Thymus-dependent monoclonal antibody-induced protection from transferred diabetes.
It is well established that long-term protection from insulin-dependent diabetes mellitus (IDDM) can be afforded to non-obese diabetic (NOD) mice by a short course of non-depleting (nd) anti-CD4 monoclonal antibodies (mAb). Since it is increasingly apparent that the CD8+ T cell plays a prominent role in the development of IDDM, we have investigated the effect of an anti-CD8 mAb (YTS 105) of the same isotype in both spontaneous and induced IDDM in NOD mice. Treatment with YTS 105 for 3 weeks was able to prevent the transfer of IDDM for a long period, and also substantially reduced spontaneous IDDM in female NOD mice. The role of the thymus in tolerance induction by these antibodies was studied. In the adult transfer model, thymectomized NOD mice, unlike their euthymic counterparts, were not protected long-term by treatment with YTS 105, and began to become overtly diabetic shortly after treatment. This was also true when the nd anti-CD4 mAb was used. Protection from spontaneous disease was not affected in the same way by thymectomy. The reasons for the observed effect of the thymus in the transfer model, and the differences between the two models that may explain the contrasting results are discussed.


Is seafloor litter contributing to sea anemone blooms?
Increasing marine litter have become a global environmental disaster. The accumulation of seafloor litter (generally includes anthropogenic litter and natural debris) could change the habitat of benthic organisms and thereby affecting their population dynamics including spatial distribution. Metridium senile fimbriatum (i.e., M. senile), a fast-growing sea anemone, has become a dominant species of benthic community in the north Yellow Sea in recent years. In this study, we tested the hypothesis that the distribution of M. senile is positively correlated with that of seafloor litter, using data collected on seafloor litter and M. senile from three fisheries-independent bottom trawl surveys in the Yellow Sea in May, August and November 2019. Gradient Forest Model (GFM) was used to select appropriate response variables for characterizing the distribution of M. senile, and evaluate the influences of potential environmental factors on M. senile distribution. Surface area of anthropogenic litter (represented as 'Anthropogenic litter'), surface area of natural debris (represented as 'Natural debris') and latitude (Lat) were identified as the most significant variables influencing the distribution of M. senile. Furthermore, Generalized Additive Mixed Model (GAMM) was applied to model the abundance distribution of M. senile in terms of significant environmental variables, and evaluate its correlations with 'Anthropogenic litter' and 'Natural debris'. The best fitting GAMM showed that the abundance of M. senile has a significantly positive association with 'Anthropogenic litter' and 'Natural debris'. We therefore speculated that accumulation of seafloor litter might contribute to the bloom of M. senile, given that seafloor litter could serve as "vectors" for M. senile dispersal and provide with a preferable "natural habitat" for their settlement.


Motor hand representation in cortical area 44.
To elucidate whether area 44 of human frontal cortex is essential for the organization of voluntary hand movements or not, the authors examined effects of single transcranial magnetic stimulation (TMS) of human area 44 on voluntary hand movement and electromyography (EMG) activities in hand muscles. Surface EMG responses were recorded from the thenar muscles of 10 normal subjects following TMS over area 44. Stimuli were applied 2 cm anterior to the primary tongue motor area. Single TMS over area 44 could easily interrupt target-oriented hand movements. Human area 44 has facilitatory and inhibitory effects over both tonic and phasic finger movements. It is shown that single TMS of area 44 produces motor evoked potential from hand muscles. Human area 44 is involved in voluntary hand movements and has direct fast-conducting corticospinal projections.


Seasonality of births and childhood inflammatory bowel disease.
In some geographical areas, including Slovakia, children with diabetes mellitus type 1 are born more often in summer than in late autumn and winter. Does this also apply to another autoimmune disorder - inflammatory bowel disease - in Slovakia? The month of birth was recorded for 30 boys and 36 girls with Crohn disease and 23 boys and 40 girls with ulcerative colitis. The monthly numbers of births were adapted to the length of the given month, divided by the number of boys or girls born in the whole Slovak children population in the same calendar month in comparable years, transformed to moving averages from three successive values each, and expressed as the fraction of the yearly total, which was equal to 1. According to the null hypothesis, there should be equal probability (1/12) of being born in any month. The significance of departures from this value was evaluated with cosinor regression using two sinusoidal functions with period lengths of 12 and 6 months. The most illustrative measure is the relation of the corridor of 95% confidence for the total approximating function to the midline estimating statistic of rhythm (the mesor) (1/12). Significant departures up or down are recognized as nonoverlapping of the mesor straight line by the confidence corridor. These were similar to those reported for childhood diabetes mellitus type 1. In our sample of Crohn disease, the number of births was markedly higher between June and October and lower between December and March. In ulcerative colitis, there was a slight increase between June and August and a decrease between December and February. The seasonal effect on births of children with later childhood-onset Crohn disease is similar to that described for diabetes mellitus type 1, i.e., maximal frequency of births in summer.


Fluorometric determination of sialic acids using malononitrile in weakly alkaline media and its application to postcolumn labeling in high-performance liquid chromatography.
A sensitive method for determination of sialic acids by monitoring the fluorescence produced with malononitrile in borate buffer has been established. Measurement of the fluorescence intensity of the reaction mixture at 430 nm with irradiation at 360 nm allowed determination of 3-60 nmol of sialic acids with high reproducibility. A few amino sugars and deoxy sugars, as well as catecholamines reacted with this reagent; however other carbohydrates, amino acids, amines, aldehydes, and carboxylic acids including alpha-keto acids, etc., showed little reactivity. This method was successfully applied to postcolumn fluorescence labeling of sialic acids in high-performance liquid chromatography.


Calculation of the individual and population doses on Danish territory resulting from hypothetical core-melt accidents at the Barsebäck reactor.
Individual and population doses on Danish territory are calculated from hypothetical, severe core-melt accidents at the Swedish nuclear plant at Barsebäck. The release fractions for these accidents are taken from WASH-1400. Based on parametric studies, doses are calculated for very unfavourable, but not incredible weather conditions. The probability of such conditions in combination with wind direction towards Danish territory is estimated. Doses to bone marrow, lungs, GI-tract and thyroid are calculated using dose models developed at Risø. These doses are found to be consistent with doses calculated with the models used in WASH-1400.


Hematopoietic cell transplantation for Mucopolysaccharidosis I in the presence of decreased cardiac function.
Severe mucopolysaccharidosis type I, (MPS IH) is a rare inherited lysosomal disorder resulting in progressive storage of proteoglycans (GAGs) in central nervous system and somatic tissues and, if left untreated, causing death within the first decade of life. Hematopoietic cell transplantation (HCT) arrests many of the features of MPS IH but carries a 10-15% risk of mortality. Decreased cardiac function can occur in MPS IH and increase the risk of HCT. Retrospective chart review was performed to determine the long-term outcome of individuals evaluated for HCT with MPS IH who had decreased cardiac function as measured by cardiac echocardiogram (echo) and ejection fraction (EF) of <50% at the time of initial evaluation. Six patients ranging in age from 1 week to 21 months (median: 4 months) had EFs ranging from 25 to 47% (median: 32%) at diagnosis and were initiated on enzyme replacement therapy (ERT) with improvement in EF in three patients by 5 months. The remaining three patients continued to have EFs <50% and continuous milrinone infusion was added in the pre-HCT period. On average, milrinone infusion was able to be discontinued post-HCT, prior to hospital discharge, within a mean of 37 days. Five patients survived HCT and are alive today with normal EFs. One patient receiving milrinone died of sepsis during HCT with a normal EF. Decreased cardiac systolic function in infants with MPS IH that fails to normalize with ERT alone may benefit from the addition of continuous milrinone infusion during HCT.


Monetary Value of Quality-Adjusted Life Years (QALY) among Patients with Cardiovascular Disease: a Willingness to Pay Study (WTP).
The aim of this study was to estimate the monetary value of a QALY among patients with heart disease and to identify its determinants. A cross-sectional survey was conducted through face-to-face interview on 196 patients with cardiovascular disease from two heart hospitals in Tehran, Iran, to estimate the value of QALY using disaggregated and aggregated approaches. The EuroQol-5 Dimension (EQ-5D) questionnaire, Visual Analogue Scale (VAS), Time Trade-Off (TTO) and contingent valuation WTP techniques were employed, first to elicit patients' preferences and then, to estimate WTP for QALY. The association of patients' characteristics with WTP for QALY, was assessed through Heckman selection model. The Mean willingness to pay per QALY, estimated by the disaggregated approach ranged from 2,799 to 3599 US dollars. It is higher than the values, estimated from aggregated methods (USD 2,256 to 3,137). However, in both approaches, the values were less than one Gross Domestic Product (GDP) per capita of Iran. Significant variables were: Current health state, education, age, marital status, number of comorbidities, and household's cost group. Our results challenge two major issues: the first, is a policy challenge which concerns the WHO recommendation to use less than 3 GDP per capita as a cost-effectiveness threshold value. The second, is an analytical challenge related to patients with zero QALY gain. More scrutiny is suggested on the issue of how patients with full health state valuation should be dealt with and what arbitrary value could be included in the estimation value of QALY when the disaggregated approach used.


On the formation of Bi2S3-cellulose nanocomposite films from bismuth xanthates and trimethylsilyl-cellulose.
The synthesis and characterization of bismuth sulfide-cellulose nanocomposite thin films was explored. The films were prepared using organosoluble precursors, namely bismuth xanthates for Bi2S3 and trimethylsilyl cellulose (TMSC) for cellulose. Solutions of these precursors were spin coated onto solid substrates yielding homogeneous precursor films. Afterwards, a heating step under inert atmosphere led to the formation of thin nanocomposite films of bismuth sulfide nanoparticles within the TMSC matrix. In a second step, the silyl groups were cleaved off by vapors of HCl yielding bismuth sulfide/cellulose nanocomposite films. The thin films were characterized by a wide range of surface sensitive techniques such as atomic force microscopy, attenuated total reflection infrared spectroscopy, transmission electron microscopy and wettability investigations. In addition, the formation of the nanoparticle directly in the TMSC matrix was investigated in situ by GI-SWAXS using a temperature controlled sample stage.


Composition and antimicrobial properties of essential oils of four Mediterranean Lamiaceae.
Essential oils from Satureja montana L., Rosmarinus officinalis L., Thymus vulgaris L., and Calamintha nepeta (L.) Savi, were chemically analysed and their antimicrobial and fungicide activities evaluated on the basis of their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). All four oils have a biotoxic effect, the most active being those from Calamintha and Thymus.


Comparative study of the cytotoxic and genotoxic potentials of zinc oxide and titanium dioxide nanoparticles.
Nanoparticles (NPs) of zinc oxide (ZnO) and titanium dioxide (TiO2) are receiving increasing attention due to their widespread applications. The aim of this study was to evaluate the toxic effect of ZnO and TiO2 NPs at different concentrations (50, 100, 250 and 500 ppm) and compare them with their respective salts using a battery of cytotoxicity, and genotoxicity parameters. To evaluate cytotoxicity, we have used human erythrocytes and for genotoxic studies human lymphocytes have been used as in vitro model species. Concentration dependent hemolytic activity to RBC's was obtained for both NPs. ZnO and TiO2 NPs resulted in 65.2% and 52.5% hemolysis at 250 ppm respectively indicating that both are cytotoxic to human RBCs. Antioxidant enzymes assays were also carried out in their respective hemolysates. Both nanoparticles were found to generate reactive oxygen species (ROS) concomitant with depletion of glutathione and GST levels and increased SOD, CAT and lipid peroxidation in dose dependent manner. ZnO and TiO2 NPs exerted roughly equal oxidative stress in terms of aforementioned stress markers. Genotoxic potential of both the NPs was investigated by in vitro alkaline comet assay. DNA damage induced by the NPs was concentration dependent and was significantly greater than their ionic forms at 250 and 500 ppm concentrations. Moreover, the nanoparticles of ZnO were significantly more genotoxic than those of TiO2 at higher concentrations. The toxicity of these NPs is due to the generation of ROS thereby causing oxidative stress.


Structural brain variation, age, and response time.
Response time (RT) generally slows with aging, but the contribution of structural brain changes to this slowing is unknown. We used voxel-based morphometry (VBM) to determine gray matter (GM) and white matter (WM) brain volumes in 9 middle-aged adults (38-58 years old) and 9 seniors (66-82 years old). We correlated brain volumes with RT assessed in both a simple visual stimulus-response task and a visual continuous recognition memory task. No GM correlations with simple RT were significant; there was one WM correlation in the right fusiform gyrus. In the memory task, faster RT was correlated (p < .05, corrected) with less GM in the globus pallidus, the parahippocampus, and the thalamus for both groups. Several Brodmann areas (BA) differed between the groups such that in each area, less GM was correlated with slower RTs in the middle-aged group but with faster RTs in the senior group (BAs 19, 37, 46, 9, 8, 6, 13, 10, 41, and 7). The results suggest that individual differences in specific brain structure volumes should be considered as potential moderating factors in cognitive brain imaging studies.


Msx genes are expressed in the carapacial ridge of turtle shell: a study of the European pond turtle, Emys orbicularis.
The turtle shell forms by extensive ossification of dermis ventrally and dorsally. The carapacial ridge (CR) controls early dorsal shell formation and is thought to play a similar role in shell growth as the apical ectodermal ridge during limb development. However, the molecular mechanisms underlying carapace development are still unknown. Msx genes are involved in the development of limb mesenchyme and of various skeletal structures. In particular, precocious Msx expression is recorded in skeletal precursors that develop close to the ectoderm, such as vertebral spinous processes or skull. Here, we have studied the embryonic expression of Msx genes in the European pond turtle, Emys orbicularis. The overall Msx expression in head, limb, and trunk is similar to what is observed in other vertebrates. We have focused on the CR area and pre-skeletal shell condensations. The CR expresses Msx genes transiently, in a pattern similar to that of fgf10. In the future carapace domain, the dermis located dorsal to the spinal cord expresses Msx genes, as in other vertebrates, but we did not see expansion of this expression in the dermis located more laterally, on top of the dermomyotomes. In the ventral plastron, although the dermal osseous condensations form in the embryonic Msx-positive somatopleura, we did not observe enhanced Msx expression around these elements. These observations may indicate that common mechanisms participate in limb bud and CR early development, but that pre-differentiation steps differ between shell and other skeletal structures and involve other gene activities than that of Msx genes.


Trends and Outcomes of Early Rehabilitation in the Intensive Care Unit for Patients With Cardiovascular Disease: A Cohort Study With Propensity Score-Matched Analysis.
The effectiveness of acute-phase cardiovascular rehabilitation (CR) in intensive care settings remains unclear in patients with cardiovascular disease (CVD). This study aimed to investigate the trends and outcomes of acute-phase CR in the intensive care unit (ICU) for patients with CVD, including in-hospital and long-term clinical outcomes. This retrospective cohort study reviewed a total of 1,948 consecutive patients who were admitted to a tertiary academic ICU for CVD treatment and underwent CR during hospitalisation. The endpoints of this study were the following: in-hospital outcomes: probabilities of walking independence and returning home; and long-term outcomes: clinical events 5 years following hospital discharge, including all-cause readmission or cardiovascular events. It evaluated the associations of CR implementation during ICU treatment (ICU-CR) with in-hospital and long-term outcomes using propensity score-matched analysis. Among the participants, 1,092 received ICU-CR, the rate of which tended to increase with year trend (p for trend <0.001). After propensity score matching, 758 patients were included for analysis (pairs of n=379 ICU-CR and non-ICU-CR). ICU-CR was significantly associated with higher probabilities of walking independence (rate ratio, 2.04; 95% CI 1.77-2.36) and returning home (rate ratio, 1.22; 95% CI 1.05-1.41). These associations were consistently observed in subgroups aged >65 years, after surgery, emergency, and prolonged ICU stay. ICU-CR showed significantly lower incidences of all-cause (HR 0.71; 95% CI 0.56-0.89) and cardiovascular events (HR 0.69; 95% CI 0.50-0.95) than non-ICU-CR. The implementation of acute-phase CR in ICU increased with year trend, and is considered beneficial to improving in-hospital and long-term outcomes in patients with CVD and various subgroups.


Induced genetic ablation of Rest leads to the alteration of stimulus-induced response of the vagal nerve.
Rest (RE1-silencing transcription factor, also called Nrsf) is involved in the maintenance of the undifferentiated state of neuronal stem/progenitor cells by preventing precocious expression of neuronal genes. In order to further investigate the function of Rest in neurons, we generated and examined mice evoking genetic ablation of Rest specifically in neural tissues by generating Rest conditional knockout mice. As the Rest knockout mice are embryonically lethal, we used a Sox1-Cre allele to excise the floxed Rest gene from the early stage of nerve cell differentiation including neural crest-derived nerve cells. Using this conditional Rest knockout Sox1-Cre; Restflox/flox mice, we have revealed the role of Rest in the parasympathetic nervous system in the stomach and heart.


Parturition and Its Relationship with Stillbirths and Asphyxiated Piglets.
The transition from an intra- to extrauterine existence is extremely challenging for the pig. This is evidenced by the fact that conservative estimates place intrapartum piglet death at between 5% and 10%. The main cause of this loss is the parturition process itself, with a long farrowing duration resulting in reduced oxygenation to the piglet via uterine contractions stretching, and in some cases, causing rupture of the umbilical cord. Sows that experience a long expulsive stage of parturition are likely compromised before the birth of the first piglet, and so any strategy to reduce stillbirth should be applied before this. Even in piglets born alive, 15% to 20% will have suffered asphyxiation because of a long cumulative farrowing duration. These individuals are significantly disadvantaged with regards to behavioural progression, colostrum intake, growth and survival extending past the lactation phase, and so require more labour and resources than littermates in order to make them viable. Given these immediate and longer-term impacts, identifying ways to correctly manage the sow before parturition leading to a reduction in farrowing duration should be a priority in order to maximise piglet performance.


Experimental detachment of the canine bile duct to evaluate mechanisms of the dilated bile duct.
The factors inducing biliary dilatation were studied morphologically and functionally by cholangiography and cholangiomanometry in experimental models of chronic biliary dilatation. These models were produced by four methods: Constriction of the lower bile duct (Group 1), formalin infusion into the duodenal papilla (Group 2), detachment of the extrahepatic bile duct (Group 3), and sphincterotomy (Group 4). Biliary dilatation was observed in the first three groups but not in the fourth group. An increase in the intraductal pressure due to blockage of the biliary outflow tract was considered to be the cause of biliary dilatation in Group 1 and 2. In Group 3, the function of the lower bile duct, including the papilla was intact, and reduced resistance of the bile duct wall and due to the loss of the support from the surrounding connective tissue was considered to have induced biliary dilatation. These results suggest that experimental chronic biliary dilatation can be produced by two approaches: 1) Blockage of bile flow in the papilla or the bile duct, and 2) detachment of the bile duct without disturbing bile flow.


A prognostic index for extranodal marginal-zone lymphoma based on the mucosa-associated lymphoid tissue International Prognostic Index and serum β2-microglobulin levels.
The mucosa-associated lymphoid tissue (MALT) International Prognostic Index (IPI) was recently proposed as a prognostic index for patients with MALT lymphoma. We aimed to investigate the prognostic value of the serum β2-microglobulin level in the context of MALT-IPI, and we proposed a new prognostic index. Survival outcomes were analysed with regard to β2-microglobulin level, MALT-IPI, and the new prognostic index in MALT lymphoma patients (n = 571). The validity of the new prognostic index was assessed using an independent cohort (n = 216). Patients with high β2-microglobulin levels had significantly worse progression-free survival (PFS) and overall survival (OS) outcomes. A high β2-microglobulin level was independently associated with poor PFS and OS. β2-microglobulin levels further stratified patients in the MALT-IPI intermediate-risk group in terms of PFS and OS. A new prognostic index based on the MALT-IPI and the β2-microglobulin level, MALT-IPI-B, was proposed. The MALT-IPI-B was able to stratify patients into subgroups having distinct PFS and OS outcomes in both the training and validation cohorts. MALT-IPI-B enabled the identification of patients with poor survival outcomes who were classified into the intermediate-risk group by the MALT-IPI. In conclusion, this new β2-microglobulin-based prognostic index may have the specific advantage of identifying high-risk patients who may require systemic treatment.


Mapping the GRIF-1 binding domain of the kinesin, KIF5C, substantiates a role for GRIF-1 as an adaptor protein in the anterograde trafficking of cargoes.
Gamma-aminobutyric acid, type A (GABAA) receptor interacting factor-1 (GRIF-1) and N-acetylglucosamine transferase interacting protein (OIP) 106 are both members of a newly identified coiled-coil family of proteins. They are kinesin-associated proteins proposed to function as adaptors in the anterograde trafficking of organelles to synapses. Here we have studied in more detail the interaction between the prototypic kinesin heavy chain, KIF5C, kinesin light chain, and GRIF-1. The GRIF-1 binding site of KIF5C was mapped using truncation constructs in yeast two-hybrid interaction assays, co-immunoprecipitations, and co-localization studies following expression in mammalian cells. Using these approaches, it was shown that GRIF-1 and the KIF5C binding domain of GRIF-1, GRIF-1-(124-283), associated with the KIF5C non-motor domain. Refined studies using yeast two-hybrid interactions and co-immunoprecipitations showed that GRIF-1 and GRIF-1-(124-283) associated with the cargo binding region within the KIF5C non-motor domain. Substantiation that the GRIF-1-KIF5C interaction was direct was shown by fluorescence resonance energy transfer analyses using fluorescently tagged GRIF-1 and KIF5C constructs. A significant fluorescence resonance energy transfer value was found between the C-terminal EYFP-tagged KIF5C and ECFP-GRIF-1, the C-terminal EYFP-tagged KIF5C non-motor domain and ECFP-GRIF-1, but not between the N-terminal EYFP-tagged KIF5C nor the EYFP-KIF5C motor domain and ECFP-GRIF-1, thus confirming direct association between the two proteins at the KIF5C C-terminal and GRIF-1 N-terminal regions. Co-immunoprecipitation and confocal imaging strategies further showed that GRIF-1 can bind to the tetrameric kinesin light-chain/kinesin heavy-chain complex. These findings support a role for GRIF-1 as a kinesin adaptor molecule requisite for the anterograde delivery of defined cargoes such as mitochondria and/or vesicles incorporating beta2 subunit-containing GABAA receptors, in the brain.


Carbon dioxide laser therapy of subclinical condyloma found by magnified penile surface scanning.
The etiology and treatment of condyloma caused by the human papilloma virus (HPV) and the association of HPV with cervical dysplasia and/or carcinoma is a major issue in current gynecologic literature. This study examined results of carbon dioxide (CO2) laser treatment of 127 high-risk males with biopsy-proved subclinical HPV infections found by magnified penile surface scanning (MPSS). At a mean follow-up of four months a 66 per cent recurrence rate of microscopic condyloma was encountered. A discussion of the causes of such a high recurrence rate is given, with conclusions on this and prior condyloma treatment series.


Eye hemodynamic data and biochemical parameters of the lacrimal fluid of patients with non-proliferative diabetic retinopathy.
This paper presents a data from examinations of patients treated in clinic of Tashkent medical academy, Uzbekistan. 165 Patients (305 eyes) with NPDR were randomly allocated to receive standard treatment as the control group, in addition to the standard treatment daily tablets of EGb 761 (Tanakan, Beaufour Ipsen Industrie, Paris, France) 120 mg as the 1st main group, or daily endonasal electrophoresis of Tanakan 40 mg as 2nd main group, within 10 days. All of the patients underwent baseline ophthalmologic examinations, definition of biochemical parameters of the lacrimal fluid and Doppler ultrasound imaging of the eye. Moreover, correlation between tear fluid and hemodynamics was calculated. This data is essential for researchers to develop diagnostic criteria for diabetic retinopathy stages. Data are also beneficial to practitioners in determining the diabetic retinopathy severity and choosing appropriate treatment.


Association of fat mass and obesity-associated (FTO) gene polymorphisms with non-communicable diseases (NCDs) in the Iranian population: A systematic review of observational studies.
Single nucleotide polymorphisms have been implicated in various diseases, most notably non-communicable diseases (NCDs). The aim of this study was to review available evidence regarding associations between FTO polymorphisms and NCDs in the Iranian population. A comprehensive search was conducted through PubMed/Medline and Scopus databases up to December 2021, as well as reference lists of pertinent articles and key journals. All observational studies that examined the association between FTO gene polymorphisms and NCDs in the Iranian population were included. There was no limitation on the publication year. The Newcastle-Ottawa Scale (NOS) was used to assess the study's quality. The initial search yielded 95 studies, of which 30 studies were included in the current systematic review. The underlying disorders were obesity, type 2 diabetes, breast and colorectal cancers, depression, and metabolic syndrome. These studies found an association between FTO gene polymorphisms and obesity in the Iranian population, but the relationship with other NCDs was debatable. Even though, other diseases such as diabetes and metabolic syndrome, which are closely related to obesity, may also be associated with FTO gene polymorphisms. FTO gene polymorphism appears to play a role in the occurrence of NCDs. Some of the study results may be misleading due to ethnic differences and the effect of other genetic factors on disease onset, which needs to be investigated further. Finally, FTO gene polymorphisms can be studied as a preventive or therapeutic target. The online version contains supplementary material available at 10.1007/s40200-022-01139-4.


Relevance of polyclonal plasma cells and post-therapy immunomodulation in measurable residual disease assessment in multiple myeloma.
Immunophenotypic profile and post-therapy alteration in antigenic expression were evaluated in normal, reactive, and aberrant plasma cells (NPC, RPC, and APC) for impact on measurable residual disease (MRD) assessment in multiple myeloma (MM). Samples from non-MM staging marrow (n = 30), Hodgkin's lymphoma (n = 30) and MM (n = 724) were prospectively evaluated for expression profiles of NPC, RPC, and APC using antigens recommended in consensus guidelines. Polyclonal NPC-RPC demonstrated aberrations for all antigens evaluated with a higher frequency of aberrancies in post-therapy samples compared to treatment naïve samples (p < 0.001%). Immunomodulation in APC was observed in 79% of post-therapy samples with a change in expression of 1, 2, and ≥3 antigens in 19.9%, 15.6%, and 43.5% samples, respectively. In 13.4% of samples, APC showed no aberrancy and aberrant status was assigned based on cytoplasmic light chain restriction (cyLCR) alone. 9% samples with an admixture of NPC and APC displayed normal cytoplasmic kappa to lambda ratio (cyKLR) when the percentage of APC of total PC (neoplastic plasma cell index, NPCI), was below 25% and 50% for kappa and lambda restricted cases, respectively. The panorama and high frequency of antigenic aberrations on polyclonal PC signify the importance of MRD assay validation on a large cohort under normal and reactive conditions. Frequent Immunophenotypic shifts in APC re-confirm the redundancy of baseline immunophenotype for MRD evaluation. Small clones of APC may be missed by assessment of cyKLR alone and therefore, surface marker aberrancy supported by cyLCR is required for definitive assignment of residual APC.


Carob pod: a new substrate for citric acid production by Aspergillus niger.
The production of citric acid from carob pod extract by A. niger in surface fermentation was investigated. A maximum citric acid concentration (85.5 g/L), citric acid productivity (4.07 g/L/d), specific citric acid production rate (0.18 g/g/d), and specific sugar uptake rate (0.358 g/g/d) was achieved at an initial sugar concentration of 200 g/L, pH of 6.5, and a temperature of 30 degrees C. Other kinetic parameters, namely, citric acid yield, biomass yield, specific biomass production rate, and fermentation efficiency were maximum at pH 6.5, temperature 30 degrees C, and initial sugar concentration 100 g/L. The external addition of methanol into the carob pod extract at a concentration up to 4% (v/v) improved the production of citric acid.


Il34-Csf1r Pathway Regulates the Migration and Colonization of Microglial Precursors.
Microglia are the major immune cells in the central nervous system (CNS). Born in peripheral hematopoietic tissues, microglial precursors colonize the CNS during early embryogenesis and maintain themselves thereafter. However, the mechanism underlying this colonization process remains elusive. We have recently demonstrated that neuronal apoptosis contributes to microglia colonization in zebrafish. Here, we further show that prior to neuronal apoptosis, microglial precursors are attracted to the proximal brain regions by brain-derived interleukin 34 (il34) and its receptor colony-stimulating factor 1 receptor a (csf1ra). In both il34- and csf1ra-deficient zebrafish larva, embryonic macrophages fail to migrate to the anterior head and colonize the CNS, but their initial development and colonization to peripheral tissues remain largely unaffected. Activation of Il34-Csf1ra pathway is sufficient to attract embryonic macrophages to the CNS independent of neuronal apoptosis. Our study shows that cytokine signaling and neuronal apoptosis synergistically orchestrate the colonization of microglia in early zebrafish development.


A rapid method for detecting specific RNA transcripts by hybridization to DNA probes in solution.
A method is described for detecting specific transcripts in crude mixtures of RNA. The method employs hybridization of single-stranded or double-stranded radioactive DNA probes in solution, followed by electrophoretic separation of the hybrid and probe on agarose and visualization by radioautography. The procedure offers the advantages of decreased preparation time and increased sensitivity over currently used methods.


The relationship between wood litter infall and relative abundance and feeding activity of subterranean termites Reticulitermes spp. in three southeastern coastal plain habitats.
We estimated the densities of termites in dead wood using a point-quarter technique in four habitats: pine plantations subject to control burning and unburned, lowland hardwood forest, and turkey oak woodland. The burned pine plantation had the highest estimated termite density, 13×106·ha-1 unburned pine plantation and lowland hardwood had estimated densities of 2.6×106·ha-1 and 2.2×106·ha-1, respectively, and the turkey oak woodland had an estimated densities of 61.9×103·ha-1. There were varying percentages of Reticulitermes flavipes and R. virginicus in the various habitats. There was nearly linear increase in percentage of pine blocks attacked by termites in the pine and hardwood forests and by the end of the growing season, nearly all had been channelized by termites. In the turkey oak habitat 70% of the pine blocks were channelized. Termites removed between 3% and 12% of the original mass of over one-fourth of the pine blocks during the growing season.Wood litter in fall was highest in the lowland hardwood forest: 2869 kg·ha-1·yr-1. Wood litter input in the long leaf pine plantation, 792 kg·ha-1·yr-1 was nearly equivalent to the three year average wood litter in fall in a Danish oak forest.


Corrigendum to "Fibroblast Growth Factor-9 Activates c-Kit Progenitor Cells and Enhances Angiogenesis in the Infarcted Diabetic Heart".
[This corrects the article DOI: 10.1155/2016/5810908.].


Risk of type 2 diabetes mellitus in patients with acute critical illness: a population-based cohort study.
This large population-based cohort study evaluated the association between certain critical illnesses and the incidence of newly diagnosed type 2 diabetes mellitus (T2DM) in Taiwan. Data were obtained from the Taiwan National Health Insurance Research Database. According to age, sex, and propensity score-matching, a cohort comprising 9528 patients with critical illness, including septicemia, septic shock, acute myocardial infarction (AMI), and stroke, and a control cohort of 9528 patients with no critical illness were identified. Cox proportional-hazard regression and competing-risk regression models were employed to evaluate the risk of developing T2DM. With the median follow-up periods (interquartile range) of 3.86 (1.64-6.93) and 5.12 (2.51-8.13) years for the patients in the critical illness and control cohorts, respectively, the risk of developing T2DM in the critical illness cohort was significantly higher than in the control cohort (adjusted hazard ratio, aHR = 1.32; 95% confidence interval, CI 1.16-1.50). In the multivariate competing-risk regression models, the aHR of T2DM was 1.58 (95% CI 1.45-1.72) in the critical illness cohort. Moreover, among the patients with these critical illnesses, those with septicemia or septic shock exhibited the highest risk of developing T2DM (aHR = 1.51, 95% CI 1.37-1.67), followed by AMI compared with the control cohort. Our results suggest that patients with certain critical illnesses are associated with a high risk of developing T2DM. Clinicians should be aware of this association and intensively screen for T2DM in patients following diagnosis of critical illness.


Unusually large solitary unicameral bone cyst: case report.
A 15-year-old boy presented with complaints of pain and swelling of the right leg. Radiography revealed a large lytic lesion involving the proximal half of the tibia. The patient was taken to surgery, where the cavity was curetted and packed with allogeneic bone graft. Tissue was sent for histopathological evaluation. The patient was kept in an above-knee cast for 4 months, after which partial weight-bearing was allowed. The histopathological diagnosis was a unicameral bone cyst. A radiograph at 1 year showed incorporation of the graft, but a small part of the cavity was still visible and there was a persistent discharge. The patient was again subjected to allogeneic bone grafting in the remaining cavity. At 3.5 years of follow-up now, the patient is walking unsupported, there is no pain, and the radiograph shows complete obliteration of the cavity. Unicameral bone cysts are usually a few centimeters in size. To the best of our knowledge, a unicameral bone cyst of such a large size has never been reported in the literature.


Integrated analysis of microbiome and host transcriptome reveals correlations between gut microbiota and clinical outcomes in HBV-related hepatocellular carcinoma.
The gut-liver axis plays a pivotal role in the pathogenesis of hepatocellular carcinoma (HCC). However, the correlations between the gut microbiome and the liver tumor transcriptome in patients with HCC and the impact of the gut microbiota on clinical outcome are less well-understood. Fecal samples collected from HBV-related HCC patients (n = 113) and healthy volunteers (n = 100) were subjected to 16S rRNA sequencing of the microbiome. After a rigorous selection process, 32 paired tumor and adjacent non-tumor liver tissues from the HCC group were subjected to next-generation sequencing (NGS) RNA-seq. The datasets were analyzed individually and integrated with clinical characteristics for combined analysis using bioinformatics approaches. We further verified the potential of the gut microbiota to predict clinical outcome by a random forest model and a support vector machine model. We found that Bacteroides, Lachnospiracea incertae sedis, and Clostridium XIVa were enriched in HCC patients with a high tumor burden. By integrating the microbiome and transcriptome, we identified 31 robust associations between the above three genera and well-characterized genes, indicating possible mechanistic relationships in tumor immune microenvironment. Clinical characteristics and database analysis suggested that serum bile acids may be important communication mediators between these three genera and the host transcriptome. Finally, among these three genera, six important microbial markers associated with tumor immune microenvironment or bile acid metabolism showed the potential to predict clinical outcome (AUC = 81%). This study revealed that changes in tumor immune microenvironment caused by the gut microbiota via serum bile acids may be important factors associated with tumor burden and adverse clinical outcome. Gut microbes can be used as biomarkers of clinical features and outcomes, and the microbe-associated transcripts of host tumors can partly explain how gut microbiota promotes HCC pathogenesis.


Adherence to home-based inspiratory muscle training in individuals with chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is an incurable progressive illness characterized by airflow limitation and respiratory failure. Inspiratory muscle training (IMT) combined with pulmonary rehabilitation increases inspiratory muscle strength and endurance, and it decreases dyspnoea. Little is known about IMT adherence, and in the present study, we aimed to evaluate adherence to home-based IMT used with automatic internet-based feedback, in patients with chronic obstructive pulmonary disease. The adherence was evaluated at an individual level by completing a before-and-after comparison between two groups. Over a 12-week study period, the participants performed two daily sessions of 30 breaths with a mechanical threshold loading training device. They were randomly assigned to either a group of people who self-reported their perceived exertion during breathing and who received automatic internet-based feedback regarding their next threshold loadings, or a group of people who performed IMT with 30% maximal inspiratory pressure and who received no feedback. The group of patients who self-reported their perceived exertion showed significantly better training adherence compared with the group of patients who received no feedback. Adherence was greater among patients who self-reported their perceived breathing exertion and received automatic internet-based feedback on the next threshold loadings compared with patients who self-reported training sessions without feedback.


Lipoprotein (a) in pregnancy: a critical review of the literature.
In this article the literature on lipoprotein (a) during normal pregnancy and pregnancy complicated by preeclampsia or intrauterine growth restriction is reviewed. MEDLINE, from January 1966 to May 2003, was searched to locate relevant articles in English. Additional publications were identified by reviewing references in selected articles. Studies were reviewed by predefined and strict criteria. It appeared that methodology and results of studies on lipoprotein (a) during normal and complicated pregnancy were very diverse. Lipoprotein (a) increased with advancing gestation or remained unaltered during normal pregnancy. Women with preeclampsia had higher, unaltered or lower lipoprotein (a) concentrations as compared to normal pregnant controls. Only few studies were in agreement with most of the review criteria. In conclusion, published studies on lipoprotein (a) in pregnancy differ substantially in the used methods to measure lipoprotein (a), sample size, study design and ethnicity of the study population. Therefore, these studies yielded conflicting results and no unequivocal view on the role of lipoprotein (a) in normal and complicated pregnancy. Recommendations for future studies are amongst others: the use of an apo(a) independent method for measuring Lp(a), inclusion of sufficient numbers of patients, the use of a longitudinal study design when the objective is to study the changes of Lp(a) during pregnancy and selection of a study population that is ethnically representative for the general population.


The L- and R-type isozymes of rat pyruvate kinase are produced from a single gene by use of different promoters.
cDNA clones for rat R-type pyruvate kinase and a genomic clone encoding both L- and R-type isozyme mRNAs were isolated. Their sequences were compared with that of the L-type isozyme cDNA to determine the sequences of mRNA and protein of the R-type isozyme and the organizations of the L- and R-type genes. Results showed that the R-type isozyme mRNA had an identical nucleotide sequence to that of the L-type except in the 5'-terminal region including the coding sequence and the length of the 3'-untranslated region. The sequence upstream of the 5th coding residue of the L-type was replaced by a 98-nucleotide coding sequence plus a 5'-untranslated region in the R-type isozyme. Therefore, the R-type subunit consists of 574 amino acids, which is 31 residues longer than the L-type at the amino terminus. The pyruvate kinase L gene is present as a single copy per haploid genome and is composed of 12 exons and 11 introns with a length of about 9.3 kilobase pairs. The first (exon R) and second (exon L) exons encode the 5'-terminal sequences specific for the R- and L-types, respectively. The remaining downstream exons encode a sequence common to both isozymes. The last exon contains the entire 3'-untranslated region, including several putative polyadenylation signals. Alternative use of these signals is reported to be responsible for generation of multiple mRNA species for the L-type, whereas the R-type uses only the first signal. The cap site is mapped 16 nucleotides upstream from the translation initiation site for the L-type, whereas multiple cap sites were suggested for the R-type. The canonical promoter of the TATA box was identified in the upstream sequence of exon L, but not in that of exon R. Instead, the 5'-flanking region of exon R contained another promoter sequence of the CAT box. Thus, we conclude that the L- and R-type isozymes of pyruvate kinase are produced from a single gene by use of different promoters.


Information bottleneck based incremental fuzzy clustering for large biomedical data.
Incremental fuzzy clustering combines advantages of fuzzy clustering and incremental clustering, and therefore is important in classifying large biomedical literature. Conventional algorithms, suffering from data sparsity and high-dimensionality, often fail to produce reasonable results and may even assign all the objects to a single cluster. In this paper, we propose two incremental algorithms based on information bottleneck, Single-Pass fuzzy c-means (spFCM-IB) and Online fuzzy c-means (oFCM-IB). These two algorithms modify conventional algorithms by considering different weights for each centroid and object and scoring mutual information loss to measure the distance between centroids and objects. spFCM-IB and oFCM-IB are used to group a collection of biomedical text abstracts from Medline database. Experimental results show that clustering performances of our approaches are better than such prominent counterparts as spFCM, spHFCM, oFCM and oHFCM, in terms of accuracy.


Genetic homogeneity of lysinuric protein intolerance.
Lysinuric protein intolerance (LPI) is an autosomal recessive disorder in which transport of the cationic amino acids lysine, arginine and ornithine is defective at the basolateral membrane of the epithelial cells in the intestine and renal tubules. LPI is unusually common in Finland, but patients have been described on all continents. Linkage analysis in Finnish LPI families recently assigned the LPI gene locus to a 10 cM interval between markers D14S72 and MYH7 on the long arm of chromosome 14. In the present study linkage analysis of LPI families from six different non-Finnish populations strongly suggests genetic homogeneity in LPI. Peak lod scores were obtained at the chromosomal area between D14S72 and MYH7 with the same markers as in the Finnish families. The non-Finnish families showed no linkage disequilibrium except in an Italian family cluster, whereas strong allelic association in the Finnish families implies that LPI in Finland is caused by a founder mutation.


Psychosocial effects of hysterectomy: literature review.
With the development of less invasive treatments, the suitability of hysterectomy as a treatment for benign symptoms is being reevaluated. This paper critically and comprehensively reviews the psychosocial outcomes of hysterectomy in areas of sexuality, pain, and psychological functioning. Medline, Pub Med, and PsychLit were searched for studies and reviews pertaining to the psychosocial outcomes of hysterectomy. Over 100 studies and reviews, in English, French, and German language, published in the past 30 years were included. Controversial theories and empirical evidence are discussed in the domains of sexuality, pain, and psychological well-being. Special attention is devoted to design, sampling, and measurement issues as well as different surgical approaches with regard to hysterectomy-oophorectomy. While hysterectomy appears to reduce pain, there do not appear strong psychosexual or psychosocial effects. Nonetheless, there may be a subgroup of women (10-20%) who report negative psychosocial outcomes such as reduced sexual interest, arousal, and orgasm, as well as elevated depressive symptoms and impaired body image. More research is necessary to establish which patients may benefit most and which may not. Directions for future research are discussed.


Caloric restriction, aerobic exercise training and soluble lectin-like oxidized LDL receptor-1 levels in overweight and obese post-menopausal women.
Elevated circulating levels of soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) have been observed in obese persons and are reduced by weight loss. However, it is not known whether combining caloric restriction (CR) with exercise training is better in reducing sLOX-1 levels than CR alone. We examined whether the addition of aerobic exercise to a weight loss intervention differentially affects sLOX-1 levels in 61 abdominally obese post-menopausal women randomly assigned to a CR only (n = 22), CR+moderate-intensity exercise (n = 22) or CR+vigorous-intensity exercise (n = 17) intervention for 20 weeks. The caloric deficit was ~2800 kcal per week for all groups. The intervention groups were similar at baseline with respect to body weight, body composition, lipids and blood pressure. However, plasma sLOX-1 levels were higher in the CR-only group (99.90 ± 8.23 pg ml(-1)) compared with both the CR+moderate-intensity exercise (69.39 ± 8.23 pg ml(-1), P = 0.01) and the CR+vigorous-intensity exercise (72.83 ± 9.36 pg ml(-1), P = 0.03) groups. All three interventions significantly reduced body weight (~14%), body fat and waist and hip circumferences to a similar degree. These changes were accompanied by a 23% reduction in sLOX-1 levels overall (-19.00 ± 30.08 pg ml(-1), P < 0.0001), which did not differ among intervention groups (P = 0.13). Changes in body weight, body fat and maximal oxygen consumption (VO(2) max) were not correlated with changes in sLOX-1 levels. In multiple regression analyses in all women combined, baseline sLOX-1 levels (β = -0.70 ± 0.06, P < 0.0001), age (β = 0.92 ± 0.43, P = 0.03) and baseline body mass index (BMI) (β = 1.88 ± 0.66, P = 0.006) were independent predictors of the change in sLOX-1 with weight loss. Weight loss interventions of equal energy deficit have similar effects on sLOX-1 levels in overweight and obese post-menopausal women, with the addition of aerobic exercise having no added benefit when performed in conjunction with CR.


Preliminary study of differentiating smears from cancerous and non-cancerous nasopharyngeal tissue using confocal Raman spectroscopy.
Current practice for diagnosing nasopharyngeal carcinoma (NPC) is based on invasive tissue biopsy. This study aims to explore the feasibility of using Raman spectroscopy to differentiate cancerous and non-cancerous nasopharyngeal tissue smears, expecting to realize minimal invasive diagnosis using smears from in vivo mucosa tissue by Raman spectroscopy. Biopsy tissue smears were acquired from 74 patients with pathologically diagnosed nasopharyngeal diseases and measured using confocal Raman spectroscopy. Both fingerprint region and high wavenumber Raman spectra were acquired with distinguish features. Multivariate statistical analysis was used to differentiate cancerous and non-cancerous groups, achieving a diagnostic sensitivity of 87.2 and specificity of 85.7 % for differentiating NPC from nasopharyngeal non-cancerous smears. This work indicates that the method has a unique advantage in microanalysis for tissue smears which may provide a promising minimal invasive (or noninvasive) diagnosing tool for cancer diagnosis.


Total hydroxyl radical reactivity measurements in a suburban area during AQUAS-Tsukuba campaign in summer 2017.
Missing hydroxyl radical (OH) reactivity from unknown/unmeasured trace species empirically accounts for 10%-30% of total OH reactivity and may cause significant uncertainty regarding estimation of photochemical ozone production. Thus, it is essential to unveil the missing OH reactivity for developing an effective ozone mitigation strategy. In this study, we conducted simultaneous observations of total OH reactivity and 54 reactive trace species in a suburban area as part of the Air QUAlity Study (AQUAS)-Tsukuba campaign for the summer of 2017 to gain in-depth insight into total OH reactivity in an area that experienced relatively high contributions of secondary pollutants. The campaign identified on average 35.3% of missing OH reactivity among total OH reactivity (12.9 s-1). In general, ozone-production potential estimation categorized ozone formation in this area as volatile organic compound (VOC)-limited conditions, and missing OH reactivity may increase ozone production potential 40% on average if considered. Our results suggest the importance of photochemical processes of both AVOCs and BVOCs for the production of missing OH reactivity and that we may underestimate the importance of reducing precursors in approach to suppressing ozone production if we ignore the contribution of their photochemical products.


Status and challenges of electrical stimulation use in chronic wound healing.
Non-healing wounds have led to a soaring clinical and socioeconomical need for advanced wound-care techniques. Electrical stimulation is an emerging therapy inspired by the wound's endogenous electric field. Promising results of clinical trials have encouraged efforts to create wearable stimulation devices, uncover multiple cellular targets, and optimize stimulation regimes. However, the field faces a translational bottleneck. This review aims to highlight the gaps between in vivo treatments and in vitro associated experiments by discussing the current knowledge of the generation, characterization, and targets of electrical stimuli. It becomes clear that enabling the translation of this technology will require increasing the complexity of the current models for skin endogenous and controlled ion transport, and investigating which stimulus has an optimum effect on cells derived from chronic wound-prone patients.


DNA comes in many forms.
Forty years ago, we learned of the major double helical structure adopted by DNA. It combined both elegance and simplicity in its design. Since then we have learned that DNA can also adopt other conformations. We now know that it can exist in a variety of triple-stranded and quadruple-stranded forms, as well as forms that are left-handed. The list of alternative conformations that can be adopted by this molecule is still growing. These conformations represent a major biological challenge to understand their role in biological systems. This type of work represents an active frontier in molecular biology today.


Acoustic source localization in anisotropic plates.
The conventional triangulation technique cannot locate the acoustic source in an anisotropic plate because this technique requires the wave speed to be independent of the propagation direction which is not the case for an anisotropic plate. All methods proposed so far for source localization in anisotropic plates require either the knowledge of the direction dependent velocity profile or a dense array of sensors. In this paper for the first time a technique is proposed to locate the acoustic source in large anisotropic plates with the help of only six sensors without knowing the direction dependent velocity profile in the plate. Experimental results show that the proposed technique works for both isotropic and anisotropic structures. For isotropic plates the required number of sensors can be reduced from 6 to 4.


Efficacy of treatments for anxiety disorders: a meta-analysis.
To our knowledge, no previous meta-analysis has attempted to compare the efficacy of pharmacological, psychological and combined treatments for the three main anxiety disorders (panic disorder, generalized anxiety disorder and social phobia). Pre-post and treated versus control effect sizes (ES) were calculated for all evaluable randomized-controlled studies (n = 234), involving 37,333 patients. Medications were associated with a significantly higher average pre-post ES [Cohen's d = 2.02 (1.90-2.15); 28,051 patients] than psychotherapies [1.22 (1.14-1.30); 6992 patients; P < 0.0001]. ES were 2.25 for serotonin-noradrenaline reuptake inhibitors (n = 23 study arms), 2.15 for benzodiazepines (n = 42), 2.09 for selective serotonin reuptake inhibitors (n = 62) and 1.83 for tricyclic antidepressants (n = 15). ES for psychotherapies were mindfulness therapies, 1.56 (n = 4); relaxation, 1.36 (n = 17); individual cognitive behavioural/exposure therapy (CBT), 1.30 (n = 93); group CBT, 1.22 (n = 18); psychodynamic therapy 1.17 (n = 5); therapies without face-to-face contact (e.g. Internet therapies), 1.11 (n = 34); eye movement desensitization reprocessing, 1.03 (n = 3); and interpersonal therapy 0.78 (n = 4). The ES was 2.12 (n = 16) for CBT/drug combinations. Exercise had an ES of 1.23 (n = 3). For control groups, ES were 1.29 for placebo pills (n = 111), 0.83 for psychological placebos (n = 16) and 0.20 for waitlists (n = 50). In direct comparisons with control groups, all investigated drugs, except for citalopram, opipramol and moclobemide, were significantly more effective than placebo. Individual CBT was more effective than waiting list, psychological placebo and pill placebo. When looking at the average pre-post ES, medications were more effective than psychotherapies. Pre-post ES for psychotherapies did not differ from pill placebos; this finding cannot be explained by heterogeneity, publication bias or allegiance effects. However, the decision on whether to choose psychotherapy, medications or a combination of the two should be left to the patient as drugs may have side effects, interactions and contraindications.


A possible secondary case of pneumococcal meningitis.
Although institutional outbreaks of pneumococcal infection have been reported, secondary cases of pneumococcal meningitis do not seem to have been described. We report two cases of pneumococcal meningitis involving the same serotype occurring in individuals with direct contact.


Comparison of spatiotemporal, kinematic, and kinetic gait characteristics in total and unicompartmental knee arthroplasty during level walking: A systematic review and meta-analysis.
This meta-analysis was performed to compare the spatiotemporal, kinematic, and kinetic gait characteristics during level walking between total knee arthroplasty (TKA) and unicompartmental knee arthroplasty (UKA). An electronic database literature search was performed to screen clinical trials which were included the studies evaluating not only spatiotemporal, kinematic, and kinetic gait parameters, but also knee range of motion and knee score (Knee Society Score and Oxford Knee Score, i.e., KSS and OKS). The data analysis was performed using statistical software Stata 14.0 and Review Manager 5.4. Thirteen studies (369 knees) that met the criteria were eventually included in this meta-analysis. The results revealed significant differences between UKA and TKA with regard to walking speed (P = 0.04), stride length (P = 0.02), maximum knee flexion at loading (P = 0.001), the 1st peak of vert-GRF (P = 0.006), the 1st valley of vert-GRF (P = 0.007), knee internal rotational moment (P = 0.04), knee extension (P < 0.00001), and KSS Function score (P = 0.05). In contrast, there were no statistical differences in the remaining spatiotemporal, kinematic, and kinetic gait parameters. Medial UKA design is superior to TKA design with regard to walking speed, stride length, maximum knee flexion at loading, the 1st peak and the 1st valley of vert-GRF, knee internal rotational moment, knee extension, and KSS Function score. And it could provide a stronger basis for physicians to make clinical decisions.


Do people learn option or strategy routines in multi-attribute decisions? The answer depends on subtle factors.
Various studies have shown that established decision routines may become detrimental in changing environments. Routines can be formed at the level of options or at the level of strategies which has been demonstrated in different lines of research. It is unclear, however, which routinization level is spontaneously preferred if both are possible and equally successful. The first experiment demonstrates that a typical multi-attribute decision task using the MouseLab procedure clearly invites strategy routinization. However, the second experiment shows that this level of routinization is massively context-dependent and will be shifted in line with subtle context cues that direct attention to different aspects of the feedback during learning. Theoretical implications for learning models of decision making are discussed.


[Electroacupuncture for treatment of simple obesity complicated with fatty liver].
To observe clinical therapeutic effect of electroacupuncture (EA) on simple obesity complicated with fatty liver. Thirty cases of such disease were treated with EA at Zhongwan (CV 12), Tianshu (ST 25), Qimen (LR 14), Daimai (GB 26), Yanglingquan (GB 34), etc.. After treatment of 3 months, the therapeutic effect and changes of B-ultrasonography of liver, body weight (BW), body mass index (BMI), fat degree, visceral fatty (VFT) content in the cross region, subcutaneous fat (FAT), waist/hip ratio (WHR) were investigated. After treatment, the total effective rate for slimming was 80.0% and the total effective rate for fatty liver was 80.0%, and body weight, BMI, fat degree, VFA, FAT and WHR significantly decreased (P < 0.01). Electroacupuncture has good slimming action and it is one of effective methods for fatty liver.


Transcriptional profiling in human HaCaT keratinocytes in response to kaempferol and identification of potential transcription factors for regulating differential gene expression.
Kaempferol is the major flavonol in green tea and exhibits many biomedically useful properties such as antioxidative, cytoprotective and anti-apoptotic activities. To elucidate its effects on the skin, we investigated the transcriptional profiles of kaempferol-treated HaCaT cells using cDNA microarray analysis and identified 147 transcripts that exhibited significant changes in expression. Of these, 18 were up-regulated and 129 were down-regulated. These transcripts were then classified into 12 categories according to their functional roles: cell adhesion/cytoskeleton, cell cycle, redox homeostasis, immune/defense responses, metabolism, protein biosynthesis/modification, intracellular transport, RNA processing, DNA modification/ replication, regulation of transcription, signal transduction and transport. We then analyzed the promoter sequences of differentially-regulated genes and identified over-represented regulatory sites and candidate transcription factors (TFs) for gene regulation by kaempferol. These included c-REL, SAP-1, Ahr-ARNT, Nrf-2, Elk-1, SPI-B, NF-kappaB and p65. In addition, we validated the microarray results and promoter analyses using conventional methods such as real-time PCR and ELISA-based transcription factor assay. Our microarray analysis has provided useful information for determining the genetic regulatory network affected by kaempferol, and this approach will be useful for elucidating gene-phytochemical interactions.


Deletion of Abi3 gene locus exacerbates neuropathological features of Alzheimer's disease in a mouse model of Aβ amyloidosis.
Recently, large-scale human genetics studies identified a rare coding variant in the ABI3 gene that is associated with an increased risk of Alzheimer's disease (AD). However, pathways by which ABI3 contributes to the pathogenesis of AD are unknown. To address this question, we determined whether loss of ABI3 function affects pathological features of AD in the 5XFAD mouse model. We demonstrate that the deletion of Abi3 locus significantly increases amyloid β (Aβ) accumulation and decreases microglia clustering around the plaques. Furthermore, long-term potentiation is impaired in 5XFAD;Abi3 knockout ("Abi3−/−") mice. Moreover, we identified marked changes in the proportion of microglia subpopulations in Abi3−/− mice using a single-cell RNA sequencing approach. Mechanistic studies demonstrate that Abi3 knockdown in microglia impairs migration and phagocytosis. Together, our study provides the first in vivo functional evidence that loss of ABI3 function may increase the risk of developing AD by affecting Aβ accumulation and neuroinflammation.


Ergothioneine supplementation in people with metabolic syndrome (ErgMS): protocol for a randomised, double-blind, placebo-controlled pilot study.
Ergothioneine is a naturally occurring metabolite of histidine found in many foods and in high amounts in mushrooms. In vivo, ergothioneine acts as an antioxidant and is widely distributed in most mammalian tissues. While ergothioneine is sold as a dietary supplement for its antioxidant and anti-inflammatory properties, to date there are no published intervention trials examining its health benefits in humans. The aim of this work was to develop a study protocol for a pilot interventional trial that will establish the primary and secondary outcomes, and the power required, for a definitive randomised controlled trial to test the hypothesis that ergothioneine supplementation is beneficial for people with metabolic syndrome. We have designed the ErgMS study as a single-centre, randomised, double-blind, placebo-controlled, 3-arm parallel, pilot intervention trial, which aims to supplement participants with either placebo, 5 or 30 mg/day ergothioneine for 12 weeks. Measurements of metabolic syndrome risk factors, serum markers of oxidative stress (lipid peroxidation), inflammation, blood platelet function and liver function will take place at baseline, and after 6 weeks and 12 weeks of supplementation. In addition, we will examine if there are any changes in the serum metabolome in response to ergothioneine supplementation. Linear regression and two-way ANOVA will be utilised to analyse the association between ergothioneine and measured variables. The ErgMS study will be the first study to address the question does ergothioneine supplementation have health benefits for people with metabolic syndrome. Study results will provide preliminary data as to which dose may improve inflammatory markers in adults with metabolic syndrome and will inform dose and primary outcome selection for a definitive randomised controlled trial. ISRCTN, ISRCTN25890011 Registered February 10th, 2021.


Draft Genome Sequence of the Marine-Derived, Anticancer Compound-Producing Bacterium Streptomyces sp. Strain GMY01.
The marine Streptomyces sp. strain GMY01 was isolated from Indonesian marine sediment. Genome mining analysis revealed that GMY01 has 28 biosynthetic gene clusters, dominated by genes encoding nonribosomal peptide synthetase and polyketide synthase.


Comparison of iSeq and MiSeq as the two platforms for 16S rRNA sequencing in the study of the gut of rat microbiome.
Amplicon-based next-generation sequencing (NGS) of the 16S ribosomal RNA (16S) regions is a culture-free method used to identify and analyze Procaryota occurring within a given sample. The prokaryotic 16S rRNA gene contains conserved regions and nine variable regions (V1-V9) frequently used for phylogenetic classification of genus or species in diverse microbial populations. This work compares the accuracy and efficacy of two platforms, iSeq and MiSeq from Illumina, used in sequencing 16S rRNA. The most important similarities and differences of 16S microbiome sequencing in 20 fecal rat samples were described. Genetic libraries were prepared according to 16S Metagenomic Sequencing Library Preparation (Illumina) for the V3 and V4 regions of the 16S. The species richness obtained using iSeq technology was lower compared to MiSeq. At the second taxonomy level (L2), the abundance of taxa was comparable for both platforms. At the L7, the taxa abundance was significantly different, and the number of taxa was higher for the MiSeq. The alpha diversity was lower for iSeq than for MiSeq, starting from the order to the species level. The beta diversity estimation revealed statistically significant differences in microbiota diversity starting from the class level to the species level in samples sequenced on two investigated platforms. This work disclosed that the iSeq platform could be used to evaluate the bacterial profile of the samples to characterize the overall profile. The MiSeq System seems to be better for a detailed analysis of the differences in the microbiota composition. KEY POINTS: • iSeq platform allows to shorten the sequencing time three times compared to the MiSeq. • iSeq can only be used for an initial and quick microbiome assessment. • MiSeq is better for a detailed analysis of the differences in the microbiota composition.


Monitoring microcirculatory alterations in oral squamous cell carcinoma following photodynamic therapy.
One of the mechanisms through which photodynamic therapy (PDT) is thought to elicit tumour destruction is by producing microvascular damage and obstruction of nutritive blood flow. The aim of this study was to directly monitor and quantify microcirculatory changes following tissue illumination by PDT for oral squamous cell carcinoma. Ten consecutive patients receiving PDT for a carcinoma in situ, a T1 or T2 tumour in the oral cavity without evidence of lymph node metastasis were selected for this study. Tumour and marginal healthy mucosa total capillary density (TCD) and functional capillary density (FCD) inside the field of illumination were measured and compared using sidestream dark-field (SDF) imaging prior to tissue illumination, immediately after PDT, and again after 15min. Baseline mean tumour TCD was 21.2±5capillaries per square millimetres (cpll/mm²) and 24.9±19cpll/mm² in the surrounding marginal healthy tissue; there were no significant differences between tumour and healthy tissue or time points. Comparisons between baseline and post-illumination time points revealed significant differences in both tumour and healthy tissue FCD (P<0.05). No significant differences in FCD were observed between the two tissues. Our findings using SDF imaging demonstrate that PDT significantly attenuates tumour and marginal healthy tissue perfusion by directly disrupting the functionality of the microcirculation.


Exogenous hydrogen sulfide protects against traumatic hemorrhagic shock via attenuation of oxidative stress.
This study was designed to investigate the protective effects of exogenous hydrogen sulfide (H(2)S) on trauma-hemorrhagic shock (T-H). Forty-eight male Sprague-Dawley rats were anesthetized, while 32 were subjected to both midline laparotomy and hemorrhagic shock (35-40 mmHg for 90 min) by bleeding them from the femoral artery. One hour later, resuscitation was initiated with Ringer lactate. NaHS (28 μmol/kg) or vehicle alone was administered intraperitoneally at the onset of resuscitation. Two hours later, eight animals from each group were re-anesthetized to determine cardiac function, blood gas concentrations, and hepatic and renal function. Superoxide dismutase activity (SOD), malondialdehyde concentrations (MDA), and the activity of myeloperoxidase (MPO) in the serum were measured and pulmonary wet/dry (W/D) ratio and histopathologic evaluations performed. NaHS resulted in an increase in mean arterial blood pressure, left ventricular pressure and positive (+dP/dt(max)) and negative (-dP/dt(max)) first derivatives of pressure as compared with the vehicle only group. The pH, PaO(2) and base excess (BE) were increased in the NaHS-treated group compared with the vehicle-treated group. Aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and serum creatinine were reduced in the NaHS-treated group. NaHS also significantly reduced the high mortality rate at 24 h otherwise caused by T-H. The NaHS-treated group showed a remarkable decrease in MDA and MPO concentrations in plasma and an increase in SOD as compared with the vehicle-treated group. Histopathologic analysis indicated less edema, congestion, inflammatory cell infiltration and necrosis in heart, lung, liver and kidney tissue in NaHS-treated group. The present study demonstrates that exogenous H(2)S administered at an appropriate dose confers protective effects after T-H and resuscitation, by preventing a decrease in the antioxidant defense system.


Oculocutaneous albinism associated with Apert's syndrome.
Five of nine patients with Apert's syndrome (acrocephalosyndactyly) showed an associated hypopigmentation of hair, skin, and eyes. The hair color of these five patients ranged from light brown to blond, the skin was pale, and the irides hazel or blue. Iris transillumination and hypopigmentation of the fundus were present and associated with absent or diffuse foveal reflexes. Unlike most forms of classic oculocutaneous albinism, however, there was good visual acuity and no pendular nystagmus. The evidence indicated that the lack of pigmentation associated with the characteristic skeletal anomalies of Apert's syndrome resulted from a disturbance of independent, genetically related, processes occurring at a common point in gestation.


Assessment of peripheral blood neutrophil respiratory burst, phagocytosis and apoptosis in obese non-insulin dysregulated horses.
Obesity is a highly prevalent condition in horses. Dysfunctional neutrophil activity has been reported in metabolically healthy obese humans, but minimal data exist regarding horses. The present study evaluated the effect of obesity on apoptosis, phagocytosis and oxidative burst activity of peripheral blood neutrophils from lean and obese non-insulin dysregulated horses. Seven lean (BCS, body condition score 4-6/9) and five obese (BCS 8-9) horses were enrolled in the study. All animals underwent two metabolic tests (OGT, oral glucose test; IRT, insulin response test) before their selection to ensure their metabolic status (non-insulin dysregulated). A single blood sample was obtained from each horse, and a discontinuous density gradient was carried out to isolate neutrophils. Phagocytosis, apoptosis and reactive oxygen species (ROS) production assays were performed for each animal. All statistical analyses were performed with unpaired two-tailed t-tests. Results indicate that neutrophils from obese non-insulin dysregulated horses have a significantly increased ROS production (P < .0001), with no changes observed on phagocytosis (P > .05) or apoptosis (P > .05) when compared to the control group. In conclusion, our results demonstrate that obesity per se, in absence of other endocrine disorders, alters neutrophil reactive oxygen species production. More research is needed to understand the role of obesity on the equine immune system of horses, and its role in the development of endocrine disorders.


Ion Mobility Spectrometry-Hydrogen Deuterium Exchange Mass Spectrometry of Anions: Part 3. Estimating Surface Area Exposure by Deuterium Uptake.
Gas-phase hydrogen deuterium exchange (HDX), collision cross section (CCS) measurement, and molecular dynamics simulation (MDS) techniques were utilized to develop and compare three methods for estimating the relative surface area exposure of separate peptide chains within bovine insulin ions. Electrosprayed [M - 3H](3-) and [M - 5H](5-) insulin ions produced a single conformer type with respective collision cross sections of 528 ± 5 Å(2) and 808 ± 2 Å(2). [M - 4H](4-) ions were comprised of more compact (Ω = 676 ± 3 Å(2)) and diffuse (i.e., more elongated, Ω = 779 ± 3 Å(2)) ion conformer types. Ions were subjected to HDX in the drift tube using D2O as the reagent gas. Collision-induced dissociation was used to fragment mobility-selected, isotopically labeled [M - 4H](4-) and [M - 5H](5-) ions into the protein subchains. Deuterium uptake levels of each chain can be explained by limited inter-chain isotopic scrambling upon collisional activation. Using nominal ion structures from MDS and a hydrogen accessibility model, the deuterium uptake for each chain was correlated to its exposed surface area. In separate experiments, the per-residue deuterium content for the protonated and deprotonated ions of the synthetic peptide KKDDDDDIIKIIK were compared. The differences in deuterium content indicated the regional HDX accessibility for cations versus anions. Using ions of similar conformational type, this comparison highlights the complementary nature of HDX data obtained from positive- and negative-ion analysis.


Plasma concentration of acetylcholine in young women.
A sensitive and specific radioimmunoassay was applied to the determination of acetylcholine (ACh) in plasma. The concentration of ACh in plasma sampled from 32 young women was 456.1 +/- 53.1 (mean +/- S.E.M.) pg/ml. No significant correlations were observed between plasma concentration of ACh and acetylcholinesterase (AChE) activity, or gonadal hormones. These data demonstrate that an amount of ACh measurable by radioimmunoassay is present in plasma and plasma ACh is not regulated by AChE activity and the menstrual cycle in young women. The origin and physiological as well as pathophysiological significance of ACh in plasma remain to be clarified.


Relationship between body mass index and serum testosterone concentration in patients receiving luteinizing hormone-releasing hormone agonist therapy for prostate cancer.
To evaluate the relationship between the body mass index (BMI) and serum testosterone concentrations in men receiving luteinizing hormone-releasing hormone (LHRH) agonist therapy for prostate cancer. A total of 66 white men were included in the present study. All subjects had received LHRH agonist therapy for ≥ 3 months. The BMI was calculated, and the subjects were classified as normal weight (i.e. BMI <25 kg/m(2)), overweight (BMI 25-30 kg/m(2)), or obese (BMI >30 kg/m(2)). The serum testosterone concentration was determined using the highly sensitive isotope dilution-liquid chromatography-tandem mass spectrometry technique. The sex hormone-binding globulin level was determined using an immunometric assay, and the free serum testosterone concentration was calculated. The median serum testosterone concentration of the patients with a BMI <25 kg/m(2) was 5.5 ng/dL. The patients with a BMI of 25-30 kg/m(2) had a median serum testosterone concentration of 3.8 ng/dL. Those patients with a BMI >30 kg/m(2) had a median concentration of 5.7 ng/dL. No significant difference in the serum testosterone concentrations among the 3 groups was found. The sex hormone-binding globulin levels declined with an increasing BMI. The concentration of free testosterone was significantly greater in the obese men. Using an ultrasensitive technique of serum testosterone measurement, the present data have shown that no difference exists in the serum testosterone concentration in the castrate range among normal weight, overweight, and obese patients receiving LHRH agonist therapy for prostate cancer. From our findings and current knowledge, more stringent follow-up or changes in dosage or dosage intervals of LHRH agonist therapy in those with a greater or high BMI is not warranted.


Posterolateral instability of the elbow in an adolescent boy with a lateral epicondyle fracture: a case report.
Posterolateral rotatory instability of elbow is considered to be due to the disruption of the ulnar part of the lateral collateral ligament (LUCL). This instability pattern may also be induced by a fracture of components of the lateral column. We present the case of a 16-year-old boy who fell on his left outstretched arm as he attempted to jump over a tennis net. On initial physical examination, the elbow had instability found on varus stress and the radial head could be felt posteriorly. With attempted valgus and supination force combined with axial loading, the elbow gapped open and the patient had a sense of increased instability. X-rays showed a fracture of the lateral humeral epicondyle and posterolateral subluxation of the elbow. In the operating room, the patient was found to have reproducible posterolateral instability of the elbow. The lateral epicondyle was found to be fractured off the humerus with the LUCL still attached to the fragment. The elbow was reduced, and the injury was stabilized with small screws and suture anchors. At 6-month follow-up, the patient was pain-free, and physical examination revealed 170° of flexion, full extension, 90° of pronation, and 65° of supination. X-rays showed healing of the fracture with concentric reduction of the elbow joint. In lateral epicondyle fractures, the affected elbow should be assessed for any signs of associated instability. If signs of clear instability are seen that would prohibit proper postinjury rehabilitation, then surgical reduction and fixation of the epicondyle with reinforcement of the LUCL is an effective method of treatment.


Friendship after a friends with benefits relationship: deception, psychological functioning, and social connectedness.
Friends with benefits (FWB) relationships are formed by an integration of friendship and sexual intimacy, typically without the explicit commitments characteristic of an exclusive romantic relationship. The majority of these relationships do not transition into committed romantic relationships, raising questions about what happens to the relationship after the FWB ends. In a sample of 119 men and 189 women university students, with a median age of 19 years and the majority identified as Caucasian (63.6 %), we assessed relationship adjustment, feelings of deception, perception of the FWB relationship and friendship, social connectedness, psychological distress, and loneliness. Results demonstrated that the majority of FWB relationships continued as friendships after the sexual intimacy ceased and that about 50 % of the participants reported feeling as close or closer to their FWB partner. Those who did not remain friends were more likely to report that their FWB relationship was more sex- than friendship-based; they also reported higher levels of feeling deceived by their FWB partner and higher levels of loneliness and psychological distress, but lower levels of mutual social connectedness. Higher levels of feeling deceived were related to feeling less close to the post-FWB friend; also, more sex-based FWB relationships were likely to result in post-FWB friendships that were either more or less close (as opposed to unchanged). FWB relationships, especially those that include more attention to friendship based intimacy, do not appear to negatively impact the quality of the friendship after the "with benefits" ends.


The Effect of Ultrasonication on the Fibrillar/ Oligomeric Structures of Aβ1-42 at Different Concentrations.
The number of disease states linked the aberrant regular protein conformations to oligomers and amyloid fibrils. Amyloid beta 1-42 (Aβ1-42) peptide is very hydrophobic and quickly forms the β-rich structure and fibrillar protein aggregates in some solutions and buffer conditions. Ultrasonication pulses can disrupt amyloid fibrils to smaller fragments and produce Aβ1-42 peptides of different sizes and oligomers. Herein, we investigated the effects of buffer and ultrasonication on Aβ1-42 structure at low and high concentrations. After ultrasonication, the Western blot results showed that Aβ1-42 fibrils were disaggregated into different sizes. The transmission electron microscopy results indicated Aβ1-42 at low concentration (25 µM) in Ham's/F12 phenol red-free culture medium formed short-size fragments and oligomers. In comparison, Aβ1-42 at higher concentration (100 µM) formed fibrils that break down into smaller fragments after ultrasonication. However, after regrowth, it formed mature fibrils again. Cell viability assay indicated that Aβ1-42 oligomers formed at a low concentration (25 µM) were more toxic to PC12 cells than other forms. In conclusion, by applying ultrasonication pulses and controlling peptide concentration and buffer condition, we can rich Aβ1-42 aggregates with a particular size and molecular structure.


Three-dimensional sonographic volume measurement of the fetal cerebellum.
The objective of this longitudinal study was to evaluate the growth of the fetal cerebellum in normal pregnancy by using three-dimensional ultrasound. Three-dimensional sonographic examinations were performed for 13 appropriate-for-gestational-age fetuses. Fetal cerebellar volume was measured every 2 to 3 weeks after 20 weeks of gestational age until delivery. The common multiplanar technique was used to calculate the fetal cerebellar volume. A curvilinear relationship was found between gestational age and cerebellar volume (R(2) = 78.6%, P < 0.0001), and normal ranges of cerebellar volume measurements for estimating the growth of the fetal cerebellum during normal pregnancy were generated. The data gathered in this study were fairly comparable with previous data obtained using three-dimensional ultrasound. However, the normal ranges of cerebellar volume that we determined were relatively wide throughout pregnancy. Our findings suggest that a standard curve for fetal cerebellar volume using three-dimensional ultrasound can play a role in the evaluation of normal cerebellar growth in the fetus. However, we do cast doubt on the reliability and reproducibility of cerebellar volume measurement using three-dimensional ultrasound. Further studies involving a larger sample size and another technique (the rotational method with VOCAL) would be needed to confirm these findings.


Transoral carotid ultrasonography using a micro convex probe with B-flow imaging for extracranial internal carotid artery dissection.
We report on transoral carotid ultrasonography using a micro convex probe with B-flow imaging for determining spontaneous extracranial internal carotid artery dissection just below the petrous portion. A 49-year-old man suffered cortical and subcortical infarction in the region of the right middle cerebral artery. Magnetic resonance angiography on the third day of admission revealed spontaneous recanalization of the right internal carotid artery associated with an intimal flap-like structure at the petrous portion. Transoral carotid ultrasonography using a micro convex probe revealed right extracranial internal carotid artery dissection, showing an increased diameter of the right extracranial internal carotid artery with double lumen formation, stenosis of the true lumen, and a mobile intimal flap in B-flow imaging. Transoral carotid ultrasonography using a micro convex probe was helpful to attempt a self-expanding stent for recanalizing right extracranial internal carotid artery dissection. The patient recovered and was discharged ambulatory. The size of the micro convex probe was optimum for transoral carotid ultrasonography in our patient. Micro convex probe is more commonly used than the standard transoral carotid ultrasonography probe, which lacks versatility. We consider that transoral carotid ultrasonography using a micro convex probe could be routinely used for ultrasonographic evaluation of extracranial internal carotid artery dissection.


Structural insights into G-protein-coupled receptor activation.
G-protein-coupled receptors (GPCRs) are the largest family of eukaryotic plasma membrane receptors, and are responsible for the majority of cellular responses to external signals. GPCRs share a common architecture comprising seven transmembrane (TM) helices. Binding of an activating ligand enables the receptor to catalyze the exchange of GTP for GDP in a heterotrimeric G protein. GPCRs are in a conformational equilibrium between inactive and activating states. Crystallographic and spectroscopic studies of the visual pigment rhodopsin and two beta-adrenergic receptors have defined some of the conformational changes associated with activation.


[Morphofunctional characteristics of the endosteum in connection with bone remodeling].
Current information on the endost structure at different stages of bone remodelling is given on the basis of the original data and literature. Possible causes and character of the bone cells activity changes during the cycle of remodelling at the decreased functional stimulation on the bone structures and under pathological conditions are discussed.


[Notable radiophysicists and radiochemists in Croatia by 1945].
Physicists and chemists were among the first potential victims of occupational exposure to ionising radiation and they were also the first to warn about the harmful effects of radiation on living organisms. This review presents the work of the first notable scientists in the field of radiation science in Croatia from the discovery of radiation (Henry Becquerel in 1896) to 1945. The beginning of radiation science and radiation protection in Croatia can be traced to the end of the 19th century. Our research of the archived material and literature not only gave a deeper insight to the life and work of some of these notable scientists, but also gave a glimpse of previously unknown facts and details important for the history and development of radiation science, radiation protection, as well as medical physics. Our research has shown that Croatian scientists not only kept pace with contemporary scientific knowledge but also made notable contributions from the very beginning.


Immunoaffinity purification and functional characterization of interphase and meiotic Drosophila nuclear lamin isoforms.
Three isoforms of a single nuclear lamin have been identified in Drosophila. Two, lamins Dm1 and Dm2, are present during interphase and are apparently in equilibrium with each other in vivo. The third, lamin Dmmit, is found in cells that have undergone nuclear envelope breakdown, either during meiosis or mitosis. All three isoforms were purified under nondenaturing conditions using a novel technique of immunoaffinity chromatography and their in vitro activities were examined. Interphase lamins Dm1 and Dm2 can assemble into filaments at physiologic ionic strength; assembly is reversible upon addition of concentrated NaCl. Negative staining of filaments formed in vitro shows long, unbranched bundles approximately 20 nm in diameter. Addition of specific antilamin antibodies blocks in vitro assembly completely. In contrast with lamins Dm1 and Dm2, lamin Dmmit remains soluble at physiologic ionic strength. These observations are consistent with the notion that lamina disassembly in vivo is due, at least in part, to changes in properties of the lamins themselves.


CXCR3 from chemokine receptor family correlates with immune infiltration and predicts poor survival in osteosarcoma.
Chemokine receptors have a crucial role in regulating tumor mediating immunity and are also implicated in the prognosis of some cancers. Here, the association between CXC chemokine receptors (CXCR2-5) and prognosis in osteosarcoma was studied. Differences between CXCR2, CXCR3, CXCR4, and CXCR5 expression and overall survival (OS) and event-free survival (EFS) were compared using Kaplan-Meier analyses. The associations of CXCR3 expression with clinical features and the prognosis were also analyzed. The signaling pathways modulated by CXCR3 were investigated. The correlations between CXCR3 and immune infiltrates were investigated. The expression of CXCR2, CXCR4, and CXCR5 was not associated with the prognosis, but CXCR3 low expression was correlated with worse OS and EFS of osteosarcoma, especially for female, patients aged less than 15.1 years, or patients without metastasis. Low CXCR3 expression was related to tumor site and histologic response (P<0.05), but not associated with other clinical characteristics. Multivariate Cox analysis revealed that CXCR3 remained independently associated with the prognosis, especially for OS (hazard ratio (HR) = 3.26, 95% CI = 1.15-9.24, P=0.026). The cell adhesion, apoptosis, metabolism, KRAS, P53, NOTCH, reactive oxygen species (ROS), PI3K/Akt/mTOR, vascular endothelial growth factor (VEGF), inflammation, and immune-related pathways such as IL-6/JAK/STAT3, TNF-α via NF-κB, Toll/NOD-like receptor, and complement were modulated by CXCR3. CXCR3 expression showed an especially positive correlation with immune infiltration of T cells CD8, macrophages M1, plasma cells, and NK cells activated. CXCR3 may be an independent risk factor for the prognosis and is most likely to benefit from immunotherapy in osteosarcoma.


Role of biliary stress manometry after biliary stricture dilation in living donor liver transplant recipients.
To report on the use of biliary manometry for determining treatment completion in living donor liver transplant recipients. Twenty of 85 patients (24%) who underwent living donor liver transplantation developed postoperative anastomotic biliary strictures. Fifteen patients underwent transhepatic biliary drainage and percutaneous dilation. In 10 patients, biliary stress manometry was used to assess treatment adequacy after a mean of 2.5 dilation sessions occurring during a mean period of 62 days (range, 5-55 days). An intrabiliary pressure of less than 20-cm H2O after an escalating intrabiliary infusion to 1,200 mL per hour for 3 minutes was defined as the success threshold (in lieu of a capped external catheter "clinical trial"). There were no complications during the infusion study. In all 10 patients in whom manometry was successful, biliary catheters were removed. One patient (who underwent manometry and catheter removal after only one dilation session) required repeat intubation 7 weeks later. The remaining nine patients (90%) remained free of evidence of biliary obstruction at a mean of 8.4 months. With Kaplan-Meier survival analysis, the probability of biliary patency at 3, 6, and 12 months was 90%. This biliary stress manometry protocol offers a promising alternative to the catheter "clinical trial" for determining endpoints for multisession anastomotic biliary stricture dilation in living donor transplant recipients.


Protonation state of Asp30 exerts crucial influence over surface loop rearrangements responsible for NO release in nitrophorin 4.
pK(a) values of ionizable residues were calculated for the crystal structures describing the pH and NO binding dependant conformations of nitrophorin 4, a pH sensitive NO carrier heme protein. Comparison of resultant H-bonding patterns allowed the identification of the amino acids that take part in signaling pH change. We carried out MD simulations to show that the protonation state of Asp30, buried in the closed conformation, is crucial for maintaining the tight packed conformation of the closed form of the complex - presenting a model for the functional decrease of NO binding affinity of nitrophorins at physiological pH.


The lateral thoracic nerve and the cutaneous maximus muscle--a novel in vivo model system for nerve degeneration and regeneration studies.
We report a novel in vivo mouse model system to study regeneration of injured motor nerve and spatiotemporal pattern of denervation in experimental nerve diseases. The lateral thoracic nerve (LTN), as a pure motor nerve, innervates the cutaneous maximus muscle (CMM) by some of the shortest and the longest motor nerve fibers in the mouse body. Its branches and nerve terminals can be imaged in whole mount preparations. Here we describe the branching pattern of the LTN and its innervation of the CMM, and characterize degeneration and regeneration over time after a LTN crush by morphological and electrophysiological analyses. We demonstrate the utility of this model in a well-established neurotoxicity paradigm and in a genetic disease model of the peripheral neuropathy. Furthermore, this system enables punch biopsies that allow repeated and multi-location examinations for LTN regeneration and CMM reinnervation over time. The presence of the LTN and the CMM in a variety of species and its easy accessibility suggests that this in vivo model system offers considerable promise for future nerve degeneration and regeneration research.


Calcium gradients and exocytosis in bovine adrenal chromaffin cells.
The relationship between the localized Ca(2+) concentration and depolarization-induced exocytosis was studied in patch-clamped adrenal chromaffin cells using pulsed-laser Ca(2+) imaging and membrane capacitance measurements. Short depolarizing voltage steps induced Ca(2+) gradients and small "synchronous" increases in capacitance during the pulses. Longer pulses increased the capacitance changes, which saturated at 16 fF, suggesting the presence of a small immediately releasable pool of fusion-ready vesicles. A Hill plot of the capacitance changes versus the estimated Ca(2+) concentration in a thin (100 nm) shell beneath the membrane gave n = 2.3 and K(d) = 1.4 microM. Repetitive stimulation elicited a more complex pattern of exocytosis: early pulses induced synchronous capacitance increases, but after five or more pulses there was facilitation of the synchronous responses and gradual increases in capacitance continued between pulses (asynchronous exocytosis) as the steep submembrane Ca(2+) gradients collapsed. Raising the pipette Ca(2+) concentration led to early facilitation of the synchronous response and early appearance of asynchronous exocytosis. We used this data to develop a kinetic model of depolarization-induced exocytosis, where Ca(2+)-dependent fusion of vesicles occurs from a small immediately releasable pool with an affinity of 1-2 microM and vesicles are mobilized to this pool in a Ca(2+)-dependent manner.