Molecular Pathways: A Novel Approach to Targeting Hypoxia and Improving Radiotherapy Efficacy via Reduction in Oxygen Demand.
Tumor hypoxia presents a unique therapeutic challenge in the treatment of solid malignancies. Its presence has been established to be a poor prognostic factor in multiple cancer types, and past hypoxia-directed approaches have yielded generally disappointing results. Previous approaches have centered on either increasing oxygen delivery or administering agents that preferentially radiosensitize or kill hypoxic cells. However, a novel and potentially more effective method may be to increase therapeutic benefit by decreasing tumor oxygen consumption via agents such as metformin or nelfinavir in a patient population that is enriched for tumor hypoxia. This promising approach is currently being investigated in clinical trials and the subject of this article.


Osmotic stress drastically inhibits active transport of carbohydrates by Escherichia coli.
In intact Escherichia coli cells, severe osmotic stress almost totally inhibited active transport of carbohydrate by all of the systems known to transport carbohydrates in E. coli: group translocation (glucose), binding-protein mediated transport (maltose), proton symport (lactose), and sodium cotransport (melibiose). Detailed study of glucose transport showed that this inhibition of transport was not secondary to the inhibition of growth by osmotic stress, but rather that the inhibition of transport of a source of carbon and energy was sufficient to cause the complete inhibition of growth observed during severe osmotic upshock. Transport and growth inhibition did not result from cell death; upshocked cells were viable and metabolically active.


Glycosaminoglycan-lipoprotein complexes from aortas of hypercholesterolemic rabbits. Part 1. Isolation and characterization.
Glycosaminoglycan-lipoprotein complexes were isolated from rabbit aortas exhibiting nearly confluent cholesterol-induced foam cell lesions by extraction with 0.15 M NaCl. Purification and characterization was achieved by gel chromatography, non-ionic differential flotation and by cellulose polyacetate electrophoresis. Analysis showed that these complexes consisted of very low density lipoproteins, heparan sulfate, chondroitin sulfate-C and hyaluronic acid. The demonstration that rabbit intimal foam cell lesions contain extractable glycosaminoglycan-lipoprotein complexes makes this animal model an excellent tool for further studies on the role of these complexes in the atherogenic process.


Antenatal glucocorticoid treatment is not associated with long-term metabolic risks in individuals born before 32 weeks of gestation.
A single course of maternal glucocorticoid treatment is effective in reducing neonatal mortality after preterm birth. However, in animals, maternal glucocorticoid treatment is associated with lifelong hyperglycaemia and hypertension, and impaired nephrogenesis in offspring. Findings from studies in humans on this topic are highly contradictory due to a number of methodological flaws, and renal function after glucocorticoid exposure has never been assessed. To assess in individuals born <32 gestational weeks whether antenatal glucocorticoid treatment for preterm birth is associated with long-term metabolical risks, including renal function, in adulthood. Birth cohort study. Multicentre study. 412 19 year olds born <32 gestational weeks from the Project On Preterm and Small-for-gestational-age infants (POPS) cohort. Maternal betamethasone 12 mg administered twice with a 24 h interval. Body composition, insulin resistance, the serum lipid profile, blood pressure and estimated renal function. We did not find any long-term adverse effects of antenatal betamethasone, with the exception of an effect on glomerular filtration rate (GFR). In 19-year-old survivors, GFR was lower after betamethasone: -5.2 ml/min (95% CI -8.9 to -1.4) per 1.73 m(2). The reduction in neonatal mortality associated with a single course of maternal betamethasone is not accompanied by long-term metabolical risks in survivors of preterm birth. The only adverse effect found was lower GFR. Although this difference was not clinically relevant at 19 years, it might predict an increased risk of chronic renal failure in prematurely born individuals who were exposed antenatally to betamethasone.


Hirayama disease: three cases.
Hirayama disease is a rare, lower cervical myelopathy affecting young adults. It is responsible for pure distal motor impairment of the upper limbs, with slow progressive development in the metameric territories of C7 to T1. It is thought to be caused by movements involved in flexing the neck. Neutral position magnetic resonance imaging (MRI) looks for abnormal cervical curvature, atrophy with flattening of the cervical spine, anterior cord hyperintensity and especially a lack of posterior apposition of the dural sac. If the condition is suspected, an MRI in flexion should be performed to show anterior displacement of the cord and dural sac, enlargement of the posterior epidural space, an increase in flattening of the cord and congestion of the epidural veins. These dynamic abnormalities tend to disappear after evolving for 10 years. We report two confirmed cases and a probable case of Hirayama disease and discuss its physiopathology.


Effects of the invasive clam Corbicula fluminea (Müller, 1774) on an estuarine microbial community.
The Asian clam Corbicula fluminea (Müller, 1774) is well recognized for its invasive behavior and high ecological and economic impacts, being classified as one of the 100 worst invasive alien species (IAS) in Europe. In this study, we performed a manipulative experiment under natural conditions to assess the effects of C. fluminea on sediments biochemistry and on the structure of an estuarine microbial (fungi and bacteria) community. We placed 5 treatments (control, rock, closed, live and open) for 2months in the Minho estuary (NW Iberian Peninsula). No differences were detected between treatments regarding the values of carbon (C), nitrite (NO2(-)), ammonium (NH4(+)), phosphate (PO4(3-)) and calcium (Ca) in the sediments; however, potassium (K) had higher values in the open treatment. Furthermore, we found that the presence of live C. fluminea stimulated fungal biomass (but not diversity) and bacterial diversity. Bioturbation activities by C. fluminea are possibly the main mechanism explaining these results; however, other factors such as the presence of other macroinvertebrate species and/or production of feces and pseudofeces by C. fluminea cannot be excluded. To our knowledge, this is the first manipulative experiment under natural conditions that clearly shows the effects of C. fluminea on an estuarine microbial community. Given the widespread distribution of this IAS and the paucity of quantitative assessments of invasive bivalves' effects on microbial communities, it will be important that future studies further investigate these processes.


Two cases of synchronous multiple thymoma.
We report two cases of synchronous double primary thymoma without myasthenia gravis. These cases suggest the possibility of multicentric thymoma and confirm the validity of a complete thymectomy.


Positive Early Childhood Experiences and School Readiness among US Preschoolers.
To characterize the relationship between positive early childhood experiences (PECEs) and school readiness, and assess whether the PECEs-school readiness relationship was robust to and/or differed across levels of adverse childhood experiences (ACEs). We analyzed national data on children ages 3-5 from 2016 to 2020 (n = 26 871) to examine associations between key PECE domains (nurturing relationships, home learning opportunities, safe and stable environments, and family routines) with being on track for school readiness, defined using a pilot, multidimensional measure called "healthy and ready to learn". Weighted univariate, bivariate, and multivariable analyses were conducted to generate nationally representative estimates. Multivariable models adjusted for sociodemographic factors and were assessed both with and without cumulative ACE exposure. Two-fifths of children were healthy and ready to learn. Exposure to PECEs was associated with higher school readiness, irrespective of relative ACE exposure. Compared with those with low PECEs, children with moderate (aOR, 2.19; 95% CI, 1.86-2.58) and high (aOR, 4.37; 95% CI, 3.58-5.34) PECEs had greater odds for being healthy and ready to learn, net of both sociodemographic factors and ACE exposure. Significant associations were robust across demographic groups (eg, race and ethnicity), ACE levels, and ACE types (eg, parental incarceration). Increasing PECEs correspond with greater likelihood of possessing capacities key for school functioning, even amidst ACEs. In concert with efforts to ameliorate early life trauma, caregivers, health care providers, educators, and systems can consider boosting PECEs to foster healthy development in childhood and beyond.


Antiobesity potential of ursolic acid stearoyl glucoside by inhibiting pancreatic lipase.
The present study was designed to evaluate the hypolipidemic effect of ursolic acid stearoyl glucoside (UASG) in high-fat diet-induced obesity. Two in vivo experiments such as high-fat diet-induced obesity mice model and lipid emulsion tolerance test in normal rats were performed. In vitro inhibition of pancreatic lipase activity was further measured to substantiate the results. In high-fat diet-induced obesity mice model, female Swiss mice were fed a high fat diet (HFD; 40% fat) with or without 1 or 2% of UASG or 0.012% orlistat for nine weeks. In lipid emulsion tolerance test male Wister rats were orally administered, lipid emulsion with or without 500 or 1000 mg/kg of UASG and the plasma triglycerides were measured from 0.5 to 5 h. Consumption of HFD containing UASG to mice for nine weeks exhibited significant reduction in lipid parameters, body weight, parametrial adipose tissue weight, liver triglyceride (TG) and different organ weight compared to HFD fed control. Further it was noted the improvement in insulin resistance induced by the HFD alone group. Furthermore, consumption of an HFD containing 1 or 2% of UASG significantly increased the fecal content and fecal triglyceride compared with the HFD group. Pre-treatment with UASG inhibited the elevated plasma triglyceride level after the oral administration of the lipid emulsion to rats. Further, UASG significantly inhibits activity of pancreatic lipase at a concentration of 2.5 mg/ml. Data obtained from the results indicated that UASG prevent high-fat diet-induced obesity in mice possibly by inhibiting pancreatic lipase activity.


Development of novel electrospun dual-drug fiber mats loaded with a combination of ampicillin and metronidazole.
Our study was performed with the aim of preparing electrospun polylactide fibers with a combination of ampicillin (AMP) and metronidazole (MNZ) and investigating their drug release behavior and the antibacterial effect on Aggregatibacter actinomycetemcomitans and other oral pathogens. AMP and MNZ were integrated as a combination in two separate fibers (dual fiber mats - DFW mix) of electrospun PLA fiber mats by means of multijet electrospinning and in a single fiber (single fiber mats - SFW mix). HPLC (high-performance liquid chromatography) was used to measure the released drug quantities. Agar diffusion tests were used to determine the antibacterial effect of the eluates on A. actinomycetemcomitans, Fusobacterium nucleatum, Porphyromonas gingivalis and Enterococcus faecalis. The neutral red test was made to examine the cytocompatibility of the eluates with human gingival fibroblasts (hGFs). The release of the active agents varied with the antibiotic concentrations initially used in the fiber mats, but also with the distribution of the active agents in one or two fibers. Of the total quantity of MNZ (AMP), the SFW mix fiber mats released >60% (>70%) within a span of 5min, and 76% (71%) after 96h. With these drug concentrations released by the fiber mats (≥5m%), an antibacterial effect was achieved on A. actinomycetemcomitans and on all other species tested. Fiber mats and their eluates have no cytotoxic influence on human gingival fibroblasts (hGFs). Electrospun AMP/MNZ-loaded polymer fibers are a potential drug delivery system for use in periodontal and endodontic infections.


Herbicidal and Antifungal Xanthone Derivatives from the Alga-Derived Fungus Aspergillus versicolor D5.
Fungi have been proved as promising and prolific sources of functional secondary metabolites with potent agricultural applications. In this study, 14 xanthone derivatives (1-14), including six new ones, versicones I-N (1-4, 7, 11), and a biogenetically related derivative (15), were isolated from the alga-derived fungus Aspergillus versicolor D5. Their structures were elucidated by comprehensive spectroscopic methods. Versicone L (4) exhibited a broad antifungal spectrum and prominent inhibitory effects on Botrytis cinerea at a minimum inhibitory concentration (MIC) of 152 μM, 7-fold stronger than that of the positive control, carbendazim (MIC = 1.05 × 103 μM). Dihydrosterigmatocystin (13) showed strong antifungal activity toward B. cinerea at MIC = 38.3 μM, almost 30-fold stronger than that of carbendazim. Meanwhile, 13 exhibited potent herbicidal activity toward Amaranthus retroflexus L. with an MIC of 24.5 μM, approximately 4-fold stronger than that of the positive control, glyphosate (MIC = 94.7 μM). Additionally, 13 also displayed remarkable activity against other weeds belonging to Amaranth sp. Analysis of the structure-herbicidal activity relationship indicated that the bifuranic ring played an important role in xanthone phytotoxicity and the presence of a double bond in the furan ring could decrease phytotoxicity. This study indicated that xanthones can be served as promising candidates for lead compounds of agrochemicals.


Influence of the bioaccessible fraction of polycyclic aromatic hydrocarbons on the ecotoxicity of historically contaminated soils.
Sequential supercritical fluid extraction together with a two-site desorption model were employed to estimate the bioaccessible fraction of polycyclic aromatic hydrocarbons (PAHs) in four historically contaminated soils. The ecotoxicity of the soils was assayed by four different contact tests. The same soils were exposed to exhaustive extraction and the extracts were returned to the soils to ensure total 100% bioaccessibility of the pollutants. Then the soils were assayed again. Statistical evaluation revealed that the predicted bioaccessible PAHs generally correlated with the ecotoxicity responses of the tests. The estimated bioaccessible fractions varied from 10 to 98%. This value increased for PAHs with higher lipophilicity and showed no correlation with the organic carbon content in the soils. The ecotoxicity tests in the study indicated different sensitivity toward PAHs and the tests employing Heterocypris incongruens and Eisenia fetida were found to be more suitable than Lemna minor and Vibrio fischeri. Mortality and growth inhibition of ostracods correlated with all the types of PAHs and earthworm growth inhibition and mortality were preferentially sensitive to PAHs with only 3-4 aromatic rings. Determination of the biota-soil accumulation factors indicated that the earthworm growth inhibition corresponded to increased accumulation of PAHs in the earthworm tissue.


Impact of Intensive Low-Density Lipoprotein Cholesterol-Lowering Therapy on Coronary Artery Plaques in Acute Coronary Syndrome.
Acute coronary syndrome (ACS) is associated with a high incidence of unstable plaques beyond the culprit lesion, leading to early recurrence of cardiovascular events. Coronary computed tomography angiography (CCTA) can be used to noninvasively observe plaques throughout the coronary arteries. To evaluate the impact of intensive low-density lipoprotein cholesterol (LDL-C)-lowering therapy on quantitative changes in coronary plaque, assessed using CCTA in a study population with ACS. In total, 81 consecutive patients with ACS who underwent CCTA at discharge and at 1-year follow-up from April 2018 to March 2020 were analyzed. The patients were divided into 2 groups: those who achieved LDL-C <70 mg/100 ml and those who did not. Changes in plaque morphology within and between the 2 groups were compared using CCTA. A total of 198 vessels were analyzed. The calcified plaque volume was significantly increased in the LDL-C <70 group (65.8 ± 80.1 mm3 to 73.6 ± 83.7 mm3, p = 0.007), whereas no significant change was observed in the LDL-C ≥70 group (106.9 ± 161.7 mm3 to 105.7 ± 137.5 mm3, p = 0.552). Percent change in low-attenuation plaque volume in the LDL <70 group was significantly lower than in the LDL-C ≥70 group (17.2 ± 90.9% vs 84.4 ± 162.6%, p = 0.020). Receiver operating characteristic curve analysis demonstrated that the target LDL-C level for low-attenuation plaque volume regression was 64 mg/100 ml. In conclusion, noninvasive CCTA demonstrated that intensive LDL-C lowering in high-risk patients with ACS could potentially lead to plaque stabilization.


Evaluation of Silicosis, Asthma, and COPD Among Sand and Gravel and Stone Surface Mine Workers.
Despite the large number of workers in surface sand and gravel mines, there are no previous studies on a cohort of these workers. A cross-sectional study of Michigan surface mine workers included a questionnaire and for those who worked ≥15 years spirometry and chest x-ray. Questionnaires were completed by 1207 miners, 111 had an X-ray and 70 had spirometry. There were no silicosis cases. There were 117 with asthma, 22 COPD, 129 saw a doctor for shortness of breath (SOB), 125 with possible work-related asthma, and 26 abnormal spirometry results. Although, no cases of silicosis were identified, there was more current asthma; and an association of current asthma, COPD and seeing a doctor for SOB with time since first worked, and obstructive changes in some nonsmokers that suggested the potential for adverse respiratory effects.


Occult Malignancy Rate of 1498 Hysterectomies or Myomectomies with Morcellation: A Retrospective Single-Arm Study.
Since April 2014, the FDA warns against the use of morcellation during minimally invasive uterine surgery because of the risk of occult malignant spreading in the abdominal cavity. It is clear, however, that more studies are needed to define the incidence of occult uterine cancers, its risk factors, preoperative identification and postoperative follow-up. The present retrospective single-arm study defines the prevalence of occult uterine malignancies in a large group of patients treated with hysterectomy or myomectomy for benign indications. In the year of 2014, 1498 women admitted for a myomectomy or hysterectomy in benign conditions at the clinic of minimally invasive surgery (Minimal Invasive Chirurgie or MIC) in Berlin (Germany) were included in this study. The morcellated uterine specimens of operated patients were histologically analyzed for the presence of cancerous tissue. We detected malignancies in three of the 1498 women (0.2%): two patients had endometrial cancer, while we observed cervical cancer in situ in the third patient. No sarcoma was found. We detected a very low prevalence of occult uterine malignancy which is in line with several other recent studies. To define a clear policy on the use of morcellation, more studies are required. In the meantime, patients should be informed about the risks of morcellation in case of undetected cancer prior to surgery.


Glutaredoxin-2 is required to control oxidative phosphorylation in cardiac muscle by mediating deglutathionylation reactions.
Glutaredoxin-2 (Grx2) modulates the activity of several mitochondrial proteins in cardiac tissue by catalyzing deglutathionylation reactions. However, it remains uncertain whether Grx2 is required to control mitochondrial ATP output in heart. Here, we report that Grx2 plays a vital role modulating mitochondrial energetics and heart physiology by mediating the deglutathionylation of mitochondrial proteins. Deletion of Grx2 (Grx2(-/-)) decreased ATP production by complex I-linked substrates to half that in wild type (WT) mitochondria. Decreased respiration was associated with increased complex I glutathionylation diminishing its activity. Tissue glucose uptake was concomitantly increased. Mitochondrial ATP output and complex I activity could be recovered by restoring the redox environment to that favoring the deglutathionylated states of proteins. Grx2(-/-) hearts also developed left ventricular hypertrophy and fibrosis, and mice became hypertensive. Mitochondrial energetics from Grx2 heterozygotes (Grx2(+/-)) were also dysfunctional, and hearts were hypertrophic. Intriguingly, Grx2(+/-) mice were far less hypertensive than Grx2(-/-) mice. Thus, Grx2 plays a vital role in modulating mitochondrial metabolism in cardiac muscle, and Grx2 deficiency leads to pathology. As mitochondrial ATP production was restored by the addition of reductants, these findings may be relevant to novel redox-related therapies in cardiac disease.


General method to derive the relationship between two sets of Zernike coefficients corresponding to different aperture sizes.
Zernike polynomials have been widely used to describe the aberrations in wavefront sensing of the eye. The Zernike coefficients are often computed under different aperture sizes. For the sake of comparison, the same aperture diameter is required. Since no standard aperture size is available for reporting the results, it is important to develop a technique for converting the Zernike coefficients obtained from one aperture size to another size. By investigating the properties of Zernike polynomials, we propose a general method for establishing the relationship between two sets of Zernike coefficients computed with different aperture sizes.


Differential herbivory on C3 versus C4 grasses by the grasshopper Ageneotettix deorum (Orthoptera: acrididae).
The hypothesis that graminivorous grasshoppers select C3 grasses over C4 grasses was tested with experiments in the field. It was found that the generalist, graminivorous grasshopper Ageneotettix deorum typically chooses C3 as opposed to C4 grasses when both types are equally available. This preference is attributed to the differences in leaf anatomies of C3 and C4 plants since crude protein, water, lignin, fiber, and silicon content or the size of the individual leaves tested do not explain the observed feeding pattern. However, examination of the actual food plant selection of actual field inhabiting grasshoppers indicates that food plant prefernce may only be a minor component of food selection in natural settings.


Exposure to a nonfunctional hot plate as a factor in the assessment of morphine-induced analgesia and analgesic tolerance in rats.
Rats not exposed to a hot plate with or without morphine and later tested on the functional hot plate with or without morphine, displayed increased paw lick latency relative to same-injected rats given pretest hot plate exposure. This analgesic effect, was termed behavioral analgesia since it, unlike morphine-induced analgesia, was not reversed by naloxone (Experiment 2). Behavioral tolerance was evident in animals exposed to the nonfunctional hot plate regardless of drug treatment and was dissociated from pharmacological tolerance. Behavioral analgesia and tolerance reported here may involve habituation to novel distractive stimuli associated with the hot plate test environment.


Reference ranges for uterine artery mean pulsatility index at 11-41 weeks of gestation.
To construct gestational age (GA)-based reference ranges for the uterine artery (UtA) mean pulsatility index (PI) at 11-41 weeks of pregnancy. A prospective cross-sectional observational study was carried out of 20 consecutive singleton pregnancies for each completed gestational week at 11-41 weeks. UtAs were examined by color and pulsed Doppler imaging, and the mean PI, as well as the presence or absence of a bilateral protodiastolic notch, were recorded. Polynomials were fitted by means of least-square regression to estimate the relationship between the mean UtA-PI and GA. A total of 620 women were included. A second-degree polynomial (Log(e) mean UtA-PI = 1.39 - 0.012 x GA + GA(2) x 0.0000198, with GA measured in days), after a natural logarithmic transformation, was selected to model our data. There was a significant decrease in the mean UtA-PI between 11 weeks (mean PI, 1.79; 95(th) centile, 2.70) and 34 weeks (mean PI, 0.70; 95(th) centile, 0.99). It then became more stable up until 41 weeks (mean PI, 0.65; 95(th) centile, 0.89). The mean UtA-PI shows a progressive decrease until the late stages of pregnancy. Reference ranges for mean UtA-PI may have clinical value in screening for placenta-associated diseases in the early stages of pregnancy, and in evaluating patients with pregnancy-induced hypertension and/or small-for-gestational age fetuses during the third trimester.


Do we need an extra dimension? A pilot study on the use of three-dimensional anorectal manometry in children with functional constipation.
Recently, a new high-definition (or three-dimensional "3D") high-resolution anorectal manometry (3D-ARM) catheter has been introduced. This catheter allows for a more detailed visualization of the anal canal. However, its clinical utility and tolerability in children with constipation are unknown. Our primary objective was to evaluate the agreement between findings from solid-state high-resolution anorectal manometry (HR-ARM) and 3D-ARM. Secondary objectives were to investigate if 3D-ARM has additional value over HR-ARM and to evaluate patient and provider experience. Prospective pilot study including children (8-18 years of age) with functional constipation scheduled for anorectal manometry. Children underwent HR-ARM and 3D-ARM consecutively. We compared manometry results of both procedures and collected data on patient and provider experience via self-developed questionnaires. Data of ten patients were analyzed (60% female, median age 14.9 years). In the majority of patients, ARMs were performed awake (n = 8, 80%). In two patients, the recto-anal inhibitory reflex (RAIR) was visualized during HR-ARM but not during 3D-ARM. Anal canal resting pressures were significantly higher during 3D-ARM compared to HR-ARM (median 77 mmHg [IQR 59-94] vs. 69 mmHg [IQR 51-91], respectively, p = 0.037). No significant anatomical or muscular abnormalities were visualized during the 3D-ARM. The majority of children identified the 3D-ARM as the more unpleasant (5/7 [71%]) and more painful procedure (6/7 [86%]) and therefore preferred the HR-ARM (4/7 [57%]). In our patient sample, 3D-ARM was associated with more discomfort without providing more useful information and even resulted in an inconsistent visualization of the RAIR.


Responses of myopes to volitional control training of accommodation.
Twelve young, low myopes were trained to control volitionally their accommodation responses and to achieve clear focus on visual targets moved progressively outward in optical distance. The trainees participated in from 15 to 40 daily training sessions (mean = 28 sessions). All demonstrated volitional control with varying degrees of control authority. Though three of the trainees were unsuccessful, the group achieved a statistically reliable extension of their far points. Post-training optometric examinations were reliably improved over pre-training examinations, but did not appear to be commensurate with the large gains in far-point extension. It was hypothesized that the learned skill may have been 'instrument-specific', i.e. it might not fully generalize to significantly improved post-training binocular performance unless it were accompanied by clinical assistance to transfer the training.


Enantioselective bio-deacylation of arylalkyl acetates using tertiary amines as additive under promiscuous conditions.
Herein, we describe the impact of the introduction of tertiary amines as additive during the enzymatic kinetic resolution via deacylation of some arylalkyl acetates 1a-8a under promiscuous conditions. Two CAL-B preparations were examined: Novozym®435 and CHIRAZYME® L-2, c.-f. C2, lyo. The influence of the introduction of seven amines is checked: Triethylamine (Et3N), Pyridine, 4-Dimethylaminopyridine (4-DMAP), 1,4-Diazabicyclo[2.2.2]octane (DABCO), Cinchonine, Cinchonidine, Quinine and Quinidine; and that in two organic solvent: diisopropylether (DIPE) and tertiobutylmethyl ether (TBME). Among the examined amines, the use of DABCO as additive recorded the best results in terms of reactivity and selectivity. It was to be highlighted that this additive was reported as an enzyme activator for the first time in the enzymatic kinetic resolution via hydrolysis of racemic acetates under non-aqueous conditions. Both CAL-B preparations showed the same behavior in the presence of the chosen additives during the biodeacylation of the resolved acetates. No direct correlation between the pKa values of several used additives and the CAL-B activation rates has been revealed. An ideal enzymatic kinetic resolution was recorded with the acetate 4a (Conv 50% and E > >200).


C-terminal lysine residues enhance plasminogen activation by inducing conformational flexibility and stabilization of activator complex of staphylokinase with plasmin.
Staphylokinase (SAK), a potent fibrin-specific plasminogen activator secreted by Staphylococcus aureus, carries a pair of lysine at the carboxy-terminus that play a key role in plasminogen activation. The underlaying mechanism by which C-terminal lysins of SAK modulate its function remains unknown. This study has been undertaken to unravel role of C-terminal lysins of SAK in plasminogen activation. While deletion of C-terminal lysins (Lys135, Lys136) drastically impaired plasminogen activation by SAK, addition of lysins enhanced its catalytic activity 2-2.5-fold. Circular dichroism analysis revealed that C-terminally modified mutants of SAK carry significant changes in their beta sheets and secondary structure. Structure models and RING (residue interaction network generation) studies indicated that the deletion of lysins has conferred extensive topological alterations in SAK, disrupting vital interactions at the interface of SAK.plasmin complex, thereby leading significant impairment in its functional activity. In contrast, addition of lysins at the C-terminus enhanced its conformational flexibility, creating a stronger coupling at the interface of SAK.plasmin complex and making it more efficient for plasminogen activation. Taken together, these studies provided new insights on the role of C-terminal lysins in establishment of precise intermolecular interactions of SAK with the plasmin for the optimal function of activator complex.


Changes in serum levels of E-selectin correlate to improved glycaemic control and reduced obesity in subjects with the metabolic syndrome.
Inflammation plays an essential role in the atherosclerotic process. Cellular adhesion molecules (CAMs) such as E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are involved in the rolling, adhesion and extravasation of monocytes and T-lymphocytes into the atherosclerotic plaque. In the present study the effect of physical exercise and pravastatin (40 mg daily) on serum levels of CAMs and a possible role of adipose tissue in regulating serum levels of CAMs were investigated. The study was designed as an unmasked randomized 2x2 factorial trial of 12 weeks duration in 32 subjects with the metabolic syndrome. Changes from baseline were studied, and correlations between changes in CAMs, anthropometric measures, regional fat distribution, glycaemic control and the adipocytokine tumour necrosis factor-a (TNF-a) and adiponectin were investigated. No significant changes in CAMs were observed in any of the intervention groups. However, when examining the whole study population regardless of intervention, changes in serum E-selectin were significantly correlated to changes in body mass index (r=0.48, p=0.006), waist circumference (r=0.48, p=0.006), fasting glucose (r=0.43, p=0.02) and HbA1c (r=0.45, p=0.01), but not to changes in visceral fat, subcutaneous fat, TNF-a or adiponectin. Changes in glycaemic control and obesity, rather than regional fat distribution, seem to influence the levels of E-selectin in subjects with the metabolic syndrome.


Introduction to nanotechnology and its applications to medicine.
Nanotechnology can be defined as the science and engineering involved in the design, synthesis, characterization, and application of materials and devices whose smallest functional organization in at least one dimension is on the nanometer scale or one billionth of a meter. At these scales, consideration of individual molecules and interacting groups of molecules in relation to the bulk macroscopic properties of the material or device becomes important, since it is control over the fundamental molecular structure that allows control over the macroscopic chemical and physical properties. Applications to medicine and physiology imply materials and devices designed to interact with the body at subcellular (i.e., molecular) scales with a high degree of specificity. This can potentially translate into targeted cellular and tissue-specific clinical applications designed to achieve maximal therapeutic affects with minimal side effects. In this review the main scientific and technical aspects of nanotechnology are introduced and some of its potential clinical applications are discussed.


First Use of Handheld Raman Spectroscopy to Analyze Omega-3 Fatty Acids in Intact Fish Oil Capsules.
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are commercially important omega-3 fatty acids found in fish oils. Here we demonstrate that a handheld Raman spectrometer can be used to quantitate these compounds in intact fish oil capsules, avoiding oxidizing risk. Partial least squares regression models were prepared by relating Raman spectral variance to EPA and DHA concentrations determined using gas chromatography-mass spectrometry (GC-MS) analysis of fatty acid methyl esters in 15 commercial samples containing 145-473 mg g-1 EPA and 101-260 mg·g-1 DHA. Handheld Fourier transform (FT)-Raman models had root mean square errors of cross-validation of 38 mg g-1, 24 mg g-1, and 32 mg·g-1 for EPA, DHA, and EPA+DHA, respectively. Models generated from a benchtop FT-Raman spectrometer had corresponding errors of 32 mg·g-1, 22 mg·g-1, and 26 mg·g-1. By comparison, average standard deviations from triplicate GC-MS analyses were 11 mg·g-1 for EPA and 9 mg·g-1 for DHA.


Structural and solution chemistry, antiproliferative effects, and serum albumin binding of three pseudohalide derivatives of auranofin.
Three pseudohalide analogues of the established gold drug auranofin (AF hereafter), of general formula Au(PEt3)X, i.e. Au(PEt3)CN, Au(PEt3)SCN and Au(PEt3)N3 (respectively denoted as AFCN, AFSCN and AFN3), were prepared and characterized. The crystal structure was solved for Au(PEt3)SCN highlighting the classical linear geometry of the 2-coordinate gold(I) center. The solution behaviour of the compounds was then comparatively analysed through 31PNMR providing evidence for an acceptable stability under physiological-like conditions. Afterward, the reaction of these gold compounds with bovine serum albumin (BSA) and consequent adduct formation was investigated by 31PNMR. For all the studied gold compounds, the [Au(PEt3)]+ moiety was identified as the reactive species in metal/protein adducts formation. The cytotoxic effects of the complexes were subsequently measured in comparison to AF against a representative colorectal cancer cell line and found to be still relevant and roughly similar in the three cases though far weaker than those of AF. These results show that the nature of the anionic ligand can modulate importantly the pharmacological action of the gold-triethylphosphine moiety, affecting the cytotoxic potency. These aspects may be further explored to improve the pharmacological profiles of this family of metal complexes.


The ecology of Lake Nakuru : VI. Synopsis of production and energy flow.
The major pathways of energy flow in Lake Nakuru (East Africa) are presented. The trophic structure of this equatorial alkaline-saline lake shows no predictable long term continuity. During the five years of this study it had a bloom of Spirulina platensis that persisted at least two years, it had periods with low algal densities and in addition it had various transitional phases with dramatic fluctuations of species composition and density.The Spirulina platensis bloom is characterized by a rich and almost unialgal bloom of the cyanophyte Spirulina platensis minor, with a mean biomass of 3,500 kJ m-3 (20 kJ ≈ 1 g dry weight). Net photosynthetic rates were very high at depths with optimal light conditions (230 kJ m-3 h-1), but algal self-shading made integrated rates modest (45 kJ m-3 24 h-1) relative to the high biomass. Of the eight primary consumers only five species contributed significantly to the consumer biomass of 220 kJ m-3: the flamingo Phoeniconaias minor, the cichlid fish Sarotherodon alcalicus grahami, the copepod Lovenula africana, the dipteran larva Leptochironomus deribae, and the rotifer Brachionus dimidiatus. Consumption rates were ≈50% of net photosynthetic rates, production rates ≈10%. Secondary consumers (90% being the pelican Pelecanus onocrotalus and the Greater Flamingo Phoenicopterus ruber) had a biomass of about 6.8 kJ m-3. Pelicans consumed almost the whole fish production (7.5 metric tons wet weight/day).At low algal densities the lake had a more diverse algal population but a reduced mean biomass of 1,500 kJ m-3 and mean net photosynthetic rates of 12 kJ m-3 24 h-1. Primary consumer species diversity and biomass were also reduced. Consumption rates sometimes exceeded primary production rates. Rotifers probably contributed ≈50% to total consumption and ≈75% to total secondary production but the estimates of their role is speculative as the relative contributions of algae, bacteria and detritus to rotifer consumption are not known. Transitional phases are characterized by rapidly changing abiotic and biotic conditions with algal breakdowns and sudden population peaks at all levels. Rotifers dominated secondary consumers, they contributed 25% to the total biomass of 380 kJ m-3, 90% to the total consumption rate of 290 kJ m-3d-1 and 95% to the total production of 41 kJ m-3d-1.The discussion focusses on problems of measuring primary production in alkaline-saline lakes, and the control of producer and consumer densities. The difficulty in assessing the importance of bacteria and rotifers is emphasized. Also questions of ecological stability and efficiency are addressed. Finally, some recommendations for conservational policy are included.


Prevalence and predicors of COVID-centred obsessive compulsive disorder among Iranian COVID-19 recovered individuals: a Bayesian analysis.
The evidence on the psychological consequences of coronavirus 2019 mainly relates to general psychiatric problems, and a few studies have reported the incidence and predictors of obsessive-compulsive disorder. To determine the prevalence of obsessive-compulsive disorder (OCD) and its predictors in Iranian COVID - 19 recovered individuals at 3-6 months, 6-12 months, and 12-18 months after recovery. In this cross-sectional analytical study, 300 participants were randomly selected based on the inclusion criteria from three hospitals in three different regions of Tehran, Iran, and were assessed by the Clinical Demographic Information Questionnaire, the Obsessive Compulsive Inventory-Revised (OCI-R), the Depression, Anxiety and Stress Scale 21 (DASS21), The Pittsburgh Sleep Quality Index (PSQI) and Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5). The obtained data were analyzed with SPSS version 26. The results showed that the mean score of OCD is 30.58 ± 15.22, with a prevalence of 71% (n = 213). Female gender (BF = 0.50, p = 0.01), sleep disturbance (BF = 0.02, p = 0.001), PTSD (BF = 0.009, p = 0.0001), depression (BF = 0.0001, p = 0.0001), and stress (BF = 0.0001, p = 0.001) are the strongest predictors of the presence of OCD in recovered COVID - 19 individuals. OCD-like symptoms was observed in the majority of COVID - 19 recovered individuals with mild to moderate severity. In addition, the stated prevalence, severity, and significance varied according to sociodemographic and health inequalities.


Rational Coarse-Grained Molecular Dynamics Simulations of Supramolecular Anticancer Nanotubes.
Peptide self-assembly has been used to design an array of nanostructures that possess functional biomedical applications. Experimental studies have reported nanofilament and nanotube formation from peptide-based drug amphiphiles (DAs). These DAs have shown to possess an inherently high drug loading with a tunable release mechanism. Herein, we report rational coarse-grained molecular dynamics simulations of the self-assembly process and the structure and stability of preassembled nanotubes at longer timescales (μs). We find that aggregation between these DAs at the submicrosecond timescale is driven by directional aromatic interactions between the drugs. The drugs form a large and high-density nucleus that is stable throughout microsecond timescales. Simulations of nanotubes characterize the drug-drug stacking and find correlations at nanometer length scales. These simulations can inform the rational molecular design of drug amphiphiles.


A quantitative enzyme-linked immunosorbent assay for honeybee venom-specific immunoglobulin G.
A quantitative enzyme-linked immunosorbent assay (ELISA) for honeybee venom-specific IgG is reported. This ELISA surmounts the problem of poor reproducibility due to nonparallelism of dilution curves in previously reported ELISAs. The assay is performed in polyvinyl "U" microtiter plates in which HBV is physically adsorbed to the wells. The antigen is sequentially overlaid with human serum albumin, unknown serum diluted in 10% normal goat serum (NGS), and peroxidase-labeled anti-human IgG in NGS. o-Phenylenediamine is used a substrate. The addition of stabilizing protein (NGS) is shown to be crucial in producing parallel dilution curves in this heterogeneous antigen-antibody system. Sensitivity is at or below 1 ng/ml. Coefficient of variation (using a midrange serum) is 12.1% for triplicate wells, 15.5% for sequential dilution, and 15.0% for six entirely separate assays. The assay correlates well with other methods, notably with the Staphylococcus aureus protein A solid-phase radioimmunoassay (r = 0.976).


P16 I NK 4a Deletion Ameliorates Damage of Intestinal Epithelial Barrier and Microbial Dysbiosis in a Stress-Induced Premature Senescence Model of Bmi-1 Deficiency.
This study aimed to determine whether Bmi-1 deficiency leads to intestinal epithelial barrier destruction and microbiota dysfunction, which members of the microbial community alter barrier function with age, and whether p16 INK4a deletion could reverse the damage of intestinal epithelial barrier and microbial dysbiosis. Intestines from Bmi-1-deficient (Bmi-1-/- ), Bmi-1 and p16 INK4a double-knockout (Bmi-1-/-p16 INK4a-/- ), and wild-type mice were observed for aging and inflammation. Duolink Proximity Ligation Assay, immunoprecipitation, and construction of p16 INK4a overexpressed adenovirus and the overexpressed plasmids of full-length, mutant, or truncated fragments for occludin were used for analyzing the interaction between p16 INK4a and occludin. High-throughput sequencing of V4 region amplicon of 16S ribosomal RNA was conducted using intestinal microbiota. We found Bmi-1 deficiency destructed barrier structure, barrier function, and tight junction (TJ) in intestinal epithelium; decreased the TJ proteins; increased tumor necrosis factor α (TNF-α)-dependent barrier permeability; and up-regulated proinflammatory level of macrophages induced by intestinal microbial dysbiosis. The transplantation of fecal microbiota from wild-type mice ameliorated TJ in intestinal epithelium of Bmi-1-/- and Bmi-1-/-p16 INK4a-/- mice. Harmful bacteria including Desulfovibrio, Helicobacter, and Oscillibacter were at a higher level in Bmi-1-/- mice. More harmful bacteria Desulfovibrio entered the epithelium and promoted macrophages-secreted TNF-α and caused TNF-α-dependent barrier permeability and aging. Accumulated p16 INK4a combined with occludin at the 1st-160th residue in cytoplasm of intestinal epithelium cells from Bmi-1-/- mice, which blocked formation of TJ and the repair of intestinal epithelium barrier. P16 INK4a deletion could maintain barrier function and microbiota balance in Bmi-1-/- mice through strengthening formation of TJ and decreasing macrophages-secreted TNF-α induced by Desulfovibrio entering the intestinal epithelium. Thus, Bmi-1 maintained intestinal TJ, epithelial barrier function, and microbiota balance through preventing senescence characterized by p16 INK4a accumulation. The clearance of p16 INK4a -positive cells in aging intestinal epithelium would be a new method for maintaining barrier function and microbiota balance. The residues 1-160 of occludin could be a novel therapeutic target for identifying small molecular antagonistic peptides to prevent the combination of p16 INK4a with occludin for protecting TJ.


Sinus histiocytosis with massive lymphadenopathy. Case report and review of a multisystemic disease with cutaneous infiltrates.
A report of a patient with the rare syndrome of sinus histiocytosis with massive lymphadenopathy is presented here. This patient is unusual in several respects, including his longevity after diagnosis, the presence of a benign monoclonal gammopathy, and the characterization of his cutaneous infiltrates by immunofluorescent monoclonal antibody markers. A review of the literature on sinus histiocytosis with massive lymphadenopathy, with particular emphasis on cutaneous manifestations, is given.


Level of marker enzymes in spermatogenesis on administration of PGF2 alpha in rats.
Intraperitoneal administration of PGF 2 alpha in rats significantly increased testicular acid phosphatase (p less than 0.05), decreased hyaluronidase (p less than 0.05), whereas the activities of 5'-nucleotidase, N-acetyl-B-glucosaminidase, B-galactosidase and uridine diphosphatase remained unaffected.


Low standardized phase angle predicts prolonged hospitalization in critically ill patients.
Evaluate the performance of phase angle (PA) in identifying malnutrition and in predicting clinical outcomes in critical adult patients. A longitudinal observational study with secondary data from Nossa Senhora da Conceição Hospital (Porto Alegre) and Risoleta Tolentino Neves Hospital (Belo Horizonte) involving critically ill patients assessed for nutritional status by subjective global assessment (SGA) and by anthropometry in the first 48 h after admission to the intensive care unit (ICU). The PA was evaluated from the realization of the bioelectrical impedance. Patients were followed up until hospital discharge to verify the other outcomes of interest: death, hospitalization time and in ICU, and duration of mechanical ventilation. A total of 169 patients (60.3 ± 16.7 years, 56.7% men, 46.7% surgical) were followed for 23.0 (14.0-40.8) days. The accuracy of standardized PA (SPA) reduced in identifying malnourished patients was 60.6% (ROC curve AUC = 0.606, 95% CI 0.519-0.694). Reduced SPA increased in about three times the chance of having malnutrition (OR = 2.79, 95% CI 1.39-5.61) and 2 times the chance of prolonged hospital stay (OR = 2.27; 95% CI 1.18-4.34) in an adjusted analysis for the origin hospital and for the severity score. Reduced SPA showed satisfactory predictive validity for malnutrition and prolonged hospital stay in critically ill patients, reinforcing the applicability of BIA in the routine of nutritional care in ICU, since it is a simple, fast and low cost method.


G6PD Deficiency Prevalence as a Cause of Neonatal Jaundice in a Neonatal Ward in Dohuk, Iraq.
The current study initiated to address the effect of glucose-6-phosphate dehydrogenase (G6PD) deficiency on the pathogenesis and the severity of neonatal hyperbilirubinemia (NHB). A total of 100 newborns with moderate to severe indirect hyperbilirubinemia and 50 normal neonates without hyperbilirubinemia had been enrolled in the current case-control study. All enrolled neonates had been tested for ABO and Rh(D) blood grouping, Total serum bilirubin measurement, complete blood count, morphology, reticulocyte counts, direct Coombs' test, and G6PD enzyme assay. From all enrolled hyperbilirubinemic neonates, 16% were G6PD deficient and this displays a statistically significant difference in comparison to controls (only 6% were G6PD deficient). Also, significant difference was found in the level of serum indirect bilirubin among G6PD-deficient neonate in comparison to G6PD nondeficient neonates which had contributed significantly to the difference in the duration of phototherapy and hospitalization among deficient neonate. Despite this, no significant difference found in the onset of presentation, reticulocytes count, and age of neonates between the two groups (G6PD-deficient and G6PD nondeficient neonates). The current study augments the etiological role of G6PD in the causation and severity of NHB in the region; however, in the absence of significant difference in the reticulocytes and the hemoglobin level, the underlying mechanism cannot be backed to the excess hemolysis alone.


Effect of exercise training in 60- to 69-year-old persons with essential hypertension.
This study sought to determine whether 9 months of low- or moderate-intensity exercise training could decrease blood pressure (BP) in hypertensive men and women (mean age 64 +/- 3 years). Patients underwent weekly BP evaluations for 1 month to ensure that they had persistently elevated BP and then completed a maximal treadmill exercise test to exclude those with overt coronary artery disease. The low- and moderate-intensity groups trained at 53 and 73% of maximal oxygen consumption (VO2 max), respectively; however, total caloric expenditure per week was similar in both groups. VO2 max did not increase in the low-intensity group with training, but increased 28% in the moderate-intensity group. Diastolic BP decreased 11 to 12 mm Hg in both training groups. Systolic BP decreased 20 mm Hg in the low-intensity group with training, which was significantly greater than the change in the control and the moderate-intensity groups. Although systolic BP decreased 8 mm Hg in the moderate-intensity training group, this reduction was not significant. Training resulted in a somewhat lower cardiac output at rest in the low-intensity group, whereas total peripheral resistance decreased slightly in the moderate-intensity training group. Plasma and blood volumes, plasma renin levels and urinary sodium excretion did not change in either group with training. Both groups manifested lower plasma norepinephrine levels after training during standing rest, but not while supine. Thus, low-intensity training may lower BP as much or more than moderate-intensity training in older persons with essential hypertension, but the underlying mechanisms are unclear.


Combined transcriptomic and proteomic analysis of harmine on Spodoptera frugiperda Sf9 cells to reveal the potential resistance mechanism.
The fall armyworm, Spodoptera frugiperda, is an important invasive pest and exhibits resistance to many insecticides. Harmine, a remarkable, natural β-carboline alkaloid, exhibits a variety of bioactivities and induces programmed cell death in Sf9 cells. In the present study, transcriptomic and proteomic analyses were combined to investigate the effects of harmine on Sf9 cells. A sublethal dose, 0.05 mM, was selected and the transcriptomic analysis revealed 2463 upregulated and 689 downregulated genes after harmine treatment. The most frequently enriched pathways of differentially expressed genes (DEGs) were mainly involved in drug and xenobiotic metabolism. The proteomics analysis revealed 36 upregulated and 77 downregulated proteins, and the results showed a nonlinear relationship with mRNA expression. All the genes related to detoxification and resistance in the transcriptome and DEGs were identified and annotated. Complete open reading frames of 27 cytochrome P450s (CYPs), 27 glutathione S-transferases (GSTs), 11 carboxylesterases (CarEs), 10 UDP-glucuronosyltransferases (UGTs) and 29 heat shock proteins (HSPs) were assembled and verified using qRT-PCR. Harmine exhibited a completely different detoxification mechanism from normal pesticides. The Sigma and Delta class GSTs and UGTs might play important roles, rather than CYP6 and CYP9 clans, CarEs or HSPs. BIOLOGICAL SIGNIFICANCE: Harmine, a natural β-carboline alkaloid, inhibits the cell proliferation and induces programmed cell death of Sf9 cells, which derived from Spodoptera frugiperda, an important world invasive pest. In the article, the combined transcriptomic and proteomic analysis is used to explore the potential solution for its resistance management. These results supporting that harmine can be applied as a novel adjuvant or pesticide. In addition, the systematically identified resistance-related genes in fall armyworm provide the foundation for potential resistance monitoring and management.


[Cephalometric analysis of the soft tissue profile in Hunan Han adults with normal occlusion].
To analyze the characteristics soft tissue profile in Hunan Han adults with normal occlusion and to explore the differences of the soft tissue profile in gender, region and race. Lateral cephalometric radiographs were performed for 323 volunteers (164 females and 159 males) from Hunan Province. The digital cephalometric radiographs were imported into the WinCeph8.0 measurement and analysis system in a same computer. According to the Holdaway analysis method, the mean and standard deviation were calculated. Then the results were compared to the data from Liaoning, Nepalese, Japanese, North American Caucasians. The normal value of cephalometric facial soft tissue profile in Han population adults with normal occlusion in Hunan Province were obtained. There were significant differences in subnasale to H line (Sn-H), upper lip tension, lower lip sulcus depth (Si-PgsLs), and soft tissue chin thickness (Pg-Pgs) between males and females (all P<0.05). Compared with Liaoning Province, significant regional differences in soft tissue facial angle (FH-NsPgs), upper lip sulcus depth (Ss-Ls), Sn-H, lower lip thickness, upper lip thickness, H angle, lower lip to H line (Li-PgsLs), Si-PgsLs, and Pg-Pgs were found in Hunan Province (all P<0.05). Compared with the Japan, significant regional differences in FH-NsPgs, nose prominence (Sn-Pn), lower lip thickness, upper lip tensity, H angle, Li-PgsLs, Si-PgsLs, and Pg-Pgs were found in Hunan Province (all P<0.05). Compared with the Nepalese, significant regional differences in Sn-Pn, Ss-Ls, Sn-H, skeletal profile convexity (A-NPs), basic upper lip thickness, upper lip tensity, H angle, Li-PgsLs and Pg-Pgs were found in Hunan Province (all P<0.05). Compared with the North America, significant regional differences in Sn-Pn, Ss-Ls, Sn-H, A-NPs, basic upper lip thickness, upper lip tensity, H angle, Li-PgsLs, Si-PgsLs and Pg-Pgs were found in Hunan Province (all P<0.05). There are both similarities and differences in facial soft tissue profile between males and females with normal occlusion in Hunan Province. The characteristics of facial soft tissue profile in Hunan Province are different from that in Liaoning area, Nepal, Japan and North America.


Abnormal phase-amplitude coupling characterizes the interictal state in epilepsy.
Objective.Diagnosing epilepsy still requires visual interpretation of electroencephalography (EEG) and magnetoencephalography (MEG) by specialists, which prevents quantification and standardization of diagnosis. Previous studies proposed automated diagnosis by combining various features from EEG and MEG, such as relative power (Power) and functional connectivity (FC). However, the usefulness of interictal phase-amplitude coupling (PAC) in diagnosing epilepsy is still unknown. We hypothesized that resting-state PAC would be different for patients with epilepsy in the interictal state and for healthy participants such that it would improve discrimination between the groups.Approach.We obtained resting-state MEG and magnetic resonance imaging (MRI) in 90 patients with epilepsy during their preoperative evaluation and in 90 healthy participants. We used the cortical currents estimated from MEG and MRI to calculate Power in theδ(1-3 Hz),θ(4-7 Hz),α(8-13 Hz),β(13-30 Hz), lowγ(35-55 Hz), and highγ(65-90 Hz) bands and FC in theθband. PAC was evaluated using the synchronization index (SI) for eight frequency band pairs: the phases ofδ, θ, α, andβand the amplitudes of low and highγ. First, we compared the mean SI values for the patients with epilepsy and the healthy participants. Then, using features such as PAC, Power, FC, and features extracted by deep learning (DL) individually or combined, we tested whether PAC improves discrimination accuracy for the two groups.Main results.The mean SI values were significantly different for the patients with epilepsy and the healthy participants. The SI value difference was highest forθ/lowγin the temporal lobe. Discrimination accuracy was the highest, at 90%, using the combination of PAC and DL.Significance.Abnormal PAC characterized the patients with epilepsy in the interictal state compared with the healthy participants, potentially improving the discrimination of epilepsy.


Inhibition of NOX2 reduces locomotor impairment, inflammation, and oxidative stress after spinal cord injury.
Spinal cord injury (SCI) results in the activation of the NADPH oxidase (NOX) enzyme, inducing production of reactive oxygen species (ROS). We hypothesized that the NOX2 isoform plays an integral role in post-SCI inflammation and functional deficits. Moderate spinal cord contusion injury was performed in adult male mice, and flow cytometry, western blot, and immunohistochemistry were used to assess NOX2 activity and expression, inflammation, and M1/M2 microglia/macrophage polarization from 1 to 28 days after injury. The NOX2-specific inhibitor, gp91ds-tat, was injected into the intrathecal space immediately after impact. The Basso Mouse Scale (BMS) was used to assess locomotor function at 24 h post-injury and weekly thereafter. Our findings show that gp91ds-tat treatment significantly improved functional recovery through 28 days post-injury and reduced inflammatory cell concentrations in the injured spinal cord at 24 h and 7 days post-injury. In addition, a number of oxidative stress markers were reduced in expression at 24 h after gp91ds-tat treatment, which was accompanied by a reduction in M1 polarization marker expression. Based on our findings, we now conclude that inhibition of NOX2 significantly improves outcome after SCI, most likely via acute reductions in oxidative stress and inflammation. NOX2 inhibition may therefore have true potential as a therapy after SCI.


Calpain mediates ischemic injury of the liver through modulation of apoptosis and necrosis.
Calpain proteases have been implicated in cell death by necrosis and more recently by apoptosis. Experiments were designed to determine the role of calpain proteases in ischemic rat liver injury by measurement of cytosolic calpain activity after different periods of ischemia-reperfusion and by evaluation of the effects of calpain inhibition on tissue injury and animal survival. Calpain activity was measured in the cytosol using Suc-Leu-Leu-Val-Try-7 amino-4 methyl coumarin, a specific fluorogenic substrate, and Cbz-Leu-Leu-Tyr-CHN2, a specific inhibitor. Calpain activity increased significantly with the duration of ischemia-reperfusion and was inhibited more than 80% by the inhibitor. Calpain inhibition resulted in a significant decrease in transaminase release and tissue necrosis and converted nonsurvival ischemic conditions to survival conditions. When the in situ terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick-end labeling assay for apoptosis was used, 35% +/- 6% of nonparenchymal cells and 16% +/- 3% of hepatocytes stained positively after 60 minutes of ischemia and 6 hours of reperfusion. In contrast, animals pretreated with the calpain inhibitor showed minimal evidence of apoptosis. This was further substantiated by gel electrophoresis assay for DNA fragmentation and by electron-microscopic evaluation. These data suggest that calpain proteases play a pivotal role in warm ischemia-reperfusion injury of the rat liver through modulation of apoptosis and necrosis.


Macrophage-Derived TGF-β and VEGF Promote the Progression of Trauma-Induced Heterotopic Ossification.
Heterotopic ossification (HO) is a pathological bone formation process caused by musculoskeletal trauma. HO is characterized by aberrant endochondral ossification and angiogenesis. Our previous studies have indicated that macrophage inflammation is involved in traumatic HO formation. In this study, we found that macrophage infiltration and TGF-β signaling activation are presented in human HO. Depletion of macrophages effectively suppressed traumatic HO formation in a HO mice model, and macrophage depletion significantly inhibited the activation of TGF-β/Smad2/3 signaling. In addition, the TGF-β blockade created by a neutralizing antibody impeded ectopic bone formation in vivo. Notably, endochondral ossification and angiogenesis are attenuated following macrophage depletion or TGF-β inhibition. Furthermore, our observations on macrophage polarization revealed that M2 macrophages, rather than M1 macrophages, play a critical role in supporting HO development by enhancing the osteogenic and chondrogenic differentiation of mesenchymal stem cells. Our findings on ectopic bone formation in HO patients and the mice model indicate that M2 macrophages are an important contributor for HO development, and that inhibition of M2 polarization or TGF-β activity may be a potential method of therapy for traumatic HO.


Oxytocin and glucose oxidation in the rat uterus.
The effects of oxytocin on the biochemical pathways of glucose oxidation were investigated in the rat uterus. In the presence of oxytocin, glucose oxidation in uterine segments obtained from Sprague-Dawley rats at diestrus increased 1.5-2.0-fold above the basal rate. A half-maximal response was observed at about 3 nM oxytocin; the maximum response was equal to or greater than the response to 1.7 nM insulin. In stripped myometrial segments (denuded of the endometrial component), oxytocin stimulated glucose oxidation at estrus only; whereas in intact uterine segments, the stimulation of oxidation was observed at both estrus and diestrus. In contrast, stimulation of oxidation by carbachol in stripped myometrial segments was independent of the estrous state of the tissue. The ratio of [1-14C]glucose to [6-14C]glucose oxidation was measured to estimate the relative involvement of the pentose phosphate and the tricarboxylic acid pathways of metabolism. In myometrial tissue, stimulation of glucose oxidation by oxytocin appeared to proceed through the tricarboxylic acid cycle. In intact uterine segments, at diestrus, glucose oxidation involved largely the pentose phosphate pathway (suggesting increased glucose metabolism in endometrial tissue), whereas at estrus, in the intact tissue segments, oxytocin increased glucose oxidation largely via the tricarboxylic acid cycle, and appeared to do so predominantly in the myometrial tissue. Carbachol-stimulated glucose oxidation appeared to proceed mainly via the tricarboxylic cycle in the myometrial tissue, irrespective of the stage of the estrous cycle. In the uterus of the Brattleboro rat (either intact uterine segments or stripped myometrial strips), oxytocin stimulated glucose oxidation only at estrus, predominantly through the tricarboxylic acid cycle. These findings suggest that oxytocin, in addition to its known effect on the contractility of uterine and myoepithelial smooth muscle, may regulate glucose metabolism in both the myometrial and endometrial components of uterine tissue.


[Cineventriculography with radionuclides and intravenous dipyridamole in the prognostic evaluation after acute myocardial infarction].
To evaluate safety and usefulness of dipyridamole-radionuclide ventriculography (D-RVG), soon after acute myocardial infarction (MI), in the prediction of future cardiac events. Traditionally performed tests were also compared. Forty-one patients (4 females) with recent MI underwent rest and dipyridamole (0.58 mg/kg of body weight) radionuclide ventriculography. The criteria for a positive test for ischemia was failure to increase left ventricular ejection fraction in 0.05 from baseline value. All patients had also coronary angiography and 36 patients underwent thallium-201 scintigraphy for comparison. The mean follow-up was 16 +/- 3 months. The following findings were considered future for events: cardiac death, reinfarction, significant angina or heart failure. During the follow-up 18 of the 20 patients who had cardiac events had shown positive dipyridamole-RVG, as opposed to 5 of 21 event-free patients (p less than 0.01). The ventriculographic criteria for a positive test and dipyridamole left ventricular ejection fraction were the strongest predictors of those medical events (p less than 0.01 and p less than 0.001). Among the 36 patients who had thallium-201 imaging, 16 subsequently had cardiac events and the scans were positive in 82% (p less than 0.01). Twelve (29%) patients experienced reactions during dipyridamole infusion although no fatal complications were noted. Dipyridamole-RVG is relatively safe and a sensitive predictor of future cardiac events soon after acute MI, although additional experience is required before this new technique should be routinely recommended as an alternative approach.


Religiosity, mood symptoms, and quality of life in bipolar disorder.
The aim of the present study was to investigate the relationship between religiosity and mood, quality of life, number of hospitalizations, and number of severe suicide attempts among bipolar disorder patients. In a cross-sectional study of bipolar disorder outpatients (N = 168), we assessed symptoms of mania [Young Mania Rating Scale (YMRS)], depression [Montgomery-Åsberg Depression Rating Scale (MADRS)], religiosity (Duke Religious Index), religious coping (Brief RCOPE), and quality of life [World Health Organization Quality of Life-Brief Version (WHOQOL-BREF)]. Sociodemographic data, number of suicide attempts, and number of hospitalizations were obtained through an interview with the individual and analysis of the patient's medical records. Logistical and linear regressions of the association between the religious indicators and clinical variables were conducted, controlling for sociodemographic variables. A total of 148 (88.1%) individuals reported some type of religious affiliation. Intrinsic religiosity [odds ratio (OR) = 0.19, 95% confidence interval (CI): 0.06-0.57, p = 0.003] and positive religious coping strategies (OR = 0.25, CI: 0.09-0.71, p = 0.01) were associated with fewer depressive symptoms. All four domains of quality of life were directly and significantly correlated with intrinsic religiosity. Positive religious coping was correlated with higher levels of the psychological (β = 0.216, p = 0.002) and environmental (β = 0.178, p = 0.028) quality-of-life domains. Negative religious coping was associated with lower scores on the psychological domain of quality of life (β = -0.182, p = 0.025). Intrinsic religiosity and positive religious coping are strongly associated with fewer depressive symptoms and improved quality of life. Negative religious coping is associated with worse quality of life. Religiosity is a relevant aspect of patients' lives and should be taken into consideration by physicians when assessing and managing bipolar disorder patients. Further longitudinal studies are needed to determine the causality and therapeutic implications of our findings.


The method for assessment of local permutations in the glomerular patterns of the rat olfactory bulb by aligning interindividual odor maps.
The comparison of odor functional maps in rodents demonstrates a high degree of inter-individual variability in glomerular activity patterns. There are substantial methodological difficulties in the interindividual assessment of local permutations in the glomerular patterns, since the position of anatomical extracranial landmarks, as well as the size, shape and angular orientation of olfactory bulbs can vary significantly. A new method for defining anatomical coordinates of active glomeruli in the rat olfactory bulb has been developed. The method compares the interindividual odor functional maps and calculates probabilistic maps of glomerular activity with adjustment. This adjustment involves rotation, scaling and shift of the functional map relative to its expected position in probabilistic map, computed according to the anatomical coordinates. The calculation of the probabilistic map of the odorant-specific response compensates for potential anatoamical errors due to individual variability in olfactory bulb dimensions and angular orientation. We show its efficiency on real data from a large animal sample recorded by two-photon calcium imaging in dorsal surface of the rat olfactory bulb. The proposed method with probabilistic map calculation enables the spatial consistency of the effects of individual odorants in different rats to be assessed and allow stereotypical positions of odor-specific clusters in the glomerular layer of the olfactory bulb to be identified.


Is Head and Neck Free Flap Reconstruction Feasible in Jehovah's Witness Patients?
Jehovah's Witnesses (JW) population are members of a religious group that refuses blood transfusion. This presents a dilemma for surgical teams when performing major surgical procedures on these patients. This study aimed to assess the safety and feasibility of undergoing microvascular free flaps for maxillofacial reconstruction in JW patients and whether the type of underlying pathology impacts outcomes. This was a multi-institutional retrospective cohort study. The sample consisted of all JW patients who have undergone microvascular free tissue transfer for maxillofacial pathology between January 2016 and January 2021. The primary predictor variable was the underlying pathology for which patients underwent head and neck free flap reconstruction; this was benign versus malignant disease. The primary outcome variables were safety, defined as discharge from the hospital with no mortality, and feasibility defined as successful free flap reconstruction. Other variables included age, race, sex, length of surgery, length of hospital stay, and intraoperative use of vasopressors. Data analysis was performed utilizing t-tests for means and χ2 for proportions. Alpha was set at < 0.05. A total of 12 participants from 7 participating sites met the inclusion criteria. There were 9 males and 3 females with a mean age of 58.3 ± 8.3 years. There were no deaths in this cohort and all patients were discharged from the hospital. All 12 free flap reconstructions were successful with no incidents of free flap loss; none of the patients received any blood transfusions or any other blood products. Subgroup analysis showed that patients treated for malignant disease versus benign disease had longer operations (11.2 ± 2.9 vs 6.3 ± 0.2 hours, P < .01) and a longer hospital length of stay (11.8 ± 4.9 vs 5.3 ± 0.5 days, P = .04). Our series supports the safety and feasibility of maxillofacial free flap reconstruction in this challenging subset of patients. Microvascular reconstructive surgeries for malignant diseases often result in longer operative times and hospital stays.


Emergent bronchofiberoptic bronchial occlusion for intractable pneumothorax with severe emphysema.
Emergent bronchofiberoptic bronchial occlusion using fibrin glue and woven polyglycolic acid mesh for persistent pneumothorax with severe emphysema is described. A 74-year-old man who had severe pulmonary dysfunction accompanying chronic emphysema was admitted with a complaint of sudden severe dyspnea. The chest X-ray on admission revealed collapse of the right lung. The patient was placed on a mechanical ventilator because of acute respiratory failure. In spite of continuous suction through a chest drainage tube, air leakage persisted. On the seventh hospital day, subcutaneous emphysema was apparent in the face and scrotum in addition to the chest. First, a double-lumen catheter was inserted into the right B5 bronchus, and fibrin glue was infused into the drainage bronchus via the double-lumen catheter. However, the procedure failed. Next, a combination of fibrin glue and woven polyglycolic acid mesh which had been cut into small pieces was introduced and pushed into the B5 bronchus using forceps. The air leakage stopped immediately after the administration. This procedure is simple and a minimally invasive method for the treatment of intractable pneumothorax in a compromised patient on a mechanical ventilator.


Effects of prostaglandins on vesicourethral smooth muscle of rabbit. Therapeutic implications.
The effects of PGF 2-alpha and PGE2 on the vesicourethral smooth muscle of the rabbit were studied in vitro. PGF2-alpha had potent contractile effects on the bladder body and comparatively less in the bladder base and the proximal urethra. PGE2 contractile effects were two times greater than PGF 2-alpha on the bladder body but minimal or absent on the base and the urethra. The effects of PGF2-alpha and PGE2 seem to be mediated through a prostaglandin receptor as indicated by competitive antagonism of both prostaglandins by N-0164, a synthetic phenyl phosphonate. It also appears that the effects of PGF2-alpha PGE2 may not be mediated through muscarinic, adrenergic, nicotinic, or histaminic receptors or direct smooth-muscle action. The therapeutic implications of PGE2 in the patients with problems of bladder emptying are discussed.


Antibody-mediated rejection in xenotransplantation: Can it be prevented or reversed?
Antibody-mediated rejection (AMR) is the commonest cause of failure of a pig graft after transplantation into an immunosuppressed nonhuman primate (NHP). The incidence of AMR compared to acute cellular rejection is much higher in xenotransplantation (46% vs. 7%) than in allotransplantation (3% vs. 63%) in NHPs. Although AMR in an allograft can often be reversed, to our knowledge there is no report of its successful reversal in a pig xenograft. As there is less experience in preventing or reversing AMR in models of xenotransplantation, the results of studies in patients with allografts provide more information. These include (i) depletion or neutralization of serum anti-donor antibodies, (ii) inhibition of complement activation, (iii) therapies targeting B or plasma cells, and (iv) anti-inflammatory therapy. Depletion or neutralization of anti-pig antibody, for example, by plasmapheresis, is effective in depleting antibodies, but they recover within days. IgG-degrading enzymes do not deplete IgM. Despite the expression of human complement-regulatory proteins on the pig graft, inhibition of systemic complement activation may be necessary, particularly if AMR is to be reversed. Potential therapies include (i) inhibition of complement activation (e.g., by IVIg, C1 INH, or an anti-C5 antibody), but some complement inhibitors are not effective in NHPs, for example, eculizumab. Possible B cell-targeted therapies include (i) B cell depletion, (ii) plasma cell depletion, (iii) modulation of B cell activation, and (iv) enhancing the generation of regulatory B and/or T cells. Among anti-inflammatory agents, anti-IL6R mAb and TNF blockers are increasingly being tested in xenotransplantation models, but with no definitive evidence that they reverse AMR. Increasing attention should be directed toward testing combinations of the above therapies. We suggest that treatment with a systemic complement inhibitor is likely to be most effective, possibly combined with anti-inflammatory agents (if these are not already being administered). Ultimately, it may require further genetic engineering of the organ-source pig to resolve the problem entirely, for example, knockout or knockdown of SLA, and/or expression of PD-L1, HLA E, and/or HLA-G.


Lower respiratory infection in humans caused by pasteurella multocida.
Pasteurella (P.) multocida commonly occurs in the upper respiratory tract of healthy domestic pets, especially cats and dogs. People become infected by biting, scratching or direct contact with the animal's saliva. Inflammation develops in the wound and limits itself to the skin and subcutaneous tissue. P. multocida may cause respiratory tract infections and severe life-threatening complications. The study aimed to identify the lower respiratory infection in humans caused by P. multocida, to determine the potential source of infection and the associated symptoms, comorbidities and applied treatment. Between January 2010 and September 2021, 14,258 patients underwent 16,255 routine flexible video bronchoscopy (FVB), and the same number of bronchoalveolar lavage fluid (BALF) samples for microbiological examination were taken. Microbiological examinations of the BALF only allowed the identification of six patients with P. multocida infection. All persons reported multiple scratches or bites and licking or kissing by their pets in the past. Productive cough with expectoration of mucopurulent discharge was the predominant symptom. A lower respiratory infection caused by P. multocida is not common in humans. It should be considered particularly in elderly patients with underlying diseases and exposure to cats and dogs.


Lignin distribution in wood cell walls determined by TEM and backscattered SEM techniques.
The lignin distribution in cell walls of spruce and beech wood was determined by high-voltage transmission-electron-microscopy (TEM) in sections stained with potassium permanganate as well as by field-emission-scanning-electron-microscopy (FE-SEM) combined with a back-scattered electron detector on mercurized specimens. The latter is a new technique based on the mercurization of lignin and the concomitant visualization of mercury by back-scattered electron microscopy (BSE). Due to this combination it was possible to obtain a visualized overview of the lignin distribution across the different layers of the cell wall. To our knowledge, this combined method was used the first time to analyse the lignin distribution in cell walls. In agreement with previous work the highest lignin levels were found in the compound middle lamella and the cell corners. Back-scattered FE-SEM allows the lignin distribution in the pit membrane of bordered pits as well as in the various cell wall layers to be shown. In addition, by using TEM as well as SEM we observed that lignin closely follows the cellulose microfibril orientation in the secondary cell wall. From these observations, we conclude that the polymerisation of monolignols is affected by the arrangement of the polysaccharides which constitute the cell wall.


Developing the public health practitioner workforce in England: lessons from theory and practice.
The paper focuses on public health practitioners who collectively represent one of three key workforce groups identified by England's Chief Medical Officer as critical to the successful delivery of national public health policy priorities. We report on two areas of work which attempt to address the following two-part question: in developing the public health practitioner workforce in England, what is needed, and how do we do it? First, we describe a five-component conceptual framework for developing the public health workforce which is grounded in data derived from a national Open Space event hosted by the University of the West of England in March 2005. The five components are (i) strategic support and oversight; (ii) national technical and professional support; (iii) national career building; (iv) local organisational development, and (v) sub-regional skills development. Key elements of each component are described in the paper. Second, we describe in some detail a new multidisciplinary skills development programme which illustrates one of the framework components (sub-regional skills development). The programme, established in January 2005, is aimed at three key groups of public health practitioners: health visitors (specialist community public health nurse), school nurses and environmental health officers. Its main features and some initial evaluation findings are presented. To be effective, activities aimed at supporting the development of the public health practitioner workforce should, where possible, aim to be congruent with core public health principles of self-determination and collective responsibility. We also conclude that leadership and vision at a national level, combined with local implementation of evidence-based training programme such as the one described could help to achieve much greater and more rapid progress in skilling up the existing public health practitioner workforce than has been possible up to now. But we note that this requires sustained investment, robust sector-wide delivery frameworks, and a group of committed local public health champions.


Subscapularis dysfunction following anterior surgical approaches to the shoulder.
Subscapularis dysfunction following open surgical exposure of the glenohumeral joint has recently received attention. Clinical studies, in particular those that have investigated the results after open shoulder stabilization or shoulder replacement surgery, indicate that anterior approaches using different subscapularis tendon take-down or incision techniques may impair subscapularis recovery and can negatively influence the final clinical outcome. This review article will focus on the potential pathogenesis, diagnosis, and clinical impact of this more and more recognized condition and summarizes the currently available literature.


Repetitive Sleep Starts in Allan-Herndon-Dudley Syndrome.
Allan-Herndon-Dudley syndrome (AHDS) is caused by mutations in the SLC16A2 gene, encoding for the monocarboxylate transporter 8 (MCT8). Central hypothyroidism and chronic peripheral thyrotoxicosis result in a severe phenotype, mainly characterized by poor growth, intellectual disability, spastic tetraparesis, and movement disorders, including paroxysmal ones (startle reaction and paroxysmal dyskinesias). Seizures are rarely reported. We conducted a retrospective analysis on video electroencephalography (EEG) recordings in four subjects with AHDS, focused on paroxysmal events. Among other manifestations recorded on EEG, we diagnosed repetitive sleep starts (RSS) in all subjects. RSS are a paroxysmal nonepileptic phenomenon occurring during sleep, similar to epileptic spasms in their clinical and electromyography characteristics, but not related to any EEG change. This is the first report on RSS in AHDS. We present video-EEG polygraphic documentation, suggesting that RSS could be underestimated or misdiagnosed. The importance of a correct diagnosis is crucial in a therapeutic perspective.


Evaluation of the efficacy of the crude extract of Aloe secundiflora in chickens experimentally infected with Newcastle disease virus.
Two replicate experiments were carried out to verify the efficacy of Aloe species (Aloaceae) as used for the control of Newcastle disease (ND) in rural poultry in free-range systems among several communities in Tanzania. Four months old local chickens free of Newcastle disease antibodies were used. Following inoculation with ND virus, body weights, clinical signs, antibody levels and mortality were monitored. Results showed that there was reduced mortality rate and the severity of clinical signs during the acute phase of the infection in Aloe treated chickens compared with the non-treated ones. However, there was no significant effect of the Aloe on the antibody levels that were attributed to the recovery of the surviving chickens. The findings of this study suggest that Aloe secundiflora could be a potential candidate on the management of Newcastle disease in chickens. Further studies are in progress to identify the active ingredients of A. secundiflora against Newcastle disease virus.


The cloning of PIG-A, a component in the early step of GPI-anchor biosynthesis.
The glycosylphosphatidylinositol (GPI) anchor is a membrane attachment structure of many proteins and occurs in a wide variety of eukaryotes from yeasts to mammals. The structure of the core of the GPI anchor is conserved in protozoa and mammals and so is its biosynthetic pathway. A complementary DNA encoding a human protein termed PIG-A (phosphatidylinositol glycan-class A) was cloned. PIG-A was necessary for synthesis of N-acetylglucosaminyl-phosphatidylinositol, the very early intermediate in GPI-anchor biosynthesis.


Increased psychological distress among young people before and during the fifth wave of COVID-19 after two years of pandemic in Hong Kong: a 6-month longitudinal study.
Despite over two years of COVID-19 worldwide, the outbreak of the Omicron variant has given rise to an unprecedented surge of infection with diverse lockdown measures implemented globally. Whether the emergence of a new wave of COVID-19 could further affect mental health in the population after nearly two years of the pandemic remains to be addressed. Furthermore, whether changes in smartphone overuse behaviours and physical activity - both of which are particularly relevant to young people - would together contribute to changes in distress symptoms during this wave of COVID-19 was also examined. A total of 248 young people from an ongoing household-based epidemiological study in Hong Kong who completed their baseline assessments prior to the Omicron variant outbreak, i.e., fifth wave of COVID-19 (July-November 2021), were invited for a 6-month follow-up study during this wave of infection (January-April 2022) (mean age = 19.7 years, SD = 2.7; 58.9% females). At both time points, levels of global distress symptoms, perceived stress, smartphone overuse, frequency of engagement in vigorous physical activity, and other potential risk and protective factors were assessed. The proportion of young people presenting moderate-to-severe distress (6-item Kessler Psychological Distress Scale ≥ 5) significantly increased from 45.6 to 54.4% during the fifth wave of COVID-19 (p < 0.010). Significantly increased levels of smartphone overuse and reduced days of vigorous physical activity were also observed during the fifth wave. Notably, increased smartphone overuse and reduced physical activity both additively and interactively contributed to elevated distress at 6 months, even after accounting for demographic characteristics, psychiatric history, childhood adversity, as well as baseline distress symptoms, resilience, and recent personal stressors. The findings suggest that the emergence of a new wave of COVID-19, specifically the Omicron outbreak, can further aggravate mental distress even after a protracted period of the pandemic. Awareness of the dynamic nature of COVID-19 is necessitated to address the pressing mental health needs of populations. Supporting young people in healthier patterns of smartphone use and physical activity can be helpful.


Genetic risk of age-related maculopathy. Population-based familial aggregation study.
To investigate to what extent age-related maculopathy (ARM) is genetically determined. Familial aggregation study based on probands derived from the population-based Rotterdam Study. First-degree relatives of 87 patients with late ARM, i.e., atrophic or neovascular macular degeneration, were compared with first-degree relatives of 135 control subjects without ARM. Presence and stage of ARM as diagnosed on fundus transparencies, odds ratio, lifetime risk, risk ratio, and population-attributable risk. Independent of other risk factors, the prevalence of early (odds ratio = 4.8, 95% confidence interval [CI] = 1.8-12.2) and late (odds ratio = 19.8, 95% CI = 3.1-126.0) ARM was significantly higher in relatives of patients with late ARM. The lifetime risk estimate of late ARM was 50% (95% CI = 26%-73%) for relatives of patients vs 12% (95% CI = 2%-16%) for relatives of controls (P < .001), yielding a risk ratio of 4.2 (95% CI = 2.6-6.8). Relatives of patients expressed the various features of ARM at a younger age. The population-attributable risk related to genetic factors was 23%. First-degree relatives of patients with late ARM developed ARM at an increased rate at a relatively young age. Our findings indicate that approximately one fourth of all late ARM is genetically determined and suggest that genetic susceptibility may play an important role in determining the onset of disease.


Amino acid specificity of fibers of the facial/trigeminal complex innervating the maxillary barbel in the Japanese sea catfish, Plotosus japonicus.
The Japanese sea catfish, Plotosus japonicus, possesses taste and solitary chemoreceptor cells (SCCs) located on the external body surface that detect specific water-soluble substances. Here, we identify two major fiber types of the facial/trigeminal complex that transmit amino acid information to the medulla. Both single and few fiber preparations respond to amino acid stimulation in the 0.1 μM to mM range. One fiber type responds best to glycine and l-alanine (i.e. Gly/Ala fibers) whereas the other fiber type is best stimulated by l-proline and glycine betaine (hereafter referred to only as betaine) (i.e. Pro/Bet fibers). We demonstrate that betaine, which does not alter the pH of the seawater and therefore does not activate the animals' highly sensitive pH sensors (Caprio et al., Science 344:1154-1156, 2014), is sufficient to elicit appetitive food search behavior. We further show that the amino acid specificity of fibers of the facial/trigeminal complex in P. japonicus is different from that in Ariopsis felis (Michel and Caprio, J. Neurophysiol. 66:247-260, 1991; Michel et al., J. Comp. Physiol. A. 172:129-138, 1993), a representative member of the only other family (Ariidae) of extant marine catfishes.


Pim-1 knockdown potentiates paclitaxel-induced apoptosis in human hormone-refractory prostate cancers through inhibition of NHEJ DNA repair.
The knockdown of Pim-1 or inhibition of Pim-1 activity significantly increased γ-H2A.X expression. The effect was correlated to apoptosis and was attributed to the inhibition of nonhomologous DNA-end-joining (NHEJ) repair activity supported by the following observations: (1) inhibition of ATM and DNA-PKcs activities, (2) down-regulation of Ku expression and nuclear localization and (3) decrease of DNA end-binding of both Ku70 and Ku80. The data suggest that Pim-1 plays a crucial role in the regulation of NHEJ repair. In the absence of Pim-1, the ability of DNA repair significantly decreases when exposed to paclitaxel, leading to severe DNA damage and apoptosis.


A Randomized Controlled Trial of Personalized Text Message Reminders to Promote Medication Adherence Among HIV-Positive Adolescents and Young Adults.
HIV-positive adolescents and young adults often experience suboptimal medication adherence, yet few interventions to improve adherence in this group have shown evidence of efficacy. We conducted a randomized trial of a two-way, personalized daily text messaging intervention to improve adherence to antiretroviral therapy (ART) among N = 105 poorly adherent HIV-positive adolescents and young adults, ages 16-29. Adherence to ART was assessed via self-reported visual analogue scale (VAS; 0-100 %) at 3 and 6-months for mean adherence level and proportion ≥90 % adherent. The average effect estimate over the 6-month intervention period was significant for ≥90 % adherence (OR = 2.12, 95 % CI 1.01-4.45, p < .05) and maintained at 12-months (6 months post-intervention). Satisfaction scores for the intervention were very high. These results suggest both feasibility and initial efficacy of this approach. Given study limitations, additional testing of this intervention as part of a larger clinical trial with objective and/or clinical outcome measures of adherence is warranted.


Methylmercury exposure during prenatal and postnatal neurodevelopment promotes oxidative stress associated with motor and cognitive damages in rats: an environmental-experimental toxicology study.
The environmental contamination by methylmercury (MeHg) is a major concern for public health. The effects of MeHg in the central nervous system (CNS) of adult animals have been extensively investigated; however, little is known about the effects of MeHg exposure during intrauterine and lactation periods on motor and cognitive functions of adolescent rats. Therefore, this study aimed to investigate the effect of MeHg exposure during intrauterine life and lactation on both motor and cognitive functions of offspring rats. Ten female Wistar rats were exposed to 40 μg/kg/day of MeHg through cookie treats from the first day of pregnancy until the last day of breastfeeding. Both motor and cognitive functions of offspring male rats were assessed by open field, rotarod, and step-down inhibitory avoidance tests. Forty-one days after birth, the hippocampus and cerebellum were collected to determine total Hg content, antioxidant capacity against peroxyl radicals (ACAP), reduced glutathione (GSH) levels, lipid peroxidation (LPO), and nitrite levels. MeHg exposure during CNS development increased Hg levels in both hippocampal and cerebellar parenchymas, triggered oxidative stress throughout ACAP and GSH decrease, increased LPO and nitrite levels. These alterations resulted in reduced spontaneous and stimulated locomotion and short- and long-term memory deficits. Therefore, damages triggered by MeHg exposure during intrauterine life and lactation had detrimental effects on oxidative biochemistry and motor and cognitive functions of offspring rats.


Surgical mesh as a scaffold for tissue regeneration in the esophagus.
Textiles in the form of surgical meshes are widely used in hernia surgery. Their porous structure allows tissue infiltration to incorporate the fabric for complete healing and device stabilization. This study was aimed to reconstitute the esophageal wall and to investigate the functional and histological consequences of a new, non-absorbable polyvinylidene fluoride (PVDF) mesh and an absorbable polyglactin 910 (Vicryl((R))) mesh. Semicircular esophageal defects of 0.5 x 1 cm were created 2 cm proximal of the cardia in 10 rabbits. This gap was bridged using either polyglactin 910 or PVDF and additionally covered by omental wrapping. The clinical outcome was observed by clinical observation, regular esophagoscopies and X-ray contrast medium examinations. Local tissue regeneration was verified by light microscopy and immunohistochemistry. After an observation period of 3 months we found no anastomotic strictures, complete mucosal regeneration, minimal inflammation reaction and initial regeneration of the muscle layer for the PVDF group. Within the polyglactin 910 group, three patch failures with consecutive anastomotic leakage occurred. The results indicate that PVDF mesh structure gives the opportunity of local tissue regeneration in the esophagus. Though re-epithelialization and muscle cell ingrowth could be detected for absorbable polyglactin 910 mesh, this implant was accompanied by a high and early rate of anastomotic leakage.


Successful clozapine continuation during chemotherapy for the treatment of malignancy: a case report.
The need for chemotherapy treatment in a cancer patient who uses clozapine raises a clinical dilemma because both therapies can cause agranulocytosis. A 45-year-old male diagnosed with schizophrenia used clozapine together with zuclopenthixol for more than 15 years. Non-Hodgkin's lymphoma was treated with chemotherapy twice, and clozapine was continued during both courses of chemotherapy. Agranulocytosis did not occur during the first treatment. During the second treatment, agranulocytosis occurred, but was attributed to chemotherapy, and blood counts recovered spontaneously. Successful concomitant use of clozapine and cancer chemotherapy is based on a limited number of case reports. However, two case reports describe persistent neutropenia or agranulocytosis, possibly related to this combination. Clozapine should only be continued during cancer chemotherapy if favoured by the risk-to-benefit ratio.


Factors associated with the development of avascular necrosis of the femoral head after non-displaced femoral neck fracture treated with internal fixation.
To identify the factors with influence on the development of avascular necrosis of the femoral head (ANFH) in patients with non-displaced femoral neck fractures treated with internal fixation. Retrospective study of cases and controls. We included non-displaced femoral neck fractures treated with internal fixation, and that presented ANFH with a postoperative follow-up of at least 2 years. The baseline variables, active comorbidities of the patients, the time for surgery and the number of screws used for osteosynthesis were recorded. Comparisons were made between the groups, those that presented ANFH and those that did not. By area under the curve, the cut-offs of age and time for surgery were located. An association between sex, active comorbidities and number of screws used and the development of ANFH was not observed. The cut-off points for age and time for surgery were≤69 years and≤43hours, respectively. No significant correlation was observed for the cut-off time for surgery. In the multivariate analysis, age≤69 years was a significant predictor of the development of ANFH (OR 4.6; 95% CI 1.1 to 17.9; P=.028). The patients aged 69 years or younger were at increased risk of developing ANFH after undisplaced femoral neck fracture treated with percutaneous screws.


Effect of deep breathing on extracted oxygen and cerebral hemoglobin levels.
This study examines the relationship between oxygen expired and functional near infrared spectroscopy (fNIRS) measured hemoglobin levels in the brain. Analysis of these two signals during normal versus deep breathing provides insight into the dynamics of cerebral physiology. Intersubject variation suggests the existence of two distinct groups with respect to oxygen extraction and hemoglobin levels.