syndrome in order to distinguish between primary and secondary cases, and for greater prognostic accuracy.


Functional circularity of legitimate Qbeta replicase templates.
Qbeta replicase (RNA-directed RNA polymerase of bacteriophage Qbeta) exponentially amplifies certain RNAs in vitro. Previous studies have shown that Qbeta replicase can initiate and elongate on a variety of RNAs; however, only a minute fraction of them are recognized as 'legitimate' templates. Guanosine 5'-triphosphate (GTP)-dependent initiation on a legitimate template generates a stable replicative complex capable of elongation in the presence of aurintricarboxylic acid, a powerful inhibitor of RNA-protein interactions. On the contrary, initiation on an illegitimate template is GTP independent and does not result in the aurintricarboxylic-acid-resistant replicative complex. This article demonstrates that the 3' and 5' termini of a legitimate template cooperate during and after the initiation step. Breach of the cooperation by dividing the template into fragments or by introducing point mutations at the 5' terminus reduces the rate and the yield of initiation, increases the GTP requirement, decreases the overall rate of template copying, and destabilizes the postinitiation replicative complex. These results revive the old idea of a functional circularity of legitimate Qbeta replicase templates and complement the increasing body of evidence that functional circularity may be a common property of RNA templates directing the synthesis of either RNA or protein molecules.


Heart rate and perceptual response to exercise with different pedalling speed in normal subjects and patients.
The perceived exertion rating (RPE) scale of Borg was used to investigate the relationship between perceived exertion and pedalling rate. Normal subjects and patients with chronic obstructive lung disease (Cold) were studied in repeated test series. Work load, applied in a random order, varied from 2.5 to 10 mkp/s (patients) and 5 to 20 mkp/s (normals). Pedalling rate varied from 2.5 to 10 mkp/s (patients) and 5 to 20 mkp/s (normals). Pedalling rate varied from 40 to 60, 80, 100 rpm. At constant work load, RPE decreases during increasing pedalling rate. With respect to validity, RPE, showing a closer relationship to work load than to heart rate, seems to reflect perception of physical stress rather than perception of physiological strain. In addition, the results raise the question of standardization of pedalling rate in bicycle ergometry.


Arsenic (+3 oxidation state) methyltransferase is a specific but replaceable factor against arsenic toxicity.
Inorganic metalloids, such as arsenic (As), antimony (Sb), selenium (Se), and tellurium (Te), are methylated in biota. In particular, As, Se, and Te are methylated and excreted in urine. The biomethylation is thought to be a means to detoxify the metalloids. The methylation of As is catalyzed by arsenic (+3 oxidation state) methyltransferase (AS3MT). However, it is still unclear whether AS3MT catalyzes the methylation of the other metalloids. It is also unclear whether other factors catalyze the As methylation instead of AS3MT. Recombinant human AS3MT (rhAS3MT) was prepared and used in the in vitro methylation of As, Se, and Te. As, but not Se and Te, was specifically methylated in the presence of rhAS3MT. Then, siRNA targeting AS3MT was introduced into human hepatocarcinoma (HepG2) cells. Although AS3MT protein expression was completely silenced by the gene knockdown, no increase in As toxicity was found in the HepG2 cells transfected with AS3MT-targeting siRNA. We conclude that AS3MT catalyzes the methylation of As and not other biomethylatable metalloids, such as Se and Te. We speculate that other methylation enzyme(s) also catalyze the methylation of As in HepG2 cells.


Anterior Glenohumeral Instability: Systematic Review of Outcomes Assessment Used in Brazil.
A review involving the six major international orthopedic journals has been published recently. It described the tools used for the evaluation of outcomes in the surgical treatment of recurrent anterior dislocation of the shoulder. There are no studies that exhibit the main outcome tools for this disease in Brazil. The authors evaluated the outcomes of clinical studies involving anterior glenohumeral instability that were published in the last decade in the two leading Brazilian orthopedic journals, Revista Brasileira de Ortopedia and Acta Ortopédica Brasileira . A review of the literature was performed, including all clinical papers published between 2007 and 2016 describing at least one outcome measure before and after surgical intervention. The outcomes were range of motion, muscle strength, physical examination testing, patient satisfaction, return to sports, imaging, complications, and functional outcomes scores. Twelve studies evaluating the clinical outcomes of surgical treatment for anterior shoulder instability were published. Ten studies (83%) were case series (level of evidence IV), 1 (8%) was a case-control study (III), and 1 was a retrospective cohort (III). On average, the number of outcomes assessed was 3.7 ± 1.7. The Rowe score was used in 9 studies (75%), and 7 (58%) papers used the University of California Los Angeles (UCLA) scale. Ten studies (83%) reported complications related to surgical treatment. The complication most frequently reported was recurrent instability, found in 9 studies (75%). The national studies have preferentially used scales considered to be of low reliability, responsiveness, and internal consistency.


Long-Term Activity and Safety of a Low-Dose Hydrocortisone Tear Substitute in Patients with Dry Eye Disease.
A clinical trial was conducted to evaluate the activity of a new artificial tear containing hyaluronic acid (HA) and low-dose hydrocortisone to control dry-eye disease (DED) symptoms. a randomized, controlled, double-masked study was carried out at the Ocular Surface and Dry Eye Center, "Luigi Sacco" University Hospital (Milan, Italy), between June 2020 and June 2021. The study involved patients with DED for at least 6 months. After an initial 7-day treatment with corticosteroid, the treatment with the new artificial tear (four-times a day for 6 months) was compared with a control HA solution. A total of 40 patients were considered. We observed a significant improvement in the frequency and intensity of DED symptoms in both groups. After corticosteroid discontinuation, the maintenance of the therapeutic advantage was observed only in the treatment group, which also showed a significant improvement of the tear film break-up time (p ≤ 0.05) and infiltrated macrophages (p < 0.05). A significant reduction in fluorescein and Lissamine staining (p < 0.05) was observed in the treatment group, suggesting damage reduction at both corneal and conjunctival levels. Intraocular pressure did not change at the end of the treatment period and was maintained within the normal range, sustaining the product's safety. Our findings support the prolonged use of the new eye drop with low-dose hydrocortisone, also in the DED initial stages, to prevent the degenerating towards a chronic condition (http://www.isrctn.com/ISRCTN16288419).


Casodex: preclinical studies.
Antiandrogens are effective drugs in the treatment of advanced prostatic cancer. The main problems associated with their use are their short half-lives, leading to fluctuating serum levels, and their non-selectivity, which leads to increases in serum LH and testosterone through centrally-mediated actions. Casodex is a pure, potent antiandrogen which, in pre-clinical studies, has been shown to have a long half-life and a high degree of peripheral selectivity. Casodex is as effective as surgical castration or medical castration with Zoladex in inhibiting the growth of a transplantable Dunning prostate tumor in rats. These properties suggest that Casodex, given once daily, would be an effective and well-tolerated monotherapy for advanced prostatic cancer.


Lapatinib sensitivities of two novel trastuzumab-resistant HER2 gene-amplified gastric cancer cell lines.
Trastuzumab (Tmab) resistance is a major clinical problem to be resolved in patients with HER2-positive gastric cancers. However, in contrast to the situation for HER2-positive breast cancer lines, the Tmab-resistant gastric cancer preclinical models that are needed to develop a new therapy to overcome this problem are not yet available. We developed three new cell lines from HER2 gene-amplified gastric cancer cell lines (GLM-1, GLM-4, NCI N-87) by a new in vivo selection method consisting of the repeated culture of small residual peritoneal metastasis but not subcutaneous tumor after Tmab treatment. We then evaluated the anti-tumor efficacy of lapatinib for these Tmab-resistant cells. We successfully isolated two Tmab-resistant cell lines (GLM1-HerR2(3), GLM4-HerR2) among the three tested cell lines. These resistant cells differed from the parental cells in their flat morphology and rapid growth in vitro, but HER2, P95HER2 expression, and Tmab binding were essentially the same for the parental and resistant cells. MUC4 expression was up- or downregulated depending on the cell line. These resistant cells were still sensitive to lapatinib, similar to the parental cells, in vitro. This growth inhibition of the Tmab-resistant cells by lapatinib was due to both G1 cell-cycle arrest and apoptosis induction via effective blockade of the PI3K/Akt and MAPK pathways. A preclinical study confirmed that the Tmab-resistant tumors are significantly susceptible to lapatinib. These results suggest that lapatinib has antitumor activity against the Tmab-resistant gastric cancer cell lines, and that these cell lines are useful for understanding the mechanism of Tmab resistance and for developing a new molecular therapy for Tmab-resistant HER2-positive gastric cancers.


Quantum dot-integrated GaN light-emitting diodes with resolution beyond the retinal limit.
Near-eye display technology is a rapidly growing field owing to the recent emergence of augmented and mixed reality. Ultrafast response time, high resolution, high luminance, and a dynamic range for outdoor use are all important for non-pixelated, pupil-forming optics. The current mainstream technologies using liquid crystals and organic materials cannot satisfy all these conditions. Thus, finely patterned light-emissive solid-state devices with integrated circuits are often proposed to meet these requirements. In this study, we integrated several advanced technologies to design a prototype microscale light-emitting diode (LED) arrays using quantum dot (QD)-based color conversion. Wafer-scale epilayer transfer and the bond-before-pattern technique were used to directly integrate 5-µm-scale GaN LED arrays on a foreign silicon substrate. Notably, the lithography-level alignment with the bottom wafer opens up the possibility for ultrafast operation with circuit integration. Spectrally pure color conversion and solvent-free QD patterning were also achieved using an elastomeric topographical mask. Self-assembled monolayers were applied to selectively alter the surface wettability for a completely dry process. The final emissive-type LED array integrating QD, GaN, and silicon technology resulted in a 1270 PPI resolution that is far beyond the retinal limit.


Re-hospitalizations within 30-days and mortality outcomes among severely visually impaired and blind patients: analysis of the National Readmission Database.
Readmissions and in-hospital mortality among patients with severe vision impairment or blindness (SVI/B) has not been fully studied. We investigated hospital outcomes for adults with SVI/B in the United States. Using the Nationwide Readmission Database year 2017, we analyzed primary outcomes for thirty-day readmission rates for patients with and without SVI/B. Secondary outcomes were in-hospital mortality rates for readmitted patients, in-hospital mortality rates for index patients, the five most common principal diagnoses for readmission, and resource utilization. 34,558 patients had an index admission for SVI/B vs. 24,600,000 who did not. Patients with SVI/B had a 13.3% [4,383] readmission rate within 30 days compared to 8.4% [2,033,329] without SVI/B. Compared to readmitted patients without SVI/B patients, those with SVI/B were older (mean [SD] age: 64.4 [SD ± 19] vs. 61.4 [SD ± 20] years) and had more comorbidities (Charlson comorbidity score ≥ 3: 79.2% [ 3,471] vs. 60.9% [1,238,299]). The mortality rate among patients readmitted with SVI/B was 5.38% [236] vs. 4.02% [81,740] for patients without SVI/B, p-value = 0.016. Top reasons for readmissions among patients with SVI/B included sepsis 12% [526], heart failure 10.5% [460)], acute renal failure 4.4% [193], complications due to type II diabetes mellitus 4.1% [178], and pneumonia 2.7% [118]. The mean length of stay for readmitted patients with SVI/B was 6.3 days (confidence interval [CI]: 6.0-6.7 days), vs. 5.6 days for patients without SVI/B (CI: 5.5-5.8 days), p-value < 0.01. The mean hospital charges for readmitted patients with SVI/B was $57,202 (CI: $53,712-$61,292) vs. $51,582 (CI: $49,966-$53,198), p-value < 0.01. Patients with SVI/B had higher readmission rates and greater mortality on readmissions than those without SVI/B. Interventional studies for optimal discharge strategies are critically needed to improve clinical and resource utilization outcomes in patients with SVI/B.


ECG changes on continuous telemetry preceding in-hospital cardiac arrests.
About 200,000 patients suffer from in-hospital cardiac arrest (IHCA) annually. Identification of at-risk patients is key to improving outcomes. The use of continuous ECG monitoring in identifying patients at risk for developing IHCA has not been studied. To describe the profile and timing of ECG changes prior to IHCA. Retrospective, observational. Single 520-bed tertiary care hospital. IHCA in adults between April 2010 and March 2012 with at least 3 hours of continuous telemetry data immediately prior to IHCA. We evaluated up to 24 hours of telemetry data preceding IHCA for changes in PR, QRS, ST segment, arrhythmias, and QTc in ventricular tachycardia cases. We determined mechanism and likely clinical cause of the arrest by chart and telemetry review. We studied 81 IHCA patients, in whom the mechanism was ventricular tachycardia/fibrillation in 14 (18%), bradyasystolic in 21 (26%), and pulseless electrical activity (PEA) in 46 (56%). Preceding ECG changes were ST segment changes (31% of cases), atrial tachyarrhythmias (21%), bradyarrhythmias (28%), P wave axis change (21%),QRS prolongation (19%), PR prolongation (17%), isorhythmic dissociation (14%), nonsustained ventricular tachycardia (6%), and PR shortening (5%). At least one of these was present in 77% of all cases, and in 89% of IHCA caused by respiratory or multiorgan failure. Bradyarrhythmias were primarily seen with IHCA in the setting of respiratory or multiorgan failure, and PR and QRS prolongation with IHCA and concomitant multiorgan failure. This is a retrospective study with a limited number of cases; each patient serves as their own control, and a separate control population has not yet been studied. ECG changes are commonly seen preceding IHCA, and have a pathophysiologic basis. Automated detection methods for ECG changes could potentially be used to better identify patients at risk for IHCA.


[Treatment of spondylolisthesis with pedicle screw instrumentation and anterior or posterior lumbar interbody fusion].
To investigate the treatment of spondylolisthesis with pedicle screw instrumentation and anterior or posterior lumbar interbody fusion. 26 patients, 14 males and 12 females, underwent spinal instrumentation with RF or SOCON instrumentation and anterior or posterior interbody fusion with TFC. Among them, 6 patients underwent RF instrumentation and posterior interbody fusion with TFC, 15 SOCON instrumentation and posterior interbody fusion with TFC, and 5 RF instrumentation and anterior interbody fusion with composite cortical ring. All the patients were followed up for an average of 22 months (range 6 - 18 months) after operation. The reduction of spondylolisthesis was 88%, and the fusion rate 89%. There was no recurrence of spondylolisthesis. High quality SOCON instrumentation may be reliable for the treatment of spondylolisthesis. Implantation of TFC into the interbody space can stabilize the fused segments, prevent the collapse of the interbody space, avoid bone resorption, remain or increase the heights of the interbody space, facilitate the union of the fused segments, and allow early mobilization.


Diversity-oriented approaches for interrogating T-cell receptor repertoire, ligand recognition, and function.
Molecular diversity lies at the heart of adaptive immunity. T-cell receptors and peptide-major histocompatibility complex molecules utilize and rely upon an enormous degree of diversity at the levels of genetics, chemistry, and structure to engage one another and carry out their functions. This high level of diversity complicates the systematic study of important aspects of T-cell biology, but recent technical advances have allowed for the ability to study diversity in a comprehensive manner. In this review, we assess insights gained into T-cell receptor function and biology from our increasingly precise ability to assess the T-cell repertoire as a whole or to perturb individual receptors with engineered reagents. We conclude with a perspective on a new class of high-affinity, non-stimulatory peptide ligands we have recently discovered using diversity-oriented techniques that challenges notions for how we think about T-cell receptor signaling.


Characterization of Caedibacter endonucleobionts from the macronucleus of Paramecium caudatum and the identification of a mutant with blocked R-body synthesis.
Cytology, DNA and host-symbiont relationships of x-like endosymbionts from Paramecium caudatum are described. The symbionts (Caedibacter caryophila, sp. nov.) live in the macronuclei of their hosts. They confer the killer trait upon their hosts and appear well adapted to their endonucleobiotic way of life. R bodies (proteinaceous ribbons associated with killing) are produced, but differ significantly from any of the four R-body classes previously described. C. caryophila and their R bodies were isolated. DNA was extracted from purified symbionts and used to demonstrate that one P. caudatum line harbors a natural mutant which is deficient in R-body production. Melting studies indicate a GC content of 34.6%. No sequence homology between the C. caryophila DNA and the coding sequence for type 51 R-body production was observed. C. caryophila is parasitic, causing the death of its hosts in starving cultures.


The first born, their dispersal, and vole cycles.
On the basis of some empirical data and the existing theory of vole cycles, a new hypothesis is proposed. It explains cyclicity as an effect of obligatory dispersal of the first seasonal cohort of young (Y1) from their natal (optimal) habitats into vacant (suboptimal) habitats. This behaviour could evolve, because it increases contribution of genetic lineages with dispersing Y1, to subsequent generation. It is assumed that the dispersal of Y1 is common among vole species, it does not change during consecutive phases of the cycle, and it does not vary between cyclic and non-cyclic populations. It results in multiannual cycles only under a certain set of spatial and climatic conditions, which are discussed in a paper. Otherwise it results in annual dynamics.


Sexual dimorphism and resource allocation in male and female shrubs of Simmondsia chinensis.
Desert populations of the evergreen dioecious shrub Simmondsia chinensis exhibit sex-related leaf and canopy dimorphisms not present in populations from more mesic coastal environments. Leaves on female shrubs have characteristically larger sizes, greater specific weights, and greater water-holding capacity than male leaves in desert habitats. In coastal scrub environments no significant difference is present, with leaf characteristics of both sexes similar to those of desert male shrubs. Desert female shrub canopies are typically relatively open with little mutual branch shading. In male shrubs canopies are more densely branched with considerable mutual shading of branches. Female plants allocate a greater proportion of their vegetative resources to leaves than do male plants. Considering total biomass, male plants allocate 10-15% of their resources (biomass, calories, glucose-equivalents, nitrogen, phosphorus) to reproductive tissues. Female allocation is dependent on seed set. At 100% seed set females would allocate 30-40% of their resources to reproduction, while female reproductive investment would equal that of males at approximately 30% seed set. Sexual dimorphism and the associated physiological characteristics in Simmondsia act as an alternative to differential habitat selection by male and female plants. Female plants respond to limited water resources in desert areas by increasing their efficiency in allocating limited resources to reproductive structures.


[Correction of hypophyseal-adrenal system function in esophageal and stomach cancer patients undergoing combined and surgical treatments].
The paper presents the data on marked dysfunction of hypothalamo-pituitary-adrenal system in patients with esophageal and gastric cancer. Patients revealed lowered levels of 11-hydroxycorticosteroids in blood plasma and 17-corticosteroids and 17-glucocorticosteroids in diurnal urine. It was matched by an elevated threshold of hypothalamic sensitivity to inhibition by glucocorticosteroids. Treatment for these disturbances which brought the function of this system to normal had a beneficial effect on the secretion and excretion of corticosteroids in the course of combined therapy and surgery and was followed by a significant decrease in hemodynamic complication incidence. The favorable clinical effect was in correlation with the decrease in hypothalamic resistance to the inhibitory effect of glucocorticoids.


Development and Evaluation of a Serious Game Application to Engage University Students in Critical Thinking About Health Claims: Mixed Methods Study.
Misleading health claims are widespread in the media, and making choices based on such claims can negatively affect health. Thus, developing effective learning resources to enable people to think critically about health claims is of great value. Serious games can become an effective learning resource in this respect, as they can affect motivation and learning. This study aims to document how user insights and input can inform the concept and development of a serious game application in critical thinking about health claims in addition to gathering user experiences with the game application. This was a mixed methods study in 4 successive phases with both qualitative and quantitative data collected in the period from 2020-2022. Qualitative data on design and development were obtained from 4 unrecorded discussions, and qualitative evaluation data were obtained from 1 recorded focus group interview and 3 open-ended questions in the game application. The quantitative data originate from user statistics. The qualitative data were analyzed thematically, and user data were analyzed using nonparametric tests. The first unrecorded discussion revealed that the students' (3 participants') assessment of whether a claim was reliable or not was limited to performing Google searches when faced with an ad for a health intervention. On the basis of the acquired knowledge of the target group, the game's prerequisites, and the technical possibilities, a pilot of the game was created and reviewed question by question in 3 unrecorded discussions (6 participants). After adjustments, the game was advertised at the Oslo Metropolitan University, and 193 students tested the game. A correlation (r=0.77; P<.001) was found between the number of replays and total points achieved in the game. There was no demonstrable difference (P=.07) between the total scores of students from different faculties. Overall, 36.3% (70/193) of the students answered the evaluation questions in the game. They used words such as "fun" and "educational" about the experiences with the game, and words such as "motivating" and "engaging" related to the learning experience. The design was described as "varied" and "user-friendly." Suggested improvements include adding references, more games and modules, more difficult questions, and an introductory text explaining the game. The results from the focus group interview (4 participants) corresponded to a large extent with the results of the open-ended questions in the game. We found that user insights and inputs can be successfully used in the concept and development of a serious game that aims to engage students to think critically about health claims. The mixed methods evaluation revealed that the users experienced the game as educational and fun. Future research may focus on assessing the effect of the serious game on learning outcomes and health choices in randomized trials.


Treatment of Thygeson's superficial punctate keratopathy with soft contact lenses.
Three patients had Thygeson's superficial punctate keratopathy; two of whom previously had required prolonged topical corticosteroid therapy for symptomatic relief. The use of therapeutic soft contact lenses provided improved visual acuity as well as symptomatic relief in all three patients. Corneal opacities faded while the soft contact lenses were in place. One patient who had been on long-term topical corticosteroids was gradually taken off this medication with the use of soft contact lens. Another patient noted only mild symptoms from acute episodes while wearing soft contact lenses; only minimal topical corticosteroids were required to control her symptoms. Two additional patients were treated with soft contact lenses. One could not tolerate soft lens wear and the other chose corticosteroid therapy instead of soft lens wear. Soft contact lenses are an acceptable alternative to topical corticosteroid therapy in the treatment of Thygeson's superficial punctate keratopathy.


The influence of gender on complications of carotid endarterectomy.
Carotid endarterectomy (CEA) effectively reduces stroke risk in properly selected patients. Subgroup analysis of the Asymptomatic Carotid Artery Study trial noted increased complications in women. Additional studies implicate female gender as a risk factor for perioperative stroke, leading some clinicians to modify the indications for CEA in women. The purpose of this study was to determine the influence of gender on the risk of perioperative complications in patients undergoing CEA. The records of all patients who underwent CEA at a university medical center from January 1995 to December 1999 were reviewed. Patient demographics, procedure related risk factors, operative details, and specific complications were entered into a database for statistical analysis. A total of 324 consecutive patients underwent CEA during the study period. There were 199 men (61%) and 125 women (39%). Among the men and women, there were no differences in age, smoking, hypertension, hypercholesterolemia, diabetes, family history, renal insufficiency, or symptomatic versus asymptomatic indications for CEA. More women than men received a carotid patch (90.4% versus 77.9%, P = 0.003). One woman died (0.8%) and no men died for a total combined 30-day mortality of 0.31% (P = not significant). Men and women did not differ in rates of stroke (1.5% versus 2.4%) or perioperative myocardial infarction (1.0% versus 0.8%). In addition, there was no difference when stroke and death rates were combined (2% versus 3.2%). The length of stay (2.2 versus 2.6 days) was also not different. There are no significant differences in rate of stroke, myocardial infarction, or 30-day mortality, between men and women following CEA. Women should not be excluded from the benefits of CEA based on perceived increased complication rates.


Machine Learning Approaches to Analyzing Adverse Events Following Durable LVAD Implantation.
This study employed machine learning approaches to analyze sequences of adverse events (AEs) after left ventricular assist device (LVAD) implantation. Data on patients implanted with the HeartWare HVAD durable LVAD were extracted from the ENDURANCE and ENDURANCE Supplemental clinical trials, with follow-up through 5 years. Major AEs included device malfunction, major bleeding, major infection, neurological dysfunction, renal dysfunction, respiratory dysfunction, and right heart failure (RHF). Time interval and transition probability analyses were performed. We created a Sankey diagram to visualize transitions between AEs. Hierarchical clustering was applied to dissimilarity matrices based on the longest common subsequence to identify clusters of patients with similar AE profiles. A total of 568 patients underwent HVAD implantation with 3590 AEs. Bleeding and RHF comprised the highest proportion of early AEs after surgery whereas infection and bleeding accounted for most AEs occurring after 3 months. The highest transition probabilities were observed with infection to infection (0.34), bleeding to bleeding (0.31), RHF to bleeding (0.31), RHF to infection (0.28), and bleeding to infection (0.26). Five distinct clusters of patients were generated, each with different patterns of time intervals between AEs, transition rates between AEs, and clinical outcomes. Machine learning approaches allow for improved visualization and understanding of AE burden after LVAD implantation. Distinct patterns and relationships provide insights that may be important for quality improvement efforts.


Manipulations during the second, but not the first, week of life increase susceptibility to cocaine self-administration in female rats.
We compared the effects of manipulations during week 1 vs week 2 of life on the propensity to self-administer cocaine. Pups received daily subcutaneous saline injections, were handled briefly, or remained undisturbed during their respective treatment periods. Animals handled during the second week of life exhibited increased locomotor response to novelty when tested on postnatal day (PND) 48, compared to all other groups. Rats were implanted with jugular catheters on PND 70 and then given the opportunity to self-administer (0.125 mg/kg/infusion) cocaine for 5 consecutive days (1 h sessions). The dose was then raised to 0.25 mg/kg/infusion for 5 days and to 0.5 mg/kg/infusion for the final 5 days of testing. Only animals manipulated during the second week of life acquired drug-taking behavior. These effects were both stimulus- and gender-specific. Females handled during the second week of life acquired cocaine self-administration (SA) at the lowest dose, and females injected during the second week of life acquired at the intermediate dose. Males injected during the second week of life showed a similar, but more variable, drug-taking pattern. There were no group differences in serum corticosterone response to novelty, although relative to undisturbed animals and those manipulated in the first week of life, female animals manipulated during the second week of life had lower basal expression of hippocampal glucocorticoid receptor mRNA in adulthood. We conclude that the second week of life in the rodent is a sensitive period during which manipulations result in a more vulnerable phenotype for the acquisition of cocaine SA.


Repeatability and agreement in optical biometry of a new swept-source optical coherence tomography-based biometer versus partial coherence interferometry and optical low-coherence reflectometry.
To estimate the repeatability of biometric parameters obtained with a new swept-source biometer and to compare the agreement with that of partial coherence interferometry (PCI) and optical low-coherence reflectometry (OLCR). Department of Ophthalmology, Helios Hospital Erfurt, Erfurt, Julius-Maximilians University, Würzburg, and Philipps University, Marburg, Germany. Prospective comparative multicenter clinical study. Biometry was taken with the use of 3 different biometers: the IOLMaster 700 swept-source biometer, the PCI-based IOLMaster 500, and the OCLR-based Lenstar LS 900. Axial length (AL), anterior chamber depth (ACD), and spherical equivalent (SE) were compared between swept-source and PCI biometry and central corneal thickness (CCT) and lens thickness (LT) between swept-source and OLCR biometry. The repeatability of swept-source biometry was evaluated on the basis of 3 measurements captured for each patient. One hundred twenty cataract eyes were included in the study. The mean difference between swept-source and PCI biometry for AL, ACD, and SE measurements was 4 μm ± 25 (SD), 17 ± 122 μm, and -0.001 ± 0.19 diopter (D), respectively. The mean difference between swept-source and OLCR biometry for LT and CCT measurements was 21 ± 122 μm and 0.15 ± 4.51 μm, respectively. Differences between swept-source biometry and the other devices distributed around zero without statistical significance. The standard deviation of repeatability for AL, ACD, LT, CCT, and SE was 8.8 μm, 9.8 μm, 2.3 μm, 19.5 μm, and 0.1 D, respectively. Swept-source biometry showed high repeatability performance for all biometric parameters. The agreement of AL, ACD, and SE between swept-source and PCI biometry as well as that of LT and CCT between swept-source and OLCR biometry was excellent. It remains to be validated whether high repeatability shown by swept-source biometry will result in better postoperative refractive outcomes. Drs. Blum and Sekundo are members of the Scientific Advisory Board of Carl Zeiss Meditec AG. Drs. Peter and Bühren are employees of Carl Zeiss Meditec AG.


The role of activation of two different sGC binding sites by NO-dependent and NO-independent mechanisms in the regulation of SACs in rat ventricular cardiomyocytes.
The mechanoelectrical feedback (MEF) mechanism in the heart that plays a significant role in the occurrence of arrhythmias, involves cation flux through cation nonselective stretch-activated channels (SACs). It is well known that nitric oxide (NO) can act as a regulator of MEF. Here we addressed the possibility of SAC's regulation along NO-dependent and NO-independent pathways, as well as the possibility of S-nitrosylation of SACs. In freshly isolated rat ventricular cardiomyocytes, using the patch-clamp method in whole-cell configuration, inward nonselective stretch-activated cation current ISAC was recorded through SACs, which occurs during dosed cell stretching. NO donor SNAP, α1-subunit of sGC activator BAY41-2272, sGC blocker ODQ, PKG blocker KT5823, PKG activator 8Br-cGMP, and S-nitrosylation blocker ascorbic acid, were employed. We concluded that the physiological concentration of NO in the cell is a necessary condition for the functioning of SACs. An increase in NO due to SNAP in an unstretched cell causes the appearance of a Gd3+ -sensitive nonselective cation current, an analog of ISAC , while in a stretched cell it eliminates ISAC . The NO-independent pathway of sGC activation of α subunit, triggered by BAY41-2272, is also important for the regulation of SACs. Since S-nitrosylation inhibitor completely abolishes ISAC , this mechanism occurs. The application of BAY41-2272 cannot induce ISAC in a nonstretched cell; however, the addition of SNAP on its background activates SACs, rather due to S-nitrosylation. ODQ eliminates ISAC , but SNAP added on the background of stretch increases ISAC in addition to ODQ. This may be a result of the lack of NO as a result of inhibition of NOS by metabolically modified ODQ. KT5823 reduces PKG activity and reduces SACs phosphorylation, leading to an increase in ISAC . 8Br-cGMP reduces ISAC by activating PKG and its phosphorylation. These results demonstrate a significant contribution of S-nitrosylation to the regulation of SACs.


Advanced clinicians' experience of participation in an escape room scenario designed to consolidate crisis resource management principles: An exploratory pilot study.
Intensive care outreach nurses are required to work as part of an ad hoc team to review and manage patients who are deteriorating outside of critical care environments. Nontechnical skills, such as those encompassed by crisis resource management principles, are essential when working in these situations. Used commercially for entertainment, escape rooms have recently been utilised by clinical educators to teach both technical and nontechnical skills. This exploratory study evaluates how advanced clinicians, intensive care outreach nurses, experience an escape room scenario designed to consolidate crisis resource management (CRM) principles. Three escape room sessions were conducted in a 1038-bed metropolitan tertiary referral hospital. A purposive sample of 12 intensive care outreach nurses were invited to participate. The participant's experience of the escape room scenario was determined by their responses to a post-escape room survey and focus group discussion. Transcripts of the audio recordings from focus group discussions were analysed using an inductive coding approach. Two primary categories emerged from analysis of the focus group discussions: (i) the clinicians' experiences of the escape room and (ii) CRM principles. The first category included descriptions of emotions, including confusion, frustration, and a dislike for puzzles. The second category included both the participants understanding of the CRM principles, and how the principles influence the work within the escape room. Escape rooms have shown promise as novel educational environments, which challenge participants. Despite initial negative descriptions of the escape room, focus group discussions demonstrated that the participants were able to recognise the impact of CRM principles and acknowledge how these affect their clinical work in an ad hoc team.


The screening, diagnosis and evaluation of genotoxic agents with batteries of bacterial tests.
Bacterial tests can be used for several related purposes: the screening for genotoxic agents, genetic analysis of the mode of action of genotoxins and attempts to predict their effects in mammals. We examine various aspects of the assembly of tests into batteries with emphasis on the genetic properties of target bacterial cells. We discuss the problems of carcinogenicity prediction, the identification of particular types of DNA lesions, the study of mutagenic specificity and the elucidation of metabolic steps towards the ultimate genotoxin.


Mutation analysis of the WFS1 gene in seven Danish Wolfram syndrome families; four new mutations identified.
Wolfram syndrome (WS) is a neuro-degenerative autosomal recessive (AR) disorder (OMIM #222300) caused by mutations in the WFS1 gene on 4p16.1. More than 120 mutations have been identified in WFS1 associated with AR WS, as well as autosomal dominant nonsyndromic low-frequency sensorineural hearing loss (LFSNHL). WFS1 variants were identified in eight subjects from seven families with WS, leading to the identification of four novel mutations, Q194X (nonsense), H313Y (missense), L313fsX360 (duplication frame shift) and F883fsX951 (deletion frame shift), and four previously reported mutations, A133T and L543R (missense), V415del (in frame triple deletion) and F883fsX950 (deletion frame shift). A mutation was found in 11/14 disease chromosomes, two subjects were homozygous for one mutation, one subject was compound heterozygous for two nucleotide substitutions (missense), one subject was compound heterozygous for a duplication and a deletion (frame shift), and in three families only one mutation was detected (Q194X and H313Y). All affected individuals shared clinically early-onset diabetes mellitus and progressive optic atrophy with onset in the first and second decades, respectively. In contrast, diabetes insipidus was present in two subjects only. Various degrees and types of hearing impairment were diagnosed in six individuals and cataract was observed in five subjects.


Hypoxia causes mitochondrial dysfunction and brain memory disorder in a manner mediated by the reduction of Cirbp.
Environmental hypoxic hazard has increasingly become a global public health issue, with impelling evidences supporting the relation between hypoxia and cognitive disorders. As a potent stressor, hypoxia causes mitochondrial dysfunction with insufficient energy production, thus the formation of brain memory disorder. Yet, the underlying molecular mechanism/s against hypoxia induced injury have yet to be identified. Here, we report that cold inducible RNA binding protein (Cirbp) attenuates hypoxia induced insufficient energy production and oxidative stress. Further analyses show that Cirbp sustains protein levels of respiratory chain complexes II (SDHB) and IV (MT-CO1), and directly binds the 3'UTR of Atp5g3 to control mitochondrial homeostasis and ATP biogenesis upon hypoxic stress. Altogether, our data establish Cirbp as a critical protective factor against hypoxic health hazard and provide novel insights into its latent regulation network.


Functional and neurobiological similarities of aging in monkeys and humans.
Aging in humans may be accompanied by alterations in several functional abilities. However, there is a great deal of individual variability in the functions that may be altered with age within and across aged people. One potential source of age-related behavioral variation may lie in a differential vulnerability of neurobiological systems to the aging process in particular individuals. Aged monkeys demonstrate behavioral and brain alterations that have many parallels with those observed in aged humans and are valuable animal models in which to investigate the interrelationships between age, behavior and neurobiological measures. This review outlines the similarities of functional and neurobiological aging in monkeys and humans, notes the variability that exists in both behavioral and neural systems in aging, and identifies some of the areas of aging that are in need of further investigation.


Neuromuscular and cardiovascular depression produced by prolonged exposure to Polymyxin B.
It has been reported previously that in cats pre-treatment for 24 to 48 hours with neomycin sulphate resulted in a change in the pattern of neuromuscular block subsequently produced with this antibiotic. The unique characteristics of neomycin-induced neuromuscular block observed during acute exposure gave way to a pattern of block usually observed with tubocurarine. In a similar experiment on six cats we have demonstrated that with polymyxin B prolonged exposure did not result in a comparable time-dependent change in the nature of the neuromuscular block it produced, in terms of train-of-four, tetanic, and post-tetanic behaviour of the neurally-elicited muscle response. The differing characteristics of neuromuscular block seen with various antibiotics, e.g. the aminoglycoside neomycin as opposed to the polypeptide polymyxin B, during acute and sub-chronic exposure is stressed. Previously observed ability of 4 aminopyridine 0.6 mg/kg to reverse the neuromuscular and cardiovascular depression during acute exposure to polymyxin B persisted in prolonged exposure.


Ipsilateral microcalcifications after breast-conserving surgery: is it possible to differentiate benign from malignant calcifications?
To analyse stereotactic biopsies of microcalcifications in patients with previous ipsilateral breast-conserving surgery (BCS) to identify the positivity rate, assess for an association between the patient's primary cancer or mammographic appearances of the microcalcifications, and the risk of recurrence. Relevant patients from 2018-2020 were identified via a retrospective review of the prospectively maintained radiological procedure database. Clinicopathological features of the patients' primary tumour and new calcifications were obtained from the hospital electronic patient record system and the national integrated medical imaging system. Thirty-one percent of recurrences post-ipsilateral BCS presented as isolated microcalcifications on mammography. Fifty-three percent of patients undergoing stereotactic biopsy of ipsilateral calcifications had recurrence. A positive margin status was associated with new or recurrent malignancy. There was no significant correlation between oestrogen-receptor status, sentinel lymph node status, adjuvant radiotherapy or chemotherapy and the risk of recurrence. Calcifications within the tumour bed were more likely to be benign while calcifications within the same quadrant but remote from the tumour bed were more likely malignant. All coarse calcifications were benign while 67% of fine linear/fine linear branching and 89% of fine pleomorphic calcifications were malignant. Increased time since diagnosis, positive margin status, fine pleomorphic and fine linear calcifications in the same quadrant as the tumour bed were associated with malignancy. Patients with coarse calcifications and calcifications within the tumour bed may avoid stereotactic biopsy and undergo short-interval surveillance.


Influential factors of saliva microbiota composition.
The oral microbiota is emerging as an influential factor of host physiology and disease state. Factors influencing oral microbiota composition have not been well characterised. In particular, there is a lack of population-based studies. We undertook a large hypothesis-free study of the saliva microbiota, considering potential influential factors of host health (frailty; diet; periodontal disease), demographics (age; sex; BMI) and sample processing (storage time), in a sample (n = 679) of the TwinsUK cohort of adult twins. Alpha and beta diversity of the saliva microbiota was associated most strongly with frailty (alpha diversity: β = -0.16, Q = 0.003, Observed; β = -0.16, Q = 0.002, Shannon; β = -0.16, Q = 0.003, Simpson; Beta diversity: Q = 0.002, Bray Curtis dissimilarity) and age (alpha diversity: β = 0.15, Q = 0.006, Shannon; β = 0.12, Q = 0.003, Simpson; beta diversity: Q = 0.002, Bray Curtis dissimilarity; Q = 0.032, Weighted UniFrac) in multivariate models including age, frailty, sex, BMI, frailty and diet, and adjustment for multiple testing. Those with a more advanced age were more likely to be dissimilar in the saliva microbiota composition than younger participants (P = 5.125e-06, ANOVA). In subsample analyses, including consideration of periodontal disease (total n = 138, periodontal disease n = 66), the association with frailty remained for alpha diversity (Q = 0.002, Observed ASVs; Q = 0.04 Shannon Index), but not beta diversity, whilst age was not demonstrated to associate with alpha or beta diversity in this subsample, potentially due to insufficient statistical power. Length of time that samples were stored prior to sequencing was associated with beta diversity (Q = 0.002, Bray Curtis dissimilarity). Six bacterial taxa were associated with age after adjustment for frailty and diet. Of the factors studied, frailty and age emerged as the most influential with regards to saliva microbiota composition. Whilst age and frailty are correlates, the associations were independent of each other, giving precedence to both biological and chronological ageing as processes of potential importance when considering saliva microbiota composition.


Effects of uridine diphosphate glucuronosyltransferase activity on the maximal secretion rate of bilirubin conjugates in the rat.
It is generally accepted that biliary secretion is rate-limiting for the plasma-to-bile transport of a saturating load of bilirubin. Previous studies from this laboratory have suggested a relationship between the hepatic bilirubin uridine diphosphate glucuronosyltransferase activity and the apparent maximal rate of bilirubin secretion (excretory transport maximum). The present study was undertaken to further investigate this relationship in rats with a wide range of transferase levels and to analyze the effects of transferase activity on the formation of bilirubin monoglucuronides and diglucuronides in vivo and in vitro. Animals with moderately decreased enzyme activity still showed a near-normal excretory transport maximum but decreased fractional amounts of conjugated bilirubins in plasma and liver and a decreased ratio of bilirubins diconjugates to monoconjugates in bile, liver, and plasma. A more pronounced decrease in the level of transferase activity yielded lower excretory transport maximum values as well. Enhanced transferase activities were obtained by pretreatment with a series of enzyme-inducing agents, usually at dosages not influencing bile flow. An enhanced transferase activity produced significant increases in bilirubin excretory transport maximum, decreased concentrations of both unconjugated and conjugated bilirubins in plasma, and an increased ratio of diconjugates to monoconjugates in bile and in liver. In all animals, the ratio of disconjugates to monoconjugates observed in bile was correlated with the ratio found after incubation of liver homogenates in vitro at low concentrations of bilirubin substrate. Overall, the relationship between bilirubin excretory transport maximum and uridine diphosphate glucuronosyltransferase activity can best be described by a hyperbolic curve. At "saturation" of the excretory transport maximum values, no increase of conjugates in liver or in plasma could be observed, suggesting that not the biliary secretion, per se, but rather the conjugation rate in vivo is rate-limiting. The latter seems lower than the in vitro assayed enzyme activity. The present investigations point to an equilibration of bilirubin pigments between plasma, liver, and bile. The in vivo conjugation rate can be estimated from the in vitro assay (but not at high enzyme activities) and determines the maximal biliary secretion rate, the ratio of diconjugates to monoconjugates in the three compartments studied, and the relative amount of conjugates in plasma. Our studies suggest that the conjugation rate in vivo rather than the biliary secretion step is the major determinant of the maximal bilirubin secretion rate.