Immune responses to wild and vaccine rubella viruses after rubella vaccination.
Antibody responses to individual structural proteins (E1, E2, and C) of the M33 wild rubella virus and the RA 27/3 live attenuated rubella strain were assayed by immunoblotting in 11 girls, following immunization with RA 27/3 rubella vaccine. Serum samples were drawn before immunization and at 10 days, 1 month, 1 year, 2 years, and 3 years afterwards. All the subjects showed antibodies to E1 glycoprotein of both the virus strains up to three years after immunization, indicating the importance of E1 in immunity. Antibodies to E1 were always present when with neutralizing activity was observed. Antibodies to E2 protein of both the viruses and to the C protein of the M33 virus gradually disappeared with time in some samples, while antibodies to C protein of the RA 27/3 virus strain were found persistently in all the sera.


Microglia: sculptors of the polycystic ovary syndrome (PCOS)-like brain?
Neuroendocrine dysfunction and transgenerational susceptibility associated with polycystic ovary syndrome (PCOS) suggest that programmed changes within the brain contribute to adult development of the syndrome. This review discusses a potentially important role for microglia in mediating prenatal androgen-programmed changes in the female brain that contribute to PCOS-like features. Several lines of evidence support a role for the brain in both the development and maintenance of polycystic ovary syndrome (PCOS), the most common cause of anovulatory infertility worldwide. Persistently elevated luteinizing hormone secretion and impaired gonadal steroid hormone feedback in PCOS patients suggest impairments within the neuronal networks that regulate the reproductive axis. Evidence from preclinical models has linked androgen excess during prenatal life with altered structure and function of the developing female brain that might underpin syndrome development in adulthood. Studies investigating the mechanisms by which excess androgens program changes in the female brain have highlighted an important role for microglia. This review discusses how these non-neuronal cells shape the developing female brain in response to excess androgens and focuses on how microglia may be involved in the development of the neuroendocrine dysfunctions associated with PCOS.


GENI-DB: a database of global events for epidemic intelligence.
We present a novel public health database (GENI-DB) in which news events on the topic of over 176 infectious diseases and chemicals affecting human and animal health are compiled from surveillance of the global online news media in 10 languages. News event frequency data were gathered systematically through the BioCaster public health surveillance system from July 2009 to the present and is available to download by the research community for purposes of analyzing trends in the global burden of infectious diseases. Database search can be conducted by year, country, disease and language. The GENI-DB is freely available via a web portal at http://born.nii.ac.jp/.


Is airway closure caused by a liquid film instability?
A physical model for small airway closure is developed, based on the assumption that closure occurs as a result of a surface tension-induced instability of the thin liquid film lining the airways. To distinguish this mechanism from others involving airway compliance, experiments were performed in rigid tubes, 1 mm in diameter, with length-to-diameter ratios between one and ten. Oil was added to the film in small increments and photographed at each stage. For total liquid volumes (V) less than some critical value (Vc) surface tension draws the oil into an axi-symmetric film on the tube walls leaving the lumen relatively unobstructed. When V exceeds Vc, the film becomes unstable and collapses, bridging the lumen and causing obstruction. The ratio of Vc to the tube diameter cubed was found to be approximately 0.7 for the entire range of tube lengths studied. These experimental findings were then used to predict airway closure in a morphometric model of the bronchial tree. Assuming that the liquid film at TLC is 10 microns and that the volume of each airway varies in direct proportion to lung volume, the model predicts that airway closure will first occur in the terminal bronchioles at a lung volume of 23% TLC, in approximate agreement with observed values of residual volume.


On the Q statistic with constant weights in meta-analysis of binary outcomes.
Cochran's Q statistic is routinely used for testing heterogeneity in meta-analysis. Its expected value (under an incorrect null distribution) is part of several popular estimators of the between-study variance, [Formula: see text]. Those applications generally do not account for use of the studies' estimated variances in the inverse-variance weights that define Q (more explicitly, [Formula: see text]). Importantly, those weights make approximating the distribution of [Formula: see text] rather complicated. As an alternative, we are investigating a Q statistic, [Formula: see text], whose constant weights use only the studies' arm-level sample sizes. For log-odds-ratio (LOR), log-relative-risk (LRR), and risk difference (RD) as the measures of effect, we study, by simulation, approximations to distributions of [Formula: see text] and [Formula: see text], as the basis for tests of heterogeneity. The results show that: for LOR and LRR, a two-moment gamma approximation to the distribution of [Formula: see text] works well for small sample sizes, and an approximation based on an algorithm of Farebrother is recommended for larger sample sizes. For RD, the Farebrother approximation works very well, even for small sample sizes. For [Formula: see text], the standard chi-square approximation provides levels that are much too low for LOR and LRR and too high for RD. The Kulinskaya et al. (Res Synth Methods 2:254-70, 2011) approximation for RD and the Kulinskaya and Dollinger (BMC Med Res Methodol 15:49, 2015) approximation for LOR work well for [Formula: see text] but have some convergence issues for very small sample sizes combined with small probabilities. The performance of the standard [Formula: see text] approximation is inadequate for all three binary effect measures. Instead, we recommend a test of heterogeneity based on [Formula: see text] and provide practical guidelines for choosing an appropriate test at the .05 level for all three effect measures.


Adult stem cell transplantation combined with conventional therapy for the treatment of end-stage liver disease: a systematic review and meta-analysis.
End-stage liver disease (ESLD) is characterized by the deterioration of liver function and a subsequent high mortality rate. Studies have investigated the use of adult stem cells to treat ESLD. Here, a systematic review and meta-analysis was conducted to determine the efficacy of a combination therapy with adult stem cell transplantation and traditional medicine for treating ESLD. Four databases-including PubMed, Web of Science, Embase, and Cochrane Library-were investigated for studies published before January 31, 2021. The main outcome indicators were liver function index, model for end-stage liver disease (MELD) scores, and Child‒Turcotte‒Pugh (CTP) scores. Altogether, 1604 articles were retrieved, of which eight met the eligibility criteria; these studies included data for 579 patients with ESLD. Combination of adult stem cell transplantation with conventional medicine significantly improved its efficacy with respect to liver function index, CTP and MELD scores, but this effect gradually decreased over time. Moreover, a single injection of stem cells was more effective than two injections with respect to MELD and CTP scores and total bilirubin (TBIL) and albumin (ALB) levels, with no significant difference in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. With respect to the TBIL levels, patients receiving mononuclear cells (MNCs) experienced a significantly greater therapeutic effect-starting from twenty-four weeks after the treatment-whereas with respect to ALB levels, CD34+ autologous peripheral blood stem cells (CD34+ APBSCs) and MNCs had similar therapeutic effects. Severe complications associated with adult stem cell treatment were not observed. Although the benefits of combination therapy with respect to improving liver function were slightly better than those of the traditional treatment alone, they gradually decreased over time.Systematic review registration: PROSPERO registration number: CRD42021238576.


Effect of the dentin cleansing techniques on dentin wetting and on the bond strength of a resin luting agent.
Remnants of the provisional cement on prepared teeth may have an adverse effect on the performance of the definitive luting agent. This in vitro study investigated the effect of different dentin cleansing techniques on the bond strength of a resin luting agent and dentin wetting. Sixty buccal or lingual coronal portions of human molar teeth were mounted, with the buccal or lingual surfaces up, in acrylic resin blocks. The specimens were prepared until the dentin was exposed and a eugenol-containing provisional cement (Temp Bond) was applied to the dentin surfaces. After mechanical removal of the cement with a carving instrument, specimens were divided into 6 groups of 10 specimens each. The dentin surfaces of the specimens were treated with 1 of 5 cleansing techniques: Group S, cleansing agent (Sikko Tim); Group C, cleansing agent (Cavity Cleanser); Group O, rotary instrumentation (OptiClean); Group OS, rotary instrument preceding Sikko Tim; and Group OC, rotary instrumentation preceding Cavity Cleanser. The remaning 10 specimens were untreated and served as controls (CT). An adhesive resin luting agent (Variolink II) was applied to all specimens. Shear bond strength (MPa) was measured using a universal testing machine at a 0.5 mm/min crosshead speed. To measure the contact angle, another 6 groups (n=5) were prepared using the same methods. Contact angle measurements were performed to assess wettability using the Axisymmetric Drop Shape Analysis-Contact Diameter (ADSA-CD) technique. Wettability measurements were made with water. Data were statistically analyzed by 1-way analysis of variance with Tukey HSD tests (alpha=.05). The effect of the dentin cleansing techniques on removing the provisional cement from the dentin surface was examined with scanning electron microscope (SEM). Specimens cleaned with all techniques showed stronger shear bond strength values than control specimens (P<.001), with the exception of C specimens. The surface cleansing techniques tested affected the dentin wetting significantly in comparison with the control group (P<.001), except for the C and the O groups. There was no significant difference in wetting between the groups C and O. The SEM observations demonstrated that the dentin cleansing techniques left differing amounts of provisional cement remnants. Specimens treated with only the cleansing agent Sikko Tim showed the highest bond strength, likely due to the solvent effect of Sikko Tim on the removal of provisional cement. The lowest bond strength was obtained with the rotary instrument. It was concluded that the provisional cement could plug the dentinal tubules into which the resin luting agent penetrates.


Characterization of a novel pH-sensitive peptide that enhances drug release from folate-targeted liposomes at endosomal pHs.
Although liposomes have proven useful for the delivery of drugs and gene therapy vectors, their potencies are often compromised by poor unloading following uptake into their target cells. We have consequently explored the properties of a novel 29-residue amphipathic peptide that was designed by arrangement of hydrophobic and hydrophilic residues to disrupt liposomes at lower peptide concentrations than previously tested peptides. The peptide was indeed found to promote pH-dependent liposome unloading with improved efficiency. A peptide of the same sequence, but half the length, however, promoted pH-dependent permeabilization only at much higher concentrations. Further characterization of the longer peptide revealed that release of liposome contents (i) occurred at a pH of approximately 6, (ii) became less efficient as the size of the encapsulated cargo increased, and (iii) was moderately suppressed in cholesterol-containing liposomes. Use of this peptide to enhance the cytotoxicity of cytosine arabinoside encapsulated in folate-targeted liposomes demonstrated an increase in drug potency of approximately 30-fold. Gene expression by a serum-stable folate-targeted liposomal vector was also measurably enhanced by inclusion of the peptide. We conclude that intracellular unloading of liposomal contents can be significantly improved by co-encapsulation of an optimally designed, pH-sensitive peptide.


Dantrolene-Na (Dantrium) blocks induction of long-term potentiation in hippocampal slices.
Long-term potentiation (LTP) is characterized by a long lasting increase in the efficacy of neurotransmission which may consist of two phases. First an induction phase, with an absolute requirement for post-synaptic activation. Second, a maintenance phase, possibly involving pre-synaptic mechanisms. An essential function for calcium ions in the induction of LTP has been established and a particular emphasis has been placed on the role of N-methyl-D-aspartate (NMDA) receptor activation in gating a postsynaptic influx of calcium. We now report that pharmacological blockade of intraneuronal calcium release with 20 microM dantrolene-sodium (dantrium) completely blocks the induction of LTP in the CA1 region of the rat hippocampal slice. This drug inhibits calcium release from the sarcoplasmic reticulum and also diminishes the rise in intraneuronal calcium ion concentrations elicited by NMDA receptor activation in cultured CA1 pyramidal cells. Dantrolene does not block NMDA gated membrane currents or voltage activated Ca2+ currents in these cells. We suggest that release of intraneuronal calcium, rather than calcium influx may be the critical post-synaptic feature underlying LTP induction. We do not however exclude a pre-synaptic involvement in the specificity and/or maintenance of long-term potentiation.


Relative contributions of fasting and postprandial glucose increments, glycemic variability, and non-glycemic factors to HbA1c in individuals with type 1 diabetes.
Evidence for contribution of basal and postprandial glucose increment, and glycemic variability to glycated hemoglobin (HbA1c) among adults with type 1 diabetes (T1D) is limited. This study aimed to capture glycemic fluctuation patterns and quantify contributions of these factors to HbA1c levels among adults with T1D. HbA1c, continuous glucose monitoring (CGM), and diet diaries were collected and pooled from two clinical trials. Available data sets were divided into HbA1c quartiles: group 1 (≤6.7%), group 2 (6.7%-7.3%), group 3 (7.3%-7.8%), and group 4 (≥7.8%). Area under curve above 110 mg/dL (AUC>110mg/dL ) in 24-h profile was defined as overall hyperglycemia and stratified with postprandial hyperglycemia (PHG, AUC>110mg/dL in 3-h period after meals) and basal hyperglycemia (BHG, AUC>110mg/dL in remaining period). Linear regression analysis was used to estimate the proportion of variance in HbA1c explained by BHG, preprandial glucose, PHG, glycemic variability, and non-glycemic factors (age, body mass index, hemoglobin, and duration). A total of 169 550 glucose data in 2409 meals recorded from 102 patients (male/female, 34/68) were included. Age and duration were 35.2 ± 12.6 and 8.9 (2.9, 13.0) years, with 51.0% using pumps. Overall, BHG was four times higher than PHG (p all <.05) and between-group comparisons showed BHG exhibited a progressive increase (group 1 vs. 2, 3, 4, p = .053, .086, .006) with fasting contribution of 76.1%, 82.6%, 81.5%, and 84.3% from group 1 to 4. The increment was not significant among groups 2, 3, and 4 (p > .05). Factors included in analysis explained a total of 74% of the variance in HbA1c, in which BHG accounted for 32.1% of variance whereas PHG accounted for 24.4%. In group with HbA1c >7.3%, BHG accounted for a higher percentage with 33.8% of the variance in HbA1c. In our study, basal hyperglycemia better predicts overall glycemic control than postprandial hyperglycemia among adults with T1D. The relative contribution of basal hyperglycemia increased gradually with HbA1c increasing and predominant strategy for insulin titration among T1D is different among different levels of glycemic control.


Evidence for the role of the right auditory cortex in fine pitch resolution.
The neural basis of human pitch perception is not fully understood. It has been argued that the auditory cortices in the two hemispheres are specialized, such that certain right auditory cortical regions have a relatively finer resolution in the frequency domain than homologous regions in the left auditory cortex, but this concept has not been tested directly. Here, we used functional magnetic resonance imaging (fMRI) to test this specific prediction. Healthy volunteers were scanned while passively listening to pure-tone melodic-like sequences in which the pitch distance between consecutive tones was varied in a parametric fashion. As predicted, brain activation in a region of right lateral auditory cortex, corresponding to the planum temporale, was linearly responsive to increasing pitch distance, even across the fine changes in pitch. In contrast, the BOLD signal at the homologous left cortical region was relatively constant as a function of pitch distance, except at the largest pitch change. The results support the model of relative hemispheric specialization and indicate that the right secondary auditory cortex has a finer pitch resolution than the left.


Bacterial colonization of the parotid duct in xerostomia.
Salivary flow rate and bacterial colonization of the parotid main duct were investigated in 17 patients referred for sialography and in 10 healthy controls. Cultures in the controls were negative whilst the patient group revealed bacterial colonization of the main duct, especially in those with the lowest flow rates. The implications of this finding in patients at high risk of endocarditis who will be undergoing sialography are discussed.


Reactive oxygen species in pulmonary inflammation by ambient particulates.
Exposure to ambient air pollution particles (PM) has been associated with increased cardiopulmonary morbidity and mortality, particularly in individuals with pre-existing disease. Exacerbation of pulmonary inflammation in susceptible people (e.g., asthmatics, COPD patients) appears to be a central mechanism by which PM exert their toxicity. Health effects are seen most consistently with PM with aerodynamic diameter < 2.5 micrometers (PM(2.5)), although 10 micrometers < PM < 2.5 micrometers can also be toxic. Through its metal, semi-quinone, lipopolysaccaride, hydrocarbon, and ultrafine constituents, PM may exert oxidative stress on cells in the lung by presenting or by stimulating the cells to produce reactive oxygen (ROS). In vivo, PM increase cytokine and chemokine release, lung injury, and neutrophil influx. In vitro analysis of PM effects on the critical cellular targets, alveolar macrophages, epithelial cells, and neutrophils, demonstrates PM- and oxidant-dependent responses consistent with in vivo data. These effects have been observed with PM samples collected over years as well as concentrated PM(2.5) (CAPs) collected in real time. Oxidative stress mediated by ROS is an important mechanism of PM-induced lung inflammation.


Phenformin and lactic acidosis: a case report and review.
Phenformin was removed from the U.S. market 20 years ago because of a high incidence of lactic acidosis. Unfortunately, this medication is still available from foreign sources. Another biguanide, metformin, was reintroduced to the United States market for the treatment of diabetes. Biguanide-induced lactic acidosis should be included in the differential diagnosis of elevated anion gap metabolic acidosis. We present a case of phenformin-induced lactic acidosis in which we were consulted at the local poison control center. We also review its pathophysiology, presentation, and treatment. A review of the actions of phenformin illustrates the mechanism of pathology that may also occur with metformin. Risk factors for the development of lactic acidosis include renal deficiency, hepatic disease, cardiac disease, and drug interaction such as cimetidine.


[Hemangiopericytoma of the liver].
The haemangiopericytoma is a rare type of vascular tumour. The article reports on a case of unusual location in the liver.


Reconstruction after periacetabular tumor resection with Lumic® endoprosthesis: What are the midterm results?
This study aimed to analyze the midterm outcomes of LUMiC® endoprosthetic reconstruction following periacetabular resection of primary bone sarcomas and carcinoma metastases. We retrospectively reviewed the charts of 21 patients (11 male [52.3%], 10 female [47.6%]; mean age 47 ± 16 years) for whom a LUMiC® endoprosthesis (Implantcast) was used to reconstruct a periacetabular defect after internal hemipelvectomy. The tumor was pathologically diagnosed as Ewing's sarcoma in six (28.5%), chondrosarcoma in 10 (47.6%), and bone metastasis from carcinoma in five (23.8%) patients. The median follow-up of patients was 57.8 months (95% confidence interval: 51.9-63.7). The implant survival rate at 1, 2, and 5 years were 95.2%, 85.7%, and 80.9%, respectively. The overall complication rate was 33.3% (n = 7). Four (19%) complications resulted in reconstruction failure. Total reoperation rate was 28.5% (n = 6). The complications were soft tissue failure/dislocation in two patients, aseptic loosening in one, infection in two, and local recurrence in two. At the time of study, seven patients were alive with no evidence of disease, seven were alive with disease, and seven died of disease. The 5-year overall survival rate and local recurrence-free survival rates were 67% and 76%, respectively. The median Musculoskeletal Tumor Society score at final follow-up was 70% (range: 50%-86.6%). We conclude that LUMiC® endoprosthesis provides good functional outcomes and a durable reconstruct. Even though this reconstruction method presents some complications, it provides a stable pelvis in the management of periacetabular malignant tumors.


Endogenous corticosteroids mediate seasonal cyclic changes in immunity of lizards.
Endogenous corticosteroid (CS) blood levels were radioimmunoassayed in fresh, field-collected lizards Chalcides ocellatus at two week-intervals throughout the four consecutive seasons. These animals were used in parallel to investigate the splenic T and B lymphocyte level, lymphoproliferative responsiveness to concanavalin A and primary antibody production in vitro against rat erythrocytes (RRBC). The recorded data indicated that fully developed splenic lymphoid tissue and powerful immune responsiveness are coincident with a continuously low CS level, and characterize the period from spring through early autumn. On the other hand, the dramatic lymphocytic destruction and impairment of immune reactivity observed in autumn and winter are associated with not only a high, but above all sustained, rise in endogenous CS levels. Apparently, exposure of lizard lymphocytes to comparatively high, yet physiologic, levels of endogenous CS for prolonged periods of time lead to impairment of their immune functions. In support, long-term administration of exogenous hydrocortisone acetate (HC) to "summer" lizards resulted in a high and lasting elevation in blood CS levels that was associated with a considerable depletion of lymphoid elements and abrogation of immune reactivity, exactly as in normal lizards collected from the field in autumn through winter. In addition, pharmacologic inhibition of CS synthesis by administration of metyrapone at the beginning of autumn greatly modulated the lizard lymphocyte response to the autumn-related immunodepression. The study thus strongly suggests that the autumn/winter-dependent immunosuppression in lizards is essentially due to a high and lasting rise in levels of endogenous CS. The results are discussed from the perspective of the role played by CS in mediating the seasonal rhythms that affect reptilian immunity.


Overexpression of gastrin-releasing peptide receptors in tumor-associated blood vessels of human ovarian neoplasms.
Peptide receptors, overexpressed in specific cancers, represent new diagnostic and therapeutic targets. In this study, receptors for the gastrin-releasing peptide (GRP), and other members of the bombesin-family of peptides, were evaluated in ovarian neoplasms. 75 primary, secondary and metastatic ovarian tumors were investigated for their bombesin-receptor subtype expression, incidence, localization and density using in vitro autoradiography on tissue sections with the universal radioligand (125)I-[D-Tyr(6), beta-Ala(11), Phe(13), Nle(14)]-bombesin(6-14) and the GRP-receptor subtype-preferring (125)I-[Tyr(4)]-bombesin. GRP-receptors were detected in 42/61 primary ovarian tumors; other bombesin-receptor subtypes (BB1, bb3) were rarely present (3/61). Two different tissue compartments expressed GRP-receptors: the tumoral vasculature was the predominant site of GRP-receptor expression (38/61), whereas neoplastic cells more rarely expressed GRP-receptors (14/61). GRP-receptor positive vessels were present in the various classes of ovarian tumors; generally, malignant tumors had a higher incidence of GRP-receptor positive vessels compared to their benign counterparts. The prevalence of such vessels was particularly high in ovarian carcinomas (16/19) and their metastases (5/5). The GRP-receptors were expressed in high density in the muscular vessel wall. Normal ovary (n=10) lacked GRP-receptors. The large amounts of GRP-receptors in ovarian tumor vessels suggest a role in tumoral vasculature and possibly angiogenesis. Further, these vessels might be targeted in vivo with bombesin analogs for diagnosis or for therapy.


[Influence of anterior cruciate reconstruction on postural stability: A pre- and postoperative comparison].
Ruptures of the anterior cruciate ligament (ACL) lead to an anteromedial rotational instability in the knee joint and, thus, to a deterioration of the patient's ability to stand (postural control). It still remains unclear whether postural control can be restored by ACL reconstruction. The aim of this study was to investigate the effect of a unilateral ACL graft on the ability to stably stand on the injured leg using computer-aided dynamic posturography (CDP); the stability indices on standing on one leg were compared pre- and postoperatively. A total of 25 patients were studied after unilateral ACL injury and subsequent ACL reconstruction using CDP. The average time of follow-up was 608 days (range 357-821 days). The ability to stably stand on the healthy and injured leg was compared and evaluated for significant differences. There was a significant improvement of postural control after ACL reconstruction. The Overall Stability Index (OSI) for the leg with ACL rupture was 3.7° ± 1.6° preoperatively and 3.0° ± 1.1° postoperatively (p < 0.05). In the postoperative comparison with the healthy leg, the value in the operated leg was 3.0° ± 1.1° and the healthy leg was 3.0° ± 1.4° (p = 0.99). ACL replacement can be improve stability compared to the preoperative value by about 21% and even the stability level of the contralateral healthy knee can be achieved.


Recruitment in a Pragmatic Randomized Trial on the Management of Unruptured Intracranial Aneurysms.
The Comprehensive Aneurysm Management (CAM) study is a pragmatic trial designed to manage unruptured intracranial aneurysm (UIA) patients within a care research framework. CAM is an all-inclusive study. Management options are allocated according to an algorithm combining pre-randomization and clinical judgment. Eligible patients are offered 1:1 randomized allocation of intervention versus conservative management and 1:1 randomization allocation of surgical versus endovascular treatment. Ineligible patients are registered. The primary outcome is survival without dependency (modified Rankin Scale score <3) at 10 years. All UIA patients at 1 center are reported. Between February 2020 and July 2021, 403 UIA patients were recruited: 179 (44%) in one of the randomized controlled trials (RCTs) and 224 (56%) in one of the registries. Conservative management was recommended for 205 of 403 patients (51%); of 198 (49%) patients considered for curative treatment, 159 (80%) were randomly allocated conservative (n = 81) or curative treatment (n = 78). These patients were younger and had larger aneurysms than those in the observation registry (P = 0.004). In 39 of 198 patients (20%), conservative management was not considered reasonable (17 patients were recommended endovascular, 2 surgery, and 20 the RCT comparing endovascular with surgical treatment). In total, 70 patients were recruited in the RCT comparing surgery and endovascular treatment. After informed discussion at time of consent, 141 of 159 patients (89%) agreed with the randomly allocated management plan, while 11% crossed over to the alternative management option. CAM was successfully integrated into routine practice. Meaningful conclusions can be obtained if multiple centers actively participate in the trial.


Detection of oligoclonal bands in unconcentrated CSF: isoelectric focusing and silver staining.
We have developed a method to detect oligoclonal IgG bands in unconcentrated CSF from patients with MS or guinea pigs with chronic relapsing experimental allergic encephalomyelitis, by isoelectric focusing (IEF) in polyacrylamide gel and silver staining. Five to 10 microliters of CSF was sufficient. The bands were identified as IgG in immunofixation after IEF.


Blood-brain barrier injury and neuroinflammation induced by SARS-CoV-2 in a lung-brain microphysiological system.
In some patients, COVID-19 can trigger neurological symptoms with unclear pathogenesis. Here we describe a microphysiological system integrating alveolus and blood-brain barrier (BBB) tissue chips that recapitulates neuropathogenesis associated with infection by SARS-CoV-2. Direct exposure of the BBB chip to SARS-CoV-2 caused mild changes to the BBB, and infusion of medium from the infected alveolus chip led to more severe injuries on the BBB chip, including endothelial dysfunction, pericyte detachment and neuroinflammation. Transcriptomic analyses indicated downregulated expression of the actin cytoskeleton in brain endothelium and upregulated expression of inflammatory genes in glial cells. We also observed early cerebral microvascular damage following lung infection with a low viral load in the brains of transgenic mice expressing human angiotensin-converting enzyme 2. Our findings suggest that systemic inflammation is probably contributing to neuropathogenesis following SARS-CoV-2 infection, and that direct viral neural invasion might not be a prerequisite for this neuropathogenesis. Lung-brain microphysiological systems should aid the further understanding of the systemic effects and neurological complications of viral infection.


Actinobacterial melanins: current status and perspective for the future.
Melanins are enigmatic pigments that are produced by a wide variety of microorganisms including several species of bacteria and fungi. Melanins are biological macromolecules with multiple important functions, yet their structures are not well understood. Melanins are frequently used in medicine, pharmacology, and cosmetics preparations. Melanins also have great application potential in agriculture industry. They have several biological functions including photoprotection, thermoregulation, action as free radical sinks, cation chelators, and antibiotics. Plants and insects incorporate melanins as cell wall and cuticle strengtheners, respectively. Actinobacteria are the most economically as well as biotechnologically valuable prokaryotes. However, the melanin properties are, in general, poorly understood. In this review an evaluation is made on the present state of research on actinobacterial melanins and its perspectives. The highlights include the production and biotechnological applications of melanins in agriculture, food, cosmetic and medicinal fields. With increasing advancement in science and technology, there would be greater demands in the future for melanins produced by actinobacteria from various sources.


Results from a large targeted screening program for alpha-1-antitrypsin deficiency: 2003 - 2015.
Alpha-1-antitrypsin deficiency (AATD) is an autosomal codominant inherited disease that is significantly underdiagnosed. We have previously shown that the combination of an awareness campaign with the offer of free diagnostic testing results in the detection of a relevant number of severely deficient AATD patients. The present study provides an update on the results of our targeted screening program (German AAT laboratory, University of Marburg) covering a period from August 2003 to May 2015. Diagnostic AATD detection test kits were offered free of charge. Dried blood samples were sent to our laboratory and used for the semiquantitative measurement of the AAT-level (nephelometry) and the detection of the S- or Z-allele (PCR). Isoelectric focusing was performed when either of the initial tests was indicative for at least one mutation. Besides, we evaluated the impact of additional screening efforts and the changes of the detection rate over time, and analysed the relevance of clinical parameters in the prediction of severe AATD. Between 2003 and 2015, 18,638 testing kits were analysed. 6919 (37.12 %) carried at least one mutation. Of those, we identified 1835 patients with severe AATD (9.82 % of the total test population) including 194 individuals with rare genotypes. Test initiatives offered to an unselected population resulted in a dramatically decreased detection rate. Among clinical characteristics, a history of COPD, emphysema, and bronchiectasis were significant predictors for Pi*ZZ, whereas a history of asthma, cough and phlegm were predictors of not carrying the genotype Pi*ZZ. A targeted screening program, combining measures to increase awareness with cost-free diagnostic testing, resulted in a high rate of AATD detection. The clinical data suggest that testing should be primarily offered to patients with COPD, emphysema, and/or bronchiectasis.


A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation.
Calcium/calmodulin (Ca2+/CaM)-dependent protein kinase II (CaMKII) couples increases in cellular Ca2+ to fundamental responses in excitable cells. CaMKII was identified over 20 years ago by activation dependence on Ca2+/CaM, but recent evidence shows that CaMKII activity is also enhanced by pro-oxidant conditions. Here we show that oxidation of paired regulatory domain methionine residues sustains CaMKII activity in the absence of Ca2+/CaM. CaMKII is activated by angiotensin II (AngII)-induced oxidation, leading to apoptosis in cardiomyocytes both in vitro and in vivo. CaMKII oxidation is reversed by methionine sulfoxide reductase A (MsrA), and MsrA-/- mice show exaggerated CaMKII oxidation and myocardial apoptosis, impaired cardiac function, and increased mortality after myocardial infarction. Our data demonstrate a dynamic mechanism for CaMKII activation by oxidation and highlight the critical importance of oxidation-dependent CaMKII activation to AngII and ischemic myocardial apoptosis.


Early separation of young rats from the mother and the development of play fighting.
Play fighting was studied in rats which were either normally reared (separated from the mother on day 30) or prematurely separated from the mother on day 15. The animals were tested in pairs on days 33, 36 and 39 of age and play fights were recorded. Play fighting behavior increased markedly after three days of social isolation. In all pairs of normally reared animals (controls, 30S) the rats with the higher pinning scores on the first day also had the higher frequency of pinning on the second and third day of the test. The same trend in the distribution of pinning was found in pairs where the normally weaned animals (30S) played with the early weaned ones (15S). The latter, however, were always pinned by the former (30S) and had significantly lower pinning scores. Such a stable distribution of pinnings did not develop during play fights in pairs of early weaned animals (Group 15S).


Effect of sodium lauryl sulfate in dissolution media on dissolution of hard gelatin capsule shells.
Sodium lauryl sulfate (SLS) is a commonly used surfactant in dissolution media for poorly water soluble drugs. However, it has occasionally been observed that SLS negatively impacts the dissolution of drug products formulated in gelatin capsules. This study investigated the effect of SLS on the dissolution of hard gelatin capsule shells. The USP paddle method was used with online UV monitoring at 214 nm (peptide bond). Empty size #0 capsule shells were held to the bottom of the dissolution vessel by magnetic three-prong sinkers. SLS significantly slowed down the dissolution of gelatin shells at pH < 5. Visually, the gelatin shells transformed into some less-soluble precipitate under these conditions. This precipitate was found to contain a higher sulfur content than the gelatin control sample by elemental analysis, indicating that SLS is part of the precipitate. Additionally, the slowdown of capsule shell dissolution was shown to be dependent on the SLS concentration and the ionic strength of the media. SLS interacts with gelatin to form a less-soluble precipitate at pH < 5. The use of SLS in dissolution media at acidic pH should be carefully evaluated for gelatin capsule products.


Antipsychotic drugs induce similar effects on the release of dopamine and noradrenaline in the medial prefrontal cortex of the rat brain.
In the present study we have compared the effects of the classical antipsychotic drug haloperidol and four different atypical antipsychotics (clozapine, risperidone, olanzapine, ziprasidone) on extracellular levels of dopamine and noradrenaline in the medial prefrontal cortex (MPFC) of conscious rats. Haloperidol (10, 100 and 800 nmol/kg), clozapine (0.3, 1, 10 and 30 micromol/kg), risperidone (100, 500 and 5000 nmol/kg), olanzapine (10, 100 and 500 nmol/kg) and ziprasidone (10, 100 and 1000 nmol/kg) were administered subcutaneously to rats. All compounds induced increases in dialysate levels of dopamine and noradrenaline in the medial prefrontal cortex. The increases induced by the four antipsychotic agents in extracellular levels of dopamine and noradrenaline displayed a striking co-variation both in dose and time. A similar co-variation was seen in the decrease of dopamine and noradrenaline, after administration of a low dose (30 nmol/kg, s.c.) of the dopamine D2/3 receptor agonist (+)-7-hydroxy-2-(N,N-di-n-propylamino) tetralin ((+)-7-OH-DPAT). It is concluded that there is a close coupling between the release of dopamine and noradrenaline in the medial prefrontal cortex. The mechanism of action of this interaction, that might be of importance for a better understanding of the mechanism of action of antipsychotic drugs, is discussed.


Does Sars-Cov-2 threaten our dreams? Effect of quarantine on sleep quality and body mass index.
COVID 19-related quarantine led to a sudden and radical lifestyle changes, in particular in eating habits. Objectives of the study were to investigate the effect of quarantine on sleep quality (SQ) and body mass index (BMI), and if change in SQ was related to working modalities. We enrolled 121 adults (age 44.9 ± 13.3 years and 35.5% males). Anthropometric parameters, working modalities and physical activity were studied. Sleep quality was evaluated by the Pittsburgh Sleep Quality Index (PSQI) questionnaire. At baseline, the enrolled subjects were assessed in outpatient clinic and after 40 days of quarantine/lockdown by phone interview. Overall, 49.6% of the subjects were good sleepers (PSQI < 5) at the baseline and significantly decreased after quarantine (p < 0.001). In detail, sleep onset latency (p < 0.001), sleep efficiency (p = 0.03), sleep disturbances (p < 0.001), and daytime dysfunction (p < 0.001) significantly worsened. There was also a significant increase in BMI values in normal weight (p = 0.023), in subjects grade I (p = 0.027) and II obesity (p = 0.020). In all cohort, physical activity was significantly decreased (p = 0.004). However, analyzing the data according gender difference, males significantly decreased physical activity as well as females in which there was only a trend without reaching statistical significance (53.5% vs 25.6%; p = 0.015 and 50.0% vs 35.9%, p = 0.106; in males and females, respectively). In addition, smart working activity resulted in a significant worsening of SQ, particularly in males (p < 0.001). Quarantine was associated to a worsening of SQ, particularly in males doing smart working, and to an increase in BMI values.


Degradation of ochratoxin a and b by the white rot funguspleurotus ostreatus.
Degradation of ochratoxin A (OTA) and B (OTB) by three selected fungi during solid state fermentation of barley contaminated with ochratoxins was compared. In presence of the soil fungusRhizopus japonicus and the white rot fungusPanerochaete chrysosporium more than 60 % of the mycotoxins remained stable, while in the white rot fungusPleurotus ostreatus only 23 % of the initial OTA and 3 % of OTB were detected after a four weeks incubation period. Kinetic studies on mycotoxin degradation byPI ostreatus demonstrated formation of ochratoxin α and presumably ochratoxin β as intermediate products, what indicates that hydrolysis is the first step in OTA and OTB degradation followed by further degradation of the intermediates.


Ex vivo treatment with poly (I:C) alleviates the exhausted phenotype of tumor-infiltrating TCD8+ cells of gastric cancer patients.
Gastric cancer is associated with the phenotypic and functional exhaustion of TCD8+ cells. On the other hand, Toll-like receptor (TLR) agonists are known to reinforce immune responses when used as adjuvants in cancer immunotherapies. Since the compromised signaling of pro-inflammatory pathways is usually associated with T cell exhaustion, the aim of the present study was to evaluate the impact of polyinosinic-polycytidylic acid (poly (I:C))-mediated TLR3 activation in restoring the normal phenotype and function of tumor-infiltrating TCD8+ cells. Peripheral blood and tumor-infiltrating TCD8+ cells of 35 gastric cancer patients were in vitro treated with increasing concentrations of poly (I:C) and the expressions of programmed death-1 (PD-1) and lymphocyte-activation gene 3 (LAG3) on these cells were examined. The peripheral TCD8+ cells of gastric cancer patients showed higher expressions of PD-1 and LAG3 along with lower proliferation compared to TCD8+ cells of the age-matched healthy control individuals. The in vitro treatment of TCD8+ cells with 100 μg/mL concentration of poly (I:C) alleviated the expression of PD-1 and LAG3 inhibitory checkpoint molecules on both peripheral and tumor-infiltrating TCD8+ cells. The mentioned dose of poly (I:C) improved the proliferation of TCD8+ cells in response to a polyclonal activator. Besides, the releases of Interferon gamma (IFN-γ) and Tumor necrosis factor alpha (TNF-α) were increased in the poly (I:C)-treated TCD8+ cells. Poly (I:C) demonstrated a potential to reduce the phenotypic and functional exhaustion of the peripheral and tumor-infiltrating TCD8+ cells and caused them to undergo more proliferation and cytokine release.


Inhibition by peripheral electric stimulation of the reinstatement of morphine-induced place preference in rats and drug-craving in heroin addicts.
To test the hypothesis that peripheral electric stimulation (PES) may suppress the reinstatement of morphine-induced conditioned place preference (CPP) in rats as well as the drug craving of detoxified heroin addicts in a frequency-dependent manner. CPP model of the rat was constructed with two compartment automatic CPP apparatus, and the craving of the heroin addicts was assessed with a visual analogue scale (VAS). (1) PES of low frequency could prevent the drug priming- or foot shock-induced reinstatement of morphine CPP; (2) this effect was naloxone-reversible, suggesting a possible involvement of endogenous opioid mechanisms; and (3) PES of low frequency could also accelerate the rate of natural decay of drug craving in heroin addicts after successful abstinence. PES might serve as a therapeutic measure for the treatment of heroin addiction.


Microvascular O2 delivery and O2 utilization during metabolic transitions in skeletal muscle. One-hundred years after the pioneering work by August Krogh.
Upon a sudden rise in work rate, ATP turnover increases immediately, whereas the adjustment of ATP resynthesis from oxidative phosphorylation is substantially slower. An "O2 deficit" (energy borrowed from substrate level phosphorylation) is therefore generated. A greater O2 deficit represents an epiphenomenon of a lower "metabolic stability" during the transition, a circumstance directly related to impaired exercise tolerance. In the search for factors responsible for the delayed adjustment of oxidative phosphorylation, we performed studies in the surgically isolated canine gastrocnemius muscle in situ. Enhancement of convective and diffusive microvascular O2 delivery, with respect to a "normal" condition, did not affect skeletal muscle V̇O2 kinetics during transitions to submaximal metabolic rates. V̇O2 kinetics, however, was slowed after experimentally impairing convective O2 delivery, a condition frequently encountered in pathological conditions. Among potential metabolic factors (pyruvate dehydrogenase activation, nitric oxide inhibition of cytochrome oxidase) a limiting role in V̇O2 kinetics was observed only for creatine kinase (CK) mediated phosphocreatine (PCr) breakdown. Following CK inhibition, faster muscle V̇O2 kinetics was observed. Thus, in skeletal muscle CK-catalysed PCr breakdown at contractions onset slows the increase of oxidative phosphorylation. By acting as a high-capacitance energy buffer, PCr breakdown delays or attenuates the increased concentrations of metabolites (such as ADP, Pi, Cr) mediating the V̇O2 increase. Upon sudden increases in ATP turnover, skeletal muscle fibers rely first on the bioenergetic pathway (PCr breakdown), which is fast to adjust to increased metabolic needs. Metabolites related to PCr breakdown regulate, but inevitably slow down, the adjustment of oxidative phosphorylation.


BVES is a novel interactor of ANO5 and regulates myoblast differentiation.
Anoctamin 5 (ANO5) is a membrane protein belonging to the TMEM16/Anoctamin family and its deficiency leads to the development of limb girdle muscular dystrophy R12 (LGMDR12). However, little has been known about the interactome of ANO5 and its cellular functions. In this study, we exploited a proximal labeling approach to identify the interacting proteins of ANO5 in C2C12 myoblasts stably expressing ANO5 tagged with BioID2. Mass spectrometry identified 41 unique proteins including BVES and POPDC3 specifically from ANO5-BioID2 samples, but not from BioID2 fused with ANO6 or MG53. The interaction between ANO5 and BVES was further confirmed by co-immunoprecipitation (Co-IP), and the N-terminus of ANO5 mediated the interaction with the C-terminus of BVES. ANO5 and BVES were co-localized in muscle cells and enriched at the endoplasmic reticulum (ER) membrane. Genome editing-mediated ANO5 or BVES disruption significantly suppressed C2C12 myoblast differentiation with little impact on proliferation. Taken together, these data suggest that BVES is a novel interacting protein of ANO5, involved in regulation of muscle differentiation.


4,5-Diazafluorene N-glycopyranosyl hydrazones as scaffolds for potential bioactive metallo-organic compounds: Synthesis, structural study and cytotoxic activity.
A series of novel N1-(4,5-diazafluoren-9-yliden)-N2-glycopyranosyl hydrazines was prepared in synthetically useful yields by treatment of 9H-4,5-diazafluoren-9-hydrazone with different unprotected monosaccharides. The reactions with the monosaccharides tested afforded stereoselectively, and exclusively, cyclic derivatives, whose structures correspond to N-β-glycopyranosyl hydrazones except for the d-arabinose derivative that agrees with the α-anomer. Several copper(II) complexes having a 2:1 ligand to metal mole ratio were also prepared. The metal complexes can bind DNA sequences and preferentially stabilize G-quadruplex DNA structures over dsDNA. The fucose, rhamnose and deoxyglucose copper(II) complexes exhibited a cytotoxic activity against cultured HeLa and PC3 tumor cells comparable to other metal complexes normally used for chemotherapeutic purposes, such as cisplatin.


[Action of dietetic correction of nutrition on the effectiveness of rehabilitation of hospitalized patients with ischemic heart disease after myocardial infarct].
218 males after myocardial infarction were under study. The dietary and other kind of treatment are effective methods of rehabilitation of patients. It was shown an improvement of clinical symptoms of disease and decreasing of body mass. Contents of total cholesterol, triglycerides, atherogenic lipoproteins and atherogenic coefficient were decreased after treatment. As result of rehabilitation 94% of patients after myocardial infarct had recovered their capability to work.


Single-step removal of arsenite ions from water through oxidation-coupled adsorption using Mn/Mg/Fe layered double hydroxide as catalyst and adsorbent.
This study developed a layered double hydroxides (Mn/Mg/Fe-LDH) material through a simple co-precipitation method. The Mn/Mg/Fe-LDH oxidized arsenite [As(III)] ions into arsenate [As(V)] anions. The As(III) and oxidized As(V) were then adsorbed onto Mn/Mg/Fe-LDH. The adsorption process of arseniate [As(V)] oxyanions by Mn/Mg/Fe-LDH was simultaneously conducted for comparison. Characterization results indicated that (i) the best Mg/Mn/Fe molar ratio was 1/1/1, (ii) Mn/Mg/Fe-LDH structure was similar to that of hydrotalcite, (iii) Mn/Mg/Fe-LDH possessed a positively charged surface (pHIEP of 10.15) and low Brunauer-Emmett-Teller surface area (SBET = 75.2 m2/g), and (iv) Fe2+/Fe3+ and Mn2+/Mn3+/Mn4+ coexisted in Mn/Mg/Fe-LDH. The As(III) adsorption process by Mn/Mg/Fe-LDH was similar to that of As(V) under different experimental conditions (initial solutions pH, coexisting foreign anions, contact times, initial As concentrations, temperatures, and desorbing agents). The Langmuir maximum adsorption capacity of Mn/Mg/Fe-LDH to As(III) (56.1 mg/g) was higher than that of As(V) (32.2 mg/g) at pH 7.0 and 25 °C. X-ray photoelectron spectroscopy was applied to identify the oxidation states of As in laden Mn/Mg/Fe-LDH. The key removal mechanism of As(III) by Mn/Mg/Fe-LDH was oxidation-coupled adsorption, and that of As(V) was reduction-coupled adsorption. The As(V) mechanism adsorption mainly involved: (1) the inner-sphere and outer-sphere complexation with OH groups of Mn/Mg/Fe-LDH and (2) anion exchange with host anions (NO3-) in its interlayer. The primary mechanism adsorption of As(III) was the inner-sphere complexation. The redox reactions made Mn/Mg/Fe-LDH lose its original layer structure after adsorbing As(V) or As(III). The adsorption process was highly irreversible. Mn/Mg/Fe-LDH can decontaminate As from real groundwater samples from 45-92 ppb to 0.35-7.9 ppb (using 1.0 g/L). Therefore, Mn/Mg/Fe-LDH has great potential as a material for removing As.


Gastric mucosal protection by acetazolamide derivatives: role of carbonic anhydrase and sulfhydryls.
Acetazolamide, a carbonic anhydrase inhibitor, prevents acute gastric hemorrhagic lesions induced by ethanol. We used acetazolamide and other carbonic anhydrase inhibitors to correlate their gastroprotective effects with the degree of inhibition of carbonic anhydrase. Since acetazolamide is a thiadiazole, we also investigated structurally related thiadiazoles that contain sulfhydryls to test the hypothesis that the protection against ethanol-induced gastric erosions is related to the presence of sulfhydryls. Dose-response studies with acetazolamide revealed that the protection did not correlate with the inhibition of carbonic anhydrase in the rat gastric mucosa. The carbonic anhydrase inhibitors sulfanilamide and ethoxzolamide, did not offer protection. Bismuthiol I, a thiadiazole with two sulfhydryls, was twice as protective as 2-amino-5-mercapto-1,3,4-thiadiazole with only one sulfhydryl group. We conclude that the protection by acetazolamide against ethanol-induced lesions is not related to the inhibition of carbonic anhydrase in the gastric mucosa. The gastroprotective effect of acetazolamide and its derivatives may be related to their content of sulfhydryls in an oxidized or reduced state.


A density distribution algorithm for bone incorporating local orthotropy, modal analysis and theories of cellular solids.
An algorithm for bone remodeling is presented which allows for both a redistribution of density and a continuous change of principal material directions for the orthotropic material properties of bone. It employs a modal analysis to add density for growth and a local effective strain based analysis to redistribute density. General re-distribution functions are presented. The model utilizes theories of cellular solids to relate density and strength. The code predicts the same general density distributions and local orthotropy as observed in reality.


Assessment of air pollution sources in an industrial atmosphere using principal component and multilinear regression analysis.
Aerosol samples collected in the industrial area of Estarreja, Portugal, were used to assess the source classes responsible for the particulate levels observed in the local atmosphere. Principal Component Analysis was applied separately to the concentrations of aerosol constituents and meteorological variables to obtain the number of Principal Components and to verify the influence of weather conditions on ambient air quality. The technique led to the conclusion that soil and transport emissions represent important aerosol sources even in this industrial environment. The quantitative contribution of each source class was calculated using Multilinear Regression Analysis; 37% of the aerosol mass had a soil origin, 8% was from sea spray, 18% resulted from transport emissions and 24% contained ammonium salts. Twelve percent of total suspended particle (TSP) mass could not be explained by any of the six Principal Components retained. Ammonium salts and two other minor Principal Components seem to result mainly from industrial emissions. More specific information about the contribution of each particular source was not possible with this technique.


Molecular cloning, characterization and expression of the complement component Bf/C2 gene in grass carp.
The complement system is an integral part of the host immune system and plays an immunoregulatory role at the interface between the innate and acquired immune responses. Factor B (Bf) serves as the catalytic subunit of complement C3 convertase in the alternative pathway (AP), while in the classical pathway (CP), this function is subjected to C2. In this study, we cloned and characterized the two Bf/C2 genes of grass carp, gcBf/C2A and gcBf/C2B. The gcBf/C2A and gcBf/C2B cDNA sequences are 2259 and 3004 bp in length, and the open reading frames (ORFs) of gcBf/C2A and gcBf/C2B were found to encode peptides of 752 and 837 amino acids, respectively. The genes share 30.7% amino acid identity with each other and 32.4-38.3% and 31.4-33% with the Bf and C2 genes in humans and mice. GcBf/C2A and gcBf/C2B were expressed in a wide range of grass carp tissues, with the highest level of expression of both genes detected in the liver. After a challenge with Aeromonas hydrophila, gcBf/C2A was significantly upregulated, especially at 4 h after infection, and the significantly higher expression of gcBf/C2B (27.3-fold) was found in the head kidney at 24 h post-challenge. The expression of gcBf/C2A was quickly upregulated at 1 day post-hatching and peaked at 5 days post-hatching. The maximum expression of gcBf/C2B was found at 1 day post-hatching. In conclusion, our data enables a better understanding of the physiological function of the Bf/C2 complement genes in vertebrates.


Common Molecular Signatures Between Coronavirus Infection and Alzheimer's Disease Reveal Targets for Drug Development.
Cognitive decline is a common consequence of COVID-19, and studies suggest a link between COVID-19 and Alzheimer's disease (AD). However, the molecular mechanisms underlying this association remain unclear. To understand the potential molecular mechanisms underlying the association between COVID-19 and AD development, and identify the potential genetic targets for pharmaceutical approaches to reduce the risk or delay the development of COVID-19-related neurological pathologies. We analyzed transcriptome datasets of 638 brain samples using a novel Robust Rank Aggregation method, followed by functional enrichment, protein-protein, hub genes, gene-miRNA, and gene-transcription factor (TF) interaction analyses to identify molecular markers altered in AD and COVID-19 infected brains. Our analyses of frontal cortex from COVID-19 and AD patients identified commonly altered genes, miRNAs and TFs. Functional enrichment and hub gene analysis of these molecular changes revealed commonly altered pathways, including downregulation of the cyclic adenosine monophosphate (cAMP) signaling and taurine and hypotaurine metabolism, alongside upregulation of neuroinflammatory pathways. Furthermore, gene-miRNA and gene-TF network analyses provided potential up- and downstream regulators of identified pathways. We found that downregulation of cAMP signaling pathway, taurine metabolisms, and upregulation of neuroinflammatory related pathways are commonly altered in AD and COVID-19 pathogenesis, and may make COVID-19 patients more susceptible to cognitive decline and AD. We also identified genetic targets, regulating these pathways that can be targeted pharmaceutically to reduce the risk or delay the development of COVID-19-related neurological pathologies and AD.


Validation of the FACT-G7 in patients with hematologic malignancies.
It is essential to evaluate the quality of life in patients with hematologic malignancies to reflect the therapeutic effect and prognosis, but lengthy assessments are often burdensome. The 7-Item Functional Assessment of Cancer Therapy-General (FACT-G7) is a brief, easy, and rapid index for evaluating quality of life. Nevertheless, there is no report about its application in Chinese patients with hematologic malignancies. The purpose of this study was to validate the Chinese version of the FACT-G7 for patients with hematologic malignancies. This study is a cross-sectional study. A total of 855 patients with hematologic malignancies completed the Functional Assessment of Cancer Therapy-General (FACT-G) and were scored the Eastern Cooperative Oncology Group Performance Status (ECOG-PS) by nurses. Cronbach's alpha, confirmatory factor analyses, Pearson's correlation, and one-way analysis of variance were conducted to evaluate internal consistent reliability, structural validity and concurrent validity. The FACT-G7 showed acceptable internal consistency, as indicated by a Cronbach's alpha of 0.73. The confirmatory factor analyses test for single-factor model fit for the FACT-G7 scale was almost adequate. The satisfactory correlations between the FACT-G7 and the FACT-G and its subscales, and ECOG-PS groups differed in FACT-G7 scores demonstrating concurrent validity. This study suggested that the Chinese version of the FACT-G7 provides a useful and rapid measure for assessing quality of life in Chinese patients with hematologic malignancies, which providing a reference for further evaluation and care.


[Engineering of a System for the Production of Mutant Human Alpha-Fetoprotein in the Methylotrophic Yeast Pichia pastoris].
A system for the production of mutant recombinant human alpha-fetoprotein (rhAFPO) lacking the glycosylation site has been engineered in the yeast Pichia pastoris. A strain of the methylotrophic yeast Pichia pastoris GS 115/pPICZ?A/rhAFP0, which produces unglycosylated rhAFPO and secretes it to the culture medium, has been constructed. Optimization and scale-up of the fermentation technology have resulted in an increase in the rhAFP0 yield to 20 mg/L. A scheme of isolation and purification of biologically active rhAFP0 has been developed. The synthesized protein has the antitumor activity, which is analogous to the activity of natural human embryonic alpha-fetoprotein.


Improving Patient Care by Incorporation of Multidisciplinary Breast Radiology-Pathology Correlation Conference.
It is well known that radiologic-pathologic correlation is critical in managing patients with breast disease. Although regular multidisciplinary conferences addressing radiologic-pathologic correlation are common at most major academic institutions, this approach is not universal in community-based settings or even some of the smaller academic practices. This study was performed to assess the impact of a weekly multidisciplinary conference on patient care to determine whether all breast practices should adopt this approach as a means to streamline and improve the quality of patient care. We reviewed cases of percutaneous breast core biopsies presented at our weekly breast radiology-pathology correlation conference from July 1, 2008, to June 30, 2012. Each reviewed case was assigned to 1 of 4 categories (concordant → concordant, concordant → discordant, discordant → discordant, and discordant → concordant) based on the "initial" and "final" impressions of concordance between radiology and pathology. Changes in concordance, histopathological diagnosis, or management that occurred during the conference were recorded prospectively and analysed. Changes in management that were considered significant included changes in recommendations for surgery, repeat core biopsy, or follow-up imaging. Of 1387 presented at the conference, 1313 (94.7%) had no change during the meeting, confirming 1279 (92.2%) concordant and 34 (2.4%) discordant cases. A total of 74 (5.3%) cases had a change during the conference: 22 of 74 (29.7%) were changed from discordant to concordant, avoiding surgical excision in 15 and short interval imaging in 7; 23 of 74 (31.1%) were changed from concordant to discordant; on excision 3 were cancer, 3 atypia, 10 benign, 2 stable on follow-up imaging, and 5 lost to follow-up; the remaining 29 of 74 (39.2%) stayed concordant after review, but had a change in management, avoiding surgery in 14 and short interval imaging in 15. Overall, as a result of this conference, repeat biopsy or excision was recommended in 23, surgery was avoided in 29, short interval imaging avoided in 22, and cancer detected in 3 cases. Our weekly breast radiology-pathology correlation conference impacted patient management in up to 5.3% of cases. These results support the need to incorporate a weekly multidisciplinary case review of breast core biopsies into all breast care practices. Such a conference maximizes cancer detection, identifies discordant cases in a timely manner, decreases follow-up imaging, and avoids unnecessary surgical intervention.


The impact of aging on the course of the azygos vein.
The human azygos vein (AV) generally runs on the right side of the vertebral column. However, a shift in its course to the middle/left side of the vertebral column, potentially as a result of aging, has been reported. The aim of this study was to understand the relationship between AV displacement and aging. Forty-seven adult cadavers were dissected. When an AV left shift was observed, long axis AV length was measured by calculating the number of vertebral bodies under the vein. We also investigated whether a crossover vein existed between AV and hemiazygos vein at the extreme left shifting point, and whether osteophytes existed along the vertebral column. Forty-four cadavers (94%) had left-shifted AVs. A weak positive correlation between age and the length of the left shift was observed (r = 0.3061, P = 0.0364). Thirty cadavers (64%) had crossover veins at the extreme left shifting point, and 24 cadavers (51%) had osteophytes along the vertebral column. There was no significant relationship between the length of left-shifted AVs and the existence of crossover veins or osteophytes. The possibility of AV displacement to the left as part of the aging process is suggested.


Zinc Fingers 10 and 11 of Miz-1 undergo conformational exchange to achieve specific DNA binding.
Miz-1 (ZBTB17) is a poly-zinc finger BTB/POZ transcription factor with 12 consecutive C2H2 zinc fingers (ZFs) that binds transcriptional start sites (TSSs) to regulate the expression of genes involved in cell development and proliferation. As of now, it is not known which of the 12 consecutive ZFs are responsible for the recognition of the 24 base pair consensus sequence found at these TSSs. Evidence suggests ZFs 7-12 plays this role. We provide validation for this and describe the structural and dynamical characterization of unprecedented conformational exchange in the linker between ZFs 10 and 11. This conformational exchange uncouples ZFs 7-10 from 11 and 12 and promotes a scanning-recognition mechanism through which the two segments cooperate to bind two sub-sites at both ends of the consensus. We further show that this can result in the coiling of TSSs as part of Miz-1's mechanism of transcriptional transactivation.


Hesperidin ameliorates functional and histological outcome and reduces neuroinflammation in experimental stroke.
Incidence of stroke is considered to be a major cause of death throughout the world. The middle cerebral artery occlusion (MCAO) for 2h followed by 22h of reperfusion model was used in male Wistar rats to study the protection of stroke by hesperidin. Hesperidin administration (50mg/kg b.wt.) once daily for 15days has improved the infarct size, reduced the neurological deficits in terms of behaviors, and protected the elevated level of thiobarbituric acid reactive species (TBARS). A significantly depleted activity of antioxidant enzymes, glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT) and superoxide dismutase (SOD) and content of glutathione (GSH) in MCAO group were protected significantly in MCAO group pretreated with hesperidin. Moreover, inflammatory mediators like TNF-α, IL-1β levels, expression of iNOS and glial fibrillary acidic protein (GFAP) were significantly attenuated in H+MCAO group as compared to MCAO group. In conclusion, prophylactic treatment with hesperidin ameliorated the functional and histological outcomes with elevated endogenous antioxidants status as well as reduced induction of proinflammatory cytokines in MCA occluded rat. We theorized that hesperidin is among the pharmacological agents that reduce free radicals and its associated inflammation and have been found to limit the extent of brain damage following stroke.


An unusual portal-systemic shunt, most likely through a patent ductus venosus. A case report.
A 46-yr-old man with cirrhosis presented with mental confusion, headache, and nausea. Colloid liver scintigraphy showed a defect in the hilar area, and portograms after superior mesenteric arteriography demonstrated varicose veins in the same area. Computed tomography revealed a sausage-shaped low-density channel connecting the hepatic hilum and the inferior vena cava, and bolus injection contrast enhancement demonstrated transit of contrast medium from the portal vein directly into the inferior vena cava through this channel. Real-time ultrasound demonstrated a large conduit contiguous from the portal vein to the inferior vena cava through and behind the liver. The catheter introduced into the inferior vena cava opacified a large opening of this shunt below the right and left hepatic vein openings. Measurements of blood pressure, ammonia, and PaO2 clearly indicated that portal vein blood was being shunted through this channel. These findings are highly suggestive of a portosystemic shunt through a patent ductus venosus.


Thin-film optical notch filter spectacle coatings for the treatment of migraine and photophobia.
Previous evidence suggests optical treatments hold promise for treating migraine and photophobia. We designed an optical notch filter, centered at 480nm to reduce direct stimulation of intrinsically photosensitive retinal ganglion cells. We used thin-film technology to integrate the filter into spectacle lenses. Our objective was to determine if an optical notch filter, designed to attenuate activity of intrinsically photosensitive retinal ganglion cells, could reduce headache impact in chronic migraine subjects. For this randomized, double-masked study, our primary endpoint was the Headache Impact Test (HIT-6; GlaxoSmithKline, Brentford, Middlesex, UK). We developed two filters: the therapeutic filter blocked visible light at 480nm; a 620nm filter was designed as a sham. Participants were asked to wear lenses with one of the filters for 2weeks; after 2weeks when no lenses were worn, they wore lenses with the other filter for 2weeks. Of 48 subjects, 37 completed the study. Wearing either the 480 or 620nm lenses resulted in clinically and statistically significant HIT-6 reductions. However, there was no significant difference when comparing overall effect of the 480 and 620nm lenses. Although the 620nm filter was designed as a sham intervention, research published following the trial indicated that melanopsin, the photopigment in intrinsically photosensitive retinal ganglion cells, is bi-stable. This molecular property may explain the unexpected efficacy of the 620nm filter. These preliminary findings indicate that lenses outfitted with a thin-film optical notch filter may be useful in treating chronic migraine.


MESP2 variants contribute to conotruncal heart defects by inhibiting cardiac neural crest cell proliferation.
Conotruncal heart defects (CTDs) are closely related to defective outflow tract (OFT) development, in which cardiac neural crest cells (CNCCs) play an indispensable role. However, the genetic etiology of CTDs remains unclear. Mesoderm posterior 2 (MESP2) is an important transcription factor regulating early cardiogenesis. Nevertheless, MESP2 variants have not been reported in congenital heart defect (CHD) patients. We first identified four MESP2 variants in 601 sporadic nonsyndromic CTD patients that were not detected in 400 healthy controls using targeted sequencing. Reverse transcription-quantitative PCR (RT-qPCR), immunohistochemistry, and immunofluorescence assays revealed MESP2 expression in the OFT of Carnegie stage (CS) 11, CS13, and CS15 human embryos and embryonic day (E) 8.5, E10, and E11.5 mouse embryos. Functional analyses in HEK 293T cells, HL-1 cells, JoMa1 cells, and primary mouse CNCCs revealed that MESP2 directly regulates the transcriptional activities of downstream CTD-related genes and promotes CNCC proliferation by regulating cell cycle factors. Three MESP2 variants, c.346G>C (p.G116R), c.921C>G (p.Y307X), and c.59A>T (p.Q20L), altered the transcriptional activities of MYOCD, GATA4, NKX2.5, and CFC1 and inhibited CNCC proliferation by upregulating p21cip1 or downregulating Cdk4. Based on our findings, MESP2 variants disrupted MESP2 function by interfering with CNCC proliferation during OFT development, which may contribute to CTDs. KEY MESSAGES: This study first analyzed MESP2 variants identified in sporadic nonsyndromic CTD patients. MESP2 is expressed in the OFT of different stages of human and mouse embryos. MESP2 regulates the transcriptional activities of downstream CTD-related genes and promotes CNCC proliferation by regulating cell cycle factor p21cip1 or Cdk4.


Effect on growth of long-term treatment with intranasal triamcinolone acetonide aqueous in children with allergic rhinitis.
Guidelines recommend treatment with intranasal corticosteroids for patients with allergic rhinitis (AR), but concerns remain about possible adverse effects. To present the 1- and 2-year growth results for children with AR treated with triamcinolone acetonide aqueous nasal spray. Thirty-nine children (aged 6.1-14.3 years at study entry) were treated with triamcinolone acetonide aqueous for 1 year, and a subset of 30 children completed a second year of treatment. The dose was physician titered to achieve control over AR symptoms. For each child, statural heights at baseline and at the 1- and 2-year (where available) visits, together with growth rates, were measured and were compared with predicted values. There were no significant differences between measured and predicted heights at the 1- and 2-year visits. The mean (SD) measured--predicted difference was 0.3 (2.2) cm (95% confidence interval, -0.4 to 1.0 cm) at the 1-year visit and 0.5 (3.0) cm (95% confidence interval, -0.6 to 1.6 cm) at the 2-year visit. Mean differences in measured and predicted growth rates were nonsignificant at the 1- and 2-year visits. Triamcinolone acetonide aqueous titered to control AR symptoms and given for 1 or 2 years had no significant effect on statural growth in children with AR.


Associations of tobacco smoking with body mass distribution; a population-based study of 65,875 men and women in midlife.
Studies indicate an effect of smoking toward abdominal obesity, but few assess hip and waist circumferences (HC and WC) independently. The present study aimed to assess the associations of smoking status and volume smoked with HC and WC and their ratio in a population with low prevalence of obesity together with high prevalence of smoking. We used cross-sectional survey data from 11 of a total 19 Norwegian counties examined in 1997-99 including 65,875 men and women aged 39-44 years. Analysis of associations were adjusted for confounding by socioeconomic position, health indicators, and additionally for BMI. Compared with never-smokers, when adjusting for confounders and in addition for BMI, mean HC remained lower while mean WC and waist-hip-ratio (WHR) were higher in current smokers. The finding of a lower HC and higher WHR level among smokers was consistent by sex and in strata by levels of education and physical activity, while the finding of higher WC by smoking was less consistent. Among current smokers, BMI-adjusted mean HC decreased whereas WC and WHR increased by volume smoked. Compared with current smokers, former smokers had higher BMI-adjusted HC, lower WHR and among women WC was lower. The main finding in this study was the consistent negative associations of smoking with HC. In line with the hypothesis that lower percentage gluteofemoral fat is linked with higher cardiovascular risk, our results suggest that smoking impacts cardiovascular risk through mechanisms that reduce the capacity of fat storage in the lower body region.


Delivery exogenous nitric oxide via cardiopulmonary bypass in pediatric cardiac surgery reduces the duration of postoperative mechanical ventilation-A meta-analysis of randomized controlled trials.
Cardiopulmonary bypass (CPB) is a major part of cardiac surgery that provokes systemic inflammatory reactions, myocardial ischemia, and ischemia and reperfusion damage. The aim of this study is to summarize the available evidence and evaluate whether exogenous nitric oxide administered via CPB circuits can improve recovery after cardiac surgery in children. A comprehensive search of the PubMed Medline, Ovid, Cochrane Library and Embase databases was conducted in September 2022. Only randomized controlled trials that compared nitro oxide with placebo or standard care were included. This pooled analysis included 5 RCTs containing 1642 patients. There were significant differences in the duration of postoperative mechanical ventilation between the nitric oxide group and the control group (mean difference -5.645 h; 95% CL = -9.978, -1.313; P = 0.01). Meta-analysis of the length of ICU stay and hospital stay showed no significant differences. Delivering nitric oxide via CPB in pediatric cardiac surgery has an effect on reducing the duration of mechanical ventilation. Considering the small effect size, we should be cautious and think comprehensively in clinical practice.


An effective model for store and retrieve big health data in cloud computing.
The volume of healthcare data including different and variable text types, sounds, and images is increasing day to day. Therefore, the storage and processing of these data is a necessary and challenging issue. Generally, relational databases are used for storing health data which are not able to handle the massive and diverse nature of them. This study aimed at presenting the model based on NoSQL databases for the storage of healthcare data. Despite different types of NoSQL databases, document-based DBs were selected by a survey on the nature of health data. The presented model was implemented in the Cloud environment for accessing to the distribution properties. Then, the data were distributed on the database by applying the Shard property. The efficiency of the model was evaluated in comparison with the previous data model, Relational Database, considering query time, data preparation, flexibility, and extensibility parameters. The results showed that the presented model approximately performed the same as SQL Server for "read" query while it acted more efficiently than SQL Server for "write" query. Also, the performance of the presented model was better than SQL Server in the case of flexibility, data preparation and extensibility. Based on these observations, the proposed model was more effective than Relational Databases for handling health data.


Sequence of a novel carbonic anhydrase-related polypeptide and its exclusive presence in Purkinje cells.
I isolated a mouse cDNA clone encoding a novel polypeptide which has strong homology with carbonic anhydrase. Unlike the other carbonic anhydrases, it has an additional N-terminal domain with a glutamic acid stretch and an arginine substitutes one of the three histidine residues which bind zinc ion. In the central nervous system, carbonic anhydrase is known to be expressed only in glia cells, but this gene is expressed in neuron, but only in Purkinje cells.


The experiences of East Asian dementia caregivers in filial culture: a systematic review and meta-analysis.
With the aging population in East Asia, the prevalence of dementia and the need for patient care is increasing. Family caregivers of people with dementia are at risk of physical and mental health problems. Filial piety culture regulates relationships within East Asian families and effects the well-being and behavior of dementia family caregivers (CGs). To systematically assess the experience of East Asian dementia caregivers in filial culture. Methods: Electronic databases, including MEDLINE, APA PsycINFO, CINAHL (via EBSCOhost), Web of Science, and Cochrane Library, were searched for relevant studies up to July 2021. Only original articles were included. Thirteen eligible studies were included, of which eight were qualitative and five were quantitative. Meta-analysis showed a negative association (r = -0.18, 95%CI [-0.28, -0.08]) between filial culture and caregiver burden. The quantitative studies identified four themes related to dementia caregivers' experiences: (1) Recognition and understanding of filial piety as part of cultural identity, (2) Role transitions- from child to CG, (3) Filial piety's constraints on CGs; (4) CGs' self-compassion through changing cultural norms of filial practice. Filial culture influences the whole process behind caregiving for East Asian dementia caregivers. At the same time, cultural transition has also brought about new connotations and practices to filial culture.


Capsule thickness of cataractous lenses with and without exfoliation syndrome.
Lens capsule thickness was measured in 105 cataractous lenses with and without exfoliation syndrome. The lenses were removed by intracapsular cryoextraction. Forty lenses (38%) showed exfoliation, while 65 (62%) were exfoliation negative. Thickness values were measured by light microscopy from the central anterior capsule, central posterior capsule and from the equator. The mean thickness values were for the central anterior capsule 8.2 +/- 3.2 mu, for the central posterior capsule 3.2 +/- 1.4 and for the equator 3.9 +/- 1.3. There was no statistical difference between the exfoliation-positive and exfoliation-negative lenses. The capsule thickness varied greatly throughout the present material. The highest value, 22.4 mu, was measured from an exfoliation-negative central anterior lens capsule of a male patient aged 33 years. The lowest value, 0.6 mu, was measured from an exfoliation-positive central posterior capsule of a male patient aged 64 years. The central posterior capsule is the thinnest area of the lens capsule. The findings call for great caution in polishing the posterior capsule during extracapsular cataract surgery. The higher complication rate in eyes with exfoliation syndrome cannot be explained by thinner lens capsules but rather on the more friable zonules.


Applications of miRNAs in cardiac development, disease progression and regeneration.
Development of the complex human heart is tightly regulated at multiple levels, maintaining multipotency and proliferative state in the embryonic cardiovascular progenitors and thereafter suppressing progenitor characteristics to allow for terminal differentiation and maturation. Small regulatory microRNAs (miRNAs) are at the level of post-transcriptional gene suppressors, which enhance the degradation or decay of their target protein-coding mRNAs. These miRNAs are known to play roles in a large number of biological events, cardiovascular development being no exception. A number of critical cardiac-specific miRNAs have been identified, of which structural developmental defects have been linked to dysregulation of miRNAs in the proliferating cardiac stem cells. These miRNAs present in the stem cell niche are lost when the cardiac progenitors terminally differentiate, resulting in the postnatal mitotic arrest of the heart. Therapeutic applications of these miRNAs extend to the realm of heart failure, whereby the death of heart cells in the ageing heart cannot be replaced due to the arrest of cell division. By utilizing miRNA therapy to control cell cycling, the regenerative potential of matured myocardium can be restored. This review will address the various cardiac progenitor-related miRNAs that control the development and proliferative potential of the heart.


Tissue-specificity of prostate specific antigens: comparative analysis of transcript levels in prostate and non-prostatic tissues.
Activation of immune defense mechanisms against tumor antigens appears to be a promising therapeutic option for advanced prostate cancer (PCa). Specific immunotherapy critically depends on target antigens that are selectively expressed in the tumorous and optional in the normal prostate tissue in sufficient amounts. Although several prostate antigens have been described and some have already been used in clinical trials, a detailed comparative evaluation of their tissue-specificity and expression levels is still lacking. We determined the transcript levels of eight prostate targets (PSA, PAP, PSCA, PSGR, Prostein, PSMA, AIbZIP, trp-p8) in 16 different tissues by quantitative PCR and calculated a tissue-specificity index (TSI) for each molecule. Besides a preferential expression in prostate for all targets, striking differences in the expression levels and TSI were revealed which may be important for the selection of appropriate antigens for immunotherapy of PCa.


Development of a Personalized mHealth Program for Cancer Symptom and Complication Management.
Based on care need assessment of colorectal and bladder cancer (CBC) patients with newly created ostomies (stomas) and caregivers, and with the input of the Wound, Ostomy, and Continence Nurses (WOCNs), we have developed an mHealth complication and symptom monitoring and self-management program, titled PRISMS.


Erroneous thyroid diagnosis due to over-the-counter biotin.
Biotin is a component of the vitamin B complex used in standard immunoassays to detect serum levels of various hormones and non-hormones, including thyrotropin (TSH) and thyroxine. These assays involve a strong bond between streptavidin and biotin, which serves as an anchor for measured analytes. Large doses of exogenous biotin for the treatment of certain medical conditions have resulted in assay interference, causing TSH to be spuriously lowered. Smaller doses of biotin found in dietary supplements also have caused assay interference. We describe four cases in which over-the-counter (OTC) biotin caused erroneous thyroid diagnosis and clinical confusion in patients with preexisting thyroid disease. Serum TSH and thyroxine were measured by the Vitros 5600 assay. Although the biotin-streptavidin interaction is sensitive for detecting serum levels of TSH, it is subject to interference by exogenous biotin at levels found in OTC products. The widespread use of OTC biotin for cosmetic purposes can adversely affect the diagnosis of the entire spectrum of functional thyroid disorders. Physicians must carefully and routinely question for the use of biotin before thyroid function testing.


pH as a biomarker of neurodegeneration in Huntington's disease: a translational rodent-human MRS study.
Early diagnosis and follow-up of neurodegenerative diseases are often hampered by the lack of reliable biomarkers. Neuroimaging techniques like magnetic resonance spectroscopy (MRS) offer promising tools to detect biochemical alterations at early stages of degeneration. Intracellular pH, which can be measured noninvasively by (31)P-MRS, has shown variations in several brain diseases. Our purpose has been to evaluate the potential of MRS-measured pH as a relevant biomarker of early degeneration in Huntington's disease (HD). We used a translational approach starting with a preclinical validation of our hypothesis before adapting the method to HD patients. (31)P-MRS-derived cerebral pH was first measured in rodents during chronic intoxication with 3-nitropropionic acid (3NP). A significant pH increase was observed early into the intoxication protocol (pH=7.17±0.02 after 3 days) as compared with preintoxication (pH=7.08±0.03). Furthermore, pH changes correlated with the 3NP-induced inhibition of succinate dehydrogenase and preceded striatum lesions. Using a similar MRS approach implemented on a clinical MRI, we then showed that cerebral pH was significantly higher in HD patients (n=7) than in healthy controls (n=6) (7.05±0.03 versus 7.02±0.01, respectively, P=0.026). Altogether, both preclinical and human data strongly argue in favor of MRS-measured pH being a promising biomarker for diagnosis and follow-up of HD.


Delirium after cardiac surgery: have we overlooked obstructive sleep apnea?
Obstructive sleep apnea is common in patients with cardiovascular disease. It is well known that cardiac surgery is a risk factor for delirium. Researchers have shown that obstructive sleep apnea is an independent risk factor for the occurrence of delirium. In this manuscript we speculate on how obstructive sleep apnea may increase the risk of delirium in patients with cardiac surgery. If this is found to be confirmed, we would have another target through which we can decrease the risk of delirium in this population.


[Nonorganic (functional) hearing loss in children].
Nonorganic (functional) hearing loss in children is characterized by hearing loss without a detectable corresponding pathology in the auditory system. It is not an uncommon disease in childhood. Typically, there is a discrepancy between elevated pure tone thresholds and normal speech discrimination in everyday life. We evaluated 85 original publications, 27 reviews and 4 textbook articles. Mean age at diagnosis was 11.3 years. Girls were affected twice as often as boys. Patient histories showed a high prevalence of emotional and school problems. Pre-existing organic hearing loss can be worsened by nonorganic causes. A brainstem audiometry should confirm the diagnosis. The differential diagnosis includes auditory processing disorder, elevated thresholds in mental retardation and auditory neuropathy. We recommend taking a personal history including biographical factors, a psychological assessment including intelligence testing and referral to a child psychiatrist. Prognosis seems to be dependent on the severity of the patient's school and/or personal problems. Categorization following the Austen-Lynch model can be a valuable prognostic factor.


Validating the performance of QC procedures.
A methodology for computing the maximum expected number of unreliable patient results produced because of an out-of-control condition for a given quality control strategy is presented along with strategies for changing the expected number of unreliable results produced and reported. The expected number of unreliable patient results reported before and after the last accepted quality control evaluation before the detection of an out-of-control condition are discussed and used as design criteria for quality control strategies that meet a laboratory's risk criteria.


Salivary gland ultrasound in clinical practice: What is its real usefulness?
Salivary gland ultrasound (SGU) provides information about structural gland abnormalities that can be graded and used for primary Sjögren's syndrome (pSS) diagnosis. Its potential role as a prognostic marker for detecting patients at high risk of lymphoma and extra-glandular manifestations is still under evaluation. We aim to assess the usefulness of SGU for SS diagnosis in routine clinical practice and its relationship with extra-glandular involvement and lymphoma risk in pSS patients. We designed a retrospective observational single-center study. Data was collected using the electronic health records of patients referred to an ultrasound outpatient clinic for evaluation over a 4-year period. Data extraction included demographics, comorbidities, clinical data, laboratory tests, SGU results, salivary gland (SG) biopsy, and scintigraphy results. Comparisons were made between patients with and without pathological SGU. The external criterion for comparison was the fulfillment of the 2016 ACR/EULAR pSS criteria. A total of 179 SGU assessments were included from this 4-year period. Twenty-four cases (13.4%) were pathological. The most frequently diagnosed conditions prior to SGU-detected pathologies were pSS (9.7%), rheumatoid arthritis (RA) (13.1%), and systemic lupus (4.6%). One hundred and two patients (57%) had no previous diagnosis (sicca syndrome work-up); of these, 47 patients (46.1%) were ANA positive and 25 (24.5%) anti-SSA positive. In this study, the sensitivity and specificity of SGU for SS diagnosis were 48% and 98% respectively, with a positive predictive value of 95%. There were statistically significant relationships between a pathological SGU and the presence of recurrent parotitis (p=.0083), positive anti-SSB antibodies (p=.0083), and a positive sialography (p=.0351). SGU shows high global specificity but low sensitivity for pSS diagnosis in routine care. Pathological SGU findings are associated with positive autoantibodies (ANA and anti-SSB) and recurrent parotitis.


Physostigmine alters onset but not duration of REM sleep in man.
Physostigmine (1.0mg) or placebo were administered intravenously over 1-h period to seven male normal volunteers beginning 35 min after sleep onset. The results indicate that physostigmine induced the onset of REM sleep but did not significantly alter the duration of individual REM sleep periods. Physostigmine significantly shortened the REM latency and the duration of the second nonREM period. After inducing the onset of the first REM period(s); physostigmine also appeared to advance succeeding REM-nonREM sleep cycles relative to sleep onset even when the duration of each cycle was unaffected.


Isometric force complexity may not fully originate from the nervous system.
In humans and animals, spatial and temporal information from the nervous system are translated into muscle force enabling movements of body segments. To gain deeper understanding of this translation of information into movements, we investigated the motor control dynamics of isometric contractions in children, adolescents, young adults and older adults. Twelve children, thirteen adolescents, fourteen young adults, and fifteen older adults completed two minutes of submaximal isometric plantar- and dorsiflexion. Simultaneously, sensorimotor cortex EEG, tibialis anterior and soleus EMG and plantar- and dorsiflexion force was recorded. Surrogate analysis suggested that all signals were from a deterministic origin. Multiscale entropy analysis revealed an inverted U-shape relationship between age and complexity for the force but not for the EEG and EMG signals. This suggests that temporal information in from the nervous system is modulated by the musculoskeletal system during the transmission into force. The entropic half-life analyses indicated that this modulation increases the time scale of the temporal dependency in the force signal compared to the neural signals. Together this indicates that the information embedded in produced force does not exclusively reflect the information embedded in the underlying neural signal.


In vivo restoration of RhoB expression leads to ovarian tumor regression.
Ovarian cancers are very aggressive cancers most often diagnosed when metastasis has already occurred in the entire peritoneal cavity. Ovarian adenocarcinoma cells present an undetectable level of RhoB GTPase. Using preclinical ovarian cancer models, we aimed to evaluate the potential use of RhoB cDNA as a tumor suppressor gene in gene therapy. RhoB restoration in vitro, through recombinant adenovirus transduction, resulted in the apoptosis of endogenous RhoB protein low-expressing cell lines (OVCAR-3 and IGROV-1) through the activation of the intrinsic apoptotic caspase cascade. We showed that a single injection of 10(8) p.f.u. of adenoviral vector encoding a reporter gene into the peritoneal cavity of ovarian tumor bearing mice can induce the gene modification of a large quantity of cells throughout the cavity. We thereby tested the effect of AdRhoB injections to treat ovarian cancer-bearing mice. The ectopic expression of RhoB, following its introduction via viral transduction into nude mice in vivo, was highly effective in suppressing tumor growth of ovarian cancer xenografts. Therapeutic agents designed to correct defects of RhoB at the molecular level may thereby provide innovative treatment options for patients not responding to standard therapies.


First report of Cryptosporidium hominis in a freshwater sponge.
Identification of Cryptosporidium oocyst is essential in ensuring water quality fit for human use, consumption, and recreation. This communication proposes the supplemental analysis of substrate-associated biofilms, in particular, freshwater sponges in improving case finding of waterborne-protozoan pathogens (WBPP) in environmental aquatic samples. In this study, a small portion of a mature freshwater sponge under the Genus Spongilla was subjected to microscopic and molecular analysis to identify the presence of Cryptosporidium. Microscopic screening with modified Kinyoun's staining (MK) and microscopic confirmation using direct antibody fluorescent testing (IFT) returned with Cryptosporidium spp. positive findings. Molecular investigation resulted in the confirmation of Cryptosporidium hominis upon sequencing of PCR products and phylogenetic analysis. This is the first report of a pathogenic protozoan, C. hominis isolated from a freshwater sponge. The results of this study provide evidence of the value of expanding water quality assessment strategies to the analysis of substrate-associated biofilms and sponges in improving case finding of WBPP in natural aquatic environments.


[Treatment of temporo-mandibular joint closed-lock using intra-articular injection of mepivacaine with immediate resolution durable in time (six months follow-up)].
The purpose of this study was to assess the value of intra-articular fluid injection under pressure, as a technique suggested for temporo-mandibular joint (TMJ) closed-lock treatment, and to determine if there is a persisting lock resolution in time. Twelve patients were studied at our centre, with a diagnosis of TMJ closed-lock, not amenable with conventional therapies. All patients underwent a MRI scan, confirming the presence of anteriorly displaced disk. This technique is based on intra-articular injection of anaesthetic (mepivacaine cloridrate) under pressure, using the so called pumping technique, that allows an inferior distraction of the condyle. The study has a six months follow-up. After closed-lock resolution all patients underwent physiotherapy with guided mouth opening, for one month. Mandibular function (maximal mouth opening) increased on average of 20.2 mm after treatment, and of 21.1 mm six months later (p=0.00000; with p<0.005). Pain decreased on average from VAS=6.75 to VAS=0.3 (p=0.00001; with p<0.005). The masticatory efficiency improved from VAS=5.25 to VAS=8.75 (p=0.002; p<0.005). Functional TMJ limitation level is significantly increased (p=0.002; p<0.005). Also, patient's efficacy judgement (mean value 3.58= good) and tolerability judgement (mean value 2.92=good) indicate that this therapy is well accepted. This technique is easy to perform, well tolerated and does not need specific instruments: it permits the resolution of TMJ closed-lock, decreases the pain and improves masticatory efficiency. All these effects persist in time. Subjects with recent closed-lock have an immediate and complete functional recovery while patients with chronic closed-lock do not.