Association between Neurodegeneration and Macular Perfusion in the Progression of Diabetic Retinopathy: A 3-Year Longitudinal Study.
The aim of this study was to explore the relation between retinal neurodegenerative changes and vessel closure (VC) in individuals with nonproliferative diabetic retinopathy (NPDR) in a follow-up period of 3 years. This is a 3-year prospective longitudinal study with four annual visits. This study involved 74 individuals with type 2 diabetes, NPDR, and Early Treatment Diabetic Retinopathy Study grades from 10 to 47, one eye/person. An age-matched healthy control population of 84 eyes was used as control group. Participants were annually examined by color fundus photography, spectral domain-optical coherence tomography (SD-OCT) and OCT-angiography (OCTA). VC was assessed by OCTA vessel density maps. SD-OCT segmentations were performed to access central retinal thickness (CRT) and retinal neurodegeneration considered as thinning of the ganglion cell plus inner plexiform layer (GCL + IPL). Type 2 diabetic individuals presented significantly higher CRT (p = 0.001), GCL + IPL thinning (p = 0.042), and decreased vessel density at the superficial capillary plexus (p < 0.001) and full retina (FR) (p = 0.001). When looking at changes occurring over the 3-year period of follow-up (Table 2), there were statistically significant decreases in GCL + IPL thickness (-0.438 μm/year; p = 0.038), foveal avascular zone circularity (-0.009; p = 0.047), and vessel density in superficial capillary plexus (-0.172 mm-1/year; p < 0.001), deep capillary plexus (DCP) (-0.350 mm-1/year; p < 0.001), and FR (-0.182 mm-1/year; p < 0.001). A statistically significant association was identified between GCL + IPL thinning and decrease in DCP vessel density (β = 0.196 [95% confidence interval: 0.037, 0.355], z = 2.410, p = 0.016), after controlling for age, gender, diabetes duration, hemoglobin A1c level, and CRT. Retinal neurodegenerative changes show a steady progression during a 3-year period of follow-up in eyes with NPDR and appear to be directly associated with progression in decreased vessel density including vascular closure through preferential involvement of the DCP. Our findings provide evidence that retinal neuropathy is linked with microvascular changes occurring in diabetic patients.


Prognostic value of plasma N-terminal pro B-type natriuretic peptide levels in pneumonia patients requiring intensive care unit admission.
Correct and early risk stratification for critically ill pneumonia patients remains an unmet medical need. This study aimed to test whether N-terminal pro B-type natriuretic peptide (NT-proBNP) can serve as a prognostic marker in this setting. This prospective study enrolled 216 pneumonia patients admitted to intensive care unit. Plasma NT-proBNP samples were obtained upon admission and primary outcome was all-cause mortality at 30 days. Meanwhile, Acute Physiology and Chronic Health Evaluation (APACHE) II and Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) 2007 minor criteria were assessed. Overall 30-day mortality was 30%. NT-proBNP levels were significantly higher in nonsurvivors than survivors (11 938 ± 13 121 vs 5658 ± 9240 pg/mL, P = 0.001). Area under receiver operating characteristic curves of NT-proBNP, APACHE II and IDSA/ATS 2007 minor criteria were not significantly different regarding prediction of mortality (0.715, 0.754 vs 0.654, P = 0.085). Adding NT-proBNP to APACHE II significantly increased the area under receiver operating characteristic curve from 0.754 to 0.794 (P = 0.048). Receiver operating characteristic analysis revealed optimal NT-proBNP and APACHE II cut-offs of 2177.5 pg/mL and 25.5, respectively. In multivariate analysis, both NT-proBNP and APACHE II values above cut-offs had a significantly higher probability of death than those below cut-offs. A categorical approach combining NT-proBNP and APACHE II cut-offs provides additional risk stratification over a single marker approach. For pneumonia patients admitted to intensive care unit, NT-proBNP strongly and independently predicts mortality, and its prognostic accuracy is comparable with APACHE II and IDSA/ATS 2007 minor criteria.


Contrary influence of clinically applied sorafenib concentrations among hepatocellular carcinoma patients.
The treatment responses of sorafenib in hepatocellular carcinoma are modest which may be due to different characteristics of cancer cells or insufficient therapeutic concentrations. This study was to clarify this issue. The anti-proliferative effects and differential expressions of 8 genes related to sorafenib anti-cancer mechanisms (tyrosine kinase receptor genes: KDR, PDGFRB; RAF cascade: RAF1, BRAF, MAP2K1, MAP2K2, MAPK1, MAPK3) were investigated in primary cultured hepatocellular carcinoma cells collected from 8 patients using clinically applied sorafenib concentrations (5, 10μg/mL). The anti-proliferative effects of sorafenib at either 5 or 10μg/mL, which were related to down-regulations of KDR, PDGFRB and/or genes in the RAF cascade, were achieved only in one patient (HCC38/KMUH). However, either 5 or 10μg/mL sorafenib promoted proliferation in 4 patients (HCC29/KMUH, HCC62/KMUH, HCC87/KMUH, HCC98/KMUH). Among them, the RAF cascade, PDGFRB and/or KDR were up-regulated in 3 patients but no gene was differentially expressed in the remaining one patient (HCC87/KMUH). Increase the sorafenib concentration to 10μg/mL paradoxically up-regulated and/or obliterated the previously down-regulated genes in the RAF cascade and/or KDR in 4 patients (HCC29/KMUH, HCC76/KMUH, HCC87/KMUH, HCC98/KMUH). Significant down-regulations of the RAF cascade and PDGFRB by sorafenib but without anti-proliferative effects were detected in one patient (HCC54/KMUH). In conclusion, influence of sorafenib on proliferation is not simply through the RAF cascade. The responses of KDR, PDGFRB and the RAF cascade to sorafenib among patients are diverse or even contrary. Increase the sorafenib concentration has potential to up-regulate genes favored angiogenesis and proliferation.


Comparison of insulin degludec with insulin glargine in insulin-naive subjects with Type 2 diabetes: a 2-year randomized, treat-to-target trial.
The aim of this study was to compare long-term safety and efficacy of the basal insulin analogue degludec with glargine in insulin-naive subjects with Type 2 diabetes. This open-label trial included a 52-week core period followed by a 52-week extension. Participants were randomized 3:1 to once-daily degludec or glargine, administered with metformin ± dipeptidyl peptidase-4 inhibitors. Basal insulin was titrated to target pre-breakfast plasma glucose 3.9-4.9 mmol/l. At end of treatment (104 weeks), mean HbA1c reductions were similar for degludec and glargine; estimated treatment difference between degludec and glargine was 1 mmol/mol (95% CI -1 to 3) [0.07% (95% CI -0.07 to 0.22)], P = 0.339 in the extension trial set (degludec 551, glargine 174), comprising subjects who completed core trial and continued into the extension trial. Overall confirmed hypoglycaemia rates (1.72 vs. 2.05 episodes/patient-year), rates of adverse events possibly or probably related to trial product (0.19 events/patient-year), weight gain (2.7 vs. 2.4 kg) and mean daily insulin doses (0.63 U/kg) were similar between treatments in the safety analysis set (degludec 766, glargine 257) comprising all treated subjects. Rates of nocturnal confirmed hypoglycaemia (0.27 vs. 0.46 episodes/patient-year; P = 0.002) and severe hypoglycaemia (0.006 vs. 0.021 episodes/patient-year, P = 0.023) were significantly lower with degludec for the safety analysis set (analysis based on intention-to-treat full analysis set comprising all randomized subjects). In Type 2 diabetes, insulin degludec in combination with oral anti-diabetic drugs, safely and effectively improves long-term glycaemic control, with a significantly lower risk of nocturnal hypoglycaemia as compared with glargine.


Tubular secretion and metabolism of dopamine, norepinephrine, methoxytyramine and normetanephrine by the rat kidney.
The fate of catecholamines released in rat kidneys was examined by microinjecting tritiated norepinephrine (NE), normetanephrine (NMN), dopamine (D) and 3-methoxytyramine (3MT) into proximal and distal tubule lumina and peritubular capillaries. [14C] Inulin included in the injectate served as a reference standard. After injection of NE, D, NMN and 3MT at 0.1 to 4.0 pg/min for 4 to 10 min into proximal tubules, 87 to 94% was recovered in the urine of the injected kidney. Less than 10% of the amines was chemically altered during passage through the nephron. After injection into capillaries, percentages secreted in the first passage through the kidney were: D, 25 +/- 5; 3MT, 47 +/- 3; NE, 13 +/- 2; and NMN, 4 +/- 3. After D capillary injections, excretion of 3MT and D from the microinjected was twice that from the contralateral kidney. Acidic metabolites, homovanillic acid and dihydroxyphenylacetic acid were excreted equally by both kidneys. There was no appreciable difference in the products excreted from left and right kidneys after NE injections. In summary, D released into the peritubular space is converted to 3MT and both compounds are secreted avidly. NE released into the peritubular circulation is converted to NMN and both compounds are secreted but to a much smaller extent than occurs with D and 3MT.


Book lung development in the embryo, postembryo and first instar of the cobweb spider, Parasteatoda tepidariorum C. L Koch, 1841 (Araneomorphae, Theridiidae).
Light and electron microscopy were used to compare spider book lung development with earlier studies of the development of horseshoe crab book gills and scorpion book lungs. Histological studies at the beginning of the 20th century provided evidence that spider and scorpion book lungs begin with outgrowth of a few primary lamellae (respiratory furrows, saccules) from the posterior surface of opisthosomal limb buds, reminiscent of the formation of book gills in the horseshoe crab. In spider embryos, light micrographs herein also show small primary lamellae formed at the posterior surface of opisthosomal limb buds. Later, more prominent primary lamellae extend into each book lung sinus from the inner wall of the book lung operculum formed from the limb bud. It appears most primary lamellae continue developing and become part of later book lungs, but there is variation in the rate and sequence of development. Electron micrographs show the process of air channel formation from parallel rows of precursor cells: mode I (cord hollowing), release of secretory vesicles into the extracellular space and mode II (cell hollowing), alignment and fusion of intracellular vesicles. Cell death (cavitation) is much less common but occurs in some places. Results herein support the early 20th century hypotheses that 1) book lungs are derived from book gills and 2) book lungs are an early step in the evolution of spider tracheae.


A case-control study in Taiwanese cohort and meta-analysis of serum ferritin in pancreatic cancer.
Pancreatic cancer is one of the most lethal diseases which lack an early diagnostic marker. We investigated whether serum ferritin (SF) reflects risk for pancreatic cancer and potential genes that may contribute ferritin and pancreatic cancer risks. We performed a meta-analysis of relevant studies on SF and pancreatic cancer risk by searching articles in PUBMED and EMBASE published up to 1 March 2020. We also collected serum samples from Taipei Medical University Joint Biobank and compared SF levels in 34 healthy controls and 34 pancreatic cancer patients. An Oncomine database was applied as a platform to explore a series of genes that exhibited strong associations between ferritin and pancreatic cancer. Herein, we show that high levels of SF can indicate risk of pancreatic cancer, suggesting SF as the new tumor marker that may be used to help pancreatic cancer diagnosis. We also found that expressions of iron homeostasis genes (MYC, FXN) and ferroptosis genes (ALOX15, CBS, FDFT1, LPCAT3, RPL8, TP53, TTC35) are significantly altered with pancreatic tumor grades, which may contribute to differential expression of ferritin related to pancreatic cancer prognosis.


Benign intramucosal melanocytic proliferation a marker for primary malignant melanoma of rectum.
Benign melanocytic proliferation in the mucosal glands of rectum is described in a 56 year old female with primary melanoma of rectum.


Pediatric olfactory home testing using regular household items: A cross-over validation study.
To develop an olfactory test that can be conducted by an untrained person using common household items and to introduce a German version of the Chemosensory Pleasure Scale for Children (CPS-C(de)). This olfactory home test was developed in phases including evaluation of odors for suitability in a home setting. Parents of 50 children (ages 6-17) were then equipped with instruction manuals and participants were tested twice in a cross-over design. A validated pediatric olfactory test (the Universal Sniff test (U-Sniff)) served as the comparative gold standard. Additionally, a Chinese-English-German "back-and-forth" translation was conducted to establish the CPS-C(de) and was tested for empirical validity. Fourteen items were tested for feasibility, and all were identified on a sufficient rate (≥66%, mean ± SD of 93.3% ± 9.5%). Bland Altman Plot analysis between home testing and the U-Sniff test was nearly identical (bias = 0.04). CPS-C(de) showed similar results to the original Chinese version and a moderate correlation was found between CPS-C(de) scores and Body Mass Index of children (r30 = -0.527, p = 0.003). Remote olfactory testing in children using household items is feasible. The CPS-C(de) may be of value for future olfactory studies.


Patients' Views About the Disclosure of Collateral Findings in Pragmatic Clinical Trials: a Focus Group Study.
Pragmatic clinical trials (PCTs) are increasingly being conducted to efficiently generate evidence to inform healthcare decision-making. Despite their growing acceptance, PCTs may involve a variety of ethical issues, including the management of pragmatic clinical trial-collateral findings (PCT-CFs), that is, information that emerges in PCTs that is unrelated to the primary research questions but may have implications for patients, clinicians, and health systems. We sought to understand patients' views about PCT-CF disclosure, including how, by whom, and the nature and extent of information provided. Prospective, qualitative focus group study. Focus groups were conducted in Baltimore, MD; Houston, TX; and Seattle, WA (overall N = 66), during July and August 2019. All groups discussed a hypothetical scenario involving the detection of a PCT-CF of contraindicated medications. Participants were asked about their reactions to the PCT-CF and issues related to its disclosure. Reactions to learning about the PCT-CF were mixed, ranging from fear of a significant health problem, anger that the contraindicated medications had gone unnoticed and/or for being included in research without their permission, to gratitude for the information. Preferences for how such disclosures are made varied but were driven by several consistent desires, namely minimizing patient harm and anxiety and demonstrating trust and respect. Many wanted their treating clinician to be informed of the PCT-CF so that they would be prepared to answer patients' questions and to discuss treatment options. The detection of PCT-CFs is likely to increase with further expansion of PCTs. As such, clinicians will undoubtedly become involved in the management of PCT-CFs. Our data illustrate some of the challenges clinicians may face when their patients are informed of a PCT-CF and the need to develop guidance for disclosing PCT-CFs in ways that align with patients' preferences and values.


Role of water structure in alkaline water electrolysis.
Herein, with the help of experimental and first-principles density functional theory (DFT)-based studies, we have shown that structural changes in the water coordination in electrolytes having high alkalinity can be a possible reason for the reduced catalytic activity of platinum (Pt) in high pH. Studies with polycrystalline Pt electrodes indicate that electrocatalytic HER activity reduces in terms of high overpotential required, high Tafel slope, and high charge transfer resistances in concentrated aqueous alkaline electrolytes (say 6 M KOH) in comparison to that in low alkaline electrolytes (say 0.1 M KOH), irrespective of the counter cations (Na+, K+, or Rb+) present. The changes in the water structure of bulk electrolytes as well as that in electrode-electrolyte interface are studied. The results are compared with DFT-based analysis, and the study can pave new directions in studying the HER process in terms of the water structure near the electrode-electrolyte interface.


Identifying a high risk cardiovascular phenotype by carotid MRI-depicted intraplaque hemorrhage.
Intraplaque hemorrhage (IPH), a component of late-stage complicated plaque, identified within carotid endarterectomy surgical specimens has been recently demonstrated to predict cardiovascular (CV) events. MRI is able to depict carotid IPH. We investigated the ability of carotid MR-depicted IPH (MR-IPH) to identify high-risk CV patients. From January 2008 to April 2011, 216 patients (mean age, 67.5 years; range 31-100) referred for neurovascular MRI at an academic tertiary care centre, underwent 3T carotid MRI with adjunct 3D high-spatial-resolution coronal imaging to detect MR-IPH. Five experienced neuroradiologists made a binary decision on the presence or absence of MR-IPH. Patients' charts were reviewed blindly for demographic and CV outcomes data. Of the patients with and without MR-IPH, 62.5 % (15/24) and 19.8 % (38/192) had a composite CV event (defined as a past myocardial infarction, coronary intervention (i.e., angioplasty, stenting or bypass graft) and/or peripheral vascular disease), respectively. The odds ratio (OR) of a composite CV event in the MR-IPH group was 6.75 (Bivariable analysis, 95 % CI 2.75-16.6, p < 0.0001) and 3.25 (Multivariable regression analysis, 1.14-9.37, p = 0.028). MR-IPH had the highest OR of a prior CV event compared to other variables including age, sex, hypertension and stenosis. The OR of individual CV events was also significant: MI (3.35, 95 % CI 2.11-14.2, p < 0.01), coronary stenting (26.4, 95 % CI 8.80-79.4, p < 0.01), coronary angioplasty (21, 95 % CI 4.84-91.1, p < 0.01), and PVD (3.35, 95 % CI 1.09-10.3, p < 0.05). MR-IPH is independently associated with prior CV events in patients who are evaluated for neurovascular disease. Carotid MR-IPH, employed easily in routine clinical practice, is emerging as an indicator of systemic vascular disease and may potentially be a useful surrogate marker of CV risk including in those already undergoing neurovascular imaging.


Discovery of a pyrrole-pyridinimidazole derivative as novel SIRT6 inhibitor for sensitizing pancreatic cancer to gemcitabine.
Pancreatic cancer is a highly aggressive cancer, and is primarily treated with gemcitabine, with increasing resistance. SIRT6 as a member of sirtuin family plays important roles in lifespan and diverse diseases, such as cancer, diabetes, inflammation and neurodegenerative diseases. Considering the role of SIRT6 in the cytoprotective effect, it might be a potential anticancer drug target, and is associated with resistance to anticancer therapy. However, very few SIRT6 inhibitors have been reported. Here, we reported the discovery of a pyrrole-pyridinimidazole derivative, 8a, as a new non-competitive SIRT6 inhibitor, and studied its roles and mechanisms in the antitumor activity and sensitization of pancreatic cancer to gemcitabine. Firstly, we found a potent SIRT6 inhibitor compound 8a by virtual screening and identified by molecular and cellular SIRT6 activity assays. 8a could effectively inhibit SIRT6 deacetylation activity with IC50 values of 7.46 ± 0.79 μM in FLUOR DE LYS assay, and 8a significantly increased the acetylation levels of H3 in cells. Then, we found that 8a could inhibit the cell proliferation and induce cell apoptosis in pancreatic cancer cells. We further demonstrate that 8a sensitize pancreatic cancer cells to gemcitabine via reversing the activation of PI3K/AKT/mTOR and ERK signaling pathways induced by gemcitabine and blocking the DNA damage repair pathway. Moreover, combination of 8a and gemcitabine induces cooperative antitumor activity in pancreatic cancer xenograft model in vivo. Overall, we demonstrate that 8a, a novel SIRT6 inhibitor, could be a promising potential drug candidate for pancreatic cancer treatment.


Mapping of cingulate motor function by cortical stimulation.
An 8-year-old boy with intractable left mesiofrontal lobe epilepsy underwent placement of stereotactic intracerebral depth electrodes to better localise the epileptogenic zone. Co-registration of preoperative MRI and post-electrode implantation CAT allowed for anatomical localisation of electrode contacts. Electrical stimulation of electrodes over the dorsal and ventral banks of the cingulate cortex on the left produced right foot dorsiflexion and right wrist and elbow flexion, respectively, demonstrating detailed representation of cingulate motor function in humans, somatotopically distributed along the banks of the cingulate sulcus, as seen in the non-human primate. [Published with video sequences].


Impact of the first wave of COVID-19 pandemic on the Hungarian university students' social and health behaviour.
The COVID-19 pandemic brought quick, severe and unexpected changes to our everyday life and also changed the traditional education pattern of Semmelweis University in the middle of academic year 2019-2020. We explored adaptive changes in Hungarian students' behaviour and their time-budget in order to determine whether quarantine and/or fear of infection were responsible for these changes. A self-administered online questionnaire was distributed to all students in the Hungarian language program (N = 7436) of Semmelweis University. Information was collected on basic demographic data, knowledge and attitude about COVID-19, methods of prevention as well as the students' behaviour before, during and after the first wave of the pandemic. Statistical analyses were processed using the IBM-SPSS 25.0 software package. The overall response rate was 11% (N = 816). Only complete responses were processed (55%, N = 447). Among these responders, 83% did not fear the pandemic. Those who greatly feared COVID-19 infection strictly kept all regulations. The number of non-smokers increased by the end of the first wave. The nutrition of 100 students (21%) became healthier and the lockdown reduced the level of physical activity. Social and health-related behaviour of medical students changed basically during the first wave of the pandemic and some changes remained after it in tobacco smoking, nutrition and sleeping habits. Time-budget of students changed significantly during the pandemic and did not return to the baseline values. Results of this study justify future multiple systematic research to analyse and better understand the short- and long-term effects of the current crisis.


Morphology study of zinc anode prepared by electroplating method for rechargeable Zn-MnO2 battery.
Zinc electrodes prepared by electrodepositing zinc on a copper plate in ZnSO4 electrolyte were studied to determine the most suitable condition of zinc anode preparation for high performance Zn-MnO2 battery. Deposition of zinc on substrate material was confirmed using X-ray diffraction (XRD) measurement. Morphological characterization of zinc anode was performed by scanning electron microscopy (SEM). It was observed that concentration of electrolyte and electrical current density influenced the morphology of zinc electrode. At 1 M ZnSO4 and current density values of 0.06-0.1 A/cm2, it was found that the morphological structure of zinc electrode was orderly arranged in a layer-by-layer structure. This indicated that the current density played an important role on deposition morphology and even on the crystal structure. Performance of electrodes was tested by a battery analyzer for 100 cycles. The results of the tests showed that the electrode with the layer-by-layer morphology yielded a high efficiency of up to 99.97% which was higher and more stable than those of the electrodes with disordered and scattered morphology. The layer-by-layer morphology is therefore a key factor for improving the performance of Zn-MnO2 cell.


Maternal hair dye use and risk of neuroblastoma in offspring.
Studies have suggested an association between maternal hair dye use and elevated risk of childhood cancer, including neuroblastoma. We analyzed data from a large case-control study to investigate the relationship between maternal hair dye use around pregnancy and risk of neuroblastoma in offspring. Cases were children with neuroblastoma diagnosed between 1992 and 1994 at hospitals in the United States and Canada participating in the Children's Cancer Group or the Pediatric Oncology Group. Random-digit dialing was used to identify one matched control for each case. Information on hair dye use was gathered from telephone interviews of 538 case and 504 control mothers. Use of any hair dye in the month before and/or during pregnancy was associated with a moderately increased risk of neuroblastoma (adjusted odds ratio (OR) = 1.6; 95% confidence interval (CI) = 1.2-2.2). Temporary hair dye use (OR = 2.0, CI = 1.1-3.7) was more strongly associated with neuroblastoma than use of permanent hair dye (OR = 1.4, CI = 1.0-2.0). Although the results of this study provide evidence of an association between maternal hair dye use and neuroblastoma, further research is necessary to evaluate effects by method of hair dye application, color, and chemical composition.


Structural Diversity of Six Coordination Polymers Based on the Designed X-Shaped Ligand 1,1,1,1-Tetrakis[(3-pyridiniourea)methyl]methane.
In this study, six coordination polymers (CPs), {[Ag₂(L)(CF₃SO₃)]·CF₃SO₃·2H₂O·DMF}n (1), {[Ag(L)]·SbF₆·4DMF·H₂O}n (2), {[Zn(L)0.5(I)₂]·3.75H₂O}n (3), {[Cd₂(L)(I)₄(H₂O)(DMF)]·4H₂O·3DMF}n (4), {[Hg₂(L)(I)₄]·H₂O·4DMF}n (5) and {[Hg₂(L)(Cl)₄]·2H₂O·3DMF}n (6), were obtained based on the designed X-shaped urea-based ligand. X-ray single crystal diffraction analysis revealed that complex 1 displayed a 3D (3,4)-connected {6·8²}{6⁴·8²}-tcj net. Complex 2 featured a 2D 4-connected {4³·6³} sheet. Complexes 3 and 5 exhibited a 1D polymeric loop chain. Complex 4 displayed a 1D polymeric fishbone chain. Complex 6 showed a 2D 4-connected {4⁴·6²}-sql sheet. Structural comparison revealed that not only the metal ions, but also the anions played crucial roles in the control of final structures.


Feasibility and Acceptability of Using FirstPlay® to Enhance Mother-Child Interaction: A pilot study of mothers' perspectives.
Although there is evidence that human touch facilitates mother-child bonding, mothers' understanding of how to connect with and develop the emotional regulation of their babies remains unclear. This study used a Storytelling Massage program to investigate mothers' experience of practicing reciprocal interactions with their children. Specifically, it explored the efficacy of multi-sensory activities for building healthy parent-child bonds. Participants included 12 mothers with children between 8 and 23 months. These mothers participated in a 6-session program on FirstPlay Infant Storytelling-Massage Intervention (FirstPlay Therapy) and attended an individual semi-structured interview after the program. Data were analyzed using a phenomenological approach. The FirstPlay program positively affected the participants' self-efficacy in parent-child bonding and parenting beliefs. Five themes were identified: "bonding with the child-connect and engage," "attending to the child's uniqueness and needs," "developing a structure and a daily routine," "feeling calm and relaxed as a person," and "gaining confidence as a mom." The results of this study further support the need for low-cost, high-impact programs that enhance parent-child interactions. Limitations of this study are discussed. Future research and practical implications are also suggested.


Ready vascular permeability of a near-infrared fluorescent agent ASP5354 for intraoperative ureteral identification enables imaging of carcinoma tissues.
This study investigates the ability of a near-infrared fluorescence (NIRF) imaging agent, ASP5354, for in vivo fluorescence imaging of esophageal squamous cell carcinoma (ESCC) tissues. The ability of ASP5354 was evaluated using a single dose of ASP5354 or indocyanine green (ICG), which was intravenously administered to a KYSE850 human ESCC xenograft mouse model. Subsequently, in vivo NIRF images of the mouse were obtained using a clinically available camera system. ASP5354-specific NIRF signals were strongly detectable in KYSE850 carcinoma tissues immediately (30 s) following ASP5354 administration compared with normal tissues. Meanwhile, ICG could not distinguish between normal and carcinomatous tissues. To elucidate the associated imaging mechanisms, the vascular permeability of ASP5354 and ICG was investigated in rat back dermis treated with saline or histamine, which enhances vascular permeability, using in vivo NIRF imaging. ASP5354 exhibited higher vascular permeability in histamine-treated skin than in normal skin. KYSE850 carcinoma tissues can be distinguished from normal tissues based on the measurement of ASP5354-specific NIRF signals, and the mechanism that enables imaging relies on the specific and rapid leakage of ASP5354 from the capillaries into the stroma of carcinoma tissues.


BCAR1 expression improves prediction of biochemical reccurence after radical prostatectomy.
Because prostate cancer exhibits a great variability in clinical outcome, biomarkers that can be used in daily practice are needed to better stratify patients into prognostic groups. Since steroid hormones play a central role in the development and progression of prostate cancer, we aimed to analyze in a matched nested case-control study the value of molecules involved in steroid signaling, to predict recurrence after radical prostatectomy, independently from standard prognostic tools. Among 1,200 patients treated by radical prostatectomy with negative margins with at least 4 years follow-up, 121 prostate cancers with biochemical relapse were matched after pathological reassessment with 121 cancers with identical clinicopathological features but without relapse. Immunohistochemistry was performed on tissue microarrays, using antibodies directed against molecules involved in androgen and estrogen signaling, including hormone receptors, enzymes (such as the five alpha reductases 1,2 and 3, aromatase, alpha-keto reductase 1C3 and squalene epoxidase), the breast cancer antiestrogen resistance 1 (BCAR1), and the proliferation marker Ki67. The median follow-up for patients without recurrence was 7 years. Both cell proliferation and BCAR1 expression were significantly associated with biochemical relapse, in univariate and multivariate analysis. In subgroup analysis, the sole predictive marker in patients with well-differentiated prostate cancer was BCAR1 (P = 0.004), whereas only proliferation (P = 0.001) was significantly associated with relapse in less-differentiated prostate cancer patients. BCAR1 is an independent predictor of recurrence after radical prostatectomy for "low risk" prostate cancer. The use of this biomarker may enable more individualized treatment approaches.


Impairment of conflict processing in alexithymic individuals.
Alexithymia is characterized by difficulties in identifying and describing feelings and in distinguishing between feelings and bodily sensations. Several researchers have examined the impairment of executive functioning in alexithymia; however, only a few studies have been specifically concerned with conflict processing in alexithymia. Utilizing the attention network test (ANT), we investigated whether alexithymia is related to or independent of executive function, especially with respect to conflict processing. Participants included 33 subjects with high alexithymia scores on the 20-item Toronto Alexithymia Scale (TAS-20) and 30 matched subjects with low alexithymia scores. On the ANT, we found a significant difference between the two groups in conflict processing, and no significant difference in alerting and orienting dimensions. These findings suggested that subjects with high alexithymia scores have selective impairment in conflict processing.


The prognosis of invasive ductal carcinoma, lobular carcinoma and mixed ductal and lobular carcinoma according to molecular subtypes of the breast.
To investigate the prognosis of females with invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), and mixed invasive ductal and lobular carcinoma (IDLC) according to hormone receptor (HR) and HER2 status. Data of 171,881 patients from the SEER database were analyzed. Propensity score matching was used to balance the covariates. Breast cancer-specific survival (BCSS) and overall survival (OS) of IDC, ILC, and IDLC were investigated. Patients with ILC were older, had lower tumor grade, higher tumor stage, larger tumor size, more nodal metastasis, higher estrogen receptor(+), lower HER2(-), and less likely to receive partial mastectomy and chemotherapy compared with IDC and IDLC. ILC and IDLC showed better prognosis than IDC after matching by Kaplan-Meier curves. Multivariate Cox regression showed better OS of ILC and IDLC compared with IDC with hazard ratio and a 95% confidence interval of 0.84 (0.77-0.90) and 0.91 (0.83-1.00), respectively. For HR(+)HER2(-) subgroup, ILC showed better OS than IDC; IDC showed worse BCSS and OS than IDLC. For HR(+)HER2(+); ILC showed better OS compared with IDLC; there were no survival differences of IDC, ILC, and IDLC for HER2(+). For HR(-)HER2(-), ILC and IDC showed better BCSS and OS compared with IDLC by multivariate analysis. The prognoses of female patients with IDC, ILC or IDLC were associated with the molecular subtypes of breast carcinoma. Management decisions should be based on pathological types and molecular subtypes.


Effects of cerebellar transcranial magnetic stimulation on ataxias: A randomized trial.
Cerebellar ataxia remains a neurological symptom orphan of treatment interventions, despite being prevalent and incapacitating. We aimed to study, in a double-blind design, whether cerebellar modulation could improve ataxia. We included patients with diagnosis of spinocerebellar ataxia type 3, multiple systems atrophy cerebellar type, or post-lesion ataxia. Patients received five sessions each of sham and active cerebellar 1 Hz deep repetitive transcranial magnetic stimulation in randomized order. Our primary outcome was the decrease in the Scale for the Assessment and Rating of Ataxia when comparing phases (active x sham). Secondary outcomes measures included the International Cooperative Ataxia Rating Scale, and other motor, cognitive, and quality of life scales. This study was registered at clinicaltrials.gov (protocol NCT03213106). Twenty-four patients aged 29-74 years were included in our trial. After active stimulation, the Scale for the Assessment and Rating of Ataxia score was significantly lower than the score after sham stimulation [median (interquartile range) of 10.2 (6.2, 16.2) versus 12.8 (9.6, 17.8); p = 0.002]. The International Cooperative Ataxia Rating Scale score also improved after active stimulation versus sham [median (interquartile range) of 29.0 (21.0, 43.5) versus 32.8 (22.0, 47.0); p = 0.005]. Other secondary outcomes were not significantly modified by stimulation. No patient presented severe side effects, and nine presented mild and self-limited symptoms. Our protocol was safe and well-tolerated. These findings suggest that cerebellar modulation may improve ataxic symptom and provide reassurance about safety for clinical practice.


Complement-fixing antibodies against denatured HLA and MICA antigens are associated with antibody mediated rejection.
We have found antibodies against denatured HLA class I antigens in the serum of allograft recipients which were not significantly associated with graft failure. It is unknown whether transplant recipients also have denatured HLA class II and MICA antibodies. The effects of denatured HLA class I, class II, and MICA antibodies on long-term graft outcome were further investigated based on their ability to fix complement c1q. In this 4-year retrospective cohort study, post-transplant sera from 975 kidney transplant recipients were tested for antibodies against denatured HLA/MICA antigens and these antibodies were further classified based on their ability to fix c1q. Thirty percent of patients had antibodies against denatured HLA class I, II, or MICA antigens. Among them, 8.5% and 21.5% of all patients had c1q-fixing and non c1q-fixing antibodies respectively. There was no significant difference on graft survival between patients with or without antibodies against denatured HLA/MICA. However, when these antibodies were further classified according to their ability to fix c1q, patients with c1q-fixing antibodies had a significantly lower graft survival rate than patients without antibodies or patients with non c1q-fixing antibodies (p=0.008). In 169 patients who lost renal grafts, 44% of them had c1q-fixing antibodies against denatured HLA/MICA antigens, which was significantly higher than that in patients with functioning renal transplants (25%, p<0.0001). C1q-fixing antibodies were more significantly associated with graft failure caused by AMR (72.73%) or mixed AMR/CMR (61.9%) as compared to failure due to CMR (35.3%) or other causes (39.2%) (p=0.026). Transplant recipients had antibodies against denatured HLA class I, II, and MICA antigens. However, only c1q-fixing antibodies were associated with graft failure which was related to antibody mediated rejection.


Management of distal extrusion of penile prosthesis: partial disassembly and tip reinforcement by double breasting or grafting.
Distal erosion and perforation of penile prosthesis have been reported in association with neurologic impairment, diabetes mellitus, and following irradiation for prostatic cancer. Once perforation occurs, reimplantation carries a higher risk of reperforation unless adequate preventive measures are taken. Aim. This is a description of a procedure whereby the point of perforation was exposed and repaired to restore distal support. In three patients with distal extrusion of penile prosthesis through the urethra, the glans was mobilized off the tip of the corpus cavernosum and the caverno-urethral fistula was disconnected from the corpus cavernosum. The fistula was sealed by primary sutures. The perforation on the corpus cavernosum side was sealed by double breasting in two cases and by grafting in one case. Prosthesis was reimplanted. Complications, recurrence of erosion, and postoperative coital pain. No complications, recurrence, or persistent pain occurred in any of the three cases. The management of the distal extrusion of penile prosthesis by partial disassembly, double breasting, or grafting may provide reliable distal support and thereby avoid reperforation and repeated extrusion.


Diketonylpyridinium Cations as a Support of New Ionic Liquid Crystals and Ion-Conductive Materials: Analysis of Counter-Ion Effects.
Ionic liquid crystals (ILCs) allow the combination of the high ionic conductivity of ionic liquids (ILs) with the supramolecular organization of liquid crystals (LCs). ILCs salts were obtained by the assembly of long-chained diketonylpyridinium cations of the type [HOOR(n)pyH]⁺ and BF₄-, ReO₄-, NO₃-, CF₃SO₃-, CuCl₄2- counter-ions. We have studied the thermal behavior of five series of compounds by differential scanning calorimetry (DSC) and hot stage polarized light optical microscopy (POM). All materials show thermotropic mesomorphism as well as crystalline polymorphism. X-ray diffraction of the [HOOR(12)pyH][ReO₄] crystal reveals a layered structure with alternating polar and apolar sublayers. The mesophases also exhibit a lamellar arrangement detected by variable temperature powder X-ray diffraction. The CuCl₄2- salts exhibit the best LC properties followed by the ReO₄- ones due to low melting temperature and wide range of existence. The conductivity was probed for the mesophases in one species each from the ReO₄-, and CuCl₄2- families, and for the solid phase in one of the non-mesomorphic Cl- salts. The highest ionic conductivity was found for the smectic mesophase of the ReO₄- containing salt, whereas the solid phases of all salts were dominated by electronic contributions. The ionic conductivity may be favored by the mesophase lamellar structure.


Roles of Protein Disulfide Isomerase in Breast Cancer.
Protein disulfide isomerase (PDI) is the endoplasmic reticulum (ER)'s most abundant and essential enzyme and serves as the primary catalyst for protein folding. Due to its apparent role in supporting the rapid proliferation of cancer cells, the selective blockade of PDI results in apoptosis through sustained activation of UPR pathways. The functions of PDI, especially in cancers, have been extensively studied over a decade, and recent research has explored the use of PDI inhibitors in the treatment of cancers but with focus areas of other cancers, such as brain or ovarian cancer. In this review, we discuss the roles of PDI members in breast cancer and PDI inhibitors used in breast cancer research. Additionally, a few PDI members may be suggested as potential molecular targets for highly metastatic breast cancers, such as TNBC, that require more attention in future research.


Mathematical model to predict COVID-19 mortality rate.
Covid-19 is a highly contagious viral infection that has recently become a pandemic. Since the beginning of the pandemic, the disease has affected millions of people and taken many people's lives. The purpose of this paper is to predict and compare the number of cases and mortality rate due to Covid-19 every quarter in 2020 and 2021 in three countries: Iran, the United States, and South Korea. The data of this study include the mortality rate of different countries of the world due to Covid-19, which has been approved by the World Health Organization (WHO). In this paper, to develop the mathematical model for mortality rate prediction, the data of the countries of Iran, the United States, and South Korea during the last two years from March 1, 2020, to March 1, 2022, have been used. In addition, the mortality trend was modeled using the MATLAB software toolbox version 2022b. During modeling, six methods including Fourier, Interpolant, Gaussian, Polynomial, Sum of Sine, and Smoothing Spline were implemented. Root Mean square error (RMSE) and final prediction error were used to evaluate the performance of these proposed methods. As a result of the analysis, it was shown that the Smoothing Spline model with the lowest error rate was capable of accurately evaluating and predicting Covid-19 incidence and mortality rate. Using RMSE, a prediction of the Covid-19 mortality rate for three countries is 3.76498 × 10-5. The values of R-Square and Adj R-sq were 1 in all the experiments, which indicates the full compliance of the prediction model. Using the proposed method, the incidence rate and mortality rate can be properly assessed and compared with each other in three countries. This provides a better view of the progression of the coronavirus outbreak in spring, summer, autumn, and winter. By using the proposed method, governments will be able to prevent disease and alert people to follow health guidelines more closely, thereby reducing infection numbers and mortality rates.


Thyroglossal duct cyst carcinoma with concurrent thyroid carcinoma: a case report.
Thyroglossal duct carcinoma is a very rare finding and its presentation is similar to that of a benign cyst, which is a relatively common developmental abnormality that may manifest as a midline, neck mass. In general the diagnosis of thyroglossal duct carcinoma is based on the pathologic examination of the mass, but needle aspiration cytology, ultrasound and computed tomography play a role in the differential diagnosis of malignancy. A further case of thyroglossal duct carcinoma and concurrent thyroid carcinoma with locoregional lymph node metastases affecting a 40-year-old woman followed up for 4 years is presented and discussed. Sistrunk's surgical technique must always be the initial treatment, but in case of carcinoma further surgery, that is, thyroidectomy with or without lymph node dissection, and treatment with radioactive iodine have to be considered according to the microscopic and clinical findings. Accurate pre-operative clinical and radiological evaluation should be performed in order to plan surgical strategy.


Hydroxychloroquine.
The only antimalarial drug approved by the Food and Drug Administration for the treatment of lupus erythematosus is hydroxychloroquine (Plaquenil) sulfate. The dosage recommended officially for this disease is vague. Retinopathy has been caused by hydroxychloroquine but not in less than six months, nor when a total dosage of less than 72 gm or a daily dose of 200 mg or less is used. The ocular risk depends on the dose/weight ratio and is almost negligible at a dosage of less than 6 mg/kg/day. At a dosage of 400 mg or more daily, the risk/benefit ratio is acceptable for a person of average weight, provided that ophthalmologic monitoring is adequate. Risk of retinal toxicity is then proportional to duration of therapy and consequent cumulative dose. Ophthalmoscopic examinations at six-month intervals should be sufficient to detect occasional adverse reactions. Such tests could be conducted by the attending physician directly, as long as no pre-existing ocular abnormality exists.


Surgical Residency Training at a University-Based Academic Medical Center.
The past two decades have been witness to some of the most dynamic changes that have occurred in surgical education in all of its history. Political policies, social revolution, and the competing priorities of a new generation of surgical trainees are defining the needs of modern training paradigms. Although the university-based academic program's tripartite mission of clinical service, research, and education has remained steadfast, the mechanisms for achieving success in this mission necessitate adaptation and innovation. The resource-rich learning environment and the unique challenges that face university-based programs contribute to its ability to generate the future leaders of the surgical workforce.


The psychological and behavioral considerations of orthognathic surgery on identical (monozygotic) twins.
The psychologic and behavioral changes that may occur with the impact of orthognathic surgery on the physical appearance of an identical twin set have been addressed. This unique situation has not been discussed in the literature with respect to reconstructive or cosmetic facial surgery. A report on elective orthognathic surgery performed on identical twins and the subsequent impact on the twin relationship due to alterations of "self-image phenomenon" is given. Such an impact was a consideration in this case. Further collective study in this area is needed but is difficult to obtain because of the rarity of occurrence of this type of case.


Clinical associations of immature breathing in preterm infants: part 1-central apnea.
Apnea of prematurity (AOP) is nearly universal among very preterm infants, but neither the apnea burden nor its clinical associations have been systematically studied in a large consecutive cohort. We analyzed continuous bedside monitor chest impedance and electrocardiographic waveforms and oxygen saturation data collected on all neonatal intensive care unit (NICU) patients <35 wk gestation from 2009 to 2014 (n = 1,211; >50 infant-years of data). Apneas, with bradycardia and desaturation (ABDs), defined as central apnea ≥10 s associated with both bradycardia <100 bpm and oxygen desaturation <80%, were identified using a validated automated algorithm. Number and duration of apnea events decreased with increasing gestational age (GA) and postmenstrual age (PMA). ABDs were more frequent in infants <31 wk GA at birth but were not more frequent in those with severe retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), or severe intraventricular hemorrhage (IVH) after accounting for GA. In the day before diagnosis of late-onset septicemia and necrotizing enterocolitis, ABD events were increased in some infants. Many infants continued to experience short ABD events in the week prior to discharge home. Frequency of apnea events is a function of GA and PMA in infants born preterm, and increased apnea is associated with acute but not with chronic pathologic conditions.


Prediction model for prolonged hospitalization following cesarean delivery.
A rise in the rate of cesarean delivery (CD) has been found to be associated with a higher length of hospital stay, making it a public health concern. We aimed to evaluate risk factors for prolonged hospitalization following CD. A retrospective cohort study, in a single tertiary medical center, was conducted (2011-2019). Cesarean deliveries were categorized into three groups according to the postpartum length of stay (a) up to 3 days (the routine post cesarean hospital stay in our center, reference group) (b) 4-9 days, and (c) 10 days or above (prolonged hospitalization). Risk factors were examined using univariate analysis as well as multivariate logistic regression. A specific risk prediction score was developed to predict the need for prolonged hospitalization and ROC curve was assessed utilizing the performance of our model. Overall, 87,424 deliveries occurred during the study period. Of them, 19,732 (22.5%) were cesarean deliveries. Hospitalization period was distributed as follows: 10,971 (55.6%) women were hospitalized for up to 3 days, 7,576 (38.4%) stayed for 4-9 days and 1,185 (6%) had a prolonged hospitalization period (≥10 days). Using multivariate analysis, multiple pregnancy (OR = 1.29, 95%CI 1.05-1.58), preterm delivery < 37 weeks (OR = 8.32, 95%CI 6.7-10.2), Apgar score < 7 (OR = 1.41, 95%CI 1.11-1.78) and non-elective CD (OR = 1.44, 95%CI 1.15-1.8) were identified as independent risk factors for prolonged hospitalization. Antenatal thrombocytopenia (PLT < 100 K) was found to be a protective factor (OR = 0.51, 95%CI 0.28-0.92). Our score model included antenatal risk factors and was found to be predicting the outcome, with an AUC of 0.845 (95%CI 0.83-0.86, p-value < 0.001). A prediction score model for prolonged hospitalization after CD may be beneficial for risk assessment and post-partum management.


Developmental changes of gene expression in heme metabolic enzymes in rat placenta.
Transcription levels of the non-specific delta-aminolevulinate synthase (ALAS-N) and heme oxygenase-1 (HO-1) in the placenta at the terminal stage of pregnancy were comparable to those in the female adult liver and in the spleen, respectively. Immunohistochemical studies demonstrated that both enzymes were exclusively expressed in the trophoblast. During gestation, transcript of ALAS-N slightly increased, while HO-1 mRNA significantly decreased. Induced acute fetal hypoxia resulted in an increase in ALAS-N mRNA and in a decrease in HO-1 mRNA. These findings indicate that placental heme metabolism is influenced by the oxygen supply.


[Indications for fine-needle aspiration and core needle biopsy for diagnosis of salivary gland tumors].
Salivary gland malignancies are rare neoplasms of the head and neck area. Preoperative clinical and imaging assessment of salivary gland masses is challenging. However, preoperative identification of malignancy is crucial for further treatment and for the course of the disease. This article presents the advantages and disadvantages of fine-needle aspiration cytology (FNAC) and core needle biopsy (CNB). Additionally, the sensitivity and specificity of both methods for predicting malignancy were analyzed. Furthermore, it is discussed which procedure is suitable for the diagnostic work-up of salivary gland tumors. This current article summarizes important and recent studies in the field of the diagnostic work-up for salivary gland lesions, with discussion of original articles, metanalyses, and systematic reviews concerning FNAC and CNB. The sensitivity and specificity of the predictive ability of FNAC for malignancy is described at between 70.0-80.0% and 87.5-97.9%. The pooled sensitivity and specificity for CNB were 92.0-98.0% and 95.0-100.0%, respectively. Tumor cell seeding or facial nerve palsy are very rare complications of both procedures. If malignancy is suspected based on clinical examination or imaging, FNAC or CNB should be performed. FNAC is easy to perform; however, an onsite cytologist is necessary. CNB has a higher sensitivity for routine diagnosis of malignancy; tumor typing and grading is facilitated by preserving the histological architecture. In conclusion, CNB is the procedure of choice in the diagnostic work-up for suspected malignant salivary gland tumors.


Risk factors for bronchiolitis obliterans: a systematic review of recent publications.
Obliterative bronchiolitis remains the major limitation to long-term survival after lung transplantation. A thorough understanding of the factors that confer high risk of developing obliterative bronchiolitis or its physiologic surrogate bronchiolitis obliterans syndrome is important to help define therapeutic strategies. We performed a systematic review of studies published since the beginning of 1990. The review excluded non-human studies, publications before 1990, small (less than 25 patients) studies that were predominantly concerned with investigating the pathogenesis of obliterative bronchiolitis, studies solely concerned with diagnosis or treatment of obliterative bronchiolitis, and overlapping studies from the same center. Onset of bronchiolitis obliterans syndrome or obliterative bronchiolitis was the outcome of interest. Acute rejection plays an important role in obliterative bronchiolitis and bronchiolitis obliterans syndrome onset, and late rejection is a significant risk factor. Lymphocytic bronchitis/bronchiolitis is also a risk factor, with some evidence that late onset is associated with greater risk. The effects of cytomegalovirus, other infectious organisms, and human leukocyte antigen matching are less clear and require further confirmation. There is little evidence that recipient and donor characteristics play a major role. This systematic review supports the view that obliterative bronchiolitis arises from alloimmunologic injury marked by clinically apparent acute rejection episodes and that inflammatory conditions, including viral infections or ischemic injury, may also play a role. Implications for therapy are discussed.


Method for tapping the parotid gland. Studies in patients with bilateral englargement of the parotid gland.
A new biopsy method for the study of the parotid gland is proposed. 60 patients with enlarged parotid gland were studied and samples in 44 of them were obtained for investigation. There was a hematoma in the tapping area of two patients but both recoved. This new-method implies a simple procedure, without serious complications that will facilitate the development of clinical studies and further investigation of the parotid gland.


Bronsted acid-catalyzed rapid enol-ether formation of 2-hydroxyindole-3-carboxaldehydes.
A one-step Bronsted acid-catalyzed synthetic methodology leading to 3-(alkoxymethylene)indolin-2-ones was developed starting from easily accessible 2-hydroxyindole-3-carboxaldehydes. The procedure simply involves a treatment of differently substituted 2-hydroxyindole-3-carboxaldehydes with various alcohols (primary/secondary/tertiary/allyl/propargyl/benzyl) in the presence of a catalytic amount of Bronsted acids such as [Formula: see text]-toluenesulfonic acid and trifluroacetic acid. A series of 19 indolin-2-one-based enol-ethers were synthesized in excellent yields, which implies the general character of our methodology. The enol-ethers produced could be used as a useful building block for the synthesis of indole-based heterocycles.


Acetyl-Coenzyme A carboxylase. Role of the prosthetic group in enzyme polymerization.
Apo-(acetyl-CoA carboxylase) completely free from the holoenzyme was prepared from biotin-deficient rat adipose tissue by using affinity chromatography. The apoenzyme does not aggregate under conditions favouring the transition of the holoenzyme to the polymeric form. Such transition is possible after the conversion of the apoenzyme into the holoenzyme in vitro, thus demonstrating the requirement of the prosthetic biotinyl group for enzyme activation.


Human papillomavirus DNA in pharyngeal scrapes as a marker of HPV-related squamous cell cancer of the oropharynx.
Recent studies have indicated that human papillomavirus is an etiologic agent for a subset of head and neck cancers associated with better prognosis, therefore, prompt confirmation of such etiology seems to be crucial for choosing the optimal therapeutic option. Standard HPV diagnosis is currently based on histopathological material. In the present study, the novel diagnostic method based on pharyngeal brush biopsy is proposed. The aim of this study was to evaluate the usefulness of the Real-Time PCR-based (RT-PCR) test in detecting HPV-related cancer of the oropharynx using superficial scraps taken from the oropharyngeal region. Ninety patients with head and neck squamous cell cancer were enrolled in the study. The presence of HPV DNA in pharyngeal superficial scrapes assessed by RT-PCR was compared to the HPV status in the tumor tissue samples determined by a combined RT-PCR/P16(INK4A) expression algorithm. Analytical sensitivity and specificity were calculated and the clinical outcome was analyzed in correlation to the HPV status. HR-HPV DNA in pharyngeal swabs was revealed in 25 cases (28.4%) and simultaneously confirmed in all corresponding tissue samples. Sensitivity and specificity of the viral status assessment in the brush biopsies in respect to the RT-PCR/P16(INK4A) 20 were 100% and 96.2%, respectively. HR-HPV positive status was associated with an excellent clinical outcome and reduced hazard ratio of recurrence and disease-related death. The proposed novel method of HPV status assessment using RT-PCR and superficial scraps appeared to be highly sensitive, specific, and useful in predicting the clinical outcome.


Brief international cognitive assessment for multiple sclerosis (BICAMS): A danish validation study of sensitivity in early stages of MS.
Cognitive impairment is highly prevalent in multiple sclerosis (MS). Due to the lack of specialized neuropsychological resources in many MS clinics, a brief cognitive monitoring tool that can be administered by other MS clinic staff is needed. BICAMS (Brief International Cognitive As-sessment for Multiple Sclerosis) has been developed and recommended by MS experts to monitor MS-related cognitive impairment. International validations of the tool are warranted. The primary aim of the study was to establish a Danish translation of BICAMS as a feasible cognitive monitoring tool and to provide a Danish contribution to the international validation of BI-CAMS. A secondary aim was to determine if BICAMS correlated with self-reported cognition. The study population comprised people with MS (pwMS) with relatively early MS and newly diagnosed. 65 pwMS were compared to healthy controls (HCs) matched on age, sex and education. PwMS and controls completed the BICAMS test battery which includes the Symbol Digit Modalities Test (SDMT, oral version), California Verbal Learning Test-II (CVLT-II) and the Brief Visuospatial Memory Test-Revised (BVMT-R). In addition, self-reported cognition, fatigue, depression and quality of life were assessed. To evaluate the reliability of the BICAMS test, all participants were retested 2-3 weeks later with alternate versions of the tests. Mean age of the MS group was 37.2 years; 63% were female and all pwMS had a relapsing-remitting disease course. MS disease duration was relatively short; mean disease duration was 3.9 years and 32 of 65 pwMS (49%) were newly diagnosed with MS, i.e. diagnosed within the last 2 years. Mean EDSS was 1.8 with a span from 0-4. Comparison of the groups showed that the MS group performed significantly below the control group on the 3 BICAMS measures: SDMT (p<0.005), CVLT-II (p<0.05) and BVMT-R (p<0.05). When the results were controlled for influence from depression and fatigue by regression analysis, group differences were limited to the SDMT (p<0.05) and the BVMT-R (p<0.05) and these group differences were only found at the retest session. The BICAMS measures were reliable over time (r = 0.90 for SDMT, r = 0.82 for CVLT-II and r = 0.68 for BVMT-R). 32.3% of the MS population was cognitively impaired on at least one of the 3 BICAMS tests (defined as -1.5 SD compared to HCs). In the MS group 20% were impaired on the SDMT; 16.9% were impaired on the BVMT-R and 10.7% were impaired on the CVLT-II. There was no relationship between BICAMS test-scores and subjectively reported cognition, fatigue or depression. The Danish translation of BICAMS was a reliable and feasible cognitive assessment tool. This finding was confirmed even in an MS population characterized by relatively early MS and high cognitive reserve. Frequency of cognitive dysfunction detected by BICAMS in this study was relatively low due to population characteristics.


A temporal profile of myocardial zinc changes after isoproterenol induced cardiac necrosis.
Changes in myocardial zinc level was followed up over a period of 5 days after producing myocardial necrosis in albino rats by subcutaneous injection of isoproterenol, 85 mg/kg body weight. Myocardial necrosis was confirmed by ECG (Lead II), histology and serum enzyme studies (SGOT, SGPT and LDH). A decrease in myocardial zinc level was observed on all the five days. The possible mechanism and the therapeutic implications of these changes are discussed.


Moringa leaf extract and green algae improve the growth and physiological attributes of Mentha species under salt stress.
Climate change, food scarcity, salt stress, and a rapidly growing population are just a few of the major global challenges. The current study examined into whether Moringa oleifera (L.) leaf extract and green algae (Ulva intestinalis) could help improve salt tolerance in Mentha species (Mentha piperita; Mentha longifolia). Moringa leaf extract (MLE) and green algae (GA) were applied to Mentha seedlings under three different salt treatments: 0 mM, 20 mM, 40 mM, 60 mM, and 90 mM, respectively. For each treatment, three biological replicates were conducted, with each replicate containing at least three plants. Mentha species were negatively affected by salt stress in terms of shoot length, fresh and dry weight, photosynthetic pigments, and antioxidant enzyme activities. However, the use of MLE and GA significantly improved the development and physiology of Mentha species under salt stress conditions. The MLE and GA treatments dramatically (p ≤ 0.001) increased SOD activity by 7% and 10%, CAT activity by 16% and 30%, APX activity by 34% and 56%, GPX activity by 12% and 47%, respectively, in Mentha piperita seedlings, which in turn strikingly increased superoxide dismutase (SOD) activity by 6% and 9%, catalase (CAT) activity by 15%, 28% and 44%, 27%, ascorbate peroxidase (APX) activity by 39% and 60%, glutathione peroxidase (GPX) activity by 23% and 58%, respectively, in Mentha longifolia seedlings, relative to the control. Aiming to answer questions about the relationship between plant extraction and traditional agricultural methods, this research greatly advances the goal of sustainable development for improving plant productivity by providing a much safer and more environmentally friendly adaptability.


Communicative intervention for children with psychiatric and communication disorders.
Many children and adolescents with psychiatric disorders exhibit severely compromised language and social communication systems. The nature and scope of their deficits make a multidisciplinary team approach essential to management in which improved functional and socially appropriate communication is a primary goal. For this reason SLPs generally play a key role in the intervention process and share responsibilities for the planning, coordination, and implementation of instructional-educational goals.


Characterizing surface viscoelastic integrity of ultra-fast photo-polymerized composites: Methods development.
Resin-Composites are now available designed for polymerization using 3 s of intense light irradiation. The aim was to develop an experimental method to probe their surface viscoelastic integrity immediately following such rapid photo-cure via macroscopic surface indentation under constant stress as a function of time. Two bulk-fill composites (Ivoclar AG) were studied: Tetric PowerFill (PFill) and PowerFlow (PFlow). Split molds were used to fabricate cylindrical {4 mm (dia) × 4 mm} paste specimens, irradiated at 23 °C at 0 mm from the top surface with a BluephasePowerCure LED-LCU, with 3 s or 5 s modes, emitting 3 and 2 W/cm2, respectively. Post-irradiation specimens were immediately transferred to an apparatus equipped with a flat-ended indentor of 1.5 mm diameter. 14 MPa compressive stress at the indentor tip was applied centrally in < 2 min and maintained constant for 2 h. Indentation (I) magnitudes were recorded in real-time (t), with I(t) data re-expressed as % indentation relative to the 4 mm specimen height. After 2 h, the indentor was unloaded and indentation recovery was monitored for a further 2 h. Parallel sets of measurements were made where indentation was delayed for 24 h. Further measurements were made with more conventional composites: EvoCeram Bulk Fill (ECeram) and Tetric EvoFlow Bulk Fill (EFlow). These were irradiated for 20 s at 1.2 W/cm2. Kinetic data were curve-fitted to exponential growth functions and key parameters analyzed by ANOVA and post-hoc tests (α = 0.05). I(t) plots looked initially similar to bulk creep/recovery: rapid deformation plus viscoelastic response; then, upon unloading: rapid (elastic) recovery followed by partial viscoelastic recovery. However, unlike multiply irradiated and stored bulk-creep specimens, the present specimens were exposed to only 3 or 5 s "occlusal" irradiation; generating "hard" surfaces. Subsequently, during the 2 h indentation, the polymer matrix network continued to harden and consolidate. Upon initial loading, I(t) reached 2-3% indentation, depending upon the formulation. Upon unloading at 2 h, elastic recovery was only ca. 1 %. Delayed loading for 24 h, generated I(t) plots of significantly reduced magnitude. Most importantly, however, the I(t) plots for ECeram and EFlow, after 20 s irradiation, showed I(t) magnitudes quite comparable to the PFill and PFlow rapid-cure composites. Macroscopic indentation creep has been shown to be a workable procedure that can be applied to rapid-cure materials to assess their immediate surface integrity and developing viscoelastic characteristics. The applied stress of 14 MPa was relatively severe and the indentation/recovery profiles of PowerFill materials with only 3 or 5 s irradiation demonstrated comparability with their established 20 s cure siblings, evidencing the suitability of the PowerCure system for clinical application.


A comparative study of oral glucose tolerance tests in Nigerian women on three types of steroidal contraceptives.
Oral glucose tolerance tests (OGTT) were performed on 146 Nigerian women volunteers using one of three types of steroidal contraceptives: high-dose combined pills; low-dose combined pills and injectable progesterone. Twenty-six appropriately matched nonusers served as controls. The OGTT curves were analysed using the H-index (HI). Women on injectable progesterone and high-dose combined pills, respectively, had significantly higher (P less than 0.05) mean HI than the controls. The low-dose combined pills had the least effect on carbohydrate metabolism.


Recent developments in cervical cancer diagnosis using deep learning on whole slide images: An Overview of models, techniques, challenges and future directions.
Integration of whole slide imaging (WSI) and deep learning technology has led to significant improvements in the screening and diagnosis of cervical cancer. WSI enables the examination of all cells on a slide simultaneously and deep learning algorithms can accurately label them as cancerous or non-cancerous. Although many studies have investigated the application of deep learning for diagnosing various diseases, there is a lack of research focusing on the evolution, limitations, and gaps of intelligent algorithms in conjunction with WSI for cervical cancer. This paper provides a comprehensive overview of the state-of-the-art deep learning algorithms used for the timely and precise analysis of cervical WSI images. A total of 115 relevant papers were reviewed, and 37 were selected after screening with specific inclusion and exclusion criteria. Methodological aspects including deep learning techniques, data sources, architectures, and classification techniques employed by the selected studies were analyzed. The review presents the most popular techniques and current trends in deep learning-based cervical classification systems, and categorizes the evolution of the domain based on deep learning techniques, citing an in-depth analysis of various models developed over time. The paper advocates for the implementation of transfer supervised learning when utilizing deep learning models such as ResNet, VGG19, and EfficientNet, and builds a solid foundation for applying relevant techniques in different fields. Although some progress has been made in developing novel models for the diagnosis of cervical cancer, substantial work remains to be done in creating standardized benchmark databases of WSI images for the research community. This paper serves as a comprehensive guide for understanding the fundamental concepts, benefits, and challenges related to various deep learning models on WSI, including their application for cervical system classification. Additionally, it provides valuable insights into future research directions in this area.


Investigation on phenol degradation capability of Scenedesmus regularis: influence of process parameters.
Phenol removal from environmental solutions has attracted much attention due to phenol's high toxicity, even at low concentrations. This study aims to reveal the phenol biodegradation capacity of Scenedesmus regularis. Batch system parameters (pH, amount of algal cell, phenol concentration) on biodegradation were examined. After 24 h of treatment, 92.16, 94.50, 96.20, 80.53, 65.32, 52 and 40% of phenol were removed by Scenedesmus regularis in aqueous solutions containing 5, 10, 15, 20, 30, 40 and 50 mg/L of phenol, respectively. To describe the correlation between degradation rate and phenol concentration, the Michaelis-Menten kinetic equation was used where Vmax and Km are 0.82 mg phenol g algea-1 h-1 and 24.97 ppm, respectively. Phenol remediation ability of S.regularis can enable the usage of the spent biomass as biofuel feedstock and animal feed makes it a 'green' environmental sustainable process.


Lycodine-type alkaloids from Lycopodiastrum casuarinoides and their acetylcholinesterase inhibitory activity.
Five previously undescribed lycodine-type alkaloids, named huperzine Y (1), 8,15-epoxy-N-demethylhuperzinine (2), 7-hydroxyl-huperzinine (3), huperzine Z (4), and huperzine D N-oxide (5), were isolated from the aerial parts and roots of Lycopodiastrum casuarinoides (Lycopodiaceae), along with ten known analogues. The structures of the new compounds were elucidated by means of spectroscopic technique (IR, UV, MS and NMR). The absolute configurations of the new compounds were established on the basis of comparison of their experimental and TD-DFT (time-dependent density functional theory) calculated ECD spectra. Moreover, all the isolates were evaluated for acetylcholinesterase (AChE) inhibitory activity. Only huperzine C showed moderate activity, with an IC50 value of 0.525 ± 0.140 μM, which was comparable with the positive control, huperzine A (IC50 = 0.143 ± 0.029 μM).


Nitrous oxide-induced conditioned taste aversions in rats: the role of duration of drug exposure and its relation to the taste aversion-self-administration "paradox".
Inhalation by rats of nitrous oxide immediately after ingestion of a solution of 0.1% saccharin resulted in a conditioned avoidance of the solution following recovery from the drug (Conditioned Taste Aversion). With a constant duration of inhalation (30 min), aversive properties of nitrous oxide in this behavioural paradigm were related to concentration over the range 0-80%. At constant concentrations (70% and 80%), the aversive potency of nitrous oxide was directly related to duration of inhalation of the gas over the range 0-4 hr. These data provide the first direct support for the hypothesis [5,6] that a major determinant of aversive potency of a drug in the taste aversion paradigm is its duration of action. Different temporal components of drug action may mediate self-administration and conditioned aversion.


Central venous catheter sepsis: the experience of the Istituto Nazionale Tumori of Milan.
The pathogenesis of sepsis of central venous catheters has been studied. Catheter exchange is a useful and effective technique for the treatment of sepsis.


Access to rural health services: research as community action and policy critique.
Although access to rural health services has been an enduring focus for a variety of scholars, little has been recorded about the intersection between health service policy, provision and access experiences. This paper identifies how community action can highlight the gaps between policy rhetoric and access experiences. Taking the case of rural New Zealand, we document how a community organisation Rural Women New Zealand (RWNZ) completed a national survey as a form of community action. This study records rural households' experiences and challenges when accessing both primary and secondary health services. A range of access problems is identified. The study also illustrates how community-based activism concerning health care need not be local or single-service focussed, but can involve a multi-service critique at the national scale. Such work highlights not only the experience but also the complexity and politics of health service access.


[Pneumology and Sports: An Outpatient Endurance Training with Sports Medical Guidance as an Effective Non-pharmacological Therapy in Pneumology - a Feasibility Study].
In the process of medical rehabilitation muscular endurance training is the main focus. Unfortunately, outpatient rehabilitation opportunities are limited and specialized pulmonary exercise groups ("lung sport groups") rarely available. Therefore we developed an outpatient endurance sports program for patients with respiratory diseases and evaluated its effectiveness. In this feasibility study 31 patients (50 ± 15 years) with diverse respiratory diseases were included. By professional functional exercise testing (incl. CPET and lactate measurement according to the standards of DGP and DGSP) the patients optimal training zone was determined and an individualized 12 week lasting aerobic endurance training with ≥ 3 sessions of 20 - 60 min/week realized. After completion of the exercise training program a significant improvement in dyspnoea (Borg-Scale: 65.7 ± 12.2 vs. 62.2 ± 12.6, p = 0.013), body constitution (BMI: 25.7 ± 3.3 vs. 24.3 ± 3.2 kg/m(2), p = 0.018; portion of body fat: 24.8 ± 5.8 vs. 23.8 ± 6.4 %, p = 0.043) as well as physical capacity (VO2 at 4 mmol/l Laktat: 24.2 ± 6.9 vs. 26.5 ± 7.6 ml/min/kg, p < 0.01; performance at 4 mmol/l Laktat: running/walking (n = 14) + 1.1 km/h, p = 0.018 and biking/bicycle ergometer (n = 17) + 8.7 Watt, p = 0.019) was recorded. These positive developments were also observed in mental and physical quality of life (quality of life questionnaire SF-36: physical score + 9.7 points, mental score + 4.5 points). The evaluated exercise program can easily be trained by the patient in a self-dependent setting and was seen to be an effective sports medical treatment in patients with diverse pulmonary diseases.


The role of autophagy in cancer development and response to therapy.
Autophagy is a process in which subcellular membranes undergo dynamic morphological changes that lead to the degradation of cellular proteins and cytoplasmic organelles. This process is an important cellular response to stress or starvation. Many studies have shed light on the importance of autophagy in cancer, but it is still unclear whether autophagy suppresses tumorigenesis or provides cancer cells with a rescue mechanism under unfavourable conditions. What is the present state of our knowledge about the role of autophagy in cancer development, and in response to therapy? And how can the autophagic process be manipulated to improve anticancer therapeutics?


A rapid and reliable semiautomated method for measurement of total abdominal fat volumes using magnetic resonance imaging.
The aim of this study was the development of a reliable and fast method to estimate total abdominal fat volumes (TAF) in diabetic subjects on the basis of T1-weighted MR images. Thirty-seven patients with diabetes were examined (age 48 +/- 13 y mean +/- SD). A semiautomated computer assisted software program was developed to quantify intraabdominal (IAF), subcutaneous (SCF), and total abdominal fat volumes (TAF). The variability of image analysis for fat measurements between two observers and within observers was assessed. Mean volumes (+/- SD) for IAF, SCF and TAF were 10.5 1 (+/- 5.0 1), 15.1 1 (+/-7.3 1) and 25.7 1 (+/-11.5 1), respectively. Inter- and intraobserver reliability was excellent (r = 0.999 to r = 1.0). Per patient, the analysis required nine minutes in addition to a scan duration of seven minutes. As this analytic method using T1-weighted MR images allows a fast and reliable quantification of TAF, IAF and SCF, it may serve as a valuable tool for respective studies in diabetic subjects.


Enterogenous cyst in the cervical spinal canal. Case report.
The case of an 11-year-old Japanese girl with an intradural and extramedullary enterogenous cyst is presented. A mass giving a low-intensity signal in comparison with the spinal cord was demonstrated on magnetic resonance imaging. Histologically, the diagnosis was confirmed on specimens stained with periodic acid-Schiff, alcian blue, mucicarmine, and immunohistochemical staining of carcinoembryonic antigen, and by electron microscopy.


Biofeedback training for constipation in adults and children.
Forty-two patients complaining of constipation with abnormal anorectal motility were studied: 20 children and 6 adult females had a decreased rectoanal inhibitory reflex (RAIR) amplitude and 16 adult females had anal hypertonia and ultra slow waves (USW). Biofeedback training was used to condition the patients to relax the anal sphincter during the desire to defecate. After two to eight (mean, 4) training sessions, the authors observed simultaneously a normal RAIR amplitude and recovery from constipation for at least six months in 15 children and five females with decreased RAIR amplitude. Nine of the adult females with hypertonia and USW were able to suppress USW but did not recover from constipation. The data suggest that biofeedback training could be useful in some groups of constipated patients.


Microbial toxins, their functional role and phylogenetic validity.
Microbially produced toxins, which appear to lack a role in microbial survival, may be antimicrobial compounds of significance to the producers. These toxin/antibiotics may act against cell metabolism shared by man or animals and other microorganisms. Protein toxin/antibiotics are produced by single species of bacteria. Those from fungi and algae are nonprotein secondary metabolites and several microorganisms may make the same or similar toxin/antibiotics.


Drug Resistance and Epigenetic Modulatory Potential of Epigallocatechin-3-Gallate Against Staphylococcus aureus.
Antimicrobial resistance of human pathogens, such as methicillin-resistant Staphylococcus aureus, is described by the World Health Organization as a health global challenge and efforts must be made for the discovery of new effective and safe compounds. This work aims to evaluate epigallocatechin-3-gallate (EGCG) epigenetic and modulatory drug potential against S. aureus in vitro and in vivo. S. aureus strains were isolated from commensal flora of healthy volunteers. Antibiotic susceptibility and synergistic assay were assessed through disk diffusion accordingly to EUCAST guidelines with and without co-exposure to EGCG at final concentrations of 250 µg/ml, 100 µg/ml, 50 µg/ml, and 25 µg/ml. Transcriptional expression of orfx, spdC, and WalKR was performed through qRT-PCR. A 90-day interventional study was performed with daily consumption of 225 mg of EGCG. Obtained data revealed a high prevalence of S. aureus colonization in healthcare workers and clearly demonstrated the antimicrobial and synergistic potential of EGCG as well as divergent resistant phenotypes associated with altered transcriptional expression of epigenetic and drug response modulators genes. Here, we demonstrate the potential of EGCG for antimicrobial treatment and/or therapeutic adjuvant against antibiotic-resistant microorganisms and report divergent patterns of epigenetic modulators expression associated with phenotypic resistance profiles.


Longitudinal changes of right ventricular deformation mechanics during trastuzumab therapy in breast cancer patients.
Trastuzumab improves dramatically the prognosis of HER2-positive breast cancer patients, but it may lead to cardiotoxicity with left ventricular (LV) systolic dysfunction. Its effects on right ventricular (RV) function have not however been elucidated. We sought to assess LV and RV deformation mechanics during treatment with trastuzumab in breast cancer patients. We studied 101 consecutive women (mean age 54.3 ± 11.4 years) receiving trastuzumab for 12 months; 62 of them (61.4%) had previously received anthracyclines and 26 (25.7%) were receiving taxanes concurrently with trastuzumab. Comprehensive two-dimensional echocardiography with speckle tracking imaging of LV and RV global longitudinal strain (GLS) and RV free wall longitudinal strain (FWLS) analyses were performed at baseline and every 3 months up to treatment completion. Cardiotoxicity was defined as a decrease of baseline LV ejection fraction > 10 percentage units to a value < 50%. At 3 months, only LV GLS was significantly reduced (-19.5 ± 2.7 to -18.7 ± 2.8, P = 0.0410), while at 6 months, LV GLS, RV GLS and RV FWLS had significantly declined reaching their lowest values (-17.9 ± 6.1, P = 0.002, -19.6 ± 5.2, P = 0.003 and -19.7 ± 5.6, P = 0.004, respectively). Ten women (9.9%) developed cardiotoxicity. A RV GLS percent change of -14.8% predicted cardiotoxicity with 66.7% sensitivity and 70.8% specificity (area under the curve 0.68, 95% confidence interval 0.54-0.81), classifying correctly 90% of women with cardiotoxicity. This cut-off is quite similar to the 15% change of LV GLS previously suggested as predictive of cardiotoxicity. Deformation mechanics of both the left and right ventricle follow similar temporal pattern and degree of impairment during trastuzumab therapy, confirming the global and uniform effect of trastuzumab on myocardial function.


A long-term, prospective, observational cohort study of the safety and effectiveness of etanercept for the treatment of patients with paediatric psoriasis in a naturalistic setting.
Psoriasis is a chronic inflammatory skin disorder that affects 125 million people worldwide, with one-third having childhood onset. The PURPOSE study evaluated long-term safety and effectiveness of etanercept in paediatric psoriasis. This observational study enrolled patients with paediatric psoriasis who were prescribed etanercept per routine care in eight EU countries. Patients were followed retrospectively (first dose prior to 30 days before enrolment) or prospectively (first dose within 30 days prior to or any time after enrolment) for five years. Safety endpoints included serious infections, opportunistic infections, malignancies, other serious adverse events (SAEs) and adverse events. Effectiveness endpoints (prospective patients) included treatment patterns, dose change/discontinuation, and physicians' global subjective assessment of change in disease severity from baseline to follow-up. In total, 72 patients were enrolled (32 prospectively, 40 retrospectively), with mean age of 14.5 years and mean disease duration of 7.1 years. No serious or opportunistic infections/malignancies were reported. Psoriasis (n=8) and subcutaneous tissue disorders (system organ class) (erythema nodosum, erythrodermic psoriasis; n=1 for each) were the most frequently reported SAEs, which occurred in six (8.3%) patients with current/recent treatment and four (7.4%) with previous treatment. Of 25 treatment-emergent SAEs, seven (28.0%) were possibly related to etanercept. Assessments of prospective patients revealed that 28 (87.5%) completed 24 weeks, five (15.6%) required at least one subsequent course, and 93.8% experienced decreased disease severity. It is possible that some rare adverse events were not noted in this relatively small sample. These real-world data are consistent with the known safety and efficacy profile of etanercept in paediatric patients with moderate to severe plaque psoriasis.


The crystal structure of D-mandelate dehydrogenase reveals its distinct substrate and coenzyme recognition mechanisms from those of 2-ketopantoate reductase.
D-Mandelate dehydrogenases (D-ManDHs), belonging to a new d-2-hydroxyacid dehydrogenase family, catalyze the conversion between benzoylformate and d-mandelate using NAD as a coenzyme. We determined the first D-ManDH structure, that of ManDH2 from Enterococcus faecalis IAM10071. The overall structure showed ManDH2 has a similar fold to 2-ketopantoate reductase (KPR), which catalyzes the conversion of 2-ketopantoate to d-pantoate using NADP as a coenzyme. They share conserved catalytic residues, indicating ManDH2 has the same reaction mechanism as KPR. However, ManDH2 exhibits significant structural variations in the coenzyme and substrate binding sites compared to KPR. These structural observations could explain their different coenzyme and substrate specificities.


Damage and repair of the immature rat cerebellum after cis-dichlorodiammineplatinum II (cis-DDP) treatment. An ultrastructural study.
The aim of this electron microscopy study was to further investigate the effects of cis-dichlorodiammineplatinum (cis-DDP) on the cerebellum of the immature rat. Ten-day-old animals were treated with cis-DDP subcutaneously and killed after 1, 7, 15 or 21 days. On postinjection day 1, cis-DDP effects were evident mainly in the external granular layer, with nuclear damage in many dividing cells, while their cytoplasm appeared to be less affected. Some binucleate cells were also present. On the contrary, in postmitotic or more differentiated cells, only cytoplasmic alterations were found. At later stages (postinjection day 7), the frequency of damaged cells in the external granular layer decreased, but there was a cellular deficit in the internal granular layer. Many postmitotic neurons underwent coagulative necrosis. Finally (postinjection days 15 and 21), the cellular deficit was partly compensated for by "reactive" structures, e.g., glial cell fibers, which underwent hypertrophy after initial edema. Moreover, packing densities of Bergmann astrocytes and oligodendrocytes were higher.


[Osteopetrosis].
Animal models of osteopetrosis have led us to consider this condition to be an immune disease. In both the hereditary from in the op/op mutant rat and in experimentally induced from by Cl2MDP, osteopetrosis is associated with immune deficiencies, such as the inhibition of the mitogenic response of T lymphocytes, the inability to develop adjuvant arthritis. In particular, the differentiation of the thymus dependent macrophages is inhibited in the mouse treated with Cl2MDP. These animal models illustrate the relationships between the immune system and the bone regeneration system. They enable the study of the relationship between T lymphocytes, macrophages and osteoclasts.


Delayed substantia nigra damage and leukoencephalopathy after hypoxic-ischemic injury.
Delayed post-anoxic encephalopathy has rarely been reported, and has most commonly been associated with carbon monoxide poisoning. The underlying pathophysiological mechanism is unknown. We describe a patient with a delayed neurologic decline after a good initial recovery from a hypoxic-ischemic event precipitated by acute blood loss. MRI revealed early globus pallidus necrosis followed by delayed substantia nigra damage and leukoencephalopathy. We suggest that anemia might play a role in this pattern of hypoxic-ischemic brain injury.


Microsurgical treatment of patients with refractory epilepsy and mesial temporal cavernous malformations: Clinical experience of a tertiary epilepsy center.
Mesiotemporal cavernous malformation can occur in 10-20% of patients with cerebral cavernomas and are frequently associated with refractory. A retrospective investigation was performed in the epilepsy clinic of a Brazilian tertiary referral epilepsy center, from January 2000 to March 2012. A total of 21 patients were included in the study. Thirteen patients (62%) evolved to Engel I; 5 (24%) to Engel II, 2 (10%) to Engel III, and 1 (5%) to Engel IV. We observed that 10 (48%) patients with 12 years or less of epilepsy duration evolved to Engel I and 1 (5%) to Engel II; whereas from a total of 10 patients with epilepsy duration of more than 12 years, 3 (30%) evolved to Engel I and 7 (70%) to Engel II, III, or IV (P < 0.001 [bilateral]; P1 ≠ P2). Postsurgical seizure outcome for temporal lobe epilepsy associated with mesiotemporal cavernomas is very satisfactory.


The effect of glycerol and other intermediates on the incorporation of 14C-fructose and 14C-glucose to hepatic triglyceride.
Mature male rats were given, orally, 14C-fructose either alone or in conjunction with dihydroxyacetone, glyceraldehyde, or glycerol. Glycerol was also administered with 14C-glucose in a dose equimolar with fructose. After 2 hr the rats were killed and the liver triglyceride fraction was separated. Estimations of the degree of incorporation of 14C from the radioactive labeled carbohydrate into the glycerol and fatty acid moieties were carried out. Dihydroxyacetone and glyceraldehyde reduced the incorporation of 14C-fructose into hepatic triglyceride to approximately equal extents, suggesting that both trioses contribute equally to alpha-glycerophosphate formation. Glycerol, however, brought about a profound increase in the amount of fructose converted to triglyceride. This effect of glycerol was not apparent to any measurable extent on glucose incorporation into triglyceride and none of the intermediates affected the proportional distribution of radioactive counts between the fatty acid and glycerol moieties of the triglyceride after 14C-fructose administration.


How populist attitudes scales fail to capture support for populists in power.
Populist attitudes are generally measured in surveys through three necessary and non-compensatory elements of populism, namely anti-elitism, people-centrism, and Manicheanism. Using Comparative Study of Electoral Systems Module 5 (2016-2020) data for 30 countries, we evaluate whether this approach explains voting for populist parties across countries in Asia, Europe and the Americas. We show that the existing scales of populist attitudes effectively explain voting for populists in countries where populist leaders and parties are in opposition but fail to explain voting for populist parties in countries where they are in power. We argue that current approaches assume "the elite" to mean "politicians", thus failing to capture attitudes towards "non-political elites" often targeted by populists in office-in particular, journalists, academics/experts, bureaucrats, and corporate business leaders. The results reveal limits to the usefulness of existing survey batteries in cross-national studies of populism and emphasize the need to develop approaches that are more generalizable across political and national contexts.


Spatial memory and hemispheric locus of lesion.
Corsi's cube test was given to 40 control and 80 brain-damaged patients to assess the relation of different aspects of spatial memory to the hemispheric locus of lesion. Spatial span was found affected by injury producing visual field defect (VFD), regardless of the side of the lesion. Delayed reproduction of a 3 cube sequence (which was within the span of every patient) was performed more poorly by patients with right hemisphere damage and VFD than by controls. This was true whether the delay was unfilled or filled with a counting activity, the two conditions being equally effective in bringing about the inferiority of the right brain-damaged group. Learning to criterion up to a maximum of 50 trails a supraspan sequence was failed by 65% of right brain-damaged patients with VFD, a percentage significantly higher than that found not only in the control group, but also in any other brain-damaged group. These findings point to the dominant role played by the posterior region of the right hemisphere in subserving spatial memory mechanisms, especially when the acquisition of stable traces is requested.


Posterior auricular artery helix root free flap-part I: radio-anatomical study.
Full-thickness defects of the distal nose are an ongoing surgical challenge. Among the available techniques, pre-auricular chondrocutaneous free flaps based on the superficial temporal artery (STA) have good aesthetic and functional outcomes. However they often require autologous venous grafts. The aim of this radio-anatomical study was to evaluate the feasibility of the helix root free flap based on the posterior auricular artery (PAA). Vascular lengths, diameters, and networks were investigated in flaps harvested from cadavers. The perfusion of the flaps was studied by injecting patent blue. Some flaps were also injected with contrast agent and studied by angiography and computed tomography. Ten flaps from seven fresh cadavers were dissected and analysed. The mean length of the PAA was 114.2 mm and the mean diameter was 2.2 mm. Perfusion was investigated in six flaps and considered good in three of these. The study results demonstrate the feasibility of PAA-based helix root free flaps. This alternative technique provides an 11 cm pedicle with vessels of appropriate calibre, facilitating any potential microsurgery. The scar is mostly hidden behind the ear. This PAA-based helix root free flap could be a reliable and promising single-stage procedure to repair complex defects of the alae nasi.


The roots of Salvia rhytidea: a rich source of biologically active diterpenoids.
Sahandinone (1), 12-deoxysalvipisone (2), miltirone (3), 7α-acetoxyroyleanone (4), and labda-7,14-dien-13-ol (5) were isolated from the roots of Salvia rhytidea Benth. (Lamiaceae). Their structures were elucidated by a combination of spectroscopic analyses including EIMS and NMR. The 13C NMR spectroscopic data were revised for the quaternary carbons of both 1 and 3 with the help of HMBC spectra in respect to the spectral data previously reported in the literature. Compounds 1 and 3, two very potent anticancer agents, were isolated in high yields from the roots of the plant. The biological activities of the plants' constituents were reported in the literature as antimicrobial, cytotoxic and antimalarial are discussed in this article.


Forty cases of twin reversed arterial perfusion sequence treated with radio frequency ablation using the multistep coagulation method: a single-center experience.
To report the pregnancy outcomes of patients with twin reversed arterial perfusion (TRAP) sequence treated by radiofrequency ablation (RFA). This was a retrospective study of TRAP sequences treated in a single center between March 2002 and February 2015. Forty patients underwent RFA with expandable tines through a multistep coagulation method between 15 and 26 gestational weeks. The primary outcome was neonatal survival to discharge. The overall survival of the pump twin was 85%. The survival rates in monochorionic-monoamniotic (MCMA) pregnancies and monochorionic-diamniotic pregnancies were 66.7% (4/6) and 87.9% (29/33), respectively. One triplet was treated successfully and delivered at 36 weeks of gestation. One of 35 live births (2.9%) had preterm premature rupture of membranes less than 34 weeks, resulting in infant death. In five intrauterine pump twin deaths, two cases were MCMA twins with cord entanglement, and three cases were MCDA twins with acardius anceps. Our study supports the effectiveness of RFA for TRAP sequence after 15 weeks of gestation. The presence of MCMA twins or acardius anceps is associated with a high risk of pump twin death after RFA. © 2016 John Wiley & Sons, Ltd.


Chitooligosaccharides as potential nutraceuticals: production and bioactivities.
Chitooligosaccharide (COS), a derivative of chitosan, can be produced by either chemical or enzymatic hydrolysis. Looking back through past research, several technological approaches have been taken to prepare COSs, and enzymatic approaches are favorable due to their environmentally friendly methods, safety, and a lack of toxicity. Similar to chitosan, COSs can also be considered potential nutraceuticals due to their versatile biological activities, water-soluble properties, and absorption properties in the intestine. Therefore, this chapter provides certain methods for the preparation of COSs and addresses their biological properties such as antihypertensive, antioxidant, antitumor, antimicrobial, and other select biological activities.