Development and Validation of Prognostic Nomograms for Patients with Duodenal Neuroendocrine Neoplasms.
BACKGROUND This study was designed to predict prognosis of patients with primary duodenal neuroendocrine neoplasms (D-NENs) by developing nomograms. MATERIAL AND METHODS Patients diagnosed with D-NENs between 1988 and 2015 were queried from the SEER database and a total of 965 appropriate cases were randomly separated into the training and validation sets. Kaplan-Meier analysis was used to generated survival curves, and the difference among the groups was assessed by the log-rank test. Independent prognostic indicators were acquired by Cox regression analysis, and were used to develop predictive overall survival (OS) and cancer-specific survival (CSS) nomograms. Harrell's concordance index (C-index), area under the curve (AUC), calibration curves, and decision curve analysis (DCA) were used to assess the efficacy of nomograms. Tumor stage was regarded as a benchmark in predicting prognostic compared with the nomograms built in this study. RESULTS The C-index was 0.739 (0.690-0.788) and 0.859 (0.802-0.916) for OS and CSS nomograms, respectively. Calibration curves exhibited obvious consistency between the nomograms and the actual observations. In addition, C-index, AUC, and DCA were better than tumor stage in the evaluative performance of nomograms. CONCLUSIONS The nomograms were able to predict the 1-, 5-, and 10-year OS and CSS for D-NENs patients. The good performance of these nomograms suggest that they can be used for evaluating the prognosis of patients with D-NENs and can facilitate individualized treatment in clinical practice.


Relationship between Health-Anxiety and Cyberchondria: Role of Metacognitive Beliefs.
The current study was designed to examine the relationship between health anxiety, cyberchondria (its constructs), and metacognitive beliefs. In addition, it also evaluated the moderating role of metacognitive beliefs in this relationship. The present study used the purposive sampling technique to acquire a sample of (N = 500) adults, among them (N = 256) women and (N = 244) men, and the age of the sample ranged from 20 to 50 years. Short Health Anxiety Inventory, Cyberchondria Severity Scale, and Metacognitions Questionnaire-Health Anxiety were used to operationalize the present study variables. The descriptive statistics revealed that all instruments have good psychometric properties, as Cronbach's alpha coefficients for all scales are ≥0.70. In addition to this, the Pearson correlation showed that all variables of the present study have a significant positive correlation with each other. Furthermore, the regression analysis described that health anxiety and metacognitive beliefs (biased thinking and beliefs about uncontrollable thoughts) were the significant positive predictors of cyberchondria. Moreover, moderation analysis showed that metacognitive beliefs significantly strengthened the association between health anxiety and cyberchondria and its constructs. The present study will help medical practitioners to understand how metacognitive beliefs and health anxiety can cause an increase in cyberchondria. This will help them to design better treatment plans for people with cyberchondria.


Post resuscitation care of out-of-hospital cardiac arrest patients in the Nordic countries: a questionnaire study.
Aim of this study was to compare post resuscitation care of out-of-hospital cardiac arrest (OHCA) patients in Nordic (Denmark, Finland, Iceland, Norway, Sweden) intensive care units (ICUs). An online questionnaire was sent to Nordic ICUs in 2012 and was complemented by an additional one in 2014. The first questionnaire was sent to 188 and the second one to 184 ICUs. Response rates were 51 % and 46 %. In 2012, 37 % of the ICUs treated all patients resuscitated from OHCA with targeted temperature management (TTM) at 33 °C. All OHCA patients admitted to the ICU were treated with TTM at 33 °C more often in Norway (69 %) compared to Finland (20 %) and Sweden (25 %), p 0.02 and 0.014. In 2014, 63 % of the ICUs still use TTM at 33 °C, but 33 % use TTM at 36 °C. Early coronary angiography (CAG) and possible percutaneous coronary intervention (PCI) was routinely provided for all survivors of OHCA in 39 % of the hospitals in 2012 and in 28 % of the hospitals in 2014. Routine CAG for all actively treated victims of OHCA was performed more frequently in Sweden (51 %) and in Norway (54 %) compared to Finland (13 %), p 0.014 and 0.042. Since 2012, TTM at 36 °C has been implemented in some ICUs, but TTM at 33 °C is used in majority of the ICUs. TTM at 33 or 36 °C and primary CAG are not routinely provided for all OHCA survivors and the criteria for these and ICU admission are variable. Best practices as a uniform approach to the optimal care of the resuscitated patient should be sought in the Nordic Countries.


A heuristic model of the effects of phenotypic robustness in adaptive evolution.
A recent theoretical, deterministic model of the effects of phenotypic robustness on adaptive evolutionary dynamics showed that a certain level of phenotypic robustness (critical robustness) is a required condition for adaptation to occur and to be maintained during evolution in most real organismal systems. We built an individual-based heuristic model to verify the soundness of these theoretical results through computer simulation, testing expectations under a range of scenarios for the relevant parameters of the evolutionary dynamics. These include the mutation probability, the presence of stochastic effects, the introduction of environmental influences and the possibility for some features of the population (like selection coefficients and phenotypic robustness) to change themselves during adaptation. Overall, we found a good match between observed and expected results, even for evolutionary parameter values that violate some of the assumptions of the deterministic model, and that robustness can itself evolve. However, from more than one simulation it appears that very high robustness values, higher than the critical value, can limit or slow-down adaptation. This possible trade-off was not predicted by the deterministic model.


Treatment burden among patients with heart failure attending cardiac clinic of Tikur Anbessa Specialized Hospital: an explanatory sequential mixed methods study.
Emerging evidences hypothesized that patients with heart failure are susceptible to experience treatment burden. Despite this fact, no attempt was made so far to address this neoteric construct in the sub-Saharan African health care context. Hence, this study aimed to assess patients' and health care providers' perspectives on how to decrease treatment burden among patients with heart failure attending the adult cardiac clinic of Tikur Anbessa Specialized Hospital (TASH). An explanatory sequential mixed methods study was conducted at the adult cardiac clinic of TASH, Addis Ababa, Ethiopia from August 01 to September 30, 2021. Simple random and purposive sampling techniques were employed to select participants for quantitative and qualitative studies, respectively. Descriptive analysis was done to summarize the quantitative data. Logistic regression analysis was performed to identify predictors of treatment burden. P value < 0.05 was considered to declare statistical significance. Qualitative data were analyzed by using thematic analysis. A total of 325 patients were enrolled in the quantitative study. For the qualitative study, 14 patients and 11 health care providers (five nurses and six medical doctors) were included. Participants mean global Treatment Burden Questionnaire (TBQ-15) score was 27.22 ± 19.35. Approximately 12% (n = 38) patients indicated high treatment burden (TBQ-15 global score ≥ 59) with a median global score of 63(60-69). Higher education level (adjusted odds ratio [AOR] = 6.66, 95% confidence interval [CI]: 1.16-38.43), presence of two and more comorbidities (AOR = 2.74, 95%CI: 1.02-7.39), daily intake of more than five pills (AOR = 7.38, 95%CI: 2.23-24.41), poor medication availability (AOR = 3.33, 95%CI: 1.33-8.36), presence of medication adverse effects (AOR = 4.04, 95%CI: 1.63-10.03), and higher monthly cost of medication (AOR = 5.29, 95%CI: 1.46-19.18) were predictors of treatment burden. Patients and healthcare providers' propositions were primarily focused on improving self-care management, structural organization of the clinic and hospital, and healthcare system provision. Our findings demonstrated that a substantial proportion of patients faced low levels of treatment burden. This study unveiled that improving self-care management, structural organization of the clinic, and healthcare system provision had paramount importance to reducing treatment burden. Hence, factors affecting treatment burden should be considered when designing tailored healthcare interventions for patients with heart failure.


The effect of operational parameters of the process of sludge ozonation on the solubilisation of organic and nitrogenous compounds.
An evaluation of various operational parameters on the process of sludge ozonation was carried out based on semi-batch experiments. Particular reference has been given to examine the main parameters affecting the solubilisation of organic matter and nitrogenous compounds. Various sets of experiments were undertaken using real sewage sludge to feed a semi-industrial ozonation plant. Applying ozone dosages between 25 and 35 mg O(3)/gTSS, the organic matter solubilisation obtained through ozonation increases proportionally to ozone dosage until a maximum value of 430 mg COD/L. Concerning the nitrogenous compounds, no variation in nitrite concentration and a low increase in nitrate concentration were attained, regardless of the applied ozone dosage. Little increase in ammonia concentration was achieved for low ozone dosages, whilst applying dosages higher than 20 mg O(3)/gTSS, the variation of ammonia increased proportionally with ozone dosage. Experiments using hydraulic retention time (HRT) between 10 and 60 min resulted in a similar COD solubilisation, confirming a rapid rate of cell lysis during ozonation of sludge.


Pediatricians' and health visitors' views towards detection and management of maternal depression in the context of a weak primary health care system: a qualitative study.
The present study's aim has been to investigate, identify and interpret the views of pediatric primary healthcare providers on the recognition and management of maternal depression in the context of a weak primary healthcare system. Twenty six pediatricians and health visitors were selected by using purposive sampling. Face to face in-depth interviews of approximately 45 minutes duration were conducted. The data were analyzed by using the framework analysis approach which includes five main steps: familiarization, identifying a thematic framework, indexing, charting, mapping and interpretation. Fear of stigmatization came across as a key barrier for detection and management of maternal depression. Pediatric primary health care providers linked their hesitation to start a conversation about depression with stigma. They highlighted that mothers were not receptive to discussing depression and accepting a referral. It was also revealed that the fragmented primary health care system and the lack of collaboration between health and mental health services have resulted in an unfavorable situation towards maternal mental health. Even though pediatricians and health visitors are aware about maternal depression and the importance of maternal mental health, however they fail to implement detection and management practices successfully. The inefficiently decentralized psychiatric services but also stigmatization and misconceptions about maternal depression have impeded the integration of maternal mental health into primary care and prevent pediatric primary health care providers from implementing detection and management practices.


[Quantitative determination of soya protein in canned meat indirect immune-enzyme a method].
Description of sample preparation of bully, immune-enzyme analysis procedure and mathematical treatment of obtained results are presented. Metrological characteristics of the method are determined.


Consumption of psychiatric drugs by patients of medical and surgical clinics in a general hospital.
to identify the prevalence of the use of psychiatric drugs among patients admitted to medical and surgical clinics of a general hospital, and also the factors related to the consumption of this type of medication. this is a transversal, descriptive, correlational study with quantitative analysis. For the collection of data, there was use of structured interviews and also reference to medical files. there was confirmation of a high prevalence of users of psychiatric drugs, which was associated to the female sex, to people who do not practice Roman Catholicism, and admittance to the clinic not covered by the Single Health System (Sistema Único de Saúde - SUS), as well as the presence of common mental disorders. Benzodiazepine drugs were the most commonly used psychiatric drugs. Among the total number of users, there has been the identification of patients who were not aware that they were receiving such medication. Doctors who are not psychiatrists were responsible for most prescriptions of psychiatric drugs. this signals the need to prepare health professionals to deal with psychological and social problems commonly found in clinical practice, in order to promote the rational use of psychiatric drugs.


The T-box transcription factors TBX2 and TBX3 in mammary gland development and breast cancer.
TBX2 and TBX3, closely related members of the T-box family of transcription factor genes, are expressed in mammary tissue in both humans and mice. Ulnar mammary syndrome (UMS), an autosomal dominant disorder caused by mutations in TBX3, underscores the importance of TBX3 in human breast development, while abnormal mammary gland development in Tbx2 or Tbx3 mutant mice provides models for experimental investigation. In addition to their roles in mammary development, aberrant expression of TBX2 and TBX3 is associated with breast cancer. TBX2 is preferentially amplified in BRCA1/2-associated breast cancers and TBX3 overexpression has been associated with advanced stage disease and estrogen-receptor-positive breast tumors. The regulation of Tbx2 and Tbx3 and the downstream targets of these genes in development and disease are not as yet fully elucidated. However, it is clear that the two genes play unique, context-dependent roles both in mammary gland development and in mammary tumorigenesis.


HCV infection, IFN response and the coding and non-coding host cell genome.
HCV is an ideal model to study how the infected cell is altered to allow the establishment of a chronic infection. After infection, the transcriptome of the cell changes in response to the virus or to the antiviral pathways induced by infection. The cell has evolved to sense HCV soon after infection and to activate antiviral pathways. In turn, HCV has evolved to block the antiviral pathways induced by the cell and, at the same time, to use some for its own benefit. In this review, we summarize the proviral and antiviral factors induced in HCV infected cells. These factors can be proteins and microRNAs, but also long noncoding RNAs (lncRNAs) that are induced by infection. Interestingly, several of the lncRNAs upregulated after HCV infection have oncogenic functions, suggesting that upregulation of lncRNAs could explain, at least in part, the increased rate of liver tumors observed in HCV-infected patients. Other lncRNAs induced by HCV infection may regulate the expression of coding genes required for replication or control genes involved in the cellular antiviral response. Given the evolutionary pressure imposed by viral infections and that lncRNAs are specially targeted by evolution, we believe that the study of proviral and antiviral lncRNAs may lead to unexpected discoveries that may have a strong impact on basic science and translational research.


Screening the expression characteristics of several miRNAs in G93A-SOD1 transgenic mouse: altered expression of miRNA-124 is associated with astrocyte differentiation by targeting Sox2 and Sox9.
MicroRNAs (miRNAs) are suspected to be a contributing factor in amyotrophic lateral sclerosis (ALS). Here, we assess the altered expression of miRNAs and the effects of miR-124 in astrocytic differentiation in neural stem cells of ALS transgenic mice. Differentially expressed miRNA-positive cells (including miR-124, miR-181a, miR-22, miR-26b, miR-34a, miR-146a, miR-219, miR-21, miR-200a, and miR-320) were detected by in situ hybridization and qRT-PCR in the spinal cord and the brainstem. Our results demonstrated that miR-124 was down-regulated in the spinal cord and brainstem. In vitro, miR-124 was down-regulated in neural stem cells and up-regulated in differentiated neural stem cells in G93A-superoxide dismutase 1 (SOD1) mice compared with WT mice by qRT-PCR. Meanwhile, Sox2 and Sox9 protein levels showed converse change with miR-124 in vivo and vitro. After over-expression or knockdown of miR-124 in motor neuron-like hybrid (NSC34) cells of mouse, Sox2 and Sox9 proteins were noticeably down-regulated or up-regulated, whereas Sox2 and Sox9 mRNAs remained virtually unchanged. Moreover, immunofluorescence results indicated that the number of double-positive cells of Sox2/glial fibrillary acidic protein (GFAP) and Sox9/glial fibrillary acidic protein (GFAP) was higher in G93A-SOD1 mice compared with WT mice. We also found that many Sox2- and Sox9-positive cells were nestin positive in G93A-SOD1 mice, but not in WT mice. Furthermore, differentiated neural stem cells from G93A-SOD1 mice generated a greater proportion of astrocytes and lower proportion of neurons than those from WT mice. MiR-124 may play an important role in astrocytic differentiation by targeting Sox2 and Sox9 in ALS transgenic mice. Cover Image for this issue: doi: 10.1111/jnc.14171.


Refractory chronic migraine: long-term follow-up using a refractory rating scale.
Refractory chronic migraine (RCM) is often associated with disability and a low quality of life (QOL). RCM ranges in severity from mild to severe. There would be a benefit both clinically and in research use in categorizing RCM patients according to severity. This study utilized a unique RCM severity rating scale, tracking the clinical course over 10 years. A total of 129 patients, ages 19-72, were assigned a severity rating of 2-10 (10 = worst). Pain level and QOL were assessed. Over the 10 years, 73% of all pts. had a 30% or more decline in pain. Pain levels improved 45% in mild pts., 42% in mod. pts., and 36% in severe pts. Pain was the same, or worse, in 4% of mild, 15% of mod., and 18% of severe pts. QOL in the mild group improved 35% over 10 years. In moderate pts., QOL improved 32%, while for the severe group QOL improved 33%. While pain and QOL improved across all three groups at the end of 10 years, the severe group remained with significantly more pain and decreased QOL than in the milder groups. The medications that helped significantly included: opioids (63% of pts. utilized opioids), frequent triptans (31%), butalbital (17%), onabotulinumtoxinA (16%), stimulants (12%), and other "various preventives" (9%). RCM pts. were rated using a refractory rating scale with the clinical course assessed over 10 years. Pain and QOL improved in all groups. In the severe group, pain and QOL improved, but still lagged behind the mild and moderate groups. Opioids and (frequent) triptans were the most commonly utilized meds.


Binding of inosine-substituted mRNA to reticulocyte ribosomes and eukaryotic initiation factors 4A and 4B requires ATP.
We examined the hypothesis that initiation of eukaryotic protein synthesis involves ATP-dependent melting of 5'-cap-proximal secondary structure in mRNA by eukaryotic initiation factors 4A and 4B. In reticulocyte lysate depleted of ribonucleoside triphosphates by pretreatment with hexokinase/glucose, initiation complex formation by native reovirus mRNA showed a strict requirement for ATP. The corresponding mRNA synthesized with ITP in place of GTP to minimize secondary structure also required ATP for binding to 40 S ribosomal subunits in complexes characteristic of initiation. In a partial reaction without ribosomes, purified eukaryotic initiation factors 4A and 4B bound and cross-linked to the capped 5'-end of oxidized mRNA. This interaction was ATP-dependent with inosine-substituted or bromouridine-containing reovirus RNAs as observed previously with native mRNA. The results indicate that if initiation involves ATP-dependent denaturation of mRNA, the effect must occur after initiation factor-mediated attachment of mRNA to the 40 S ribosomal subunit.


Tissue Distribution of the 27.8 kDa Receptor and its Dynamic Expression in Response to Lymphocystis Disease Virus Infection in Flounder (Paralichthys olivaceus).
Lymphocystis disease virus (LCDV) enters and infects the gill cells of flounder (Paralichthys olivaceus) via a 27.8 kDa membrane protein receptor. In the present study, immunohistochemistry was performed to locate the tissue distribution of this molecule in healthy flounder and showed that it was widely distributed in the tissues tested. Indirect enzyme-linked immunosorbent assay (ELISA) showed that the expression of the receptor in healthy flounder was highest in the gills and stomach, then in the skin, intestine and liver, followed by the spleen, head kidney, heart, ovary and brain and finally the kidney. On LCDV infection, ELISA indicated that the expression of the receptor, as determined by ELISA, was significantly upregulated in all tissues of LCDV-infected flounder compared with controls, but this expression decreased over the 4 weeks post infection. In contrast, real-time quantitative polymerase chain reaction demonstrated that the copy number of the LCDV gene in the tissues increased with time post infection, and that viral loads were higher in the tissues with higher expressions of the receptor. These results point to a correlation between high expression of the 27.8 kDa receptor and efficient LCDV propagation. The wide tissue distribution of the receptor might be one reason why LCDV can infect various tissues leading to systemic infection.


A comparison of the microcirculation in rat fast glycolytic and slow oxidative muscles at rest and during contractions.
We compared the microcirculation of the predominantly glycolytic (cortex of tibialis anterior, TA) and purely oxidative (soleus) muscles of the rat. The TA has wider (3.4 +/- 0.1 microns diameter compared to 2.7 +/- 0.05 microns), longer (405 +/- 29 and 205 +/- 17 microns), and straighter capillaries. Velocity of RBCs at rest is higher in TA (0.30 +/- 0.02 mm/sec) and reaches a higher value during contractions at 1 Hz (0.38 +/- 0.04 mm/sec) more quickly than in soleus (0.21 +/- 0.02-0.28 +/- 0.03 mm/sec). The number of continuously perfused capillaries in TA increased during contractions, but there was little change in soleus. A computer program was devised to estimate the proportion of time spent stationary by RBCs in the capillaries. This was greater in soleus than in TA at rest and was reduced in TA only during contractions. The transit time (TT) through capillaries was much reduced in TA during contractions (from 1.69 +/- 0.17 to 0.78 +/- 0.13 sec) but remained unchanged in soleus (1.17 +/- 0.21 and 0.97 +/- 0.13 sec). The lack of functional hyperemia in soleus may be a direct consequence of this invariability in the TT.


Age-appropriate solid oral formulations for pediatric applications with a focus on multiparticulates and minitablets: Summary of September 2019 EuPFI workshop.
This paper presents the output of a workshop held at the 11th Annual Conference of EuPFI (European Paediatric Formulation Initiative), in September 2019 in Malmo, Sweden, on the development of multiparticulates and minitablets as pediatric formulations. The workshop focused on three specific facets of pediatric drug development, namely selection of the formulation platform, selection of the package or dosing device, and administration of minitablets/multiparticulates with soft food. The workshop discussion indicated significant interest in the use of these dosage forms, filled into stick-packs or capsules, as age-appropriate formulations for younger children, along with a growing consensus that larger sized tablets and capsules designed for adults are often also suitable for adolescents. Among the areas that were identified as technical challenges were: understanding the acceptability of multiparticulates and minitablets relative to alternate formulations; the need for a streamlined approach to compatibility testing with soft foods; the desire to avoid the need to co-administer these products with soft food; and the need for more suitable dosing devices.


Co-transplantation of bone marrow-derived endothelial progenitor cells improves revascularization and organization in islet grafts.
Bone marrow-derived early endothelial progenitor cells (BM-EPCs) are a clinical tool for enhancing revascularization. However, the therapeutic efficacy of co-transplantation of BM-EPC with islets has not been investigated. In this study, marginal mass islets were co-transplanted with or without BM-EPCs under the kidney capsules of syngeneic streptozotocin-induced diabetic mice. Using green fluorescent protein transgenic (GFP-Tg) mice as BM-EPC and islet donors or recipients, the role of EPCs in revascularization was assessed for graft morphology, vascular density and fate of EPCs by immunohistochemistry. Islet-EPC co-transplantation improved the outcome of islet transplantation as measured by glucose tolerance, serum insulin level and diabetes reversal rate, compared with transplantation of islets alone. Between groups, the morphology of islet grafts showed significant differences in size and composition of grafted endocrine tissues. Significantly more vessel density derived from donors and recipients was detected with islet-EPC co-transplantation. Abundant GFP-Tg mice-derived BM-EPCs (GFP-EPCs) were observed in or around islet grafts and incorporated into CD31-positive capillaries. Remaining GFP-EPCs expressed VEGF. In conclusion, co-transplantation of islets with BM-EPCs could improve the outcome of marginal mass islet transplantation by promoting revascularization and preserving islet morphology.


Extracorporeal membrane oxygenation to support repeated whole-lung lavage in a patient with pulmonary alveolar proteinosis in life threatening dyspnoe--a case report.
Pulmonary alveolar proteinosis is a rare disorder that is characterized by a large accumulation of lipoproteinaceous material within the alveoli. This causes respiratory failure due to a restriction of gas exchange and changes in the ventilation/perfusion ratio. Clinical symptoms are variable and depend on the severity of damage of the lung parenchyma. Treatment method is whole-lung lavage, where the accumulated lipoproteinaceous material is removed using large quantities of saline. This case report describes a 45 year old patient with advanced pulmonary alveolar proteinosis. Due to the presence of severe global respiratory insufficiency, this patient could not undergo the classic whole-lung lavage using a double-lumen tube and selective lung ventilation. The whole-lung lavage was performed with the support of veno-venous extracorporeal membrane oxygenation. A total of 27 l of warm saline was used. According to the current published literature, whole-lung lavage with extra-corporeal membrane oxygenation support is a very rare treatment method. Even when taking into account all of the risks associated with whole-lung lavage and v-v extracorporeal membrane oxygenation support, we found that this technique is very effective and, without a doubt, it saved the life of our patient.


Potential application of Micellar nanoreactor for electron transfer reactions mediated by a variety of oxidants: A review.
Surfactant, either natural or synthetic, forms a different type of aggregates among which 'Micelle' is truly an important dynamic surfactant aggregate, having a different region to interact with several organic, inorganic, and biomolecules; therefore the practical use of micelle is rapidly growing day-to-day. Surfactant-micelle, looks like a reactor of nano-dimension, govern a variety of reactions in aqueous media extensively. Oxidation is one of the vital reaction, take a part in the course of several organic transformations which are not very easy to execute in water media alone due to the solubility problem. Moreover, in order to achieve a quick transformation overcoming several difficulties the utility of micellar media became an excellent innovation, that's why nowadays, the surfactant and its aggregates are a focus of interest to the researcher of synthetic field and thus its practical applicability has been tremendously cultivated over the few decades. It is, therefore, useful to introduce some basic concepts regarding the aggregation of surfactants. Subsequently, we emphasize the importance of micellar media on the kinetics of oxidation reactions mediated by several metal ions with a special emphasis on their catalytic role.


Intensive care complications in liver and multivisceral transplantation.
The complications concerning liver and intestinal transplant surgery have relevance for the field of intensive care because they share some characteristics with those following complex long-term surgery. Thus, in this article we shall try to describe complications that are specific to liver and multivisceral transplants. A review of the existing literature on this topic reveals a large number of studies dedicated to early as well as late surgical complications, and immunosuppressive treatment, while there are far fewer contributions describing complications exclusively concerning intensive care. We shall thus attempt to focus on certain aspects where, besides the literature data, we have personal experience. In particular we want to underline the implications of failure in the functional recovery of the graft; alterations in water, electrolyte, and glycemic balance; as well as neurological, respiratory, renal, nutritional, and infective complications.


Clinicopathological factors related to cervical lymph node metastasis in a patient with carcinoma of the oral floor.
Tumors developing into the muscle layer and tumor thickness > or =5 mm are the most important risk factors associated with nodal metastasis. It is necessary to identify the risk factors associated with cervical metastasis in patients with oral floor cancer to reveal the role of elective neck dissection for oral floor cancer. Forty-eight patients with oral floor cancer were retrospectively analyzed for a correlation between clinicopathologic factors and cervical lymph node metastasis using Fisher's exact test and a logistic regression test. Univariate analysis showed significantly positive correlations for growth type, mitosis, perineural invasion, vascular invasion, lymphatic invasion, depth, thickness, and infiltration growth ratio. Multivariate analysis had a significantly positive correlation with nest formation and depth in all patients, and with thickness in patients with T1 or T2. In patients with bilateral cervical lymph node metastasis, lymph node metastasis was significantly positively correlated with perineural invasion.


Steroid receptor RNA activator: Biologic function and role in disease.
Steroid receptor RNA activator (SRA) is a type of long noncoding RNA (lncRNA) which coordinates the functions of various transcription factors, enhances steroid receptor-dependent gene expression, and also serves as a distinct scaffold. The novel, profound and expanded roles of SRA are emerging in critical aspects of coactivation of nuclear receptors (NRs). As a nuclear receptor coactivator, SRA can coactivate androgen receptor (AR), estrogen receptor α (ERα), ERβ, progesterone receptor (PR), glucocorticoid receptor (GR), thyroid hormone receptor and retinoic acid receptor (RAR). Although SRA is one of the least well-understood molecules, increasing studies have revealed that SRA plays a key role in both biological processes, such as myogenesis and steroidogenesis, and pathological changes, including obesity, cardiomyopathy, and tumorigenesis. Furthermore, the SRA-related signaling pathways, such as the mitogen-activated protein kinase (p38 MAPK), Notch and tumor necrosis factor α (TNFα) pathways, play critical roles in the pathogenesis of estrogen-dependent breast cancers. In addition, the most recent data demonstrates that SRA expression may serve as a new prognostic marker in patients with ER-positive breast cancer. Thus, elucidating the molecular mechanisms underlying SRA-mediated functions is important to develop proper novel strategies to target SRA in the diagnosis and treatment of human diseases.


Parent-child interaction and children's depression: the relationships between parent-child interaction and children's depressive symptoms in Taiwan.
This study examines how perceptions of parenting and family messages are associated with the depressive symptoms of early adolescents (N = 454, boys = 224; girls = 210; age, M = 12, S.D. = 1.01) from East Taiwan. Results show that higher levels of parental care and low levels of parental indifference were associated with lower depression scores. Moreover, perceptions of positive messages regarding children themselves, their world, and their future were found to negatively associate with depression, whereas negative messages had an opposite effect. Basically, girls' depressive symptoms were more related to maternal messages, and boys' were more related to paternal messages.


Erratum to "Cumulative dairy cow genetic change from selection and crossbreeding over the last 2 decades in New Zealand closely aligns to model-based predictions published in 2000" (JDS Commun. 2:51-54).
[This corrects the article DOI: 10.3168/jdsc.2020-0043.].


Enzymatic response of the eucalypt defoliator Thyrinteina arnobia (Stoll) (Lepidoptera: Geometridae) to a bis-benzamidine proteinase Inhibitor. i.
Ingestion of proteinase inhibitors leads to hyperproduction of digestive proteinases, limiting the bioavailability of essential amino acids for protein synthesis, which affects insect growth and development. However, the effects of proteinase inhibitors on digestive enzymes can lead to an adaptive response by the insect. In here, we assessed the biochemical response of midgut proteinases from the eucalypt defoliator Thyrinteina arnobia (Stoll) to different concentrations of berenil, a bis-benzamidine proteinase inhibitor, on eucalyptus. Eucalyptus leaves were immersed in berenil solutions at different concentrations and fed to larvae of T. arnobia. Mortality was assessed daily. The proteolytic activity in the midgut of T. arnobia was assessed after feeding on plants sprayed with aqueous solutions of berenil, fed to fifth instars of T. arnobia for 48 h before midgut removal for enzymatic assays. Larvae of T. arnobia were able to overcome the effects of the lowest berenil concentrations by increasing their trypsin-like activity, but not as berenil concentration increased, despite the fact that the highest berenil concentration resulted in overproduction of trypsin-like proteinases. Berenil also prevented the increase of the cysteine proteinases activity in response to trypsin inhibition.


Development of a novel functional biosensor with a short Ca(2+)-dependent deoxyribozyme.
We develop a novel functional biosensor on a deoxyribozyme. A 5'-end-immobilized short Ca(2+)-dependent deoxyribozyme (dCGCTGGCAGGCTACAACGAGTCTTC) binds to a target RNA substrate (rGAAGACA decrease UGCCAGCG; decrease denotes an RNA cleavage site), and acts as an enzyme in the presence of Ca2+. It cleaves the target RNA substrate at one site of rAp decrease U in the asymmetric internal loop.


FTO alleviates cerebral ischemia/reperfusion-induced neuroinflammation by decreasing cGAS mRNA stability in an m6A-dependent manner.
Microglia-mediated inflammation is a major contributor to the brain damage in cerebral ischemia and reperfusion (I/R) injury, and N6-Methyladenosine (m6A) has been implicated in cerebral I/R injury. Here, we explored whether m6A modification is associated with microglia-mediated inflammation in cerebral I/R injury and its underlying regulatory mechanism using an in vivo mice model of intraluminal middle cerebral artery occlusion/reperfusion (MCAO/R) and in vitro models of primary isolated microglia and BV2 microglial cells subjected to oxygen-glucose deprivation and reoxygenation (OGD/R) were used. We found microglial m6A modification increased and microglial fat mass and obesity-associated protein (FTO) expression decreased in cerebral I/R injury in vivo and in vitro. Inhibition of m6A modification by intraperitoneal injection of Cycloleucine (Cyc) in vivo or transfection of FTO plasmid in vitro significantly alleviated brain injury and microglia-mediated inflammatory response. Through Methylated RNA immunoprecipitation sequencing (MeRIP-Seq), RNA sequencing (RNA-Seq) and western blotting, we found that m6A modification promoted cerebral I/R-induced microglial inflammation via increasing cGAS mRNA stability to aggravate Sting/NF-κB signaling. In conclusion, this study deepens our understanding on the relationship of m6A modification and microglia-mediated inflammation in cerebral I/R injury, and insights a novel m6A-based therapeutic for inhibiting inflammatory response against ischemic stroke.


[Pulmonary toxicity of antineoplastic agents--with special reference to current findings on pulmonary toxicity of bleomycin].
Pulmonary toxicity due to antitumor agents, chiefly bleomycin pulmonary toxicity including clinical feature, histopathology, pathophysiology, biochemical changes, common clinical settings (risk factors), and prevention was reviewed. Moreover, pulmonary toxicity from methotrexate, busulfan, cyclophosphamide, mitomycin C, 6-mercaptopurine, nitrosourea and procarbazine was reviewed.


Integration of Artificial Intelligence, Blockchain, and Wearable Technology for Chronic Disease Management: A New Paradigm in Smart Healthcare.
Chronic diseases are a growing concern worldwide, with nearly 25% of adults suffering from one or more chronic health conditions, thus placing a heavy burden on individuals, families, and healthcare systems. With the advent of the "Smart Healthcare" era, a series of cutting-edge technologies has brought new experiences to the management of chronic diseases. Among them, smart wearable technology not only helps people pursue a healthier lifestyle but also provides a continuous flow of healthcare data for disease diagnosis and treatment by actively recording physiological parameters and tracking the metabolic state. However, how to organize and analyze the data to achieve the ultimate goal of improving chronic disease management, in terms of quality of life, patient outcomes, and privacy protection, is an urgent issue that needs to be addressed. Artificial intelligence (AI) can provide intelligent suggestions by analyzing a patient's physiological data from wearable devices for the diagnosis and treatment of diseases. In addition, blockchain can improve healthcare services by authorizing decentralized data sharing, protecting the privacy of users, providing data empowerment, and ensuring the reliability of data management. Integrating AI, blockchain, and wearable technology could optimize the existing chronic disease management models, with a shift from a hospital-centered model to a patient-centered one. In this paper, we conceptually demonstrate a patient-centric technical framework based on AI, blockchain, and wearable technology and further explore the application of these integrated technologies in chronic disease management. Finally, the shortcomings of this new paradigm and future research directions are also discussed.


The ecological importance of insect frass: allelopathy in eucalypts.
Our previously published experiments on allelopathic effects of insect frass in Eucalyptus communities (Silander et al. 1983) have been criticized on the grounds that our estimates of annual frass production were exscessive (Ohmart 1985). However, we spanned the entire array of estimates of frass fall available from eucalypt communities, and we demonstrated allelopathic effects at even the lowest levels suggested by Ohmart. We suggest that average values of frass fall per hectare are irrelevant because they ignore both large scale variation among sites in time and space, and small scale variation in patchiness of frass accumulation. At the ecological scales relevant to germinating seeds, frass concentrations in local pockets may be considerably higher than the averages calculated for the entire ground surface.


Comparison of efficacy dimenhydrinate and metoclopramide in the treatment of nausea due to vertigo; a randomized study.
This study aimed to compare the therapeutic efficacy of dimenhydrinate and metoclopramide in patients with nausea and vertigo. A prospective, double-blind, randomized clinical trial was performed on patients who presented to the emergency department (ED) with nausea and vertigo in the six month period between Nov 1st 2012 and May 1st 2013. Adult patients who were 18 to 65 years old presenting to the ED with nausea and vertigo or motion sickness were included in the study. A total of 200 patients were divided into 2 groups who were admitted to ED with complaints of vertigo accompanied by nausea. In the first group, 50 mg dimenhydrinate and 10 mg metoclopramide infusions were given intravenously for 15 min. The efficacy of treatment was measured by using a 10 mm Visual Analog Scale (VAS) performed at 0, 15 and the 30th minute. The primary outcome variable was a reduction in vertigo intensity documented on the VAS at the 30th minute after medication administration. A total of 200 patients were included in the randomization (n=100 in both groups). The baseline vertigo VAS scores were 7.57±1.42 in the dimenhydrinate (DMT) group and 7.27±1.40 in the metoclopramide (MTP) group (p=0.09). In the 30th minute of treatment, the average vertigo VAS score was 2.46 ± 2.39 in the DMT group and 2.31±1.96 in the MTP group; no significant differences were detected between groups. The baseline nausea VAS scores were 7.62±1.48 in the DMT group and 7.45±1.27 in the MTP group (p=0.36). In the 30th minute of treatment the average vertigo VAS score decreased to 2.27±2.24 in the DMT group and 2.70±2.48 in the MTP group, no significant differences were detected between groups. No significant differences were detected between nausea VAS changes and vertigo VAS changes at 30th minutes of the treatment (p=0.06, p=0.85 respectively). Rescue medication need was similar in both treatment groups (p=0.94). No significant differences were detected about the side effects which are sedation (p=0.56) and hypotension (p=0.57). In conclusion, this prospective, double-blind, randomized study showed that both DMT and MTP have similar efficacy in reducing nausea and vertigo symptoms in the ED.


Isomer-specific analysis of nonylphenol and their transformation products in environment: A review.
Nonylphenols (NPs) are crucial fine chemicals widely employed in producing industrial and consumer surfactants that ultimately enter the environment through various pathways, leading to environmental pollution. NPs are suspected endocrine-disrupting chemicals that may accumulate in the body over time, resulting in unusual reproductive function. Due to limitations in analytical methods, NPs have typically been quantified as a whole in some studies. However, NPs are a mixture of multibranched structures, and different NP isomers exhibit distinct environmental behaviors and toxic effects. Therefore, it is critical to analyze environmental and human biological samples at the isomer-specific level to elucidate the contamination characteristics, human exposure load, and toxic effects of NPs. Accurately analyzing NP samples with various isomers, metabolites, and transformation products presents a significant challenge. This review summarizes recent advances in analytical research on NPs in technical products, environmental, and human biological samples, particularly emphasizing the synthesis and separation of standards and the transformation of NP homolog isomers in samples. Finally, the review highlights the research gaps and future research directions in this domain.


Natural history and prognostic factors of primary biliary cirrhosis in Taiwan: a follow-up study up to 18 years.
The natural history of primary biliary cirrhosis (PBC) has been little studied in Asia. We conducted a Taiwanese cohort study on the natural history of PBC and analysed the prognostic factors. This study enrolled 96 consecutive PBC patients between 1985 and 2006 to evaluate the baseline characteristics and outcomes. There were 74 females and 22 males. Eighty-five were positive for antimitochondrial antibodies in sera, and 11 were negative. The clinical manifestations and prognosis were similar between these two groups. In a median follow-up of 47.5+/-55.8 months, 27 patients died. Multivariate analysis indicated that the independent prognostic factors were serum albumin (P=0.021), creatinine (P=0.033) and ursodeoxycholic acid treatment (P=0.008). Besides, 42 patients developed adverse outcomes. Albumin (P<0.001), bilirubin (P=0.019) and prothrombin time (PT) (P=0.010) were significant factors. Moreover, a Mayo risk score <5, a Model for End-Stage Liver Disease (MELD) score <6, a Child-Pugh stage A and early liver histology were associated with favourable outcomes. Serum albumin, bilirubin and PT were independent prognostic factors of adverse outcomes for Taiwanese PBC patients. Besides, the Mayo risk score, the MELD score, the Child-Pugh stage and liver histology were also validated to predict survival.


The case of the Marquis de Causan (1804): an early account of visual loss associated with spinal cord inflammation.
The recent discovery of disease specific and pathogenic autoantibodies in neuromyelitis optica (NMO, Devic's disease) has revived the interest in this intriguing yet often devastating condition. While the history of classic multiple sclerosis has been studied extensively, only very little is known so far about the early history of NMO. Here we discuss a now forgotten report by the famous French anatomist and pathologist Antoine Portal (1742-1832), first physician to Louis XVIII and founding and lifelong president of the Académie Nationale de Médecine. Portal's report, which fascinated some of the most renowned 19th century pioneers in the field of neurology but fell into oblivion later, represents the first account of visual loss in a patient with spinal cord inflammation but no brain pathology in the Western literature known so far--published more than 60 years prior to Thomas Clifford Allbutt's much cited note on a patient with myelitis and a "sympathetic eye disorder".


Implications of using approximate Bloch-McConnell equations in NMR analyses of chemically exchanging systems: application to the electron self-exchange of plastocyanin.
The validity of a series of approximate solutions of the Bloch-McConnell equations normally applied in the analyses of chemically exchanging systems is evaluated, using the electron self-exchange (ESE) in the blue copper protein plastocyanin from Anabaena variabilis as an example. The evaluation is based on a comparison with the results of a complete analysis of the NMR signals of chemically exchanging nuclei that allows an independent and accurate determination of all the involved parameters. The complete analysis is based on the general solution of the Bloch-McConnell equations. It includes a simultaneous analysis of the chemical shift, and the transverse and longitudinal relaxation rates of the observed nuclei as well as the variation of these parameters with the molar fractions of the exchanging species and the rate of the chemical exchange process. The linear prediction model method was used in the data analysis to achieve the highest possible precision. Surprisingly, it is found that the fast exchange condition may not be fulfilled even in cases where a single exchange-averaged NMR signal is observed, and the Larmor frequency and relaxation rates depend linearly on the molar fractions of the exchanging species. In such cases the use of approximate solutions in the analysis of the transverse relaxation rates and the pseudo-contact shifts can lead to erroneous results. In limiting cases close to the fast exchange and slow exchange regimes correct values of some of the parameters can be obtained using the second order approximate solution of the Bloch-McConnell equations. In contrast, the complete analysis of the NMR signals results in an accurate determination of the exchange rates and the NMR parameters of the exchanging sites. This, in turn, can provide information about the structure and function of a protein undergoing chemically exchange. For the investigated plastocyanin the complete analysis results in an accurate determination of the paramagnetic enhancement of the nuclear relaxation rates, the paramagnetic chemical shift, the electron relaxation rate, the electron self-exchange rate, and the distances between the nuclei and the paramagnetic metal ion, viz. the Cu2+ ion.


Inhibition of phosphodiesterase activity of human spermatozoa by spermine.
Sperm motility and metabolism are dependent upon the levels of cyclic AMP. Our studies have demonstrated that spermine by inhibiting sperm phosphodiesterase activity could regulate sperm physiology.


Application of targeted maximum likelihood estimation in public health and epidemiological studies: a systematic review.
The targeted maximum likelihood estimation (TMLE) statistical data analysis framework integrates machine learning, statistical theory, and statistical inference to provide a least biased, efficient, and robust strategy for estimation and inference of a variety of statistical and causal parameters. We describe and evaluate the epidemiological applications that have benefited from recent methodological developments. We conducted a systematic literature review in PubMed for articles that applied any form of TMLE in observational studies. We summarized the epidemiological discipline, geographical location, expertize of the authors, and TMLE methods over time. We used the Roadmap of Targeted Learning and Causal Inference to extract key methodological aspects of the publications. We showcase the contributions to the literature of these TMLE results. Of the 89 publications included, 33% originated from the University of California at Berkeley, where the framework was first developed by Professor Mark van der Laan. By 2022, 59% of the publications originated from outside the United States and explored up to seven different epidemiological disciplines in 2021-2022. Double-robustness, bias reduction, and model misspecification were the main motivations that drew researchers toward the TMLE framework. Through time, a wide variety of methodological, tutorial, and software-specific articles were cited, owing to the constant growth of methodological developments around TMLE. There is a clear dissemination trend of the TMLE framework to various epidemiological disciplines and to increasing numbers of geographical areas. The availability of R packages, publication of tutorial papers, and involvement of methodological experts in applied publications have contributed to an exponential increase in the number of studies that understood the benefits and adoption of TMLE.


Neuroinflammation changes with periodontal inflammation status during periodontitis in wild-type mice.
To investigate neuroinflammation under different periodontal status. Experimental periodontitis was induced by molar ligation (Lig group) or periodontal injection of lipopolysaccharide (LPS, Lps group). Periodontal status was assessed by alveolar bone resorption and periodontal inflammation. Micro-computed tomography and haematoxylin-eosin staining were performed to assess alveolar bone resorption and periodontal inflammation, respectively. Neuroinflammation was assessed by glial cell proliferation and proinflammatory factor expression. Microgliosis was determined by immunofluorescence. Astrogliosis was determined by immunohistochemistry. Expressions of tumour necrosis factor-alpha (TNF-α) and interleukin (IL)-1β were assessed by enzyme-linked immunosorbent assay. Microgliosis and astrogliosis in the Lig group were notable with molar ligation for 2 weeks and 4 weeks (p < .05), but were only slightly different similar from the control group by week 12. Microgliosis and astrogliosis in the Lps group were significant with LPS injection for 4 and 8 weeks (p < .05). The groups displayed a positive correlation between the degree of periodontal inflammation and the number of glial cells (p < .05). Expressions of IL-1β and TNF-α in the Lps group were significantly increased with LPS injection for 8 weeks (p < .05). In the Lig group, only TNF-α was highly expressed with molar ligation for 12 weeks (p < .05). Both models demonstrated that the inflammatory response in the hippocampus of mice can change during periodontitis depending on the periodontal inflammation status.


Arsenic in the health of ecosystems: spatial distribution in water, sediment and aquatic biota of Pampean streams.
A survey of arsenic and phosphorus in Pampean streams of Buenos Aires province was performed. Nitrates and ammonia were also determined. Stream water was sampled as well as stream sediment and filamentous algae. Results show that 32 streams exceeded the arsenic recommended guidelines for human consumption of 10 μg L-1 and six exceeded recommended values for aquatic organisms' protection of 50 μg L-1. The average concentration found was 36.54 μg L-1 and areas with more concentration of As are located in the southern region of the province, in streams that are tributaries of the Atlantic Ocean. Other regions with high As concentration are the Matanza River tributaries and the Arrecifes River tributaries. No differences of As concentration was found between stream sediments. Also, no seasonal pattern of As concentration was observed in one stream sampled during a year, but a positive correlation between As and the conductivity (p = 0.0002) and pH (p = 0.01) of the streams was found. Also, As bioaccumulation was detected for all the algae sampled, but no correlation between As accumulated and As in the stream water was found. Ammonia levels exceeded recommended guidelines for human consumption in the Argentinean law in 30 streams. The characterization performed in this study provides relevant information on the distribution of arsenic and its origin and mobility.


Anticonvulsant effects of melatonin in amygdala-kindled rats.
Different doses of melatonin (50-100 mg/kg i.p.) were tested for their ability to suppress complex partial seizures in the amygdala kindling model of the rat. Thirty minutes after injection of 75 or 100 mg/kg melatonin, the current threshold necessary to elicit epileptic afterdischarges (ADT) was significantly increased by about 200 or 250%, respectively. These doses were also sufficient to suppress generalised seizures at threshold current. All doses of melatonin decreased body temperature by more than 0.5 degrees C, but caused no pronounced ataxia. Seizure susceptibility in terms of ADT changed with the time of the day but seems not to depend on the circadian variation of endogenous melatonin, since the highest ADT was found in the morning when endogenous melatonin levels are low.


Role of endothelium in hyperemia during cortical spreading depression (CSD) in the rat.
The purpose of this study was to examine whether endothelium-mediated dilation is responsible for the cortical hyperemia that occurs during cortical spreading depression (CSD) in rats using three different approaches. The first approach taken was the acute pharmacological inhibition of the predominant endothelium-centered dilator systems, using indomethacin, a cyclooxygenase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, and miconazole, a cytochrome P-450 epoxygenase inhibitor. The second approach used was the acute general pharmacological impairment of endothelial function by the intravascular administration of phorbol 12, 13-dibutyrate (PDBu). The third approach taken was the chronic impairment of endothelium-dependent dilator responses by diet in insulin resistant (IR) rats. Cerebral blood flow (CBF) was measured using laser Doppler flowmetry. CSD was elicited by the topical application of potassium chloride. Pharmacological inhibition of endothelium-dependent dilator factors did not affect CSD. For example, with 20 mg/kg L-NAME, CBF peak of the first series of CSDs was 377 +/- 67% of baseline CBF. After drug administration, CBF peaks of the second and the third series of CSDs were 451 +/- 67% and 390 +/- 69% (n=5, P=n.s.), respectively. Control and IR animals and those treated with indomethacin, miconazole and PDBu showed similar results. We also calculated the area under the CBF curve to fully represent the extent of hyperemia during CSD. However, there were no significant differences in the CBF area with any treatment compared to control animals. Thus, our results provide strong evidence that endothelium-mediated mechanisms have minimal effects on the CSD-associated hyperemia.


Honeymoon, medical treatment or big business? An analysis of the meanings of the term "reproductive tourism" in German and Israeli public media discourses.
Infertile couples that travel to another country for reproductive treatment do not refer to themselves as "reproductive tourists". They might even be offended by this term. "Tourism" is a metaphor with hidden connotations. We will analyze these connotations in public media discourses on "reproductive tourism" in Israel and Germany. We chose to focus on these two countries since legal, ethical and religious restrictions give couples a similar motivation to travel for reproductive care, while the cultural backgrounds and conceptions of reproduction are different. Our research shows that the use of the metaphor "reproductive treatment" and its hidden messages depends on the writers' intention and the target population. Although the phenomenon of patients travelling for reproductive treatment can fit into the definitions of tourism, the term emphasizes aspects that do not reflect patients' reality. In both the German and the Israeli public media debate the term "reproductive tourism" is either used to criticize the economic aspects of the phenomenon or to attract patients as potential clients. Ethicists should be cautious when borrowing metaphors like "reproductive tourism" from the public debate. Our findings support Penning's suggestion to use instead an unloaded term like cross-border reproductive care to describe the phenomenon in a more neutral way and to make it explicit whenever criticism is necessary.


Formulation design and mechanism study of hydrogel based on computational pharmaceutics theories.
Formulation design and mechanism study of the drug delivery system (DDS) is an important but difficult subject in pharmaceutical research. The study of formulation factors is the most time- and labor-consuming work of formulation design. In this paper, a multiscale computational pharmaceutics strategy was developed to guide the systematic study of formulation factors of a typical polymer-based DDS, hydrogel, and further to guide the formulation design. According to the strategy, the combination of solubility parameter (δ) and diffusion coefficient (D) calculated by the AA-MD simulation was suggested as the general evaluation method for the matrix screening of the hydrogels at the pre-formulation stage. At the formulation design stage, the CG-MD simulation method was suggested to predict the morphology and drug-releasing behavior of the hydrogels under different formulation factors. The influence mechanism can be explained by the combination of multiple parameters, such as the microstructure diagram, the radius of gyration (Rg), the radial distribution function (RDF), and the free diffusion volume (Vdiffusion). The simulation results are in good agreement with the in vitro release experiment, indicating that the strategy has good applicability.


Suppression of autophagy enhanced growth inhibition and apoptosis of interferon-β in human glioma cells.
Interferon-beta (IFN-β) is a cytokine with anti-viral, anti-proliferative, and immunomodulatory effects. In this study, we investigated the effects of IFN-β on the induction of autophagy and the relationships among autophagy, growth inhibition, and apoptosis induced by IFN-β in human glioma cells. We found that IFN-β induced autophagosome formation and conversion of microtubule associated protein 1 light chain 3 (LC3) protein, whereas it inhibited cell growth through caspase-dependent cell apoptosis. The Akt/mTOR signaling pathway was involved in autophagy induced by IFN-β. A dose- and time-dependent increase of p-ERK 1/2 expression was also observed in human glioma cells treated with IFN-β. Autophagy induced by IFN-β was suppressed when p-ERK1/2 was impaired by treatment with U0126. We also demonstrated that suppression of autophagy significantly enhanced growth inhibition and cell apoptosis induced by IFN-β, whereas inhibition of caspase-dependent cell apoptosis impaired autophagy induced by IFN-β. Collectively, these findings indicated that autophagy induced by IFN-β was associated with the Akt/mTOR and ERK 1/2 signaling pathways, and inhibition of autophagy could enhance the growth inhibitory effects of IFN-β and increase apoptosis in human glioma cells. Together, these findings support the possibility that autophagy inhibitors may improve IFN-β therapy for gliomas.


Rotator Cuff Tears at the Musculotendinous Junction: Classification and Surgical Options for Repair and Reconstruction.
Although uncommon, rotator cuff tears that occur medially at the musculotendinous junction can result from acute trauma, anatomic force imbalance, or medial row cuff failure following a previous rotator cuff repair. The quality of the torn muscle and tendon along with the length of the remnant tendon stump should be considered before deciding on the most appropriate repair technique. When muscle and tendon quality are sufficient, the tear can often be repaired directly to the remnant tendon stump and compressed onto the greater tuberosity. If the remnant tendon stump is degenerative, of insufficient length, or lacks tendon in which to place sutures, an allograft patch can be used to augment the repair. When the quality of the remaining muscle and tendon are poor or when the muscle is retracted too far medially and is nonmobile, a bridging technique such as superior capsule reconstruction is preferable. The purpose of this report is to (1) highlight that medial cuff failure can occur both primarily and after previous repair; (2) define and classify the 3 major tear patterns that are encountered, and (3) describe the authors' preferred techniques for medial cuff repair that specifically address each of the major tear patterns.


TOPALi: software for automatic identification of recombinant sequences within DNA multiple alignments.
TOPALi is a new Java graphical analysis application that allows the user to identify recombinant sequences within a DNA multiple alignment (either automatically or via manual investigation). TOPALi allows a choice of three statistical methods to predict the positions of breakpoints due to past recombination. The breakpoint predictions are then used to identify putative recombinant sequences and their relationships to other sequences. In addition to its sophisticated interface, TOPALi can import many sequence formats, estimate and display phylogenetic trees and allow interactive analysis and/or automatic HTML report generation. TOPALi is freely available from http://www.bioss.ac.uk/software.html


Adult-onset primary Ewing's sarcoma of the right atrium: a case report.
Primary cardiac tumors, which are only detected in 0.001-0.03% of autopsies, are rare. Only 25% of primary cardiac tumors are malignant, of which 95% are sarcomas. Ewing's sarcoma, one of the Ewing's sarcoma of family tumors, is thought to be derived from neural crest cells. While Ewing's sarcoma usually presents in the bone of children, Ewing's sarcoma of cardiac origin is rare, with only a few reports described in the literature. The prognosis is unpredictable because of the scarcity and unestablished treatment. We herein report an extremely rare case of primary cardiac Ewing's sarcoma in the right atrium of a 64-year-old man. The patient is a 64-year-old Japanese male who was referred to our hospital to treat a floating mass of the right atrium (RA). Although the patient was asymptomatic, we performed an operation to urgently resect the floating mass on the next day of admission due to the risk of pulmonary embolism. The operation was performed under cardiopulmonary bypass and cardiac arrest. We resected the tumor with at least 1.5 cm of the RA wall as a margin. The postoperative pathological diagnosis of the mass was compatible with a primitive neuroectodermal tumor (PNET, a form of Ewing's sarcoma). The cells were positive for CD56, CD99, and Vimentin and negative for S-100 and Desmin. Although no malignant cells were observed in the margin of the resected RA wall and the sarcoma was completely resected, he was transferred to another hospital to receive adjuvant postoperative chemotherapy to improve the prognosis by preventing subclinical micrometastasis. We experienced an extremely rare case of primary cardiac Ewing's sarcoma in the right atrium of a 64-year-old man, which was successfully resected under cardiac arrest. Although the sarcoma was completely resected, postoperative chemotherapy and long-term follow-up are recommended for patients with primary cardiac sarcoma because of the high rates of metastasis and recurrence.


Mindlink: A stigma-free youth-friendly community-based early-intervention centre in Korea.
In many Asian countries, youth mental health services are not well-developed and access to treatment is generally delayed. Here, we present a community-based service model based on our experience with Mindlink, the first early-intervention centre of its kind in Korea. We describe the history of this mental health early-intervention service and the characteristics of users, as well as its intervention programmes and research directions. We also propose ways to further develop youth mental health services. A community-based early-intervention service for youth was first introduced in 2012, when a special team was formed in a community mental health centre of Korea. As the numbers of young clients increased, a youth-friendly, early-intervention centre called Mindlink was opened in 2016. Mindlink targets those aged 15-30 years with mental illness less than 5 years in duration. Its goal is to detect mental illness in young people early and provide comprehensive multidisciplinary interventions. It provides intensive case management and group programmes including cognitive-behavioural therapy, family intervention, psychoeducation, behavioural activation and physical health promotion. The Korean government has officially announced that the Mindlink model is effective and is currently in the process of scaling it up on a national level. An accessible, youth-friendly, stigma-free, community mental health centre such as Mindlink allows early detection and appropriate management of mental illness in young patients.


Prenatal stress suppresses the prefrontal and amygdaline EEG changes associated with a sexually-motivated state in male rats.
The medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) participate in the modulation of several motivated behaviors, such as the sexual behavior. Both structures are sensitive to stress when it is experienced mainly in critical periods of the life-cycle, such as the prenatal period. This study evaluated the effects of prenatal stress on electroencephalographic activity (EEG) of the mPFC and BLA during sexual motivation. EEG was recorded in the mPFC and BLA of male rats assigned to either a prenatally-stressed group (SG, dam immobilized from days 14 to 21of pregnancy), or a control group (CG), during the following conditions: awake-quiet state without sexual motivation, and awake-quiet state with sexual motivation. Compared to CG, fewer SG subjects presented copulatory responses and their levels of sexual motivation were lower. The CG subjects with sexual motivation showed a higher absolute power (AP) of the 14-30Hz band in the left mPFC and BLA than those without sexual motivation. The SG showed a lower AP of the 4-7 and 8-13Hz bands in the left BLA. Thus, prenatal stress suppressed the prefrontal and amygdaline EEG changes associated with a sexually-motivated state. EEG data show that stress affects the functioning of these two brain structures and so could interfere with the adequate processing of sexual stimuli. These findings contribute to understanding the brain mechanisms that underlie the effect of prenatal stress on the processing of sexual stimuli in male rats.


[Impact of corticosteroid withdrawal in chronic urticaria: a prospective study of 17 patients].
Although two reports have indicated benefits of oral steroids in acute urticaria, the 2003 French guidelines emphasized their inefficacy in the treatment of idiopathic chronic urticaria, and the lack of studies. We present the results of a prospective study in 17 patients presenting severe chronic urticaria who agreed to stop taking oral steroids over a one-year period. This single-centre prospective study included adults (1) presenting chronic urticaria as defined by the French consensus conference committee on chronic urticaria (2003), (2) exhibiting at least two of the following three criteria: sleep disturbance due to itching, repeated angioedema, general symptoms; (3) unresponsive or mildly improved by antihistaminic (anti-H1) therapy; (4) receiving oral steroids at least three days per month. After inclusion in the study, oral steroids were stopped either immediately or gradually, on a case-by-case basis. Two different anti-H1 agents were prescribed at inclusion with follow-up visits two, four and 12 months after complete withdrawal of oral steroids. Seventeen patients were included (M/F sex-ratio: 0.54; mean age: 40 years). General signs (fever, arthralgia, various pains), delayed pressure urticaria, and idiopathic cutaneous vasculitis were noted respectively, in seven, nine and three cases. Oral steroids had been taken for three to 30 days per month before inclusion. Three patients had received prior treatment (e.g., immunosuppressants), with no improvement. After withdrawal of oral steroids, (1) 47% of patients presented a short relapse and/or worsening of chronic urticaria, (2) three patients dropped out of the study at four months (persistence of chronic urticaria unacceptable to patients, despite a clinical score showing mild response), (3) six (35%) had complete remission of chronic urticaria at 12 months, with delayed pressure urticaria in three of these cases, (4) eight (47%) had partial remission, five of whom had delayed pressure urticaria, (5) lasting remission of general symptoms. Our study shows that most cases of chronic urticaria are managed without oral steroids since inefficacy of anti-H1 drugs is generally only temporary. After withdrawal of oral steroids, a short increase in chronic urticaria was frequently observed with constant remission from extracutaneous signs and/or histological evidence of vasculitis. We suggest an active role of oral steroids in the failure of anti-H1 therapy. Moreover, oral steroids do not seem to confer any benefits in delayed pressure urticaria, and pending further prospective controlled studies, we recommend that these drugs be prescribed sparingly in chronic urticaria.


Antidepressant prescriptions have not fully reflected evolving evidence from cumulative network meta-analyses and guideline recommendations.
This study compares three major elements of evidence-based medicine (EBM) practices, namely evidence synthesis, clinical practice guidelines (CPGs), and real-world prescriptions in the United States, regarding antidepressant treatments of major depression over the past 3 decades. We conducted network meta-analyses (NMAs) of antidepressants every 5 years up to 2016 based on a comprehensive data set of double-blind randomized controlled trials. We identified CPGs and extracted their recommendations. We surveyed the prescriptions in the United States at 5-year intervals up to 2015. Most drugs recommended by CPGs presented favorable performance in efficacy and acceptability in NMAs. However, CPG recommendations were often in terms of drug classes rather than individual drugs, whereas NMAs suggested distinctive difference between drugs within the same class. The update intervals of all CPGs were longer than 5 years. All the antidepressants prescribed frequently in the United States were recommended by CPGs. However, changes in prescriptions did not correspond to alterations in CPGs or to apparent changes in the effects indicated by NMAs. Many factors including marketing efforts, regulations, or patient values may have played a role. Enhancements including accelerating CPG updates and monitoring the impact of marketing on prescriptions should be considered in future EBM implementation.


Changing chronic pain experience.
Training in relaxation is a prominent component in multi-disciplinary approaches to the management of chronic pain, although its specific potency in modulating pain has not yet been established. Using a within-session design, the specific effects of relaxation induction were evaluated in a group of benign chronic pain patients (n = 24), and compared to similar patients undergoing a control procedure (n = 22). The results indicated that irrespective of the focus of pain complaint, induction of relaxation over a 20 min period led to significant and sizeable reductions in both sensory and affective pain experience. The overall intensity of pain was significantly reduced. These effects were shown to be reliable and independent of onset level of sensory experience or depression. No significant changes occurred in the control group over a comparable period. The implications of these results were discussed with respect to the process by which relaxation reduces pain.


Hepatic S4a + S5 and bile duct resection for gallbladder carcinoma.
In the surgical treatment of gallbladder cancer, segment 4a + 5 hepatic resection and bile duct resection is usually recommended for T2 and/or T3 gallbladder cancer involving hepatic parenchyma without hepatic biliary confluence. This procedure does not affect liver function excessively, provided there is correct identification of hepatic S4a and S5, the most important aspect of this procedure. In this paper, the technique of hepatic S4a + 5 and bile duct resection is described in detail. This surgical procedure could be a useful option for the surgical treatment of the hepatobiliary pancreatic malignancies. Surgeons should therefore master the surgical techniques for this procedure.


Chemoprevention of colon cancer by calcium, vitamin D and folate: molecular mechanisms.
Recent findings have indicated that dietary calcium, vitamin D and folate can modulate and inhibit colon carcinogenesis. Supporting evidence has been obtained from a wide variety of preclinical experimental studies, epidemiological findings and a few human clinical trials. Important molecular events and cellular actions of these micronutrients that contribute to their tumour-modulating effects are discussed. They include a complex series of signalling events that affect the structural and functional organization of colon cells.


Compatibility of mechanical and computerized axiographs: a pilot study.
There is little known information comparing axiographic data obtained with a mechanical device and data obtained with a computerized device. However, long-term follow-up of patients may necessitate comparison of previously made mechanical axiographic data with records obtained through computer-aided axiography. The purpose of this study was to compare measurements between mechanical and computerized axiographs in recording the rotational and translation movements of the mandible. The study enrolled 31 subjects with no detectable clinical signs of temporomandibular disorders. A single operator obtained 3 separate axiographic tracings of right and left condylar paths for each subject, using repeated opening, closing, protrusive, and retrusive movements. Data were collected for both the mechanical (SAM Axiograph Axo 200), and the computerized axiographs (SAM Axiotron and Axo 500). Angular (degrees) and linear measurements (mm) for the mechanical axiograph were made from the tracings obtained on grid paper using a compass, ruler, and protractor. The computer performed the measurements for the computerized axiograph tracings. All parameters were compared statistically with a Wilcoxon signed rank test (alpha = .05). The same operator remeasured all mechanical axiographic tracings for 20 subjects 1 week later to evaluate measurement error. Chronbach's alpha was used as a measure of consistency between the 2 measurements. Mean opening and closing angles varied between 52.4 and 54.2 degrees, and mean protrusive, and retrusive angles varied between 50.1 and 54.9 degrees. Mean opening and closing distances varied between 11.4 and 12.3 mm, and mean protrusive and retrusive distances varied between 8.2 and 8.7 mm. Comparison with the Wilcoxon signed rank test showed no significant differences for any parameter tested. There were high and medium inter-item correlations between repeated measurements of the manual device when Chronbach's alpha was applied, but these results were not sufficient to prove consistency between 2 consecutive measurements. The results showed nonsignificant differences between the recordings of the mechanical and computerized axiographs tested. The authors hypothesize that minor differences may be attributed to hand-measuring errors for the tracings generated by the mechanical axiograph. This study is limited due to the impact of poor precision of the manual device on the study results when these recordings are compared to another instrument. Therefore, it is not possible to conclude that data from the manual and the computerized axiographs are compatible with each other.


Mutagenicity of polycyclic aromatic hydrocarbons and quinones on Salmonella typhimurium TA97.
18 polycyclic aromatic hydrocarbons (PAHs) and 7 quinones were tested for mutagenicity using Salmonella typhimurium TA97, TA98 and TA100 with or without metabolic activation. In the presence of metabolic activation, TA97 was more susceptible to mutation than either TA98 or TA100 by many of PAHs tested. PAHs such as 1-methylphenanthrene, fluoranthene, pyrene, benzo[a]pyrene, benzo[e]pyrene and perylene had high mutagenic effects on TA97 in the presence of metabolic activation. 1,6- and 1,8-pyrenequinones were also highly mutagenic on TA97 in the presence or absence of metabolic activation. It appears that pyrene is mutagenic through its metabolic conversion to pyrenequinones.


Does fear of cancer recurrence differ between cancer types? A study from the population-based PROFILES registry.
Knowledge of factors associated with fear of cancer recurrence (FCR) may inform intervention development and improve patient care. The aims were (1) to compare FCR severity between cancer types and (2) to identify associations between FCR, demographics, medical characteristics, information provision and health-related quality of life. Cross-sectional data were obtained from the Patient Reported Outcomes Following Initial Treatment and Long-Term Evaluation of Survivorship registry. We included stage I and II survivors diagnosed with melanoma (n = 469), colorectal cancer (n = 861), endometrial cancer (n = 688), thyroid cancer (n = 218), Hodgkin (n = 103) and non-Hodgkin lymphoma (n = 276). Cancer survivors completed questionnaires on FCR (Impact of Cancer scale - Health Worries subscale), satisfaction with information provision (European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire (EORTC-QLQ) INFO25, satisfaction scale) and health-related quality of life (EORTC-QLQ C30, Short Form 36-item). A total of 2615 survivors completed the Impact of Cancer scale - Health Worries subscale. No significant differences in FCR severity were found between any of the cancer types (p = 0.063). A younger age, female gender, stage II disease, a shorter time since diagnosis, scheduled follow-up appointments and comorbidity were associated with higher FCR (p < 0.01). Satisfaction with information provision was negatively correlated with FCR severity (r = -0.16, p < 0.05). Demographic and medical factors accounted for 6% of explained variance in FCR. The full model, also including health-related quality of life, explained 15% and 19%, respectively. Fear of cancer recurrence seems to be a universal concern of cancer survivors rather than a cancer type-specific problem. Gender, age and medical factors were identified as risk factors. Copyright © 2015 John Wiley & Sons, Ltd.


Simvastatin induces estrogen receptor-alpha (ER-alpha) in murine bone marrow stromal cells.
Simvastatin has been shown to stimulate osteogenesis both in vitro and in vivo. However, the mechanism by which simvastatin exerts its effects is still unclear. We previously reported that simvastatin promotes bone morphogenetic protein 2 (BMP-2) expression, induces osteoblastic differentiation, and inhibits adipocytic differentiation in mouse bone marrow stromal cells (BMSCs), and that this occurs, at least in part, via a BMP-2-dependent pathway. The aim of this study was to investigate further the mechanisms by which simvastatin stimulates osteogenesis in mouse BMSCs. To determine whether simvastatin-mediated osteogenesis was dependent on BMP-2, mouse BMSCs were treated with nonimmune normal mouse IgG or BMP-2 neutralizing antibodies combined with different concentrations of simvastatin. Surprisingly, the stimulatory effect of simvastatin on alkaline phosphatase (ALP) activity was not completely blocked by neutralizing BMP-2 monoclonal antibody treatment. Interestingly, we found that estrogen receptor-alpha (ER-alpha) protein levels increased after mouse BMSCs were treated with simvastatin for 72 h in a concentration-dependent manner. Moreover, the stimulatory effect of simvastatin on ALP activity in BMSCs was blocked by the estrogen receptor agonist ICI 182,780, and cotreatment with 17-beta-estradiol and simvastatin increased ALP activities by two-to threefold in the BMSCs compared with treatment with simvastatin alone. These results suggest that simvastatin-induced in vitro osteogenesis in mouse BMSCs is mediated, at least in part, by induction of ER-alpha and not by BMP-2 alone. These results provide new insight into the mechanisms of simvastatin-induced bone formation in BMSCs.


Bone mineral properties and 3D orientation of human lamellar bone around cement lines and the Haversian system. Corrigendum.
The article by Grünewald et al. [IUCrJ (2023). 10, 189-198] is corrected.


Benefits and harms of treatments for chronic nonspecific low back pain without radiculopathy: systematic review and meta-analysis.
Currently, there are no published studies that compare nonpharmacological, pharmacological and invasive treatments for chronic low back pain in adults and provide summary statistics for benefits and harms. The aim of this review was to compare the benefits and harms of treatments for the management of chronic low back pain without radiculopathy and to report the findings in a format that facilitates direct comparison (Benefit-Harm Scale: level 1 to 7). Systematic review and meta-analysis of randomized controlled trials, including trial registries, from electronic databases up to 23rd May 2022. Adults with chronic nonspecific low back pain, excluding radicular pain, in any clinical setting. Comparison of pain at immediate-term (≤2 weeks) and short-term (>2 weeks to ≤12 weeks) and serious adverse events using the Benefit-Harm Scale (level 1 to 7). This was a registered systematic review and meta-analysis of randomized controlled trials. Interventions included nonpharmacological (acupuncture, spinal manipulation), pharmacological and invasive treatments compared to placebo. Best evidence criteria was used. Two independent reviewers conducted eligibility assessment, data extraction and quality appraisal. The search retrieved 17,362 records. Three studies provided data on the benefits of interventions, and 30 provided data on harms. Studies included interventions of acupuncture (n=8); manipulation (n=2); pharmacological therapies (n=9), including NSAIDs and opioid analgesics; surgery (n=8); and epidural corticosteroid injections (n=3). Acupuncture (standardized mean difference (SMD) -0.51, 95%CI -0.88 to -0.14, n=1 trial, moderate quality of evidence, benefit rating of 3) and manipulation (SMD -0.39, 95%CI -0.56 to -0.21, n=2 trials, moderate quality of evidence, benefit rating of 5) were effective in reducing pain intensity compared to sham. The benefit of the other interventions was scored as uncertain due to not being effective, statistical heterogeneity preventing pooling of effect sizes, or the absence of relevant trials. The harms level warnings were at the lowest (eg, indicating rarer risk of events) for acupuncture, spinal manipulation, NSAIDs, combination ingredient opioids, and steroid injections, while they were higher for single ingredient opioid analgesics (level 4) and surgery (level 6). There is uncertainty about the benefits and harms of all the interventions reviewed due to the lack of trials conducted in patients with chronic nonspecific low back pain without radiculopathy. From the limited trials conducted, nonpharmacological interventions of acupuncture and spinal manipulation provide safer benefits than pharmacological or invasive interventions. However, more research is needed. There were high harms ratings for opioids and surgery.


Large surface of cultured human epithelium obtained on a dermal matrix based on live fibroblast-containing fibrin gels.
The aim of this study was to develop a new keratinocyte culture system on a dermal equivalent suitable for skin wound closure. Our dermal matrix is based on a fibrin gel from plasma cryoprecipitate containing live human fibroblast (from human foreskin). Keratinocytes obtained from primary culture according to the Rheinwald and Green method, were seeded on the gel at different seeding ratios. In all cases, the keratinocytes plated on the dermal equivalent grew to confluence and stratified epithelium was obtained within 10-15 days in culture. Early expression of basal membrane proteins was detected by immunostaining with laminin and type IV collagen antibodies. Cell proliferation was detected both in the epidermal layer and in the fibroblast embedded in the gel as assessed by BrdU incorporation. Detachment of composite cultures from dishes or flasks is a simple and quick procedure without the need for dispase treatment. Grafting of composite cultures to nude mice gave rise to an orderly stratified, orthokeratinized epithelium resembling human epidermis. A number of advantages including a large expansion factor without the need of 3T3 feeder layer, the availability of fibrin/plasma cryoprecipitate from blood banks and the versatile manipulation of composite cultures suggest that this system could be suitable for the definitive coverage of severely burned patients.


Congenital mydriasis combined with aneurysmal dilatation of a persistent ductus arteriosus Botalli: a rare syndrome.
Abstract. A child with congenital mydriasis and aneurismal dilatation of persistent ductus arteriosus is described. We discuss congenital mydriasis as a separate entity and in combination with heart diseases.


Reduced-dose of doublet chemotherapy combined with anti-EGFR antibodies in vulnerable older patients with metastatic colorectal cancer: Data from the REVOLT study.
To assess the toxicity patterns and effectiveness of doublet chemotherapy when administered at reduced doses of 20% (FOLFOX or FOLFIRI) in combination with anti-EGFR antibodies (cetuximab or panitumumab) in old, vulnerable patients with metastatic colorectal cancer (mCRC). We performed a retrospective observational study of RAS and BRAF wild-type, vulnerable patients aged ≥70 years with previously untreated mCRC. The primary endpoint was safety, and secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). One hundred and eighteen patients were collected from 14 selected Italian centres. The median age was 75 (range, 70-85). Geriatric screening by G8 tool gave a score ≤ 14 in all patients. In total, 75 and 43 patients received FOLFOX or FOLFIRI, respectively, in combination with panitumumab (53%) or cetuximab (47%). The overall incidence of grade (G) 3-4 neutropenia was 11.8%, and for skin rash 11%. The most frequent adverse events were G1-2 skin rash (49.1%), G1-2 diarrhea (21.1%) and G1-2 nausea (17.7%). The ORR was 57.3%. Stable disease was observed in 29.1% of patients, with a disease control rate of 86.4%. With a median follow-up of 18 months, the median PFS was 10.0 months (95% confidence interval [CI]: 8.5-11.4), while the median OS was 18.0 months (95% CI: 16.0-19.9). No statistically significant difference was observed between the regimens in terms of ORR, PFS (p = 0.908), and OS (p = 0.832). This study shows that with an appropriate design, including reduced doses, vulnerable older patients best tolerate chemotherapy when combined with anti-EGFR antibodies.


Alternative splicing of the Izumo1 gene ensures triggering gamete fusion in mice.
IZUMO1 is a sperm acrosomal membrane protein that is essential for mammalian fertilization through recognition of JUNO on the oocyte surface and accompanying IZUMO1-JUNO complex formation. Here, we report a new Izumo1 gene splicing variant (IZUMO1_v2) with a unique 52-amino-acid-long signal sequence transcribed from Exon 1b. Although the mRNA amount of Izumo1_v2 is 76 times lower than that of the original Izumo1 (IZUMO1_v1) in the testis, the cell-oocyte assay indicates that IZUMO1_v2-expressing COS-7 cells have the ability to attach to the oocyte equivalent of IZUMO1_v1. To clarify the physiological function of IZUMO1_v2, we produced an IZUMO1_v1-specific knockout mouse line with a nine-base deletion adjacent to the initial methionine codon of IZUMO1_v1 by the CRISPR/Cas9 system. The IZUMO1_v1 knockout male mice carry 0.19-fold lower level of IZUMO1 protein in the spermatozoon; however, reduction in fertility was only minimally affected compared to the wild-type mice, suggesting that only a small fraction of IZUMO1 is sufficient for triggering sperm-egg fusion. We propose that the alternative splicing generating IZUMO1_v2 might function as a fail-safe in mouse for when splicing is disturbed.


Effectiveness of internet-delivered cognitive behavioural therapy in reducing sickness absence among young employees with depressive symptoms: study protocol for a large-scale pragmatic randomised controlled trial.
Depression is a highly prevalent condition with typical onset in early adulthood. Internet-delivered cognitive behavioural therapy (iCBT) is a promising cost-effective and more widely available alternative to face-to-face CBT. However, it is not known whether it can reduce sickness absence in employees showing depressive symptoms. The randomised controlled trial component of the DAQI (Depression and sickness absence in young adults: a quasi-experimental trial and web-based treatment intervention) project aims to investigate if iCBT is effective in reducing sickness absence compared with care as usual (CAU) among young employees with depressive symptoms in primary care provided in an occupational health setting. This study will use a randomised controlled single-centre service-based trial of an existing iCBT programme (Mental Hub iCBT for Depression) to evaluate whether or not this treatment can reduce the number of sickness absence days in public sector employees aged 18-34 years who present at the occupational health service with mild depressive symptoms (score ≥9 on the Beck Depression Inventory-IA). Control participants will be offered CAU, with no constraints regarding the range of treatments. The active condition will consist of seven weekly modules of iCBT, with support from a web therapist. Primary outcome will be participants' all-cause sickness absence as indicated in employer's and national administrative records up to 6 months from study entry. Secondary outcomes relating to long-term sickness absence (over 11 calendar days) for mental and musculoskeletal disorders and psychotropic medication use will be obtained from the Finnish Social Insurance Institution's administrative records; and short sickness absence spells (up to 11 calendar days) will be extracted from employer's records. Analyses will be conducted on an intention-to-treat basis. The Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa has approved the study (HUS/974/2019). The results will be published in peer-reviewed scientific journals and in publications for lay audience. ISRCTN10877837.


Corrigendum: Oral Administration of α-Asarone Promotes Functional Recovery in Rats With Spinal Cord Injury.
[This corrects the article DOI: 10.3389/fphar.2018.00445.].


[Cystic pneumatosis affecting the sigmoid. Information provided by colonic mucography (double contrast enema) and endoscopy. One case; diagnostic significance of the "puzzle" appearance (author's transl)].
On the basis of one case of colonic sub-mucosal cystic pneumatosis explored by double contrast enema, the authors emphasise the pathognomic diagnostic value of the "puzzle" appearance. This appearance is made by precise adaptation of the opaque colonic mucosa depressed in the form of a "cupola" over the intraparietal gas bubble which results in the deformity. Endoscopy failed to reveal the disorder in the case reported here.


A controlled evaluation of monthly maintenance interpersonal psychotherapy in late-life depression with varying levels of cognitive function.
To evaluate the effect of maintenance Interpersonal Psychotherapy (IPT) on recurrence rates and time to recurrence of major depression in elderly patients with varying levels of cognitive function. Two-year maintenance study of monthly maintenance IPT vs supportive clinical management (CM) in remitted depressed elderly who were participants in a previously reported placebo-controlled study of maintenance paroxetine and IPT (Reynolds et al., 2006). We used Cox regression analysis to test interactions between cognitive status (Dementia Rating Scale score) and treatment (IPT, CM) with respect to recurrence of major depression. We observed a significant interaction between cognitive status and treatment: lower cognitive performance was associated with longer time to recurrence in IPT than in CM (58 weeks vs 17 weeks) (HR = 1.41 [95% CI = 1.04, 1.91], p = 0.03). Subjects with average cognitive performance showed no effect of maintenance IPT vs CM on time to recurrence (38 vs 32 weeks, respectively). Monthly maintenance IPT confers protection against recurrence of major depression in elders with lower cognitive functioning.


Criticality in the conformational phase transition among self-similar groups in intrinsically disordered proteins: Probed by salt-bridge dynamics.
Intrinsically disordered proteins (IDP) serve as one of the key components in the global proteome. In contrast to globular proteins, they harbor an enormous amount of physical flexibility enforcing them to be retained in conformational ensembles rather than stable folds. Previous studies in an aligned direction have revealed the importance of transient dynamical phenomena like that of salt-bridge formation in IDPs to support their physical flexibility and have further highlighted their functional relevance. For this characteristic flexibility, IDPs remain amenable and accessible to different ordered binding partners, supporting their potential multi-functionality. The current study further addresses this complex structure-functional interplay in IDPs using phase transition dynamics to conceptualize the underlying (avalanche type) mechanism of their being distributed across and hopping around degenerate structural states (conformational ensembles). For this purpose, extensive molecular dynamics simulations have been done and the data analyzed from a statistical physics perspective. Investigation of the plausible scope of 'self-organized criticality' (SOC) to fit into the complex dynamics of IDPs was found to be assertive, relating the conformational degeneracy of these proteins to their functional multiplicity. In accordance with the transient nature of 'salt-bridge dynamics', the study further uses it as a probe to explain the structural basis of the proposed criticality in the conformational phase transition among self-similar groups in IDPs. The analysis reveal scale-invariant self-similar fractal geometries in the structural conformations of different IDPs. The insights from the study has the potential to be extended further to benefit structural tinkering of IDPs in their functional characterization and drugging.