Gene expression profiling of the ageing rat vibrissa follicle.
The application of gene expression profiling to the study of chronological ageing has the potential to illuminate the molecular mechanisms underlying a complex and active process. For example, ageing of the skin and its constituent organs has myriad phenotypic consequences, and a better understanding of the means by which these changes arise has important corollaries for intervention strategies. We used a transcriptional profiling approach to investigate changes in gene expression associated with ageing of the large vibrissa follicle of the Wistar rat. Follicle mRNA isolated from male Wistar rats at 1 and 18 months of age was hybridized to Clontech Atlas 1.2 Rat cDNA macroarrays. Confirmation of array results was provided by the use of Northern blotting and immunohistochemistry. Seven transcripts displayed at least a 1.6-fold increase in expression with age, of which APOD (2.5-fold), GSTM2 (2.0-fold) and NPY (1.8-fold) showed the greatest increases. Decreased expression was found in 19 transcripts, most notably in ALOX12 (13.3-fold) and GAP43 (12.6-fold) expression. Follicular ageing is characterized by transcriptional changes associated with diverse aspects of keratinocyte metabolism, proliferation and development.


Conservative treatment of Angle Class III malocclusion with anterior crossbite.
Angle Class III malocclusion is characterized by anteroposterior dental discrepancy which might be associated or not with skeletal changes. Class III molar relationship is associated with vertical or lingually tipped mandibular incisors and a usually concave profile. These characteristics seriously affect facial esthetics and most frequently are the reason why patients seek orthodontic treatment. This case was presented to the committee of the Brazilian Board of Orthodontics and Facial Orthopedics (BBO) as part of the requisites to become a BBO Diplomate.


Eating Disorders in Adolescent and Young Adult Males: Presenting Characteristics.
Data on the clinical characteristics of adolescent males with eating disorders are limited. The purpose of this study was to describe the demographic characteristics, presenting vital signs, laboratory results, and relevant risk factors for eating disorders among males presenting to an outpatient adolescent and young adult medicine practice. Retrospective chart review of male eating disorder patients aged of 11-25 years presenting to the University of California, San Francisco Adolescent and Young Adult Eating Disorder Program between June 1, 2011, and November 1, 2014. Charts were reviewed for demographic and clinical characteristics and risk factors for eating disorders. Thirty-three patients were included; mean age was 16 years. Patients presented with mean heart rate was 58.7 bpm, and orthostatic heart rate change was 22 bpm, with 51.5% meeting Society for Adolescent Health and Medicine hospital admission criteria. Mean percent of median body mass index was 88%. Of patients with available laboratory data, 33.3% were anemic, 23.8% leukopenic, 19.0% thrombocytopenic, and 10.0% neutropenic. Half had a history of a psychiatric disorder; 41.5% had a history of overweight or obesity, and 12.1% had a family history of an eating disorder. The DSM-IV-TR and DSM-5 diagnostic criteria were retrospectively applied to patients, with an increase in diagnosis of anorexia nervosa from 36.4% to 48.5%. Diagnoses of Eating Disorder Not Otherwise Specified, now Other Specified Feeding or Eating Disorder in DSM-5, decreased from 62.6% to 45.5%. Male patients with eating disorders presented with significant abnormalities; patients were bradycardic and orthostatic; and more than half met Society for Adolescent Health and Medicine admission criteria. Patients with available laboratory data demonstrated significant abnormalities consistent with malnutrition. Given that eating disorders are less likely to be detected in males, it is important to recognize early signs of malnutrition, particularly in those who present within the normal body mass index range for age.


The europe second wave of COVID-19 infection and the Italy "strange" situation.
At the end of February 2020 COVID-19 infection appeared in Italy, with consequent diffusion, in few weeks, in almost all the Europe. Despite that human-to-human is the recognized main virus transmission way, several authors supposed pollution-to-human mechanisms to justify the appearance of contagious in Italy. However, these works often suffered of a lack of analysis of possible overlapping of different variables, other than only environmental ones. After a decreasing of detected cases in summer, Europe faced with the appearance of a COVID-19 second wave. In this context the Italy situation appeared to be "strange". Indeed, compared with the other selected Countries (France, Germany, UK, and Spain), the Italian infection cases resulted to be lower, in the same analysed period. This work is devoted to find a possible justification of the unexpected situation found in Italy. A comparison of the imposed restrictions in the considered Countries allows to highlight that some policies result more effective to limit the virus spread. This clearly shows that the imposed constraints and the people capacities to receipt them are fundamental parameters that must be always accounted in the determination of the virus expansion. The lesson provided by Italy should be achieved by other member states where the COVID-19 sanitary crisis results to be worse. It is evident that the re-opening of ordinary activities involving people interactions, in Autumn, may contribute to promote a larger SARS-CoV-2 diffusion also in Italy. Author strongly highlights that pollution-to-human transmission mechanisms cannot be proposed whiteout considering the complexity of human-to-human interactions, that can be modified by imposed restrictions. It is fundamental to understand that a more precise acknowledge of the variables that should be considered in model predictions, instead of a need of more precise point prediction, will contribute to increase the reliability and the comprehension of the virus diffusion mechanisms, that is fundamental to face this pandemic period.


MBD2 facilitates tumor metastasis by mitigating DDB2 expression.
Despite past extensive studies, the pathoetiologies underlying tumor metastasis remain poorly understood, which renders its treatment largely unsuccessful. The methyl-CpG-binding domain 2 (MBD2), a "reader" to interpret DNA methylome-encoded information, has been noted to be involved in the development of certain types of tumors, while its exact impact on tumor metastasis remains elusive. Herein we demonstrated that patients with LUAD metastasis were highly correlated with enhanced MBD2 expression. Therefore, knockdown of MBD2 significantly attenuated the migration and invasion of LUAD cells (A549 and H1975 cell lines) coupled with attenuated epithelial-mesenchymal transition (EMT). Moreover, similar results were observed in other types of tumor cells (B16F10). Mechanistically, MBD2 selectively bound to the methylated CpG DNA within the DDB2 promoter, by which MBD2 repressed DDB2 expression to promote tumor metastasis. As a result, administration of MBD2 siRNA-loaded liposomes remarkably suppressed EMT along with attenuated tumor metastasis in the B16F10 tumor-bearing mice. Collectively, our study indicates that MBD2 could be a promising prognostic marker for tumor metastasis, while administration of MBD2 siRNA-loaded liposomes could be a viable therapeutic approach against tumor metastasis in clinical settings.


Close relationship between high HbA1c levels and methemoglobin generation in human erythrocytes: The enhancement of oxidative stress in the process.
This study aimed to investigate the effect of diabetic plasma on human red blood cells (RBCs) in order to highlight the amplification mechanisms of oxidative stress (OS) in relation to methemoglobin (metHb) production, a potential bio-indicator that could be related to diabetes disease. Normal RBCs were co-incubated with the diabetic plasma of 24 patients at different HbA1c levels, for 0, 24, and 48 h in order to assess cell turbidity and hemoglobin (Hb) stability. Hb and metHb production were quantified inside and outside RBCs. Malonaldehyde (MDA) level and cell morphology were concomitantly evaluated. The cell turbidity was significantly decreased in the group co-incubated with diabetic plasma at high HbA1c levels (0.074 ± 0.010 AU) compared to the control group (0.446 ± 0.019 AU). A significant decrease in intracellular Hb (0.390 ± 0.075 AU) and its stability (0.600 ± 0.001 AU) were revealed. Also, we found an important increase of metHb levels inside RBCs (0.186 ± 0.017 AU) and in its supernatant (0.086 ± 0.020 AU) after 48 h. Consequently, MDA absorbance increased significantly (0.320 ± 0.040 AU) in RBCs exposed to diabetic plasma with high HbA1c. These findings suggest that poor glycemic control in diabetes leads to metHb generation which is the main factor of the OS amplification.


Micelle-catalyzed reaction between ninhydrin and nickel dipeptide complex [Ni(II)-Gly-Tyr]+.
The interaction of nickel dipeptide complex [Ni(II)-Gly-Tyr](+) with ninhydrin has been investigated in the absence and presence of cationic cetyltrimethylammonium bromide (CTAB) and gemini (16-s-16, s=4, 5, 6) surfactants spectrophotometrically at 80°C and pH 5.0. The product formed was the same and the reaction followed first- and fractional-order kinetics with respect to [Ni(II)-Gly-Tyr](+) and [ninhydrin], respectively, in both aqueous as well as micellar media. In the presence of CTAB, rate increased and reached up to a maximum, then decreased. Also, whereas typical rate constant (k(Ψ)) increase and leveling-off regions, just like CTAB, were observed with geminis, the latter produced a third region of increasing k(Ψ) at higher concentrations. This unusual third-region effect of the gemini micelles is assigned to changes in their micellar morphologies. The micellar catalysis is explained in terms of pseudo-phase model. The binding constants and the values of activation parameters such as activation energy (E(a)), enthalpy of activation (ΔH(#)) and entropy of activation (ΔS(#)) have been evaluated.


Insulin analogues and management of diabetes mellitus.
The introduction of insulin analogues, of which insulin lispro is the prototype, marks a very important milestone in the management of patients with diabetes mellitus. It differs from regular human insulin in its quicker onset and shorter duration of action. In various clinical trials, insulin lispro was found to be superior to regular human insulin in controlling postprandial hyperglycemia without increasing the risk of hypoglycemia. It improved the quality of life of diabetic patients by providing more flexibility to meal plans. Recently, another short acting insulin analogue called insulin aspart has been tried in clinical studies with benefits similar to insulin lispro. The turn of the millennium is now witnessing the development of long acting insulin analogues like insulin glargine, which can provide continuous low-level basal insulin concentrations similar to natural settings. In this review, we discuss the potential of insulin analogues in the modern management of diabetes with emphasis on insulin lispro.


Identical Choroid Plexus Cysts in Monozygotic Monochorionic Twins.
Choroid plexus cysts have been infrequently reported with chromosomal abnormalities.Isolated choroid plexus cysts in a monozygotic twin pair hints to a genetically determined pathway as a possible cause.


Factors Impacting Family Planning Use in Mali and Senegal.
The total fertility rate in Mali (6.2) is the third highest in the world. Despite sociocultural similarities, the total fertility rate in neighboring Senegal is 4.2. The aim of this study is to identify factors which may help to explain the differences between the two countries and which may thereby inform family planning policy in Mali. A cross-sectional study was conducted with a convenience sample of 602 married women aged 16-50 from urban and rural sites in southern Mali and Senegal. A total of 298 respondents from Mali and 304 from Senegal completed a structured questionnaire between July and October 2018. In total, 11.1% of the Malian respondents and 30.9% of the Senegalese respondents were currently using family planning, and 34.6% and 40.5%, respectively, had ever used a modern family planning method. Pressure from husbands was cited as a primary influence for having more children (in 50.3% of Malians and 45.4% of Senegalese, p = 0.000). Women's age, education level, and knowledge of different contraceptive methods were associated with ever use of contraceptives. After adjustment for confounders, discussing family planning with one's husband was the strongest predictor of contraceptive use among both Senegalese (OR = 3.4, 95% CI (1.9-6.3), p = 0.000) and Malian respondents (OR = 7.3, (4.1-13.3), p = 0.000).


[Cerebral blood flow in moyamoya disease].
Regional cerebral blood flow in forty cases of moyamoya disease was investigated by intravenous 133Xe injection method. Twenty-one cases were children and other nineteen were adults. No or only slight neurological deficit were found at the CBF studies. CBF was calculated by initial slope index. For investigation of the relation between hemispheric blood flow and age, the regression curve was calculated and that with highest correlation was chosen. In normal group, the relationship between hemispheric CBF and age was correlated to following equation: y = 146.5-58.4 log x (r = -0.903). In contrast, in moyamoya disease, it was correlated to following equation: log y = 2.04-0.23 log x (r = -0.730). It can be said that CBF of the whole brain in moyamoya disease is below normal. The distribution of the rCBF was characteristic in moyamoya disease. There are low CBF values in the frontal and temporal lobes and relatively high values in the occipital lobes as compared with normal CBF distribution. These results are thought to indicate the importance of blood circulation to the brain from the vertebro-basilar arterial system. Moreover a comparison of these CBF results with the six stages of basal moyamoya seen angiographically was investigated in child cases. As the stage of moyamoya disease progressed, the hemispheric CBF decreased gradually and the distribution of blood flow gradually changed from a predominance of flow to the frontal lobes to a predominance of flow to the occipital lobes.


Accelerated growth after recombinant human growth hormone treatment of children with chronic renal failure.
We studied the effect of recombinant human growth hormone treatment on five boys, aged 4.6 +/- 1.8 years, who had chronic renal failure secondary to congenital renal diseases (mean creatinine clearance (+/- SD): 18.3 +/- 6.3 ml/min/1.73 m2 (0.32 +/- 0.11 ml/sec/1.73 m2]. Patients received 0.125 mg/kg of growth hormone three times per week for 1 year. Before beginning treatment, the children had a mean annual growth velocity of 4.9 +/- 1.4 cm/yr (range 3.0 to 6.3 cm/yr), with a mean standard deviation score for a height of -2.98 +/- 0.73 (range -2.16 to -3.59). At the end of therapy, the mean growth velocity had increased to 8.9 +/- 1.2 cm/yr (range 7.5 to 10.7 cm/yr), and the mean height standard deviation score improved to -2.36 +/- 0.83 (range -1.15 to -3.18). Bone age advancement was consistent with the period of growth. Routine laboratory determinations, including results of glucose tolerance testing, did not vary significantly from pretreatment levels. These preliminary data indicate that growth-retarded children with chronic renal failure can respond to exogenous growth hormone therapy with a marked acceleration in growth velocity.


Rotavirus infection in horses. Genome profile analysis of a rotavirus isolated from an infected foal.
Electrophoretic analysis in polyacrylamide gel (PAGE) of the equine rotavirus 106/88/LI/EQ, isolated from the diarrhea of an 18 day old foal was compared to the bovine strain NCDV. There was a notable difference in the migration of some segments of the viral RNA. Bands 2 and 3 of the equine rotavirus comigrated while there was a clear separation of segments 7, 8 and 9. Moreover, the migration of segments 1, 4 and 5 revealed a lower molecular weight than the corresponding segments of NCDV.


Coping and family relationships in stress resistance: a study of job satisfaction of nurses in Singapore.
This study examined the role of coping strategies and family relationships in mitigating the negative effect of work stress on nurses. The findings indicated that nurses who adapted to work stress with high job satisfaction were more inclined to adopt approach coping methods (problem orientation, ability enhancement, and change of perspective) than those who reported low job satisfaction under high work stress. The stress-resistant nurses were also distinguished by a less frequent use of defensive or avoidance coping in handling of their emotional reactions to stress. They perceived greater family support than did the distressed nurses. Implications of the findings and limitation of the study were discussed.


Localised structuring of metal-semiconductor cores in silica clad fibres using laser-driven thermal gradients.
The molten core drawing method allows scalable fabrication of novel core fibres with kilometre lengths. With metal and semiconducting components combined in a glass-clad fibre, CO2 laser irradiation was used to write localised structures in the core materials. Thermal gradients in axial and transverse directions allowed the controlled introduction, segregation and chemical reaction of metal components within an initially pure silicon core, and restructuring of heterogeneous material. Gold and tin longitudinal electrode fabrication, segregation of GaSb and Si into parallel layers, and Al doping of a GaSb core were demonstrated. Gold was introduced into Si fibres to purify the core or weld an exposed fibre core to a Si wafer. Ga and Sb introduced from opposite ends of a silicon fibre reacted to form III-V GaSb within the Group IV Si host, as confirmed by structural and chemical analysis and room temperature photoluminescence.


Copy mutants of plasmid R1: effects of base pair substitutions in the copA gene on the replication control system.
Five different copA copy mutants of plasmid R1 have been identified by nucleotide sequencing. Independent measurements of the activities of the mutant inhibitor RNA and of the mutant target properties were carried out using several different methods. Correlation of these measurements with the location of th nucleotide substitutions resulted in the following conclusions: (1) The copy number of plasmid R1 is controlled primarily by interaction between the CopA RNA molecule and its target, the RepA mRNA. (2) The binding of th inhibitor to its target is based on nucleotide interactions within two complementary sequences of ten nucleotides and dependent on the secondary structure of the active site. (3) The secondary structure of both the CopA target and the CopA RNA is a stem-loop structure. Mutations in the loop region interfere with binding affinity between inhibitor and target, whereas mutations in the upper stem mainly interfere with secondary structure. Mutations in the latter region create temperature-dependent copy number phenotypes.


Methylene Blue Infiltration As a Method for Distinguishing Superficial and Deep Infections.
There are no established objective methods to reliably differentiate between superficial and deep infection in the setting of total hip arthroplasty. We employed a technique of distinguishing superficial and deep infections by infiltrating methylene blue to a prosthetic hip during infection workup to determine its effectiveness and to characterize its utility in defining the joint cavity where deep debridement is required. An analysis was conducted on 35 patients who preoperatively received an injection of methylene blue under radiological guidance to their total hip arthroplasty. Where established periprosthetic joint infection (PJI) criteria were not met, without signs of methylene blue beyond the deep fascia, the infection was considered superficial, and debridement remained superficial to the deep fascia. Where diagnosis of PJI was confirmed preoperatively or the presence of methylene blue in the wound cavity confirmed deep contamination, the prosthesis was addressed with methylene blue staining defining the joint cavity as a guide for debridement. There were 11 patients who had no methylene blue extrusion into the superficial compartment and did not meet PJI criteria. Eight patients failed to meet PJI criteria preoperatively, but had extrusion of methylene blue, confirming a deep infection intraoperatively. There were 16 patients who met PJI criteria preoperatively with methylene blue acting as a visual guide to the joint space. Infiltrating methylene blue in a prosthetic hip is useful in differentiating between superficial or deep infections where PJI workup is indeterminate. Where deep infection is present, its utility in defining the joint cavity may be advantageous.


Carcinogenic tryptophan pyrolysis products in airborne particles and rain water.
This is the first report that carcinogenic tryptophan pyrolysis products are present in airborne particles and rain water. The airborne particles were collected from August 1988 through October 1988 at 4 locations in Japan. The amounts of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) in the air were 0.23 +/- 0.17 pg/m3 air (mean +/- SD, n = 18) and 0.16 +/- 0.15 pg/m3 air (n = 18), respectively. Moreover, these carcinogens were detected in rain water. These results indicate that Trp-P-1 and Trp-P-2 are ubiquitous environmental components.


[Surveillance of sexually transmitted diseases: practical approach (author's transl)].
Even today we still do not have enough precise information either on the number of diseases which should be included in this collective concept or on the frequency of the diseases and their complications. Information is also lacking on methods for measuring these frequencies and assuring satisfactory surveillance. Various methods of gauging the frequency of these diseases are examined and evaluated and a practical surveillance programme is suggested.


Blood culture fluorescence rates predict severity and mortality of invasive pneumococcal pneumonia.
Invasive pneumococcal pneumonia is associated with high rates of mortality. Clinical assessment tools have poor sensitivity for predicting clinical outcomes. Molecular measurements of bacterial load correlate closely with clinical outcome but require specialist facilities and expertise. This study describes how routine blood culture testing can estimate bacterial load and predict clinical outcome for invasive pneumococcal pneumonia. Between December 2009 to March 2014, clinical and laboratory data were collected for 50 patients with Streptococcus pneumoniae bacteraemia secondary to community-acquired pneumonia. Fluorescence rates (FR) were calculated from growth curves generated by BACTEC blood culture analysers by dividing change in fluorescence units (FU), measured at the first point of detectable fluorescence and at the point of automated BACTEC positivity, by time in hours. The mean age of the patients was 70.6 years (49.6-86.3). Forty patients survived invasive pneumococcal disease and ten patients died. These two groups did not significantly differ by demographic or clinical characteristics. The mean FR for the non-survival group (3.62 × 10(-3) FU/h) was significantly higher (p < 0.001) than that of the survival group (1.73 × 10(-3) FU/h). FR did not vary by serotype. We determined that an FR of 2.59 × 10(-3) FU/h might represent a useful threshold for predicting high mortality risk with a sensitivity of 91 % and a specificity of 97 %. Our FR calculation uses cheap and accessible routine blood culture techniques to predict mortality in a small retrospective cohort study. In patients admitted to hospital with pneumococcal bacteraemia and, potentially, other organisms, this single tool could guide early escalation of clinical care.


Metformin for Treatment of Acute COVID-19: Systematic Review of Clinical Trial Data Against SARS-CoV-2.
Observational and preclinical data suggest metformin may prevent severe coronavirus disease 2019 (COVID-19) outcomes. We conducted a systematic review of randomized, placebo-controlled clinical trials of metformin treatment for COVID-19 to determine whether metformin affects clinical or laboratory outcomes in individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and present a structured summary of preclinical data. Two independent reviewers searched PubMed, Scopus, Cochrane COVID-19 Study Register, and ClinicalTrials.gov on 1 February 2023 with no date restrictions for trials where investigators randomized adults with COVID-19 to metformin versus control and assessed clinical and/or laboratory outcomes of interest. The Cochrane Risk of Bias 2 tool was used to assess bias. Two reviewers extracted data pertaining to prespecified outcomes of each interest from each included trial. The synthesis plan was developed a priori and was guided by Synthesis Without Meta-analysis (SWiM) guidelines. Summary tables and narrative synthesis were used (PROSPERO, 2022, CRD42022349896). Three randomized trials met inclusion criteria. In two of the trials investigators found that metformin improved clinical outcomes (prevented need for oxygen and prevented need for acute health care use), and in the third trial a larger portion of adults with diabetes were enrolled but results did show a direction of benefit similar to that of the other trials in the per-protocol group. In the largest trial, subjects were enrolled during the delta and omicron waves and vaccinated individuals were included. The certainty of evidence that metformin prevents health care use due to COVID-19 was moderate per Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Many preclinical studies have shown metformin to be effective against SARS-CoV-2. Limitations include inclusion of only three trials and heterogeneity between trials. Future trials will help define the role of metformin in COVID-19 treatment guidelines.


A study on human serum albumin influence on glycation of fibrinogen.
Although in vivo glycation proceeds in complex mixture of proteins, previous studies did not take in consideration the influence of protein-protein interaction on Maillard reaction. The aim of our study was to test the influence of human serum albumin (HSA) on glycation of fibrinogen. The isotopic labeling using [(13)C6] glucose combined with LC-MS were applied as tool for identification possible glycation sites in fibrinogen and for evaluation the effect of HSA on the glycation level of selected amino acids in fibrinogen. The obtained data indicate that the addition of HSA protects the fibrinogen from glycation. The level of glycation in presence of HSA is reduced by 30-60% and depends on the location of glycated residue in sequence of protein.


Cross-modal plasticity in sensory deprived animal models: From the thalamocortical development point of view.
Over recent decades, our understanding of the plasticity of the central nervous system has expanded enormously. Accordingly, it is now widely accepted that the brain can adapt to changes by reorganizing its circuitry, both in response to external stimuli and experience, as well as through intrinsic mechanisms. A clear example of this is the activation of a deprived sensory area and the expansion of spared sensory cortical regions in individuals who suffered peripheral sensory loss. Despite the efforts to understand these neuroplastic changes, the mechanisms underlying such adaptive remodeling remains poorly understood. Progress in understanding these events may be hindered by the highly varied data obtained from the distinct experimental paradigms analyzed, which include different animal models and neuronal systems, as well as studies into the onset of sensory loss. Here, we will establish the current state-of-the-art describing the principal observations made according to the time of sensory deprivation with respect to the development of the thalamocortical connectivity. We will review the experimental data obtained from animal models where sensory deprivation has been induced either before or after thalamocortical axons reach and invade their target cortical areas. The anatomical and functional effects of sensory loss on the primary sensory areas of the cortex will be presented. Indeed, we consider that the comparative approach of this review is a necessary step in order to help deciphering the processes that underlie sensory neuroplasticity, for which studies in animal models have been indispensable. Understanding these mechanisms will then help to develop restorative strategies and prostheses that will overcome the functional loss.


Triiodothyronine effects on RNA polymerase activities in isolated neuronal and glial nuclei of the mature rat brain cortex.
Our previous study demonstrated that a high level of nuclear triiodothyronine receptors (NT3R), which are identical to the hepatic NT3R, exists in neuronal nuclei of the cerebral cortex from an adult rat brain. To investigate whether thyroid hormone acts through binding to nuclear receptors, we measured RNA polymerase activities in isolated neuronal and glial nuclei of cerebral cortices prepared from three groups of rats with different T3 levels: T3 (20 micrograms/100 g BW/d, for three days)-injected hyperthyroid rats, control normal rats, and thyroidectomized rats. The enzyme activities in both nuclear fractions were assayed under the condition of dose-response linearity. When RNA polymerase I activity in neuronal nuclei from control rats was expressed as 100%, the activities from T3-injected and hypothyroid rats were 112.3 +/- 3.4% (n = 5, P less than .05) and 86.9 +/- 3.5% (n = 5, P less than .05), respectively. The increase in the enzyme activities were parallel to the increase in T3 content in neuronal nuclei among the groups. Glial nuclear RNA polymerase I showed the same tendency in response to T3, although the enzyme activity was smaller than from neuronal nuclei. RNA polymerase II, however, showed no significant change in response to altered T3 levels. The existence of numerous receptors and an induction of increased RNA polymerase I activity by T3 in neuronal nuclei raise the possibility that thyroid hormone through a NT3R pathway in the cerebral cortex of even the mature rat brain.


On-resin N-terminal peptoid degradation: Toward mild sequencing conditions.
A novel approach to sequentially degrade peptoid N-terminal N-(substituted)glycine residues on the solid-phase using very mild conditions is reported. This method relies on the treatment of resin-bound, bromoacetylated peptoids with silver perchlorate in THF, leading to an intramolecular cyclization reaction to liberate the terminal residue as a N-substituted morpholine-2,5-dione, resulting in a truncated peptoid upon hydrolysis and a silver bromide byproduct. Side-chain functional group tolerance is explored and reaction kinetics are determined. In a series of pentapeptoids possessing variable, non-nucleophilic side-chains at the second position (R(2) ), we demonstrate that sequential N-terminal degradation of the first two residues proceeds in 87% and 74% conversions on average, respectively. We further demonstrate that the degradation reaction is selective for peptoids, and represents substantial progress toward a mild, iterative sequencing method for peptoid oligomers. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 726-736, 2016.


Unmasking Hypoxia in Cirrhosis Patients: Six-Minute Walk Test as a Screening Tool for Hepatopulmonary Syndrome.
Hepatopulmonary syndrome (HPS) is one of the complications of advanced cirrhosis which has a serious impact on prognosis of patient. Finding arterial deoxygenation early and initiating higher-level treatment is one of the most critical strategies in the therapy of HPS. In this study, we aimed to assess the utility of six-minute walk test (6MWT) in the diagnosis of HPS. We have enrolled 100 consecutive cirrhosis patients referred to the Liver Clinic of a tertiary care centre of India for >1 year. The Child-Pugh score and the MELD score were used to determine the severity of cirrhosis. All the patients underwent transthoracic contrast echocardiography, arterial blood gas measurements on room air, 6MWT, and chest imaging. A total of 100 patients were included in the study after fulfilling the inclusion criteria. HPS was present in 21 out of 100 patients (21%). Median (twenty fifth to seventy fifth percentile) MELD score in patients with HPS was 29 (26-33), which was significantly higher as compared to patients without HPS 22 (14.5-26); P <.0001. The 6MWT was positive in 20 (95.23%) HPS patients, while only 1 patient (4.77%) of HPS had negative 6MWT. If 6MWT is positive, then there was 76.92% probability of HPS and if 6MWT is negative, then 98.65% chances of no HPS. The 6MWT is a simple and effective screening test for HPS, it helps in identifying the patients early who have a potential to deteriorate. This simple intervention would help in prioritizing patients for liver transplantation as liver transplant is the only effective treatment for HPS.


Oxidative stress, phosphate and creatinine levels are independently associated with vascular endothelial growth factor levels in patients with chronic renal failure.
Elevated VEGF levels has been reported in patients with chronic renal failure (CRF), but the reasons for its higher level in renal insufficiency remain unknown. We assessed VEGF, SOX markers: total peroxide, Cu/Zn superoxide dismutase (Cu/Zn SOD), the levels of autoantibodies against oxidized LDL (OxLDL-Ab), and inflammation markers: high sensitivity C-reactive protein (hs CRP), interleukine-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) in 55 CRF patients and 18 controls. The patients with CRF showed a significant increase in plasma levels of VEGF, markers of inflammation, total peroxide and Cu/Zn SOD levels compared with controls. The strong positive associations were between VEGF and creatinine, urea, phosphate and CaxP product (all p<0.0001), Cu/Zn SOD (p<0.001) and hs CRP levels (p<0.01). VEGF showed a strong inverse relationship with eGFR (p<0.0001). In multiple regression analysis increased Cu/Zn SOD, phosphate and creatinine levels were found to be independent factors affecting VEGF. This study documented significant elevation in plasma values of VEGF in patients with CRF, which appears early during the progression of renal insufficiency. Increased oxidative stress, phosphate levels and impaired elimination by kidney were the main factors affecting the plasma levels of this growth factor in CRF patients.


Treatment of ameloblastoma in children.
Clinicopathological data were collected for six children with ameloblastoma less than 16 years old. They were all treated initially by conservative surgery and satisfactory results without jaw deformities were finally attained. One of the histological characteristics of ameloblastoma in children is the prevalence of the plexiform type, which is thought to behave less aggressively than the follicular type. Conservative treatment is acceptable initial treatment of ameloblastoma in children who can be followed up in a precise, detailed manner.


Replicated studies of two randomized trials of angiotensin-converting enzyme inhibitors: further empiric validation of the 'prior event rate ratio' to adjust for unmeasured confounding by indication.
Using data from the United Kingdom General Practice Research Database (GPRD) randomized controlled trials (RCTs) were replicated to determine whether identifiable study characteristics and/or analytic methods influence the validity of observational studies. This study reports GPRD replications of 2 RCTs that investigated whether angiotensin-converting enzyme inhibitors (ACEIs) improve cardiovascular outcomes in patients without congestive heart failure at high risk for cardiovascular disease (heart outcomes prevention evaluation (HOPE) and EUROPA). The GPRD studies replicated to the extent feasible all aspects of these RCTs except for randomization. With adjustment for confounders using conventional biostatistical techniques, both GPRD studies exhibited results divergent from the RCTs. Myocardial infarction, stroke, congestive heart failure, and coronary revascularization were increased in the Exposed group of both GPRD studies; whereas these outcomes either were decreased or unchanged by ACEI therapy in both RCTs. The results also were analyzed with a new method that appears to adjust for both identified and unmeasured confounders. With this methodology that employs the ratio of event rates between the Exposed and Unexposed cohorts prior to study start time to adjust the study hazard ratio (HR), the GPRD results for myocardial infarction, stroke, and coronary revascularization were largely similar to those found in the two RCTs. This study provides additional empiric evidence suggesting that this new analytic methodology, 'prior events rate ratio (PERR)' adjustment, is a promising solution for the vexing problem of 'unmeasured confounding' in observational studies. Additional statistical simulations are needed to fully appreciate the applicability and limitations of this method.


Study on the interaction between Cu phen2+3 and bovine serum albumin by spectroscopic methods.
In this work, the interaction between Cu(phen)(2+)(3) and bovine serum albumin (BSA) was investigated by fluorescence spectroscopy combined with UV-vis absorption and circular dichroism (CD) spectroscopic techniques under physiological conditions. The fluorescence data proved that the fluorescence quenching of BSA by Cu(phen)(2+)(3) was the result of the Cu(phen)(2+)(3) -BSA complex formation. The binding constants (K (a)) between Cu(phen)(2+)(3) and BSA at four different temperatures were calculated according to the modified Stern-Volmer equation. The enthalpy change (DeltaH) and entropy change (DeltaS) were calculated to be 10.74 kJ mol(-1) and 54.35 J mol(-1) K(-1), respectively, which indicated that electrostatic interactions played a major role in the formation of Cu(phen)(2+)(3) -BSA complex. The distance r between the donor (BSA) and acceptor[Cu(phen)(2+)(3)] was obtained to be 3.55 nm based on Förster's energy transfer theory. The synchronous fluorescence and CD spectroscopy results showed that the polarity of the residues increased and the lost of the alpha-helix content of BSA (from 59.84 to 53.70%). These indicated that the microenvironment and conformation of BSA were changed in the presence of Cu(phen)(2+)(3).


Report on investigation of ISO 10993-12 extraction conditions.
The international standard ISO 10993-12 describes extraction conditions for generating extracts of medical devices to be used in testing of biological safety. Questions about the adequacy of the extraction conditions (and their variations) for hazard identification drove the development and execution of a round robin study. Four relevant device materials were each evaluated by four laboratories following an established protocol that specified multiple options of extraction solvent, temperature, duration, and ratio of solvent volume to quantity of test article. The resulting samples were analysed by three instrumental methods to identify and quantify extracted organic and elemental substances; however, quantification was not achieved due to lab resource constraints, and only numbers of compounds were reported. Results showed an increased number of volatile organic compounds extracted with organic solvents; however, no clear effect of varying the other extraction parameters could be discerned. Quantification of a small subset of analytes showed sensitivity that may be adequate for hazard identification. An unplanned post hoc comparison of results across labs showed differing numbers of compounds detected; however, fundamental differences in sample preparation and specific analysis methods as well as lack of quantification render the results poorly suited to either exonerate or indict the adequacy of chemical characterization as practiced by the participating laboratories.


Agriculture-induced environmental Kuznets curve: the case of China.
This study investigates the long-run equilibrium relationship among carbon dioxide (CO2) emissions, real income, energy consumption, and agriculture, thus testing the existence of the agriculture-induced environmental Kuznets curve (EKC) hypothesis in the case of China for the period of 1971-2014. The level relationship among the variables in the conducted model is confirmed by the bounds test approach under the autoregressive distributed lag (ARDL) mechanism. Error correction model under the ARDL mechanism suggests that short-run values of CO2 emissions converge to its long-run equilibrium level by 73.8% speed of adjustment every year by the contribution of energy consumption, real income, and agriculture. ARDL estimation results suggest that real income and energy consumption have a positive, elastic impact; agricultural development has positive, inelastic impact on CO2 emissions where squared real income has a negative and inelastic impact on air pollution. Conditional Granger causality test results reveal that there are unidirectional causalities running from real income, squared real income, energy consumption, and agricultural development in long run as well as in the short run.


Nutritional deficiencies in inflammatory bowel disease: therapeutic approaches.
Malnutrition is common in inflammatory bowel diseases (IBD), mainly in Crohn's disease (CD) because the small bowel is primarily affected. We reviewed the literature to highlight the importance of proper nutrition management. A PubMed search was performed for English-language publications from 1999 through 2012. Manuscripts comparing nutritional approaches for IBD patients were selected. We identified 2025 manuscripts: six meta-analyses, 170 clinical-trials, 692 reviews. The study findings are discordant. In adult CD, enteral nutrition plays a supportive role, steroid therapy remaining the first choice treatment. In CD children enteral nutrition may represent the primary therapy. As regards parenteral nutrition, there are no large randomized studies, although mild improvements in morbidity have been described as a result of parenteral nutrition in malnourished surgical IBD patients. Specific micronutrient deficiencies are common in IBD. A number of factors may contribute to micronutrient deficiencies, and these include: dietary restriction, disease activity and surgery. The possible therapeutic roles of omega-3 fatty-acids, probiotics and prebiotics have been studied, but the results are still preliminary. Protein-energy malnutrition and micronutrient depletion are clinical concerns in IBD patients. Enteral nutrition, parenteral nutrition and micronutrient supplementation are cornerstone of the multidisciplinary management of IBD patients.


Effects of Plant Elicitors on Growth and Gypenosides Biosynthesis in Cell Culture of Giao co lam (Gynostemma pentaphyllum).
Giao co lam (Gynostemma pentaphyllum (Thunb.) Makino) is used in Northeast and Southeast Asia countries for the treatment of various diseases, including hepatitis, diabetes, and cardiovascular disease. G. pentaphyllum saponins (gypenosides) are the major components responsible for the pharmacological activities. In this study, different concentrations of abiotic (25-200 μM methyl jasmonate-MeJA and salicylic acid-SA) or biotic elicitors (1-5 g/L yeast extract-YE and Fusarium biomass) were used as plant elicitors, in order to investigate their influences on cell growth and gypenosides accumulation in G. pentaphyllum suspension cells. Suspension cells were grown on a MS medium containing 2.0 mg/L KIN and 0.5 mg/L IBA, with initial inoculum sizes of 3 g and shaking speeds of 120 rpm for 18 days. Gypenoside and Rb1 contents were measured by colorimetric and HPLC methods. Among three elicitors, SA was suitable for gypenosides accumulation in individual treatment. The cell biomass had the same values in elicitated and control suspension cells. Gypenosides content in cells treated with 100 μM salicylic acid after 6 days of culture reached a maximum value of 79.721 mg gypenoside/g dry biomass (including 0.093 mg ginsenoside Rb1/mg dry weight), which was 2.18-folds higher than that of the natural product. The elicitation promises an efficiency strategy for the production gypenosides in Gynostemma pentaphyllum suspension cells.


Disease self-management needs of adolescents with cancer: perspectives of adolescents with cancer and their parents and healthcare providers.
The ability for adolescents with cancer (AWC) to engage in disease self-management may result in improved cancer outcomes and quality-of-life ratings for this group. Despite this, a comprehensive self-management program for this group is yet to be developed. To ensure that self-management programming developed for AWC meets the needs of this group, discussion with key stakeholders (i.e., AWC, parents, and healthcare providers) is required. A descriptive qualitative design was used. Adolescents (n = 29) who varied in age (12 to 18 years) and type of cancer, their parents (n = 30) and their healthcare providers (n = 22) were recruited from one large tertiary-care oncology center. Audio-taped semi-structured individual and focus-group interviews were conducted with participants. Transcribed data were organized into categories that reflected emerging themes. Four major themes, which captured the self-management needs of AWC, emerged from the data. These themes were: (1) disease knowledge and cancer care skills, (2) knowledge and skills to support effective transition to adult healthcare, (3) delivery of AWC-accessible healthcare services, and (4) supports for the adolescent with cancer. In order to provide comprehensive, relevant, and acceptable self-management programs to AWC, the voices of this population, their parents, and healthcare providers should be considered. Findings from this study will be used to develop and evaluate cancer self-management programming for AWC. Self-management represents an important avenue for exploration into improving cancer outcomes and quality of life for survivors of cancers during adolescence.


Early Hippocampal Sharp-Wave Ripple Deficits Predict Later Learning and Memory Impairments in an Alzheimer's Disease Mouse Model.
Alzheimer's disease (AD) is characterized by progressive memory loss, and there is a pressing need to identify early pathophysiological alterations that predict subsequent memory impairment. Hippocampal sharp-wave ripples (SWRs)-electrophysiological signatures of memory reactivation in the hippocampus-are a compelling candidate for this purpose. Mouse models of AD show reductions in both SWR abundance and associated slow gamma (SG) power during aging, but these alterations have yet to be directly linked to memory impairments. In aged apolipoprotein E4 knockin (apoE4-KI) mice-a model of the major genetic risk factor for AD-we find that reduced SWR abundance and associated CA3 SG power predicted spatial memory impairments measured 1-2 months later. Importantly, SWR-associated CA3 SG power reduction in young apoE4-KI mice also predicted spatial memory deficits measured 10 months later. These results establish features of SWRs as potential functional biomarkers of memory impairment in AD.


[Fetal surgery in the head-neck area. Current status and new possibilities with the endoscope].
Fetal surgery is defined as the intrauterine surgical correction of malformations that endanger the unborn child's life in prenatal stages of development or lead to death or severe damage of the child postnatally. Such surgery is a clinical reality now. Indications for intrataurine surgical procedures also exist for head and neck abnormalities, especially in the upper respiratory tract. These include exposure and temporary obstruction of the fetal trachea for correction of pulmonary hypoplasia in cases with congenital diaphragmatic hernias, prenatal tracheotomy in cases of laryngeal atresia for the correction of lethal pulmonary overdistension, and resection of embryonic tumors that obstruct the respiratory tract. The relatively high surgical risk resulting in particular from preterm labor occurring postoperatively may be reduced by employing minimally invasive techniques. Endoscopic procedures render opening of the uterus unnecessary and are of particular importance. In part of the procedures, only endoscopic surgery has led to therapeutic success rates justifying its clinical use. Further reduction of the operative risk suggests prenatal interventions, even in cases with non-lethal conditions. More diseases of the head and neck may thus be included in the spectrum of indications. One example is prenatal correction of a cleft lip and palate, which until now has only been performed in animal experiments. The particular characteristics of fetal wound healing allow this to take place without scarring up to a certain stage in pregnancy. This offers the prospect of a surgical correction that is invisible externally and avoids growth-impeding scars. The particular ethical and legal aspects of fetal surgery are discussed.


Flesinoxan, a 5-HT1A receptor agonist/alpha 1-adrenoceptor antagonist, lowers intraocular pressure in NZW rabbits.
alpha1-Adrenoceptor antagonists and 5-HT1A receptor agonists reduce intraocular pressure (IOP) in the rabbit. The aims of this study were firstly, to determine the IOP-lowering effects of flesinoxan and selected other hybrid 5-HT1A receptor agonists/alpha1-adrenoceptor antagonists, and secondly, to investigate the mechanism of action of the IOP response to flesinoxan. IOP and total outflow facility were measured in rabbits after administration of hybrid drugs. Inositol phosphates accumulation assays were performed using standard methodologies. Topical unilateral instillation of the drugs caused dose-related reductions of IOP. Comparison of the compounds tested revealed a potency order of WB 4101 > flesinoxan > 5-methyl-urapidil > or = BMY7378 > urapidil. WB-4101 caused a small increase in total outflow facility whereas flesinoxan had no effect. Measurement of the IC50 values for inhibition of phenylephrine-stimulated inositol phosphates accumulation in rabbit iris-ciliary body revealed a potency order of WB 4101 > 5-methyl-urapidil > flesinoxan > BMY 7378 = urapidil. Topical flesinoxan was ineffective in reversing phenylephrine-induced mydriasis, yet, pretreatment with the 5-HT1A receptor antagonists MDL 73005EF and pindolol only partially blocked the hypotensive effect of topical flesinoxan. The present studies indicate the potent and efficacious IOP-lowering capabilities of flesinoxan and certain other ligands with affinity for 5-HT1A receptors/alpha1-adrenoceptors. The exact mechanisms by which these drugs lower IOP in the rabbit are complex but our results indicate that flesinoxan likely reduces aqueous secretion.


Mental health trajectories after juridical divorce: Does personality matter?
This study investigated whether the Big Five personality dimensions were associated with mental health trajectories and/or intervention effects of a digital divorce intervention from juridical divorce to 12 months following juridical divorce. The study utilized a randomized controlled trial study design (N = 676) and measured mental health outcomes (anxiety, depression, somatization, and stress) at study inclusion (i.e., at juridical divorce) and 3-, 6-, and 12 months after juridical divorce. Big Five personality dimensions were measured 1 month post study inclusion. The study found that neuroticism is the personality dimension most predictive of post-divorce mental health outcomes. Specifically, divorcees with higher neuroticism scores indicated worse mental health immediately following divorce, but their symptom levels decreased more rapidly over a 12 months period after juridical divorce compared with lower neuroticism divorcees. It is also notable that their mean scores for the mental health outcomes remained higher at all time points (3, 6, and 12 months post baseline), relative to those lower in neuroticism. Findings are discussed in light of divorce-adjustment-theory and the stress-buffering model.


Synthesis of 4'-epi-iodo-4'-deoxy-daunorubicin, a potential cancer radiotherapeutic agent.
We have prepared 4'-epi-iodo-4'-deoxy-daunorubicin (IDDNR)(1), a doxorubicin analog, via a 5-step synthesis involving a protected daunorubicin triflate derivative (4). This triflate derivative will allow the facile and regiospecific nucleophilic preparation of I-125 or Br-80 m labelled analogs of IDDNR. Auger electron-emitting I-125- or Br-80 m-labelled analogs of IDDNR may have potential as cancer radiotherapeutic agents.


[The effect of high dosage vitamin C treatment on the carbohydrate and lipid metabolism in diabetics using insulin].
In 19 insulin-dependent diabetics under compensated metabolic conditions the influence of a highly-dosed short-term vitamin C-treatment with 2,000 mg of ascorbic acid on the carbohydrate and fat metabolism was examined during a stay in hospital. Under the treatment with vitamin C low concentrations of blood glucose in the daily profile are observed, in which case this effect of ascorbic acid on the carbohydrate metabolism cannot be statistically ascertained. Triglyceride, cholesterol, FFA-concentrations and glycerol concentrations are not influenced.


In Vitro and In Vivo Assessment of Nonionic Iodinated Radiographic Molecules as Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Tumor Perfusion Agents.
The aim of this study was to evaluate 4 nonionic x-ray iodinated contrast agents (CAs), commonly used in radiographic procedures, as novel chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) agents by assessing their in vitro exchange properties and preliminary in vivo use as tumor enhancing agents. The CEST properties, as function of pH (range, 5.5-7.9) and of radio frequency conditions (irradiation field strength range of 1-9 μT and time of 1-9 seconds), have been determined at 7 T and 310 K for 4 x-ray CAs commonly used in clinical settings, namely, iomeprol, iohexol, ioversol, and iodixanol. Their in vivo properties have been investigated upon intravenous injection in a murine HER2+ breast tumor model (n = 4 mice for each CA) using both computed tomography (CT) and MRI modalities. The prototropic exchange rates measured for the 4 investigated iodinated molecules showed strong pH dependence with base catalyzed exchange rate that was faster for monomeric compounds (20-4000 Hz in the pH range of 5.5-7.9). Computed tomography quantification showed marked (up to 2 mg I/mL concentration) and prolonged accumulation (up to 30 minutes postinjection) inside tumor regions. Among the 4 agents we tested, iohexol and ioversol display good CEST contrast properties at 7 T, and in vivo results confirmed strong and prolonged contrast enhancement of the tumors, with elevated extravasation fractions (74%-91%). A strong and significant correlation was found between CT and CEST-MRI tumor-enhanced images (R = 0.70, P < 0.01). The obtained results demonstrate that iohexol and ioversol, 2 commonly used radiographic compounds, can be used as MRI perfusion agents, particularly useful when serial images acquisitions are needed to complement CT information.


Erratum: Measuring functional disability in children with developmental disorders in low-resource settings: validation of Developmental Disorders-Children Disability Assessment Schedule (DD-CDAS) in rural Pakistan.
[This corrects the article DOI: 10.1017/gmh.2020.10.].


Over-expression of EPB41L3 promotes apoptosis of human cervical carcinoma cells through PI3K/AKT signaling.
Cervical cancer is a significant malignancy of the female reproductive system. This study aimed to investigate the functions of Erythrocyte Membrane Protein Band 4.1 Like 3 (EPB41L3) in cervical cancer and to explore its underlying mechanisms. Expression of EPB41L3 in cervical cancer was analyzed by in-depth mining in The Cancer Genome Atlas (TCGA) clinical sequencing database. Patients with high expression of EPB41L3 had a good prognosis. EPB41L3 was overexpressed in HeLa and SiHa cells by a chemically synthesized lentivirus; its overexpression significantly inhibited cell proliferation, promoted apoptosis of HeLa and SiHa cells, and suppressed tumorigenesis in nude mice bearing HeLa cells. The results of microarray analysis showed that EPB41L3 overexpression led to marked gene expression changes, including 258 up-regulated genes and 168 down-regulated genes. Furthermore, EPB41L3 overexpression inhibited PI3K and AKT phosphorylation, leading to the apoptosis of cervical cancer cells. EPB41L3 overexpression inhibits cell proliferation, promotes apoptosis of cervical cancer cells, and suppresses tumorigenicity in vivo. Our findings suggest that EPB41L3 might be a new diagnostic biomarker and a therapeutic target for cervical cancer.


Synthetic green fluorescent protein chromophore analogues with a positive charge at the phenyl-like group.
Synthetic green fluorescent protein (GFP) chromophore analogues with a positive charge at the phenyl-like group have the highly electrophilic amidine carbon, smaller LUMO-HOMO energy gap, red-shifted electronic absorptions and fluorescent emissions, and accelerated E-Z thermoisomerization rates. They are water-labile and their hydrolysis results in ring-opening of the imidazolinone moiety with a half life around 25-37 h in D2O at 25 °C.


Glaucoma as a neuropathy amenable to neuroprotection and immune manipulation.
Glaucoma, once thought as a single disease, is actually a group of diseases of the optic nerve involving loss of retinal ganglion cells. The process of cell death occurs in a characteristic pattern of optic neuropathy, a broad term for a certain pattern of damage to the optic nerve (the bundle of nerve fibers that carries information from the eye to the brain). Untreated glaucoma leads to permanent damage of the optic nerve and resultant visual field loss, which can progress to blindness. Worldwide, it is estimated that about 66.8 million people have visual impairment as a result of glaucoma, with 6.7 million suffering from blindness.


Biochemical polymorphism and the 2,3-diphosphoglycerate in the sheep red blood cells.
There was no significant difference in the level of 2,3-DPG in the red blood cells of sheep of different haemoglobin types (Hb A and Hb B) or potassium types (HK and LK). However, low glutathione (GSHL) sheep had significantly higher (p less than 0.01) level of 2,3-DPG in their red blood cells than high glutathione (GSHH) sheep. There was also significant effect of interactions between glutathione, haemoglobin and potassium types (p less than 0.05) and glutathione and haemoglobin types (p less than 0.01) on red cell 2,3-DPG levels.


DNA breaks and repair in the mouse leukemia L1210 cells exposed to three different types of interstrand DNA cross-linkers.
DNA breaks and repair in mouse leukemia L1210 cells treated with 3 different types of cross-linkers, mitomycin C (MMC), 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitroso ure a hydrochloride (ACNU) and SN-07 (a macromolecular antibiotic), were studied. Measured in D37 values, MMC gave the highest number of cross-links per lethal 'hit' directly after the 1-h treatment in the alkaline elution assay, followed by ACNU and SN-07. A good dose-response increase in induced interstrand DNA cross-linking frequency was observed in cells treated with 2.5-10 micrograms/ml MMC and with 10-100 micrograms/ml ACNU for 1 h with and without 24-h post-incubation. After 6-h post-incubation, the highest frequency of cross-linking was observed in cells treated with 2.5 micrograms/ml MMC and 30 micrograms/ml ACNU, while cross-link production continued in the cells treated with SN-07 for 12-h post-incubation. No significant increase in DNA breaks was observed in cells treated with MMC throughout 24-h post-incubation. The highest frequency of single-strand DNA breaks in cells treated with ACNU was observed immediately after the treatment and they disappeared after 6-h post-incubation. After 24-h post-incubation, a marked enhancement of the DNA breaks was observed in cells treated with SN-07 and the cells contained double-strand DNA breaks also. RNA synthesis was not affected in the cells treated with 10 micrograms/ml MMC and slightly inhibited to 70% of control in those treated with 100 micrograms/ml ACNU, while DNA synthesis in both cells was significantly inhibited after 24-h post-incubation. By contrast, both RNA and DNA synthesis were completely inhibited in cells treated with 8.0 micrograms/ml SN-07.


Leiomyosarcoma of the submandibular gland. Report of a case and review of the literature.
This report describes the first case of primary leiomyosarcoma of the submandibular salivary glands and emphasizes the role of immunohistochemical study for a correct diagnosis of this tumour. In line with results of international literature, we associated surgery with radiotherapy and 2 years postoperatively there was no sign of recurrence.


HIV seroprevalence in sexually transmitted disease clients in a low-prevalence southern state. Evidence of endemic sexual transmission.
We studied human immunodeficiency virus (HIV) seroprevalence and risk factors in 3052 clients attending three large public, sexually transmitted disease (STD) clinics in central North Carolina in mid-1988. Anonymous self-administered questionnaires linked to HIV serologies obtained by testing extra blood from syphilis serologies without personal identifiers showed the following characteristics of the respondents: 60% were men, 81% were black, the median age was 24 years, 5% were injecting drug users since 1978, 7% reported a history of syphilis, and 8% of men were homosexual or bisexual. HIV seropositivity was found in 76 subjects (2.5%), including 46% of the homosexual men, 25% of the bisexual men, 1.6% of the heterosexual men, and 0.6% of the women. Elevated HIV seroprevalence rates were found in subjects with a history of or seroreactivity for syphilis (HIV-positive rate of 53% in homosexual or bisexual men, 9% in heterosexual men, 3% in women) and with histories of gonorrhea (HIV-positive rate of 37% in homosexual or bisexual men, 2.6% in heterosexual men, 1% in women), and intercourse (41% in homosexual or bisexual men, 2% in women), prostitute contact (5% in heterosexual men), and sex with casual partners (2% in women). Even a state with a low incidence of acquired immunodeficiency syndrome can include subpopulations with a high HIV seroprevalence, apparently disseminated endemically in association with bacterial STDs.


Dynamics of selected MHC class I and II molecule expression in the course of HPV positive CIN treatment with the use of human recombinant IFN-gamma.
Studies consistently reveal downregulation of major histocompatibility complex (MHC)-I molecules or/and selective loss of individual MHC-I alleles and upregulation of MHC-II molecules in the areas of cervical intraepithelial neoplasia (CIN) and in cervical cancers. In vitro studies demonstrated the interferon-gamma (IFN-gamma) potential of MHC class I and II molecule upregulation followed by increased cytolytic response against some cervical cancer cell lines. In vivo assessment of the correlation between regression/persistence state of CIN and the IFN-gamma-induced changes in both class of selected MHC molecule expression. Seventeen subjects with CIN I/CIN II associated with high-risk HPV infection underwent uniform IFN-gamma treatment (four intracervical injections over 2-day interval for a total dose of 6,000,000 IU). Immunohistochemical staining has been performed within cervical punch biopsy specimens with the use of monoclonal antibody reacting with HLA-DR, HLA-HC and HLA-Bw4, and the mean proportion of given molecules expressing keratinocytes was counted before, immediately after and 2 months after IFN-gamma treatment The analysis revealed a rapid and significant increase of the HLA-Bw4 proportion in response to IFN-gamma, persistent in the group of complete responders (with CIN clearance). No significant changes in the proportion of HLA-HC 10 positive cells in response to IFN-gamma administration was demonstrated, nor a significant increase in HLA-DR positivity; however, the transient trend towards increasing the proportion of HLA-DR immediately after treatment completion was observed. Upregulation of selected MHC class I allele expression, but not necessary MHC class II or heavy chain fragments of MHC-I, induced by IFN-gamma correlates with the resolution of cervical intraepithelial lesions and high-risk HPV DNA clearance in vivo.


[Expert Opinion Questionnaire About Chest CT Scan Using A Negative Pressure Isolation Strecher in COVID-19 Patients: Image Quality and Infection Risk].
To survey perceptions of certified physicians on the protocol of chest CT in patients with coronavirus (COVID-19) using a negative pressure isolation stretcher (NPIS). This study collected questionnaire responses from a total of 27 certified physicians who had previously performed chest CT with NPIS in COVID-19 isolation hospitals. The nine surveyed hospitals performed an average of 116 chest CT examinations with NPIS each year. Of these, an average of 24 cases (21%) were contrast chest CT. Of the 9 pulmonologists we surveyed, 5 (56%) agreed that patients who showed abnormalities in serum D-dimer required contrast chest CT. All 9 surveyed radiologists agreed that the image quality of the chest CT with NPIS was sufficient for CT image interpretation regarding pneumonia or pulmonary embolism. Furthermore, in our 9 surveyed infectionologists, 5 (56%) agreed that a risk of secondary infection in the CT room after temporary opening of NPIS could be prevented through a process of disinfection. Experienced physicians considered that the effects of NIPS on chest CT image quality was minimal in patients with COVID-19, and the risk of CT room contamination was easily controlled.


Leukocyte telomere length in healthy Caucasian and African-American adolescents: relationships with race, sex, adiposity, adipokines, and physical activity.
To examine the relationships of race, sex, adiposity, adipokines, and physical activity to telomere length in adolescents. Leukocyte telomere length (T/S ratio) was assessed cross-sectionally in 667 adolescents (aged 14-18 years; 48% African-Americans; 51% girls) using a quantitative polymerase chain reaction method. Generalized estimating equations analyses were performed. Telomere length was greater in the African-American adolescents than in the Caucasian adolescents (age- and sex-adjusted T/S ratio ± SE, 1.32 ± 0.01 vs 1.27 ± 0.01: P = .014) and greater in girls than in boys (age- and race-adjusted T/S ratio ± SE, 1.31 ± 0.01 vs 1.27 ± 0.01; P = .007). None of the adiposity or adipokine measures explained a significant proportion of the variance in telomere length. Vigorous physical activity was positively associated with telomere length (adjusted R(2) = 0.019; P = .009) and accounted for 1.9% of the total variance only in girls. This study, conducted in a biracial adolescent cohort, demonstrated that (1) race and sex differences in telomere length have already emerged during adolescence; (2) adiposity and adipokines are not associated with telomere length at this age; and (3) the antiaging effect of vigorous physical activity may begin in youth, especially in girls.


The influence of omnivorous elaterid larvae on the microbial carbon cycle in different forest soils.
Data are presented on the influence of Athous subfuscus larvae (Coleoptera, Elateridae) on the microbial carbon cycle in the biotically most active horizons of three contrasting beech forest soils: the Ah horizon of a mull soil on limestone (Göttinger Wald, FRG), the F/H horizon of a moder soil on new red sandstone (Solling area, FRG) and in the F/H horizon of a lime ameliorated area close to the second site. Gut content analyses demonstrated that the larvae of A. subfuscus are humiphagous and that this unspecific feeding behaviour is widely independent of soil conditions. Differences in 14C incorporation demonstrated that only the larvae in the F/H horizon of the limed moder soil directly affected primary decomposer organisms. However, the burrowing activity of the larvae in the topsoil indirectly modified the time course of beech leaf-litter decomposition in the litter layer of all three soils. The microflora of the mull soil contained 2.6%, that of the moder soil 0.7% and that of the limed moder soil 2.2% of total C. The metabolic quotient (qCO2, 10°C) of the soil microflora was 0.0010 (mgCO2-C·mg-1 biomass-C·h-1) in the mull soil, 0.0034 in the moder soil and 0.0012 in the limed moder soil. The A. subfuscus larvae generally reduced the size of the microbial C pool (<-30%) and increased the metabolic quotient of the microflora (>+50%). Considering these soil-independent effects of A. subfuscus on the C turnover of the soil microflora, the burrowing activity of humiphagous soil arthropods may generally increase nutrient availability to primary producers. The results of this study reveal that some of the micro- and mesoscale effects of humiphagous arthropods on the microbial carbon turnover in beech forest soils are surprisingly similar, even under very different soil conditions. The long-term modification of the time course of leaf litter decomposition, in contrast, indicates that the influence of humiphagous arthropods on the formation of the humus layer is soil-specific. There are profound differences in the role of humiphagous arthropods in limed moder soils and in naturally base-rich soils. It is concluded that liming increases competition within the microfloral population due to accelerated humification. The negative effect of A. subfuscus on 14C mineralization in the limed substrate could thus be explained by its effects on a microflora that was strongly limited by the availability of carbon.


Inositol 1,4,5-trisphosphate 3-kinase A is a novel microtubule-associated protein: PKA-dependent phosphoregulation of microtubule binding affinity.
Inositol 1,4,5-trisphosphate 3-kinase A (IP(3)K-A) is a brain specific and F-actin-binding protein. We recently demonstrated that IP(3)K-A modulates a structural reorganization of dendritic spines through F-actin remodeling, which is required for synaptic plasticity and memory formation in brain. However, detailed functions of IP(3)K-A and its regulatory mechanisms involved in the neuronal cytoskeletal dynamics still remain unknown. In the present study, we identified tubulin as a candidate of IP(3)K-A-binding protein through proteomic screening. By various in vitro and in vivo approaches, we demonstrated that IP(3)K-A was a novel microtubule-associated protein (MAP), and the N terminus of IP(3)K-A was a critical region for direct binding to tubulin in dendritic shaft of hippocampal neurons. Moreover, PKA phosphorylated Ser-119 within IP(3)K-A, leading to a significant reduction of microtubule binding affinity. These results suggest that PKA-dependent phosphorylation and microtubule binding of IP(3)K-A are involved in its regulatory mechanism for activity-dependent neuronal events such as local calcium signaling and its synaptic targeting.


The TEACL method of DNA-DNA hybridization: technical considerations.
This paper emanated from a conference concerning the value, accuracy, and technical considerations of DNA-DNA hybridization for evolutionary studies. Our laboratory has been performing the so-called TEACL (tetraethylammonium chloride) method, and we have amassed sufficient data to indicate that this method is very powerful if performed properly with correct analyses. Here we address five technical considerations: (1) We present empirical data that size correction for tracer length is legitimate and accurate. (2) We show that the error of delta Tm measurement does not significantly increase with increasing distance up to at least 10 degrees C. (3) The error distribution for delta Tm does not deviate from the expected normal distribution indicating parametric statistics are probably legitimate for analyses. (4) Using a known phylogeny we examined the resolving power of the technique by showing that at least five taxa can be correctly placed in phylogenies with a maximum delta Tm of 2.5 degrees C. (5) To date, all our data sets based on DNA-DNA hybridization are very robust with respect to analytical procedures in that every algorithm used on the data sets has yielded identical trees with nearly identical branch lengths. Nevertheless, we point out that theoretical analyses of distance data (as generated by DNA-DNA hybridization) are lacking, especially with regard to tests of the molecular clock hypothesis.


Bio-Inspired Supramolecular Chemistry Provides Highly Concentrated Dispersions of Carbon Nanotubes in Polythiophene.
In this paper we report the first observation, through X-ray diffraction, of noncovalent uracil-uracil (U-U) dimeric π-stacking interactions in carbon nanotube (CNT)-based supramolecular assemblies. The directionally oriented morphology determined using atomic force microscopy revealed highly organized behavior through π-stacking of U moieties in a U-functionalized CNT derivative (CNT-U). We developed a dispersion system to investigate the bio-inspired interactions between an adenine (A)-terminated poly(3-adeninehexyl thiophene) (PAT) and CNT-U. These hybrid CNT-U/PAT materials interacted through π-stacking and multiple hydrogen bonding between the U moieties of CNT-U and the A moieties of PAT. Most importantly, the U···A multiple hydrogen bonding interactions between CNT-U and PAT enhanced the dispersion of CNT-U in a high-polarity solvent (DMSO). The morphology of these hybrids, determined using transmission electron microscopy, featured grape-like PAT bundles wrapped around the CNT-U surface; this tight connection was responsible for the enhanced dispersion of CNT-U in DMSO.


NIH stumbles on 'pass the harasser'.
Agency allowed transfer of grants and handed new money to David Gilbert, despite "severe" behavior.


Low circulating Dickkopf-1 and its link with severity of spinal involvement in diffuse idiopathic skeletal hyperostosis.
Dickkopf-1 (DKK-1) is an inhibitor of osteoblastogenesis, and its lower levels are linked to new bone formation. The aim of this study was therefore to explore serum levels of DKK-1 and to evaluate DKK-1's association with the severity of spinal involvement in diffuse idiopathic skeletal hyperostosis (DISH). Serum levels of total and functional DKK-1 and C-reactive protein (CRP) were measured in 37 patients with DISH and 22 healthy age and sex-matched controls. Plain radiographs of the cervical and thoracic spine were performed, and the diagnosis of DISH was defined using the Resnick criteria. Patients were divided into three groups based on spinal involvement. Bone mineral density (BMD) and bone turnover markers were evaluated in patients with DISH. The levels of total serum DKK-1 were significantly lower in patients with DISH than in healthy controls (p<0.0001). Importantly, low serum levels of DKK-1 were associated with more severe spinal involvement in DISH, independent of age, sex, disease duration, CRP, bone turnover markers or BMD. However, these findings were less significant for functional DKK-1. These observations indicate that DKK-1 may play a significant role in bone formation during DISH.


Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes Cockayne syndrome, xeroderma pigmentosum, and Fanconi anemia.
Cockayne syndrome (CS) is a genetic disorder characterized by developmental abnormalities and photodermatosis resulting from the lack of transcription-coupled nucleotide excision repair, which is responsible for the removal of photodamage from actively transcribed genes. To date, all identified causative mutations for CS have been in the two known CS-associated genes, ERCC8 (CSA) and ERCC6 (CSB). For the rare combined xeroderma pigmentosum (XP) and CS phenotype, all identified mutations are in three of the XP-associated genes, ERCC3 (XPB), ERCC2 (XPD), and ERCC5 (XPG). In a previous report, we identified several CS cases who did not have mutations in any of these genes. In this paper, we describe three CS individuals deficient in ERCC1 or ERCC4 (XPF). Remarkably, one of these individuals with XP complementation group F (XP-F) had clinical features of three different DNA-repair disorders--CS, XP, and Fanconi anemia (FA). Our results, together with those from Bogliolo et al., who describe XPF alterations resulting in FA alone, indicate a multifunctional role for XPF.


Oxidative stress and life span determination in the nematode Caenorhabditis elegans.
The free radical theory of aging proposes that oxidative stress is one of the determinants of an organism's life span. In Caenorhabditis elegans, genetic or environmental changes have been shown to modulate life span. Here we discuss whether changes in the generation and destruction of free radicals are implicated in these life span modulations. Changes in culture oxygen concentrations that are considered to reflect free radical generation perturb the life span. The life spans under high and low oxygen concentrations were shorter and longer, respectively, than those under normoxic conditions. Short-term exposure to high oxygen concentration lengthens the life span. This is considered to be the result of an increase in antioxidant defense induced by short-term oxidative stress. Mutations in genes such as age-1 and daf-2 that compose the insulin-like signaling network conferred oxidative stress resistance and an increase in Mn-SOD gene expression as well as life span extension.


Diagnosis of pancreatic solid pseudopapillary neoplasms using cell-blocks and immunohistochemical evaluation of endoscopic ultrasound-guided fine needle aspiration biopsy specimens.
Preoperative diagnostic imaging of pancreatic solid pseudopapillary neoplasms (SPNs) is challenging. A few studies have investigated the role of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for the diagnosis of SPN. We investigated the diagnostic yield of cell-blocks and immunohistochemistry (IHC) for SPN using EUS-FNA specimens without cytological evaluation. We retrospectively analysed the histopathology records of patients with suspected SPN, who underwent EUS-FNA biopsy between January 1997 and January 2020. Diagnosis based on cell-blocks (haematoxylin-eosin staining with complementary IHC) was compared with the definitive surgical diagnosis. This study included 25 patients (24 were women). Patients' mean age was 33.7 years (range 12-78 years). The most common symptom was abdominal pain. SPN was an incidental finding in 52% of the patients. The mean lesion size was 4.3 cm (range 1.2-11.4 cm), and the most common endosonographic features included solid-cystic (56%) or solid (40%) tumours. Final diagnoses included SPNs (n = 23) and non-functioning neuroendocrine tumours (n = 2). The overall accuracy of EUS-FNA was 80%. Tumour cells showed immunopositivity for β-catenin, CD10, CD99 and progesterone receptor (PR) in 93.7%, 87.5%, 83.3% and 66.6% of patients, respectively. No SPN showed immunopositivity for chromogranin A. Intention-to-diagnose analysis showed that the diagnostic accuracy of EUS-FNA for SPNs using cell blocks and complementary IHC without cytological evaluation was fairly good. Evaluation of β-catenin, CD 10, CD99 and PR expression must be included in the IHC panel for diagnostic confirmation of SPNs using EUS-FNA biopsy specimens.


Biological roles of A-to-I editing: implications in innate immunity, cell death, and cancer immunotherapy.
Adenosine-to-inosine (A-to-I) editing, a key RNA modification widely found in eukaryotes, is catalyzed by adenosine deaminases acting on RNA (ADARs). Such RNA editing destabilizes endogenous dsRNAs, which are subsequently recognized by the sensors of innate immune and other proteins as autologous dsRNAs. This prevents the activation of innate immunity and type I interferon-mediated responses, thereby reducing the downstream cell death induced by the activation of the innate immune sensing system. ADARs-mediated editing can also occur in mRNAs and non-coding RNAs (ncRNAs) in different species. In mRNAs, A-to-I editing may lead to missense mutations and the selective splicing of coding regions. Meanwhile, in ncRNAs, A-to-I editing may affect targeting and disrupt ncRNAs maturation, leading to anomalous cell proliferation, invasion, and responses to immunotherapy. This review highlights the biological functions of A-to-I editing, its role in regulating innate immunity and cell death, and its potential molecular significance in tumorigenesis and cancer targeted therapy and immunotherapy.


Genome-wide meta-analysis revealed several genetic loci associated with serum uric acid levels in Korean population: an analysis of Korea Biobank data.
The serum uric acid (SUA) level is an important determinant of gout, hypertension, metabolic syndrome, and cardiovascular disease. Although previous genome-wide studies have identified multiple genetic variants associated with SUA, most genetic analyses have focused on individuals with European ancestry; thus, understanding of the genetic architecture of SUA is currently limited for Asian populations. We conducted a genome-wide meta-analysis based on Korea Biobank data consistent with three cohorts; namely, the Korean Genome and Epidemiology Study (KoGES) Ansan and Ansung, KoGES Health Examinee, and KoGES Cardiovascular Disease Association studies. In total, 60,585 participants aged ≥40 years were included in the analysis of the three cohorts. We used logistic regression analyses to perform genome-wide association study (GWAS) adjustments for confounding variables. Subsequently, a meta-analysis was conducted by combining the analyses of the three GWASs. We identified 8,105 variants at 22 genetic loci with a P value < 5 × 10-8. Among these, six novel genetic loci associated with SUA in the Korean population were identified (rs4715517 in HCRTR2, rs145099458 in 3.2 kb 3' of MLXIPL, rs1137642 in B4GALT1, rs659107 in LOC105378410, rs7919329 in LOC107984274, and rs2240751 in MFSD12). Our meta-analysis provides insights into the genetic architecture of SUA in the Korean population. Further studies are warranted to replicate the study results and elucidate the specific role of these variants in SUA homeostasis.


Tracking Restoration of Park and Urban Street Settings in Coronary Artery Disease Patients.
The physiological effects of natural and urban environments on the cardiovascular system of coronary artery disease (CAD) patients are not fully understood. This controlled field study examines the effects of restorative walking in a park vs. in an urban street environment on CAD patients' stress parameters and cardiac function. Twenty stable CAD patients were randomly allocated to 7 days controlled walking in a city park or in an urban street environment group. The relationship between different environmental exposures and health effects was analyzed using Wilcoxon signed-rank test and exact Mann-Whitney U test. The mean reduction in cortisol levels and negative effects after the walk on the first day was greater in the city park than in the urban street exposed group, while a reduction in negative effects in the urban group were greater after seven days. The reduction in diastolic blood pressure (DBP) in the park group was evident on the seventh day before the walk (-4 mm Hg, p = 0.031) and 60 min after the walk (-6.00 mm Hg, p = 0.002). The cortisol slope was negatively associated with the DBP changes (r = -0.514, p < 0.05). Physical activity in a green environment with noise and air pollution levels lower than in an urban environment has a greater positive effect on CAD patients' stress level and hemodynamic parameters. Mitigating green environmental influences may allow urban residents to maintain health and reduce disability.


Alternative respiratory oxidases to study the animal electron transport chain.
Oxidative phosphorylation is a common process to most organisms in which the main function is to generate an electrochemical gradient across the inner mitochondrial membrane (IMM) and to make energy available to the cell. However, plants, many fungi and some animals maintain non-energy conserving oxidases which serve as a bypass to coupled respiration. Namely, the alternative NADH:ubiquinone oxidoreductase NDI1, present in the complex I (CI)-lacking Saccharomyces cerevisiae, and the alternative oxidase, ubiquinol:oxygen oxidoreductase AOX, present in many organisms across different kingdoms. In the last few years, these alternative oxidases have been used to dissect previously indivisible processes in bioenergetics and have helped to discover, understand, and corroborate important processes in mitochondria. Here, we review how the use of alternative oxidases have contributed to the knowledge in CI stability, bioenergetics, redox biology, and the implications of their use in current and future research.


BCL2 and miR-15/16: from gene discovery to treatment.
In 1984, we investigated the t(14;18) chromosomal translocations that frequently occur in patients with follicular lymphoma. We first identified a locus on chromosome 18 involved in these translocations with the chromosome 14 containing the immunoglobulin heavy chain locus. Within this region on chromosome 18, we then discovered a gene that we called BCL2, which was activated by the translocations. Since that time, many studies determined that BCL2 is one of the most important oncogenes involved in cancer by inhibiting apoptosis. In 2002, we studied 13q deletions in chronic lymphocytic leukemia (CLL) and found that the microRNA cluster miR-15a/miR-16-1 (miR-15/16) is deleted by 13q deletions. In 2005, we discovered that miR-15/16 function as tumor suppressors by directly targeting BCL2. Thus the loss of two negative regulators of BCL2 expression results in overexpression of BCL2. Very recently, a specific BCL2 inhibitor ABT-199 (Venetoclax) was developed and approved by FDA for CLL treatment. Thus it took 32 years from fundamental discovery of a critical oncogene to the development of a drug capable to cure CLL. In this review, we discuss the discovery, functions and clinical relevance of miR-15/16 and BCL2.


Platelet-derived growth factor-induced signaling pathways interconnect to regulate the temporal pattern of Erk1/2 phosphorylation.
The biological outcome of Erk1/2 activation is specified by the duration and magnitude of its phosphorylation, as well as its subcellular localization. In the present study, we investigated how the cross-talk between signaling pathways induced by platelet-derived growth factor receptor β (PDGFRβ) regulates the temporal pattern of Erk1/2 activation. We demonstrated that Src kinase activity was necessary for rapid Erk1/2 phosphorylation in PDGF-BB-stimulated cells. A delay in the onset of Erk1/2 activation was also observed upon phospholipase C (PLC) inhibition; this effect was found to be mediated by protein kinase C (PKC). In addition, we observed that both the PI3K pathway and RasGAP negatively regulated the strength of Erk1/2 phosphorylation. In contrast, interfering with SHP2 binding to PDGFRβ did not affect the pattern of Erk1/2 activation. Interestingly, changes in the kinetics and amplitude of Erk1/2 activation were transmitted to the transcriptional level and affected c-fos expression. In conclusion, cross-talk with other PDGFRβ-induced signaling pathways is important for fine-tuning of the pattern of Erk1/2 activation.


Bleomycin in the treatment of recalcitrant warts.
Bleomycin is gaining increasing popularity in the treatment of warts, but its efficacy has not been examined in well-controlled studies. We evaluated bleomycin in a double-blind placebo-controlled crossover study in recalcitrant warts treated unsuccessfully by conventional methods. Patients were assigned alternately to placebo or bleomycin groups and treated by intralesional injections of bleomycin, 1 U/ml, or saline, at 2-week intervals. If warts persisted, patients were changed after two injections to the alternate group and retreated with up to two further injections. Forty patients entered the study. Of 151 warts treated with intralesional bleomycin, 123 were cured after one or two injections (81%). The cure rate for plantar warts (60%) was lower than that for periungual warts (94%) and warts elsewhere on the extremities (95%). Fifty-five warts were injected with normal saline; none was cured. Responding warts showed a hemorrhagic eschar and healed without scarring, atrophy, or pigmentary change. Pain was usually mild and patient acceptance superior to that with liquid nitrogen. There was no evidence of systemic toxicity. Bleomycin is highly efficacious in the treatment of recalcitrant warts, is convenient, and has high patient acceptance. Long-term safety requires further study.


Measurement of water-holding capacity in fermented milk using near-infrared spectroscopy combined with chemometric methods.
We investigated the use of near-infrared spectroscopy (NIR) for measuring water-holding capacity (WHC) in fermented milk. Increased WHC ensures improved texture and decreased syneresis in fermented dairy products and also improves cheese yield. NIR combined with partial least-squares-discriminant analysis (PLS-DA) was found to be a promising rapid and non-invasive method with no pretreatment of the samples for prediction of WHC in fermented milk samples. Analysis of the chemical bonds in the region 10 700-4500 cm-1 (935-2200 nm) of the electromagnetic spectrum was able to distinguish between samples with high vs. low WHC. This technique was successfully used to screen different strains of lactic acid bacteria for their ability to provide fermented milk with increased WHC, which is of great importance for use in various dairy products.


Congenital complete heart block and long Q-T syndrome requiring ventricular pacing for control of refractory ventricular tachycardia and fibrillation.
A three-year-old girl with congenital complete heart block presented with repeated bouts of ventricular tachycardia and ventricular fibrillation. The ECG was remarkable for both complete heart block and a long Q-T interval, when corrected for rate. The Q-T interval was longer than the Q-T interval of children with congenital complete heart block and of children without heart disease. Overdrive ventricular pacing was necessary to control the arrhythmias. A prolonged Q-T interval in patients with complete heart block, even in the presence of a normal QRS duration, may predispose the patient to sudden death. Permanent pacing can suppress these arrhythmias by overdriving.


Plasma Levels of Alanine Aminotransferase in the First Trimester Identify High Risk Chinese Women for Gestational Diabetes.
Alanine aminotransferase (ALT) predicts type 2 diabetes but it is uncertain whether it also predicts gestational diabetes mellitus (GDM). We recruited 17359 Chinese women with ALT measured in their first trimester. At 24-28 weeks of gestation, all women underwent a 50-gram 1-hour glucose challenge test (GCT) followed by a 75-gram 2-hour oral glucose tolerance test if GCT result was ≥7.8 mmol/L. Restricted cubic spline analysis was used to examine full-range risk associations of ALT levels with GDM. Relative excess risk due to interaction, attributable proportion due to interaction and synergy index were used to estimate additive interaction between high ALT and overweight/obesity for GDM. Finally, 1332 (7.7%) women had GDM. ALT levels were positively associated with GDM risk without a clear threshold. Using ALT levels <22 U/L as the referent, the middle ALT levels (≥22 to <40 U/L) [odds ratio (OR) (95% confidence intervals): 1.41(1.21-1.65)] and high ALT levels (≥40 U/L) [1.62 (1.31-2.00)] were associated with increased GDM risk. Maternal overweight/obesity greatly enhanced the OR of ALT ≥22 U/L from 1.44 (1.23-1.69) to 3.46 (2.79-4.29) with significant additive interactions. In conclusion, elevated ALT levels in the first trimester even within normal range predicted GDM risk, further enhanced by overweight/obesity.


Response of myocardial metabolites to graded regional ischemia: 31P NMR spectroscopy of porcine myocardium in vivo.
The changes in myocardial high energy phosphates and pH during regional ischemia, and their potential role in mediating functional abnormalities, is unclear. To determine the degree of regional blood flow reduction required to induce changes in high energy phosphates and pH, and to correlate these metabolic changes with alterations in blood flow, 31P nuclear magnetic resonance spectroscopy was employed in an in vivo porcine model of graded coronary stenosis. Simultaneous measurements of regional blood flow and phosphate compounds were made during various steady-state degrees of regional ischemia in which subendocardial blood flow was reduced by as much as 80%. ATP did not fall over the total range of graded ischemia, while phosphocreatine (PCr), inorganic phosphate (Pi), and pH all changed progressively after blood flow was reduced below 50% of normal. The ratio of PCr/Pi (a measure of the energy reserve of the myocardium) was strongly correlated to subendocardial blood flow (r = 0.94) and declined by 25% when blood flow was reduced by only 21% below normal. These findings indicate that PCr/Pi is a sensitive marker of ischemia and support the hypothesis that the in vivo energy status of the myocardium is closely coupled to myocardial blood flow.


Enhanced Photoluminescent Properties and Crystalline Morphology of LiBaPO₄:Tm3+ Phosphor through Microwave Sintering Method.
An investigation of the photoluminescent properties and crystalline morphology of blue emitting LiBa1-xPO4:xTm3+ phosphors with various concentrations (x = 0.005-0.030) of Tm3+ ions were synthesized by microwave sintering. For comparison, the LiBa1-xPO4:xTm3+ powders sintered at the same sintering condition but in a conventional furnace were also investigated. LiBaPO₄ without second phase was formed no matter which furnace was used. More uniform grain size distributions are obtained by microwave sintering. When the concentration of Tm3+ ion was x = 0.015, the luminescence intensity reached a maximum value, and then decreased with the increases of the Tm3+ concentration due to concentration quenching effect. The microwave sintering significantly enhanced the emission intensity of LiBa1-xPO4:xTm3+ phosphors. Additionally, the d-d interaction is the key mechanism of concentration quenching for LiBaPO₄:Tm3+. The chromaticity (x, y) for all LiBa1-xPO₄:xTm3+ phosphors are located at (0.16, 0.05), which will be classified as a blue region.


Systematic symptom screening in patients with advanced cancer treated in certified oncology centers: results of the prospective multicenter German KeSBa project.
Guidelines recommend a structured symptom screening (SC) for especially advanced cancer patients (CPs). The aim of this multicenter German prospective quality assurance project KeSBa (Kennzahl Symptom- und Belastungserfassung) was to gain knowledge on SC procedures in Oncology Centers (OCs) for advanced cancer patients and a first impression on the consequences of SC. The KeSBa project consisted of three phases: pilot, 3 months screening and feedback phase. Participating OCs decided to use either the Minimal Documentation System (MIDOS) or the Integrated Palliative care Outcome Scale (IPOS) and defined the cutoff values for positive screening results. Out of 172 certified German OCs, 40 (23%) participated in the KeSBa pilot phase, 29 (16.8%) in the 3 months screening phase using MIDOS (n = 18, 58.6%) or IPOS (n = 11, 41.3%) and in the feedback round. 25/29 performed paper-based screening (86.2%). 2.963 CPs were screened. Results were documented for 1255 (42.2%, SC +) positive and 874 (29.5%, SC-) negative screenings depending on the center´s schedules: 452 SC + CPs (28.4%) and 42 SC- CPs (2.6%) had contact to specialized palliative care or other supportive specialist teams afterwards, 458 SC + CPs (28.8%) and 605 SC- CPs (38.1%) remained in standard oncology care. In the feedback round missing resources (personal and IT) and improved communication were mentioned most often. Routine SC is feasible in advanced CPs treated in OCs but associated with considerable workload. In 42.2% of CPs SC was classified as positive, indicating the need of further diagnostics or professional judgment. SC requires staff and IT resources.


Purification of the major cysteine proteinase (cruzipain) from Trypanosoma cruzi by affinity chromatography.
The major cysteine proteinase from Trypanosoma cruzi, cruzipain, can be obtained essentially homogeneous, starting from crude epimastigote extracts, in one step, by affinity chromatography on Cystatin-Sepharose (specific for cysteine proteinases) or ConA-Sepharose (specific for high mannose N-linked glycoproteins). The methods offer considerable potential for enzyme purification from scarce sources, such as other parasite stages or radioactively labelled material with high specific radioactivity.