Planktonic contact rates in homogeneous isotropic turbulence: theoretical predictions and kinematic simulations.
The key role played by turbulence in the environment of plankton and larval fish populations has become appreciated in recent years. In particular, the turbulent enhancement of encounter rates between different species of microorganisms, either swimming or passively advected by the flow, is well established. However, most of the current modelling approaches are rather ad hoc, giving rise to ambiguities in the specification of certain key parameters. In this paper, the encounter problem in a turbulent flow of large Reynolds number is re-examined from first principles and a number of new formulae will be established for different swimming strategies. The key innovation is the proposal of a model form for the conditional joint probability density function of predator and prey velocities when the organisms are separated by their given contact radius, R. Particular attention will be paid to the case when a microorganism follows a random trajectory, due to a combination of its own swimming and the action of the flow. The theoretical predictions are subsequently tested against corresponding quantities derived from a series of kinematic simulations of a turbulent-like flow field. Good agreement is demonstrated between the predictions and simulations.


A comparison of calcium-activated potassium channel currents in cell-attached and excised patches.
Single channel currents from Ca-activated K channels were recorded from cell-attached patches, which were then excised from 1321N1 human astrocytoma cells. Cells were depolarized with K (110 mM) so that the membrane potential was known in both patch configurations, and the Ca ionophore A23187 or ionomycin (20-100 microM) was used to equilibrate intracellular and extracellular [Ca] (0.3 or 1 microM). Measurements of intracellular [Ca] with the fluorescent Ca indicator quin2 verified that [Ca] equilibration apparently occurred in our experiments. Under these conditions, where both membrane potential and intracellular [Ca] were known, we found that the dependence of the channel percent open time on membrane potential and [Ca] was similar in both the cell-attached and excised patch configuration for several minutes after excision. Current-voltage relations were also similar, and autocorrelation functions constructed from the single channel currents revealed no obvious change in channel gating upon patch excision. These findings suggest that the results of studies that use excised membrane patches can be extrapolated to the K-depolarized cell-attached configuration, and that the relation between [Ca] and channel activity can be used to obtain a quantitative measure of [Ca] near the membrane intracellular surface.


Current and novel biomarkers of thrombotic risk in COVID-19: a Consensus Statement from the International COVID-19 Thrombosis Biomarkers Colloquium.
Coronavirus disease 2019 (COVID-19) predisposes patients to thrombotic and thromboembolic events, owing to excessive inflammation, endothelial cell activation and injury, platelet activation and hypercoagulability. Patients with COVID-19 have a prothrombotic or thrombophilic state, with elevations in the levels of several biomarkers of thrombosis, which are associated with disease severity and prognosis. Although some biomarkers of COVID-19-associated coagulopathy, including high levels of fibrinogen and D-dimer, were recognized early during the pandemic, many new biomarkers of thrombotic risk in COVID-19 have emerged. In this Consensus Statement, we delineate the thrombotic signature of COVID-19 and present the latest biomarkers and platforms to assess the risk of thrombosis in these patients, including markers of platelet activation, platelet aggregation, endothelial cell activation or injury, coagulation and fibrinolysis as well as biomarkers of the newly recognized post-vaccine thrombosis with thrombocytopenia syndrome. We then make consensus recommendations for the clinical use of these biomarkers to inform prognosis, assess disease acuity, and predict thrombotic risk and in-hospital mortality. A thorough understanding of these biomarkers might aid risk stratification and prognostication, guide interventions and provide a platform for future research.


Psychiatric symptoms and psychosocial problems in primary health care as seen by doctors.
All visits at a primary health care centre in Sweden were studied during four weeks. The frequency of psychiatric symptoms or psychosocial problems noted by the doctors was recorded on a special form in addition to routine registration of diagnoses. Such problems were noted in 553 out of 3 205 visits, corresponding to 17.3%. Considerable variation in registering problems was found between individual physicians and between different categories of doctors. The most common problems were nervousness, anxiety, psychosomatic disorders, and depression. Mental problems were especially common in connection with gastritis, precordial pain, and abdominal pain. There was a difference between the sexes: 20% of the female patients had mental problems registered compared with 14% of the male patients. Psychiatric diagnoses, however, were registered in only 6% of all cases. Of the 553 patients with mental problems, 16% were considered in need of a specialist, 52% could be dealt with at the health centre, and for 32% no special treatment for the mental problems was regarded necessary. One conclusion is that the routine registration of diagnoses at the health centre covers only some of the mental problems and is therefore insufficient in terms of planning psychiatric resources and the training of doctors. Possible reasons for the differences found are discussed.


[A new method to test vertical ocular deviations using perilimbal light reflexes].
To develop a new diagnostic technique to determine vertical ocular deviations when the center of the pupil is covered by swollen eyelids in up- and downgaze. In upgaze (downgaze) the reflex of a diagnostic lamp held at about 50 cm distance from the patient is observed on the lower (upper) limbus. In the case of an asymmetric reflex, prisms are used to obtain symmetrical reflexes. The amount of prisms indicates the size of the vertical misalignment. In five healthy volunteers, the angles of vertical changes of gaze position were plotted against the prism size needed to recenter the perilimbal reflex. There was a linear correlation between the amount of upgaze changes in degrees and the strength of prisms used for compensation in degrees. This linear correlation was also found in downgaze. For both the correlation coefficient was r = 0.98 +/- 0.01. In upgaze the slope of the average regression line was 0.55 +/- 2.3 degrees, in downgaze - 4.1 +/- 0.8 degrees. A prism of 1 degrees corresponds in upgaze to a vertical deviation of about 1.3 +/- 0.14 degrees, in downgaze to a deviation of about 1.1 +/- 0.07 degrees. These results demonstrate that the perilimbal light reflex test is suitable for measuring simulated vertical ocular deviations. Therefore, the test may also be used in patients with vertical deviations who cannot be measured with classical methods. The method is more exact for measurements in upgaze.


DPP-4 inhibitor and alpha-glucosidase inhibitor equally improve endothelial function in patients with type 2 diabetes: EDGE study.
Alpha glucosidase inhibitor (GI) attenuates postprandial hyperglycemia (PPH) and reduces the risk of cardiovascular events in patients with impaired glucose tolerance or type 2 diabetes. Dipeptidyl peptidase 4 (DPP-4) inhibitors also attenuate PPH. PPH is one of the factors leading to endothelial dysfunction which is an early event in the pathogenesis of atherosclerosis. Furthermore, DPP-4 inhibitors protect endothelial function through a GLP-1-dependent mechanism. However, the impact of these two types of drugs on endothelial dysfunction in patients with type 2 diabetes has not been fully elucidated. We compared the effects of sitagliptin, a DPP-4 inhibitor, and voglibose, an alpha GI, on endothelial function in patients with diabetes. We conducted a randomized prospective multicenter study in 66 patients with type 2 diabetes who did not achieve the treatment goal with sulfonylurea, metformin or pioglitazone treatment; 31 patients received sitagliptin treatment and 35 patients, voglibose treatment. The flow-mediated dilatation (FMD) of the brachial artery was measured in the fasting state at baseline and after 12 weeks of treatment. The primary endpoint was a change in FMD (ΔFMD) from the baseline to the end of follow-up. The effects of sitagliptin and voglibose on FMD were assessed by ANCOVA after adjustment for the baseline FMD, age, sex, current smoking, diabetes duration and body mass index. Secondary efficacy measures included changes in HbA1c, GIP, GLP-1, C-peptide, CD34, lipid profile, oxidative stress markers, inflammatory markers and eGFR and any adverse events. ΔFMD was significantly improved after 12 weeks of treatment in both groups, and there was no significant difference in ΔFMD between the two groups. There were no significant differences in changes in HbA1c, GIP, GLP-1, C-peptide, lipid profile, oxidative stress marker, inflammatory marker and eGFR between the two groups. Compared with voglibose, sitagliptin significantly increased the circulating CD34, a marker of endothelial progenitor cells. Adverse events were observed in 5 patients in only the voglibose group (diarrhea 1, nausea 1, edema 2 and abdominal fullness 1). Sitagliptin improved endothelial dysfunction just as well as voglibose in patients with type 2 diabetes. Sitagliptin had protective effects on endothelial function without adverse events. registered at http://www.umin.ac.jp/ctrj/ under UMIN000003951.


Comparison of in vitro and in vivo bioassays to measure thyroid hormone disrupting activity in water extracts.
Environmental chemicals can induce thyroid disruption through a number of mechanisms including altered thyroid hormone biosynthesis and transport, as well as activation and inhibition of the thyroid receptor. In the current study six in vitro bioassays indicative of different mechanisms of thyroid disruption and one whole animal in vivo assay were applied to 9 model compounds and 4 different water samples (treated wastewater, surface water, drinking water and ultra-pure lab water; both unspiked and spiked with model compounds) to determine their ability to detect thyroid active compounds. Most assays correctly identified and quantified the model compounds as agonists or antagonists, with the reporter gene assays being the most sensitive. However, the reporter gene assays did not detect significant thyroid activity in any of the water samples, suggesting that activation or inhibition of the thyroid hormone receptor is not a relevant mode of action for thyroid endocrine disruptors in water. The thyroperoxidase (TPO) inhibition assay and transthyretin (TTR) displacement assay (FITC) detected activity in the surface water and treated wastewater samples, but more work is required to assess if this activity is a true measure of thyroid activity or matrix interference. The whole animal Xenopus Embryonic Thyroid Assay (XETA) detected some activity in the unspiked surface water and treated wastewater extracts, but not in unspiked drinking water, and appears to be a suitable assay to detect thyroid activity in environmental waters.


Expression of cytoskeletal elements in proliferating cells following radiation exposure.
Previous work has demonstrated that radiation exposure modulates the expression of a series of genes, including those that encode cytoskeletal elements. The experiments reported here were designed to examine (1) the comparative effects of neutrons administered at high versus low dose-rates, (2) the comparative effects of neutrons on cycling versus resting cells and (3) the comparative effects of neutrons versus gamma-rays on beta- and gamma-actin mRNA accumulation in Syrian hamster embryo (SHE) cells 1 and 3 h post-irradiation. JANUS fission-spectrum neutrons from Argonne National Laboratory's JANUS reactor administered at high (12 cGy/min) dose-rates had little effect on resting cells, but at very low dose-rates (0.1 cGy/min) had a repressive effect on gamma-actin mRNA accumulation. Increased accumulation of beta-actin mRNA was detected following the exposure of cells to neutrons administered at high dose-rates, but repression of beta-actin mRNA was observed when neutrons were administered at low dose-rates. Cycling cells (unexposed and neutron irradiated) in all cases expressed higher levels of all actin-specific mRNAs than resting cells; beta-actin mRNA (but not gamma-actin mRNA) was induced to a greater extent in cycling cells than in resting cells during the first hour following neutron exposure. In resting cells, however, low dose-rate neutrons were more effective than low dose-rate gamma-rays at repressing both gamma- and beta-actin mRNA accumulation. These results demonstrate the differential effects of radiation quality (neutrons versus gamma-rays) and cell-cycle state on the modulation of actin isotype-specific gene expression.


Calmodulin-like protein enhances myosin-10 translation.
Myosin-10 (Myo10) is involved in processes ranging from filopodial formation and extension to spindle orientation during cell division. Myo10 contains three IQ motifs that bind calmodulin and calmodulin-like protein (CLP) as light chains. We recently found that CLP expression up-regulates Myo10, leading to increased Myo10-dependent cell motility and filopodial extension [R.D. Bennett, et al., J. Biol. Chem. 282 (2007) 3205-3212]. CLP-dependent Myo10 up-regulation occurs without increase in Myo10 mRNA. We followed Myo10 degradation in vivo and in vitro and found that it was unaffected by CLP. Myo10 decayed rapidly with a half-life of approximately 2.5h. Using an in vitro transcription/translation system we determined that CLP increased Myo10 translation, resulting in a higher relative accumulation of Myo10 in the presence than in the absence of CLP. Our data suggest that CLP functions to increase translation of Myo10 possibly by acting as a chaperone for the emerging Myo10 heavy chain protein.


Optically active carbon: kinetic resolution of c76 by asymmetric osmylation.
The chiral fullerene C(76) was kinetically resolved by asymmetric osmylation providing an example of an optically active allotrope of a pure element. C(76) recovered from the treatment of racemic C(76) with OsO(4) and a chiral alkaloid ligand, showed a specific rotation [alpha](D) of -4000 degrees (> 97 percent enantiomeric excess) and a circular dichroism spectrum corresponding to the ultraviolet spectrum. Regenerated C(76) formed by reducing the asymmetrically osmylated C(76) with SnCl(2) was enriched in the opposite enantiomer. Analysis of the local curvature of the C(76) molecule indicated that OsO(4) should selectively add to 2 of the 30 types of bonds in C(76). This regioselectivity was supported chromatographically and interpreted in terms of the kinetic resolution.


Alcohol use disorder pharmacotherapy and treatment in primary care (ADaPT-PC) trial: Impact on identified barriers to implementation.
Background: A minority of individuals meeting diagnostic criteria for alcohol use disorders (AUD) receive any type of formal treatment. Developing options for AUD treatment within primary care settings is imperative to increase treatment access. A multi-faceted implementation intervention including provider and patient education, clinician reminders, development of local champions and ongoing facilitation was designed to enhance access to AUD pharmacotherapy in primary care settings at three large Veterans Health Administration (VHA) facilities. This qualitative study compared pre-implementation barriers to post-implementation barriers identified via provider interviews to identify those barriers addressed and not addressed by the intervention to better understand the limited impact of the intervention. Methods: Following the nine-month implementation period, primary care providers at the three participating facilities took part in qualitative interviews to collect perceptions regarding which pre-implementation barriers had and had not been successfully addressed by the intervention. Participants included 20 primary care providers from three large VHA facilities. Interviews were coded using common coding techniques for qualitative data using the Consolidated Framework for Implementation Research (CFIR) codebook. Summary reports were created for each CFIR construct for each facility and the impact of each CFIR construct on implementation was coded as positive, neutral, or negative. Results: Some barriers identified during pre-implementation interviews were no longer identified as barriers in the post-implementation interviews. These included Relative Advantage, Relative Priority, and Knowledge & Beliefs about the Innovation. However, Compatibility, Design Quality & Packaging, and Available Resources remained barriers at the end of the implementation period. No substantial new barriers were identified. Conclusions: The implementation intervention appears to have been successful at addressing barriers that could be mitigated with traditional educational approaches. However, the intervention did not adequately address structural and organizational barriers to implementation. Recommendations for enhancing future interventions are provided.


Natural history of atopic dermatitis and its relationship to serum total immunoglobulin E in a population-based birth cohort study.
We investigated the natural history of atopic dermatitis (AD) in a population-based birth cohort and assessed whether children at risk of visible eczema at 5 years of age can be identified from total immunoglobulin E (IgE) levels measured at 8, 12 and 18 months. AD data collected included a whole body examination for visible eczema at 49 months (4 years) and 61 months (5 years) of age and parent completed questionnaire data throughout their early lives. Children were divided into four groups based on their natural history of early AD: persistent (AD at 1, 6, 18, 30 and 42 months, n = 34), intermittent early onset (before 18 months of age, n = 495), intermittent late onset (18-42 months of age, n = 273) and unaffected (n = 429). Visible eczema at 5 years of age was present in 12.2% (117/957) (95% confidence interval [CI] 10.1-14.3%) of the children. Levels of total IgE at 8, 12 and 18 months of age were associated with early onset of AD, but not with AD of later onset. For all four natural history groups, the geometric mean total IgE at 12 months was higher in those who subsequently had visible eczema than those who did not. However, the degree of overlap was such that total IgE at 12 months of age was a poor predictor of eczema at age five. A cutoff point of 78 kU/l had the highest positive predictive value for visible eczema at 5 years of age of 28.6%, with a sensitivity of 12% and specificity of 95%.


Cryoablation of recurrent sacrococcygeal tumors.
To review the safety and efficacy of cryoablation of recurrent sacrococcygeal tumors. The radiology departmental ablation database was retrospectively searched for cases of cryoablation performed to treat recurrences of sacrococcygeal tumors between January 1, 2010, and August 1, 2011. Patient demographics, procedure technical parameters, and patient outcomes were reviewed. Five cases of recurrent chordoma and one recurrent myxopapillary ependymoma were treated with cryoablation in six patients whose ages ranged from 31 to 80 years. The tumors measured 14-39 mm in maximal dimension. Cryoablation was performed with the use of computed tomography guidance (n = 5) or a combination of ultrasound and magnetic resonance imaging guidance (n = 1). Sterile fluid was instilled to displace adjacent bowel and/or vagina in four cases, and electromyography monitoring was performed in two cases with adjacent nerve roots. Two patients with recurrent chordoma were treated for palliation of pain, with complete pain relief in one patient (pain recurred after 6 wk) and immediate reduction in pain from a score of six to a score of two on a 10-point scale in the other (pain recurred after 7 mo). Four tumors were treated for local control, with no evidence of recurrence on follow-up imaging at 3, 6, 12, and 15 months. No serious complication occurred. Limited results suggest cryoablation to be a safe and relatively effective means of treating recurrent sacrococcygeal neoplasms for local control or palliation of pain in this small series with short-term follow-up.


Contextualized access to electronical health records in cardiology.
In this paper, we propose a new approach for accessing the electronical health records (EHR), and we apply it to the cardiology medical specialty. Though the use of EHR improves the storage and access to the information in it regarding the previous health records in papers, it entails the risk of having the same problems of huge size and of becoming inoperative and really difficult to handle, especially if the user is looking for a specific data item. Our proposal is based on the contextualization of the access, providing the user with the most important information for the assistance act in which he/she is involved. To do this, we define the set of possible contexts and consider different aspects of the pertinence of the documents to each context. We do it by using fuzzy logic and pay special attention to the efficiency, due to the huge size of the involved databases. Our proposal does not limit the access to the EHR, but establishes a prioritization based on the access needs, which provides the system with an additional advantage, easily enabling the use of new terminals and devices like tablet PCs and PDAs, which have great limitations in the interfaces.


Analysis of unstable recombinant Saccharomyces cerevisiae population growth in selective medium.
Widely applied selection strategies for plasmid-containing cells in unstable recombinant populations are based upon synthesis in those cells of an essential, selection gene product. Regular partitioning of this gene product combined with asymmetric plasmid segregation produces plasmid-free cells which retain for some time the ability to grow in selective medium. This theory is elaborated here in terms of a segregated model for an unstable recombinant population which predicts population growth characteristics and composition based upon experimental data for stable strain growth kinetics, plasmid content, and selection gene product stability. Analytical solutions from this model are compared with an unsegregated phenomenological model to evaluate the effective specific growth rate of plasmid-free cells in selective medium. Model predictions have been validated using experimental growth kinetics and flow cytometry data for Saccharomyces cerevisiae D603 populations containing one of the plasmids YCpG1ARS1, YCpG1DeltaR8, YCpG1DeltaR88, YCpG1DeltaH103, YCpG1DeltaH200, pLGARS1, and pLGSD5. The recombinant strains investigated encompass a broad range of plasmid content (from one to 18 plasmids per cell) and probability alpha of plasmid loss at division (0.05 <or= alpha <or= 0.42). Experimental data for all strains considered is inconsistent with the hypothesis that plasmid-free cells are unable to grow in selective medium. For a given value of a, the fraction of plasmid-containing cells in the population decreases with increasing plasmid content and increases for less stable selection gene products. This conceptual framework and mathematical model will aid in strain development for greater effective stability.


Appraising efficiency of OpSite as coolant in drilling of bone.
During drilling of bone, which is common in clinical surgeries, heat generation increases local temperature in the drilling site. Transmission of excessive heat to the surrounding bone tissue can cause thermal osteonecrosis. Consequently, it may lead to failure of implants and fixation screws or delay in healing process. Using cooling is a method for limiting temperature elevation. In this study, through comparing three conditions of drilling without cooling, external cooling with normal saline, and external cooling with OpSite spray, the efficiency of OpSite as coolant is studied. In this regard, 2 drill bit diameters, 3 drilling speeds, and 3 drilling feed-rates are considered as drilling variables in the experiments. For the whole experiments, while cooling with normal saline resulted in lower maximum temperatures than without cooling condition, OpSite had even better results and limited the temperature elevation during drilling of bone efficiently. OpSite spray, which has lower infection risks than normal saline on one hand and lower maximum temperature rise with all combinations of drilling parameters on the other hand, can be considered in clinical surgeries for cooling applications.


Hysteroscopy in cases of cervical polyps.
To assess the usefulness of hysteroscopy in cases of cervical polyps, we studied 78 patients with a lesion found during a routine gynecological examination. All women were referred for diagnostic hysteroscopy followed by endoscopic polypectomy. In 83.3% of the cases intrauterine investigation confirmed primary diagnosis - a polyp peduncle in the cervical canal. Sixty-five of those lesions were the only pathologic condition, and six (7.7%) were associated with an endometrial polyp. In the remaining 16.7% of examined patients, primary polyps identified as cervical polyps appeared to be endometrial. All women admitted to the study were successfully treated by hysteroscopy. Our results suggest that endoscopic evaluation of the uterine cavity in women with cervical polyps can clarify the initial diagnosis. Hysteroscopy allows not only a precise visualisation of the polyp peduncle but also gives the possibility to identify and treat concurrent asymptomatic intrauterine pathological conditions.


Tonic-to-phasic shift of lumbo-pelvic muscle activity during 8 weeks of bed rest and 6-months follow up.
Prior motor control studies in unloading have shown a tonic-to-phasic shift in muscle activation, particularly in the short extensors. Tonic muscle activity is considered critical for normal musculoskeletal function. The shift from tonic-to-phasic muscle activity has not been systematically studied in humans in unloading nor at the lumbo-pelvic (LP) region. Ten healthy young male subjects underwent 8 wk of bed rest with 6-mo follow up as part of the "Berlin Bed-Rest Study." A repetitive knee movement model performed in the prone position is used to stimulate tonic holding LP muscle activity, as measured by superficial EMG. Tonic and phasic activation patterns were quantified by relative height of burst vs. baseline electromyographic linear-envelope signal components. Statistical analysis shows a shift toward greater phasic activity during bed rest and follow up (P < 0.001) with a significant interaction across muscles (P < 0.001) specifically affecting the short lumbar extensors. These changes appear unrelated to skill acquisition over time (P all > or = 0.196). This change of a shift from tonic LP muscle activation to phasic is in line with prior research on the effects of reduced weight bearing on motor control.


InsNET: Accurate Basal and Bolus Insulin Dose Prediction for Closed Loop Diabetes Management.
It has been demonstrated that closed-loop diabetes management results in better glycemic control and greater compliance than open-loop diabetes management. Deep learning models have been used to implement different components of artifical pancreas. In this work, a novel deep learning model InsNET has been proposed to estimate the basal and bolus insulin level and insulin bolus in patients with type I diabetes utilizing subcutaneous insulin infusion pumps for closed loop diabetes management system. The proposed InsNET is formed with a Wide-Deep combination of LSTM and GRU layers. Additionally, physical activity level has been included as an input in comparison to previous models where only past glucose levels (CGM), meal intake (CHO) and past insulin dosage were used as inputs. The proposed model was tested on In-silico data, and it achieved a Mean Absolute Error (MAE) of 0.002 and Root Mean Squared Error (RMSE) of 0.007 for UVA/Padova Dataset and MAE of 0.001 and RMSE OF 0.003 for mGIPsim Dataset.Clinical relevance- Insulin dose determination is an important as aspect of artificial pancreas. This work describes a deep learning model to determine accurate basal and bolus insulin dosage.


Inflammatory carcinoma of the breast. Clinical review and summary of the Vanderbilt experience with multi-modality therapy.
Inflammatory breast cancer is a distinct clinicopathologic entity that accounts for 1 percent of all cases of breast cancer. The diagnosis should be strongly suspected on the basis of the distinctive clinical findings, which include edema of the breast, inflammation, wheals, and a typical reddish-purple color of the overlying skin. Pathologic examination usually shows infiltration of the dermal lymphatics with carcinoma. Evidence of distant metastatic spread is more frequent than with other types of breast cancer and is seen in approximately 30 percent of patients. The five-year disease-free survival rate is less than 5 percent when local therapy alone (mastectomy and/or local radiotherapy) is used. The addition of combination chemotherapy to high-dose local radiotherapy has improved the five-year survival rate to approximately 30 percent. The potential for long-term survival is limited to the subgroup of patients with only local-regional disease at the time of diagnosis. Patients with inflammatory breast cancer should be treated with combined-modality therapy using combination chemotherapy and high-dose radiotherapy to the breast, since this approach is potentially curative. The fatalism formerly associated with this diagnosis is no longer warranted, particularly in patients with local-regional disease. Failure to employ intensive combined-modality treatment will deny some patients a chance for long-term survival.


Evaluation of neonatal exposure to cocaine on learning, activity, startle, scent marking, immobility, and plasma cocaine concentrations.
Prenatal cocaine treatment produces equivocal effects on spatial learning and memory; however, no data are available on neonatal treatment as a model of human third-trimester exposure. Sprague-Dawley rats were treated on postnatal days (P) 1-10 or 11-20 with cocaine (15 mg/kg x 4 per day at 2-h intervals) or saline (P1-P20) and evaluated as adults in the Morris water maze and on tests of activity, startle, scent marking, swimming immobility, and sequential learning. Neonatal cocaine had no effect on mortality; however, early treatment reduced body weight, whereas later treatment did not. Neonatal cocaine had no effects on exploratory activity, swimming ability, sequential learning, multiday activity rhythms, scent marking, or swimming immobility, but augmented acoustic startle amplitude in the early-treated group. Neonatal cocaine also produced an interaction on spatial learning in which the cocaine early-treated males performed slightly more efficiently than controls. Plasma cocaine concentrations were significantly higher in the early-treated group than the later-treated group despite receiving the same weight-adjusted doses. It was concluded that neonatal cocaine, when administered during a stage of brain development analogous to human third trimester, induces few behavioral effects based on the assessments used in this study.


Maternal prenatal social contact during the COVID-19 pandemic predicts infant birth weight.
Social connectedness and mental health have been associated with infant birth weight, and both were compromised by the COVID-19 pandemic. We sought to examine whether changes in maternal prenatal social contact due to the COVID-19 pandemic were associated with infant birth weight and if maternal prenatal mental health mediated this association. A longitudinal study of mothers and their infants born during the first wave of the COVID-19 pandemic. The sample consisted of 282 United States-based mother-infant dyads. Depressive symptoms were measured with the Beck Depression Inventory-II, anxiety was measured with the State Anxiety Inventory, and stress was measured using the Perceived Stress Scale 14. We also asked participants about pandemic-related changes in social contact across various domains. Adjusted birth weight was calculated from birth records or participant-report when birth records were unavailable. Decreases in social contact during the pandemic were associated with lower adjusted infant birth weight (B = 76.82, SE = 35.82, p = .035). This association was mediated by maternal prenatal depressive symptoms [Effect = 15.06, 95 % CI (0.19, 35.58)] but not by prenatal anxiety [95 % CI (-0.02, 32.38)] or stress [95 % CI (-0.31, 26.19)]. These findings highlight concerns for both mothers and infants in the wake of the COVID-19 pandemic, since birth weight can have long-term health implications and the social restructuring occasioned by the pandemic may lead to lasting changes in social behavior.


Cole-Cole, linear and multivariate modeling of capacitance data for on-line monitoring of biomass.
This work evaluates three techniques of calibrating capacitance (dielectric) spectrometers used for on-line monitoring of biomass: modeling of cell properties using the theoretical Cole-Cole equation, linear regression of dual-frequency capacitance measurements on biomass concentration, and multivariate (PLS) modeling of scanning dielectric spectra. The performance and robustness of each technique is assessed during a sequence of validation batches in two experimental settings of differing signal noise. In more noisy conditions, the Cole-Cole model had significantly higher biomass concentration prediction errors than the linear and multivariate models. The PLS model was the most robust in handling signal noise. In less noisy conditions, the three models performed similarly. Estimates of the mean cell size were done additionally using the Cole-Cole and PLS models, the latter technique giving more satisfactory results.


Right sinus of Valsalva aneurysm.
Aneurysms in the sinuses of Valsalva (SVA) are the least frequent and occur due to a weakness in the aortic wall that forms part of the sinus. This causes dilatation and the formation of a blind pocket in one of the aortic sinuses (usually he right sinus and less frequently the posterior one). It may be congenital or acquired: in a congenital SVA, the condition is frequently associated with Marfan's syndrome or other connective tissue disorders; instead, acquired forms of sinus of Valsalva aneurysm are associated with infections (syphilis, bacterial endocarditis, and tuberculosis), atherosclerosis and medial cystic necrosis, traumatic and degenerative diseases, abuse of drugs or alcoholism. Despite SVA is a well-known anomaly, autopsy images or reviews of the condition are very uncommon. Indeed we report here a fatal case of SVA in a 58-year-old homeless man found dead on the street. The autopsy, performed to determine the cause of death, releaved a massive aneurysm (in excess of 4 cm) involving the right coronary sinus of the aorta. In this case, the aneurysm may be an accidental finding: in effect we found no tromboses inside the aneurysm and the ostium was not obstructed, therefore the cause of death could be attribuited to fatal arrhythmia.


Group B streptococcal beta-hemolysin induces mortality and liver injury in experimental sepsis.
New Zealand White rabbits were challenged with the wild-type (wt) group B streptococci (GBS) serotype III strain (COH1) and its isogenic nonhemolytic (NH) and hyperhemolytic (HH) mutants. Mortality differed significantly between rabbits infected with the HH mutant IN40 (67%), compared with rabbits infected with the wt COH1 strain (27%) and the NH strains COH1-20 and COH1:cylEDeltacat (13% and 0%, respectively; P<.05). Histopathologically, disseminated septic microabscesses surrounded by necrotic foci were found exclusively in the livers of HH mutant IN40-infected animals. Serum transaminase levels were 20-fold higher in the HH-infected group, compared with rabbits infected with the other strains. Positive TUNEL (in situ terminal deoxynucleotide transferase-mediated dUTP nick end labeling) staining and activation of caspase-3 in hepatocytes were more frequent in HH-infected than in wt-infected animals and absent in the NH mutant COH1-20-infected group, indicating that GBS beta-hemolysin triggers apoptotic pathways in hepatocytes. This work provides the first evidence that GBS beta-hemolysin plays a crucial role in the pathophysiology of GBS sepsis by inducing liver failure and high mortality.


Obesity-stimulated aldosterone release is not related to an S1P-dependent mechanism.
Aldosterone has been identified as an important factor in obesity-associated hypertension. Here, we investigated whether sphingosine-1-phosphate (S1P), which has previously been linked to obesity, increases aldosterone release. S1P-induced aldosterone release was determined in NCI H295R cells in the presence of S1P receptor (S1PR) antagonists. In vivo release of S1P (100-300 µg/kgbw) was investigated in pithed, lean Sprague Dawley (SD) rats, diet-obese spontaneous hypertensive rats (SHRs), as well as in lean or obese Zucker rats. Aldosterone secretion was increased in NCI H295R cells by S1P, the selective S1PR1 agonist SEW2871 and the selective S1PR2 antagonist JTE013. Treatment with the S1PR1 antagonist W146 or fingolimod and the S1PR1/3 antagonist VPbib2319 decreased baseline and/or S1P-stimulated aldosterone release. Compared to saline-treated SD rats, plasma aldosterone increased by ~50 pg/mL after infusing S1P. Baseline levels of S1P and aldosterone were higher in obese than in lean SHRs. Adrenal S1PR expression did not differ between chow- or CD-fed rats that had the highest S1PR1 and lowest S1PR4 levels. S1P induced a short-lasting increase in plasma aldosterone in obese, but not in lean SHRs. However, 2-ANOVA did not demonstrate any difference between lean and obese rats. S1P-induced aldosterone release was also similar between obese and lean Zucker rats. We conclude that S1P is a local regulator of aldosterone production. S1PR1 agonism induces an increase in aldosterone secretion, while stimulating adrenal S1PR2 receptor suppresses aldosterone production. A significant role of S1P in influencing aldosterone secretion in states of obesity seems unlikely.


Antibody-Drug Conjugate Payloads; Study of Auristatin Derivatives.
Auristatins are important payloads used in antibody drug conjugates (ADCs), and the most well-known compound family member, monomethyl auristatin (MMAE), is used in two Food and Drug Administration (FDA)-approved ADCs, Adcetris® and Polivy®. Multiple other auristatin-based ADCs are currently being evaluated in human clinical trials and further studies on this class of molecule are underway by several academic and industrial research groups. Our group's main focus is to investigate the structure-activity relationships (SAR) of novel auristatins with the goal of applying these to next generation ADCs. Modifications of the auristatin backbone scaffold have been widely reported in the chemical literature focusing on the terminal subunits: P1 (N-terminus) and P5 (C-terminus). Our approach was to modulate the activity and hydrophilic character through modifications of the central subunits P2-P3-P4 and thorough SAR study on the P5 subunit. Novel hydrophilic auristatins were observed to have greater potency in vitro and displayed enhanced in vivo antitumor activity when conjugated via protease-cleavable linkers and delivered intracellularly. Analysis of ADC aggregation also indicated that novel hydrophilic payloads enabled the synthesis of high-drug-to-antibody ratio (DAR) ADCs that were resistant to aggregation. Modification of the central peptide subunits also resulted in auristatins with potent cytotoxic activity in vitro and these azide-modified auristatins contain a handle for linker attachment from the central portion of the auristatin backbone.


Molecular changes in normal appearing white matter in multiple sclerosis are characteristic of neuroprotective mechanisms against hypoxic insult.
Multiple sclerosis is a chronic inflammatory disease of the CNS leading to focal destruction of myelin, still the earliest changes that lead to lesion formation are not known. We have studied the gene-expression pattern of 12 samples of normal appearing white matter from 10 post-mortem MS brains. Microarray analysis revealed upregulation of genes involved in maintenance of cellular homeostasis, and in neural protective mechanisms known to be induced upon ischemic preconditioning. This is best illustrated by the upregulation of the transcription factors such as HIF-1alpha and associated PI3K/Akt signalling pathways, as well as the upregulation of their target genes such as VEGF receptor 1. In addition, a general neuroprotective reaction against oxidative stress is suggested. These molecular changes might reflect an adaptation of cells to the chronic progressive pathophysiology of MS. Alternatively, they might also indicate the activation of neural protective mechanisms allowing preservation of cellular and functional properties of the CNS. Our data introduce novel concepts of the molecular pathogenesis of MS with ischemic preconditioning as a major mechanism for neuroprotection. An increased understanding of the underlying mechanisms may lead to the development of new more specific treatment to protect resident cells and thus minimize progressive oligondendrocyte and axonal loss.


Isolation of rough mutants of Klebsiella aerogenes and their synthesis of polysaccharides.
Two mutants which lacked both capsular and lipopolysaccharide O-antigen polysaccharides were isolated from Klebsiella aerogenes serotype 2 by phage selection; these were designated rough mutants. The polysaccharide fractions solubilized by partial acid hydrolysis of the lipopolysaccharide from both the wild type and mutants were chromatographed on Sephadex G-50. Analysis of the fractions obtained confirmed that the rough mutants lacked the galactan portion of the molecule, which is analogous to the Salmonella O-antigen polysaccharide. Membranes prepared from wild-type K. aerogenes, from a non-mucoid strain (lacking capsule only), and from one of the rough mutants were used in incubation mixtures to compare the biosynthesis of polysaccharides by these organisms. The incorporation of sugar nucleotides into both lipid intermediates and polymer was followed. Results show that the transferases were apparently present in all membranes, while the polymerases were absent in both the non-mucoid and rough mutants.


[First and second wave of the aggregation of platelets in patients with acute virus myocarditis and its treatment].
The author carried out an analysis of first and second wave of the aggregation of platelets in patients with acute virus myocarditis in connection with the stage of clinical course of the disease and therapy done.


The use of Cariogram to evaluate caries-risk profiles in orthodontic patients.
This article describes the usefulness of Cariogram software in three orthodontic patients with high-, medium-, and low-risk caries profiles. Caries-related indicators and information needed for the Cariogram model were registered. The prebonding decayed and filled surfaces (DFS) indices for patient 1 (15-year-old girl) and patient 2 (18-year-old woman) were >5, while in patient 3 (15-year-old boy), the DFS index was <2. The data were entered into the interactive Cariogram software, which shows the various caries-related indicators. Patients 1, 2, and 3 had 6%, 58%, and 87%, respectively, actual chance of avoiding new caries. Patient 1 had high lactobacilli and medium mutans streptococci scores and a high caries risk. Patient 2 had a high DFS index and low buffer capacity, resulting in a medium caries risk. Patient 3 had low mutans streptococci and high lactobacilli scores and a low DFS index, resulting in a low caries risk. The Cariogram is available free online and is a useful educational model to illustrate a patient's caries risk.


AIDS-related lymphoma diagnosed by flow cytometry of a pleural effusion.
We have presented a case in which flow cytometry of pleural fluid was applied in the diagnosis of an AIDS-related lymphoma. Flow cytometric evaluation of malignant effusions is a less invasive means of diagnosing these neoplasms than tissue biopsy.


Dystrophinopathy-associated dysfunction of Krebs cycle metabolism.
Duchenne muscular dystrophy is a deadly muscle-wasting disorder caused by loss of dystrophin protein. Studies suggest that metabolic alterations are important to disease pathogenesis. Because muscle accounts for ~40% of body mass, we hypothesized that dystrophy-mediated metabolic changes would be measurable in biofluids and that a metabolomic analysis of urine would provide insight into the metabolic status of dystrophic muscle. Using the mdx mouse model, we performed a large-scale metabolomic screen at 1 and 3 months. While 10% of metabolites were altered at age 1 month, 40% were changed at 3 months. Principal component analysis distinguished wild-type from mdx animals, with the greatest separation at 3 months. A critical distinguishing pathway was Krebs cycle metabolite depletion in mdx urine. Five of seven detected Krebs cycle metabolites were depleted in mdx urine, with succinate being the most robustly affected metabolite. Using selected reaction monitoring mass spectrometry, we demonstrated that muscle-specific dystrophin expression corrects mdx succinate depletion. When subjected to downhill treadmill running, wild-type and mdx mice expressing recombinant dystrophin in skeletal muscle displayed significant increases in urinary succinate levels. However, mdx succinate levels were unchanged, suggesting urinary succinate depletion may reflect an inability to upregulate the Krebs cycle following exercise. Finally, we show that supplementing the Krebs cycle in an ex vivo fatigue/recovery assay significantly impacts mdx muscle performance but has no effect on wild-type muscle. Our results suggest that global metabolic impairment is associated with mdx disease progression and that Krebs cycle deficiencies are a downstream consequence of dystrophin loss.


Relation of protein kinase A and protein kinase C to signaling pathways of hematopoietic factors in leukemia cell lines.
In terms of growth, differentiation, and signaling pathways of hematopoietic factors, the effects of protein kinase C (PKC) activator, 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and protein kinase A(PKA) activator, dibutyryl cyclic adenosine monophosphate (dbcAMP) were examined in vitro using three factor-responsive myeloid leukemia cell lines. TPA suppressed the growth of OCI/AML-1 and OCI/AML-5 cells but stimulated the proliferation of OCI/AML-4 cells. TPA differentiated OCI/AML-4 and OCI/AML-5 cells to macrophage-like cells. dbcAMP suppressed the growth of the three without differentiation. The stimulation of TPA induced tyrosine phosphorylation of some proteins in OCI/AML-4 and OCI/AML-5 cells. Their molecular weights were the same as those phosphorylated by hematopoietic factors. The patterns of phosphorylated proteins were different between the two. TPA induced the phosphorylation of MAP kinase, but not that of JAK2 protein in three cell lines. The stimulation of dbcAMP did not induce tyrosine phosphorylation in three cell lines. Overnight exposure of TPA inhibited the tyrosine phosphorylation induced by hematopoietic factors, although that of dbcAMP did not. We suggest a close relation of PKC to signaling pathways of hematopoietic factors, however, the ways of relation were diverse among the cell lines and the clear mechanism explaining its effects on growth and differentiation was not elucidated.


[Organic and psychogenic causes of psychopathology: co-construction between the brain and culture].
Rather than attempting to reduce findings to fit a particular standard of explanation, understanding into mental diseases should abandon the dichotomy between organic and psychogenic causes and instead investigate what can be explained at each level from genes, materials, cells and circuits across the spheres of psychology, society and culture, and focus on how findings can be clinically applied. Using this "pluralistic" approach, the author attempts herein to deepen understanding of mental disorders as diseases of mentality. The author depicts the process and significance of mental disorders and introduces the concept of "cultural affordance" while touching on a pathogenic framework comprising both organic and psychogenic causes, namely "culture" and "the brain". This approach has been little considered to date during psychopathological research when attempting to understand disease state and implement clinical application.


Visualization of size-dependent tumour retention of PEGylated nanographene oxide via SPECT imaging.
PEGylated nanosized graphene oxides (NGO-PEG) and related derivatives have attracted extensive attention owing to their unique properties, which confer significant theranostic benefits for cancer treatment. The size of NGO-PEG varies largely, from tens of nanometers to micrometers, and the optimal size range with the most efficient tumor retention in vivo remains to be determined. For this purpose, we designed different sizes of NGO-PEG, specifically, ultra-small NGO-PEG (usNGO-PEG, sub-50 nm) and NGO-PEG (over 50 nm) and compared their biological behaviors in vitro and in vivo. Both NGO-PEGs exhibited nearly identical physicochemical properties and low cytotoxicity. Following Cy5.5 tagging, confocal microscopy fluorescence imaging revealed faster and higher dynamic cellular uptake of usNGO-PEG than NGO-PEG. Longitudinal, non-invasive visualization of the NGO-PEGs using single proton emission computed tomography (SPECT) imaging with 125I-radiolabeling revealed that tumor retention of usNGO-PEG was significantly higher and longer compared to that of NGO-PEG, whereas the blood circulation and biodistribution of both NGO-PEGs were similar in major organs. In conclusion, Sub-50 nm was further confirmed to be the favorable size for efficient tumor accumulation of PEGylated GO via the enhanced permeability and retention (EPR) effect. We propose that the sub-50 nm NGO-PEG designed in this study may be effectively utilized to develop novel PEGylated GO-based nanoplatforms for multifunctional cancer nanotheranostics.


Cicatrising conjunctivitis with anti-basement membrane autoantibodies in ectodermal dysplasia.
To report circulating and mucosa-deposited anti-basement membrane zone autoantibodies in a series of six ectodermal dysplasia patients with severe bilateral cicatrising conjunctivitis and blindness due to both corneal disease and intractable surface inflammation. We also report clinical improvement with steroid-sparing systemic immunosuppression combined with clearance of bacterial colonisation. Conjunctival and buccal immunohistopathology, and serological analysis using a panel of epithelial basement membrane zone proteins including the bullous pemphigoid antigen 180 (BP180) were carried out as part of an ocular pemphigoid work-up in each patient. The degree of photophobia, conjunctival inflammation and visual acuity were monitored to evaluate the response to immunosuppression. The mean duration of follow-up was 31 (SD 6) months. Four of the six patients showed positive immunopathology: direct immunofluorescence testing of the conjunctiva in one patient demonstrated linear IgA deposition along the basement membrane zone, and IgG and IgM in the buccal mucosa of another patient. Circulating autoantibodies to BP180 were detected in two other patients. Treatment with systemic immunosuppression, combined with clearance of bacterial colonisation, reduced the severity of photophobia and degree of conjunctival inflammation in 5/6 (83%) patients. Systemic immunosuppression, used as steroid-sparing therapy, combined with clearance of bacterial colonisation can control inflammation and disabling photophobia, and allow improvement in vision, in a subgroup of ectodermal dysplasia patients who have severe cicatrising conjunctivitis which shares clinical and immunopathological features with ocular mucous membrane pemphigoid.


[Health social organizations as a way of public/private management].
This work has as objective to analyze the implementation process of the Health Social Organizations (OSS), in the State of São Paulo, focusing the role played by factors as administrative and financial autonomy, direction proposed by the Management Contract and the use of instruments and innovative management practices, as factors that give condition to the gain of efficiency of these OSS facing the Direct Administration units (AD). The adopted approach was the Comparative Study, which proposes the establishment of possibilities, from the confrontation between two units (HOSS and HAD), to identify the elements capable of explaining this difference of performance between the two models of management. The research points to the positive influence of the administrative and financial autonomy, to the direction given to the work processes by goals setting in the Management Contract and innovative management technologies with the intensive use of the information as base for taking decisions. This result, far from indicating the complete conversion of AD to the publicizing by the OSS model, points to the possibilities and limits of development of AD, by the incorporation of management technologies in the OSS environment.


"Latex-fruit syndrome": frequency of cross-reacting IgE antibodies.
An association between allergies to latex proteins and to various foods has been reported and confirmed by RAST and immunoblotting inhibition. However, no significant data had been collected on the frequency of specific IgE antibodies to fruits in these patients and the frequency of a history of fruit intolerance. Serum samples of 136 patients with well-documented, clinically relevant, immediate-type hypersensitivity against latex proteins were analyzed for IgE antibodies against a panel of different fruits. Patient history of food intolerance was documented by a standardized questionnaire. Fruit-specific IgE antibodies were detected in 69.1% of serum samples. Cross-reacting IgE antibodies recognizing latex and fruit allergens (papaya, avocado, banana, chestnut, passion fruit, fig, melon, mango, kiwi, pineapple, peach, and tomato) were demonstrated by RAST-inhibition tests. Of our patients, 42.5% reported allergic symptoms after ingestion of these fruits and a total of 112 intolerance reactions were recorded. However, fruit-specific IgE antibodies were detected only in serum samples from 32.1% of the patients who perceived symptoms due to these fruits. Thus, serologic tests seem to be of low significance for prediction o food allergy in latex-allergic patients.


Phase IB Dose Escalation and Expansion Study of AKT Inhibitor Afuresertib with Carboplatin and Paclitaxel in Recurrent Platinum-resistant Ovarian Cancer.
Preclinically, AKT kinase inhibition restores drug sensitivity in platinum-resistant tumors. Here the pan-AKT kinase inhibitor afuresertib was given in combination with paclitaxel and carboplatin (PC) in patients with recurrent platinum-resistant epithelial ovarian cancer (PROC) and primary platinum-refractory ovarian cancer (PPROC). Part I was a combination 3+3 dose escalation study for recurrent ovarian cancer. Patients received daily continuous oral afuresertib at 50-150 mg/day with intravenous paclitaxel (175 mg/m2) and carboplatin (AUC5) every 3 weeks for six cycles followed by maintenance afuresertib at 125 mg/day until progression or toxicity. Part II was a single-arm evaluation of the clinical activity of this combination in recurrent PROC (Cohort A) or PPROC (Cohort B). Patients received oral afuresertib at the MTD defined in Part I in combination with PC for six cycles, followed by maintenance afuresertib. Primary endpoints were safety and tolerability of afuresertib in combination with PC (Part I, dose escalation), and investigator-assessed overall response rate (ORR) as per RECIST version 1.1 (Part II). Twenty-nine patients enrolled into Part I, and 30 into Part II. Three dose-limiting toxicities of grade 3 rash were observed, one at 125 mg and two at 150 mg afuresertib. The MTD of afuresertib in combination with PC was therefore identified as 125 mg/day. The most common (≥50%) drug-related adverse events observed in Part I of the study were nausea, diarrhea, vomiting, alopecia, fatigue, and neutropenia and, in Part II, were diarrhea, fatigue, nausea, and alopecia. The Part II ORR in the intention to treat patients was 32% [95% confidence interval (CI), 15.9-52.4] by RECIST 1.1 and 52% (95% CI, 31.3-72.2) by GCIG CA125 criteria. Median progression-free survival was 7.1 months (95% CI, 6.3-9.0 months). Afuresertib plus PC demonstrated efficacy in recurrent PROC with the MTD of afuresertib defined as 125 mg/day.


Flow-cytometric analysis of leukocyte activation induced by polyethylene-terephthalate with and without pyrolytic carbon coating.
Leukocyte activation is one test for the evaluation of blood-materials interaction. The expression of adhesion molecules analyzed by flow cytometry provides a simple method to evaluate leukocyte activation by biomaterials: any change in these molecules can be predictive of the inflammatory activity of the materials. In this study the contact between leukocytes and uncoated polyethylene terephthalate or pyrolytic carbon-coated polyethylene terephthalate (PET and PET-PC, respectively) was inspected by analyzing whether the expression of some adhesion molecules involved in leukocyte activation, namely LFA-1 (CD11a/ CD18), Mac-1/CR3 (CD11b/CD18), and LECAM-1 (CD62L) can be modified. By flow cytometry expression of the adhesion molecules can be studied separately on lymphocytes and myeloid cells. The materials tested reduced the total numbers of both leukocytes and neutrophils, although not significantly. Neither PET nor PET-PC changed the expression of the adhesion molecules in lymphocytes: this suggests that no specific immune response is stimulated. On the contrary, statistically significant changes were observed for monocytes and granulocytes: the percentage of cells expressing Mac-1 and the density of such antigens on cell membranes increased while the percentage of LECAM-1 positive cells decreased. Similar changes were observed when the cells underwent the inflammatory stimulus provided by an in vitro challenge with bacterial endotoxin. Our results demonstrated that polyethylene terephthalate activates leukocytes by modifying the expression in neutrophils of the molecules involved in the early phase of the inflammatory response. Even after coating PET with pyrolytic carbon, the ability of this material to activate circulating leukocytes was maintained.


Enhanced External Counterpulsation as a Novel Treatment for Post-acute COVID-19 Sequelae.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic. As patients recover from COVID-19, some continue to report persisting symptoms weeks to months after acute infection. These effects have been referred to as post-acute sequelae of SARS-CoV-2 infection (PASC). We report the case of a 38-year-old woman suffering from PASC symptoms following acute COVID-19 in October 2020. During her acute infection phase, she had a home recovery and reported her predominant symptoms as fatigue, headaches, body pain, and shortness of breath. After most of her symptoms were resolved, she continued to have periodic episodes of fatigue and headaches, along with random shortness of breath while at rest and during activities for months beyond the acute phase of the illness. She also noted the presence of "brain fog," as if lacking the same clarity that she had prior to her illness. These symptoms persisted for three months before the patient underwent enhanced external counterpulsation (EECP) therapy in one-hour sessions, three times per week. This therapy was chosen based on the mechanism of action of EECP benefiting patients with ischemic cardiovascular diseases. After one week, her "brain fog" had improved, with shortness of breath improving after 1.5 weeks. The patient reported returning to pre-COVID health and fitness after approximately five weeks of EECP treatment. To our knowledge, this is the first case of using EECP for post-COVID shortness of breath, fatigue, and "brain fog."


Arthroscopic Bony Resection for Treatment of Symptomatic Bipartite Patella.
Bipartite patella is a common pathology, affecting 2% to 3% of the population. Usually these cases are bilateral and asymptomatic. However, a patient with a bipartite patella may complain of pain, which is most likely related to fragment mobility. Conservative treatment with physiotherapy, immobilization, and nonsteroidal drugs are encouraged during the initial 6 months following diagnosis. This option is effective in most patients. For patients who do not improve with these conservative measures, surgical intervention is indicated. Many surgical treatment options have been described including excision of the fragment, as well as fixation. Fragment excision has demonstrated positive outcomes and is associated with an asymptomatic return to sport activities. The purpose of this Technical Note is to describe our preferred arthroscopic technique for the treatment of symptomatic bipartite patella.


Prevalence and risk factors associated with gastrointestinal parasites in ruminant livestock in the Coastal Savannah zone of Ghana.
Gastrointestinal (GIT) parasite infections result in significant economic losses to ruminant livestock production. To determine the prevalence and risk factors associated with GIT parasite infections in livestock from Ghana, a cross-sectional survey was conducted in cattle and small ruminants kept under different management systems in the Coastal Savannah zone from October 2014 to February 2015. Faecal samples were collected from 328 cattle and 502 small ruminants (sheep and goats) and examined by formal ether concentration microscopy. The management systems and environmental conditions of the farm or household were observed, and a questionnaire administered to the livestock owners. Overall, 90.8% (754/830) of livestock were infected with at least one of ten different parasites (Eimeria, Strongylid nematodes, Toxocara, Trichuris, Schistosoma, Dicrocoelium, Paramphistomum, Fasciola, Moniezia and Thysaniezia), with Eimeria the most prevalent (78.4%). Most (64.5%) livestock had coinfections with two to five parasites with parasite intensity mostly light and at least one parasite was found in 98.6% (140/142) of the herds. Binary logistic regression models were generated to assess the risk factors associated with infection. Earthen floor was positively associated with strongylid infection, multiple ruminant species with Paramphistomum infection and flock size (>25 animal) with Thysaniezia, Dicrocoelium and Fasciola infections. Separating young animals from older animals was negatively associated with Strongylid infection, feed supplementation with Thysaniezia infection and small ruminant species with Paramphistomum and Toxocara infections. The findings from this study suggests that good sanitation, proper husbandry practices and improved nutrition can improve livestock health and production in Ghana.


[Evaluation of institution-overlapping treatment planning conferences in psychiatric care in the city of Wolfsburg].
Beginning with 1.9.2001 institution-overlapping treatment planning conferences are being carried out for mentally disturbed and handicapped persons, for whom a service based on paragraphs 39, 40 German Social Legislation is applied. In this study we report on the results of the evaluation. The survey contains analysis of files, interviews with clients, questioning of persons in charge as well as interviews with the experts who took part in the institution-overlapping treatment planning conferences. The results show that the majority of the clients, the persons in charge and the experts think that the treatment planning conferences are an important and necessary instrument. The cost-benefit ratio is mainly reasonable. Positive changes have been achieved for 80% of the clients. Within a short time the symptoms of two thirds of the clients have decreased. Above all a reduction of unemployment and with alcoholics a high rate of abstinence could be recorded. To increase acceptance and efficiency of the treatment planning conferences, this system must be developed further.


7SK snRNA: a noncoding RNA that plays a major role in regulating eukaryotic transcription.
The human 7SK small nuclear RNA (snRNA) is an abundant noncoding RNA whose function has been conserved in evolution from invertebrates to humans. It is transcribed by RNA polymerase III (RNAPIII) and is located in the nucleus. Together with associated cellular proteins, 7SK snRNA regulates the activity of the positive transcription elongation factor b (P-TEFb). In humans, this regulation is accomplished by the recruitment of P-TEFb by the 7SK snRNA-binding proteins, hexamethylene bisacetamide (HMBA)-induced mRNA 1/2 (HEXIM1 or HEXIM2), which inhibit the kinase activity of P-TEFb. P-TEFb regulates the transition of promoter proximally paused RNA polymerase II (RNAPII) into productive elongation, thereby, allowing efficient mRNA production. The protein composition of the 7SK small nuclear ribonucleoprotein (snRNP) is regulated dynamically. While the Lupus antigen (La)-related protein 7 (LARP7) is a constitutive component, the methylphosphate capping enzyme (MePCE) associates secondarily to phosphorylate the 5' end of 7SK snRNA. The release of active P-TEFb is closely followed by release of HEXIM proteins and both are replaced by heterogeneous nuclear ribonucleoproteins (hnRNPs). The released P-TEFb activates the expression of most cellular and viral genes. Regulated release of P-TEFb determines the expression pattern of many of the genes that respond to environmental stimuli and regulate growth, proliferation, and differentiation of cells.


Acute biliary pancreatitis and cholecystolithiasis in a child: one time treatment with laparoendoscopic "rendez-vous" procedure.
Acute biliary pancreatitis (ABP) is rare in childhood and endoscopic sphincterotomy should be avoided in the child due to the risk of both early and late complications but, when necessary, the optimal timing between endoscopic procedure and cholecystectomy is still uncertain. A nine years old child with acute biliary pancreatitis underwent successful laparo-endoscopic "Rendez-Vous" procedure in which endoscopic drainage of the common bile duct and laparoscopic cholecystectomy were performed simultaneously. This is the first case reported of laparo-endoscopic Rendez-Vous in a child. The excellent outcome of this patient and the review of the literature concerning other available options for the treatment of such cases suggest that this procedure offers great advantages, especially in children, of reducing the required number of treatments, the risk of ineffectiveness, the number of anaesthesia, the length of hospital stay and the risk of iatrogenic morbidity.


[Emigration of physicians from Africa: focus on Malawi].
The migration of physicians out of developing nations to rich, western countries contributes heavily to the healthcare problems in Africa. African physicians emigrate primarily to the USA, UK and Canada. In their land of origin, there is often a severe shortage of physicians, while the need for physicians has increased due to HIV/AIDS and the introduction of antiretroviral therapy. Training capacity in Africa is limited. Of the 256 physicians who have graduated from the College of Medicine in Malawi, 60% reside in Malawi; most work in the public sector. Of those who moved abroad, 59% are obtaining specialised postgraduate training. The problem of brain drain in Malawi appears to be limited at this time. However, given the severe shortage of physicians, training capacity should be increased and career prospects, remuneration and working conditions should be improved.


Evaluating Educational Material from the Perspective of Informal Caregivers of Children with Hydrocephalus: A Qualitative Study.
We evaluated whether educational material about hydrocephalus and its treatment previously developed by health professionals corresponded with the daily life of caregivers of children with hydrocephalus. We conducted a qualitative study at a university hospital in Brazil, interviewing 32 informal caregivers of children with hydrocephalus. The methodological framework of Bardin content analysis was used to analyze the data. The educational material adequately represented caregivers' experience regarding daily life, surgery experiences, and care needed by children with hydrocephalus. In addition, the educational material may help to identify the signs and symptoms of ventriculoperitoneal shunt. However, the material did not address the limitations of children disabled with hydrocephalus in daily life. From the perspective of informal caregivers of children with hydrocephalus, the educational material corresponded with families' daily life and surgical experience and may be used by health professionals to reinforce important points for the care for children with hydrocephalus, facilitating the health education process.


In vivo comparison of two human norovirus surrogates for testing ethanol-based handrubs: the mouse chasing the cat!
Human noroviruses (HuNoV), a major cause of acute gastroenteritis worldwide, cannot be readily cultured in the lab. Therefore, a feline calicivirus (FCV) is often used as its surrogate to, among other things, test alcohol-based handrubs (ABHR). The more recent laboratory culture of a mouse norovirus (MNV) provides an alternative. While MNV is closer to HuNoV in several respects, to date, no comparative testing of FCV and MNV survival and inactivation on human hands has been performed. This study was designed to address the knowledge gap. The rates of loss in viability during drying on hands were -1.91 and -1.65% per minute for FCV and MNV, respectively. When the contaminated skin was exposed for 20 s to either a commercial ABHR with 62% (v/v) ethanol or to 75% (v/v) ethanol in water, FCV infectivity was reduced by <1 log₁₀ while that of MNV by nearly 2.8 log₁₀. Extending the contact time to 30 s reduced the FCV titer by almost 2 log₁₀ by both test substances and that of MNV by >3.5 log₁₀ by the commercial ABHR while 75% ethanol did not show any noticeable improvement in activity as compared to the 20 s contact. An 80% (v/v) aqueous solution of ethanol gave only a 1.75 log₁₀ reduction in MNV activity after 20 s. The results show significant differences in the ethanol susceptibility of FCV and MNV in contact times relevant to field use of ABHR and also that 62% ethanol was a more effective virucide than either 75% or 80% ethanol. These findings indicate the need for a review of the continuing use of FCV as a surrogate for HuNoV.


Shutterless solution for simultaneous focal plane array temperature estimation and nonuniformity correction in uncooled long-wave infrared camera.
In uncooled long-wave infrared (LWIR) microbolometer imaging systems, temperature fluctuations of the focal plane array (FPA) result in thermal drift and spatial nonuniformity. In this paper, we present a novel approach based on single-image processing to simultaneously estimate temperature variances of FPAs and compensate the resulting temperature-dependent nonuniformity. Through well-controlled thermal calibrations, empirical behavioral models are derived to characterize the relationship between the responses of microbolometer and FPA temperature variations. Then, under the assumption that strong dependency exists between spatially adjacent pixels, we estimate the optimal FPA temperature so as to minimize the global intensity variance across the entire thermal infrared image. We make use of the estimated FPA temperature to infer an appropriate nonuniformity correction (NUC) profile. The performance and robustness of the proposed temperature-adaptive NUC method are evaluated on realistic IR images obtained by a 640 × 512 pixels uncooled LWIR microbolometer imaging system operating in a significantly changed temperature environment.


p300-mediated acetylation of COMMD1 regulates its stability, and the ubiquitylation and nucleolar translocation of the RelA NF-κB subunit.
Nucleolar sequestration of the RelA subunit of nuclear factor (NF)-κB is an important mechanism for regulating NF-κB transcriptional activity. Ubiquitylation, facilitated by COMMD1 (also known as MURR1), acts as a crucial nucleolar-targeting signal for RelA, but how this ubiquitylation is regulated, and how it differs from cytokine-mediated ubiquitylation, which causes proteasomal degradation of RelA, is poorly understood. Here, we report a new role for p300 (also known as EP300) in controlling stimulus-specific ubiquitylation of RelA, through modulation of COMMD1. We show that p300 is required for stress-mediated ubiquitylation and nucleolar translocation of RelA, but that this effect is indirect. We also demonstrate that COMMD1 is acetylated by p300 and that acetylation protects COMMD1 from XIAP-mediated proteosomal degradation. Furthermore, we demonstrate that COMMD1 acetylation is enhanced by aspirin-mediated stress, and that this acetylation is absolutely required for the protein to bind RelA under these conditions. In contrast, tumour necrosis factor (TNF) has no effect on COMMD1 acetylation. Finally, we demonstrate these findings have relevance in a whole tissue setting. These data offer a new paradigm for the regulation of NF-κB transcriptional activity, and the multiple other pathways controlled by COMMD1.


Challenges in Implementation of the ANISA Protocol at the Matiari Site, Pakistan.
The Aetiology of Neonatal Infection in South Asia (ANISA) study is a population-based study with sites in Bangladesh, India and Pakistan. It aims to determine community-acquired incidence, etiology and associated risk factors for neonatal infections. Matiari, a rural site in Pakistan, was chosen for the study due to its high neonatal mortality rate and the presence of an established pregnancy and birth surveillance system. This article summarizes various challenges, remedial measures taken and lessons learned during the implementation of the ANISA study protocol in the unique rural setting of Matiari where the majority of births take place at home and accessibility to health care is limited. Achieving and maintaining project targets of early registration of birth and collection of biological specimens in households have been challenging in Matiari. Capturing births of study subjects that occur outside the catchment areas and those taking place during public holidays and acquiring parental consent for specimen collection from healthy controls require extensive community mobilization. Contamination and power outages that affect the laboratory equipment are 2 of the major logistic challenges faced. We keep track of pregnancy outcomes through mobile phones and reimburse the costs for birth notifications to the caller. We created separate dedicated mobile teams that visit newborns outside the catchment area and carry out possible serious bacterial infection assessments. We also formed mobile teams for specimen collection from residences of newborns as there is no facility for specimen collection at this site. Our study personnel work on holidays and weekends to improve the study's performance. We nurture strong community liaison by employing staff from within the community. We train the study physicians on communication and counseling skills required for overcoming refusal for referral and specimen collection. The contamination rate is controlled by repeated training and supervision and extensive monitoring of phlebotomy activities. The majority of phlebotomy procedures are recorded on video in the field to provide feedback to phlebotomists for improving their performance. The contextual challenges faced in field implementation of the ANISA protocol in the rural setting of Matiari are unique. These challenges are being successfully addressed through hard work, strict monitoring and improvisation. This experience can be used for improving study performance in similar settings elsewhere.


The impact of baseline cervical malalignment on the development of proximal junctional kyphosis following surgical correction of thoracolumbar adult spinal deformity.
The objective of this study was to identify the effect of baseline cervical deformity (CD) on proximal junctional kyphosis (PJK) and proximal junctional failure (PJF) in patients with adult spinal deformity (ASD). This study was a retrospective analysis of a prospectively collected, multicenter database comprising ASD patients enrolled at 13 participating centers from 2009 to 2018. Included were ASD patients aged > 18 years with concurrent CD (C2-7 kyphosis < -15°, T1S minus cervical lordosis > 35°, C2-7 sagittal vertical axis > 4 cm, chin-brow vertical angle > 25°, McGregor's slope > 20°, or C2-T1 kyphosis > 15° across any three vertebrae) who underwent surgery. Patients were grouped according to four deformity classification schemes: Ames and Passias CD modifiers, sagittal morphotypes as described by Kim et al., and the head versus trunk balance system proposed by Mizutani et al. Mean comparison tests and multivariable binary logistic regression analyses were performed to assess the impact of these deformity classifications on PJK and PJF rates up to 3 years following surgery. A total of 712 patients with concurrent ASD and CD met the inclusion criteria (mean age 61.7 years, 71% female, mean BMI 28.2 kg/m2, and mean Charlson Comorbidity Index 1.90) and underwent surgery (mean number of levels fused 10.1, mean estimated blood loss 1542 mL, and mean operative time 365 minutes; 70% underwent osteotomy). By approach, 59% of the patients underwent a posterior-only approach and 41% underwent a combined approach. Overall, 277 patients (39.1%) had PJK by 1 year postoperatively, and an additional 189 patients (26.7%) developed PJK by 3 years postoperatively. Overall, 65 patients (9.2%) had PJF by 3 years postoperatively. Patients classified as having a cervicothoracic deformity morphotype had higher rates of early PJK than flat neck deformity and cervicothoracic deformity patients (p = 0.020). Compared with the head-balanced patients, trunk-balanced patients had higher rates of PJK and PJF (both p < 0.05). Examining Ames modifier severity showed that patients with moderate and severe deformity by the horizontal gaze modifier had higher rates of PJK (p < 0.001). In patients with concurrent cervical and thoracolumbar deformities undergoing isolated thoracolumbar correction, the use of CD classifications allows for preoperative assessment of the potential for PJK and PJF that may aid in determining the correction of extending fusion levels.


Adding Telephone and Text Support to an Obesity Management Program Improves Behavioral Adherence and Clinical Outcomes. A Randomized Controlled Crossover Trial.
Behavioral treatment strategies improve adherence to lifestyle intervention for adults with obesity, but can be time and resource intensive when delivered via traditional face-to-face care. This study aimed to investigate the efficacy and optimal timing of using telephone calls and text message as adjunctive tools to support a community-based obesity management program. This 8-month randomized controlled crossover trial recruited 61 adults with class III obesity (BMI > 40 kg/m2) enrolled in a publicly funded obesity management service (OMS). Participants were randomly assigned to receive telephone and text message support in addition to standard OMS care, or standard OMS care alone. After 4 months, participants crossed over to the alternative sequence. The technological support was based on self-determination theory. Outcome measures included diet, physical activity, anthropometry, self-efficacy, and treatment self-regulation. Telephone and text message support improved lifestyle intervention adherence and clinical outcomes when compared with standard care. Participants who received the intervention in the first 4-month period lost 4.87 kg, compared with no weight loss (+ 0.38 kg) in the standard care only group. There was no evidence to indicate an optimal timing of the intervention, with both groups achieving significant results by the end of the intervention. These results suggest a high degree of promise for the incorporation of telephone and text message support into community-based obesity management services. The findings have the potential to improve existing practices and reduce the burden on the health care system by demonstrating a resource-effective improvement to obesity management service delivery.


In vitro and in vivo activities of novel 2-(thiazol-2-ylthio)-1beta-methylcarbapenems with potent activities against multiresistant gram-positive bacteria.
SM-197436, SM-232721, and SM-232724 are new 1beta-methylcarbapenems with a unique 4-substituted thiazol-2-ylthio moiety at the C-2 side chain. In agar dilution susceptibility testing these novel carbapenems were active against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) with a MIC(90) of </=4 micro g/ml. Furthermore, SM-232724 showed strong bactericidal activity against MRSA, in contrast to linezolid, which was bacteriostatic up to four times the MIC. SM-232724 showed good therapeutic efficacy comparable to those of vancomycin and linezolid against systemic infections of MRSA in cyclophosphamide-treated mice. The MICs of SM-197436, SM-232721, and SM-232724 for streptococci, including penicillin-intermediate and penicillin-resistant Streptococcus pneumoniae strains, ranged from </=0.063 to 0.5 micro g/ml. These drugs were the most active beta-lactams tested against Enterococcus faecium, and the MIC(90) s for ampicillin-resistant E. faecium ranged between 8 and 16 micro g/ml, which were slightly higher than the value for linezolid. However, time-kill assays revealed the superior bactericidal activity of SM-232724 compared to those of quinupristin-dalfopristin and linezolid against an E. faecium strain with a 4-log reduction in CFU at four times the MIC after 24 h of exposure to antibiotics. In addition, SM-232724 significantly reduced the numbers of bacteria in a murine abscess model with the E. faecium strain: its efficacy was superior to that of linezolid, although the MICs (2 micro g/ml) of these two agents are the same. Among gram-negative bacteria, these three carbapenems were highly active against Haemophilus influenzae (including ampicillin-resistant strains), Moraxella catarrhalis, and Bacteroides fragilis, and showed antibacterial activity equivalent to that of imipenem for Escherichia coli, Klebsiella pneumoniae, and Proteus spp. Thus, these new carbapenems are promising candidates for agents to treat nosocomial bacterial infections by gram-positive and gram-negative bacteria, especially multiresistant gram-positive cocci, including MRSA and vancomycin-resistant enterococci.


Comparison of agar gel (CLOtest) or reagent strip (PyloriTek) rapid urease tests for detection of Helicobacter pylori infection.
Rapid urease tests (RUTs) are used commonly as a convenient method to detect Helicobacter pylori infection. New rapid tests have been commercially available with promotional literature suggesting enhanced utility. We compared CLOtest to a new reagent strip RUT, PyloriTek. Gastric antral mucosal biopsy specimens were obtained from 102 patients for comparison between CLOtest and PyloriTek (204 specimens). Biopsy specimens obtained from a nearby area were stained using the Genta stain for determination of H. pylori status. The RUT to be used first was selected randomly. Sixty-five of the 102 patients had peptic ulcer disease, two had gastric cancer, and 35 had dyspepsia; 61 patients had active H. pylori infection. There were one false-negative and three false-positive CLOtest results, compared with one false-negative and 13 false-positive PyloriTek results (p < 0.02 for incorrect categorization with PyloriTek). Sensitivity and specificity were 98 and 92% compared with 98 and 68% for CLOtest and PyloriTek, respectively. An erroneous categorization of H. pylori status occurred in 3.9% (95% confidence interval [CI]: 1-9.7%) with CLOtest compared with 13.7% (95% CI: 7.7 -22%) with PyloriTek. When the PyloriTek was scored at 1 h (0-1 h) after obtaining the specimen, the accuracy improved; erroneous categorization of H. pylori status occurred in only 2.9% (95% CI: 0.6-8.3%). Used according to manufacturer instructions, the new reagent strip RUT PyloriTek has too many false-positive results for use in a clinical situation. In contrast, when the test was interpreted within 1 h, accuracy was comparable to that of CLOtest.


The Association Between ABO Blood Type and Mortality Among Severely Injured Trauma Patients.
Prior research has reported an association among trauma patients between blood type O and adverse events. More recently, another study reported that severely injured trauma patients of mostly O Rh positive blood type were more likely to die. The objective of the current study is to examine whether the same increased association is observed for blood type O severely injured patients in a more generalizable population comprised of Rh positive and Rh negative individuals. Patients admitted to a Level-I academic trauma center between 2015 and 2018 with severe injury (Injury Severity Score >15) were included in this retrospective cohort study. Logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) for the association between blood type and mortality. Among 3,913 patients, a majority were either blood type O (47.5%) or A (34.7%) and 60% were Rh positive. There was no observed difference in complication rates by blood type, and there was no observed significant association with death overall or by cause of death. There were weak, increased associations for blood type B (OR 1.61, 95% CI 0.74-3.53) and type O (OR 1.57, 95% CI 0.90-2.76) compared with blood type A patients. Contrary to prior research, the current results suggest no association between blood type and mortality among severely injured trauma patients.


Factors influencing the choice to use modern natural family planning.
A discrepancy exists between the interest in modern methods of natural family planning (NFP) and their actual use in developed countries. To explore reasons for this discrepancy, we analyzed data from a questionnaire administered to postpartum women in Berlin (n = 223) and Cracow (n = 233). Knowledge of NFP, past use of NFP and expected effects of abstinence on the partnership were independently associated with interest in using NFP, but not the choice to do so among those interested. Desire for future pregnancies, importance of religious belief and location in Cracow were independently associated with the choice to use NFP among those interested. Perceived accuracy of observation to identify the fertile time and acceptance of own body were independently associated with both interest in and choice to use NFP. Frequency of intercourse had no effect on interest. These results suggest that increased access and cultural support would likely lead to a higher prevalence of NFP use in developed countries.


Endodermal sinus tumor. Report of a case with remission following chemotherapy.
The case of a 33-year-old white female with an endodermal sinus tumor of the ovary who manifested remission of her disease as a result of the intermittent administration of chlorambucil is described. This remission following chemotherapy with a single alkylating agent is unusual.


Window of opportunity in rheumatoid arthritis - definitions and supporting evidence: from old to new perspectives.
The therapeutic window of opportunity in rheumatoid arthritis (RA) is often referred to. However, some have questioned whether such a period, in which the disease is more susceptible to disease-modifying treatment, really exists. Observational studies are most frequently referenced as supporting evidence, but results of such studies are subject to confounding. In addition formal consensus on the definition of the term has never been reached. We first reviewed the literature to establish if there is agreement on the concept of the window of opportunity in terms of its time period and the outcomes influenced. Second, a systemic literature search was performed on the evidence of the benefit of early versus delayed treatment as provided by randomised clinical trials. We observed that the concept of the window of opportunity has changed with respect to timing and outcome since its first description 25 years ago. There is an 'old definition' pointing to the first 2 years after diagnosis with increased potential for disease-modifying treatment to prevent severe radiographic damage and disability. Strong evidence supports this concept. A 'new definition' presumes a therapeutic window in a pre-RA phase in which the biologic processes could be halted and RA development prevented by very early treatment. This definition is not supported by evidence, although is less well studied in trials. Some suggestions for future research in this area are made.


Relative Risks for Dementia among Individuals with Glaucoma: A Meta-Analysis of Observational Cohort Studies.
To investigate the relative risks (RRs) for dementia among individuals with glaucoma. We conducted a search of PubMed, Web of Science, Scopus, and Cochrane databases for observational cohort studies examining the association between glaucoma and dementia until March 2023. Two authors independently screened all titles and abstracts according to predefined inclusion and exclusion criteria. Pooled RR and 95% confidence intervals (CIs) were generated using random-effect models. The meta-analysis included 18 cohort studies conducted in eight countries and involving 4,975,325 individuals. The pooled RR for the association between glaucoma and all-cause dementia was 1.314 (95% CI, 1.099-1.572; I2 = 95%). The pooled RRs for the associations of open-angle glaucoma with Alzheimer dementia and Parkinson disease were 1.287 (95% CI, 1.007-1.646; I2 = 96%) and 1.233 (95% CI, 0.677-2.243; I2 = 73%), respectively. The pooled RRs for the associations of angle-closure glaucoma with all-cause dementia and Alzheimer dementia were 0.978 (95% CI, 0.750-1.277; I2 = 17%) and 0.838 (95% CI, 0.421-1.669; I2 = 16%), respectively. No evidence of publication bias was detected in the Begg-Mazumdar adjusted rank correlation test (p = 0.47). Based on current observational cohort studies, there is evidence supporting that glaucoma is a risk factor for dementia in the adult population.


A new procyanidin B from Campylospermum zenkeri (Ochnaceae) and antiplasmodial activity of two derivatives of (±)-serotobenine.
Phytochemical investigation of the stem bark of Campylospermum zenkeri led to the isolation of five known compounds: (Z,Z)-9,12-octadecadienoic acid (1), serotobenine (2), agathisflavone (3), lophirone A (4) and lophirone F (5), together with a new derivative of procyanidin B, a catechin dimer named zenkerinol (6). Serotobenine (2) is structurally related to decursivine which shows moderate activity against D6 and W2 strains of Plasmodium falciparum. For a better understanding of structure-activity relationships, three new semi-synthetic derivatives of serotobenine (2) have been prepared. These are: serotobenine monopropionate (2a), serotobenine monopivalate (2b) and serotobenine cyclohexyl ether (2c) respectively. Two of them (2a) and (2b), were evaluated for their antiplasmodial activity against P. falciparum 3D7 strain in a parasite lactate-dehydrogenase (pLDH) assay. Compound 2b was more active than compound 2a based on their IC50 values (36.6 and 123 μM, respectively).


Blocks in the pseudouridimycin pathway unlock hidden metabolites in the Streptomyces producer strain.
We report a metabolomic analysis of Streptomyces sp. ID38640, a soil isolate that produces the bacterial RNA polymerase inhibitor pseudouridimycin. The analysis was performed on the wild type, on three newly constructed and seven previously reported mutant strains disabled in different genes required for pseudouridimycin biosynthesis. The results indicate that Streptomyces sp. ID38640 is able to produce, in addition to lydicamycins and deferroxiamines, as previously reported, also the lassopeptide ulleungdin, the non-ribosomal peptide antipain and the osmoprotectant ectoine. The corresponding biosynthetic gene clusters were readily identified in the strain genome. We also detected the known compound pyridindolol, for which we propose a previously unreported biosynthetic gene cluster, as well as three families of unknown metabolites. Remarkably, the levels of most metabolites varied strongly in the different mutant strains, an observation that enabled detection of metabolites unnoticed in the wild type. Systematic investigation of the accumulated metabolites in the ten different pum mutants identified shed further light on pseudouridimycin biosynthesis. We also show that several Streptomyces strains, able to produce pseudouridimycin, have distinct genetic relationship and metabolic profile with ID38640.


Microvascular integrity and the time course of myocardial sodium accumulation after acute infarction.
Loss of membrane permeability caused by ischemia leads to cellular sodium accumulation and myocardial edema. This phenomenon has important implications to left ventricular structure and function in the first hours after myocardial infarction. We hypothesized that during this period of time, after prolonged coronary occlusion and complete reflow, the rate of myocardial sodium accumulation is governed by microvascular integrity. We used 3-dimensional (23)Na MRI to monitor myocardial sodium content changes over time in an in vivo closed-chest canine model (n=13) of myocardial infarction and reperfusion. Infarcts with microvascular obstruction (MO) defined by both radioactive microspheres and contrast-enhanced (1)H MRI showed a slower rate of sodium accumulation as well as lower blood flow at 20 minutes and 6 hours after reperfusion. Conversely, the absence of MO was associated with faster rates of sodium accumulation and greater blood flow restoration. In addition, infarct size by (23)Na MRI correlated best with infarct size by triphenyltetrazolium chloride and contrast-enhanced (1)H MRI at 9 hours after reperfusion. We conclude that in reperfused myocardial infarction, sodium accumulation is dependent on microvascular integrity and is slower in regions of MO compared with those with patent microvasculature. Finally, (23)Na MRI can be a useful tool for monitoring in vivo myocardial sodium content in acute myocardial infarction.


Spatial regulation of exocytic site and vesicle mobilization by the actin cytoskeleton.
Numerous studies indicate a role for the actin cytoskeleton in secretion. Here, we have used evanescent wave and widefield fluorescence microscopy to study the involvement of the actin cytoskeleton in secretion from PC12 cells. Secretion was assayed as loss of ANF-EmGFP in widefield mode. Under control conditions, depolarization induced secretion showed two phases: an initial rapid rate of loss of vesicular cargo (tau = 1.4 s), followed by a slower, sustained drop in fluorescence (tau = 34.1 s). Pretreatment with Latrunculin A changed the kinetics to a single exponential, slightly faster than the fast component of control cells (1.2 s). Evanescent wave microscopy allowed us to examine this at the level of individual events, and revealed equivalent changes in the rates of vesicular arrival at the plasma membrane immediately following and during the sustained phase of release. Co-transfection of mCherry labeled β-actin and ANF-EmGFP demonstrated that sites of exocytosis had an inverse relationship with sites of actin enrichment. Disruption of visualized actin at the membrane resulted in the loss of specificity of exocytic site.


Aplasia of cochlear nerves and olfactory bulbs in association with SOX10 mutation.
A 17-month-old boy was referred with profound sensorineural hearing loss (SNHL), severe visual impairment and developmental delay. Neuroimaging identified hypomyelination and cochlear nerve aplasia. He was noted to have fair skin and hair and multiple areas of cutaneous hyperpigmentation. Previous investigations including karyotype, array comparative genomic hybridization (aCGH) and a full metabolic screen were normal. A novel missense mutation of the highly conserved high mobility group (HMG) domain of SOX10 was identified (Q174P:c.521A>C). This case represents the first description of aplasia of the cochlear nerve due to a SOX10 mutation.


AQP1, AQP5, Bcl-2 and p16 in pharyngeal squamous cell carcinoma.
This study aimed to link expression patterns of AQP1, AQP5, Bcl-2 and p16 to clinicopathological characteristics of oro-hypopharyngeal squamous cell carcinomas. Immunohistochemical expression of AQP1, AQP5, Bcl-2 and p16 was investigated in 107 consecutive oro-hypopharyngeal squamous cell carcinoma cases. Molecular interrelationship and correlations with clinicopathological parameters and survival were computed. AQP1 was expressed exclusively by a subgroup of basaloid-like squamous cell carcinomas. AQP5 was detected in 25.2 per cent of the samples, showing significant association with the absence of p16 and Bcl-2 (p = 0.018; p = 0.010). In multivariate analysis, overexpression of p16 was significantly correlated with favourable overall survival (p = 0.014). AQP5 defined a subset of patients with Bcl-2-negative and p16-negative tumours with a poor clinical outcome. AQP1 was found to be a marker of a subgroup of aggressive basaloid-like squamous cell carcinomas. These findings suggest that AQP1 and AQP5 are interesting candidates for further studies on risk group classification and personalised treatment of oro-hypopharyngeal squamous cell carcinomas.