Correlation of visuospatial memory ability with right parietal EEG spindling during sleep.
Individual differences in human sleep EEG spindling were shown to be associated with psychometric measures of cognitive ability. Previous results revealed a frequency- and region specificity of this effect, suggesting that only fast, but not slow spindle-related oscillatory activity over the frontal region correlated with cognitive performance. Our aim is to test the hypothesis that region-specific spindle-type oscillatory activity is related to specific cognitive abilities reflecting the cortical localization of the corresponding cognitive function. The visuospatial abilities are the focus of the present report. Nineteen healthy volunteers were tested with the Rey-Osterrieth Complex Figure (ROCF) test and memory performances correlated with the spindle analysis of the second night's polysomnographic recordings. Correlations were age-corrected and subjected to descriptive data analysis. ROCF recall performances at 3 and 30 minutes delay, correlated positively and significantly with fast sleep spindle density measured over the right parietal area. No significant relationship between recognition performance and sleep EEG variables emerged. Slow spindle density did not correlate with test performances. Our findings converge with other data suggesting the involvement of right parietal functioning in visuospatial abilities. Moreover, these results support the hypothesis that region-specific differences in fast sleep spindling could be markers of specific neuropsychological performances.


[Induced abortion in The Netherlands in the twentieth century; from taboo to revolutionary change].
Between 1890 and 1945 the number of induced (criminal) abortions increased in Amsterdam; from 1945 up until the 1960s the number decreased slightly. In 1965 the number of induced abortions that took place in Amsterdam was estimated at more than 2000. Complications were frequent and included infections, septicaemia, damage caused by injected soap and sometimes air embolism. Women in Amsterdam often used primitive methods of contraception, but effective methods, such as condoms and diaphragms, were also used to some degree. Oral contraception was introduced in The Netherlands in 1962. Its use increased rapidly and consequently many doctors were confronted with problems surrounding contraception, including failures and abortion requests. After a television programme on abortion in 1967, requests for abortion surged. Hospitals set up multidisciplinary abortion committees to assess the requests, but soon it became evident that the women themselves were better able to judge whether they should undergo the procedure. Abortion clinics were established outside hospitals. Support from the feminist movement played a role after changes were already underway. The nationwide number of abortions increased to 21,000 in 1972 and to about 25,000 in the 1990s. The number remained stable, even among teenagers, because caregivers placed a great deal of emphasis on adequate contraception.


A proof-of-principle study: The potential application of MiniHap biomarkers in ancestry inference based on the QNome nanopore sequencing.
Haplotyped SNPs convey forensic-related information, and microhaplotypes (MHs), as the most representative of this kind of marker, have proved the potential value for human forensics. In recent years, nanopore sequencing technology has developed rapidly, with its outstanding ability to sequence long continuous DNA fragments and obtain phase information, making the detection of longer haplotype marker possible. In this proof-of-principle study, we proposed a new type of forensic marker, MiniHap, based on five or more SNPs within a molecular distance less than 800 bp, and investigated the haplotype data of 56 selected MiniHaps in five Chinese populations using the QNome nanopore sequencing. The sequencing performance, allele (haplotype) frequencies, forensic parameters, effective number of alleles (Ae), and informativeness (In) were subsequently calculated. In addition, we performed principal component analysis (PCA), phylogenetic tree, and structure analysis to investigate the population genetic relationships and ancestry components among the five investigated populations and 26 worldwide populations. MiniHap-04 exhibited remarkable forensic efficacy, with 148 haplotypes reported and the Ae was 66.9268. In addition, the power of discrimination (PD) was 0.9934, the probability of exclusion (PE) was 0.9898, and the In value was 0.7893. Of the 56 loci, 85.71% had PD values above 0.85, 66.07% had PE values above 0.54, 67.86% had Ae values over 7.0%, and 55.36% were with In values above 0.2 across all samples, indicating that most of the MiniHaps are suitable for individual identification, paternity testing, mixture deconvolution, and ancestry inference. Moreover, the results of PCA, phylogenetic tree and structure analysis demonstrated that this MiniHap panel had the competency in continental population ancestry inference, but the differentiation within intracontinental/linguistically restricted subpopulations was not ideal. Such findings suggested that the QNome device for MiniHap detection was feasible and this novel marker has the potential in ancestry inference. Yet, the establishment of a more comprehensive database with sufficient reference population data remains necessary to screen more suitable MiniHaps.


Toward Building Protein Force Fields by Residue-Based Systematic Molecular Fragmentation and Neural Network.
Accurate force fields are crucial for molecular dynamics investigation of complex biological systems. Building accurate protein force fields from quantum mechanical (QM) calculations is challenging due to the complexity of proteins and high computational costs of QM methods. In order to overcome these two difficulties, here we developed the residue-based systematic molecular fragmentation method to partition general proteins into only 20 types of amino acid dipeptides and one type of peptide bond at level 1. The total energy of proteins is the combination of the energies of these fragments. Each type of the fragments is then parametrized using neural network (NN) representation of the QM reference. Adopting NN representation can circumvent the limitation of the analytic form of classical molecular mechanics (MM) force fields. Using MM force fields as the baseline, our method adds NN representation of QM corrections at the length scale of amino acid dipeptides. We tested our force fields for both homogeneous and heterogeneous polypeptides. Energy and forces predicted by our force fields compare favorably with full QM calculations from tripeptides to decapeptides. Our development provides an efficient and accurate method of building protein force fields fully from ab initio QM calculations.


Energy Analysis of Aluminosilicate Zeolites with Comprehensive Ranges of Framework Topologies, Chemical Compositions, and Aluminum Distributions.
The contents and locations of Al in the zeolite frameworks are one of the key factors determining the physicochemical properties of zeolites. Systematic evaluation of the characteristics of zeolites with a wide variety of framework topologies, a wide range of Si/Al ratios, and various locations of Al is of great significance, but very challenging due to the limitation of the realizable ranges of Al contents in zeolites as well as the limited information on the Al locations obtained from the current analytical techniques. Here, we report the systematic analysis of the energetics of aluminosilicate zeolites with 209 existing framework topologies at different Si/Al ratios using molecular mechanics. More than 43 000 initial structures were generated to give comprehensive views of the energetics of zeolites. The results coincide well with the structural knowledge obtained experimentally. It was revealed that the relation between the relative framework energies versus the Al contents varies in accordance with the topologies, suggesting that the relative stability of zeolites depends not only on the topologies, but also on the substituting contents of Al. For particular topologies with the same Al contents, in addition, comparisons between random and specific distributions of Al showed that zeolite with Al at a particular T site is energetically more stable than those with random distributions, suggesting the inherent influences of the Al locations. The contents and locations of Al in zeolites likely have a certain preference that may reflect the range of chemical compositions, the Al distributions, and consequently the physicochemical properties of realizable aluminosilicate zeolites.


Localization and properties of bovine photoreceptor 5'-nucleotidase.
The main light-activated enzyme of the vertebrate photoreceptor is cGMP phosphodiesterase, whose product is GMP. GMP would be broken down to guanosine by the enzyme 5'-nucleotidase on the cytoplasmic (extradiscal) surface of the disks. The presence of 5'-nucleotidase on the cytoplasmic surface was verified by using sucrose continuous gradients to show its association with the photoreceptors and by using disk preparation and concanavalin A binding to demonstrate its presence on the extradiscal surface. Further studies using detergents and freeze-thaw showed that an even higher 5'-nucleotidase activity is present on the intradiscal surface; however, it is the smaller cytoplasmic surface activity that is potentially relevant to the physiology. The 5'-nucleotidase on the extradiscal surface is light insensitive, has a broad optimal pH range, shows a divalent cation dependence, and is competitively inhibited by nucleoside di- and triphosphates. When the data determined experimentally were extrapolated to physiological conditions, we obtained a decay time constant for GMP breakdown by 5'-nucleotidase in the range of 0.4 to 1.06 s. This time constant is in the range of the time constants of the fall of rod cell receptor potential, suggesting a possible role for GMP level in visual transduction.


Cost-effectiveness of macrogol 4000 compared to lactulose in the treatment of chronic functional constipation in the UK.
To estimate the cost-effectiveness of macrogol 4000 compared to lactulose in the treatment of chronic functional constipation, from the perspective of the National Health Service (NHS) in the UK. A decision model depicting the management of chronic functional constipation was constructed using clinical outcomes and resource use values derived from patients suffering from chronic functional constipation in The Health Improvement Network (THIN) Database. The model was used to estimate the cost-effectiveness of a general practitioner (GP) prescribing macrogol 4000 relative to lactulose to treat adults >/=18 years of age suffering from chronic functional constipation. Forty-two per cent (95% confidence interval [CI]: 38%; 46%) of macrogol 4000-treated patients are expected to be successfully treated within 3 months after starting treatment, compared to 31% (95% CI: 27%; 37%) of lactulose-treated patients. Patients' health status at 3 months was estimated to be 0.213 (95% CI: 0.200; 0.223) and 0.210 (95% CI: 0.197; 0.220) quality-adjusted life years (QALYs) in the macrogol 4000 and lactulose groups, respectively. The total 3-monthly NHS cost of treating patients with macrogol 4000 or lactulose was estimated to be pound115 (95% CI: pound98; pound132) and pound102 (95% CI: pound86; pound119), respectively. Hence, the cost per QALY gained with macrogol 4000 was estimated to be pound4333. Within the limitations of the model, treatment with macrogol 4000 relative to lactulose is expected to increase the probability of being successfully treated by 35% at 3 months (p<0.0001), although this yields only a 1% improvement in health gain. Nevertheless, macrogol 4000 affords a cost-effective addition to the range of laxatives available for this potentially resource-intensive condition, since it is clinically more effective than lactulose and the cost-effective strategy from the perspective of the NHS.


Waveform difference between skin conductance and skin potential responses in relation to electrical and evaporative properties of skin.
The shapes of skin conductance (SC) and skin potential (SP) responses are often similar, but can also be very different due to an unexplained cause. Using a new method to measure SC and SP simultaneously at the same electrode, this difference was investigated in a new way by comparing their temporal peak differences. SC, SP, skin susceptance (SS), and transepidermal water loss (TEWL) were recorded from 40 participants during relaxation and stress. The SP response could peak anywhere between the onset of an SC response to some time after the peak of an SC response. This peak time difference was associated with the magnitude of the SCR, the hydration of the skin, and the filling of the sweat ducts. Interpretation of the results in light of existing biophysical theories suggests that this peak difference may indicate the hydraulic capacity state of the sweat ducts at the time of a response.


Embolic middle cerebral artery occlusion (MCAO) for ischemic stroke with homologous blood clots in rats.
Clinically, thrombolytic therapy with use of recombinant tissue plasminogen activator (tPA) remains the most effective treatment for acute ischemic stroke. However, the use of tPA is limited by its narrow therapeutic window and by increased risk of hemorrhagic transformation. There is an urgent need to develop suitable stroke models to study new thrombolytic agents and strategies for treatment of ischemic stroke. At present, two major types of ischemic stroke models have been developed in rats and mice: intraluminal suture MCAO and embolic MCAO. Although MCAO models via the intraluminal suture technique have been widely used in mechanism-driven stroke research, these suture models do not mimic the clinical situation and are not suitable for thrombolytic studies. Among these models, the embolic MCAO model closely mimics human ischemic stroke and is suitable for preclinical investigation of thrombolytic therapy. This embolic model was first developed in rats by Overgaard et al.(1) in 1992 and further characterized by Zhang et al. in 1997(2). Although embolic MCAO has gained increasing attention, there are technical problems faced by many laboratories. To meet increasing needs for thrombolytic research, we present a highly reproducible model of embolic MCAO in the rat, which can develop a predictable infarct volume within the MCA territory. In brief, a modified PE-50 tube is gently advanced from the external carotid artery (ECA) into the lumen of the internal carotid artery (ICA) until the tip of the catheter reaches the origin of the MCA. Through the catheter, a single homologous blood clot is placed at the origin of the MCA. To identify the success of MCA occlusion, regional cerebral blood flow was monitored, neurological deficits and infarct volumes were measured. The techniques presented in this paper should help investigators to overcome technical problems for establishing this model for stroke research.


Radiation properties of channel waveguide discontinuities: a comparison of theoretical and experimental results.
An orthonormal mode approach is presented for characterizing the radiation properties of waveguide discontinuities. The approach, which can be used to accurately estimate power loss and crosstalk in intersecting waveguides as well as polarization extinction in proton exchanged polarizers, requires only a knowledge of the optical mode profile, the operating wavelength, and the bulk substrate index. To demonstrate the validity of the technique, theoretical predictions for polarization extinction are compared to measured values for a proton exchanged polarizer fabricated on x-cut LiNbO(3) and operated at 0.82 microm. Excellent agreement between theory and experiment is obtained for all polarizer lengths.


Advancements in Hepatocellular Carcinoma: Potential Preclinical Drugs and their Future.
Hepatocellular carcinoma (HCC) is one of the foremost causes of tumor-affiliated demises globally. The HCC treatment has undergone numerous developments in terms of both drug and non-drug treatments. The United States Food and Drug Administration (FDA) has authorized the usage of a variety of drugs for the treatment of HCC in recent years, involving multi-kinase inhibitors (lenvatinib, regorafenib, ramucirumab, and cabozantinib), immune checkpoint inhibitors (ICIs) (pembrolizumab and nivolumab), and combination therapies like atezolizumab along with bevacizumab. There are currently over a thousand ongoing clinical and preclinical studies for novel HCC drugs, which portrays a competent setting in the field. This review discusses the i. FDA-approved HCC drugs, their molecular targets, safety profiles, and potential disadvantages; ii. The intrial agents/drugs, their molecular targets, and possible benefits compared to alternatives, and iii. The current and future status of potential preclinical drugs with novel therapeutic targets for HCC. Consequently, existing drug treatments and novel strategies with their balanced consumption could ensure a promising future for a universal remedy of HCC in the near future.


Bio-Inspired Muco-Adhesive Polymers for Drug Delivery Applications.
Muco-adhesive drug delivery systems continue to be one of the most studied for controlled pharmacokinetics and pharmacodynamics. Briefly, muco-adhesive polymers, can be described as bio-polymers that adhere to the mucosal (mucus) surface layer, for an extended residency period of time at the site of application, by the help of interfacial forces resulting in improved drug delivery. When compared to traditional drug delivery systems, muco-adhesive carriers have the potential to enhance therapeutic performance and efficacy, locally and systematically, in oral, rectal, vaginal, amongst other routes. Yet, the achieving successful muco-adhesion in a novel polymeric drug delivery solution is a complex process involving key physico-chemico-mechanical parameters such as adsorption, wettability, polymer chain length, inter-penetration and cross-linking, to list a few. Hence, and in light of accruing progress, evidence and interest, during the last decade, this review aims to provide the reader with an overview of the theories, principles, properties, and underlying mechanisms of muco-adhesive polymers for pharmaceutics; from basics to design to characterization to optimization to evaluation to market. A special focus is devoted to recent advances incorporating bio-inspired polymers for designing controlled muco-adhesive drug delivery systems.


Humic acids-based one-step fabrication of SERS substrates for detection of polycyclic aromatic hydrocarbons.
A facile one-step approach to fabricate substrates for surface-enhanced Raman scattering (SERS) detection of polycyclic aromatic hydrocarbons (PAHs) was explored by reduction of silver nitrate with humic acids (HAs). This simple process readily delivers silver nanoparticles (Ag NPs) decorated with HAs (HAs-Ag NPs), and an average diameter of 50 nm. More importantly, it compares favorably to Ag NPs prepared by the usual sodium citrate method, HAs-Ag NPs show excellent SERS activity for PAHs and display a remarkable capacity to absorb aromatic molecules through presumed π-π stacking interactions. Furthermore, the HAs-Ag NPs displayed good SERS stability, possibly due to the fact that HAs form loose coils or networks around the nanoparticles thus preventing aggregation. The investigation of qualitative and quantitative detection of PAHs on HAs-Ag NPs indicate that different PAHs can be distinguished easily from their discriminant SERS peaks, and the SERS responses exhibited a linear dependence on PAH concentrations over two orders of magnitude, with tens of nM detection limits. In addition, the HAs-Ag NPs performed well in the multicomponent analysis of PAH mixtures by the SERS technique without pre-separation.


Naringenin attenuates the progression of liver fibrosis via inactivation of hepatic stellate cells and profibrogenic pathways.
There is no effective treatment for hepatic fibrosis. Previously, we demonstrated that naringenin possesses the ability to prevent experimental chronic liver damage. Therefore, the objective of this work was to investigate whether naringenin could reverse carbon tetrachloride (CCl4)-induced fibrosis in rats and, if so, to search for the mechanisms involved. CCl4 was given to male Wistar rats (400 mg/kg, three times per week, i. p.) for 12 weeks; naringenin (100 mg/kg twice per day, p. o.) was administered from weeks 9-12 of the CCl4 treatment. Liver damage and oxidative stress markers were measured. Masson's trichrome, hematoxylin-eosin staining and immunohistochemistry were performed. Zymography assays for MMP-9 and MMP-2 were carried out. TGF-β, CTGF, Col-I, MMP-13, NF-κB, IL-1β, IL-10, Smad7, pSmad3 and pJNK protein levels were determined by western blotting. In addition, α-SMA and Smad3 protein and mRNA levels were studied. Naringenin reversed liver damage, biochemical and oxidative stress marker elevation, and fibrosis and restored normal MMP-9 and MMP-2 activity. The flavonoid also preserved NF-κB, IL-1β, IL-10, TGF-β, CTGF, Col-I, MMP-13 and Smad7 protein levels. Moreover, naringenin decreased JNK activation and Smad3 phosphorylation in the linker region. Finally, α-SMA and Smad3 protein and mRNA levels were reduced by naringenin administration. The results of this study demonstrate that naringenin blocks oxidative stress, inflammation and the TGF-β-Smad3 and JNK-Smad3 pathways, thereby carrying out its antifibrotic effects and making it a good candidate to treat human fibrosis, as previously demonstrated in toxicological and clinical studies.


[Effectiveness of excitation energy migration in the phycobilisomes of red marine macroalgae].
Phycobilisomes (PBS) were isolated from talloms of sea red macroalgae: annual Gloiopeltis furcata from illuminated and shaded shoal and perennial Ahnfeltia tobuchiensis. The spectral changes have shown that R-phycoerythrin, phycocyanin, allophycocyanin, allophycocyanin B were contained in PBS of the algae under study. The efficiency of energy migration to the ultimate acceptor-allophycocyanin B is twice as low in Ahnfeltia tobuchiensis (0.41) as in that of Gloiopeltis furcata, which may be due to the difference in the tallom age. Greater efficiency of excitation energy transfer from phycoerythrin to phycocyanin (0.93), from phycocyanin to allophycocyanin (0.98), from the latter to allophycocyanin B (0.96), as well as from phycoerythrin to allophycocyanin B (0.89) in PBS of shaded G. furcata combined with a relatively higher content of R-phycoerythrin, seems to be the result of algae adaptation to low illumination conditions.


Relation between the heavy chain complementarity region 3 characteristics and rheumatoid factor binding properties.
Among the rheumatoid factors (RFs), monospecific and polyspecific types can be distinguished. However the molecular basis responsible for their different specificity is not well understood. In a previous report, we have shown that the binding of the majority of the polyspecific antibodies is salt-sensitive. No binding to IgG was observed under high ionic strength (0.3-0.5 M NaCl). This salt-sensitivity was only observed for 18% of the monospecific RFs. Here, we have analyzed 14 RFs representing the 3 different groups (6 salt-insensitive monospecific, 4 salt-sensitive monospecific and 4 salt-sensitive polyspecific RFs). By analysis of the amino acid composition and the distribution of polar and non-polar residues of their heavy chain complementarity-determining region 3 (H-CDR3) in relation to mono/polyspecificity, salt-sensitivity and reactivity against human IgG subclasses, we have identified common structural features responsible for their different binding properties. Salt-sensitive RFs (mono as well as polyspecific antibodies) were characterized by long H-CDR3's (15.3+/-2.7) that contained large numbers of hydrophilic residues such as arginine and serine, while salt-insensitive RFs had more hydrophobic H-CDR3's of smaller length (11.3+/-2.4). In addition, for the monospecific RFs, remarkably similar hydrophilicity H-CDR3 profiles were found that were correlated with their specificity for IgG subclasses. These observations confirm the importance of the H-CDR3 for the binding of RFs to IgG. Furthermore, on the basis of their shorter H-CDR3's and their rather unique H-CDR3 hydrophilicity profiles, it is likely that the majority of the monospecific RFs should be considered as a group of RFs that is independent of the polyspecific RF repertoire.


Relationship between Aging-Related Skin Dryness and Aquaporins.
Skin function deteriorates with aging, and the dermal water content decreases. In this study, we have analyzed the mechanism of aging-related skin dryness focusing on aquaporins (AQPs), which are the water channels. Mice aged 3 and 20 months were designated as young and aged mice, respectively, to be used in the experiments. No differences were observed in transepidermal water loss between the young mice and aged mice. However, the dermal water content in aged mice was significantly lower than that in young mice, thus showing skin dryness. The expression of AQP1, AQP3, AQP4, AQP7, and AQP9 was observed in the skin. All the mRNA expression levels of these AQPs were significantly lower in aged mice. For AQP3, which was expressed dominantly in the skin, the protein level was lower in aged mice than in young mice. The results of the study showed that the expression level of AQPs in the skin decreased with aging, suggesting the possibility that this was one of the causes of skin dryness. New targets for the prevention and treatment of aging-related skin dryness are expected to be proposed when the substance that increases the expression of AQP3 is found.


The phage fought the cells, and the phage won: a satellite symposium at the ASV 2023 annual meeting.
This satellite symposium was focused on the molecular arms race between bacteria and their predators, the bacteriophages: who's the friend and who's the foe? This Gem recounts highlights of the talks and presents food for thought and additional reflections on the current state of the field.


Lipopolysaccharide potentiates the effect of hepatocyte growth factor on hepatocyte replication in rats by augmenting AP-1 activity.
The liver regenerates by replication of differentiated hepatocytes after damage or removal of part of the liver. Although several growth factors and signaling pathways are activated during regeneration, it is unclear as to which of these are essential for hepatocyte replication. We show here that low- (1 mg/kg) and high- (10 mg/kg) dose hepatocyte growth factor (HGF) induced replication of 2.1% and 11.1% of hepatocytes in rats, respectively. Lipopolysaccharide (LPS), an inducer of the acute phase response, augmented hepatocyte replication in response to low- and high-dose HGF by 4- and 2-fold, respectively. HGF alone induced moderate levels of c-Jun-N-terminal kinase (JNK) and p44/p42 mitogen-activated protein kinase (MAPK), resulting in moderate levels of AP-1-DNA binding activity. The combination of LPS + HGF increased JNK and AP-1-DNA binding activity more than levels seen with LPS or HGF alone. The activation of Stat3 that was observed after administration of LPS + HGF, but not HGF alone, could contribute to increased transcription of AP-1 components. Because phosphorylation of the c-Jun component of AP-1 by JNK increases its ability to activate transcription, the AP-1 in hepatocytes from animals treated with LPS + HGF may be more active than in rats treated with LPS or HGF alone. LPS may contribute to hepatocyte replication by potentiating the effect of HGF on the activation of both AP-1-DNA binding and transcriptional activity.


Metformin and Its Sulfenamide Prodrugs Inhibit Human Cholinesterase Activity.
The results of epidemiological and pathophysiological studies suggest that type 2 diabetes mellitus (T2DM) may predispose to Alzheimer's disease (AD). The two conditions present similar glucose levels, insulin resistance, and biochemical etiologies such as inflammation and oxidative stress. The diabetic state also contributes to increased acetylcholinesterase (AChE) activity, which is one of the factors leading to neurodegeneration in AD. The aim of this study was to assess in vitro the effects of metformin, phenformin, and metformin sulfenamide prodrugs on the activity of human AChE and butyrylcholinesterase (BuChE) and establish the type of inhibition. Metformin inhibited 50% of the AChE activity at micromolar concentrations (2.35 μmol/mL, mixed type of inhibition) and seemed to be selective towards AChE since it presented low anti-BuChE activity. The tested metformin prodrugs inhibited cholinesterases (ChE) at nanomolar range and thus were more active than metformin or phenformin. The cyclohexyl sulfenamide prodrug demonstrated the highest activity towards both AChE (IC50 = 890 nmol/mL, noncompetitive inhibition) and BuChE (IC50 = 28 nmol/mL, mixed type inhibition), while the octyl sulfenamide prodrug did not present anti-AChE activity, but exhibited mixed inhibition towards BuChE (IC50 = 184 nmol/mL). Therefore, these two bulkier prodrugs were concluded to be the most selective compounds for BuChE over AChE. In conclusion, it was demonstrated that biguanides present a novel class of inhibitors for AChE and BuChE and encourages further studies of these compounds for developing both selective and nonselective inhibitors of ChEs in the future.


Functional reorganization of locomotor kinematic synergies reflects the neuropathology in a mouse model of spinal cord injury.
Spinal cord injury (SCI) disrupts motor commands to modular structures of the spinal cord, limiting the ability to walk. Evidence suggests that these modules are conserved across species from rodent to human and subserve adaptive walking by controlling coordinated joint movements (kinematic synergies). Since SCI causes uncoordinated joint movements of the lower limbs during walking, there may be a disorder of the modular structures that control them. To gain insights into this complex process, we recorded the kinematics of intact and SCI mice when walking on a treadmill and applied principal component analysis to extract kinematic synergies. Most SCI mice walked stably on the treadmill, but their kinematic synergies were generally different from those of intact mice. We classified the kinematic synergies of SCI mice into three groups based on the similarity of the extracted first three synergy components. We found that these three groups had different degrees of spinal cord damage. This suggests that differences in kinematic synergies reflect underlying SCI neuropathology. These results may help guide the development of different rehabilitation approaches and future physiological experiments to understand the mechanisms of motor control and recovery.


Lues maligna in a chronic alcoholic patient.
Lues maligna, which is characterized by noduloulcerative lesions, is a rare form of secondary syphilis. It is mainly seen in either HIV-infected or malnourished patients suffering from a depression in immunity. We presented a chronic alcoholic, HIV negative male patient with noduloulcerative lesions diagnosed as lues maligna based on his skin eruptions, results of serologic tests, and, histopathologic findings. We believe that chronic alcoholism could be the cause of immunosuppression in our case and wanted to emphasize the possibility of an association between lues maligna and chronic alcoholism.


The clinical features and impact of SARS-CoV-2/COVID-19 infection in children with Cystic Fibrosis (CF): A Qatari experience.
SARS-CoV-2 in children with cystic fibrosis (CF) has been reported to cause mild illness without pre-existing severe lung disease. This review described the clinical presentation and course of COVID-19 infection in children with CF in Qatar. The pediatric CF registry of 51 patients in Qatar was reviewed for COVID-19 cases from February 2020 to February 2022. Demographics, vaccination status, symptoms, and course were reviewed. Data were expressed as median, range, frequencies, and percentages. The study included eight patients with CF below 18 years of age infected with COVID-19. The incidence of COVID-19 in children with CF was 15.7%. The median age was 11 (2-18) years. Half of the cohort were males. Seven patients were pancreatic sufficient (I1234V mutation), and one was pancreatic insufficient (3129del4 mutation). The median baseline FEV1 was 91 (78-107%) predicted. None had received CFTR modulators or undergone a lung transplant. Three patients were vaccinated before their infections. Two of them were asymptomatic. Six patients (75%) had a cough and flu-like symptoms. Three patients had a fever. Two patients were hospitalized due to pulmonary exacerbation; both had mild CF-lung disease. None required respiratory support. We report a favorable outcome of COVID-19 infection in children with CF, similar to published international studies. Our findings are attributable to the community-dominant milder CFTR mutation, precautionary measures, and causative COVID-19 strain. More longitudinal data are needed to study these factors as potential protective mechanisms.


[Dissociative phenomena in a sample of outpatients].
The study describes the frequency and the quality of dissociative phenomena and their relationship with axis I disorders and the psychopathological severity in outpatients. The sample (N=383) was subjected to MINI diagnostic interview and self-assessment scales DES and SCL-90. The data were analysed using SPSS. The 11,0% of subjects has a score ≥20 on DES. The 5,2% has no dissociative symptoms. The absorption images is the most frequent dissociative phenomenon, the less common is the dissociation amnesia. A relationship between dissociative phenomena and conditions unemployment, marital separation and single parties and an inverse relationship with age founded. Dissociative phenomena are more frequent in participants who have been diagnosed at least one axis I disorder and their severity is positively correlated with the number of diagnosed diseases and scores to the General Symptomatic Index. Our results point towards the existence of three types of dissociative experiences. The first type, represented by the factor absorption/imaginative involvement, is expressed along a continuum from normal to pathological; a second type, represented by the factor depersonalization/derealization, occurs in a significantly more intense and specific among subjects with axis I disorders; the latest manifestation dissociative, described by the dissociation amnesia, seems to have a predominantly typological feature that qualifies it as an experience not commonly distributed in the general population. The identifying of dissociative symptoms is necessary for the psychopathologic evaluation and to improve the effectiveness of treatment programs.


Dopamine D2/D3 imbalance during migraine attack and allodynia in vivo.
To evaluate in vivo the dynamics of endogenous dopamine (DA) neurotransmission during migraine ictus with allodynia. We examined 8 episodic migraineurs and 8 healthy controls (HC) using PET with [11C]raclopride. The uptake measure of [11C]raclopride, nondisplaceable binding potential (BPND), would increase when there was a reduction in endogenous DA release. The opposite is true for a decrease in [11C]raclopride BPND. Patients were scanned twice: one PET session was during a spontaneous migraine ictus at rest, followed by a sustained thermal pain threshold (STPT) challenge on the trigeminal region, eliciting an allodynia experience; another was during interictal phase. Striatal BPND of [11C]raclopride in migraineurs did not differ from HC. We found a significant increase in [11C]raclopride BPND in the striatum region of migraineurs during both headache attack and allodynia relative to interictal phase. However, when compared to the migraine attack at rest, migraineurs during the STPT challenge had a significant sudden reduction in [11C]raclopride BPND in the insula. Such directional change was also observed in the caudate of HC relative to the interictal phase during challenge. Furthermore, ictal changes in [11C]raclopride BPND in migraineurs at rest were positively correlated with the chronicity of migraine attacks, and negatively correlated with the frequency during challenge. Our findings demonstrate that there is an imbalanced uptake of [11C]raclopride during the headache attack and ictal allodynia, which indicates reduction and fluctuation in ictal endogenous DA release in migraineurs. Moreover, the longer the history and recurrence of migraine attacks, the lower the ictal endogenous DA release.


Laboratory and epidemiologic experience with methicillin-resistant Staphylococcus aureus in the USA.
Methicillin-resistant Staphylococcus aureus (MRSA) was a rare occurrence in US hospitals until the mid-1970s. Since that time outbreaks of MRSA infection have been reported in both large and small hospitals, in rehabilitation facilities, and in nursing homes. Transmission has been documented not only between hospitals, but between long-term care facilities and hospitals, and between the community and hospitals. Patient-to-patient spread within hospitals appears to result from transient colonization of the hands of health care workers, with colonized or infected patients being the intrahospital reservoir for the organisms. The best opportunity for control of outbreaks of MRSA infection within hospitals may depend on the rapid recognition of newly admitted patients who are colonized or infected. The laboratory plays a crucial role in this by providing prompt and accurate information indicating the presence of MRSA. Susceptibility test methods found to be most reliable for detecting MRSA in the USA include the broth microdilution MIC determination (performed in salt-supplemented broth), the Bauer-Kirby test with slight modification, or oxacillin-salt agar screening plates.


Effects of coupled homogeneous chemical reactions on the response of large-amplitude AC voltammetry: extraction of kinetic and mechanistic information by Fourier transform analysis of higher harmonic data.
Large-amplitude ac voltammograms contain a wealth of kinetic information concerning electrode processes and can provide unique mechanistic insights compared to other techniques. This paper describes the effects homogeneous chemical processes have on ac voltammetry in general and provides experimental examples using two well-known chemical systems: one simple and one complex. Oxidation of [Cp*Fe(CO)(2)](2) (Cp* = η(5)-pentamethylcyclopentadienyl) in noncoordinating media is a reversible one-electron process; in the presence of nucleophiles, however, the resulting ligand-induced disproportionation changes the process to a multiple step regeneration. The chemical kinetic parameters of the regeneration mechanism were discerned via analysis of the third and higher harmonics of Fourier-transformed ac voltammetry data. Comparison of experimental data to digital simulations provides clear evidence that the reaction proceeds via a rapid pre-equilibrium between the electrogenerated monocation and the coordinating ligand; simultaneous fitting of the first nine harmonics indicates that k(f) = 7500 M(-1) s(-1) and k(r) = 100 s(-1), and that the unimolecular decomposition of the corresponding intermediate occurs with a rate constant of 2.2 s(-1). The rapid cis(+) → trans(+) isomerization of the electrogenerated cis-[W(CO)(2)(dpe)(2)](+), where dpe = 1,2-diphenylphosphinoethane, was examined to illustrate the effects of a simpler EC mechanism on the higher harmonics; a rate constant of 280 s(-1) was determined. These results not only shed new light on the chemistry of these systems, but provide a clear demonstration that the higher harmonics of ac voltammetry provide mechanistic insights into coupled homogeneous processes far more detailed than those that are readily accessible with dc techniques.


Medical Assistance in Dying (MAiD) in Canada: A Critical Analysis of the Exclusion of Vulnerable Populations.
Canadian medical assistance in dying (MAiD) legislation was introduced in 2016. Although Bill C-14 attempted to balance patient autonomy and the protection of the vulnerable, recent court challenges suggest that an ideal balance has not been achieved. Numerous advocacy initiatives as well as a parliamentary review currently focus on three specific populations: mature minors, patients requesting MAiD via an advance directive and patients with a mental illness as the sole underlying condition. This article approaches these issues from an ethical and legal lens. We first outline a policy review on existing MAiD legislation in 11 jurisdictions. We then use the Oakes test (a critical assessment tool in the Carter v Canada case) to determine whether the restrictions on the three above-mentioned groups are consistent with the Canadian Charter of Rights and Freedoms. Finally, we consult our literature review to propose reasonable solutions that would be more consistent with the Charter.


Anchoring Drugs to a Zinc(II) Coordination Polymer Network: Exploiting Structural Rationale toward the Design of Metallogels for Drug-Delivery Applications.
A new series of coordination polymers (CPs) were synthesized and crystallographically characterized by single-crystal X-ray diffraction with the aim of developing drug-delivery systems via metallogel formation. Structural rationale was employed to design such coordination-polymer-based metallogels. As many as nine CPs were obtained by reacting two bis(pyridyl)urea ligands, namely, 1,3-dipyridin-3-ylurea (3U) and 1,3-dipyridin-4-ylurea (4U), and the sodium salt of various nonsteroidal antiinflammatory drugs, namely, ibuprofen (IBU), naproxen (NAP), fenoprofen (FEN), diclofenac (DIC), meclofenamic acid (MEC), mefenamic acid (MEF), and Zn(NO3)2. All of the CPs displayed 1D polymeric chains that were self-assembled through various hydrogen-bonding interactions involving the urea N-H and carboxylate O atoms and, in a few cases, lattice-occluded water molecules. The reacting components of the CPs produced five metallogels in dimethyl sulfoxide/water. The gels were characterized by rheology and transmission electron microscopy. Three selected metallogelators, namely, 3UMEFg, 3UNAPg, and 3UMECg, showed in vitro anticancer, cell imaging, and multidrug delivery for antibacterial applications, respectively. The shear-thinning properties of 3UMECg (rheoreversibility and injectability) make it a potential candidate for plausible topical application.


Microalga propels along vorticity direction in a shear flow.
Using high-speed digital holographic microscopy and microfluidics, we discover that, when encountering fluid flow shear above a threshold, unicellular green alga Dunaliella primolecta migrates unambiguously in the cross-stream direction that is normal to the plane of shear and coincides with the local fluid flow vorticity. The flow shear drives motile microalgae to collectively migrate in a thin two-dimensional horizontal plane and consequently alters the spatial distribution of microalgal cells within a given suspension. This shear-induced algal migration differs substantially from periodic rotational motion of passive ellipsoids, known as Jeffery orbits, as well as gyrotaxis by bottom-heavy swimming microalgae in a shear flow due to the subtle interplay between torques generated by gravity and viscous shear. Our findings could facilitate mechanistic solutions for modeling planktonic thin layers and sustainable cultivation of microalgae for human nutrition and bioenergy feedstock.


Current steering and current focusing in cochlear implants: comparison of monopolar, tripolar, and virtual channel electrode configurations.
To compare the effects of Monopole (Mono), Tripole (Tri), and "Virtual channel" (Vchan) electrode configurations on spectral resolution and speech perception in a crossover design. Nine experienced adults who received an Advanced Bionics CII/90K cochlear implant participated in a crossover design using three experimental strategies for 2 wk each. Three strategies were compared: (1) Mono; (2) Tri with current partly returning to adjacent electrodes and partly (25 or 75%) to the extracochlear reference; and (3) a monopolar "Vchan" strategy creating seven intermediate channels between two contacts. Each strategy was a variant of the standard "HiRes" processing strategy using 14 channels and 1105 pulses/sec/ channel, and a pulse duration of 32 microsec/phase. Spectral resolution was measured using broadband noise with a sinusoidally rippled spectral envelope with peaks evenly spaced on a logarithmic frequency scale. Speech perception was measured for monosyllables in quiet and in steady-state and fluctuating noises. Subjective comments on music experience and preferences in everyday use were assessed through questionnaires. Thresholds and most comfortable levels with Mono and Vchan were both significantly lower than levels with Tri. Spectral resolution was significantly higher with Tri than with Mono; spectral resolution with Vchan did not differ significantly from the other configurations. Moderate but significant correlations between word recognition and spectral resolution were found in speech in quiet and fluctuating noise. For speech in quiet, word recognition was best with Mono and worst with Vchan; Tri did not significantly differ from the other configurations. Pooled across the noise conditions, word recognition was best with Tri and worst with Vchan (Mono did not significantly differ from the other configurations). These differences were small and insufficient to result in a clear increase in performance across subjects if the result from the best configuration per subject was compared with the result from Mono. Across all subjects, music appreciation and satisfaction in everyday use did not clearly differ between configurations. (1) Although spectral resolution was improved with the tripolar configuration, differences in speech performance were too small in this limited group of subjects to justify clinical introduction. (2) Overall spectral resolution remained extremely poor compared with normal hearing; it remains to be seen whether further manipulations of the electrical field will be more effective.


[Perinatal mortality and diabetes mellitus].
A comparative study of the pattern of perinatal mortality from diabetes mellitus and in the control group with due account of structural changes in placentas of women suffering from diabetes mellitus was performed. The results allowed one to evaluate the influence of the "risk factors" of maternal diabetes and complications of pregnancy on the rate of perinatal mortality and to show the main causes leading to stillbirths and neonatal deaths with diabetes embryo- and fetopathies.


Matrix metalloproteinases in stem cell regulation and cancer.
Since Gross and Lapiere firstly discovered matrix metalloproteinases (MMPs) as important collagenolytic enzymes during amphibian tadpole morphogenesis in 1962, this intriguing family of extracellular proteinases has been implicated in various processes of developmental biology. However, the pathogenic roles of MMPs in human diseases such as cancer have also garnered widespread attention. The most straightforward explanation for their role in cancer is that MMPs, through extracellular matrix degradation, pave the way for tumor cell invasion and metastasis. While this notion may be true for many circumstances, we now know that, depending on the context, MMPs may employ additional modes of functionality. Here, we will give an update on the function of MMPs in development and cancer, which may directly regulate signaling pathways that control tissue homeostasis and may even work in a non-proteolytic manner. These novel findings about the functionality of MMPs have important implications for MMP inhibitor design and may allow us to revisit MMPs as drug targets in the context of cancer and other diseases.


Quashing ownership: health reform law bans new physician-owned hospitals.
With nearly 70 Texas hospitals with some type of physician investment, the state is a national leader in the physician-owned hospital industry. And, members of that industry say it has been good for patients. But the health system reform law Congress passed earlier this year slams the door on new physician-owned hospitals by prohibiting them from obtaining a Medicare provider number.


Virus-induced silencing of a plant cellulose synthase gene.
Specific cDNA fragments corresponding to putative cellulose synthase genes (CesA) were inserted into potato virus X vectors for functional analysis in Nicotiana benthamiana by using virus-induced gene silencing. Plants infected with one group of cDNAs had much shorter internode lengths, small leaves, and a "dwarf" phenotype. Consistent with a loss of cell wall cellulose, abnormally large and in many cases spherical cells ballooned from the undersurfaces of leaves, particularly in regions adjacent to vascular tissues. Linkage analyses of wall polysaccharides prepared from infected leaves revealed a 25% decrease in cellulose content. Transcript levels for at least one member of the CesA cellulose synthase gene family were lower in infected plants. The decrease in cellulose content in cell walls was offset by an increase in homogalacturonan, in which the degree of esterification of carboxyl groups decreased from approximately 50 to approximately 33%. The results suggest that feedback loops interconnect the cellular machinery controlling cellulose and pectin biosynthesis. On the basis of the phenotypic features of the infected plants, changes in wall composition, and the reduced abundance of CesA mRNA, we concluded that the cDNA fragments silenced one or more cellulose synthase genes.


Acute orbital pseudotumors: classification and CT features.
Acute orbital pseudotumors are inflammatory lesions of unknown etiology that may affect part or, less often, all of the tissue within the orbit. A retrospective computed tomographic (CT) study of 16 patients demonstrated that these lesions occur in one of five specific anatomic patterns: anterior, posterior, diffuse, lacrimal, or myositic. The most common location was lacrimal followed by anterior pseudotumors. Posterior, most common location was lacrimal followed by anterior pseudotumors. Posterior, diffuse, and myositic pseudotumors were equally frequent. Localization on the basis of clinical features correlated with the CT localization. Illustrative cases of each of the five types are included. The role of CT in evaluating the therapeutic response is discussed.


Utilization trends in inpatient endoscopic retrograde cholangiopancreatography (ERCP): A cross-sectional US experience.
Study aims The goal of our study was to determine the current trends for inpatient utilization for endoscopic retrograde cholangiopancreatography (ERCP) and its economic impact in the United States between 2002 and 2013. Patients and methods A Nationwide Inpatient Sample from 2002 through 2013 was examined. We identified ERCPs using International Classification of Diseases (ICD-9) codes; Procedure codes 51.10, 51.11, 52.13, 51.14, 51.15, 52.14 and 52.92 for diagnostic and 51.84, 51.86, 52.97 were studied. Rate of inpatient ERCP was calculated. The trends for therapeutic ERCPs were compared to the diagnostic ones. We analyzed patient and hospital characteristics, length of hospital stay, and cost of care after adjusting for weighted samples. We used the Cochran-Armitage test for categorical variables and linear regression for continuous variables. Results A total of 411,409 ERCPs were performed from 2002 to 2013. The mean age was 59 ± 19 years; 61 % were female and 57 % were white. The total numbers of ERCPS increased by 12 % from 2002 to 2011, which was followed by a 10 % decrease in the number of ERCPs between 2011 and 2013. There was a significant increase in therapeutic ERCPs by 37 %, and a decrease in diagnostic ERCPs by 57 % from 2002 to 2013. Mean length of stay was 7 days (SE = 0.01) and the mean cost of hospitalization was $20,022 (SE = 41). Conclusions Our large cross-sectional study shows a significant shift in ERCPs towards therapeutic indications and a decline in its conventional diagnostic utility. Overall there has been a reduction in inpatient ERCPs.


Chronic arthritis in adolescence.
Musculoskeletal complaints, and joint pain in particular, are common symptoms among adolescents presenting to primary care providers. In this article, the distinction between arthralgia and arthritis is described, and important inflammatory arthropathies seen in teenagers are addressed. The current nomenclature of juvenile idiopathic arthritis is used to address each of the major clinical entities that account for chronic arthritis in teens, including oligoarthritis, polyarthritis, systemic arthritis, psoriatic arthritis, and spondyloarthropathy. Diagnostic criteria, important comorbidities, and principles of management are summarized with identification of antiinflammatory, immunosuppressive, and cytokine-specific biological agents and their relative uses. Other categories of chronic arthritis are also discussed, including infection-associated reactive arthritis, Lyme disease, joint disease of inflammatory bowel disease, as well as chronic arthritis as a dimension of other autoimmune diseases. In addition to the biomedical dimension of these disorders, the psychological impact and developmental context of persistent pain and musculoskeletal abnormality in adolescents are commented on.


In Vitro Combination of Isavuconazole with Echinocandins against Azole-Susceptible and -Resistant Aspergillus spp.
In vitro combinations of isavuconazole with echinocandins were evaluated against 30 Aspergillus strains with a two-dimensional checkerboard microdilution method and an agar-based diffusion method. With the checkerboard method, the three combinations showed indifferent interactions for all strains. With the agar-based method, indifferent interactions were found for all strains for isavuconazole-micafungin and isavuconazole-anidulafungin. For the isavuconazole-caspofungin combination, indifference was found in 24/30 strains, synergism in 4/30 strains, and antagonism in 2/30 strains.


Autism spectrum disorder and air pollution: A systematic review and meta-analysis.
Despite the widely-known effects of air pollution, pollutants exposure surrounding pregnancy and the risk for autism spectrum disorder (ASD) in newborns remains controversial. The purpose of our study was to carry out a systematic review and meta-analyses of the risk of ASD in newborns following air pollution exposure during the perinatal period (preconception to second year of life). The PubMed, Cochrane Library, Embase and ScienceDirect databases were searched for articles, published up to July 2020, with the keywords "air pollution" and "autism". Three models were used for each meta-analysis: a global model based on all risks listed in included articles, a pessimistic model based on less favorable data only, and an optimistic model based on the most favorable data only. 28 studies corresponding to a total of 758 997 newborns were included (47190 ASD and 703980 controls). Maternal exposure to all pollutants was associated with an increased risk of ASD in newborns by 3.9% using the global model and by 12.3% using the optimistic model, while the pessimistic model found no change. Each increase of 5 μg/m3 in particulate matter <2.5 μm (PM2.5) was associated with an increased risk of ASD in newborns, regardless of the model used (global +7%, pessimistic +5%, optimistic +15%). This risk increased during preconception (global +17%), during pregnancy (global +5%, and optimistic +16%), and during the postnatal period (global +11% and optimistic +16%). Evidence levels were poor for other pollutants (PM10, NOx, O3, metals, solvents, styrene, PAHs, pesticides). PM2.5 was associated with a greater risk than PM10 (coefficient 0.20, 95CI -0.02 to 0.42), NOx (0.29, 0.08 to 0.50) or solvents (0.24, 0.04 to 0.44). All models revealed that exposure to pollutants, notably PM2.5 during pregnancy, was associated with an increased risk of ASD in newborns. Pregnancy and postnatal periods seem to be the most at-risk periods.


Psychological Pathways Linking Public Trust During the Coronavirus Pandemic to Mental and Physical Well-being.
The well-being of the public during the 2019 coronavirus (COVID-19) pandemic is deeply rooted in institutional trust in the government's risk communication effort. The objective of this study was to examine the psychological pathway through which public trust in the government is associated with mental and physical well-being. We collected cross-sectional data from 501 participants aged ≥18 years using an online panel. Public trust in the government was assessed as our exposure variable. We screened for psychological distress by combining the Patient Health Questionnaire and the General Anxiety Disorder scale. Physical well-being was examined using self-rated health. We further assessed the roles of risk perceptions. The author conducted a one-way analysis of variance (ANOVA), Pearson's correlations, multivariable regressions, and mediation analyses (using the Preachers and Hayes' approach). Participants were 55.29% female, 67.86% Caucasian/white with a mean age of 32.44 ± 11.94 years. Public trust in the government regarding COVID-19 was negatively correlated with psychological distress (r = -0.20; p < 0.001) and positively associated with physical well-being (r = 0.13; p < 0.001). After adjusting for sociodemographic and socioeconomic factors, public trust remained negatively associated with psychological distress (β = -0.19; 95% confidence intervals, [CI] -0.30, -0.09) and positively associated with physical well-being (β = 0.26; 95% CI [0.16, -0.37]). Perceived self-efficacy to practice COVID-19 protective behavior partially mediated the relationship between public trust and psychological distress (13.07%); and physical well-being (28.02%). Perceived self-efficacy to protect self against COVID-19 infection can serve as a psychological pathway through which public trust may be associated with mental and physical health.


Barriers to and facilitators of the provision of a youth-friendly health services programme in rural South Africa.
Youth-friendly health services are a key strategy for improving young people's health. This is the first study investigating provision of the Youth Friendly Services programme in South Africa since the national Department of Health took over its management in 2006. In a rural area of South Africa, we aimed to describe the characteristics of the publicly-funded primary healthcare facilities, investigate the proportion of facilities that provided the Youth Friendly Services programme and examine healthcare workers' perceived barriers to and facilitators of the provision of youth-friendly health services. Semi-structured interviews were conducted with nurses of all eight publicly-funded primary healthcare facilities in Agincourt sub-district, Mpumalanga Province, South Africa. Thematic analysis of interview transcripts was conducted and data saturation was reached. Participants largely felt that the Youth Friendly Services programme was not implemented in their primary healthcare facilities, with the exception of one clinic. Barriers to provision reported by nurses were: lack of youth-friendly training among staff and lack of a dedicated space for young people. Four of the eight facilities did not appear to uphold the right of young people aged 12 years and older to access healthcare independently. Breaches in young people's confidentiality to parents were reported. Participants reported that provision of the Youth Friendly Services programme is limited in this sub-district, and below the Department of Health's target that 70% of primary healthcare facilities should provide these services. Whilst a dedicated space for young people is unlikely to be feasible or necessary, all facilities have the potential to be youth-friendly in terms of staff attitudes and actions. Training and on-going support should be provided to facilitate this; the importance of such training is emphasised by staff. More than one member of staff per facility should be trained to allow for staff turnover. As one of a few countrywide, government-run youth-friendly clinic programmes in a low or middle-income country, these results may be of interest to programme managers and policy makers in such settings.


The online 18O/16O analysis: development and application.
Oxygen is a globally important element, in inorganic compounds it is involved in key structural compounds of the earth, and it is providing functional groups for most organic compounds. Oxygen isotope ratio analyses on these compounds provide information on the oxygen sources and (formation) reactions in which the compound was involved. Therefore generally applicable analytical methods for the delta18O determination are highly desirable. After a description of online high temperature "carbon reduction" methods for the conversion of oxygen in the compounds mentioned into CO and discussion of problems involved, especially in analysis of inorganic substances like carbonates and silicates, selected examples for the application of these carbon reduction methods will be presented. The well-known correlation of delta18O values of cellulose (in tree rings) to that of (leaf) water is used since the 1970's as climate indicator. The observed enrichment in 18O in cellulose by about 27% in comparison to leaf water is attributed to an oxygen equilibrium isotope effect between carbonyl groups and water. But not all carbohydrates show this "general"18O enrichment relative to water. By means of a recently published model a non-statistical oxygen isotope distribution in carbohydrates is postulated. Oxygen isotope discrimination has been recognized long ago as an important principle of authenticity evaluation in food and beverages. Though many basic mechanisms of isotope discrimination in nature are known, the corresponding application of data is often based only on empirical observations in this field. The fact that oxygen in natural organic plant material is derived from three sources (CO2, H2O, O2) with distinct differences in and that their incorporation by different reactions implies oxygen isotope effects of different sizes, is therefore of special importance, and it is attempted by means of individual isotopic increments of functional groups to predict global delta18O values of natural and nature-identical compounds. Vice versa delta18O values can also give hints on the elucidation of biosynthetic pathways.


Characterization of adipose tissue-derived cells isolated with the Celution system.
The therapeutic potential of using stem cells is tremendous. Mesenchymal stromal cells (MSC) have now been isolated in various tissues including bone marrow (BM), muscle, skin and adipose tissue. Among them, adipose tissue could be one of the most suitable cell sources for cell therapy, because of its easy accessibility, minimal morbidity and abundance of stem cells. The large numbers of stem cells in adipose tissue means that clinically relevant stem cell numbers could be extracted from the tissue, potentially eliminating the need for in vitro expansion. To utilize these characteristics of adipose tissue fully, Cytori Therapeutics Inc. has developed a closed system called Celution to isolate and concentrate stem cells and regenerative cells automatically from adipose tissue. Adipose tissue-derived cells were isolated using the Celution system. The output from the Celution was characterized using multicolor FACS analysis with CD31, CD34, CD45, CD90, CD105 and CD146. The multidifferentiation potential of the cells was analyzed using adipogenic and osteogenic media. Our results showed that cells from the Celution are composed of heterogeneous cell populations including adipose-derived stem cells (ASC) (CD31- CD34+ CD45- CD90+ CD105- CD146-), endothelial (progenitor) cells (CD31+ CD34+ CD45- CD90+ CD105- CD146+) and vascular smooth muscle cells (CD31- CD34+ CD45- CD90+ CD105- CD146+). We also confirmed the output contains cells able to differentiate into adipogenic and osteogenic phenotypes. Our results show that cells isolated with the Celution and manually are equivalent. Cells from adipose tissue can be processed by Celution within the time frame of a single surgical procedure. This system could provide a 'real-time' treatment setting that is cost-effective and safe.


Probing the self-ionization of liquid water with ab initio deep potential molecular dynamics.
The chemical equilibrium between self-ionized and molecular water dictates the acid-base chemistry in aqueous solutions, yet understanding the microscopic mechanisms of water self-ionization remains experimentally and computationally challenging. Herein, Density Functional Theory (DFT)-based deep neural network (DNN) potentials are combined with enhanced sampling techniques and a global acid-base collective variable to perform extensive atomistic simulations of water self-ionization for model systems of increasing size. The explicit inclusion of long-range electrostatic interactions in the DNN potential is found to be crucial to accurately reproduce the DFT free energy profile of solvated water ion pairs in small (64 and 128 H2O) cells. The reversible work to separate the hydroxide and hydronium to a distance [Formula: see text] is found to converge for simulation cells containing more than 500 H2O, and a distance of [Formula: see text] 8 Å is the threshold beyond which the work to further separate the two ions becomes approximately zero. The slow convergence of the potential of mean force with system size is related to a restructuring of water and an increase of the local order around the water ions. Calculation of the dissociation equilibrium constant illustrates the key role of long-range electrostatics and entropic effects in the water autoionization process.


L-delta-(alpha-Aminoadipoyl)-L-cysteine-D-valine synthetase: production of dipeptides containing valine residue at its C-terminus.
L-delta-(alpha-Aminoadipoyl)-L-cysteine-D-valine synthetase (ACVS) has been recently studied as a model enzyme for peptide synthetases. It was found that in the absence of alpha-aminoadipic acid but in the presence of several cysteine analogues it was incorporated into several analogue dipeptides upon incubation of the potential cysteine analogues with ACVS. [(14)C]Cysteine was incorporated into the[(14)C]cysteinyl-valine analogue dipeptides. Notably, [(14)C]valine incorporation in the presence of N-acylated cysteine analogues was observed. The alpha-aminoadipic acid activation site is influential, inhibitory or promotive, on the production of these putative dipeptide products. The production of dipeptide analogues, containing valine or analogues at the C-terminus, leads to the speculation that the biosynthetic direction of ACV could be from the C-terminus to the N-terminus.


Assessment of the cytotoxic, genotoxic, and apoptotic potential of flurbiprofen in HeLa and HepG2 cell lines.
In the literature, the anticancer potential of flurbiprofen isn't fully understood. In this study, the cytotoxic, genotoxic, and apoptotic effects of flurbiprofen were evaluated in human cervical and liver cancer cells. Cytotoxicity was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and it was observed that cytotoxicity increased in a concentration- and time-dependent manner. Genotoxicity was determined using alkaline Comet assay. DNA damage increased in a concentration-dependent manner. Early apoptosis was evaluated using real-time polymerase chain reaction, and it was found that apoptotic gene levels increased while antiapoptotic gene levels decreased. Late apoptosis and cell cycle analyzes were determined using flow cytometry. No evidence of late apoptosis was observed, and no significant arrest was found in the cell cycle. In conclusion, it seems that flurbiprofen has a cytotoxic, genotoxic, and apoptotic effects in both human cancer cell lines. Moreover, the findings indicate that flurbiprofen is effective at the gene level and induces apoptosis with an intracellular pathway.


Ovarian cancer screening-ultrasound; impact on ovarian cancer mortality.
Although ovarian cancer (OC) is the most lethal of all female malignancies, debate still exists concerning the benefits and harms of the screening programs and their impact on long-term survival and mortality from the disease. The most widely tested screening strategies have focused on transvaginal ultrasound (TVU) and on algorithms that measure serum levels or interval changes of cancer antigen-125 (CA-125) either individually or in combination. Transvaginal ultrasound can identify size and morphology changes of the ovary that may signal a developing malignancy; yet, it is still accused of having a low specificity. There is preliminary evidence that screening can improve survival, but the impact of screening on mortality from OC is still unclear and warrants further validation. In spite of having many published prospective studies, up to-date, none have been able to demonstrate conclusively a reduction in mortality from OC both in the screened general or high-risk population. Data from the US Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial has not shown survival or mortality benefits in the general population. Most prospective trials have reported a decrease in stage at detection (with the exception of the PLCO trial), thereby allowing treatment to be initiated when the disease is most curable. Research is in progress to develop new diagnostic tests and novel biomarkers, which when used in combination can increase the accuracy and outcomes of screening. In this review article, we will discuss the debate provoked on OC screening programs and the impact of using ultrasound on the reduction of OC-related mortality.


Feature Selection Based on High Dimensional Model Representation for Hyperspectral Images.
In hyperspectral image analysis, the classification task has generally been addressed jointly with dimensionality reduction due to both the high correlation between the spectral features and the noise present in spectral bands, which might significantly degrade classification performance. In supervised classification, limited training instances in proportion with the number of spectral features have negative impacts on the classification accuracy, which is known as Hughes effects or curse of dimensionality in the literature. In this paper, we focus on dimensionality reduction problem, and propose a novel feature-selection algorithm, which is based on the method called high dimensional model representation. The proposed algorithm is tested on some toy examples and hyperspectral datasets in comparison with conventional feature-selection algorithms in terms of classification accuracy, stability of the selected features and computational time. The results show that the proposed approach provides both high classification accuracy and robust features with a satisfactory computational time.


Drug poisoning deaths in Sweden show a predominance of ethanol in mono-intoxications, adverse drug-alcohol interactions and poly-drug use.
Over a 10-year period (1998-2007) all deaths in Sweden classified by forensic pathologists as fatal drug poisonings (N = 6894) were retrieved from a toxicology database (TOXBASE) belonging to the National Board of Forensic Medicine. The deaths were further classified as suicides N = 2288 (33%), undetermined N = 2260 (33%) and accidental N = 2346 (34%). The average age (± SD) of all victims was 49.1 ± 15.9 years and men 47.4 ± 15.6 years were 5-year younger than women 52.2 ± 15.8 years (p < 0.01). Most of the deceased (78%) were poly-drug users although a single drug (mono-intoxications) was found in 22% of all poisoning deaths (p < 0.001). The number of drugs in blood samples varied from 1 to 12 with a median of 3-4 per case. Mono-intoxication deaths were mostly ethanol-related (N = 976) and the mean and median blood-alcohol concentration (BAC) was 3.06 g/L and 3.10 g/L, respectively. The BAC decreased as the number of additional drugs in blood increased from 2.15 g/L with one drug to 1.25 g/L with 6 or more drugs. The mean (median) concentrations of non-alcohol drugs in mono-intoxication deaths were morphine (N = 93) 0.5mg/L (0.2mg/L), amphetamine (N = 39) 2.0mg/L (1.2mg/L), dextropropoxyphene (N = 33) 3.9 mg/L (2.9 mg/L), dihydro-propiomazine (N = 32) 1.6 mg/L (1.0mg/L) and 7-amino-flunitrazepam (N = 28), 0.4 mg/L (0.3mg/L). Elevated blood morphine in these poisoning deaths mostly reflected abuse of heroin as verified by finding 6-monoacetyl morphine (6-MAM) in the blood samples. When investigating drug poisoning deaths a comprehensive toxicological analysis is essential although the results do not reveal the extent of prior exposure to drugs or the development of pharmacological tolerance. The concentrations of drugs determined in post-mortem blood are one element in the case. The autopsy report, the police investigation, the findings at the scene and eye-witness statements should all be carefully considered when the cause and manner of death are determined.


The relationship between climate change and malaria in South-East Asia: A systematic review of the evidence.
Background: Climatic change is an inescapable fact that implies alterations in seasons where weather occurrences have their schedules shift from the regular and magnitudes intensify to more extreme variations over a multi-year period. Southeast Asia is one of the many regions experiencing changes in climate and concurrently still has endemicities of malaria. Given that previous studies have suggested the influence of climate on malaria's vector the Anopheles mosquitoes and parasite the Plasmodium group, this study was conducted to review the evidence of associations made between malaria cases and climatic variables in Southeast Asia throughout a multi-year period. Methods: Our systematic literature review was informed by the PRISMA guidelines and registered in PROSPERO: CRD42022301826 on 5 th February 2022. We searched for original articles in English and Indonesian that focused on the associations between climatic variables and malaria cases. Results: The initial identification stage resulted in 535 records of possible relevance and after abstract screening and eligibility assessment we included 19 research articles for the systematic review. Based on the reviewed articles, changing temperatures, precipitation, humidity and windspeed were considered for statistical association across a multi-year period and are correlated with malaria cases in various regions throughout Southeast Asia. Conclusions: According to the review of evidence, climatic variables that exhibited a statistically significant correlation with malaria cases include temperatures, precipitation, and humidity. The strength of each climatic variable varies across studies. Our systematic review of the limited evidence indicates that further research for the Southeast Asia region remains to be explored.


Lipoprotein lipase and uptake of chylomicron triacylglycerol and cholesterol by perfused rat mammary tissue.
The role of lipoprotein lipase in the uptake of chylomicron triacylglycerol and cholesterol from blood was studied in perfused inguinal-abdominal mammary tissue of rats lactating 10-15 days. Lipoprotein lipase activity in the tissue was reduced, from 0.47 to 0.10 units/g, by removing the anterior pituitary gland from lactating rats 2 days before the experiment. Perfused mammary tissue of normal lactating rats took up 12% of the chylomicron triacylglycerol infused, whereas the tissue of hypophysectomized lactating rats took up less than 1%. About two-thirds of the triacylglycerol taken up was retained as glyceride, and the rest was hydrolyzed and released to the perfusing fluid as fatty acids and glycerol. Autoradiographic studies of perfused tissues of normal lactating rats showed that both the acyl and glycerol moieties derived from chylomicron triacylglycerol were incorporated into milk lipid droplets. Perfused mammary tissue of normal lactating rats also took up 15% of the chylomicron cholesterol infused, whereas the tissue of hypophysectomized lactating rats took up less than 1%. The findings demonstrate that chylomicron cholesterol is taken up with triacylglycerol by lactating mammary tissue, and that uptake of both lipids is markedly suppressed when lipoprotein lipase activity is low, as in tissue of hypophysectomized rats. It is proposed that uptake of triacylglycerol from chylomicrons by mammary tissue requires the action of lipoprotein lipase, while uptake of cholesterol is dependent on reduction of the triacylglycerol core, resulting from action of the enzyme on the core and uptake of lipolytic products by the tissue.


Toward improved myocardial maturity in an organ-on-chip platform with immature cardiac myocytes.
In vitro studies of cardiac physiology and drug response have traditionally been performed on individual isolated cardiomyocytes or isotropic monolayers of cells that may not mimic desired physiological traits of the laminar adult myocardium. Recent studies have reported a number of advances to Heart-on-a-Chip platforms for the fabrication of more sophisticated engineered myocardium, but cardiomyocyte immaturity remains a challenge. In the anisotropic musculature of the heart, interactions between cardiac myocytes, the extracellular matrix (ECM), and neighboring cells give rise to changes in cell shape and tissue architecture that have been implicated in both development and disease. We hypothesized that engineered myocardium fabricated from cardiac myocytes cultured in vitro could mimic the physiological characteristics and gene expression profile of adult heart muscle. To test this hypothesis, we fabricated engineered myocardium comprised of neonatal rat ventricular myocytes with laminar architectures reminiscent of that observed in the mature heart and compared their sarcomere organization, contractile performance characteristics, and cardiac gene expression profile to that of isolated adult rat ventricular muscle strips. We found that anisotropic engineered myocardium demonstrated a similar degree of global sarcomere alignment, contractile stress output, and inotropic concentration-response to the β-adrenergic agonist isoproterenol. Moreover, the anisotropic engineered myocardium exhibited comparable myofibril related gene expression to muscle strips isolated from adult rat ventricular tissue. These results suggest that tissue architecture serves an important developmental cue for building in vitro model systems of the myocardium that could potentially recapitulate the physiological characteristics of the adult heart. Impact statement With the recent focus on developing in vitro Organ-on-Chip platforms that recapitulate tissue and organ-level physiology using immature cells derived from stem cell sources, there is a strong need to assess the ability of these engineered tissues to adopt a mature phenotype. In the present study, we compared and contrasted engineered tissues fabricated from neonatal rat ventricular myocytes in a Heart-on-a-Chip platform to ventricular muscle strips isolated from adult rats. The results of this study support the notion that engineered tissues fabricated from immature cells have the potential to mimic mature tissues in an Organ-on-Chip platform.


Pulsed-field gel electrophoresis diversity of human and bovine clinical Salmonella isolates.
Pulsed-field gel electrophoresis (PFGE) characterization of 335 temporally and spatially matched clinical, bovine, and human Salmonella enterica subsp. enterica isolates revealed 167 XbaI PFGE patterns. These isolates were previously classified into 51 serotypes and 73 sequence types, as determined by multilocus sequence typing. Discriminatory power of PFGE (Simpson's index, D = 0.991) was considerably higher than that of multilocus sequence typing (D = 0.920) or serotyping (D = 0.913). Although 128 PFGE types each only represented a single isolate, 8 PFGE types represented >4 isolates, including (i) three serotype Enteritidis and Heidelberg patterns that were only identified among human isolates, (ii) two PFGE patterns (each representing serotypes Bardo and Newport) that were significantly more common among bovine isolates as compared with human isolates; (iii) two PFGE types that each includes two serotypes (4,5,12:i:- and Typhimurium; Thompson and 1,7:-:1,5); and (iv) one PFGE type that includes eight Typhimurium isolates from humans and cattle. Characterization of isolates collected over multiple farm visits indicated that given specific PFGE types persisted over time on 11 farms. On an additional seven farms, isolates with a given sequence type represented multiple PFGE type, which typically only differed by <3 bands, suggesting PFGE type diversification during strain persistence. Sixteen PFGE types were isolated from 2 or more farms, including two widely distributed serotype Newport-associated PFGE types each found on 10 farms. In six instances two or three human isolates collected in the same county in the same or consecutive months represented the same subtypes, suggesting small human case clusters. PFGE-based characterization and surveillance of human and animal isolates can provide improved understanding of Salmonella diversity and epidemiology, including identification of possible host-associated and common, widely distributed PFGE types.


Antibody response to the tumor-associated inhibitor of apoptosis protein survivin in cancer patients.
Antibody reactivity against survivin, a recently identified tumor-associated protein, was determined in sera from patients with lung (n = 51) or colorectal cancer (n = 49). The same collection of sera was tested for the presence of antibodies against p53. Eleven sera from lung cancer patients and four sera from colorectal cancer patients reacted with purified recombinant survivin in an ELISA (21.6% and 8.2%, respectively), whereas four sera from lung cancer patients and nine sera from colorectal cancer patients contained anti-p53 antibodies (7.8% and 18.4%, respectively). The increase in prevalence when anti-survivin and anti-p53 antibodies were determined in parallel was statistically significant (29.4% versus 7.8%, P = 0.005 in lung cancer population; 26.6% versus 8.2%, P = 0.015 in colorectal cancer population). The high prevalence of anti-survivin antibodies makes these antibodies an attractive novel marker for the diagnosis of lung and colorectal cancer, particularly in patients lacking anti-p53 antibodies.


Shorter stay, longer life: age at migration and mortality among the older Mexican-origin population.
In this article, we investigate the association between age at migration and mortality during a 13-year period in a sample of Mexican American immigrants 65 and older at baseline. We employ the Hispanic Established Populations for Epidemiologic Studies of the Elderly (H-PESE) to control for mortality-related health and social factors. Our analyses show that the immigrant generation does not represent a homogeneous mortality risk category. Individuals who migrated to the United States in mature adulthood have a considerably lower risk of death than individuals who migrated in childhood or midlife. Chronic conditions or functional capacity do not account for these differences. Our findings suggest that standard risk pools may differ significantly on the basis of genetic and unmeasured life-course factors. A better understanding of the late-life immigrant mortality advantage has important implications for more effective and targeted social and medical interventions.


A review of the reporting and handling of missing data in cohort studies with repeated assessment of exposure measures.
Retaining participants in cohort studies with multiple follow-up waves is difficult. Commonly, researchers are faced with the problem of missing data, which may introduce biased results as well as a loss of statistical power and precision. The STROBE guidelines von Elm et al. (Lancet, 370:1453-1457, 2007); Vandenbroucke et al. (PLoS Med, 4:e297, 2007) and the guidelines proposed by Sterne et al. (BMJ, 338:b2393, 2009) recommend that cohort studies report on the amount of missing data, the reasons for non-participation and non-response, and the method used to handle missing data in the analyses. We have conducted a review of publications from cohort studies in order to document the reporting of missing data for exposure measures and to describe the statistical methods used to account for the missing data. A systematic search of English language papers published from January 2000 to December 2009 was carried out in PubMed. Prospective cohort studies with a sample size greater than 1,000 that analysed data using repeated measures of exposure were included. Among the 82 papers meeting the inclusion criteria, only 35 (43%) reported the amount of missing data according to the suggested guidelines. Sixty-eight papers (83%) described how they dealt with missing data in the analysis. Most of the papers excluded participants with missing data and performed a complete-case analysis (n=54, 66%). Other papers used more sophisticated methods including multiple imputation (n=5) or fully Bayesian modeling (n=1). Methods known to produce biased results were also used, for example, Last Observation Carried Forward (n=7), the missing indicator method (n=1), and mean value substitution (n=3). For the remaining 14 papers, the method used to handle missing data in the analysis was not stated. This review highlights the inconsistent reporting of missing data in cohort studies and the continuing use of inappropriate methods to handle missing data in the analysis. Epidemiological journals should invoke the STROBE guidelines as a framework for authors so that the amount of missing data and how this was accounted for in the analysis is transparent in the reporting of cohort studies.


GC/GC-MS analysis, isolation and identification of bioactive essential oil components from the Bhutanese medicinal plant, Pleurospermum amabile.
We have hydrodistilled the essential oil (EO) from the aerial parts of the Bhutanese medicinal plant, Pleurospermum amabile using a Clevenger apparatus and evaluated this EO by GC/GC-MS and NMR analysis followed by testing for bioactivity. The GC-MS analysis identified 52 compounds with (E)-isomyristicin as a major component (32.2%). Repeated purification yielded four compounds; (E)-isomyristicin (1), (E)-isoapiol (2), methyl eugenol (3) and (E)-isoelemicin (4). Compound 2 and the mother EO showed the best antiplasmodial activity against the Plasmodium falciparum strains, TM4/8.2 (chloroquine and antifolate sensitive) and K1CB1 (multidrug resistant). They exhibited mild antibacterial activity against Bacillus subtilis. None of the test samples showed cytotoxicity.


Structural and Functional Characterization of an Electron Transfer Flavoprotein Involved in Toluene Degradation in Strictly Anaerobic Bacteria.
(R)-Benzylsuccinate is the characteristic initial intermediate of anaerobic toluene metabolism, which is formed by a radical-type addition of toluene to fumarate. Its further degradation proceeds by activation to the coenzyme A (CoA)-thioester and β-oxidation involving a specific (R)-2-benzylsuccinyl-CoA dehydrogenase (BbsG) affiliated with the family of acyl-CoA dehydrogenases. In this report, we present the biochemical properties of electron transfer flavoproteins (ETFs) from the strictly anaerobic toluene-degrading species Geobacter metallireducens and Desulfobacula toluolica and the facultatively anaerobic bacterium Aromatoleum aromaticum We determined the X-ray structure of the ETF paralogue involved in toluene metabolism of G. metallireducens, revealing strong overall similarities to previously characterized ETF variants but significantly different structural properties in the hinge regions mediating conformational changes. We also show that all strictly anaerobic toluene degraders utilize one of multiple genome-encoded related ETF paralogues, which constitute a distinct clade of similar sequences in the ETF family, for β-oxidation of benzylsuccinate. In contrast, facultatively anaerobic toluene degraders contain only one ETF species, which is utilized in all β-oxidation pathways. Our phylogenetic analysis of the known sequences of the ETF family suggests that at least 36 different clades can be differentiated, which are defined either by the taxonomic group of the respective host species (e.g., clade P for Proteobacteria) or by functional specialization (e.g., clade T for anaerobic toluene degradation).IMPORTANCE This study documents the involvement of ETF in anaerobic toluene metabolism as the physiological electron acceptor for benzylsuccinyl-CoA dehydrogenase. While toluene-degrading denitrifying proteobacteria use a common ETF species, which is also used for other β-oxidation pathways, obligately anaerobic sulfate- or ferric-iron-reducing bacteria use specialized ETF paralogues for toluene degradation. Based on the structure and sequence conservation of these ETFs, they form a new clade that is only remotely related to the previously characterized members of the ETF family. An exhaustive analysis of the available sequences indicated that the protein family consists of several closely related clades of proven or potential electron-bifurcating ETF species and many deeply branching nonbifurcating clades, which either follow the host phylogeny or are affiliated according to functional criteria.


Gastric neuroendocrine neoplasms: tumour clonality and malignancy-associated large X-chromosomal deletions.
Type I gastric carcinoid tumours associated with corporal (body of stomach) atrophic gastritis (CAG) are benign tumours developing as the final step of a hyperplastic precursor sequence. The neoplastic nature of these tumours has been assumed but never proved. Type III gastric carcinoid tumours and neuroendocrine carcinomas are malignant neoplasms without known precursor lesions. To assess the neoplastic nature of type I carcinoids, the clonal status of 35 tumours from 23 female patients was investigated using the human androgen receptor (HUMARA) gene test, which is based on the pattern of X-chromosome inactivation. For comparison, the same test was also performed on four type III carcinoids and two neuroendocrine carcinomas. DNA extracted from paraffin sections was digested with Hha I restriction enzyme and then amplified by polymerase chain reaction (PCR) using established HUMARA primers. The PCR products were analysed in an automated DNA sequencer. In a complementary analysis of the same tumours, loss of heterozygosity (LOH) on the X chromosome was studied using three polymorphic markers (DXS989, DXS1003, DXS1192) in a PCR-microsatellite-based technique. After exclusion of non-informative cases, 14 of 16 type I carcinoids were found to be monoclonal on the basis of the pattern of X-chromosome inactivation. Monoclonality was also documented in one of three type III carcinoids and in the single neuroendocrine carcinoma, on the basis of LOH at the HUMARA locus, which per se can be regarded as evidence for clonality. Extensive LOH of the X chromosome involving at least two markers, was found in all metastasizing tumours (two type III carcinoids and two neuroendocrine carcinomas), but in none of the 27 benign carcinoids of types I and III. These results indicate that most type I carcinoids are true monoclonal neoplasms and that malignant evolution in gastric neuroendocrine tumours is associated with extensive allelic deletion of one X chromosome.


Current Applications of Nanoemulsions in Cancer Therapeutics.
Nanoemulsions are pharmaceutical formulations composed of particles within a nanometer range. They possess the capacity to encapsulate drugs that are poorly water soluble due to their hydrophobic core nature. Additionally, they are also composed of safe gradient excipients, which makes them a stable and safe option to deliver drugs. Cancer therapy has been an issue for several decades. Drugs developed to treat this disease are not always successful or end up failing, mainly due to low solubility, multidrug resistance (MDR), and unspecific toxicity. Nanoemulsions might be the solution to achieve efficient and safe tumor treatment. These formulations not only solve water-solubility problems but also provide specific targeting to cancer cells and might even be designed to overcome MDR. Nanoemulsions can be modified using ligands of different natures to target components present in tumor cells surface or to escape MDR mechanisms. Multifunctional nanoemulsions are being studied by a wide variety of researchers in different research areas mainly for the treatment of different types of cancer. All of these studies demonstrate that nanoemulsions are efficiently taken by the tumoral cells, reduce tumor growth, eliminate toxicity to healthy cells, and decrease migration of cancer cells to other organs.


A dental look at the autistic patient through orofacial pain.
Abstract Autism is a neurodevelopmental disorder characterized by impaired social interaction and restricted interests, compromised communication skills, and repetitive patterns of behavior. Both social and behavioral problems, which may include hyperactivity and quick frustration, may hinder the detection of other important pathologies such as orofacial pain. This is aggravated by the invasive nature of oral exploration, which may trigger violent and self-injurious responses, such as temper tantrums and/or head banging, which make the work of professionals extremely difficult during diagnoses, follow-up examinations, and dental treatments. In addition, mercury-containing amalgams used to treat dental caries (the most common form of acute orofacial pain) have been associated with higher rates of severe autism in children. The purpose of this review is to describe the current state of the art regarding the co-occurrence of orofacial pain and autism spectrum disorder, and how these conditions may interrelate clinically and neurobiologically.


Divergent ecosystem responses within a benthic marine community to ocean acidification.
Ocean acidification is predicted to impact all areas of the oceans and affect a diversity of marine organisms. However, the diversity of responses among species prevents clear predictions about the impact of acidification at the ecosystem level. Here, we used shallow water CO(2) vents in the Mediterranean Sea as a model system to examine emergent ecosystem responses to ocean acidification in rocky reef communities. We assessed in situ benthic invertebrate communities in three distinct pH zones (ambient, low, and extreme low), which differed in both the mean and variability of seawater pH along a continuous gradient. We found fewer taxa, reduced taxonomic evenness, and lower biomass in the extreme low pH zones. However, the number of individuals did not differ among pH zones, suggesting that there is density compensation through population blooms of small acidification-tolerant taxa. Furthermore, the trophic structure of the invertebrate community shifted to fewer trophic groups and dominance by generalists in extreme low pH, suggesting that there may be a simplification of food webs with ocean acidification. Despite high variation in individual species' responses, our findings indicate that ocean acidification decreases the diversity, biomass, and trophic complexity of benthic marine communities. These results suggest that a loss of biodiversity and ecosystem function is expected under extreme acidification scenarios.


[Surgical strategy in traumatic lesions of the popliteal artery].
An examination and treatment of 32 patients with injured popliteal arteries are analyzed. Among the etiological factors there were gunshot wounds (16), crushed (4), punctured-incised (7) and blunt (7) traumas. Combined injuries of the popliteal vein were diagnosed in 12 patients, and injuries of the bones--in 16 patients. Errors were made in 19 cases at the prehospital stage: late diagnosis of the injury (11), transporting the patient in the state of shock (5), ligation of the popliteal artery (3). The term of extremity ischemia more than 8 hours was noted in 13 admitted patients. Decompensation of circulation was diagnosed in 22 patients. The primary amputation was performed on 6 patients with moist gangrene. Vascular reconstructions were made in 26 cases including the autovenous prosthesis and circular suture. Secondary amputations were fulfilled to 6 patients. Three patients died. Good results were obtained in 20 cases.


Plasma proteomics-based biomarkers for predicting response to mesenchymal stem cell therapy in severe COVID-19.
The objective of this study was to identify potential biomarkers for predicting response to MSC therapy by pre-MSC treatment plasma proteomic profile in severe COVID-19 in order to optimize treatment choice. A total of 58 patients selected from our previous RCT cohort were enrolled in this study. MSC responders (n = 35) were defined as whose resolution of lung consolidation ≥ 51.99% (the median value for resolution of lung consolidation) from pre-MSC to 28 days post-MSC treatment, while non-responders (n = 23) were defined as whose resolution of lung consolidation < 51.99%. Plasma before MSC treatment was detected using data-independent acquisition (DIA) proteomics. Multivariate logistic regression analysis was used to identify pre-MSC treatment plasma proteomic biomarkers that might distinguish between responders and non-responders to MSC therapy. In total, 1101 proteins were identified in plasma. Compared with the non-responders, the responders had three upregulated proteins (CSPG2, CTRB1, and OSCAR) and 10 downregulated proteins (ANXA1, AGRG6, CAPG, DDX55, KV133, LEG10, OXSR1, PICAL, PTGDS, and S100A8) in plasma before MSC treatment. Using logistic regression model, lower levels of DDX55, AGRG6, PICAL, and ANXA1 and higher levels of CTRB1 pre-MSC treatment were predictors of responders to MSC therapy, with AUC of the ROC at 0.910 (95% CI 0.818-1.000) in the training set. In the validation set, AUC of the ROC was 0.767 (95% CI 0.459-1.000). The responsiveness to MSC therapy appears to depend on baseline level of DDX55, AGRG6, PICAL, CTRB1, and ANXA1. Clinicians should take these factors into consideration when making decision to initiate MSC therapy in patients with severe COVID-19.