Mitochondrial Health Index Correlates with Plasma Circulating Cell-Free Mitochondrial DNA in Bipolar Disorder.
Background: Although mitochondria dysfunction is known to play an essential role in the pathophysiology of bipolar disorder (BD), there is a glaring gap in our understanding of how mitochondrial dysfunction can modulate clinical phenotypes. This study aimed to evaluate the composite mitochondrial health index (MHI) in BD subjects and non-psychiatry controls (Non-psychiatry controls). We will also explore whether lower MIH will be related to higher cell-free mtDNA (ccf-mtDNA) levels and poor clinical outcomes. Methods: Fourteen BD-I patients and 16 age- and sex-matched non-psychiatry controls were enrolled for this study. Peripheral blood mononuclear cells (PBMCs) were used to measure the enzymatic activities of citrate synthase and complexes I, II, and IV and mtDNA copy number. ccf-mtDNA was evaluated by qPCR in plasma. Mitochondrial quality control (MQC) proteins were evaluated by western blotting. Results: One-Way ANCOVA after controlling for age, sex, body mass index (BMI), and smoking status showed that patients with BD present a decrease in the MHI compared to non-psychiatry controls, and higher ccf-mtDNA levels, which was negatively correlated with MHI. Because the MQC network is essential to maintain mitochondrial health, we also evaluated the relationship between MQC-related proteins with MHI and ccf-mtDNA. Our results showed that MHI negatively correlated with Fis-1 and positively with Opa-1 and LC3. Moreover, we found a negative correlation between ccf-mtDNA, Opa-1, and LC3 and a positive correlation between cff-mtDNA and Fis-1. Finally, we found that subjects with longer illness duration, higher depressive symptom scores, and worse functional status had lower MHI and higher ccf-mtDNA. Conclusion: In summary, the present findings corroborate previous studies and provide strong support for the hypothesis that mitochondrial regulation and function are integral parts of the pathogenesis of BD.


Investigating the Relationships between COVID-19 Quality of Life, Loneliness, Happiness, and Internet Addiction among K-12 Teachers and School Administrators-A Structural Equation Modeling Approach.
It is well acknowledged that the roles of both school administrators and teachers have changed due to the global education crisis caused by COVID-19. During this challenging and critical period, it is essential to investigate how those working in the education sector who undertake strategic tasks for sustainable education are affected by the new conditions brought about by the COVID-19 pandemic. This study investigates the interrelationships between COVID-19 quality of life, loneliness, happiness, and Internet addiction. The research was designed according to the relational survey model, was conducted with 432 school administrators and teachers working in K-12 schools. The research data was collected through online questionnaires, and structural equation modelling (SEM) was used to test and analyze proposed hypotheses. The study's results revealed a positive relationship between the COVID-19 related quality of life and loneliness, and that loneliness significantly positively predicts Internet addiction. In this context, due to the impact of COVID-19 on the life quality, the participants' loneliness levels significantly increased, and this increase in loneliness caused them to become addicted to using the Internet. Interestingly, it was also determined that a positive relationship exists between loneliness and happiness and that as the loneliness of individuals increased, their level of happiness also increased. In many studies conducted prior to the COVID-19 pandemic, a negative relationship was revealed between loneliness and happiness. In the current study conducted during the pandemic, the relationship between the two variables was positive. SEM results revealed that COVID-19 directly affects the quality of life, Internet addiction, loneliness, and happiness of school administrators and teachers. Furthermore, it was determined that Internet addiction indirectly affects the relationship between loneliness and happiness.


Isotope and affinity tags in photoreactive substance P analogues to identify the covalent linkage within the NK-1 receptor by MALDI-TOF analysis.
Photoreactive analogues of substance P (biotin sulfone-spacer (amino pentanoic or Gly(3))-Arg-Pro-Lys-Pro-(pBzl)Phe-Gln-Phe-Phe-Gly-Leu-Met(O(2))NH(2)) with or without isotope (deuterium) labeling have been synthesized. Deuteriums were present on (d)-biotin or epibiotin sulfone (D(3)), on the Gly(3) spacer linker (D(6)), or on the Gly in position 9 of SP (D(2)). Therefore, peptide analogues could be either unlabeled or tri-, penta-, or hexadeuterated. Results obtained with the use of these peptide analogues show that (d)-biotin sulfone and epibiotin sulfone are not recognized with the same affinity by streptavidin, with (d)-biotin sulfone displaying better affinity for the protein. Photolabeling of the human NK-1 receptor with a 1:1 molar ratio of nondeuterated and deuterated photoreactive substance P (SP) analogues in position 5, followed by combined digestions, purification, and MALDI-TOF mass spectrometry analysis, made the identification of the domain of the receptor covalently linked by the photoreactive SP analogue easier. Indeed, doublets in mass spectra were specific for the covalent complex whereas single peaks could be attributed to contaminating species. This method is particularly suitable when minute amounts of complex have to be analyzed, as in the case of highly hydrophobic G-protein coupled receptors.


Basic concepts about genes, inactivity and aging.
Remarkably, 80-year-old humans who have partaken in lifelong aerobic or strength training have maximal aerobic capacities or muscle strengths comparable with that of sedentary individuals aged 50 or 55-year-old, respectively. Such delays in functional aging are clinically significant because lower aerobic and lower strength capacities increase the risk of premature death. In this short review, we speculate that the lack of daily physical activity induces evolutionarily selected mechanisms to use or lose, one of which is related to nutritional status.


Comparison of selected metals content in Cambodian striped snakehead fish (Channa striata) using solar drying system and open sun drying.
The content of 12 elements in Cambodian dried striped snakehead fish was determined using inductively coupled plasma mass spectrometry. The present study compares the level of the trace toxic metals and nutritional trace elements in the fish processed using solar drying system (SDS) and open sun drying (OSD). The skin of SDS fish has lower level of As, Pb, and Cd compared to the OSD sample. As such, the flesh of the fish accumulated higher amount of toxic metals during OSD compared to SDS. However, arsenic was detected in both samples within the safe limit. The nutritional elements (Fe, Mn, Mg, Se, Mo, Cu, Ni, and Cr) were higher in the skin sample SDS fish compared to OSD fish. These beneficial metals were not accumulated in the flesh sample SDS fish demonstrating lower level compared to drying under conventional system. The reddish coloration of the SDS fish was due to the presence of high Cu content in both the skin and flesh samples which possibly account for no mold formation 5 days after packaging. As conclusion, drying of Cambodian C. striata using solar-assisted system has proven higher content of the nutritious elements compared to using the conventional system despite only slight difference in the toxic metals level between the two systems.


Reading Behaviors through Patterns of Finger-Tracking in Italian Children with Autism Spectrum Disorder.
The paper proposes an ecological and portable protocol for the large-scale collection of reading data in high-functioning autism spectrum disorder (ASD) children based on recording the finger movements of a subject reading a text displayed on a tablet touchscreen. By capitalizing on recent evidence that movements of a finger that points to a scene or text during visual exploration or reading may approximate eye fixations, we focus on recognition of written content and function words, pace of reading, and accuracy in reading comprehension. The analysis showed significant differences between typically developing and ASD children, with the latter group exhibiting greater variation in levels of reading ability, slower developmental pace in reading speed, less accurate comprehension, greater dependency on word length and word frequency, less significant prediction-based processing, as well as a monotonous, steady reading pace with reduced attention to weak punctuation. Finger-tracking patterns provides evidence that ASD readers may fail to integrate single word processing into major syntactic structures and lends support to the hypothesis of an impaired use of contextual information to predict upcoming stimuli, suggesting that difficulties in perception may arise as difficulties in prediction.


A coevolution experiment between Flavobacterium johnsoniae and Burkholderia thailandensis reveals parallel mutations that reduce antibiotic susceptibility.
One interference mechanism of bacterial competition is the production of antibiotics. Bacteria exposed to antibiotics can resist antibiotic inhibition through intrinsic or acquired mechanisms. Here, we performed a coevolution experiment to understand the long-term consequences of antibiotic production and antibiotic susceptibility for two environmental bacterial strains. We grew five independent lines of the antibiotic-producing environmental strain, Burkholderia thailandensis E264, and the antibiotic-inhibited environmental strain, Flavobacterium johnsoniae UW101, together and separately on agar plates for 7.5 months (1.5 month incubations), transferring each line five times to new agar plates. We observed that the F. johnsoniae ancestor could tolerate the B. thailandensis-produced antibiotic through efflux mechanisms, but that the coevolved lines had reduced susceptibility. We then sequenced genomes from the coevolved and monoculture F. johnsoniae lines, and uncovered mutational ramifications for the long-term antibiotic exposure. The coevolved genomes from F. johnsoniae revealed four potential mutational signatures of reduced antibiotic susceptibility that were not observed in the evolved monoculture lines. Two mutations were found in tolC: one corresponding to a 33 bp deletion and the other corresponding to a nonsynonymous mutation. A third mutation was observed as a 1 bp insertion coding for a RagB/SusD nutrient uptake protein. The last mutation was a G83R nonsynonymous mutation in acetyl-coA carboxylayse carboxyltransferase subunit alpha (AccA). Deleting the 33 bp from tolC in the F. johnsoniae ancestor reduced antibiotic susceptibility, but not to the degree observed in coevolved lines. Furthermore, the accA mutation matched a previously described mutation conferring resistance to B. thailandensis-produced thailandamide. Analysis of B. thailandensis transposon mutants for thailandamide production revealed that thailandamide was bioactive against F. johnsoniae, but also suggested that additional B. thailandensis-produced antibiotics were involved in the inhibition of F. johnsoniae. This study reveals how multi-generational interspecies interactions, mediated through chemical exchange, can result in novel interaction-specific mutations, some of which may contribute to reductions in antibiotic susceptibility.


Detecting protein-protein interactions with a novel matrix-based protein sequence representation and support vector machines.
Proteins and their interactions lie at the heart of most underlying biological processes. Consequently, correct detection of protein-protein interactions (PPIs) is of fundamental importance to understand the molecular mechanisms in biological systems. Although the convenience brought by high-throughput experiment in technological advances makes it possible to detect a large amount of PPIs, the data generated through these methods is unreliable and may not be completely inclusive of all possible PPIs. Targeting at this problem, this study develops a novel computational approach to effectively detect the protein interactions. This approach is proposed based on a novel matrix-based representation of protein sequence combined with the algorithm of support vector machine (SVM), which fully considers the sequence order and dipeptide information of the protein primary sequence. When performed on yeast PPIs datasets, the proposed method can reach 90.06% prediction accuracy with 94.37% specificity at the sensitivity of 85.74%, indicating that this predictor is a useful tool to predict PPIs. Achieved results also demonstrate that our approach can be a helpful supplement for the interactions that have been detected experimentally.


Ablation of atrial tachycardia originating from the noncoronary sinus: case report and literature review.
This report describes a patient with atrial tachycardia who underwent radiofrequency catheter ablation. Two applications of radiofrequency energy were received at different sites within 1 week. Initially, right atrium mapping indicated that the earliest activation site was located at the His-bundle region (HBR). However, the first application of radiofrequency near HBR appeared to be ineffective. Moreover, a degree III atrioventricular block and inferior ST-segment elevation was temporally observed during the therapy, which recovered after drug treatment. As later aortic sinus mapping showed that the activation site located at the noncoronary sinus (NCS) preceded the one at HBR, and this activation terminated at atrial tachycardia, a second application of radiofrequency was performed at NCS without any complications. In addition, a literature review of the clinical features of atrial tachycardia at the NCS is also summarized in the present report.


[Neuro-otologic findings in multiple sclerosis].
Neuro-otologic examination is very important in evaluation of balance system. Multiple sclerosis (MS) is the most common chronic, debilitating disease characterized by focal demyelinization that develop throughout of the central nerves system at varying time. Patients with MS presented various complaints and signs, so the aim of the study was the neuro-otologic presentation of multiple findings in patients with MS and comparison with reviewing literature. The study was carried out in 32 patients with MS (21 with relapsing-remitting, 9 with secondary progressive, 1 with primary progressive and 1 with progressive/relapsing types) the mean age was 38 +/- 10 years. Clinical neuro-otologic examinations were performed in all patients paying special attention to eye movement ability. Vertigo as the first symptom was found in 18.8% of patients but up to 68% of patients would complain this symptom at some point of disease. The hearing impairment and tinnitus complains 6.2% patients, optic neuritis 28% patients and double vision 46.9% of them. A few types of eye movement disorder like abnormalities of fixation, gaze-evoked nystagmus, acquired pendular nystagmus and vertical nystagmus in 46.8% patients were observed. The clinical signs of internuclear ophthalmoplegia were noticed in 2 patients. Disturbance in voluntary gaze either in smooth pursuit test (31.3%) and in saccadic test (43.8%) were seen. The multifocal nature of MS explain why this disease are so commonly subject to defect different part of nerve system. Careful neuro-otologic assessment of every patient with MS is necessary to confirm and monitoring the course of disease.


Microwave preparation of raw vermiculite for use in removal of copper ions from aqueous solutions.
This study sought to determine optimum conditions for the microwave exfoliation of raw vermiculite and examined the removal characteristics of copper ions from water by the processed vermiculite. When 100 g of raw vermiculite was irradiated at 440 W for 330 s, 66% of the raw vermiculite was exfoliated. The dry density and specific surface area of the exfoliated vermiculite were 0.28 g/cm3 and 54.6 m2/g, respectively. When considering the dry density (2.78 g/cm3) and specific surface area (11.1 m2/g) of the raw vermiculite, microwave irradiation resulted in an approximate 10 times expansion and a five-fold increase in specific surface area. Serial batch tests were conducted to determine the removal characteristics of the exfoliated vermiculite for copper ions in aqueous solutions. Copper was most effectively removed by exfoliated vermiculite with an initial pH of 5. Exfoliated vermiculite at this pH also produced the highest first-order rate constants and instantaneous partition coefficient. These results indicate that exfoliated vermiculite can be prepared by microwave irradiation instead of conventional heat processes for use as a copper ion adsorbent.


Alcoholism treatment offset effects: an insurance perspective.
This study investigates whether alcoholism treatment costs are offset by reductions in other medical treatment costs by comparing people treated for alcoholism with a matched comparison group. The alcoholism treatment group is defined by diagnoses of alcohol dependence, abuse, or psychoses from health insurance claims field between January 1980 and June 1987. A comparison sample was matched on age, gender, and insurance coverage. In this primarily methodological study, expected costs for nonalcoholism treatments were calculated from standardized regressions. Offset effects were measured from the insurer's perspective through differences in expected total nonalcoholism treatment costs in the periods preceding and following alcoholism treatment. Members of the alcoholism treatment group were more likely than the comparison group to be hospitalized and to need other (nonalcoholism) medical treatment, thus incurring higher total costs. Offset effects emerged for patients with alcohol abuse and without mental psychosis comorbidities.


HLA-B*2704, an allotype associated with ankylosing spondylitis, is critically dependent on transporter associated with antigen processing and relatively independent of tapasin and immunoproteasome for maturation, surface expression, and T cell recognition: relationship to B*2705 and B*2706.
B*2704 is strongly associated to ankylosing spondylitis in Asian populations. It differs from the main HLA-B27 allotype, B*2705, in three amino acid changes. We analyzed the influence of tapasin, TAP, and immunoproteasome induction on maturation, surface expression, and T cell allorecognition of B*2704 and compared some of these features with B*2705 and B*2706, allotypes not associated to disease. In the tapasin-deficient .220 cell line, this chaperone significantly influenced the extent of folding of B*2704 and B*2705, but not their egress from the endoplasmic reticulum. In contrast, B*2706 showed faster folding and no accumulation in the endoplasmic reticulum in the absence of tapasin. Surface expression of B*2704 was more tapasin dependent than B*2705. However, expression of free H chain decreased in the presence of this chaperone for B*2705 but not B*2704, suggesting that more suboptimal ligands were loaded on B*2705 in the absence of tapasin. Despite its influence on surface expression, tapasin had little effect on allorecognition of B*2704. Both surface expression and T cell recognition of B*2704 were critically dependent on TAP, as established with TAP-deficient and TAP-proficient T2 cells. Both immunoproteasome and surface levels of B*2704 were induced by IFN-gamma, but this had little effect on allorecognition. Thus, except for the differential effects of tapasin on surface expression, the tapasin, TAP, and immunoproteasome dependency of B*2704 for maturation, surface expression, and T cell recognition are similar to B*2705, indicating that basic immunological features are shared by the two major HLA-B27 allotypes associated to ankylosing spondylitis in human populations.


Conservative therapy is associated with worse clinical features and biochemical derangements than renal replacement therapy: a retrospective study in Kumasi, Ghana.
The incidence of end stage kidney disease (ESKD) is increasing in Ghana as with the rest of the world. This study compared the sociodemographic, diagnostic characteristics (clinical, biochemical and imaging) and clinical outcomes of ESKD patients who chose either renal replacement therapy (RRT) or conservative therapy as well as the factors that influenced their choice. We retrospectively reviewed the records of 382 ESKD patient from 2006 to 2018. The data was collected from the Nephrology Clinic at the Komfo Anokye Teaching Hospital (KATH). Sociodemographic, diagnostic (clinical, biochemical and imaging) and therapeutic data were obtained, organized and analyzed with Statistical Package for the Social Sciences (SPSS). Of the 382 patients, 321 had conservative therapy whiles 61 had renal replacement therapy. The mean age of participants was 47.71 ± 16.10 years. Bipedal swelling (16.8%), fatigue (10.4%) and facial swelling (9.2%) were the major clinical features. Chronic glomerulonephritis (31.4%), hypertension (30.3%) and diabetes mellitus nephropathy (28.2%) were the most frequent predisposing conditions. Nifedipine (82.0%), bisoprolol (32.8%), aspirin (19.7%), ranitidine (26.2%), metformin (13.1%) and lasix (78.7%) were commonly used by the RRT patients than their conservative therapy counterparts. Compared to their RRT counterparts, patients on conservative therapy were more on irbesartan/lisinopril (57.9%) and sodium hydro carbonate (NaHCO3) (52.0%). Diastolic blood pressure (DBP) (p = 0.047), uremic gastritis (p = 0.007), anaemia, uraemia, haematuria and hyperkalaemia (p < 0.001) were more common in conservative therapy patients than RRT patients with RRT patients showing better corticomedullary differentiation (38.1% vs. 27.7%, p < 0.001) and normal echotexture (15.0% vs. 11.6%, p = 0.005). Age, gender, occupation and duration of illness were significantly associated with the decision to opt for conservative therapy. Patients on conservative therapy have worse clinical outcomes than their RRT counterparts. Early referrals to nephrologist as well as subsidized RRT should be targeted.


Gut-Kidney Impairment Process of Adenine Combined with Folium sennae-Induced Diarrhea: Association with Interactions between Lactobacillus intestinalis, Bacteroides acidifaciens and Acetic Acid, Inflammation, and Kidney Function.
Extensive evidence suggests that gut microbiota may interact with the kidneys and play central roles in the pathogenesis of disease. However, the association of gut microbiota-kidneys in diarrhea remains unclear. A diarrhea mouse model was constructed by combining adenine with Folium sennae. We analyzed the characteristics of the gut content microbiota and short chain fatty acids (SCFAs); and explored the potential link between gut content microbiota, SCFAs, intestinal inflammatory response and kidney function. Characteristic bacteria Lactobacillus intestinalis and Bacteroides acidifaciens were enriched in the gut contents of mice. The productions of SCFAs were remarkably inhibited. Model mice presented an increased trend of creatinine (Cr), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), a decreased trend of blood urea nitrogen (BUN) and secretory immunoglobulin A (SIgA). The pathological analysis proved obvious damage to the kidney structure. Lactobacillus intestinalis and Bacteroides acidifaciens exisited in the correlations with acetic acid, intestinal inflammatory response and kidney function. Adenine combined with Folium sennae-induced diarrhea, altered the structure and function of the gut content microbiota in mice, causing the enrichment of the characteristic bacteria Lactobacillus intestinalis and Bacteroides acidifaciens. The interactions between Lactobacillus intestinalis, Bacteroides acidifaciens and acetic acid, intestinal inflammation, and kidney function might be involved in the process of gut-kidney impairment in adenine, combined with Folium sennae-induced diarrhea.


Evaluation of RGD-targeted albumin carriers for specific delivery of auristatin E to tumor blood vessels.
Induction of apoptosis in endothelial cells is considered an attractive strategy to therapeutically interfere with a solid tumor's blood supply. In the present paper, we constructed cytotoxic conjugates that specifically target angiogenic endothelial cells, thus preventing typical side effects of apoptosis-inducing drugs. For this purpose, we conjugated the potent antimitotic agent monomethyl-auristatin-E (MMAE) via a lysosomal cleavable linker to human serum albumin (HSA) and further equipped this drug-albumin conjugate with cyclic c(RGDfK) peptides for multivalent interaction with alphavbeta3-integrin. The RGD-peptides were conjugated via either an extended poly(ethylene glycol) linker or a short alkyl linker. The resulting drug-targeting conjugates RGDPEG-MMAE-HSA and RGD-MMAE-HSA demonstrated high binding affinity and specificity for alphavbeta3-integrin expressing human umbilical vein endothelial cells (HUVEC). Both types of conjugates were internalized by endothelial cells and killed the target cells at low nM concentrations. Furthermore, we observed RGD-dependent binding of the conjugates to C26 carcinoma. Upon i.v. administration to C26-tumor bearing mice, both drug-targeting conjugates displayed excellent tumor homing properties. Our results demonstrate that RGD-modified albumins are suitable carriers for cell selective intracellular delivery of cytotoxic compounds, and further studies will be conducted to assess the antivascular and tumor inhibitory potential of RGDPEG-MMAE-HSA and RGD-MMAE-HSA.


The M184V mutation: what it does, how to prevent it, and what to do with it when it's there.
The M184V mutation is selected by lamivudine (3TC) and emtricitabine (FTC) and is a common mutation in HIV-infected patients. Virus with the M184V mutation has a high level of resistance to 3TC and FTC but has been shown to have favorable effects on the susceptibility of some other NRTIs and can delay clinical and immunologic progression by decreasing viral fitness. While it is always better not to have any drug resistance so that 3TC and FTC are available as active antiretroviral agents, it is important to take advantage of the beneficial effects of the M184V mutation when it is present.


VHL status regulates transforming growth factor-β signaling pathways in renal cell carcinoma.
To evaluate the role of pVHL in the regulation of TGF-β signaling pathways in clear cell renal cell carcinoma (ccRCC) as well as in non-ccRCC; the expression of pVHL, and the TGF-β pathway components and their association with clinicopathological parameters and patient's survival were explored. Tissue samples from 143 ccRCC and 58 non-ccRCC patients were examined by immunoblot. ccRCC cell lines were utilized for mechanistic in-vitro studies. Expression levels of pVHL were significantly lower in ccRCC compared with non-ccRCC. Non-ccRCC and ccRCC pVHL-High expressed similar levels of pVHL. Expression of the TGF-β type I receptor (ALK5) and intra-cellular domain were significantly higher in ccRCC compared with non-ccRCC. In non-ccRCC, expressions of ALK5-FL, ALK5-ICD, pSMAD2/3, and PAI-1 had no association with clinicopathological parameters and survival. In ccRCC pVHL-Low, ALK5-FL, ALK5-ICD, pSMAD2/3, and PAI-1 were significantly related with tumor stage, size, and survival. In ccRCC pVHL-High, the expression of PAI-1 was associated with stage and survival. In-vitro studies revealed that pVHL interacted with ALK5 to downregulate its expression through K48-linked poly-ubiquitination and proteasomal degradation, thus negatively controlling TGF-β induced cancer cell invasiveness. The pVHL status controls the ALK5 and can thereby regulate the TGF-β pathway, aggressiveness of tumors, and survival of the ccRCC and non-ccRCC patients.


Acute renal injury from thrombotic microangiopathy associated with enteritis in New Zealand white rabbits.
Over a 3-y period, 12 adult New Zealand white (NZW) rabbits were presented for postmortem examination following variably long periods of inappetence and soft-to-liquid stool production. Postmortem findings included serosanguineous fluid in abdominal and thoracic cavities, dark-red-to-white renal foci, reddened intestinal serosa, and pulmonary edema. Microscopically, mesangial changes and thrombi were observed in renal glomeruli, and mild-to-severe enteritis was observed. These findings resemble hemolytic uremic syndrome, which typically follows enterocolitis associated with Shiga toxin (Stx)-producing Escherichia coli infection. In our case series, various gram-negative bacteria, most commonly E. coli, were isolated from the intestinal tracts; however, Stx production was not demonstrated. Evidence of Encephalitozoon cuniculi infection, a common cause of renal disease in rabbits, was also not found. Our cases suggest that gram-negative enteric bacteria should be included in the differential diagnosis of renal disease in NZW rabbits, especially in cases with an accompanying clinical history of gastrointestinal disorder.


A DNA vaccine encoding a cell-surface protein antigen of Streptococcus mutans protects gnotobiotic rats from caries.
A cell-surface protein antigen (PAc) of Streptococcus mutans is considered a virulence factor because it may mediate initial attachment of Streptococcus mutans to tooth surfaces. Thus, inhibiting PAc is predicted to provide protection against caries. To develop vaccines against dental caries, we constructed a DNA vaccine, pCIA-P, which encodes two high-conservative regions of PAc. Expression of the recombinant protein was obtained in eukaryotic cells in vitro and in vivo. In this report, we provide evidence that fewer caries lesions, and high levels of PAc-specific salivary IgA antibody and serum IgG antibody, were observed in gnotobiotic rats following targeted salivary gland (TSG) administration of pCIA-P. This study shows that the recombinant DNA vaccine pCIA-P could induce protective anti-caries immune responses and that TSG immunization is a promising strategy for the inhibition of dental caries.


Oral health patterns among schoolchildren in Mafraq Governorate, Jordan.
Little is known about the oral hygiene patterns among schoolchildren in Jordan. A school-based cross-sectional study was performed from January to March 2010. A simple random sampling method was used. Each student participant completed a detailed questionnaire regarding oral hygiene habits. Data were coded and analyzed using SPSS software version 16. The chi-square was used, odds ratio (OR) and the 95% confidence limits (Cl) for gum bleeding were estimated. The results showed that nearly one fourth of the children indicating that they brush their teeth twice or more daily (regular pattern). Furthermore, 17% of the schoolchildren never brush their teeth at all. There is a higher proportion, 22.1%, of rural children that never brush their teeth compared to 14.6% of the urban students. Dental flossing among primary schoolchildren in Mafraq Governorate is very rare: 97.2% of the children stated that they had never used dental floss in their life. Furthermore, one fourth of the schoolchildren did not have a tooth brush. While 15.0% of them have a shared toothbrush with their families. The findings of this study indicate that oral health habits in Mafraq Governorate are poor and need to be improved. Based upon these finding, community-oriented oral health programs should be established.


Multicentric osteoid osteoma with a nidus located in the epiphysis.
We present a 13-year-old girl who was referred to our clinic with a 5-month history of right leg pain relieved by salicylates. Initial CT examination demonstrated a lesion in the posterior tibial cortex in keeping with an osteoid osteoma. This was resected and the diagnosis confirmed by histology. However, her pain recurred 2 weeks after the operation and further imaging identified a further nidus in the epiphysis. We present the imaging findings in this unique case of multicentric osteoid osteoma with one nidus located in the epiphysis.


How do community health committees contribute to capacity building for maternal and child health? A realist evaluation protocol.
The proposed research is part of ongoing operations research within World Vision's Access: Infant and Maternal Health Programme. This study aims to identify key context features and underlying mechanisms through which community health committees build community capacity within the field of maternal and child health. This may help to improve programme implementation by providing contextually informed and explanatory findings for how community health committees work, what works best and for whom do they work for best for. Though frequently used within health programmes, little research is carried out on such committees' contribution to capacity building-a frequent goal or proposed outcome of these groups. The scarce information that does exist often fails to explain 'how, why, and for whom' these committees work best. Since such groups typically operate within or as components of complex health interventions, they require a systems thinking approach and design, and thus so too does their evaluation. Using a mixed methods realist evaluation with intraprogramme case studies, this protocol details a proposed study on community health committees in rural Tanzania and Uganda to better understand underlying mechanisms through which these groups work (or do not) to build community capacity for maternal and child health. This research protocol follows the realist evaluation methodology of eliciting initial programme theories, to inform the field study design, which are detailed within. Thus far, the methodology of a realist evaluation has been well suited to the study of community health committees within these contexts. Implications for its use within these contexts are discussed within. Institutional Review Boards and the appropriate research clearance bodies within Ireland, Uganda and Tanzania have approved this study. Planned dissemination activities include via academic and programme channels, as well as feedback to the communities in which this work occurs.


Modifiers of the effect of short-term variation in PM2.5 on mortality in Beijing, China.
Epidemiologic studies have reported associations between short-term exposure to particulate matter <2.5 μm in aerodynamic diameter (PM2.5) and mortality, but the role of modifiers remains unclear with studies reporting inconsistent results. We evaluated the impact of individual (age, gender and education) and township (geographic area, socioeconomic status, background air pollution and road density) level factors on the relationship between short-term variation in PM2.5 with cause-specific mortality in Beijing (population: 21.7 million in 2016), China. Daily PM2.5 concentrations in each township (n = 327; township population: 2000-359,400; township area: 1-392 km2) within Beijing were estimated by kriging with external drift using measurements from 35 air quality monitoring stations and geographic variables. Time-stratified case-crossover analysis with township-level mortality data from Oct. 1st, 2012 to Dec. 31st, 2013 was then used to examine associations between PM2.5 exposure estimates and cause-specific mortality, stratified by the potential effect modifiers. A 10-μg/m3 increase in PM2.5 concentration was associated with a 0.17% [95% confidence interval (CI): 0.05%-0.29%] and 0.27% (95%CI:0.01%-0.52%) increase in non-accidental and stroke mortality with no lag, a 0.81% (95%CI:0.39%-1.23%) and 0.96% (95%CI:0.35%-1.57%) increase in respiratory disease (RD) and chronic obstructive pulmonary disease (COPD) mortality at a lag of two-day moving average. For individual-level effect modifiers, the elderly showed higher effects for all the specific causes of mortality; those with lower education level showed higher effects for non-accidental, cardiovascular disease and stroke mortality; females showed higher effects for non-accidental and cause-specific cardiovascular diseases. For township-level effect modifiers, effect estimates tended to be larger for suburban areas, areas of lower road density, lower PM2.5 and lower socioeconomic status. Short-term exposure to township-level ambient PM2.5 was associated with increased mortality in Beijing, with indications of effect modification by both individual and township-level factors.


[Sexual function and dysfunction: from theory to practice].
Sexual dysfunctions are common phenomena in healthy as well as in ill populations. The introduction of PDE5-inhibitors gave primary health-care physicians and specialists a tool to treat erectile dysfunction. This focused the attention on the need of physicians to be trained to discuss helpfully sexual issues. Sexual dysfunctions are biopsychosocial phenomena with many causes, including specific diseases and some treatments. These dysfunctions can be a cause for much distress. It seems that nowadays people are more prepared to ask sexual questions than physicians are ready to discuss and answer them. In this issue of Harefuah, we present many aspects of a combined, multi-professional, biopsychosocial model, for identifying and treating sexual dysfunctions. We also propose some ideas that could serve medical professionals in their efforts to better deal with sexual matters.


Prevalence and distribution of ocular onchocerciasis in three ecological zones in Nigeria.
The African Programme for Onchocerciasis Control (APOC) sponsored a baseline study in Nigeria between 1998 and 1999 on the prevalence and distribution of Onchocerciasis. The randomly selected 1,064 subjects in the baseline study underwent detailed eye examination in Cross River (rain forest), Taraba (savanna) and Kogi (forest-savanna) States. This paper compares and contrasts the public health significance of ocular onchocerciasis in these ecological zones. A blindness prevalence of 2.4% was recorded in the study, onchocerciasis being responsible for 30.2% of the bilaterally blind subjects. Onchocerciasis-induced blindness prevalence was relatively high in the rain forest and forest savanna zones of Cross River and Kogi States, Cross River having the highest site-specific prevalence (50.0%), followed by Kogi (41.7%). Taraba recorded only 27.3%. Other conditions identified included glaucoma, optic nerve disease and cataract rates of which were also found to be high among the population (6.9%, 6.5 % and 8.9% respectively). Anterior segment onchocercal lesions, punctate and sclerosing keratitis were the predominant features of the infection in the savanna zone (14.1% and 6.3% respectively), while posterior segment lesions were much more common in the forest zone. The need to sustain the present efforts to control onchocerciasis through mass ivermectin treatment is recommended.


A two-photon fluorescent probe for formaldehyde detection and regeneration in living cells.
A two-photon excited fluorescent probe CMB-1 has been rationally developed for the detection and regeneration of formaldehyde based on a novel nucleophilic addition of a secondary amine to FA and subsequential alcoholysis reactivity mechanism. It enables a specific turn-on response towards formaldehyde and facilitates the monitoring of exogenous and endogenous formaldehyde in living cells via both one- and two-photon microscopy, with minimal influence on its native homeostasis and local concentration.


The role of positron emission tomography in the management of pancreatic cancer.
The role of positron emission tomography (PET) and PET/computed tomography (CT) in the assessment of a patient presenting with cancer of the pancreas is discussed in the overall context of the management of this condition. The clinical limitations persist, with many patients presenting late with unresectable disease and poor prospects for novel drug therapies. PET and PET/CT are best at diagnosing and staging but are relatively inefficient in the detection of nodal disease. The detection of late disease manifestations such as metastatic spread is often of little clinical consequence. PET/CT may be considered as a first-line imaging investigation but evidence for this approach needs to accrue. Overall detection sensitivity at diagnosis varies between 90% and 95% and specificity from 82% to 100%, whereas for staging, sensitivity data vary from 61% to 100% and specificity data from 67% to 100%.


Antineoplastic agents. 599. Total synthesis of dolastatin 16.
The first 23-step total synthesis of the cyclodepsipeptide dolastatin 16 (1) has been achieved. Synthesis of the dolaphenvaline and dolamethylleuine amino acid units using simplified methods improved the overall efficiency. The formation of the 25-membered macrocycle employing lactonization with 2-methyl-6-nitrobenzoic anhydride completed a key step in the synthesis. Regrettably, the synthetic dolastatin 16 (1), while otherwise identical (by X-ray crystal structure and spectral analyses) with the natural product, did not reproduce the powerful (nanomolar) cancer cell growth inhibition displayed by the natural isolate. Presumably this result can be attributed to conformation(s) of the synthetic dolastatin 16 (1) or to a chemically undetected component isolated with the natural product.


HEMATOPOIETIC STEM CELL TRANSPLANT IN AGGRESSIVE T AND NK/T CELL LYMPHOMA - ROLE OF UPFRONT AUTOLOGOUS TRANSPLANT IN NODAL PERIPHERAL T-CELL LYMPHOMA.
Aggressive T and NK/T-cell lymphoma are known to have a high risk of relapse and poor long-term prognosis. Hematopoietic stem cell transplantation has been performed as part of consolidation or salvage treatment. We retrospectively studied the outcomes of autologous (A) and allogeneic (allo) hematopoietic stem cell transplantation (SCT) in aggressive T and NK/T-cell lymphoma at our center between 2010 to 2020. Patients with nodal peripheral T-cell lymphoma (PTCL) that were younger than 65 years old who did not receive upfront autologous SCT (ASCT) at first complete remission were selected from our registry data for further comparison. Thirty-six patients underwent ASCT, and 16 patients underwent alloSCT. In the ASCT cohort, 18 patients with nodal PTCL who underwent upfront ASCT at first complete remission (upfront ASCT) were compared with 15 patients with nodal PTCL who were in first complete remission after single-line induction but did not receive ASCT. The two-year progression-free survival (PFS) and overall survival (OS) rates for the ASCT cohort were 58% and 73%, respectively. The two-year PFS and OS for the alloSCT cohort were 47% (P=0.35, P=0.02, respectively). Twenty-four patients who received SCT at first remission (21 ASCT and three alloSCT) had a two-year PFS and OS of 75% and 89%, respectively. In comparison, 28 patients who received SCT at relapse/refractory (15 ASCT and 13 alloSCT) had a two-year PFS and OS of 40% and 50%, respectively (P=0.047, P=0.024, respectively). Patients in complete remission prior to transplantation (n=42) had a two-year PFS and OS of 59% and 73%, respectively. In contrast, patients in partial remission prior to transplantation (n=10) had a two-year PFS and OS of 40% and 48%, respectively (p>0.05). Non-relapse mortality occurred in 6% and 43% of ASCT and AlloSCT, respectively. Multivariate analysis revealed that EBV-positivity at diagnosis indicated poorer PFS. EBV-positivity at diagnosis and more than two prior lines of treatment at transplant were associated with poorer OS. For nodal PTCL, the two-year PFS and OS were 79% and 100% for the upfront ASCT cohort and 78% and 92% for the non-upfront ASCT cohort, respectively (p>0.05). Hematopoietic SCT is a feasible treatment option for aggressive T and NK/T-cell lymphoma. Patients who underwent SCT at first remission had better survival rates than those who underwent SCT at relapse/refractory. Nevertheless, due to the limited sample size of the current study, the role of upfront ASCT in patients with nodal PTCL who achieved first complete remission remains unclear.


[Relationship between functional social support and vital satisfaction in the elderly].
To determine the relationship between functional social support and vital satisfaction of the elder retirement adult. Comparative cross-sectional study in retired adults aged 60 years and more. Two groups were integrated (high and low satisfaction) evaluated with Moral Scale of Satisfaction of the Geriatric Center of Philadelphia modified and validated by Montorio. The sample size was calculated with comparative cross-sectional studies formula, presence of the social support of 80 % in the group of high satisfaction and 50 % in the one of low satisfaction (n = 29). The selection was made at random using the payroll listing of retirees. Social demographic variables were studied. Relationship between the retirement and functional social support was evaluated with the scale of Functional Social Support of Duker-UNC-11. Sociodemographic characteristics and those related to the retirement did not present significant statistical differences (p > 0.05) in the groups of high and low satisfaction. There was an association between the functional social support and the vital satisfaction with odds ratio of 3.00 (95%CI = 1.08-8.32). Functional social support and vital satisfaction in the elderly were associated.


The Potential of Virgin Olive Oil from cv. Chondrolia Chalkidikis and Chalkidiki (Greece) to Bear Health Claims according to the European Legislation.
The European food legislation authorizes the use of certain health claims based on a scientific basis. This study aimed to evaluate the fatty acid, tocopherol, and polar phenol composition of virgin olive oil (VOO) from cv. Chondrolia Chalkidikis and Chalkidiki regarding the fulfillment of official requirements for the health claims of 'oleic acid', 'vitamin E', and 'olive oil polyphenols'. The examination of representative industrial VOOs from 15 olive mills of the Chalkidiki regional unit showed that the two cultivars yield oils contained the necessary concentrations of the responsible bioactive compounds. This evidence was further substantiated by a four harvest study whereby olives from different maturity stages were sampled from three olive groves. Oils were extracted at a laboratory scale and examined for their content in the above-mentioned three categories of constituents. Oils produced at industrial scale from olives harvested on the 'technological optimum' stage according to the olive grove proprietor were also analyzed. Extra virgin olive oil of the studied cultivars can safely bear the generic claims for 'oleic acid' and 'vitamin E'. The cultivars present great potential regarding the total hydroxytyrosol and tyrosol content of the extracted oil required to attain the third health claim that may be influenced negatively by manufacturing practices.


Structure of human estrogen and aryl sulfotransferase gene. Two mRNA species issued from a single gene.
Estrone sulfate is the predominant form of estrogens found in the circulation in women and could thus serve as precursor for active estrogens in target tissues by removal of the sulfate group through the action of endogenous steroid sulfatase. Recently, we isolated a cDNA encoding human placental estrogen sulfotransferase that differs from brain aryl sulfotransferase only in the 5'-noncoding sequence. To increase our knowledge of the regulation and tissue-specific expression of sulfotransferase gene, we screened a lambda EMBL3 library of human leucocyte genomic DNA using the estrogen sulfotransferase cDNA as probe and isolated a clone containing almost the whole gene sequence. Sequencing of the gene indicates that it is included in approximately 7.7 kilobases and contains nine short exons separated by eight introns. The two first exons, named exon 1a and exon 1b, are noncoding and correspond to the 5'-untranslated sequences of human brain and human placental estrogen sulfotransferase cDNAs, respectively. Transfection of chloramphenicol acetyltransferase reporter gene vectors containing the 5'-flanking sequence upstream from exon 1a and exon 1b in human adrenal adenocarcinoma cells indicates that both sequences possess promoter activity. The present results thus indicate that brain aryl sulfotransferase and placental human placental estrogen sulfotransferase mRNA species are transcribed from a single gene by alternate exon 1a and exon 1b promoters, respectively. Using DNA from panels of human/rodent somatic cell hybrids and amplification of the gene by polymerase chain reaction, the human placental estrogen sulfotransferase gene was assigned to chromosome 16.


Accelerated Corneal Endothelial Cell Loss after Phacoemulsification in Patients with Mildly Low Endothelial Cell Density.
By evaluating preoperative endothelial cell density (ECD), ECD loss after phacoemulsification can be predicted. In this retrospective cross-sectional study, we compared outcomes of phacoemulsification with different levels of preoperative ECD. Three-hundred-and-fifty-three patients aged between 18 and 90 years received phacoemulsification at Chang Gung Memorial Hospital. Age (p = 0.003), preoperative logMAR (p = 0.048), cataract grade (p = 0.005), preoperative ECD (p < 0.001), operation time (p = 0.043), phacoemulsification time (p = 0.001), and phacoemulsification energy (p < 0.001) were significantly associated with postoperative ECD change (%). Patients were divided into three groups according to preoperative ECD levels. Level of ECD, coefficient of variation (CV), cell hexagonality (HEX), central corneal thickness (CCT), visual acuity, underlying diseases, and complications were analyzed. With regard to groups, 29, 71, and 252 patients were respectively allocated into the markedly low (group A; ECD below 1000 cells/mm2), mildly low (group B; ECD between 1000 to 2000 cells/mm2), and normal (group C; ECD above 2000 cells/mm2) ECD level groups. The highest CV (40.8 ± 13.9%; p < 0.001) and lowest HEX (58.4 ± 14.6%; p < 0.001) were found in group A. Significant ECD loss was found in group B (28.9 ± 9.2%) as compared to group A (19.9 ± 5.4%) and C (15.0 ± 12.0%) (p < 0.001). No significant differences were found with regard to changes in CV (p = 0.941), HEX (p = 0.937), CCT (p = 0.346), and logMAR (p = 0.557) among the three groups. In conclusion, preoperative ECD level could be a novel predictive value for postoperative cell loss, which was the most prominent in mildly low ECD level group. Less phacoemulsification energy, earlier surgical intervention, or novel topical medications could be suggested for patients with an ECD range from 1000 to 2000 cells/mm2.


Short-term follow-up in 6 months is unnecessary for asymptomatic breast lesions with benign concordant results obtained at ultrasonography-guided 14-gauge core needle biopsy.
We investigated whether short-term follow-up in 6 months was appropriate for asymptomatic benign concordant lesions on ultrasonography-guided core needle biopsy (ultrasonography-guided CNB). Of 1,111 lesions, 944 underwent follow-up within 4 to 9 months after CNB, and 359 of 944 underwent a 2nd follow-up within 9 to 15 months. One hundred sixty-seven underwent a 1st follow-up within 9 to 15 months. Follow-up intervals were classified according to an interval of 6 and 12 months with 2 different methods. First, 944 and 167 lesions were classified into the 6- and 12-month groups. Second, 944 and 526 lesions (sum of 167 and 359 lesions) were classified into the 6- and 12-month groups. Clinicopathologic factors were compared between the 2 groups. None of the benign concordant lesions were malignant; 1.4% of the lesions showed progression in the 6-month group, not significantly different from 1.2% and .8% of the 12-month group. Mean age, mean lesion size, final assessments, and specific or nonspecific pathologies were not different between the 2 groups. Short-term follow-up in 6 months is unnecessary for asymptomatic benign concordant breast lesions at ultrasonography-guided CNB.


[Mebendazole-medicated-salt in the control of hookworm infection].
From 1984-1987, mass application of mebendazole-medicated salt was studied for the control of hookworm infection in 5 pilot areas (Wuming, Shanlin, Bobai, Guilin and Rongxian Counties) in Guangxi Zhuang Autonomous Region. The dosages of mebendazole (mixed with salt) administered were 15mg, 25mg, 30mg, 40mg, 50mg, 30mg, 70mg, 80mg, 100mg or 200mg per person per day for 15, 20 or 30 days. The results showed that 40mg/day for 15-20 days could result in stool egg negative conversion rates of 92.3 to 94.4%, while 50mg/day for 30 days resulted in 96.9 to 100%. Concurrently, the hookworm infection rate in pilot areas dropped by 57.9-71.7% in a short time; whereas the stool egg negative conversion rate of Ascaris lumbricoides was as high as 99.1% to 100% at the same dosage, when the dosage of 100mg/day for 30 days was given, the egg negative reversion rate for Trichuris trichiura was 97.6%. Promising result was also recorded concerning the tolerance of the medicated salt, as the side effects in the inhabitants were mild. In conclusion, the authors considered that the application of mebendazole-medicated salt was a simple and effective measure in controlling hookworm infection, especially in the light of solving the problem of incomplete mass detection and selected mass treatment. Furthermore, it is much more economic from the cost-effect point of view.


Platelet reactivity is a stable and global phenomenon in aspirin-treated cardiovascular patients.
In healthy subjects, platelet hyperreactivity is a global phenomenon--as opposed to agonist-specific--and epinephrine-induced platelet aggregation (EPA) is a reliable marker of this phenotype. Few data are available on platelet reactivity and the relationship between EPA and aggregation induced by other agonists in cardiovascular patients. It was the objective of this study to characterise platelet reactivity in stable cardiovascular patients treated with aspirin and to derive a composite index integrating several aggregation pathways, suitable for selecting patients with extreme phenotypes for further proteomics analysis. Platelet reactivity to agonists was assessed in 110 patients twice, two weeks apart. Factorial analysis was used to determine whether the results obtained with the different agonists could be summarised in a single composite index. EPA correlated with the aggregation values obtained with each of the other agonists, with correlation coefficients of 0.44 to 0.55 (p < 0.001). We constructed a composite "platelet reactivity" index that included 60% of the information provided by each agonist. The results obtained at the first patient visit were consistent with those obtained at the second visit (r = 0.78, p<0.01). No clinical or biological parameters correlated with the composite index. The extreme phenotypes of six selected subjects were confirmed 12 months after the second visit. In conclusion, platelet reactivity in aspirin-treated cardiovascular patients is a global phenomenon that can be summarised by a composite index based on the aggregation responses to various agonists and integrating several activation pathways. This index is not dependent on clinical or biological variables, suggesting that genetic factors regulate platelet reactivity in these patients.


Chimeric Chikungunya viruses are nonpathogenic in highly sensitive mouse models but efficiently induce a protective immune response.
Chikungunya virus (CHIKV) is an important pathogen causing outbreaks of highly debilitating and often chronic, arthralgic human disease. We have designed chimeric alphaviruses encoding CHIKV-specific structural proteins but no structural or nonstructural proteins capable of interfering with development of cellular antiviral response. These chimeras demonstrate a highly attenuated phenotype in both immunocompetent and immunocompromised (A129) mice. However, after a single vaccination, they induced protective immune response against subsequent CHIKV challenge, characterized by high titers of neutralizing antibodies. The rational design of alphavirus genomes provides a strong basis for the development of new recombinant alphaviruses with irreversible, highly attenuated, cell type-restricted phenotypes.


Paediatric day-case anaesthesia and pain control.
More surgery on children is being carried out on a day-case basis and we review the anaesthetic management. Selection of appropriate patients and procedures is vital and careful preparation of children and families minimizes fear and anxiety and streamlines the organizational aspects of care. Simple, noninvasive general-anaesthetic techniques with modern agents are recommended. Good analgesia is important and is based upon local or regional blockade, nonsteroidal antiinflammatory drugs and paracetamol, with opioids being reserved for rescue analgesia. Omission of opioids helps to minimize postoperative emesis. Discharge home is facilitated by clear instructions about activities, dressings, wound care and continuing pain control. Oral clonidine premedication, new, safer local anaesthetic agents, ultrasound guidance for blocks and prolongation of single-injection caudal blocks with clonidine or ketamine are recent developments. Guidelines for safe sedation and analgesia for procedures are available. Behavioural and cognitive changes can be seen in children after anaesthesia and surgery and parents should be informed of this possibility. Children benefit particularly from day care and recent advances in anaesthesia and pain management have allowed a huge expansion of this modality of care with a consequent reduction in the need for children to be in hospital.


pH-responsive polymeric micelles self-assembled from amphiphilic copolymer modified with lipid used as doxorubicin delivery carriers.
In the present study, a novel pH-responsive amphiphilic copolymer, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)] conjugated poly(β-amino esters) (DSPE-b-PEG-b-PAE-b-PEG-b-DSPE), was designed and successfully synthesized via Michael-type step polymerization. The chemical structure of the pentablock copolymer was confirmed with proton nuclear magnetic resonance (1H-NMR) and Fourier transform infrared (FT-IR) spectroscopy. The copolymer was able to self-assemble into core/shell polymeric micelles in aqueous solution at low concentrations, and its critical micelle concentration (CMC) value was 4.5 mg l-1 determined by fluorescence spectrophotometry. The pKb value of the copolymer was about 6.5, confirmed by acid-base titration, indicating the pH-sensitivity of the polymeric micelle. The hydrodynamic diameter, distribution and zeta potential of the polymeric micelles at different pH conditions were monitored by dynamic light scattering (DLS). Doxorubicin (DOX) was encapsulated into the core of the micelles with a high drug loading content (15.9%) and entrapment efficacy (60.4%). In vitro experiments demonstrated that the release behaviour of DOX from the DOX-loaded polymeric micelles (DOX-PMs) was pH-triggered. When the pH decreased from 7.4 to 5.0, the drug release rate was markedly accelerated. MTT assay showed that the copolymer had negligible cytotoxicity whereas the DOX-PMs displayed high toxicity for tumour cells such as B16F10, HepG2 and HeLa cell lines. The results demonstrated that these pH-sensitive polymeric micelles could be used as potential anti-cancer drug carriers for cancer chemotherapy with controlled release.


Efficacies of tea components on doxorubicin induced antitumor activity and reversal of multidrug resistance.
Considering of novel biochemical modulation by some foods and beverages, we have performed screening for green tea components that have enhancing effects on doxorubicin (DOX) induced antitumor activity. Components, such as caffeine, theanine, (-)-epigallocatechin gallate (EGCG) and flavonoids have inhibitory effects on the DOX efflux from Ehrlich ascites carcinoma cells. Thus, it is suggested that EGCG and flavonoids may enhance DOX induced antitumor activity and increase the DOX concentrations in tumors through the inhibition of DOX efflux. It is expected that these components in green tea exhibit low toxicity and that there are few side effects of drinking green tea in combination with an antitumor agent. We think that the intake of a favorite beverage favors a positive mental attitude of a patient and increases the efficacy of the chemotherapeutic index, and that this efficacy is useful for improving the quality of life on cancer chemotherapy. In DOX resistant P388 leukemia cell bearing mice theanine increased the DOX induced efficacy through an increase in the DOX concentrations in the tumors. Theanine attacked the same transport process for DOX in both types of cells, elevated the DOX concentration and increased the DOX induced antitumor activity.


Health concerns for African American youth.
African American youth today face many challenges that can result in poor decisions and lead to high risk behavior. This nation has experienced a decrease in the number of teen pregnancies, but among African American youth the rates are still too high. African American youth also struggle with alcohol and drug addiction and limited access to health care. In short, there are many challenges to providing appropriate health care to our youth.


Vertical distribution of soil seed bank and the ecological importance of deeply buried seeds in alkaline grasslands.
Soil seed banks play a central role in vegetation dynamics and may be an important source of ecological restoration. However, the vast majority of seed bank studies examined only the uppermost soil layers (0-10 cm); hence, our knowledge on the depth distribution of seed bank and the ecological significance of deeply buried seeds is limited. The aim of our study was to examine the fine-scale vertical distribution of soil seed bank to a depth of 80 cm, which is one of the largest studied depth gradients so far. Our model systems were alkaline grasslands in East-Hungary, characterised by harsh environmental conditions, due to Solonetz soil reference group with Vertic horizon. We asked the following questions: (1) How do the seedling density and species richness of soil seed bank change along a vertical gradient and to what depth can germinable seeds be detected? (2) What is the relationship between the depth distribution of the germinable seeds and the species traits? In each of the five study sites, four soil cores (4 cm diameter) of 80 cm depth were collected with an auger for soil seed bank analysis. Each sample was divided into sixteen 5-cm segments by depth (320 segments in total). Samples were concentrated by washing over sieves and then germinated in an unheated greenhouse. Soil penetration resistance was measured in situ next to each core location (0-80 cm depth, 1-cm resolution). We tested the number and species richness of seedlings observed in the soil segments (N = 320), using negative binomial generalized linear regression models, in which sampling layer and penetration resistance were the predictor variables. We ran the models for morphological groups (graminoids/forbs), ecological groups (grassland species/weeds) and life-form categories (short-lived/perennial). We also tested whether seed shape index, seed mass, water requirement or salt tolerance of the species influence the vertical distribution of their seed bank. Germinable seed density and species richness in the seed bank decreased with increasing soil depth and penetration resistance. However, we detected nine germinable seeds of six species even in the deepest soil layer. Forbs, grassland species and short-lived species occurred in large abundance in deep layers, from where graminoids, weeds and perennial species were missing. Round-shaped seeds were more abundant in deeper soil layers compared to elongated ones, but seed mass and ecological indicator values did not influence the vertical seed bank distribution. Our research draws attention to the potential ecological importance of the deeply buried seeds that may be a source of recovery after severe disturbance. As Vertisols cover 335 million hectares worldwide, these findings can be relevant for many regions and ecosystems globally. We highlight the need for similar studies in other soil and habitat types to test whether the presence of deep buried seeds is specific to soils with Vertic characteristics.


Classification and mutation prediction from non-small cell lung cancer histopathology images using deep learning.
Visual inspection of histopathology slides is one of the main methods used by pathologists to assess the stage, type and subtype of lung tumors. Adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) are the most prevalent subtypes of lung cancer, and their distinction requires visual inspection by an experienced pathologist. In this study, we trained a deep convolutional neural network (inception v3) on whole-slide images obtained from The Cancer Genome Atlas to accurately and automatically classify them into LUAD, LUSC or normal lung tissue. The performance of our method is comparable to that of pathologists, with an average area under the curve (AUC) of 0.97. Our model was validated on independent datasets of frozen tissues, formalin-fixed paraffin-embedded tissues and biopsies. Furthermore, we trained the network to predict the ten most commonly mutated genes in LUAD. We found that six of them-STK11, EGFR, FAT1, SETBP1, KRAS and TP53-can be predicted from pathology images, with AUCs from 0.733 to 0.856 as measured on a held-out population. These findings suggest that deep-learning models can assist pathologists in the detection of cancer subtype or gene mutations. Our approach can be applied to any cancer type, and the code is available at https://github.com/ncoudray/DeepPATH .


Interferon α2b increases MMP-13 and IL-10 expression in Kupffer cells through MAPK signaling pathways.
Kupffer cells play critical roles in both progression and resolution of liver fibrosis. Interferon α2b is an important immunoregulator which has anti-fibrotic effect in addition to its antiviral effect. It remained unclear whether the anti-fibrotic effect of interferon α2b is mediated by regulating functions of Kupffer cells. Primary isolated Kupffer cells were cultured with interferon α2b and the expression of matrix metalloproteinase-13, interleukin-10, transforming growth factor -β1 and tumor necrosis factor-α were measured. To investigate the role of mitogen-activated protein kinase pathways in regulating cytokines production by interferon α2b-stimulated Kupffer cells, inhibitors were given before cells were treated with interferon a2b. Cell purity was more than 98%. Stimulating Kupffer cells with interferon α2b led to a dramatic increase in matrix metalloproteinase-13 and interleukin-10 expression. In contrast, the values of tumor necrosis factor-α and transforming growth factor -β1 remained unchanged throughout the 24-hour observation period. Inhibited ERK1/2 pathway prevented interferon α2b-triggered matrix metalloproteinase-13 production, while inhibited p38MAPK, ERK1/2 or JNK signaling pathways all blocked interleukin-10 expression. Interferon α2b may exert anti-fibrotic effect by elevating the level of matrix metalloproteinase-13 and interleukin-10 in Kupffer cells, in a mitogen-activated protein kinase signaling pathways-dependent manner.


[Hydatid cyst of the posterior fossa].
Hydatidosis is an endemic affection in Tunisia. Cerebral echinococcosis is a relatively rare entity accounting for only 1-2% of all hydatid cysts in humans. Extradural hydatid cyst of the posterior fossa is a very uncommon site for the disease. We report the case of a four-year-old child admitted for high intracranial pressure. Brain CT scan showed an extradural posterior fossa cyst without enhancement after contrast medium injection. Operative finding revealed a hydatid cyst. The histological examination of the tissue sample confirmed the diagnosis. The patient was given albendazole post operatively. She feels well six months later.


Effects of oral dehydroepiandrosterone on bone density in young women with anorexia nervosa: a randomized trial.
Young women with anorexia nervosa (AN) have subnormal levels of dehydroepiandrosterone (DHEA) and estrogen that may be mechanistically linked to the bone loss seen in this disease. The purpose of this study was to compare the effects of a 1-yr course of oral DHEA treatment vs. conventional hormonal replacement therapy (HRT) in young women with AN. Sixty-one young women were randomly assigned to receive oral DHEA (50 mg/d) or HRT (20 micro g ethinyl estradiol/0.1 mg levonorgestrel). Anthropometric, nutrition, and exercise data were acquired every 3 months, and bone mineral density (BMD) and body composition were measured by dual energy x-ray absorptiometry (DXA) every 6 months over 1 yr. Serum samples were obtained for measurements of hormones, proresorptive cytokines, and bone formation markers, and urine was collected for determinations of bone resorption markers at each visit. In initial analyses, total hip BMD increased significantly and similarly (+1.7%) in both groups. Hip BMD increases were positively correlated with increases in IGF-I (r = 0.44; P = 0.030) and the bone formation marker, bone-specific alkaline phosphatase increased significantly only in the DHEA treatment group (P = 0.003). However, both groups gained significant amounts of weight over the year of therapy, and after controlling for weight gain, no treatment effect was detectable. There was no significant change in lumbar BMD in either group. Both bone formation markers, bone-specific alkaline phosphatase and osteocalcin, increased transiently at 6-9 months in those subjects receiving DHEA compared with the estrogen-treated group (P < 0.05). Both DHEA and HRT significantly reduced levels of the bone resorption markers, urinary N-telopeptides (P < 0.05). There was a positive correlation between changes in IGF-I and changes in weight, body fat determined by DXA, and estradiol for both groups. In addition, patients receiving DHEA exhibited improvement on three validated psychological instruments (Eating Attitudes Test, Anorexia Nervosa Subtest, and Spielberger Anxiety Inventory). Both DHEA and HRT had similar effects on hip and spinal BMD. Over the year of treatment, maintenance of both hip and spinal BMD was seen, but there was no significant increase after accounting for weight gain. Compared with HRT, DHEA appeared to have anabolic effects, evidenced by the positive correlation between increases in hip DXA measurements and IGF-I and significant increases in bone formation markers. Both therapies significantly decreased bone resorption. Replicating results from studies of the elderly, DHEA resulted in improvements in specific psychological parameters in these young women.


Success of chemotherapy and a liver transplant in a pediatric patient with hepatic angiosarcoma: A case report.
Hepatic angiosarcoma is an extremely rare diagnosis in children, with fewer than 50 pediatric cases reported in the literature worldwide. This aggressive vascular sarcoma carries a very dismal prognosis and is known to be resistant to radiation, chemotherapy, and other vascular-targeted agents. Complete surgical resection is felt to provide the best chance for long-term survival. In patients with tumors not amenable to resection, a liver transplant can be considered. However, very few such transplants have been reported, given that they remain controversial due to high cancer recurrence and mortality post-transplant. Herein, we report the unique case of a 2-year-old child with localized hepatic angiosarcoma not amendable to resection who successfully underwent a liver transplant and received chemotherapy with six cycles of doxorubicin, docetaxel, and ifosfamide.


Terahertz quasi non-diffraction Bessel vortex beam generation using three lattice types reflective metasurface.
Bandwidth, orbital-angular momentum (OAM) divergence, and mode purity are the three critical issues for the practical terahertz orbital angular momentum manipulation, especially in the next sixth-generation (6G) communication system. Here we propose the broadband high-order Bessel vortex beam carrying multiple OAM modes reflective metasurface in the terahertz domain. The simulation results agree with the theoretical expectation, and the diffracting divergence of OAM vortex beam characteristics has been alleviated. The research on the relationship between the varieties of lattice type and mode purity is also relatively scarce. Henceforth, a comparison study has been conducted between three lattice types, i.e., square lattice, triangular lattice, and concentric ring lattice. And corresponding results of the relationship of mode purity with those lattice types show that the concentric ring lattice has the best performance.


Gender specific effects of a mild stressor on alcohol cue reactivity in heavy social drinkers.
Stress plays an important role in the development and maintenance of alcohol-abuse. Some of the effects of stress on alcohol-related behaviours, however, appear to be gender-dependent. The present study set out to examine the effects of stress on feelings of desire for alcohol, skin conductance response and alcohol consumption in the presence of alcohol-related cues in relation to gender. Participants were heavy non-dependent alcohol drinkers. Thirty-two (16 males) participants drinking more than 21 units of alcohol per week were randomly allocated to undergo the experimental stress (based on the 'Trier Social Stress' Test) or the non-stress procedure before the alcohol cue exposure procedure, during which participants handled and smelled their preferred drink. Mood and saliva cortisol level changes were used as indices of the stress effects, while alcohol craving, skin conductance and alcohol consumption were the cue reactivity measures. Self ratings of anxiety and tension increased and cortisol levels remained high in the stress compared to the non-stress condition; no gender differences were found. Stress induced gender-specific effects with regard to skin conductance response and alcohol consumption measurements. Stressed females did not show an increase from baseline in the skin conductance response during the alcohol cue-exposure session, which was observed in the non-stressed females; they also consumed less alcohol than males under stress. Female participants respond less to alcohol-related cues when in a negative mood state. Such a finding suggests that females when in a negative mood may be less sensitive to positive incentive processes mediating cue reactivity compared to males.


Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in Adults.
Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) is the most common subtype of B-ALL in adults and its incidence increases with age. It is characterized by the presence of BCR-ABL oncoprotein that plays a central role in the leukemogenesis of Ph+ ALL. Ph+ ALL patients traditionally had dismal prognosis and long-term survivors were only observed among patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1). However, feasibility of allo-HSCT is limited in this elderly population. Fortunately, development of increasingly powerful tyrosine kinase inhibitors (TKIs) from the beginning of the 2000's dramatically improved the prognosis of Ph+ ALL patients with complete response rates above 90%, deep molecular responses and prolonged survival, altogether with good tolerance. TKIs became the keystone of Ph+ ALL management and their great efficacy led to develop reduced-intensity chemotherapy backbones. Subsequent introduction of blinatumomab allowed going further with development of chemo free strategies. This review will focus on these amazing recent advances as well as novel therapeutic strategies in adult Ph+ ALL.


[TIA--an emergency?].
Transient ischemic attacks (TIA) can be a sign of impending stroke and as such an indication of atherosclerotic disease or other impending vascular catastrophe. We discuss clinical presentation, pathophysiologic mechanisms, diagnostic procedures and guidelines for therapy using data from four TIA cases sharing certain symptoms but differing in etiology.


Intraventricular Haemorrhage Complicated by Hydrocephalus in an Acutely Encephalopathic Preterm Infant.
Intraventricular haemorrhage (IVH) is characterized by bleeding of the immature subependymal germinal matrix in preterm infants, but the pathogenesis is multifactorial. IVH and posthaemorrhagic hydrocephalus (PHH) are common causes of neonatal morbidity and mortality among preterm infants. We describe a preterm male infant who was born clinically stillbirth; became moderately severe encephalopathic. He had bilateral IVH (III right and IV left) with consequent PHH. His incredible outcome following a stormy perinatal period appears intriguing. Long-term follow-up is needed to evaluate the severity of deficits as he matures. Whether therapeutic cooling would have made a difference or not is debatable.


Two Means Together? Effects of Response Bias and Sensitivity on Communicative Action Detection.
Numerous lines of research suggest that communicative dyadic actions elicit preferential processing and more accurate detection compared to similar but individual actions. However, it is unclear whether the presence of the second agent provides additional cues that allow for more accurate discriminability between communicative and individual intentions or whether it lowers the threshold for perceiving third-party encounters as interactive. We performed a series of studies comparing the recognition of communicative actions from single and dyadic displays in healthy individuals. A decreased response threshold for communicative actions was observed for dyadic vs. single-agent animations across all three studies, providing evidence for the dyadic communicative bias. Furthermore, consistent with the facilitated recognition hypothesis, congruent response to a communicative gesture increased the ability to accurately interpret the actions. In line with dual-process theory, we propose that both mechanisms may be perceived as complementary rather than competitive and affect different stages of stimuli processing.


ATF1 promotes the malignancy of lung adenocarcinoma cells by transcriptionally regulating ZNF143 expression.
The clinical oncogenic functions and mechanisms of activating transcription factor 1 (ATF1) in the progression of lung adenocarcinoma have not been completely elucidated. In this study, by employing human lung adenocarcinoma tissues and cells, we detect the correlation of ATF1 expression with the clinicopathological features and prognosis of patients with lung adenocarcinoma and find that ATF1 promotes lung adenocarcinoma cell proliferation and migration by transcriptionally enhancing zinc finger protein 143 (ZNF143) expression. ATF1 and ZNF143 are strongly expressed in lung adenocarcinoma tissues compared with those in the adjacent normal tissues, and high ATF1 and ZNF143 expressions are related to poor disease-free survival of lung adenocarcinoma patients. ATF1 overexpression results in increased proliferation and migration of lung adenocarcinoma cells, whereas knockdown of ATF1 inhibits cell proliferation and migration. Furthermore, ATF1 transcriptionally regulates the expression of ZNF143, and ATF1 and ZNF143 expressions are positively correlated in lung adenocarcinoma tissues. ZNF143 knockdown blocks lung adenocarcinoma cell migration, which is mediated by ATF1 upregulation. Hence, this study provides a potential therapeutic candidate for the treatment of lung adenocarcinoma.


Presentation of burn injuries and their management outcome.
To study the causes of burns and presentation of burn patients to POF Hospital and their overall management outcome. A cross sectional study of 111 burn patients presenting primarily to and admitted in Pakistan Ordinance Factory (POF) Hospital from December 2004 to August 2005 were included in the study. Patients of any age, any degree of burns and both sexes were included. Patients presenting after more than one week post burn or patients referred from other hospitals were excluded. A detailed history and examination was done before treatment was started. For statistical analysis, patients were divided into different age groups. The place of acquiring burns, the causes and mechanisms of burns and overall management outcome was studied and results expressed as means and percentages. Mean age of patients was 18.96 years, 37.8% of the patients were children less than 10 years of age (Group 1), 39.6% were males more than 10 years of age (Group II), and 22.5% were females more than 10 years of age (Group III). Overall, 55% of the patients were males and 45% were females. Mean total body surface area (TBSA) burnt was 11-20%. In group-I patients, the place of burns was their home. The burns occurred at home in 31.8% of Group II patients, and 96% of Group III patients. The place of burns was workplace in 61.3% of Group II patients, and only 4% of Group III patients. The mechanism of burn was scalding in 73.8% of Group I, flame burns in 40.9% of Group II patients and 72% of Group III patients. 25% of Group II patients got electrical burn. The overall mortality was 29.7%. The cause of burns was scalding at home in the majority of children less than ten years of age (Group I). Similarly the majority of group-II patients got burns at workplace in the form of either flame burns or electric burns. Many of the females more than ten years of age (Group III) got flame burns at home (suicidal, homicidal or accidental).


Effect of growth hormone on the activity of some lysosomal enzymes in neutrophilic polymorphonuclear leukocytes of hypopituitary dwarfs.
Elevated activities of beta-D-glucuronidase, myeloperoxidase, and lysozyme were found in polymorphonuclear leukocytes (PMNs) of both hypopituitary dwarfs and normal subjects after the administration of growth hormone (GH), as compared to the activities in PMNs from blood drawn immediately before the administration of GH. During in vitro incubation, GH was able to inhibit the release of lysosomal enzymes from resting PMNs. This inhibition may be one of the reasons for the elevated lysosomal enzyme activities observed in PMNs after the administration of GH. GH can also affect hexose monophosphate shunt (HMPS) activity and superoxide production by PMNs. The activity of HMPS is stimulated by GH in resting PMNs, while in PMNs incubated with zymosan the GH inhibits both HMPS and superoxide production.


High Incidence of Congenital Syphilis after Implementation of the Brazilian Ministry of Health Ordinances Related to Maternal Diagnostics.
The increasing rates of maternal and congenital syphilis (CS) infections are public health concerns and need further investigation in order to provide better assistance in epidemiological surveillance and new strategies for the assistance and prevention of CS. In December 2011, the Brazilian Ministry of Health (BMH) implemented ordinance number 3.242, reinforced in 2012 by ordinance number 77, aiming to improve the quality of the syphilis diagnosis system using rapid tests. Here, we evaluate the incidence, lethality, and possible factors associated with CS in Salvador, Bahia, in the pre-resolution period (2007 to 2011) and post-resolution (2012 to 2016). An observational, ecological time-series study is conducted using secondary data collected from the National Notifiable Diseases Information System (SINAN). Linear regression analysis to estimate increases or reductions in the mean incidence over time is also performed. A total of 5470 CS cases are analyzed. The incidence ranges from 2.1 cases per 1000 live births in 2007 to 17.1 cases per 1000 live births in 2019, showing a progressive increase in incidence over the years and reduction of lethality in the post-resolution period. The number of CS cases reported prior to the implementation of the ordinances (2007-2011) does not reveal a significant increase in the incidence. However, in the post-ordinances period (2012-2019), there is an average increase of the number of CS cases by three times over the years, with an average increase of 1.8 new cases annually. Our findings highlight the importance of diagnosis and support information in strategies for CS prevention. Furthermore, these data show a positive impact of resolutions on the diagnosis and evolution of the disease.


Molecular dynamics in the membranes of helper T cells.
We provide evidence that redistributions and interactions of integral proteins in the fluid membranes of helper T (Th) cells may play important roles in Th-cell activation. A particular monoclonal antibody, 3D3, directed to a clonotypic determinant on the T-cell receptor (TCR) of the cloned Th-cell line D10, had previously been shown to be distinctively capable of directly activating D10 cells at low concentrations. We demonstrate here by immunofluorescence experiments that it is also distinctively able itself to produce a clustering (capping) of the TCRs on the D10 cell surface. Simultaneously, by means of double-immunofluorescence experiments, we find that the 3D3-induced clustering of the TCRs distinctively produces a co-clustering of the accessory molecule CD4 with the TCR clusters, although the CD4 and TCR molecules are normally independent of one another in the D10 cell membrane. These results, and related ones previously obtained from studies of the interactions of D10 Th cells with antigen-presenting cells, are analyzed to suggest that the membrane clustering of TCRs and the induced TCR-CD4 interactions are critical to the signaling events in Th-cell activation.


The essence of nursing in the shifting reality of Israel today.
Israel's healthcare system is undergoing constant transformation; nurses' roles and education are changing accordingly. Israel's severe shortage of physicians has led to an increase in nurses' authority and responsibilities. The nursing profession is addressing many questions particularly in light of its expanded responsibilities and the current lack of legislation related to the practice of nursing. Additionally Israel is coping with an increasing shortage of nurses and the rapid development of innovative technologies. This article describes Israel's shifting reality and the nation's responses to these changing conditions. Responses include increasing financial support, enhancing educational opportunities, expanding the nursing role, and using new technologies.


The effect of late pregnancy feed allowance on the milk composition of the sow's colostrum and milk.
The composition of colostrum and milk and of sows fed either 3.4 kg or 1.0 kg daily of a conventional sow diet during the last 14 days of gestation was investigated. The fat content of colostrum of the very restrictedly fed sows was higher compared with the standard fed sows. There was a significantly decrease in the crude protein and immunoglobulin contents of colostrum during the first 4 h post farrowing. The milk composition 14 days after farrowing was not affected by the late pregnancy feeding level. The composition of milk was significantly correlated with the 3 week litter weight. The colostrum IgG content was not correlated to the mortality of piglets during the first week post favouring. The content of crude protein and immunoglobulins in the milk was not correlated with the frequency of post weaning diarrhoea.


[Molecular physiology of adrenoreceptors].
The paper reviews some problems of theoretical investigation of the spatial of adrenergic drugs and their receptors, citing results recently obtained by the authors. It includes the chapters as follows: Introduction; Conformation - activity relationships of ligands; Theoretical conformational analysis; Noradrenaline; Classification and some models of adrenergic receptors; Problems of ligands productive conformation selection and the description of receptor topography; Principles of choice of ligands; Criteria for productive conformation selection; Productive conformations of beta 2-adrenergic agonists and beta 2-receptor topography; Productive conformations of alpha 1-adrenergic receptor ligands and alpha 1-receptor topography; Structure-activity relationships of some ligands in the light of adrenergic beta 2- and alpha 1-receptors topography; Possible role of calcium ion in the interaction of adrenergic agonists with receptors.


Restoration of miR-424 suppresses BCR-ABL activity and sensitizes CML cells to imatinib treatment.
MicroRNAs (miRNAs) are small noncoding RNAs that participate in many biological processes by posttranscriptionally regulating gene expression. Dysregulation of miRNA expression has been shown to be typical of many neoplasms. Chronic myeloid leukemia (CML) is a disorder of hematopoietic stem cells carrying the Philadelphia (Ph) chromosome and an oncogenic BCR-ABL tyrosine kinase fusion gene. While the development of tyrosine kinase inhibitors (TKIs) like imatinib has revolutionized treatment of CML, it has become increasingly clear in recent years that TKI treatment alone will not be curative in many cases. Thus, further dissection of the regulatory networks that drive BCR-ABL-induced malignant transformation may help to identify other novel therapeutic approaches that complement TKI treatment. In this study we demonstrate that the expression of miR-424 is markedly low in CML cell lines and patient samples at time of diagnosis. With the aid of bioinformatics analysis we revealed a conserved target site for miR-424 in the 3'-untranslated region (UTR) of the ABL gene. Via luciferase assays, we showed that miR-424 directly targets BCR-ABL. Overexpression of miR-424 was shown to suppress proliferation and induce apoptosis of K562 cells as well as sensitize these cells to imatinib treatment. These findings strongly suggest that miR-424 acts as a tumor suppressor by downregulating BCR-ABL expression. Up-regulation of miR-424 in CML cells may therefore have a therapeutic effect against this disease.


Association of Overlapping, Nonconcurrent, Surgery With Patient Outcomes at a Large Academic Medical Center: A Coarsened Exact Matching Study.
Assess the safety of overlapping surgery before implementation of new recommendations and regulations. Overlapping surgery is a longstanding practice that has not been well studied. There remains a need to analyze data across institutions and specialties to draw well-informed conclusions regarding appropriate application of this practice. Coarsened exact matching was used to assess the impact of overlap on outcomes amongst all surgical interventions (n = 61,524) over 1 year (2014) at 1 health system. Overlap was categorized as: any, beginning, or end overlap. Study subjects were matched 1:1 on 11 variables. Serious unanticipated events were studied including unplanned return to operating room, readmission, and mortality. In all, 8391 patients (13.6%) had any overlap and underwent coarsened exact matching. For beginning/end overlap, matched groups were created (total matched population N = 4534/3616 patients, respectively). Any overlap did not predict unanticipated return to surgery (9.8% any overlap vs 10.1% no overlap; P = 0.45). Further, any overlap did not predict an increase in reoperation, readmission, or emergency room (ER) visits at 30 or 90 days (30D reoperation 3.6% vs 3.7%; P = 0.83, 90D reoperation 3.8% vs 3.9%; P = 0.84) (30D readmission 9.9% vs 10.2%; P = 0.45, 90D readmissions 6.9% vs 7.0%; P = 0.90) (30D ER 5.4% vs 5.6%; P = 0.60, 90D ER 4.8% vs 4.7%; P = 0.71). In addition, any overlap was not associated with mortality over the surgical follow-up period (90D mortality 1.7% vs 2.1%; P = 0.06). Beginning/end overlap had results similar to any overlap. Overlapping, nonconcurrent surgery is not associated with an increase in reoperation, readmission, ER visits, or unanticipated return to surgery.


Management of cancer treatment-related diarrhea. Issues and therapeutic strategies.
The cancer treatment-related diarrhea caused by acute graft-versus-host disease (GVHD) and chemotherapeutic agents, particularly fluoropyrimidines and irinotecan, significantly affects patient morbidity and mortality. The mechanisms causing cancer treatment-related diarrhea are not fully understood, but histopathologic evidence points to a multifactorial process that causes an absorptive and secretory imbalance in the small bowel. Cancer treatment-related diarrhea could be life-threatening, yet assessment and treatment are not currently standardized. Several clinicians participated in a closed roundtable meeting to review the mechanisms of chemotherapy-induced diarrhea (CID) and GVHD-induced diarrhea, management issues in cancer treatment-induced diarrhea, and pharmacologic approaches to treatment. The meeting produced a proposal for new treatment guidelines and an algorithm, which include the use of octreotide for the management of CID- and GVHD-induced diarrhea. The development of diarrhea assessment guidelines that expand on the current National Cancer Institute criteria and allow for better patient management was also proposed.


The pherophorins: common, versatile building blocks in the evolution of extracellular matrix architecture in Volvocales.
Green algae of the order Volvocales provide an unrivalled opportunity for exploring the transition from unicellularity to multicellularity. They range from unicells, like Chlamydomonas, through homocytic colonial forms with increasing cooperation of individual cells, like Gonium or Pandorina, to heterocytic multicellular forms with different cell types and a complete division of labour, like Volvox. A fundamental requirement for the evolution of multicellularity is the development of a complex, multifunctional extracellular matrix (ECM). The ECM has many functions, which can change under developmental control or as a result of environmental factors. Here molecular data from 15 novel proteins are presented. These proteins have been identified in Chlamydomonas reinhardtii, Gonium pectorale, Pandorina morum and Volvox carteri, and all belong to a single protein family, the pherophorins. Pherophorin-V1 is shown to be a glycoprotein localized to the 'cellular zone' of the V. carteri ECM. Pherophorin-V1 and -V2 mRNAs are strongly induced not only by the sex inducer, which triggers sexual development at extremely low concentrations, but also by mechanical wounding. Like the extensins of higher plants, which are also developmentally controlled or sometimes inducible by wounding, the pherophorins contain a (hydroxy-)proline-rich (HR) rod-like domain and are abundant within the extracellular compartment. In contrast to most extensins, pherophorins have additional globular A and B domains on both ends of the HR domains. Therefore pherophorins most closely resemble a particular class of higher plant extensin, the solanaceous lectins (e.g. potato lectin), suggesting multivalent carbohydrate-binding functions are present within the A and B domains and are responsible for cross-linking. Our results suggest that pherophorins are used as the building blocks for the extracellular scaffold throughout the Volvocales, with the characteristic mesh sizes in different ECM structures being a result of the highly diverse extensions of the HR domains. Pherophorins have therefore been a versatile element during the evolution of ECM architecture in these green algae.


Effect of Oxidized Low-Density Lipoprotein on Head and Neck Squamous Cell Carcinomas.
Cardiovascular disease (CVD) and cancer are two major causes of death worldwide. The question is, "Could there be a link between these two pathologies in addition to their shared, common risk factors?" To find some answers, we studied the effect of oxidized low-density lipoproteins (oxLDL) on head and neck cancer (HNC) cell lines, since oxLDL is a major contributor to atherosclerosis and the principal cause of CVD. In this study, we exposed three HNC cell lines (Detroit 562, UPCI-SCC-131 and FaDu) to oxLDL. We investigated two oxLDL receptors, CD36 and Lox-1, using immunofluorescence. Cancer cell migration was evaluated using Boyden chambers and the Wnt/β-catenin pathway was investigated using Western blotting. We demonstrated that the expression of CD36 and Lox-1 significantly increases after exposure to oxLDL. Moreover, we found that oxLDL reduces the migration of HNC cell lines, an observation that is in line with an increased degradation of β-catenin under oxLDL. Finally, the inhibition of CD36 with sulfosuccinimidyl oleate (SSO) reverses the inhibition of cell migration. In conclusion, we report that oxLDL seems to induce an increase in CD36 expression on HNC cell lines, enhancing the uptake of these lipids in cells to finally decrease cancer cell migration via the CD36/β-catenin pathway.


Cost-effectiveness analysis of lenvatinib plus pembrolizumab compared with chemotherapy for patients with previously treated mismatch repair proficient advanced endometrial cancer in China.
Aims: This study aimed to evaluate the cost-effectiveness of lenvatinib plus pembrolizumab (LP) vs. chemotherapy for patients with previously treated mismatch repair proficient advanced endometrial cancer in China. Methods: A lifetime of partitioned survival Markov was used to evaluate the overall lifetime, total costs, quality adjusted life years (QALYs), and incremental cost effectiveness ratio (ICER) across a 10-years time horizon in the study 309-KEYNOTE-775 clinical trial. Direct costs and utility values were gathered from available literature. The willingness to pay (WTP) was defined at $37,663.26 per QALY. Sensitivity analyses were carried out to determine the model's uncertainty. Results: According to the baseline analysis, the LP group gained 4.02 total life years and 3.13 QALYs for $93,496.69, whereas the chemotherapy group gained 2.86 total life years and 2.24 QALYs for $30,578.04. LP versus chemotherapy resulted in an incremental cost of $62,918.65, with an ICER of $70,962.09/QALY, which was higher than China's WTP threshold ($37,663.26/QALY). The ICERs were most sensitive to the cost of pembrolizumab and the cycle of LP delivered, according to the sensitivity analysis. However, changing the range of those parameters has no influence on the model's results. Conclusion: Our present analysis suggests that LP treatment is not cost-effective for patients with previously treated mismatch repair proficient advanced endometrial cancer. However, LP treatment may be a cost-effective treatment option if the price is reduced.