Compromised Dynamic Cerebral Autoregulation in Patients With Depression.
Background: Patients with depression tend to have various comorbid neurological symptoms, but the mechanisms remain unclear. The purpose of this study was to analyze the characteristics of dynamic cerebral autoregulation in depressed patients. Methods: Patients (aged ≥ 18 years) who were diagnosed with depression [17-item Hamilton Depression Rating Scale (HAMD) > 17] or suspected of depression (HAMD > 7) were enrolled in this study. Medically healthy volunteers were recruited as controls. The subjects also received the 7-item HAMD. We simultaneously recorded noninvasive continuous arterial blood pressure and bilateral middle cerebral artery blood flow velocity from each subject. Cerebral autoregulation was assessed by analyzing the phase difference using transfer function analysis. Results: This study enrolled 54 patients with suspected depression, 45 patients with depression, and 48 healthy volunteers. The mean phase difference values were significantly lower in the patients with depression (F = 9.071, P < 0.001). In the multiple regression analysis, depression was negatively correlated with the phase difference values. Conclusions: Dynamic cerebral autoregulation was compromised in patients with depression and negatively correlated with the depression score. Improving dynamic cerebral autoregulation may be a potential therapeutic method for treating the neurological symptoms of depression.


[Colonization of methicillin-resistant Staphylococcus aureus in the mouse intestinal tract].
Mice were infected intravenously with rifampicin-resistant strains selected out of methicillin-resistant Staphylococcus aureus (MRSA) strains and examined for colonization of these organisms in the intestinal tract. Three of four MRSA strains colonized in the cecum of more than 80% of the mice inoculated with approximately 10(7) cfu/mouse. The extent of colonization paralleled the lethal activity, which was inversely related to the methicillin resistivity: moderately resistant strains (MIC: 12.5 micrograms/ml) tended to show more potent pathogenicity than highly resistant ones (MIC: > or = 100 micrograms/ml). Distribution and localization of the organisms in the mice infected with a moderately resistant and highly pathogenic strain S. aureus 1-6 RFPr were studied by autobacteriography. Within one day after infection, colonies of the infecting organisms were distributed all over the body and were especially dense in the liver and spleen. On day 3, the organisms in the liver and spleen disappeared, while many colonies were observed in the intestinal tract. The organisms in the intestinal tract remained for 14 days after infection. In the autobacteriograms of the mice infected with Escherichia coli KC-14 RFPr, such persistency in the intestinal tract was not demonstrated. When viable cell counts of the cecum contents of the mice infected with S. aureus 1-6 RFPr (approximately 10(7) cfu/mouse) were made, the organisms were detected as early as 3 hr after infection and then gradually increased to more than 4 logs cfu/g on day 7. With E. coli KC-14 RFPr, a few colonies were detected transiently in the cecum contents of mice at an early stage infection, but the organisms did not increase and disappeared by day 3 after infection. These results show that the colonization in the mouse intestinal tract is a specific phenomenon to the S. aureus species including MRSA strains.


Egalitarianism in surgical training: let equity prevail.
This study aimed to quantify core surgical trainee (CST) differential attainment (DA) related to three cohorts; white UK graduate (White UKG) versus black and minority ethnic UKG (BME UKG) versus international medical graduates (IMGs). The primary outcome measures were annual review of competence progression (ARCP) outcome, intercollegiate Membership of the Royal College of Surgeons (iMRCS) examination pass and national training number (NTN) selection. Intercollegiate Surgical Curriculum Programme (ISCP) portfolios of 264 consecutive CSTs (2010-2017, 168 white UKG, 66 BME UKG, 30 IMG) from a single UK regional post graduate medical region (Wales) were examined. Data collected prospectively over an 8-year time period was analysed retrospectively. ARCP outcomes were similar irrespective of ethnicity or nationality (ARCP outcome 1, white UKG 60.7% vs BME UKG 62.1% vs IMG 53.3%, p=0.395). iMRCS pass rates for white UKG vs BME UKG vs IMG were 71.4% vs 71.2% vs 50.0% (p=0.042), respectively. NTN success rates for white UKG vs BME UKG vs IMG were 36.9% vs 36.4% vs 6.7% (p=0.023), respectively. On multivariable analysis, operative experience (OR 1.002, 95% CI 1.001 to 1.004, p=0.004), bootcamp attendance (OR 2.615, 95% CI 1.403 to 4.871, p=0.002), and UKG (OR 7.081, 95% CI 1.556 to 32.230, p=0.011), were associated with NTN appointment. Although outcomes related to BME DA were equitable, important DA variation was apparent among IMGs, with iMRCS pass 21.4% lower and NTN success sixfold less likely than UKG. Targeted counter measures are required to let equity prevail in UK CST programmes.


Metabolic syndrome and its components in Polish women of childbearing age: a nationwide study.
Abnormal body mass and related metabolic disorders may affect female reproductive health. The purpose of the study was to determine the prevalence of underweight, overweight, obesity, lipid and glucose metabolism disorders, hypertension, and metabolic syndrome, among Polish women of childbearing age. One thousand five hundred eighty-eight non-pregnant Polish women of childbearing age (20-49 years) who participated in the Multi-Centre National Population Health Examination Survey (WOBASZ II study) in 2013-2014, were assigned to 3 age groups: 20-29 years (n = 403), 30-39 years (n = 600) and 40-49 years (n = 585). Measurements of weight, height, waist circumference, blood pressure, blood lipids, and blood glucose were taken. For statistical analysis, the Kruskal-Wallis, Chi-Square, and Cohran-Armitage tests were used. Of the participants, 4.3% were determined to be underweight, 25.2% were overweight, 15% were obese, and 53.1% had abdominal obesity. With age, the prevalence of both excessive body mass and abdominal obesity tended to increase, and that of underweight to decrease. Frequency of hypercholesterolemia and hypertriglyceridemia found in the whole group were 50% and 12.6% respectively, and also tended to rise with age. Low serum HDL-cholesterol (high density lipoprotein cholesterol) levels were found in 15.1% of the participants. Prevalence of impaired fasting glucose in the whole group was 8.2% and tended to increase with age. Diabetes was found in 1.2% of the participants and its prevalence also tended to rise with age, at the borderline of significance. Frequency of arterial hypertension and metabolic syndrome in the whole group was 15.7% and 14.1% respectively and both tended to increase with age. Overweight and obesity, especially of abdominal type, and the related metabolic abnormalities are common in Polish women of childbearing age. Their prevalence tends to increase with age. Underweight is relatively common in the youngest age group.


Ageism and overestimation of cognitive difficulties in older people: a review.
Stigmatization related to age (i.e., ageism) is a widespread phenomenon in the modern industrial societies where older people are perceived as cognitively incompetent. Therefore negative stereotypes about age-related cognitive decline may have a detrimental influence on older adults on their cognitive performance. The aim of the present review is to understand how stereotypes can influence the performance of the elderly on cognitive tests. We first describe the stereotype threat phenomenon by providing an overview of situations likely to produce stereotype threat, as well as contextual and personal characteristics that moderate its effects. Possible mechanisms underlying these influences on cognitive performance are also presented. Secondly, we address self-stereotyping, which explains long-term negative effects of stereotypes and their unconscious influence on older adults' cognitive performance. However, some age stereotypes have also positive effects on aged people, as shown by some studies describing such beneficial effects of positive stereotypes on cognitive performance. Finally we try to understand why negative age stereotyping has a much stronger influence on important behavioral outcomes among older adults than does positive age stereotyping. Given all these results, we examine how negative age stereotypes may impact older adults' cognitive performance in real-world settings such as during a cognitive assessment.


MRI in the Management of Prostate Cancer.
Multiparametric MRI has a changing role in prostate cancer diagnosis. Internationally recognized consensus documents such as prostate imaging reporting and data system version have been developed and adapted to standardize the acquisition and reporting of prostate MRI. The improvement in scanning techniques and development of highly sensitive functional sequences have improved the detection of clinically significant prostate cancer as well as treatment planning and follow up. This has led to a recent NICE recommendation to use prostate MRI as the initial investigation in men with clinically suspected localized disease. The results of several recent international MRI prostate trials are influencing the way imaging is used to stratify which patients require a prostate biopsy as well as how MRI guidance is used to target biopsies.


Unilateral Cervical Facet Fractures: Relevance of Acute Disc Injury in Conservative Treatment Failure.
Case-control study. Analyze association between imaging factors related to the failure of conservative treatment in isolated subaxial cervical facet fractures. Facet fracture (F1, F2, and F3 AOSpine) may be stable or unstable depending on clinical and imaging variables, which are not well established. As a result, differences in fracture management lead to differences in surgical or conservative indications, and there is no evidence to predict conservative treatment failure. Patients were categorized into two groups: six patients (16.2%) with conservative treatment failure (defined as the appearance of neurological symptoms, listhesis >3.5 mm, kyphotic deformation >11°, and/or non-union), and 31 patients (83.7%) with successful conservative management (defined as complete consolidation confirmed by computed tomography [CT] at the 6-month followup). All participants were fitted with rigid collars of the Miami type, and standardized follow-up was performed until consolidation or failure. CT and magnetic resonance imaging (MRI) was used to examine imaging characteristics. Sagittal balance parameters were assessed using CT, and signs of acute disc injury, prevertebral edema, facet synovitis, and interspinous hyperintense signal were assessed using MRI. Thirty-seven patients were diagnosed with unilateral cervical facet fractures between 2009 and 2020. In this sample, acute disc injury had a significative association to failure of conservative treatment in F2 and F3 AOSpine facet fractures, 100% of the failure group presented with traumatic disc injury compared to 9.7% of the successful group, for the other variables: prevertebral edema, 83.7% vs. 41.9%; facet synovitis, 100% vs. 77.4%; and interspinous hyperintensity, 71.4% vs. 38.7%, respectively. With conservative management, all F1 fractures healed successfully. Conservative treatment failed in 20% of F2 fractures and 50% of F3 fractures, respectively. In terms of cervical sagittal balance parameters, there were no significant differences between groups. Conservative management was successful in all F1 fractures. In F2 and F3 types, there was a significant association between acute disc injury and conservative treatment failure.


A new adaptive light beam focusing principle for scanning light stimulation systems.
In this article a novel principle to achieve optimal focusing conditions or rather the smallest possible beam diameter for scanning light stimulation systems is presented. It is based on the following methodology: First, a reference point on a camera sensor is introduced where optimal focusing conditions are adjusted and the distance between the light focusing optic and the reference point is determined using a laser displacement sensor. In a second step, this displacement sensor is used to map the topography of the sample under investigation. Finally, the actual measurement is conducted, using optimal focusing conditions in each measurement point at the sample surface, that are determined by the height difference between camera sensor and the sample topography. This principle is independent of the measurement values, the optical or electrical properties of the sample, the used light source, or the selected wavelength. Furthermore, the samples can be tilted, rough, bent, or of different surface materials. In the following the principle is implemented using an optical beam induced current system, but basically it can be applied to any other scanning light stimulation system. Measurements to demonstrate its operation are shown, using a polycrystalline silicon solar cell.


Preoperative Prevalence of Staphylococcus aureus in Cardiothoracic and Neurological Surgical Patients.
Methicillin-resistant Staphylococcus aureus (MRSA) is a global cause of both hospital and community-acquired infection. This retrospective, observational study determined the prevalence of MRSA carriers in cardiothoracic and neurological surgical patients presenting to an outpatient preoperative assessment center in Columbus, OH. Aggressive skin and soft-tissue infection may be caused by MRSA with potentially fatal complications. Cardiothoracic and neurological surgical patients are at high risk for surgical-site infection. Results indicated that 4.25% of the sample carried MRSA and 25.25% carried methicillin-sensitive S. aureus.


Srsf2P95H/+ co-operates with loss of TET2 to promote myeloid bias and initiate a chronic myelomonocytic leukemia-like disease in mice.
Recurrent mutations in RNA splicing proteins and epigenetic regulators contribute to the development of myelodysplastic syndrome (MDS) and related myeloid neoplasms. In chronic myelomonocytic leukemia (CMML), SRSF2 mutations occur in ~50% of patients and TET2 mutations in ~60%. Clonal analysis indicates that either mutation can arise as the founder lesion. Based on human cancer genetics we crossed an inducible Srsf2P95H/+ mutant model with Tet2fl/fl mice to mutate both concomitantly in hematopoietic stem cells. At 20-24 weeks post mutation induction, we observed subtle differences in the Srsf2/Tet2 mutants compared to either single mutant. Under conditions of native hematopoiesis with aging, we see a distinct myeloid bias and monocytosis in the Srsf2/Tet2 mutants. A subset of the compound Srsf2/Tet2 mutants display an increased granulocytic and distinctive monocytic proliferation (myelomonocytic hyperplasia), with increased immature promonocytes and monoblasts and binucleate promonocytes. Exome analysis of progressed disease demonstrated mutations in genes and pathways similar to those reported in human CMML. Upon transplantation, recipients developed leukocytosis, monocytosis, and splenomegaly. We reproduce Srsf2/Tet2 co-operativity in vivo, yielding a disease with core characteristics of CMML, unlike single Srsf2 or Tet2 mutation. This model represents a significant step toward building high fidelity and genetically tractable models of CMML.


The role of chewing lice (Phthiraptera: Philopteridae) as intermediate hosts in the transmission of Hymenolepis microps (Cestoda: Cyclophyllidea) from the willow ptarmigan Lagopus lagopus (Aves: Tetraonidae).
The cestode Hymenolepis microps is an intestinal parasite of tetraonid birds, including the willow ptarmigan (Lagopus lagopus). This parasite is able to maintain a high prevalence and intensity throughout the year, even in a subarctic environment in bird populations with relatively low host densities, indicating effective transmission routes. Willow ptarmigan consume mainly vegetal material and active consumption of invertebrates is confined to the first two or three weeks of life. Ptarmigan are infected by different species of ectoparasites, of which two species of feather lice, Lagopoecus affinis and Goniodes lagopi, are the most abundant. In this study, we explored the hypothesis that feather lice may be suitable intermediate hosts for H. microps. We applied histological techniques and light microscopy to investigate lice for the presence of larval cestode stages (cysticercoids). We found 12 cysticercoid-like structures inside chewing lice collected on L. lagopus hosts harbouring H. microps. In addition, a polymerase chain reaction (PCR) screening of Ischnocera lice DNA, targeting the 18S rRNA gene of the cestode, showed positive results for two different short fragments of the 18S rRNA gene of H. microps which were sequenced from lice collected on birds. Both independent lines of evidence support the hypothesis that Ischnocera lice might be suitable intermediate hosts in the life cycle of H. microps in L. lagopus.


Quest for singlet fission of organic sulfur-containing systems in the higher lying singlet excited state: application prospects of anti-Kasha's rule.
In this study, we explore the possibilities of the deactivating pathways of organic thione containing systems through first-principles calculations. We particularly pay attention to the second lying singlet excited state, S2, due to its large energy difference from the lowest lying S1 state in the sulfur-containing systems. Several theoretical models including the previously synthesized thiones and the strategically designed molecules are investigated to search for the basic conjugation unit that exhibits the prospect of S2 fission. Various molecular motifs and different substituents are combined to maneuver the relative alignment of the relevant low excited energy states. The results lead us to conclude that the thione derivatives, under rational and delicate molecular designs, may be engineered to possess a sufficiently high S2-S1 energy gap as high as 2 eV and that these systems may exhibit S2 fission to triplet excitons in the red to near infrared region.


Increased malonyl-CoA and diacylglycerol content and reduced AMPK activity accompany insulin resistance induced by glucose infusion in muscle and liver of rats.
Glucose infusion in rats for 1-4 days results in insulin resistance and increased triglyceride, whole tissue long-chain fatty acyl-CoA (LCA-CoA), and malonyl-CoA content in red skeletal muscle. Despite this, the relation between these alterations and the onset of insulin resistance has not been defined. We aimed to 1) identify whether the changes in these lipids and of diacylglycerol (DAG) precede or accompany the onset of insulin resistance in glucose-infused rats, 2) determine whether the insulin resistance is associated with alterations in AMP-activated protein kinase (AMPK), and 3) assess whether similar changes occur in liver and in muscle. Hyperglycemia (17-18 mM) was maintained by intravenous glucose infusion in rats for 3 or 5 h; then euglycemia was restored and a 2-h hyperinsulinemic clamp was performed. Significant (P < 0.01) muscle and liver insulin resistance first appeared in red quadriceps and liver of the glucose-infused group at 5 h and was associated with a twofold increase in DAG and malonyl-CoA content and a 50% decrease in AMPK and acetyl-CoA carboxylase (ACC) phosphorylation and AMPK activity. White quadriceps showed qualitatively similar changes but without decreases in AMPK or ACC phosphorylation. Triglyceride mass was increased at 5 h only in liver, and whole tissue LCA-CoA content was not increased in liver or either muscle type. We conclude that the onset of insulin resistance induced by glucose oversupply correlates temporally with increases in malonyl-CoA and DAG content in all three tissues and with reduced AMPK phosphorylation and activity in red muscle and liver. In contrast, it was not associated with increased whole tissue LCA-CoA content in any tissue or triglyceride in muscle, although both are observed at later times.


Rhythm perception, production, and synchronization during the perinatal period.
Sensori-motor synchronization (SMS) is the coordination of rhythmic movement with an external rhythm. It plays a central role in motor, cognitive, and social behavior. SMS is commonly studied in adults and in children from four years of age onward. Prior to this age, the ability has rarely been investigated due to a lack of available methods. The present paper reviews what is known about SMS in young children, infants, newborns, and fetuses. The review highlights fetal and infant perception of rhythm and cross modal perception of rhythm, fetal, and infant production of rhythm and cross modal production of rhythm, and the contexts in which production of rhythm can be observed in infants. A primary question is whether infants, even newborns, can modify their spontaneous rhythmical motor behavior in response to external rhythmical stimulation. Spontaneous sucking, crying, and leg movements have been studied in the presence or absence of rhythmical auditory stimulation. Findings suggest that the interaction between movement and sound is present at birth and that SMS can be observed in special conditions and within a narrow range of tempi, particularly near the infant's own spontaneous motor tempo. The discussion centers on the fundamental role of SMS in interaction and communication at the beginning of life.


An Expanded Role for HLA Genes: HLA-B Encodes a microRNA that Regulates IgA and Other Immune Response Transcripts.
We describe a novel functional role for the HLA-B locus mediated by its intron-encoded microRNA (miRNA), miR-6891-5p. We show that in vitro inhibition of miR-6891-5p impacts the expression of nearly 200 transcripts within the B-lymphoblastoid cell line (B-LCL) COX, affecting a large number of metabolic pathways, including various immune response networks. The top affected transcripts following miR-6891-5p inhibition are those encoding the heavy chain of IgA. We identified a conserved miR-6891-5p target site on the 3'UTR of both immunoglobulin heavy chain alpha 1 and 2 (IGHA1 and IGHA2) transcripts and demonstrated that this miRNA modulates the expression of IGHA1 and IGHA2. B-LCLs from IgA-deficient patients expressed significantly elevated levels of miR-6891-5p when compared with unaffected family members. Upon inhibition of miR-6891-5p, IgA mRNA expression levels were increased, and IgA secretion was restored in the B-LCL of an IgA-deficient patient. These findings indicate that miR-6891-5p regulates IGHA1 and IGHA2 gene expression at the posttranscriptional level and suggest that increase in miR-6891-5p levels may contribute to the etiology of selective IgA deficiency.


A pepper-pot emittance meter for low-energy heavy-ion beams.
A novel emittance meter has been developed to measure the four-dimensional, transverse phase-space distribution of a low-energy ion beam using the pepper-pot technique. A characteristic feature of this instrument is that the pepper-pot plate, which has a linear array of holes in the vertical direction, is scanned horizontally through the ion beam. This has the advantage that the emittance can also be measured at locations along the beam line where the beam has a large horizontal divergence. A set of multi-channel plates, scintillation screen, and ccd camera is used as a position-sensitive ion detector allowing a large range of beam intensities that can be handled. This paper describes the design, construction, and operation of the instrument as well as the data analysis used to reconstruct the four-dimensional phase-space distribution of an ion beam. Measurements on a 15 keV He(+) beam are used as an example.


Dynamic transition in supercritical iron.
Recent advance in understanding the supercritical state posits the existence of a new line above the critical point separating two physically distinct states of matter: rigid liquid and non-rigid gas-like fluid. The location of this line, the Frenkel line, remains unknown for important real systems. Here, we map the Frenkel line on the phase diagram of supercritical iron using molecular dynamics simulations. On the basis of our data, we propose a general recipe to locate the Frenkel line for any system, the recipe that importantly does not involve system-specific detailed calculations and relies on the knowledge of the melting line only. We further discuss the relationship between the Frenkel line and the metal-insulator transition in supercritical liquid metals. Our results enable predicting the state of supercritical iron in several conditions of interest. In particular, we predict that liquid iron in the Jupiter core is in the "rigid liquid" state and is highly conducting. We finally analyse the evolution of iron conductivity in the core of smaller planets such as Earth and Venus as well as exoplanets: as planets cool off, the supercritical core undergoes the transition to the rigid-liquid conducting state at the Frenkel line.


Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema: A Case Report With a Review of Management Options.
Angiotensin-converting enzyme inhibitors (ACEIs) are widely used for heart failure, renal failure, diabetic nephropathy, stroke, arterial hypertension, and a number of other cardiovascular or related conditions. ACEI-induced angioedema is a rare entity but can result in life-threatening emergencies. It mainly occurs in patients starting on ACEI as an antihypertensive. We present a case of lisinopril-induced angioedema in an African American patient managed in the emergency department. After appropriate evaluation, the patient was declared safe to be observed in the emergency department. Intubation was not performed. Early identification of angioedema is paramount, and emergency physicians should maintain airways or intubate such patients if indicated. There should be a high level of suspicion of angioedema in patients taking ACEIs if they present with symptoms of respiratory compromise.


Autoimmune Addison's disease after treatment with interleukin-2 and tumor-infiltrating lymphocytes.
Autoimmune thyroiditis with hypothyroidism is a well-known complication of immunotherapy with interleukin-2 (IL-2) with or without lymphokine-activated killer (LAK) cells. To date, however, no cases of IL-2/LAK-induced autoimmune adrenalitis with adrenal insufficiency have been reported. We describe a patient who developed primary adrenal insufficiency following IL-2/tumor-infiltrating lymphocytes (TIL) immunotherapy for renal cell carcinoma. A 64-year-old male with renal cell carcinoma metastatic to bone, skin, lung, and the central nervous system presented for IL-2/TIL treatment. Nine months earlier, he had undergone a right nephrectomy and adrenalectomy. He had already received two courses of IL-2 and one course of IL-4 following surgery. Dynamic studies of adrenal function performed prior to IL-2/TIL immunotherapy demonstrated intact cortisol and aldosterone responses to ACTH as well as negative adrenal antibodies. One week after IL-2/TIL therapy, the patient developed a nonanion gap metabolic acidosis, hypotension and hypoglycemia. Adrenocortical function was re-evaluated demonstrating blunted cortisol and aldosterone responses to ACTH with an elevated plasma ACTH confirming the presence of primary adrenal insufficiency. Adrenal antibodies were now positive. Hydrocortisone and fludrocortisone were given with a good clinical response. We suggest immunotherapy with IL-2/TIL may cause adrenal insufficiency by activating autoimmune adrenalitis.


Unveiling the invisible: mathematical methods for restoring and interpreting illuminated manuscripts.
The last 50 years have seen an impressive development of mathematical methods for the analysis and processing of digital images, mostly in the context of photography, biomedical imaging and various forms of engineering. The arts have been mostly overlooked in this process, apart from a few exceptional works in the last 10 years. With the rapid emergence of digitisation in the arts, however, the arts domain is becoming increasingly receptive to digital image processing methods and the importance of paying attention to this therefore increases. In this paper we discuss a range of mathematical methods for digital image restoration and digital visualisation for illuminated manuscripts. The latter provide an interesting opportunity for digital manipulation because they traditionally remain physically untouched. At the same time they also serve as an example for the possibilities mathematics and digital restoration offer as a generic and objective toolkit for the arts.


Bronchoscopic evaluation of unexplained recurrent and persistent pneumonia in children.
Persistent or recurrent pneumonia in children can pose a significant challenge to paediatricians and respiratory physicians. The aim of this study is to determine the role of flexible bronchoscopy (FB) in evaluation of recurrent or persistent pneumonia that remain otherwise unexplained by non-invasive diagnostic tests in children. Retrospective evaluation of patients who underwent FB with an indication of recurrent or persistent pneumonia from 1997 to 2011. Among 2600 FB procedures, 434 (17%) were performed with the indication of recurrent or persistent pneumonia. There were 237 (54%) boys. Median age at presentation was 84 months, and median duration of symptoms was 9 months. FB led to specific diagnosis in 33% of the cases. The most common diseases diagnosed by FB were malacia disorders (n: 32, 7%), aspirated foreign body (n: 30, 7%), endobronchial tuberculosis (n: 20, 5%), congenital airway anomalies (n: 14, 3%), mucus plugs (n: 14, 3%), pulmonary haemosiderosis (n: 12, 3%) and middle lobe syndrome (n: 11, 3%). During FB, only 6% of the patients had minor complications such as transient hypoxia, stridor and tachycardia. In our study, FB proved to be a safe and effective tool in evaluation of children with persistent or recurrent pneumonia. FB is indicated for children with recurrent or persistent pneumonia where the underlying diagnosis remains unclear even after non-invasive diagnostic tests.


State-of-the-art materials for ultrasound-triggered drug delivery.
Ultrasound is a unique and exciting theranostic modality that can be used to track drug carriers, trigger drug release and improve drug deposition with high spatial precision. In this review, we briefly describe the mechanisms of interaction between drug carriers and ultrasound waves, including cavitation, streaming and hyperthermia, and how those interactions can promote drug release and tissue uptake. We then discuss the rational design of some state-of-the-art materials for ultrasound-triggered drug delivery and review recent progress for each drug carrier, focusing on the delivery of chemotherapeutic agents such as doxorubicin. These materials include nanocarrier formulations, such as liposomes and micelles, designed specifically for ultrasound-triggered drug release, as well as microbubbles, microbubble-nanocarrier hybrids, microbubble-seeded hydrogels and phase-change agents.


Palladium-catalyzed stereoretentive olefination of unactivated C(sp3)-H bonds with vinyl iodides at room temperature: synthesis of β-vinyl α-amino acids.
A method is reported for palladium-catalyzed N-quinolyl carboxamide-directed olefination of the unactivated C(sp(3))-H bonds of phthaloyl alanine with a broad range of vinyl iodides at room temperature. This reaction represents the first example of the stereoretentive installation of multisubstituted terminal and internal olefins onto unactivated C(sp(3))-H bonds. These methods enable access to a wide range of challenging β-vinyl α-amino acid products in a streamlined and controllable fashion, beginning from simple precursors.


The Singapore heroin control programme.
In 1975 Singapore experienced a sudden heroin epidemic, and within two years an estimated 3 per cent of the males, 15-24, were involved. In 1977 the Government responded with an all-out enforcement strategy aimed at rapid containment. Demand reduction involved the large scale arrest of suspected users, and the immediate commitment of those with positive urines to Drug Rehabilitation Centres. The primary rehabilitation emphasis is on instilling discipline, social responsibility and sound work habits. Releases are placed on two years of compulsory supervision with a 5-day cycle for reporting and urine specimens. Sixty-three per cent show no detected drug use within the first year of supervision. Supply reduction efforts are equally strong and, while these were not immediately successful in limiting availability, heroin is currently very scarce and expensive. While there is some evidence of the substitution of cannabis, psychotropic drugs and alcohol, the number of new heroin cases is minimal. Overall, the epidemic appears to have been controlled.


Copper-catalyzed Mannich-type oxidative β-functionalization of tertiary amines.
A copper-catalyzed Mannich-type oxidative β-functionalization reaction of amines has been developed. In the presence of an oxidant and a copper catalyst, tertiary amines reacted with N-tosylimines, providing synthetically important 1,3-diamines and enamines, respectively. Preliminary mechanistic studies suggested that the oxidation of the tertiary amine to the enamine intermediate triggers subsequent Mannich-type reactions with N-tosylimines and thus enables the direct β-functionalization of the tertiary amines.


[Endothelial progenitor cell biology in retinopathy of prematurity].
Endothelial progenitor cells (EPC) play an important function in vasculogenesis and acquire a capability for vascular repair and formation as they differentiate. We examined the kinetics of EPCs from the viewpoint of EPC biology by creating oxygen-induced retinopathy (OIR) in a mouse model imitating retinopathy of prematurity (ROP), which causes pathological retinal neovascularization. Delayed differentiation, mobilization, and tissue recruitment of EPCs were obvious in the vaso-oblitelative phase, but they were promoted in the vascular proliferative state. Moreover, pathological retinal vasculature in OIR was repaired by the intravitreally transplanted definitive EPCs. These results suggest that delay of bone marrow derived EPC differentiation is a factor of morbid retinal blood vessels' formation in OIR. Aberrant kinetics of bone marrow derived EPC contribute to the formation of the retinal blood vessels, and it was proved that understanding and improving EPC differentiation can constitute a diagnostic and remedial base concept in the diagnosis of ROP.


Antibiotics--1975.
In the author's opinion, nearly all common pediatric infections can be treated with penicillin G, oxacillin or nafcillin, ampicillin, sulfa, or kanamycin. Nevertheless, the pediatrician should also be knowledgable concerning the indications for use of the other antibiotics mentioned in this review.


Replaced common hepatic artery originating from the superior mesenteric artery and prepancreatic, anterior course in a patient with cephalic pancreaticoduodenectomy - case report.
The presence of hepatic arterial variations is particularly important for patients undergoing cephalic pancreaticoduodenectomy, because it can lead to unnecessary incidents or postoperative complications. We present the case of a patient with pancreatic head neoplasm in which the cephalic pancreaticoduodenectomy was performed and the origin of common hepatic artery from superior mesenteric artery, with an anterior, prepancreatic course.


Role of membrane association and Atg14-dependent phosphorylation in beclin-1-mediated autophagy.
During autophagy, a double membrane envelops cellular material for trafficking to the lysosome. Human beclin-1 and its yeast homologue, Atg6/Vps30, are scaffold proteins bound in a lipid kinase complex with multiple cellular functions, including autophagy. Several different Atg6 complexes exist, with an autophagy-specific form containing Atg14. However, the roles of Atg14 and beclin-1 in the activation of this complex remain unclear. We here addressed the mechanism of beclin-1 complex activation and reveal two critical steps in this pathway. First, we identified a unique domain in beclin-1, conserved in the yeast homologue Atg6, which is involved in membrane association and, unexpectedly, controls autophagosome size and number in yeast. Second, we demonstrated that human Atg14 is critical in controlling an autophagy-dependent phosphorylation of beclin-1. We map these novel phosphorylation sites to serines 90 and 93 and demonstrate that phosphorylation at these sites is necessary for maximal autophagy. These results help clarify the mechanism of beclin-1 and Atg14 during autophagy.


The effects of highly selective vagotomy on secretion and emptying of the stomach.
The results of a prospective study of 60 patients with nonobstructive duodenal ulcer treated by highly selective vagotomy show that the gastric acid secretion postoperatively is effectively reduced. Judgment of completeness of highly selective vagotomy is only possible by means of an intragastric pH-metry during operation. The Hollander test answers it insufficiently. In a number of patients, highly selective vagotomy caused a fast initial phase of gastric emptying of porradge. The impression is that the contractional activity of the antrum has the same pattern before and after highly selective vagotomy.


Redundant and regulatory roles for Toll-like receptors in Leishmania infection.
Toll-like receptors (TLRs) are germline-encoded, non-clonal innate immune receptors, which are often the first receptors to recognize the molecular patterns on pathogens. Therefore, the immune response initiated by TLRs has far-reaching consequences on the outcome of an infection. As soon as the cell surface TLRs and other receptors recognize a pathogen, the pathogen is phagocytosed. Inclusion of TLRs in the phagosome results in quicker phagosomal maturation and stronger adaptive immune response, as TLRs influence co-stimulatory molecule expression and determinant selection by major histocompatibility complex (MHC) class II and MHC class I for cross-presentation. The signals delivered by the TCR-peptide-MHC complex and co-stimulatory molecules are indispensable for optimal T cell activation. In addition, the cytokines induced by TLRs can skew the differentiation of activated T cells to different effector T cell subsets. However, the potential of TLRs to influence adaptive immune response into different patterns is severely restricted by multiple factors: gross specificity for the molecular patterns, lack of receptor rearrangements, sharing of limited number of adaptors that assemble signalling complexes and redundancy in ligand recognition. These features of apparent redundancy and regulation in the functioning of TLRs characterize them as important and probable contributory factors in the resistance or susceptibility to an infection.


Isolated limb perfusion in primary and recurrent melanoma: indications and results.
In advanced melanoma of the limbs with in-transit metastasis, melphalan with isolated limb perfusion (M-ILP) produces around 50% complete remissions (CR). The combination of melphalan with tumour necrosis factor-alpha (TNFalpha) and interferon-gamma (IFNgamma) in isolated limb perfusion (TIM-ILP) gives around 80% CR. A prospective randomised phase II study compared 32 patients who received TIM-ILP with 32 patients who received TM-ILP (without IFNgamma). The overall remission rate (ORR) and the CR rate were superior with TIM-ILP as compared to TM-ILP, 100% vs. 91% and 78% vs. 69% respectively, but the differences are not significant. Given the efficacy of M-ILP on in-transit metastasis, the procedure was tested as an adjunct to surgery in high-risk (Breslow > or = 1.5 mm) primary melanoma of the limbs. Through the combined effort of the melanoma groups of the European Organization for Research and Treatment of Cancer (EORTC), the World Health Organization (WHO), and the North American Perfusion Group, 832 evaluable patients from 16 centres were entered in a phase III study. Median followup is 6.4 years. There was a trend for a longer disease-free interval after M-ILP. The difference is significant if the patients without elective lymph node dissection (ELND) are separately analysed, with a high significance in the 1.5 to 3 mm thickness subgroup. The occurrence of in-transit metastases was reduced from 6.6% to 3.3% by M-ILP. There was, however, no benefit of M-ILP in terms of survival. Prophylactic M-ILP cannot be recommended as a standard adjunct to surgery in high-risk primary limb melanoma. TIM-ILP or TM-ILP is a regional therapy with a very high regional response rate on melanoma in-transit metastasis.


Network analysis of time-lapse microscopy recordings.
Multicellular organisms rely on intercellular communication to regulate important cellular processes critical to life. To further our understanding of those processes there is a need to scrutinize dynamical signaling events and their functions in both cells and organisms. Here, we report a method and provide MATLAB code that analyzes time-lapse microscopy recordings to identify and characterize network structures within large cell populations, such as interconnected neurons. The approach is demonstrated using intracellular calcium (Ca(2+)) recordings in neural progenitors and cardiac myocytes, but could be applied to a wide variety of biosensors employed in diverse cell types and organisms. In this method, network structures are analyzed by applying cross-correlation signal processing and graph theory to single-cell recordings. The goal of the analysis is to determine if the single cell activity constitutes a network of interconnected cells and to decipher the properties of this network. The method can be applied in many fields of biology in which biosensors are used to monitor signaling events in living cells. Analyzing intercellular communication in cell ensembles can reveal essential network structures that provide important biological insights.


CT reconstruction and MRI fusion of 3D rotational angiography in the evaluation of pediatric cerebrovascular lesions.
Complex neurovascular lesions in children require precise anatomic understanding for treatment planning. Although 3DRA is commonly employed for volumetric reformation in neurointerventional procedures, the ability to reconstruct this data into CT-like images (3DRA-CT) is not widely utilized. This study demonstrates the feasibility and usefulness of 3DRA-CT and subsequent MRI fusion for problem solving in pediatric neuroangiography. This retrospective study includes 18 3DRA-CT studies in 16 children (age 9.6 ± 3.8 years, range 2-16 years) over 1 year. After biplane 2D-digital subtraction angiography (DSA), 5-second 3DRA was performed with selective vessel injection either with or without subtraction. Images were reconstructed into CT sections which were post-processed to generate multiplanar reformation (MPR) and maximum intensity projection (MIP) images. Fusion was performed with 3D T1 MRI images to precisely demonstrate neurovascular relationships. Quantitative radiation metrics were extracted and compared against those for the entire examination and for corresponding biplane 2D-DSA acquisitions. In all 18 cases, the 3DRA procedure and MRI fusion were technically successful and provided clinically useful information relevant to management. The unsubtracted and subtracted 3DRA acquisitions were measured to deliver 5.9 and 132.2%, respectively, of the mean radiation dose of corresponding biplane 2D-DSA acquisitions and contributed 1.2 and 12.5%, respectively, to the total procedure dose. Lower radiation doses, high spatial resolution, and multiplanar reformatting capability make 3DRA-CT a useful adjunct to evaluate neurovascular lesions in children. Fusing 3DRA-CT data with MRI is an additional capability that can further enhance diagnostic information.


Inhibition of lung calcium-independent phospholipase A2 by surfactant protein A.
The effect of lung surfactant protein A (SP-A) on lung phospholipase A2 (PLA2) activity was investigated. SP-A was purified from bovine surfactant obtained by lung lavage. PLA2 was assayed using radiolabeled 1,2-dipalmitoyl phosphatidylcholine (DPPC) in surfactant-like unilamellar liposomes with Ca(2+)-free acidic (pH 4) or 10 mM Ca2+, alkaline (pH 8.5) buffer. SP-A significantly inhibited Ca(2+)-independent acidic PLA2 of rat lung homogenate or isolated lamellar bodies but had no effect on the Ca(2+)-dependent alkaline enzyme. Lamellar body PLA2 was inhibited by 50% with 0.25 micrograms SP-A/microgram lamellar body protein. Similar inhibition by SP-A was observed when 1-palmitoyl,2-oleoyl PC (POPC) was the substrate. Binding assay showed binding of 125I-labeled SP-A to DPPC but not to POPC, indicating that removal of substrate was not the mechanism for inhibition of the enzyme by SP-A. Chemical reduction or alkylation of SP-A abolished its inhibitory effect on PLA2 activity. Inactivation of endogenous SP-A in isolated lamellar bodies or surfactant increased Ca(2+)-independent PLA2 activity in these fractions. The presence of SP-A in liposomes stimulated the uptake of DPPC by isolated granular pneumocytes in primary culture but significantly inhibited its degradation. These results indicate that the Ca(2+)-independent acidic PLA2 has a role in the metabolism of internalized surfactant phospholipid and that SP-A can modulate the activity of this enzyme.


Outcome analysis of shunt surgery in hydrocephalus.
To study the clinical outcome of shunt surgeries in children suffering from hydrocephalus. A prospective study of 50 children with hydrocephalus who underwent a ventriculo-peritoneal shunt insertion over a period of two years. These patients were then followed up for shunt related complications, shunt revisions and outcome. Twenty six of the 50 patients (52%) suffered from complications. The most common complications were shunt blockage (n=7) and shunt infection (n=6). These complications necessitated repeated shunt revisions. Infective complications of hydrocephalus are more likely to leave behind an adverse neurological outcome in the form of delayed milestones and mental retardation.


Specific changes in circulating cytokines and growth factors induced by exercise stress testing in asymptomatic aortic valve stenosis.
We evaluated exercise-induced changes in the profile of circulating cytokines and growth factors in patients with AS. We studied 32 consecutive asymptomatic moderate-to-severe AS patients and 32 age and sex-matched controls. Plasma levels of interleukin (IL)-6, IL-10, hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and transforming growth factor (TGF)-β were measured at 4 time points, i.e. at rest, at peak bicycle exercise, one hour and 24 hours after a symptom-limited exercise. Exercise increased all the 5 markers in both groups (all p<0.0001). The maximum levels of all tested cytokines were higher in the AS group (all p<0.05) compared with controls. In AS patients the highest levels of VEGF, IL-6, and IL-10 were observed one hour after exercise, while in the control group at peak exercise. In both groups maximum TGF- β levels were observed one hour after exercise. HGF levels were higher at peak and one hour after test in the AS group (p = 0.0001), however the maximum value in AS was observed at peak while in controls after test. In both groups TGF-β was the only marker that remained increased 24 hours after exercise compared with the value at rest (p = 0.0001). The cytokines and growth factors showed no association with heart rate and the workload. In asymptomatic patients with moderate-to-severe AS, exercise produces a different pattern of changes in circulating cytokines and growth factors, and maximum levels of all tested cytokines were significantly higher in AS patients compared with the control group.


High Resolution Melting as a rapid, reliable, accurate and cost-effective emerging tool for genotyping pathogenic bacteria and enhancing molecular epidemiological surveillance: a comprehensive review of the literature.
Rapid, reliable and accurate molecular typing methods are essential for outbreaks detection and infectious diseases control, for monitoring the evolution and dynamics of microbial populations, and for effective epidemiological surveillance. The introduction of a novel method based on the analysis of melting temperature of amplified products, known as High Resolution Melting (HRM) since 2002, has found applications in epidemiological studies, either for identification of bacterial species or molecular typing, as well as an extensive and increasing use in many research fields. HRM method is based on the use of saturating third generation dyes, advanced real-time PCR platforms, and bioinformatics tools. To describe, by a comphrehensive review of the literature, the use, application and usefulness of HRM for the genotyping of bacterial pathogens in the context of epidemiological surveillance and public health. A literature search was carried out during July-August 2016, by consulting the biomedical databases PubMed/Medline, Scopus, EMBASE, and ISI Web of Science without limits. The search strategy was performed according to the following keywords: high resolution melting analysis and bacteria and genotyping or molecular typing. All the articles evaluating the application of HRM for bacterial pathogen genotyping were selected and reviewed, taking into account the objective of each study, the rationale explaining the use of this technology, and the main results obtained in comparison with gold standards and/or alternative methods, when available. HRM method was extensively used for molecular typing of both Gram-positive and Gram-negative bacterial pathogens, representing a versatile genetic tool: a) to evaluate genetic diversity and subtype at species/subspecies level, based also on allele discrimination/identification and mutation screening; b) to recognize phylogenetic groupings (lineage, sublineage, subgroups); c) to identify antimicrobial resistance; d) to detect and screen for mutations related to drug-resistance; e) to discriminate gene isoforms. HRM method showed, in almost all instances, excellent typeability and discriminatory power, with high concordance of typing results obtained with gold standards or comparable methods. Conversely, for the evaluation of genetic determinants associated to antibiotic-resistance or for screening of associated mutations in key gene fragments, the sensitivity and specificity was not optimal, because the targeted amplicons did not encompass all the crucial mutations. Despite the recent introduction of sequencing-based methods, the HRM method deserves consideration in research fields of infectious diseases, being characterized by low cost, rapidity, flexibility and versatility. However, there are some limitations to HRM assays development, which should be carefully considered. The most common application of HRM for bacterial typing is related to Single Nucleotide Polymorphism (SNP)-based genotyping with the analysis of gene fragments within the multilocus sequence typing (MLST) loci, following an approach termed mini-MLST or Minim typing. Although the resolving power is not totally correspondent to MLST, the Simpson's Index of Diversity provided by HRM method typically >0.95. Furthermore, the cost of this approach is less than MLST, enabling low cost surveillance and rapid response for outbreak control. Hence, the potential of HRM technology can strongly facilitate routine research and diagnostics in the epidemiological studies, as well as advance and streamline the genetic characterization of bacterial pathogens.


Top-Cited Articles in Problem-Based Learning: A Bibliometric Analysis and Quality of Evidence Assessment.
The aims of this study were to identify characteristics of the top-cited articles in problem-based learning (PBL) and assess the quality of evidence provided by these articles. The most frequently cited articles on PBL were searched in April 2015 in the Science Citation Index Expanded database (List A) and Google Scholar database (List B). Eligible articles identified were reviewed for key characteristics. The Oxford Centre for Evidence-Based Medicine guidelines were used in assessing the level of evidence. The number of citations varied (62 to 923 on List A and 218 to 2,859 on List B). Countries that contributed the majority of articles in both lists were the United States, Netherlands, United Kingdom, and Canada. No significant correlations were found between number of citations and number of years since published (p=0.451), number of authors (p=0.144), females in authorship (p=0.189), non-medical authors (p=0.869), number of institutions (p=0.452), and number of grants (p=0.143), but a strong correlation was found with number of countries involved (p=0.007). Application of the Oxford hierarchy of evidence showed that 36 articles were at levels 4 and 5 of evidence. This study found that research articles represented approximately one-third of PBL articles assessed and reported mainly on questionnaire-based studies. The most highly cited articles occupied top-ranking positions in the journals in which they were published. The lower level of evidence observed in most top-cited articles may reflect the significance of innovative ideas or content of these articles. These findings have implications for dental educators and dental researchers.


Ly6C(low) and not Ly6C(high) macrophages accumulate first in the heart in a model of murine pressure-overload.
Cardiac tissue remodeling in the course of chronic left ventricular hypertrophy requires phagocytes which degrade cellular debris, initiate and maintain tissue inflammation and reorganization. The dynamics of phagocytes in left ventricular hypertrophy have not been systematically studied. Here, we characterized the temporal accumulation of leukocytes in the cardiac immune response by flow cytometry and fluorescence microscopy at day 3, 6 and 21 following transverse aortic constriction (TAC). Cardiac hypertrophy due to chronic pressure overload causes cardiac immune response and inflammation represented by an increase of immune cells at all three time points among which neutrophils reached their maximum at day 3 and macrophages at day 6. The cardiac macrophage population consisted of both Ly6C(low) and Ly6C(high) macrophages. Ly6C(low) macrophages were more abundant peaking at day 6 in response to pressure overload. During the development of cardiac hypertrophy the expression pattern of adhesion molecules was investigated by qRT-PCR and flow cytometry. CD11b, CX3CR1 and ICAM-1 determined by qRT-PCR in whole cardiac tissue were up-regulated in response to pressure overload at day 3 and 6. CD11b and CX3CR1 were significantly increased by TAC on the surface of Ly6C(low) but not on Ly6C(high) macrophages. Furthermore, ICAM-1 was up-regulated on cardiac endothelial cells. In fluorescence microscopy Ly6C(low) macrophages could be observed attached to the intra- and extra-vascular vessel-wall. Taken together, TAC induced the expression of adhesion molecules, which may explain the accumulation of Ly6C(low) macrophages in the cardiac tissue, where these cells might contribute to cardiac inflammation and remodeling in response to pressure overload.


Factors affecting the test-retest variability of Heidelberg retina tomograph and Heidelberg retina tomograph II measurements.
To evaluate the test-retest variability of stereometric parameter measurements made with the Heidelberg retina tomograph (HRT) and Heidelberg retina tomograph-II (HRT-II), and to establish which parameter(s) provided the most repeatable and reliable measurements with both devices. An investigation into the factors affecting the repeatability of the measurements of this parameter(s) was conducted. 43 ocular hypertensive and 31 glaucoma subjects were recruited to a test-retest study. One eye from each subject underwent HRT and HRT-II imaging by two observers on each of two occasions within 6 weeks of each other. Lens grading was carried out by LOCS III grading and Scheimpflug camera generated densitogram analysis. Rim area (RA) and mean cup depth measurements were found to be least variable. Both inter-test reference height difference and image quality had a strong relation (R(2)>0.5, p<0.0001) with inter-test RA difference and, together, are responsible for 70% of RA measurement variability. Image quality was influenced by lens opacity, cylindrical error, and age. Inter-test RA measurement differences were unrelated to the observer or visit interval. RA represents an appropriate measure for monitoring glaucomatous progression. Reference height difference and image quality were the factors that most influenced RA measurement variability. Image analysis strategies that address these factors may reduce test-retest variability.


Enterovirus and herpesviridae family as etiologic agents of lymphomonocytary meningitis, Southern Brazil.
Viral meningitis is a common infectious disease of the central nervous system (CNS) that occurs worldwide. The aim of this study was to identify the etiologic agent of lymphomonocytary meningitis in Curitiba, PR, Brazil. During the period of July 2005 to December 2006, 460 cerebrospinal fluid (CSF) samples with lymphomonocytary meningitis were analyzed by PCR methodologies. Fifty nine (12.8%) samples were positive. Enteroviruses was present in 49 (83%) samples and herpes virus family in 10 (17%), of these 6 (10%) herpes simplex virus, 1 (2%) Epstein Barr virus, 2 (3%) human herpes virus type 6 and 1 (2%) mixed infection of enterovirus and Epstein Barr virus. As conclusion enterovirus was the most frequent virus, with circulation during summer and was observed with higher frequency between 4 to 17 years of age. PCR methodology is an important method for rapid detection of RNA enterovirus and DNA herpesvirus in CSF.


Left hemispheric specialization for learned, skilled, and purposeful action.
Three-dimensional motion analyses were performed on trajectories of repetitive "slicing" gestures by 4 participants with left-hemisphere lesions and limb apraxia, 6 participants with right-hemisphere lesions, and 7 neurologically intact participants. Left hemispheric lesioned participants with apraxia, but not right hemispheric lesioned participants showed impaired coupling of spatial and temporal aspects of wrist trajectories and deficits in interjoint coordination. Both groups of brain-lesioned participants differed from control participants in the 3-D plane of the wrist motion. The deficits of some right hemispheric lesioned participants in controlling the plane of wrist motion may be a consequence of left hemispatial neglect with rightward deviations. In contrast, the deficits of apraxic participants in controlling wrist trajectories and coordinating joint motions seem to reflect a deficit in these participants for the movement plan.


Mechanism of Ca2+ disruption in Alzheimer's disease by presenilin regulation of InsP3 receptor channel gating.
Mutations in presenilins (PS) are the major cause of familial Alzheimer's disease (FAD) and have been associated with calcium (Ca2+) signaling abnormalities. Here, we demonstrate that FAD mutant PS1 (M146L)and PS2 (N141I) interact with the inositol 1,4,5-trisphosphate receptor (InsP3R) Ca2+ release channel and exert profound stimulatory effects on its gating activity in response to saturating and suboptimal levels of InsP3. These interactions result in exaggerated cellular Ca2+ signaling in response to agonist stimulation as well as enhanced low-level Ca2+signaling in unstimulated cells. Parallel studies in InsP3R-expressing and -deficient cells revealed that enhanced Ca2+ release from the endoplasmic reticulum as a result of the specific interaction of PS1-M146L with the InsP3R stimulates amyloid beta processing,an important feature of AD pathology. These observations provide molecular insights into the "Ca2+ dysregulation" hypothesis of AD pathogenesis and suggest novel targets for therapeutic intervention.


Impact of a prognostic 40-gene expression profiling test on clinical management decisions for high-risk cutaneous squamous cell carcinoma.
Objective: To determine how results from a prognostic 40-gene expression profiling (40-GEP) test would impact clinician management decisions and how their choices would align with a National Comprehensive Cancer Network (NCCN) compliant, risk-directed management plan for high-risk cutaneous squamous cell carcinoma (cSCC).Methods: Clinicians attending a national dermatology conference were presented with 40-GEP test validation data. They were asked to rate clinicopathological features and molecular test results to assess their opinion of how concerning each is to cSCC prognosis. When presented with vignettes describing patients with NCCN-defined high-risk features, clinicians were asked to select a treatment plan using pre-test (no 40-GEP results), then, post-test (40-GEP Class 1, 2A, or 2B results) methodology along with corresponding metastasis rates for each test group.Results: Risk factors deemed of highest concern for metastatic outcomes were a Class 2B 40-GEP result, perineural invasion, immunosuppression, invasion beyond subcutaneous fat, and tumor diameter >1 cm on the scalp. When presented with a 40-GEP result that indicated reduced risk of metastasis (Class 1), clinicians altered their treatment management plan accordingly. Specifically, there was significant reduction in the recommendations for sentinel lymph node biopsy, adjuvant radiation or chemotherapy, follow-up time, and nodal imaging. By comparison, when a 40-GEP result indicated an increased risk of metastasis (Class 2B), significant risk-appropriate increases in management intensity was observed for the aforementioned clinical decisions.Conclusion: Integration of 40-GEP results impacted management decisions in a significant and risk-appropriate manner for high-risk cSCC patient scenarios, while remaining aligned with national guidelines for patient management.


[Serological and immunohistochemical studies in pregnant women with systemic lupus erythematosus].
The present report is a detailed, prospective analysis of 29 pregnancies in 19 patients with systemic lupus erythematosus (SLE). The clinical pregnant status was correlated with maternal serologic patterns. Poor obstetrical prognosis was associated with low or declining complement (C3 and C4) levels and rising antinuclear and anti-DNA antibody titers. Complement levels reflected clinical changes more accurately than either antinuclear factor. A smooth antepartum course and successful delivery occurred when complement values remained normal. Immunohistochemical studies showed granular or linear depositions of immunoglobulin and complement on syncytial trophoblast and stromal tissue in placenta with SLE. Slight deposits of IgG were observed on the stromal tissue in normal placenta. Immune complex deposition on the trophoblast correlated to both serologic evaluation and course of SLE pregnancy. Obstetrical prognosis can be evaluated by serial determinations of serologic status. These data suggest that declining levels of maternal complements in SLE may be partly due to immune complex deposition in the placenta, resulting in the increased placental dysfunction.


The Energy Compensation of the HRG Based on the Double-Frequency Parametric Excitation of the Discrete Electrode.
In this study, for energy compensation in the whole-angle control of Hemispherical Resonator Gyro (HRG), the dynamical equation of the resonator, which is excited by parametric excitation of the discrete electrode, is established, the stability conditions are analyzed, and the method of the double-frequency parametric excitation by the discrete electrode is derived. To obtain the optimal parametric excitation of the resonator, the total energy stability of the resonator is simulated for the evolution of the resonator vibration with different excitation parameters and the free precession of the standing wave by the parametric excitation. In addition, the whole-angle control of the HRG is designed, and the energy compensation of parametric excitation is proven by the experiments. The results of the experiments show that the energy compensation of the HRG in the whole-angle control can be realized using discrete electrodes with double-frequency parametric excitation, which significantly improves the dynamic performance of the whole-angle control compared to the force-to-rebalance.


Use of topic modeling to assess research trends in the journal Gynecologic Oncology.
There is scant research identifying thematic trends within medical research. This work may provide insight into how a given field values certain topics. We assessed the feasibility of using a machine learning approach to determine the most common research themes published in Gynecologic Oncology over a thirty-year period and to subsequently evaluate how interest in these topics changed over time. We retrieved the abstracts of all original research published in Gynecologic Oncology from 1990 to 2020 using PubMed. Abstract text was processed through a natural language processing algorithm and clustered into topical themes using latent Dirichlet allocation (LDA) prior to manual labeling. Topics were investigated for temporal trends. We retrieved 12,586 original research articles, of which 11,217 were evaluable for subsequent analysis. Twenty-three research topics were selected at the completion of topic modeling. The topics of basic science genetics, epidemiologic methods, and chemotherapy experienced the greatest increase over the time period, while postoperative outcomes, reproductive age cancer management, and cervical dysplasia experienced the greatest decline. Interest in basic science research remained relatively constant. Topics were additionally reviewed for words indicative of either surgical or medical therapy. Both surgical and medical topics saw increasing interest, with surgical topics experiencing a greater increase and representing a higher proportion of published topics. Topic modeling, a type of unsupervised machine learning, was successfully used to identify trends in research themes. The application of this technique provided insight into how the field of gynecologic oncology values the components of its scope of practice and therefore how it may choose to allocate grant funding, disseminate research, and participate in the public discourse.


Usefulness of End-to-Side Bridging Anastomosis of Sural Nerve to Tibial Nerve: An Experimental Research.
Repair of sensorial nerve defect is an important issue on peripheric nerve surgery. The aim of the present study was to determine the effects of sensory-motor nerve bridging on the denervated dermatomal area, in rats with sensory nerve defects, using a neural cell adhesion molecule (NCAM). We compared the efficacy of end-to-side (ETS) coaptation of the tibial nerve for sural nerve defect repair, in 32 Sprague-Dawley rats. Rats were assigned to 1 of 4 groups: group A was the sham operated group, group B rats had sural nerves sectioned and buried in neighboring muscles, group C experienced nerve sectioning and end-to-end (ETE) anastomosis, and group D had sural nerves sectioned and ETS anastomosis was performed using atibial nerve bridge. Neurological evaluation included the skin pinch test and histological evaluation was performed by assessing NCAM expression in nerve terminals. Rats in the denervated group yielded negative results for the skin pinch tests, while animals in the surgical intervention groups (group C and D) demonstrated positive results. As predicted, there were no positively stained skin specimens in the denervated group (group B); however, the surgery groups demonstrated significant staining. NCAM expression was also significantly higher in the surgery groups. However, the mean NCAM values were not significantly different between group C and group D. Previous research indicates that ETE nerve repair is the gold standard for peripheral nerve defect repair. However, ETS repair is an effective alternative method in cases of sensorial nerve defect when ETE repair is not possible.


Indications and adequacy of automated peritoneal dialysis in 74 patients.
Experience with chronic intermittent peritoneal dialysis is reviewed to focus on automated peritoneal dialysis (APD) regimens, adequacy and indications. From 1969 to 1990, 74 ESRD patients were treated: 59 patients with Intermittent Peritoneal Dialysis (IPD: 30-40 l x 3/week) and fifteen patients with hour Daily Peritoneal Dialysis (DPD: 25 l x 6 nights/week). Fourty-four patients were regularly treated with IPD. Of these 33 were adequately dialysed, maintaining residual renal function, whilst oligo-anuric patients developed underdialysis. DPD patients were adequately dialysed, having satisfactory peritoneal clearances. Peritonitis rate was 1/19.2 pt months in IPD patients and 1/13.4 pt months in DPD patients. Technique survival was 78% at the end of the first year, and 52% the second year. IPD is adequate only for low body weight patients with residual renal function. In-hospital IPD must be taken into account only for patients unable to perform dialysis without partner assistance. Home DPD, like CCPD and NPD, is generally adequate and yields fairly good quality of life, but the cost is high, probably because of limited ADP diffusion. Prescription must be therefore restricted to patients unable to perform dialysis with working partners, workers who cannot cope with CAPD exchanges, and CAPD failures.


Bilateral axillary pseudoangiomatous stromal hyperplasia in a premenopausal woman: A case report with imaging findings.
Pseudoangiomatous stromal hyperplasia is a benign proliferative mesenchymal lesion of the breast. To date, only a few cases of axillary pseudoangiomatous stromal hyperplasia with imaging findings have been reported in the literature. Herein, we report a rare case of pseudoangiomatous stromal hyperplasia in both axillae in a previously healthy 46-year-old woman and describe the imaging findings, including ultrasonography and computed tomography findings.


Prognostic severity scores for patients with COPD exacerbations attending emergency departments.
Reported predictors of the adverse evolution of patients with chronic obstructive pulmonary disease exacerbations (eCOPD) are various and inconsistent in the bibliography. To develop clinical prediction rules for short-term outcomes in eCOPD patients attending an emergency department (ED). Prospective cohort study of patients with an eCOPD. Short-term outcomes were admission to an intensive care unit (ICU), admission to an intermediate respiratory care unit (IRCU) and death in these groups. Multivariate logistic regression models were developed for each of the outcomes. Predictors of ICU or IRCU admission were use of long-term home oxygen therapy (LT-HOT) or non-invasive mechanical ventilation (NIMV), elevated PCO2 and decreased pH upon ED arrival (area under the curve [AUC] 0.87 in the derivation sample; 0.89 in the validation sample). Among those admitted to an ICU or IRCU, predictors of death were increased age, use at home of LT-HOT or NIMV, use of inspiratory accessory muscles upon ED arrival and altered Glasgow Coma Scale (<15 points) (AUC 0.78). Three clinical predictors available in the ED can be used to create a simple score to predict the need for intensive treatment among eCOPD patients. Such a score can be a tool for clinical practice.


Chimeric Mouse With Humanized Liver Is an Appropriate Animal Model to Investigate Mode of Action for Porphyria-Mediated Hepatocytotoxicity.
Porphyrinogenic compounds are known to induce porphyria-mediated hepatocellular injury and subsequent regenerative proliferation in rodents, ultimately leading to hepatocellular tumor induction. However, an appropriate in vivo experimental model to evaluate an effect of porphyrinogenic compounds on human liver has not been fully established. Recently, the chimeric mouse with humanized liver (PXB mice) became widely used as a humanized model in which human hepatocytes are transplanted. In the present study, we examined the utility of PXB mice as an in vivo experimental model to evaluate the key events of the porphyria-mediated cytotoxicity mode of action (MOA) in humans. The treatment of PXB mice with 5-aminolevulinic acid, a representative porphyrinogenic compound, for 28 days caused protoporphyrin IX accumulation, followed by hepatocyte necrosis, increased mitosis, and an increase in replicative DNA synthesis in human hepatocytes, indicative of cellular injury and regenerative proliferation, similar to findings in patients with porphyria or experimental porphyria models and corresponding to the key events of the MOA for porphyria-mediated hepatocellular carcinogenesis. We conclude that the PXB mouse is a useful model to evaluate the key events of the porphyria-mediated cytotoxicity MOA in humans and suggest the utility of PXB mice for clarifying the human relevancy of findings in mice.


Not all glucocorticoid-induced obesity is the same: differences in adiposity among various diagnostic groups of Cushing syndrome.
The cAMP signaling pathway is implicated in bilateral adrenocortical hyperplasias (BAHs), which are often associated with ACTH-independent Cushing syndrome (CS). Although CS is invariably associated with obesity and is frequently associated with PKA signaling defects, we recently reported that its different forms appear to also present with variable weight gain and adiposity. The present study was aimed at characterizing further the phenotypic and molecular differences in periadrenal adipose tissue (PAT) among patients with subtypes of CS, by anthropometric/biochemical analyses and quantification of PKA expression and activity in BAHs in comparison to a non-CS group with aldosterone producing adenomas (APAs). Glucocorticoid levels, serum parameters, and BMI were analyzed among a larger patient cohort including those with different forms of CS, APAs, and Cushing disease. Abdominal CT scans were available for a small subset of patients examined for fat distribution. PAT collected during adrenalectomy was assayed for PKA activity, cAMP, and PKA expression. BMI and BMI z-score were lower in adults with PPNAD with PRKAR1A mutations and in pediatric patients with PPNAD with and without PRKAR1A mutations, respectively. Patients with PPNAD had higher cAMP levels in PAT and different fat distribution. Thus, PKA activity in PAT differed between CS diagnostic groups. Increased cAMP and PKA activity may have contributed to phenotypic differences among subtypes of CS. In agreement with the known roles of cAMP signaling in the regulation of adiposity, patients with PPNAD were less obese than other patients with CS.


Optimum angles for a full-Stokes scanning polarimeter.
In this work, the four optimum azimuthal angles are determined for a full-Stokes scanning polarimeter comprising a rectangular prism, quarter-wave plate, and four linear polarizers. The determinant and condition numbers of the measurement matrix are used as objective functions in an optimization procedure. Illustrative examples with optimum angles and commonly used angles of linear polarizers are presented to evaluate the sensitivity of the polarimeter in estimating the incident Stokes vector, in error cases involving fluctuations in the detected flux and/or errors in the azimuthal angles of the linear polarizers. Our results show that optimum angles produce smaller errors than commonly used angles, when deriving the incident Stokes vectors.


Concentric photothermal coagulation with basket-integrated optical device for treatment of tracheal stenosis.
A basket-integrated optical device is developed to consistently treat tubular tissue by centering an optical diffuser in the lumen. Four nitinol arms in conjunction with the optical diffusing applicator are deployed to induce homogeneous circumferential light emission and concentric photothermal coagulation on tracheal tissue. A 1470-nm laser light is employed for the tissue testing at various irradiation conditions and evaluated in terms of thermal gradient and temperature evolution. Preliminary experiments on liver tissue demonstrate the concentric development of the radial thermal coagulation in the tissue (eccentric ratio = ~5.5%). The interstitial tissue temperature increases with the total amount of energy delivery (around 65°C). Ex vivo trachea testing yields up to 16.5% tissue shrinkage due to dehydration as well as uniform ablation of the cilia and goblet cells in a mucosa layer under 7-W irradiation for 10 s. The proposed optical device may be a feasible therapeutic method to entail the circumferential coagulation in the tubular tissues in a reliable manner.


β-globin genes: mutation hot-spots in the global thalassemia belt.
The concurrence of malaria and hemoglobinopathies, observed in malaria endemic regions, reflects the phenomenon of natural selection. Since the life cycle of the malaria parasite has an erythrocytic stage, abnormalities in the red blood cells (RBCs) hinder the parasite's survival in the human host. Hemoglobin (Hb) variants affect the life span of RBCs and thus lower the chance of infection by the parasite. While a change in just one of the Hb genes offers some protection against malaria, change in both alleles results in β-thalassemia major (β-TM). A striking geographical heterogeneity of β-thalassemia (β-thal) has been observed. Moving from Mexico in the west to China towards the east, the spectrum of mutations in the β-globin gene has been seen to vary. In the western end of the thalassemia belt, defects in the first intervening sequence (IVS-I) and exon 2 of the β-globin gene are more common, while on the eastern coast, IVS-II and exon 1 are also vulnerable to mutations. The worldwide increase in the incidence of β-TM mandates the need for efficient measures to reduce β-thal births, and the geographical heterogeneity of β-thal alleles reduces the burden of genetic testing of fetuses suspected of carrying a mutant allele. In the present review, the common mutations in the global thalassemia belt have been illustrated, and the possible factors that affect the mutagenicity of sites have been discussed. A biogeographic analysis that may provide insight into the non biological factors influencing different loci in the β-globin gene in different geographical regions is suggested.


[Dissociation of conceptual and linguistic information based on a case study].
Grouping the stimuli that we perceive in abstract categories is basic to understand our surroundings. Research gathered in the last few years with neuroimage techniques and brain damaged patients shows the role of the left temporal area in the organization of the semantic categories. A young aphasic patient study is reported who, after a cerebral haemorrhagia in the left temporo-parieto-occipital area, shows significant semantic difficulties. The results of this woman in several linguistic and semantic tasks indicate that her difficulties are conceptual rather than linguistics, since she makes well any task that does not demand access to the meaning of the words, but she fails in those tasks which require to understand the concepts. The results of this patient show the key role that the left temporal area has in the organization of the semantic categories. As consequence of the injury in that zone, the patient shows an organization of the stimuli based more in associative criteria than taxonomic and guided by the experience and functional adaptation the daily routine.


Combined effects of Cordyceps sinensis and methotrexate on hematogenic lung metastasis in mice.
We investigated antitumor effects of water extracts of Cordyceps sinensis (WECS). WECS (100 microg/ml) induced apoptosis of B16 melanoma cells after 48 h exposure in vitro as determined by both the TUNEL (TdT-mediated dUTP-biotin nick end labeling) method and the detection of a DNA ladder. In vivo, combined treatment with WECS and methotrexate (MTX) in mice intravenously inoculated with B16 melanoma cells was conducted. Although MTX caused a significant and severe decrease in body weight compared with that in control mice starting 16 days after the start of administration, the mice given both MTX and WECS did not show a significant decrease in body weight. The mean survival time (days) of the control mice, MTX-treated mice (15 mg/kg/day, s.c.), and WECS-treated mice (200 mg/kg/day, p.o.) was 25.0 +/- 0.3, 25.6 +/- 1.3, and 25.7 +/- 1.0 (mean +/- S.E.M. of 6-7 mice), respectively. On the other hand, mean survival time (days) of mice given the combination of MTX and WECS was 28.2 +/- 0.7, significantly longer than the control value. WECS might be beneficial in the prevention of tumor metastasis as an adjuvant agent in cancer chemotherapy.


Flexoelectric spectroscopy.
Flexoelectricity is an increasingly popular subject because it can be extremely large in thin films and permits switching of devices in nonpolar (non-piezoelectric) crystals via application of inhomogeneous stresses. However, recent work has been limited to macroscopic measurement of voltage or strain. Here, we discuss the vibrational spectroscopy of flexoelectricity as a recommended new tool for thin-film characterization, with special emphasis upon incommensurate crystals.


[Normal values of alpha 1 antitrypsin in the mestizo Mexican population].
Serum levels of alpha 1 antitrypsin (AAT) were determined in 100 mestizo individuals from Mexico. They were selected among those whose ancestors lived in Mexico at least for three generations, no clinical incidence of acute or chronic disease. Concentration ranged from 57-148 UI/ml and are lower than those reported in the literature. No age or sex differences were found. A total of 95% of the population fall between 68-136 UI/ml.


The inhibitory effect of interferon-alpha on the serotonin-induced impairment of human NK cell activity in whole blood.
Serotonin (5-HT) at a concentration of 10(-4) to 10(-10) M impaired the cytotoxicity of human natural killer cells in whole blood. 5-HT added at the onset of the short-term cytotoxic assay had a pronounced inhibitory effect. It is very likely that the 5-HT2 receptor is involved in the inhibition of cytotoxicity because ketanserin, an inhibitor of the 5-HT2 receptor, partially prevented the effect of 5-HT. Treatment with 10(2)-10(4) IU/ml of interferon-alpha before or after the application of 5-HT decreased its inhibitory effect on the cytotoxicity. Radioligand binding studies revealed that the antagonistic effect of interferon was not due to the competition for the 5-HT2 receptors. Cycloheximide, an inhibitor of protein synthesis, did not block the suppression of natural killer activity by 5-HT, but it exerted a blocking effect on the acquisition of resistance to 5-HT induced by interferon.


PARASITE VIRULENCE AND HOST IMMUNE DEFENSE: HOST IMMUNE RESPONSE IS RELATED TO NEST REUSE IN BIRDS.
The evolution of parasite virulence has been hypothesized to be related to the mode of parasite transmission; horizontally transmitted parasites can afford to damage their hosts more than vertically transmitted parasites because increased virulence does not reduce the probability of transmission to new hosts. This relationship between mode of transmission and virulence would particularly select for improved immune defense in hosts that are subject to horizontally transmitted parasites. Among avian hosts, hole nesters and colonial nesters frequently reuse nest sites because of nest-site limitation, and this results in an increased frequency of horizontal transmission. Comparison of the size of two organs involved in the immune defense between pairs of bird species being either hole or open nesters, or colonially or solitarily nesting birds, respectively, revealed that the size of the bursa of Fabricius and the spleen were consistently larger in hole nesters than in open nesters, and similarly in colonially breeding bird species than in solitarily breeding species. These results support the hypothesis that mode of parasite transmission affects the evolution of immune defence in hosts.


Reduced synthesis of hepatic and plasma proteins in rats during diethyl ether anaesthesia.
The effect of diethyl ether anaesthesia on in vivo hepatic protein synthetic rates was tested in male Wistar rats. Protein synthesis was measured by an isotope technique after correction for measured levels of precursor specific radioactivity. It was shown that usual anaesthetic levels of diethyl ether reduced the rate of synthesis of liver proteins with 20% compared to a group receiving no anaesthesia. The synthesis/secretion of plasma proteins was much more inhibited, with approximately 70-80%, compared to animals either receiving no anaesthesia or pentobarbital. Monitoring of ether concentrations therefore seems necessary in experiments in which the hepatic capacity for protein synthesis/secretion is measured.


Role of nuclear factor kappaB in liver health and disease.
NF-kappaB (nuclear factor kappaB) is a heterodimeric transcription factor that is constitutively expressed in all cell types and has a central role as a transcriptional regulator in response to cellular stress. In the present review, we discuss the role of NF-kappaB signalling in the maintenance of liver homoeostasis as well as in the pathogenesis of a wide variety of conditions affecting the liver, including viral hepatitis, steatohepatitis, cirrhosis and hepatocellular carcinoma. Much of the current knowledge of NF-kappaB signalling in the liver relates to the canonical pathway, the IKK [IkappaB (inhibitor of kappaB) kinase] complex and the RelA subunit. We explore the weaknesses of the experimental approaches to date and suggest that further work is needed to investigate in detail the discreet functions of each of the Rel subunits in liver physiology and disease.


Acaricidal and cytotoxic activities of extracts from selected genera of Australian Lamiaceae.
Crude foliar extracts of 67 species from six subfamilies of Australian Lamiaceae were screened by whole organism contact toxicity on the polyphagous mite Tetranychus urticae Koch (Acari: Tetranychidae) by using a Potter precision spray tower. Cytotoxicity assessments against insect cell lines from Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae) and Drosophila melanogaster (Meigen) (Diptera: Drosophilidae) also were made. The Spodoptera cell line was more susceptible to extracts than the Drosophila cellline. No direct correlation was observed between the two screening methods, but several interesting relationships were identified. Extracts from subfamilies Ajugoideae, Scutellarioideae, Chloanthoideae, Viticoideae and Nepetoideae showed acaricidal activity, whereas only those from Ajugoideae and Nepetoideae displayed potent cytotoxic effects. A range of activities was observed for the 25 species of Plectranthus, 14 of which showed moderate-to-high contact toxicity against T. urticae. Overall, the lowest toxicity was observed for extracts from the plant subfamily Prostantheroideae, which showed little contact toxicity or cytotoxicity for the 18 extracts studied.


Therapeutic Effect of Matrine on Collagen-Induced Arthritis Rats and Its Regulatory Effect on RANKL and OPG Expression.
To investigate the effect of matrine on rats with collagen-induced arthritis (CIA) and its regulatory effect on receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG) expression. Wistar rats (n = 6) and CIA rats (n = 30) were randomly divided into six groups: healthy, CIA control, low/medium/high matrine (25, 50, or 100 mg/kg, once per day for six weeks), and methotrexate (MTX) (2 mg/kg, once per week for six weeks). The degree of joint damage was evaluated by X-ray and HE staining. Bone marrow suppression was assessed by routine blood analysis. In addition, the levels of serum RANKL and OPG in the rats were measured by ELISA. The level of joint swelling and degree of joint damage assessed by ankle swelling measurements, AI score, X-ray, and HE staining were alleviated in the CIA rats treated with MTX or different doses of matrine. Furthermore, no obvious inhibitory effect was observed on the bone marrow of the CIA rats, regardless of the dose of matrine or treatment with 2 mg/kg MTX (P > 0.05). The levels of OPG in serum and the ratio of OPG/RANKL were higher, and RANKL expression was lower in the low/medium/high matrine group compared with that of the CIA control group. The serum levels of OPG and OPG/RANKL ratio increased with the matrine dose, while the opposite was observed for RANKL expression. Matrine treatment was associated with a lower degree of bone destruction, increased OPG expression and OPG/RANKL ratio, and decreased RANKL expression in CIA rats. Thus, matrine may represent a novel drug candidate for the treatment of RA.


APOE ε4 allele, along with G206D-PSEN1 mutation, alters mitochondrial networks and their degradation in Alzheimer's disease.
Alzheimer's disease remains the most common neurodegenerative disorder, depicted mainly by memory loss and the presence in the brain of senile plaques and neurofibrillary tangles. This disease is related to several cellular alterations like the loss of synapses, neuronal death, disruption of lipid homeostasis, mitochondrial fragmentation, or raised oxidative stress. Notably, changes in the autophagic pathway have turned out to be a key factor in the early development of the disease. The aim of this research is to determine the impact of the APOE allele ε4 and G206D-PSEN1 on the underlying mechanisms of Alzheimer's disease. Fibroblasts from Alzheimer's patients with APOE 3/4 + G206D-PSEN1 mutation and homozygous APOE ε4 were used to study the effects of APOE polymorphism and PSEN1 mutation on the autophagy pathway, mitochondrial network fragmentation, superoxide anion levels, lysosome clustering, and p62/SQSTM1 levels. We observed that the APOE allele ε4 in homozygosis induces mitochondrial network fragmentation that correlates with an increased colocalization with p62/SQSTM1, probably due to an inefficient autophagy. Moreover, G206D-PSEN1 mutation causes an impairment of the integrity of mitochondrial networks, triggering high superoxide anion levels and thus making APOE 3/4 + PSEN1 fibroblasts more vulnerable to cell death induced by oxidative stress. Of note, PSEN1 mutation induces accumulation and clustering of lysosomes that, along with an increase of global p62/SQSTM1, could compromise lysosomal function and, ultimately, its degradation. The findings suggest that all these modifications could eventually contribute to the neuronal degeneration that underlies the pathogenesis of Alzheimer's disease. Further research in this area may help to develop targeted therapies for the treatment of Alzheimer's disease.


Cytofluorometric and cytophotometric measurements by using the exposure control device in the automatic photomicroscope.
A simple method for quantitative measurements of staining and fluorescence intensities in microscopic preparation is described. The procedure is based on the use of the automatic exposure capability of the Zeiss Photomicroscope, in which the measuring value on the scale of the exposure control device after an arbitrary time permits the assessment of the light intensity on the point photosensor. The method has been checked through the study of chromatin staining and fluorescence by dyes and fluorochromes which are utilized in nucleic acids cytochemistry. The correpondence between these measurements and those obtained by using other methods is briefly discussed.


Update on pediatric chest imaging.
Even in the high-technology medical imaging arena, the decision of how to first image pediatric chest disease is quite simple: by plain chest radiograph, including frontal and lateral views. The diagnosis can often be made or suggested on the basis of these films or with other basic imaging procedures, such as fluoroscopy or esophagram. From this point onward the decision how to proceed with further imaging such as ultrasound, computed tomography, nuclear medicine imaging, or magnetic resonance imaging, will depend on the probability of gaining further helpful information. Beginning with a concise differential diagnosis allows one to proceed in a logical manner through the diagnostic work-up in a time-effective and cost-effective manner. One must keep in mind that in some cases the diagnosis cannot be made radiologically and must be left to the pathologist. In these cases the work-up should end when no further progress is possible toward making the diagnosis. In the pediatric age group, one should always strive to limit the amount of unnecessary radiation exposure.


Life-threatening hypokalaemia on a low-carbohydrate diet associated with previously undiagnosed primary hyperaldosteronism [corrected].
Low-carbohydrate diets are popular and fashionable for weight loss despite lack of evidence about long-term effects. Many individuals attempting to lose weight have hypertension, especially those with diabetes, and the prevalence of hyperaldosteronism among hypertensive patients is higher than previously recognized. We present a patient with Type 2 diabetes and previously undiagnosed hyperaldosteronism who developed life-threatening hypokalaemia while following a low-carbohydrate diet. A 60-year-old man with diet-treated Type 2 diabetes and hypertension presented with generalized muscle weakness and serum potassium of 1.9 mmol/l. He had succeeded in losing three and a half stones during the previous 4 months by adhering strictly to a low-carbohydrate diet. HbA(1c) was 4.8% and plasma aldosterone:renin ratios were elevated suggestive of increased aldosterone secretion. On a low-calorie mixed diet serum potassium levels were maintained in the low-normal range over the following 165 days. The adrenals were normal on CT scanning and blood pressure responded dramatically to the addition of spironolactone on day 212 (125/83 mmHg). The prevalence of primary hyperaldosteronism in the hypertensive population, based on elevation of plasma renin:aldosterone ratio, is approximately 6%. The majority of these people are normokalaemic and remain undiagnosed. However, when carbohydrate intake is restricted such individuals are at increased risk of potentially life-threatening metabolic derangements.


Updated Management Protocol for Multisystem Inflammatory Syndrome in Children (MIS-C).
The multisystem inflammatory syndrome in children (MIS-C) is a post-viral immunological or hyper-inflammatory complication of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection commonly seen in older children, who commonly present with fever, multi-systemic involvement including myocardial dysfunction and shock, and hyper-inflammation. The treatment of MIS-C is adapted from the treatment of other immunological or hyper-inflammatory conditions and these treatment protocols are not uniform across the globe, and more so, in India. We propose a uniform management protocol for MIS-C based on our experience of treating MIS-C cases, available evidence till now, and recent guidelines. The aims are to identify children with MIS-C with high sensitivity, recognize other infections or inflammatory processes, stratify treatment based on severity, and manage hyper-inflammatory syndrome.


The Migration of Lynch Victims' Families, 1880-1930.
We examine the relationship between the lynching of African Americans in the southern United States and subsequent county out-migration of the victims' surviving family members. Using U.S. census records and machine learning methods, we identify the place of residence for family members of Black individuals who were killed by lynch mobs between 1882 and 1929 in the U.S. South. Over the entire period, our analysis finds that lynch victims' family members experienced a 10-percentage-point increase in the probability of migrating to a different county by the next decennial census relative to their same-race neighbors. We also find that surviving family members had a 12-percentage-point increase in the probability of county out-migration compared with their neighbors when the household head was a lynch victim. The out-migration response of the families of lynch victims was most pronounced between 1910 and 1930, suggesting that lynch victims' family members may have been disproportionately represented in the first Great Migration.


A vibrating beam MEMS accelerometer for gravity and seismic measurements.
This paper introduces a differential vibrating beam MEMS accelerometer demonstrating excellent long-term stability for applications in gravimetry and seismology. The MEMS gravimeter module demonstrates an output Allan deviation of 9 μGal for a 1000 s integration time, a noise floor of 100 μGal/√Hz, and measurement over the full ±1 g dynamic range (1 g = 9.81 ms-2). The sensitivity of the device is demonstrated through the tracking of Earth tides and recording of ground motion corresponding to a number of teleseismic events over several months. These results demonstrate that vibrating beam MEMS accelerometers can be employed for measurements requiring high levels of stability and resolution with wider implications for precision measurement employing other resonant-output MEMS devices such as gyroscopes and magnetometers.


Protective actions in the late phase--intervention criteria and decision-making.
Major countermeasures in the late phase of a nuclear or radiological accident where long-lived radionuclides have been dispersed in the environment are relocation/resettlement, foodstuff restrictions, agricultural countermeasures and clean-up of contaminated areas. There has essentially been a broad acceptance internationally of the principles for their introduction, but it has not been possible to reach an agreement for the purpose of defining a net benefit based upon the exact weighting to be attached to each of the attributes influencing the decision on intervention, e.g. socio-psychological attributes. Optimisation of protection, i.e. maximising the net benefit, is not a question of developing radiation protection philosophy to fully include socio-psychological factors but rather to include these factors--in parallel with the radiological protection factors--in cooperation between radiation protection experts and e.g. experts in social and psychological sciences under the responsibility of the decision-maker, who will take the final decision on the introduction of long-term countermeasures.