Economic evaluation and budget impact analysis of dengue vaccination following pre-vaccination serological screening in India.
To evaluate the budget impact and cost-effectiveness of dengue vaccination following pre-vaccination serological screening in India. We used a static cohort model (combination of decision tree and Markov model) to compare dengue disease and cost burden with and without dengue vaccination program with serological screening for a hypothetical cohort of 10-year-old adolescents. Budget impact was expressed in terms of total budget required for implementation of vaccination programme. Program impact was expressed in terms of disability-adjusted life-years (DALYs) averted. Cost effectiveness was expressed as costs per DALY averted. All costs are expressed in 2018 US dollars. Sensitivity analysis was performed for ICERs in different vaccination scenarios. The total budget for implementation of dengue vaccination programme is approximately around US$ 530 million (INR 3620 crores). Our model results suggest dengue vaccination result in a net gain of almost 86,000 DALYS. We found the Dengue vaccine to be a cost-effective intervention with an ICER of $3364 (INR 2,30,098) which is less than three-times GDP per capita of India ($6047; INR 413,601). One-way sensitivity analysis shows that the ICER is most affected by the overall incidence of dengue infections followed by vaccine price. Probabilistic sensitivity analysis shows that ICER for dengue vaccination varied from $1182 (INR 80,837) to $6367 (INR 435,439). Our study shows that dengue vaccine with pre-vaccination serological screening programme is a cost-effective intervention with the conservative estimates.


Characterization of the interferences of systemic azole antifungal drugs with adrenal steroid biosynthesis using H295R cells and enzyme activity assays.
Azole antifungals, designed to inhibit fungal CYP51, have a liability to inhibit human CYP enzymes. Whilst drug-metabolizing CYPs are covered in preclinical safety assessment, those metabolizing endogenous bioactive molecules are usually not. Posaconazole and itraconazole were recently found to cause pseudohyperaldosteronism with hypokalemia and hypertension by inhibiting CYP11B1-dependent adrenal cortisol biosynthesis. Because this was overlooked in preclinical safety assessment, the present study tested whether applying adrenal carcinoma H295R cells could have predicted this liability and whether other systemic triazole antifungals interfere with adrenal steroidogenesis. Forskolin-stimulated H295R cells were exposed to systemic triazole antifungals that are currently used, and key adrenal steroids were quantified by UHPLC-MS/MS. To support the findings from the H295R model, activity assays for steroidogenic enzymes were performed. The analysis of the steroid profiles and product/substrate ratios predicted the CYP11B1 and CYP11B2 inhibition by posaconazole and itraconazole. Comparison of their steroid profiles allowed distinguishing their effects and suggested inhibition of adrenal androgen synthesis by posaconazole but not itraconazole, which was confirmed by CYP17A1 17,20-lyase activity measurements. In line with clinical observations, there was no evidence from these experiments for an inhibition of either CYP11B1/2 or CYP17A1 by voriconazole, fluconazole or isavuconazole. However, itraconazole and isavuconazole exerted an overall inhibition of steroidogenesis by a mechanism warranting further investigations. In conclusion, analyses of steroid profiles from the H295R assay and product/substrate ratios provide important information on the interference of a chemical with adrenal steroidogenesis and the underlying mechanism. This approach facilitates prioritization of further investigations, including enzyme expression and activity studies.


Novel quinazoline-quinoline alkaloids with cytotoxic and DNA topoisomerase II inhibitory activities.
Two new synthetic analogues of luotonins A and F, 7-acetylaminoluotonin A (6) and 3-[3H(quinazolino-4-one)]quinoline (7) were synthesized. The new analogues, along with four natural quinazoline-quinoline alkaloids, luotonins A (1), B (2), E (3), F (4) and a synthetic deoxoluotonin F (5), showed cytotoxic activity (IC(50) 1.8-40.0 microg/mL) and DNA topoisomerase II inhibition at a concentration of 25 microM.


Global trends and challenges in deceased donor kidney allocation.
Worldwide, the number of patients able to benefit from kidney transplantation is greatly restricted by the severe shortage of deceased donor organs. Allocation of this scarce resource is increasingly challenging and complex. Striking an acceptable balance between efficient use of (utility) and fair access to (equity) the limited supply of donated kidneys raises controversial but important debates at ethical, medical, and social levels. There is no international consensus on the recipient and donor factors that should be considered in the kidney allocation process. There is a general trend toward a reduction in the influence of human leukocyte antigen mismatch and an increase in the importance of other factors shown to affect posttransplant outcomes, such as cold ischemia, duration of dialysis, donor and recipient age, and comorbidity. Increased consideration of equity has led to improved access to transplantation for disadvantaged patient groups. There has been an overall improvement in the transparency and accountability of allocation policies. Novel and contentious approaches in kidney allocation include the use of survival prediction scores as a criterion for accessing the waiting list and at the point of organ offering with matching of predicted graft and recipient survival. This review compares the diverse international approaches to deceased donor kidney allocation and their evolution over the last decade.


Pathways for the utilization of N-acetyl-galactosamine and galactosamine in Escherichia coli.
Among enteric bacteria, the ability to grow on N-acetyl-galactosamine (GalNAc or Aga) and on D-galactosamine (GalN or Gam) differs. Thus, strains B, C and EC3132 of Escherichia coli are Aga+ Gam+ whereas E. coli K-12 is Aga- Gam-, similarly to Klebsiella pneumoniae KAY2026, Klebsiella oxytoca M5a1 and Salmonella typhimurium LT2. The former strains carry a complete aga/kba gene cluster at 70.5 min of their gene map. These genes encode an Aga-specific phosphotransferase system (PTS) or IIAga (agaVWE) and a GalN-specific PTS or IIGam (agaBCD). Both PTSs belong to the mannose-sorbose family, i.e. the IIB, IIC and IID domains are encoded by different genes, and they share a IIA domain (agaF). Furthermore, the genes encode an Aga6P-deacetylase (agaA), a GalN6P deaminase (agaI), a tagatose-bisphosphate aldolase comprising two different peptides (kbaYZ) and a putative isomerase (agaS), i.e. complete pathways for the transport and degradation of both amino sugars. The genes are organized in two adjacent operons (kbaZagaVWEFA and agaS kbaYagaBCDI) and controlled by a repressor AgaR. Its gene agaR is located upstream of kbaZ, and AgaR responds to GalNAc and GalN in the medium. All Aga- Gam- strains, however, carry a deletion covering genes agaW' EF 'A; consequently they lack active IIAga and IIGam PTSs, thus explaining their inability to grow on the two amino sugars. Remnants of a putative recombination site flank the deleted DNA in the various Aga- Gam- enteric bacteria. Derivatives with an Aga+ Gam- phenotype can be isolated from E. coli K-12. These retain the DeltaagaW' EF 'A deletion and carry suppressor mutations in the gat and nag genes for galactitol and N-acetyl-glucosamine metabolism, respectively, that allow growth on Aga but not on GalN.


Detection of bovine papillomavirus type 14 DNA sequences in urinary bladder tumors in cattle.
Bovine papillomavirus type 14 (BPV-14) is a novel Deltapapillomavirus (δPV) which is most closely related to BPV-1, -2, and -13, well-known members of the δPV genus. So far BPV-14 has been detected in cutaneous neoplastic lesions in cattle and in feline sarcoids. As BPV-14 may share biological and pathological properties with BPV-1, -2 and -13, it has been hypothesized that, like other δPVs, BPV-14 could be associated with bovine bladder neoplasia. In this study, 50 tumors of the urinary bladder of cattle were diagnosed. DNA was extracted from all tumor samples as well as from 25 normal bladder samples and submitted to BPV-14 L1 PCR and subsequent amplicon sequencing analysis. BPV-14 L1 DNA sequences of specific 195bp amplicons were obtained from 17 of 50 (34%) tumor DNA isolates; no BPV-14 DNA was detected from 25 normal samples. Amplicons revealed a 99% homology with the corresponding BPV-14 L1 DNA region (GenBank accession number KP276343.1). Co-infections by two or three δPV types were also seen. This study reveals the presence of BPV-14 DNA alone or in combination with other δPV DNA in bovine bladder tumors alone and suggests that BPV-14 could also be involved in bladder neoplasia as its E5 oncoprotein has the potential to induce cell proliferation. Furthermore, this is the first study to show the presence of BPV-14 in Europe, suggesting that BPV-14, like other δPVs, has a worldwide distribution.


Surgical Management of Dysplasia and Cancer in Inflammatory Bowel Disease.
Patients with inflammatory bowel disease are at an increased risk of cancer secondary to long-standing intestinal inflammation. Surgical options must take into account the significant risk of synchronous disease at other colonic sites. Ileal pouch anal anastomosis is a viable option for patients with ulcerative colitis, but this should be restricted to early cancers that are unlikely to require preoperative or postoperative radiation treatment.


Behavioral effects of mefloquine in tail suspension and light/dark tests.
Mefloquine hydrochloride has been used widely in the past few decades for malaria prophylaxis and treatment. However, in recent years, it has fallen out of favor due to reports of exposure being linked to numerous neuropsychiatric effects, including emotional disturbances. In this study we examined the effects of different doses (5, 25, or 100 mg/kg) of mefloquine relative to vehicle on male C57BL/6 J mice in two tests of emotional behavior, the light-dark box and the tail suspension test. It was found that mefloquine exposure reduced anxiety-linked behaviors in the light-dark box and reduced total immobility times in the tail suspension test, especially at higher doses. Our results lend support to the notion that mefloquine exposure could induce emotional disinhibition.


Ductal carcinoma in situ of the breast. Heterogeneity of individual lesions.
The increased prevalence of ductal carcinoma in situ (DCIS) has produced a growing awareness of the importance of its diverse patterns. These differences in pattern have become clinically significant as predictive indicators of success for planned local excisions of small DCIS lesions. The authors reviewed 100 sequentially collected DCIS cases from a consultation practice. Recognizing the bias of such a series toward exclusion of easily recognizable comedo DCIS, the authors investigated the spectrum of mixed pattern lesions to identify variations and common features in the architectural arrangement of the various histologic patterns. Patterns of atypical ductal hyperplasia (ADH) with specific criteria of recognition were intermixed in 17 cases (11 cribriform, 1 solid, 1 micropapillary, 4 mixed). Thirty-three cases of DCIS consisted of mixed patterns of comedo and noncomedo types. No case of comedo DCIS with associated areas of ADH was identified. In all cases of combined DCIS and ADH, the more advanced patterns of DCIS were present in the central portion of the lesion, with the ADH components arranged peripherally. This tendency for the more severely atypical areas to be located centrally was present throughout the study. Different patterns of DCIS are frequently present within individual lesions (46 of 100), and the more advanced features of architectural atypia are regularly present centrally. This strongly supports the hypothesis that these lesions develop from a central focus and expand peripherally. Also, those lesions with low-grade DCIS at the periphery may be as amenable to local excision for cure as purely low-grade lesions.


Programmable self-regulated molecular buffers for precise sustained drug delivery.
Unlike artificial nanosystems, biological systems are ideally engineered to respond to their environment. As such, natural molecular buffers ensure precise and quantitative delivery of specific molecules through self-regulated mechanisms based on Le Chatelier's principle. Here, we apply this principle to design self-regulated nucleic acid molecular buffers for the chemotherapeutic drug doxorubicin and the antimalarial agent quinine. We show that these aptamer-based buffers can be programmed to maintain any specific desired concentration of free drug both in vitro and in vivo and enable the optimization of the chemical stability, partition coefficient, pharmacokinetics and biodistribution of the drug. These programmable buffers can be built from any polymer and should improve patient therapeutic outcome by enhancing drug activity and minimizing adverse effects and dosage frequency.


Identification of T-kinin-Leu(T-kinin-containing peptide) released from T-kininogen by cathepsin D of granulomatous tissues in rats.
Acid proteinases of granulomatous tissues in rats with carrageenin-induced inflammation released kinin from T-kininogen. By column chromatography on pepstatin-Sepharose 4B, two types of acid proteinase seems to be responsible for kinin release. One of the acid proteinase was identified as cathepsin D from SDS-polyacrylamide gel electrophoresis and Western-blot analysis, using anti-rat liver cathepsin D IgG. Cathepsin D alone could not release T-kinin, but T-kinin-containing peptides. The T-kinin-containing peptides were separated into two peptides by reverse-phase high-performance liquid chromatography. From determination of its amino acid composition and its immunoreactivity toward anti-bradykinin antiserum, one of the T-kinin-containing peptides was identified as T-kinin-Leu.


Agglomerate formation and growth mechanisms during melt agglomeration in a rotary processor.
The purpose of this study was to investigate the effect of the binder particle size and the binder addition method on the mechanisms of agglomerate formation and growth during melt agglomeration in a laboratory scale rotary processor. Lactose monohydrate was agglomerated with molten polyethylene glycol (PEG) 3000 by adding the PEG either as solid particles from the size fraction 0-250, 250-500, or 500-750 microm or as droplets with a median size of 25, 48, or 69 microm. It was found that the PEG particle size, the PEG droplet size, and the massing time significantly influenced the agglomerate size and size distribution. Agglomerate formation and growth were found to occur primarily by distribution and coalescence for the PEG size fraction 0-250 microm and mainly by the immersion mechanism for the PEG size fractions 250-500 and 500-750 microm. When the PEG was sprayed upon the lactose, the mechanism of agglomerate formation was supposed to be a mixture of immersion and distribution, and the agglomerate growth was found to occur by coalescence regardless of the PEG mean droplet size. Compared to high shear mixers and conventional fluid bed granulators, the mechanisms of agglomerate formation and growth in the rotary processor resembled mostly those seen in the fluid bed granulator.


Synthesis of Spiroindenyl-2-Oxindoles through Palladium-Catalyzed Spirocyclization of 2-Bromoarylamides and Vinyl Bromides.
An expeditious approach to the construction of spiroindenyl-2-oxindoles was developed via a palladium-catalyzed spirocyclization reaction of 2-bromoarylamides with vinyl bromides. The reaction formed spiropalladacycles as the intermediates via carbopalladation and the C-H functionalization of 2-bromoarylamides. The spiropalladacycles reacted with vinyl bromides to form spiroindenyl-2-oxindoles. A Heck process rather than vinylic C-H functionalization was involved in the reaction.


Hepatitis E seroprevalence and related risk factors among seafood processing workers: a cross-sectional survey in Shandong Province, China.
This study aimed to assess the seroprevalence of hepatitis E virus (HEV) infection and the potential risk factors for acquiring HEV infection in the seafood processing factories in Yantai City of Shandong Province, China. A cross-sectional study was conducted in five randomly selected seafood processing factories in Yantai City. Subjects were 15-66 years of age and were raw seafood processing workers, semi-finished products processing workers, and administrative staff, etc. Each participant completed a structured questionnaire and agreed to blood drawing. Anti-HEV IgG antibody was detected in the blood samples by ELISA method. A total of 1028 of 1044 eligible workers were tested for HEV IgG antibody (response rate 98.5%). The prevalence of HEV IgG seropositivity was found to be 22.20%. Occupation was significantly associated with anti-HEV IgG antibody seropositivity (p<0.05). Subjects who had direct contact with raw seafood had a higher anti-HEV IgG antibody prevalence (32.54%) than the semi-finished products processing workers (24.74%) and less exposed group (11.85%). HEV seroprevalence in the workers showed an increasing trend with the increase in working years, and this phenomenon was most obvious in raw seafood processing workers. There is a higher risk of HEV infection in those who have direct contact with raw seafood. This study will help identify the risk factors for HEV infection and provide guidance on controlling HEV infection in the seafood processing occupations.


Gut-focused hypnotherapy for Functional Gastrointestinal Disorders: Evidence-base, practical aspects, and the Manchester Protocol.
Despite their high prevalence and advances in the field of neurogastroenterology, there remain few effective treatment options for functional gastrointestinal disorders (FGIDs). It is recognized that approximately 25% of sufferers will have symptoms refractory to existing therapies, causing significant adverse effects on quality of life and increased healthcare utilization and morbidity. Gut-focused hypnotherapy, when delivered by trained therapists, has been shown to be highly effective in severe refractory FGIDs. However, hypnotherapy continues to be surrounded by much misunderstanding and skepticism. The purpose of this review is to provide a contemporary overview of the principles of gut-focused hypnotherapy, its effects on gut-brain interactions, and the evidence-base for its efficacy in severe FGIDs. As supplementary material, we have included a hypnotherapy protocol, providing the reader with an insight into the practical aspects of delivery, and as a guide, an example of a script of a gut-focused hypnotherapy session.


Reporter gene assays for investigating GPCR signaling.
Luciferase-based assays are applied to evaluate various cellular processes due to their sensitivity and feasibility. The field of GPCR research has also benefited from this enzymatic reaction both in deorphanization campaigns and in delineation of the signaling pathways. Here, we describe the details of this assay in GPCR studies in 96-well format and will provide examples where the assay can show constitutive activity of an orphan GPCR and demonstrate the impact of cell type on the efficacy and potency of ligands.


Molecular characterization of the follicular development of BMP15-edited pigs.
The regulatory role of BMP15 on porcine ovarian follicular development still remains unclear. This study reveals that biallelic editing of BMP15 impairs SMAD signaling and inhibits granulosa cell proliferation, resulting in porcine follicular development arrest and ovarian hypoplasia. Bone morphogenetic protein 15 (BMP15) is a member of the transforming growth factor beta (TGF-β) superfamily, which is critical for facilitating ovarian folliculogenesis in mono-ovulatory mammalian species but is not essential in polyovulatory mice. Our previously established BMP15-edited pigs presented varied female reproductive phenotypes, suggesting the important role of BMP15 in ovarian folliculogenesis in polyovulatory pigs. To understand the regulatory mechanism underlying the effect of BMP15 on porcine ovarian follicular development, we molecularly characterized infertile biallelic-BMP15-edited gilts with ovarian hypoplasia. We found that an absence of BMP15 proteins in biallelic-BMP15-edited gilts can lead to premature activation of primordial follicles, possibly through the upregulation of KITLG-KIT-PI3K-AKT signaling pathways. However, this absence severely impaired SMAD (Sma and Mad proteins from Caenorhabditis elegans and Drosophila, respectively) signaling, causing severely reduced granulosa cell proliferation, leading to the arrest of follicular development during the preantral stage and ovarian hypoplasia, resulting in complete infertility. Our study expands the understanding of the molecular functions of BMP15 in nonrodent polyovulatory mammals.


Risk Factors for Poor Outcome in Hypertensive Intraventricular Hemorrhage Treated by External Ventricular Drainage with Intraventricular Fibrinolysis.
External ventricular drainage (EVD) combined with intraventricular fibrinolysis (IVF) is a commonly accepted surgical approach for some cases of hypertensive intraventricular hemorrhage (HIVH). We aimed to investigate the association between preoperative factors and outcome in patients with HIVH treated by EVD plus IVF. Records from March 2010 to March 2016 were searched for HIVH treated by EVD plus IVF. We divided this population into the favorable outcome group and the unfavorable outcome group according to the Glasgow Outcome Scale. Preoperative demographic data, radiologic findings, and clinical factors were compared in each group. Univariate and multivariable logistic regression were used to assess the relationship between factors and outcome in HIVH. Of 267 patients included in this study, 136 had a favorable outcome and 131 had a poor outcome. Multivariate analyses showed that age (odds ratio [OR], 18.229; 95% confidence interval [CI], 1.503-221.16), Glasgow Coma Scale score (OR, 12.686; 95% CI, 1.5-107.312), blood neuron specific enolase (OR, 9.463; 95% CI, 1.178-76.012), third ventricle hematoma (OR, 15.311; 95% CI, 1.287-497.914), and fourth ventricle hematoma (OR, 25.258; 95% CI, 1.851-125.767) were associated with poor outcome of EVD in patients with HIVH. Fourth ventricle hematoma, third ventricle hematoma, high blood neuron specific enolase value, low Glasgow Coma Scale score, and old age were risk factors for poor outcome in HIVH treated with EVD plus IVF. EVD was not suitable, particularly in patients with brainstem compression caused by fourth ventricle hemorrhage, regardless of use of IVF.


Breast cancer survivors' typhoid vaccine responses: Chemotherapy, obesity, and fitness make a difference.
To investigate breast cancer survivors' inflammatory responses to typhoid vaccine as a window into their innate immune response to novel pathogens. This double-blind crossover trial randomized 158 breast cancer survivors to either the vaccine/saline placebo or the placebo/vaccine sequence. The relative contributions of age, cardiorespiratory fitness (VO2peak), type of cancer treatment, central obesity, and depression to interleukin (IL)-6, IL-1 receptor antagonist (IL-1Ra), and WBC vaccine responses were assessed pre-injection and 1.5, 3, 4.5, 6, and 7.5 h post-injection. The vaccine produced larger IL-6, IL-1Ra, and WBC responses than placebo, ps < 0.0001. Prior chemotherapy, higher central obesity, and lower VO2peak were associated with smaller vaccine responses after controlling for baseline inflammation. Vaccine response was summarized by the percent increase in area under the curve (IL-6, WBC) or average post-injection mean (IL-1Ra) for vaccine relative to placebo. Women who received chemotherapy had smaller vaccine responses than women who did not for both IL-6 (44% vs 78%, p <.001) and WBC (26% vs 40%, p <.001); IL-1ra response was not significantly moderated by chemotherapy. Women whose central adiposity was one standard deviation above the mean had smaller vaccine responses than women with average adiposity for IL-6 (33% vs 54%, p <.001), WBC (20% vs 30%, p <.001), and IL-1Ra (2.0% vs 3.2%, p <.001). Women with an average level of VO2peak had smaller vaccine responses than women whose VO2peak was one standard deviation above the mean for IL-6 (54% vs 73%, p <.001), WBC (30% vs 40%, p <.001), and IL-1Ra (3.2% vs. 4.1%, p = 0.01). Age and depression did not significantly moderate vaccine responses. This study provided novel data on chemotherapy's longer-term adverse immune consequences. The data also have an important public health message: even relatively low levels of fitness can benefit the innate immune response to a vaccine.


A washing apparatus for microcentrifugation assays.
The use of centrifugation techniques for separating labeled compounds that are bound to tissue fractions from unbound substrate is widespread in biochemistry. An apparatus is described for simultaneously washing 24 microcentrifuge tubes. The apparatus provides for removing solutions from the tubes and filling tubes with washing solution. This apparatus permits the rapid and reproducible analysis of large numbers of samples.


[Prognostic importance of a positive test of myocardial 99mTc-Sn-pyrophosphate accumulation in patients with stable stenocardia].
The paper reports the results of a retrospective study of the frequency of complications of chronic coronary disease in 51 patients with stable angina subjected to myocardial 99mTc-Sn-pyrophosphate scintigraphy at rest at first screening. In the group with positive scintigraphic results, myocardial infarction and death from cardiac causes was five times as frequent within the next five years as it was in the group where myocardial incorporation of the drug was not observed. The frequency of complications was higher in cases where positive scintigraphic results were combined with cardiomegaly and electrocardiographic signs of transitory ischemia. Positive scintigraphic test with 99mTc-Sn-pyrophosphate can indicate future aggravation of the disease in patients with stable angina pectoris.


[Impression Formation in the Diagnosis and Treatment of Mental Disorders].
The first item of any psychopathological assessment is "general impression". There is some research under the heading of "impression formation" which shows that the outer appearance of a person decides about how a person is perceived by others and how others react. Impression formation is an important factor in social interaction. This is of special importance in mental disorders, which may express themselves in a distorted impression formation. As impression formation is by and large an emotional process, measurement can be done by adjective lists. An example is the bipolar MED rating scale. Such lists can be used in therapy to help patients and therapists to understand the problem and initiate modifications. A special group intervention in occupational therapy is described. Results suggest that impression formation is quite objective, that self- and observer judgments coincide and that therapy can help to adopt a less irritating outer appearance.


[Application Status and Prospects of Precision Nursing Under the Concept of Enhanced Recovery After Surgery].
With the development of enhanced recovery after surgery (ERAS), major breakthroughs have been made in this field of study. However, the research fields still need to be continuously expanded to meet the needs of patients. The concept of precision therapy is widely applied in the field of nursing. Under the concept of ERAS, practical studies of applying precision nursing for the perioperative period have already been conducted, exploring such issues as precision nursing assessment, precision nursing intervention design, precision risk prediction model, and information technology to assist precision nursing practice. Research findings have preliminarily validated the safety and effectiveness of applying precision nursing for ERAS in the perioperative period. Herein, we reviewed the reported findings of relevant research published in recent years and identified the following problems in the implementation of precision nursing under the ERAS concept, a lack of implementation standards, challenges concerning the the role of nurses, a lack of high-quality research evidence in the existing literature, and a relevant big data processing platform that China does not have and therefore cannot carry out data sharing, integration, mining, and utilization. We also made suggestions for effective improvement and discussed research prospects. In the future, multidisciplinary collaboration, translational medical research, and the development of various innovative tools are to be strengthened to help improve the quality and effectiveness of nursing care. We hope to provide reference for improving the scientific and targeted implementation of precision nursing for ERAS in the perioperative period.


Positioning membrane proteins by novel protein engineering and biophysical approaches.
Membrane proteins are unique, in that they can function properly only when they are bound to cellular membranes in a distinct manner. Therefore, positioning of membrane proteins with respect to the membrane is required in addition to the three-dimensional structures in order to understand their detailed molecular mechanisms. Atomic-resolution structures of membrane proteins that have been determined to date provide the atom coordinates in arbitrary coordinate systems with no relation to the membrane and therefore provide little or no information on how the protein would interact with the membrane. This is especially true for peripheral membrane proteins, because they, unlike integral proteins, are devoid of well-defined hydrophobic transmembrane domains. Here, we present a novel technique for determination of the configuration of a protein-membrane complex that involves protein ligation, segmental isotope labeling, polarized infrared spectroscopy, membrane depth-dependent fluorescence quenching, and analytical geometry algorithms. We have applied this approach to determine the structure of a membrane-bound phospholipase A2. Our results provide an unprecedented structure of a membrane-bound protein in which the z-coordinate of each atom is the distance from the membrane center and therefore allows precise location of each amino acid relative to the membrane. Given the functional significance of the orientation and location of membrane-bound proteins with respect to the membrane, we propose to specify this structural feature as the "quinary" structure of membrane proteins.


Template activity of poly(2'-fluoro-2'-deoxyinosinic acid) for murine leukemia virus reverse transcriptase.
The 2'-substituted analog of poly(inosinic acid) ((I)n), poly(2'-fluoro-2'-deoxyinosinic acid) ((dIfl)n) served as an effective template for the RNA-directed DNA polymerase (reverse transcriptase) from Moloney murine leukemia virus. When assayed under the same conditions, the parent compound (I)n showed little, if any, template activity. In the presence of other templates, i.e. poly (2-O-methylcytidylic acid), (dIfl)n could also assume the role of primer for the reverse transcriptase reaction, whereas, again, (I)n failed to do so.


Estrogen replacement reverses ovariectomy-induced vaginal hyperalgesia in the rat.
The loss of ovarian function in women through aging or oophorectomy is often associated with the development of vaginal hyperalgesia that can be alleviated with estrogen replacement. This study examined if ovariectomy in rats would similarly give rise to vaginal hyperalgesia, and, if so, whether estrogen replacement would alleviate it. Female rats were trained to perform an operant response to escape vaginal distention delivered by inflating a balloon located in mid-vaginal canal. Percent escape responses to eight different volumes of distention measured in normally cycling rats were compared with measures made in the same rats following ovariectomy (OVX) or sham ovariectomy (shamOVX), and then, in the OVX group, estrogen replacement (OVX+E2). Pressures exerted by the eight volumes on the vaginal wall were also measured, thereby permitting assessment of vaginal tone. Whereas overall escape response percentages after OVX, but not shamOVX, were significantly higher to the largest six distention volumes compared with responses during cycling, there were individual differences in the amount of hyperalgesia. Following OVX+E2, escape response percentages decreased in all but one rat. Vaginal tone after OVX, shamOVX or OVX+E2 did not differ from overall vaginal tone in cycling rats. Ovariectomy in rats evokes a variable amount of vaginal hyperalgesia that can be alleviated by estrogen replacement in most cases. Thus, the ovariectomized rat appears to provide a useful model for the study of mechanisms underlying the dyspareunia that is associated with loss of ovarian function in women.


Deferasirox, a trivalent iron chelator, ameliorates neuronal damage in hemorrhagic stroke models.
Intracranial hemorrhage (ICH) is a devastating disease with high mortality and morbidity. After ICH, iron released from the hematoma plays a crucial role in secondary brain injury. Deferasirox (DFR) is a trivalent iron chelator, which was approved to treat iron overload syndrome after transfusion. The aim of the present study was to investigate the protective effects of DFR in both in vitro and in vivo ICH models. Using a hemin-induced SH-SY5Y cell damage model, we performed an intracellular bivalent iron (Fe2+) accumulation assay, cell death assay, oxidative stress assessments, and Western blotting analysis. Moreover, the effects of DFR intraventricular administration on hematoma, neurological deficits, and histological alteration were evaluated in an in vivo ICH mouse model by collagenase. DFR significantly suppressed the intracellular Fe2+ accumulation and cell death caused by hemin exposure. These effects were related to the suppression of both reactive oxygen species and lipid peroxidation over-production. In Western blotting analysis, hemin increased the expression of ferritin (an iron storage protein), LC3 and p62 (autophagy-related markers), phosphorylated p38 (a stress response protein), and cleaved-caspase3 and cleaved-poly (adenosine diphosphate ribose) polymerase (PARP) (apoptosis-related makers). However, DFR suppressed the increase of these proteins. In addition, DFR attenuated the neurological deficits until 7 days after ICH without affecting hematoma and injury area. Furthermore, DFR also suppressed microglia/macrophage activation in peri-hematoma area at 3 days after ICH. These findings indicate that DFR might be a useful therapeutic agent for the therapy of ICH.


Sequence analysis of the fragment of the phosphoprotein gene of Polish distemper virus isolates.
The nucleotide sequence analysis of the 429 bp fragment of the P gene of 11 Polish field isolates of Canine distemper virus (CDV), reference strains and other virus isolates available in the GenBank was the aim of the studies. High homology between all dog strains from east-southern region of Poland and reference strains of CDV was demonstrated. It was estimated as 97-100 % for CDV-OND; 96.7-99.8 % for CDV-Rock; 96.7-99.8 % for CDV-LED and 96.3-97.9 % for A75-17. The 100 % homology of the nucleotide sequence was observed between CDV Pulawy 92, CDV Pulawy 97 and the reference CDV-OND. The homology between CDV-OND and viruses isolated from the mink and ferret was estimated as 97.7 % and 98.4 %, respectively. Virus strains isolated from blue foxes demonstrated the highest homology to CDV-OND - equal to 97.7 % for DV 79 and 99.5 % for DV 92. The fox isolate from 1992 had higher level of homology to dog isolates (96.5-99.5 %) than the strain isolated from the fox in 1979 (97.2-98.8 %). The phylogenetic tree has two main lineages representing two separated genetic groups: I containing PDV and II containing all distemper virus strains isolated from terrestrial carnivores. CDV strains isolated from dogs from Pulawy region between 1992-1998 and from the fox (DV 92) formed the separate lineage containing also reference strains. They differed from the native isolates from the mink and ferret as well as from Japanese strains of CDV.


Effects of subacute cadmium exposure and subsequent deferiprone treatment on cadmium accumulation and on the homeostasis of essential elements in the mouse brain.
Cadmium (Cd) is а hazardous multi-organ toxin. In this study, we provide the first results about the effect of oral administration of deferiprone (DFP) on Cd accumulation and on the homeostasis of essential elements in the brain of Cd-exposed mice. Adult Institute of Cancer Research (ICR) male mice were randomized into four experimental groups: untreated controls - administered distilled water for 28 days; Cd-exposed group - exposed to 18 mg/kg body weight (b.w.) Cd(II) acetate for 14 days followed by the administration of distilled water for two weeks; Cd + DFP (low dose) - Cd-intoxicated mice subsequently treated with 19 mg/kg b.w. DFP for two weeks; and Cd + DFP (high dose) - Cd-exposed mice administered high-dose DFP (135 mg/kg b.w.) for 14 days. Brains were subjected to inductively coupled plasma-mass spectrometry (ICP-MS) and histological analysis. The results revealed that exposure of mice to Cd for 14 days significantly increased Cd concentration and significantly decreased magnesium (Mg), phosphorus (P), and zinc (Zn) contents in the brain compared to untreated controls. This effect was accompanied by necrotic-degenerative changes in both the cerebrum and cerebellum. Oral administration of low-dose DFP to Cd-exposed mice decreased the concentration of the toxic metal in the brain by 16.37% and restored the concentration of the essential elements to normal control values. Histological analysis revealed substantially improved cerebral and cerebellar histoarchitectures. In contrast, oral administration of high-dose DFP increased Cd content and significantly decreased selenium (Se) concentration in the brain. Necrotic neurons and Purkinje cells were still observed in the cerebral and cerebellar cortices. The results demonstrated that oral administration of DFP at low doses has a better therapeutic potential for the treatment of Cd-induced brain damage compared to high doses.


Digital Health Technologies in Clinical Trials: An Ontology-Driven Analysis to Inform Digital Sustainability Policies.
Digital health technologies (DHTs) can facilitate the execution of de-centralized trials that can offer opportunities to reduce the burden on participants, collect outcome data in a real-world setting, and potentially make trial populations more diverse and inclusive. However, DHTs can also be a significant source of electronic waste (e-waste). In recognition of the potential health and environmental impact from DHT use in trials, private and public institutions have recently launched initiatives to help measure and manage this e-waste. But in order to develop sound e-waste management policies, it will be necessary to first estimate the current volume of e-waste that results from the use of DHTs in trials. A Web Ontology Language (OWL)-compliant ontology of DHTs was created using a list of 500 DHT device names derived from a mixture of public and private sources. The U.S. clinical trials registry, ClinicalTrials.gov, was then queried to identify and classify trials using any of the devices in the ontology. The ClinicalTrials.gov records from this search were then analyzed to characterize the volume and properties of trials using DHTs, as well as estimating the total volume of individual DHT units that have been provisioned (or are planned to be provisioned) for clinical research. Our ontology-driven search identified 2326 unique clinical trials with a reported "actual" enrollment of 200,947 participants and a "planned" enrollment of an additional 4,094,748 participants. The most-used class of DHTs in our ontology was "wearables," (1852 trials), largely driven by the use of smart watches and other wrist-worn sensors (estimated to involve 149,391 provisioned devices). The most-used subtype of DHTs in trials was "subcutaneous" devices (367 trials), driven by the prevalent use and testing of glucose monitors (estimated to involve 17,666 provisioned devices). Thousands of trials, involving hundreds of thousands of devices, have already been completed, and many more trials (potentially involving millions more devices) are planned. Despite the great opportunities that are afforded by DHTs to the clinical trial enterprise, if the industry lacks the ability to track DHT use with sufficient resolution, the result is likely to be a great deal of e-waste. A new ontology of DHTs, combined with rigorous data science methods like those described in this paper, can be used to provide better information across the industry, and in turn, help create a more sustainable and equitable clinical trials enterprise.


Fifteen 4-(2-meth-oxy-phen-yl)piperazin-1-ium salts containing organic anions: supra-molecular assembly in zero, one, two and three dimensions.
Fifteen 4-(2-meth-oxy-phen-yl)piperazin-1-ium salts containing organic anions have been prepared and structurally characterized. In the isostructural 4-chloro-benzoate and 4-bromo-benzoate salts, C11H17N2O+·C7H4ClO2 - (I) and C11H17N2O+·C7H4BrO2 - (II), and the 4-iodo-benzoate salt C11H17N2O+·C7H4IO2 - (III), the ions are linked by N-H⋯O hydrogen bonds, forming centrosymmetric R 4 4(12) four-ion aggregates; a similar aggregate is formed in the 2-chloro-benzoate salt (V), isomeric with (I). In the 2-fluoro-benzoate salt C11H17N2O+·C7H4FO2 - (IV), and the isomorphous pair of salts, the 2-bromo-benzoate (VI), isomeric with (II) and 2-iodo-benzoate (VII), isomeric with (III), N-H⋯O and C-H⋯π(arene) interactions link the components into three-dimensional arrays. Four-ion R 4 4(12) aggregates are also found in the 2-methyl-benzoate, 4-amino-benzoate and 4-nitro-benzoate salts, C11H17N2O+·C8H7O2 - (VIII), C11H17N2O+·C7H6NO2 - (IX) and C11H17N2O+·C7H4NO4 - (X), but those in (IX) are linked into complex sheets by an additional N-H⋯O hydrogen bond. In the 3,5-dinitrobenzoate salt, C11H17N2O+·C7H3N2O6 -·2H2O (XI), N-H⋯O and O-H⋯O hydrogen bonds link the components into a complex ribbon structure. In the picrate salt, C11H17N2O+·C6H2N3O7 - (XII), the four-ion aggregates are linked into chains of rings by C-H⋯O hydrogen bonds. In the hydrogen maleate salt, C11H17N2O+·C4H3O4 - (XIII), two- and three-centre hydrogen bonds link the ions into a ribbon structure while both anions contain very short but asymmetric O-H⋯O hydrogen bonds, having O⋯O distances of 2.4447 (16) and 2.4707 (17) Å. O-H⋯O Hydrogen bonds link the anions in the hydrogen fumarate salt (XIV), isomeric with (XIII), into chains that are linked into sheets via N-H⋯O hydrogen bonds. In the hydrogen (2R,3R)-tartrate salt, C11H17N2O+·C4H5O6 -·1.698H2O (XV), the anions are linked into sheets by O-H⋯O hydrogen bonds. Comparisons are made with the structures of some related compounds.


Griseococcin (1) from Bovistella radicata (Mont.) Pat and antifungal activity.
To evaluate the antimicrobial and microbicidel activity of B. radicata fermentation broth, the broth was purified by DEAE-cellulose and sephadex LC-20 column. The compounds were submitted to spectral analyses (HPLC, FT-IR, 1D and 2D NMR etc.). The purified compounds were identified as the Griseococcin(s) which were naphthoquinone derivatives, the Chemical formula and MW of Griseococcin (1) was determined as C37O10H43N and 661 Da. only Griseococcin (1) has good antimicrobial activity among the Griseococcin(s). The zone of inhibition (ZOI), minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) or minimum fungicidal concentration (MFC) of Griseococcin (1) were used to investigate the antimicrobial activity. Antifungal activity of Griseococcin (1) was significant, especially for main pathogenic fungus Trichophyton rubrum and Trichophyton mentagrophytes, MFC/MIC of Griseococcin (1) was 1, while MFC/MIC of postive control was greater than 4, the fungicidal effect of Griseococcin (1) was better than that of positive control. In this paper, the secondary metabolite compound Griseococcin (1) from B. radicata was purified. The purified compound can restrain main pathogens (T. rubrum and T. mentagrophytes) leading to tinea pedis. The antifungal activity of Griseococcin (1) was similar to that of the positive control and the fungicidal effect of Griseococcin (1) was better than that of positive control, it might be suitable for pharmaceutical industries.


Effects of MicroRNA-19b on the Proliferation, Apoptosis, and Migration of Wilms' Tumor Cells Via the PTEN/PI3K/AKT Signaling Pathway.
Wilms' tumor (WT) is a most common renal cancer that occurs among children, and microRNA-19b (miR-19b) usually participates in various human cancers. Importantly, the PTEN/PI3K/Akt signaling pathway plays a key role in cell apoptosis, growth and proliferation. Thus, our present study aims to investigate the effect of miR-19b on the PTEN/PI3K/Akt signaling pathway during WT cell proliferation, migration, and apoptosis. WT tissues and adjacent normal tissues from WT patients were collected. qRT-PCR was applied to detect miR-19b expression in both the WT tissues and the adjacent normal tissues, immunohistochemistry was applied to detect the protein expressions of PTEN, P13K, and p-Akt, SK-NEP-1 cells were divided into the blank, negative control (NC), miR-19b mimics and miR-19b inhibitors groups. MTT assay, propidium iodide (PI) staining, Annexin-V/PI double-staining, Transwell assay and Western blotting were performed to examine cell proliferation, cycle, apoptosis, migration, and invasion, and the protein expressions of PTEN, P13K, Akt, and p-Akt. Increased miR-19b expression, positive expression rates of P13K and Akt, decreased PTEN expression rate, a negative correlation between PTEN expression and tumor lymph node metastasis, and a positive correlation between the expression of P13K and Akt and the clinical stages were observed in the WT tissues. The miR-19b inhibitors group exhibited decreased cell proliferation, cell cycle progression, migration and invasion, and protein expressions of PI3K and p-Akt but increased PTEN protein expression compared with the blank and NC groups. Thus, inhibition of miR-19b suppresses the progression of WT by modulating the PTEN/PI3K/AKT signaling pathway. J. Cell. Biochem. 118: 3424-3434, 2017. © 2017 Wiley Periodicals, Inc.


The effects of lithium carbonate on healthy volunteers: mood stabilization?
A 2-month lithium-placebo double-blind cross-over study was carried out with 17 healthy volunteers. Their mood was self-rated: twice daily (AM, PM) with the Visual Analogue Mood Scale (VAMS); weekly with the analogue scales for subjective states and body symptoms; and three times (basal and at the end of each treatment period) with the Profile of Mood States (POMS). Memory and reaction time were also assessed, but did not show any change. The mean VAMS score decreased during lithium treatment, but the mean mood variability, a measure of the mean successive differences between consecutive mood ratings (delta squared), did not change significantly. There was a tendency toward decreased mood variability on lithium, both during the full 1-month treatment period and in the last week of treatment, when all volunteers had a lithium serum level ranging from 0.6 to 1.0 mEq/liter. The lower mean VAMS scores on lithium could be attributed to lithium-induced dysphoric mood as recorded on the analogue scales and POMS. However, very large inter- and intraindividual differences in response to lithium were observed. Actually, lithium even had an opposite effect on some volunteers' mood. The data and problems involved with assessment of mood and its changes are discussed.


Comparative Study of Curvature Sensing Mediated by F-BAR and an Intrinsically Disordered Region of FBP17.
Membrane curvature has emerged as an intriguing physical principle underlying biological signaling and membrane trafficking. The CIP4/FBP17/Toca-1 F-BAR subfamily is unique in the BAR family because its structurally folded F-BAR domain does not contain any hydrophobic motifs that insert into membrane. Although widely assumed so, whether the banana-shaped F-BAR domain alone can sense curvature has never been experimentally demonstrated. Using a nanobar-supported lipid bilayer system, we found that the F-BAR domain of FBP17 displayed minimal curvature sensing in vitro. In comparison, an alternatively spliced intrinsically disordered region (IDR) adjacent to the F-BAR domain has the membrane curvature-sensing ability greatly exceeding that of F-BAR domain alone. In living cells, the presence of the IDR delayed the recruitment of FBP17 in curvature-coupled cortical waves. Collectively, we propose that contrary to the common belief, FBP17's curvature-sensing capability largely originates from IDR, and not the F-BAR domain alone.


Cancer Risk in Patients With Empyema: A Nationwide Population-Based Study.
This study aimed to evaluate cancer risk and possible risk factors in patients diagnosed with empyema. A total of 31,636 patients with newly diagnosed empyema between January 1, 1999 and December 31, 2010 were included in this study. Standardized incidence ratios (SIRs) were calculated to compare the cancer incidence in these empyema patients to that in the general population. Adjusted hazard ratios were also calculated to investigate whether characteristics increased cancer risk. During the 12-year study period, 2,654 cancers occurred in 31,636 patients with empyema, yielding an SIR of 2.67 (95% confidence interval [CI] 2.57-2.78). We excluded cancer that occurred within 1 year to avoid surveillance bias. The cancer risk remained significantly increased (SIR 1.50, 95% CI 1.41-1.58). Specifically, patients with empyema had higher SIR of cancers of the head and neck (1.50, 95% CI 1.41-1.58), esophagus (2.56, 95% CI 1.92-3.33), stomach (1.49, 95% CI 1.16-1.89), liver and biliary tract (2.18, 95% CI 1.93-2.45), and lung and mediastinum (1.62, 95% CI 1.39-1.86). Age ≥ 60, male sex, diabetes mellitus, and liver cirrhosis were independent risk factors for cancer development. Our study demonstrates an increased incidence of cancer development in patients with empyema, and patients' age ≥ 60, men, and those with diabetes mellitus and liver cirrhosis showed a higher incidence of developing cancer compared to the general population. The association between such kind of infection and secondary malignancy may be elucidated by further study.


Incidence and prevalence of juvenile idiopathic arthritis in Catalonia (Spain).
To ascertain the incidence and prevalence of juvenile idiopathic arthritis (JIA) in Catalonia (autonomous region in northeast Spain), examined according to the currently established disease subtypes. Before initiating the study, we conducted an educational programme on paediatric rheumatology, addressed to all general paediatricians in Catalonia. A 2-year (2004-2006), prospective, population-based study was then carried out to determine the incidence of JIA. Prospective and retrospective data retrieval was performed to calculate prevalence. The International League of Associations for Rheumatology (ILAR, Edmonton revision) classification criteria were applied. Over the study period, 145 new cases of JIA were diagnosed. The mean annual incidence was 6.9/10⁵ children aged less than 16 years (range 5.8-8.1 years; 9.0 years for girls and 4.8 years for boys). On separate analysis of patients ≤ 6 and > 6 years, the distribution in younger children was found to be similar for both girls and boys, whereas in older children, most girls belonged to the oligoarthritis and polyarthritis subgroups, and boys to the enthesitis-related arthritis and undifferentiated subgroups. The calculated prevalence of JIA (31 October 2006) was 39.7 (36.1-43.7)/10⁵ children younger than 16. The relative risk of girls having JIA was 2.1 [95% confidence interval (CI) 1.7-2.7, p < 0.001]. In 70% of patients, the diagnosis was established before the age of 7. Subgroup distribution of prevalent cases mirrored that of incident cases. This is the first population-based study on the epidemiology of JIA in Catalonia. Incidence and prevalence rates are lower than those reported for several areas in Nordic countries of Europe. Oligoarthritis was the most common subtype.


A mixed-method study into quality of life for bladder cancer patients.
A diagnosis of cancer can come as a shock to patients, and the fear it engenders can have a powerful impact on quality of life, even if the prognosis is good. This research posed qualitative and quantitative questions to a group of patients, and revealed issues that might help nurses improve the way they care for and educate these patients to improve their quality of life.


CT-guided fine needle aspiration of a periaortic collection.
Patients with infected aortic grafts suffer considerable morbidity and mortality. Therefore, it is important to make the diagnosis of infection to provide a reasonable chance for survival. Clinical signs of infection are usually apparent in the postoperative period. If absent, the diagnosis becomes more difficult. CT scanning is beneficial in detecting periaortic fluid and gas collections; however, it cannot differentiate postoperative gas from infection in all cases. This is especially true during the first 2 weeks after operation. CT-guided fine needle aspiration can provide a safe and reliable means to answer this clinical question.


Exploitation of an ancient escape circuit by an avian predator: relationships between taxon-specific prey escape circuits and the sensitivity to visual cues from the predator.
The painted redstart Myioborus pictus uses visual displays to flush, pursue, and then capture an abundance of brachyceran Diptera that are equipped with giant fiber escape circuits. This paper investigates the relationships between features of the giant fiber system, the structure of visual stimuli produced by redstarts and their effectiveness in eliciting escape reactions by flies. The results show that dipterous taxa having large-diameter giant fibers extending short distances from the brain to motor neurons involved in escape are flushed at greater distances than taxa with longer and small-diameter giant fibers. The results of behavioral tests show the importance of angular acceleration of expanding image edges on the compound eye in eliciting escape responses. Lateral motion of stimulus profile edges as well as structured visual profiles additionally contribute to the sensitivity of one or more neural systems that trigger escape. Retinal subtense and angular velocity are known to trigger physiological responses in fly giant fiber circuits, but the contributions of edge length and lateral motion in a looming stimulus suggest that escape pathways might also receive inputs from circuits that are tuned to different types of motion. The present results suggest that these several properties of escape pathways have contributed to the evolution of foraging displays and plumage patterns in flush-pursuing birds.


Cytotoxic action of cis-unsaturated fatty acids on human cervical carcinoma (HeLa) cells: relationship to free radicals and lipid peroxidation and its modulation by calmodulin antagonists.
Specific fatty acids such as linoleic acid (LA), gamma-linolenic acid (GLA), dihomo gamma linolenic acid (DGLA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) showed cytotoxicity towards human cervical (HeLa) cells in vitro. Cyclo-oxygenase inhibitor, indomethacin; lipoxygenase inhibitor, nordihydroguiaretic acid (NDGA); anti-oxidant, vitamin E; and calmodulin antagonists, trifluoperazine (TFP) and chlorpromazine (CPZ) blocked the cytotoxic action of these fatty acids. GLA-induced free radical generation and lipid peroxidation were also inhibited by indomethacin, NDGA, vitamin E, TFP and CPZ. Both indomethacin and NDGA also showed significant anti-oxidant property. These results suggest that fatty acid-induced cytotoxic action against HeLa cells is a free radical dependent process and that it can be modulated by calmodulin antagonists. These results are in contrast to those observed by us earlier with human breast cancer cells where in it was found that the tumoricidal action of fatty acids can be blocked by anti-oxidants but not by cyclo-oxygenase (CO) and lipoxygenase (LO) inhibitors. From these results it can be suggested that though free radicals are the mediators of the tumoricidal action of fatty acids, the mechanism of their production may be different in different types of tumor cells.


Community-acquired pneumonia in children.
Community-acquired pneumonia (CAP) remains a frequent cause of morbidity and mortality worldwide even in industrialised countries, and its incidence is highest among children aged <5 years. Over the last two years, three international guidelines have been updated with new evidence concerning the incidence, aetiology and management of childhood CAP, but there are still some major problems in standardisation. The main aim of this review is to consider the available data concerning the aetiology, diagnosis, evaluation of severity, and treatment of paediatric CAP. Analysis of the literature shows that there are a number of unanswered questions concerning the management of CAP, including its definition, the absence of a paediatric CAP severity score, the difficulty of identifying its aetiology, the emergence of resistance of the most frequent respiratory pathogens to the most widely used anti-infectious agents, and the lack of information concerning the changes in CAP epidemiology following the introduction of vaccines against respiratory pathogens. More research is clearly required in various areas, and further efforts are needed to increase vaccination coverage with the already available vaccines in order to reduce the occurrence of the disease.


[Perinatal complications in patients with chronic renal failure].
Pregnant patients with chronic renal insufficiency (CRI) have a high risk of perinatal complications and deterioration of renal filtration (RF). To report perinatal complications and changes of RF according to disease severity. Cross-sectional study including 28 pregnant patients grouped into three categories of CRI according to initial creatinine (Cr): mild CRI < 1.5, moderate CRI 1.5-2.5 and severe CRI > 2.5 mg/dL. Pre-labor vs initial perinatal complications and changes in endogenous creatinine clearance (CrCI) were reported. Descriptive statistics and Student t-test were used for statistical analyses. Mild CRI was found in 50%, moderate in 35.72% and severe in 14.28% of patients. Maternal complications were as follows. Mild CRI: Cesarean (35.72%), deterioration of RF (21.42%) and worsening of systemic arterial hypertension (SAH) (7.14%); moderate CRI: Cesarean (28.57%), deterioration of RF (28.57%) and worsening of SAH (14.28%); severe CRI: Cesarean (14.28%), deterioration of RF (14.28%) and anemia (14.28%). Fetal complications were as follows. Mild CRI: prematurity (25%), fetal growth restriction (FGR) (7.14%) and fetal death (7.14%), moderate CRI: prematurity (21.42%), FGR (3.57%) and no reassuring fetal status (NRFS) (3.57%), severe CRI: prematurity (14.28%), NRFS (7.14%) and respiratory insufficiency (7.14%). Mild CRI showed a reduction of endogenous CrCI (p = 0.03) not shown in other categories. An elevated frequency of complications was found, with the most serious occurring in patients with severe CRI. Deterioration of RF was found in patients with mild CRI.


Construction of the novel immune risk scoring system related to CD8+ T cells in uterine corpus endometrial carcinoma.
Uterine corpus endometrial carcinoma (UCEC) is a gynecological malignant tumor with high incidence and poor prognosis. Although immunotherapy has brought significant survival benefits to advanced UCEC patients, traditional evaluation indicators cannot accurately identify all potential beneficiaries of immunotherapy. Consequently, it is necessary to construct a new scoring system to predict patient prognosis and responsiveness of immunotherapy. CIBERSORT combined with weighted gene co-expression network analysis (WGCNA), non-negative matrix factorization (NMF), and random forest algorithms to screen the module associated with CD8+ T cells, and key genes related to prognosis were selected out by univariate, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analyses to develop the novel immune risk score (NIRS). Kaplan-Meier (K-M) analysis was used to compare the difference of survival between high- and low- NIRS groups. We also explored the correlations between NIRS, immune infiltration and immunotherapy, and three external validation sets were used to verify the predictive performance of NIRS. Furthermore, clinical subgroup analysis, mutation analysis, differential expression of immune checkpoints, and drug sensitivity analysis were performed to generate individualized treatments for patients with different risk scores. Finally, gene set variation analysis (GSVA) was conducted to explore the biological functions of NIRS, and qRT-PCR was applied to verify the differential expressions of three trait genes at cellular and tissue levels. Among the modules clustered by WGCNA, the magenta module was most positively associated with CD8+ T cells. Three genes (CTSW, CD3D and CD48) were selected to construct NIRS after multiple screening procedures. NIRS was confirmed as an independent prognostic factor of UCEC, and patients with high NIRS had significantly worse prognosis compared to those with low NIRS. The high NIRS group showed lower levels of infiltrated immune cells, gene mutations, and expression of multiple immune checkpoints, indicating reduced sensitivity to immunotherapy. Three module genes were identified as protective factors positively correlated with the level of CD8+ T cells. In this study, we constructed NIRS as a novel predictive signature of UCEC. NIRS not only differentiates patients with distinct prognoses and immune responsiveness, but also guides their therapeutic regimens.


Secretory component and lactoferrin in pure pancreatic juice in chronic pancreatitis.
To evaluate pathophysiological roles of proteins in pancreatic secretion, immunoreactive lactoferrin (LF) and secretory component (SC) were measured in the first fraction of the pure pancreatic juice obtained endoscopically from 17 control, 21 suspected (SCP), 14 noncalcified (NCP), and 14 calcified chronic pancreatitis (CCP) subjects. The protein and amylase tended to decrease both in concentration and output from control to CCP. LF concentration was elevated in CCP (18.0 +/- 4.9 micrograms/ml) when compared with controls (2.3 +/- 0.2 micrograms/ml), and LF output in NCP (12.3 +/- 3.8 micrograms/min) was increased from controls (3.8 +/- 0.6 micrograms/min). The combination of high LF concentration with low protein output was observed in 10/14 in CCP but 0/14 in NCP and can be a biochemical discriminator of CCP from NCP. SC concentrations were also elevated in NCP (8.5 +/- 2.0 micrograms/ml) and CCP (5.6 +/- 1.6 micrograms/ml) from controls (1.2 +/- 0.2 micrograms/ml). SC outputs in SCP (9.8 +/- 3.1 micrograms/min) and NCP (21.1 +/- 4.8 micrograms/min) were increased from controls (1.7 +/- 0.3 micrograms/min), but there was no further increase in CCP. Hypersecretion of LF and SC in chronic pancreatitis is different, especially in CCP, although the mechanisms for hypersecretion are unknown.


Direct cytoplasmic delivery of RNAi therapeutics through a non-lysosomal pathway for enhanced gene therapy.
The first approved RNAi therapeutics, ONPATTRO, in 2017 moves the concept of RNA interference (RNAi) therapy from research to clinical reality, raising the hopes for the treatment of currently incurable diseases. However, RNAi therapeutics are still facing two main challenges-susceptibility to enzymatic degradation and low ability to escape from endo/lysosome into the cytoplasm. Therefore, we developed disulfide-based nanospheres (DBNPs) as universal vehicles to achieve efficient RNA delivery to address these problems. Notably, the DBNPs possess unique and desirable features, including improved resistance to nuclease degradation, direct cytoplasmic delivery through thiol-mediated cellular uptake, and cytosolic environment-responsive release, greatly enhancing the bioavailability of RNA therapeutics. Additionally, DBNPs are superior in terms of overcoming formidable physiological barriers, including vascular barriers and impermeable tumor tissues. Owning to these advantages, the DBNPs exhibit efficient gene silencing effect when delivering either small interfering RNA (siRNA) or microRNA in various cell lines and generate remarkable growth inhibition in the zebrafish and mouse model of pancreatic tumors as compared to traditional delivery vectors, such as PEI. Therefore, DBNPs have potential application prospect in RNAi therapy both in vitro and in vivo. STATEMENT OF SIGNIFICANCE: RNA interference (RNAi) therapeutics could target and alter any disease-related mRNA translation, thus have great potential in clinical application. Delivery efficiency of RNA modalities into cell cytoplasm is the main problem that currently limit RNAi therapeutics to release their full potential. Most of the known delivery materials suffer from the endo/lysosomal entrapment and enzymatic degradation during endocytosis-dependent uptake, resulting unsatisfied efficiency of the cytoplasmic release. Here, we developed disulfide-based nanospheres could directly transfer RNA modalities into the cytoplasm and significantly enhance the delivery efficiency, thus holding great potential in RNAi therapy.


Semaphorin 4D activates the MAPK pathway downstream of plexin-B1.
Semaphorins are a large family of transmembrane and secreted proteins that signal primarily through the receptor plexin. Semaphorins have been characterized in the nervous system as axon guidance cues; however, they have also been shown to control development of other cellular systems such as the vasculature and lungs. As the role of semaphorins outside of the nervous system has broadened, so has elucidation of the intracellular signalling pathways they initiate. Previously, we and others have shown that plexin-B1 activates RhoA through the binding and activation of RhoGEF (guanine nucleotide-exchange factor)/LARG (leukaemia-associated RhoGEF) in response to semaphorin 4D stimulation. In the present study, we show that semaphorin 4D activates the MAPK (mitogen-activated protein kinase) pathway. We have found that the mechanism of activation requires the C-terminus of plexin-B1 and the activation of RhoA.


Occupational activity and cognitive aging: a case-control study based on the Maastricht Aging Study.
BACKGROUND/STUDY CONTEXT: Occupational activity is associated with cognitive functioning in older age. The mental exercise hypothesis attributes this association to differences in mental exercise at work. A case-control design was used to test the mental exercise hypothesis. Primary and secondary school teachers (aged between 25.29 and 79.01 years) and non-teacher controls were matched for level of occupation, educational level, age, and gender. Regression analyses were used to analyze the data. Possible confounders (such as precareer intelligence and depressive status) were taken into account. Teachers had superior verbal fluency and working memory scanning abilities. The results are in line with the mental exercise hypothesis.


Changes in serum and tissue carcinoembryonic antigen with growth of a human gastric cancer xenograft in nude mice.
We established a human gastric cancer xenograft which, when inoculated into nude mice, showed a positive correlation between tumor growth and the serum level of carcinoembryonic antigen (CEA). Serum CEA levels in the mice rose continuously with increasing tumor weight after inoculation, showing a correlation coefficient of 0.96. A positive correlation was also observed between the tissue CEA level and tumor weight, the former increasing along with the latter. Furthermore, the level of serum CEA closely paralleled that of tissue CEA. The serum CEA level fell after tumor extirpation, with a half-life of approximately 86 h. These results suggest that the elevation of serum CEA is attributable to the gain in tumor weight as well as the increase of CEA production in the tumor tissue. Thus, human gastric cancer xenografts in nude mice are a good model for examining the biological role of CEA.


Efficient production of anti-fluorescein and anti-lysozyme as single-chain anti-body fragments (scFv) by Brevibacillus expression system.
Expression of scFv in Brevibacillus choshinensis was tested using combinations of three different promoters and four different secretion signals. Two model scFv constructs, i.e., His-scFvFLU and His-scFvHEL, were successfully expressed with some of the combinations. Ni Sepharose column and size exclusion chromatography resulted in fairly pure preparations of these two proteins. The purified His-scFvFLU inhibited fluorescence from fluorescein, while the purified His-scFvHEL inhibited lysozyme activity. Relatively high yield of His-scFvFLU (∼40%) and His-scFvHEL (∼30%) was achieved with the expression and purification system described here.


Preoperative sentinel lymph node identification, biopsy and localisation using contrast enhanced ultrasound (CEUS) in patients with breast cancer: a systematic review and meta-analysis.
To evaluate whether contrast-enhanced ultrasound (CEUS)-guided core biopsy of the sentinel lymph node (SLN) could identify metastatic nodes preoperatively and reduce the number of surgical SLN biopsies in patients with breast cancer and normal axillary B-mode ultrasound; and to establish whether CEUS SLN identification and localisation is a viable alternative to standard lymphatic mapping using isotope and blue dye. A search of several electronic databases was performed and identified studies were assessed using QUADAS-2 for methodological quality. Pooled estimates of sensitivity and specificity for identification of nodal metastases were calculated. Eleven prospective studies and one retrospective study with 1,520 participants were included. The SLN identification and localisation rate for CEUS-guided skin marking was 70-100%, CEUS guided-wire localisation was 89-97%, and CEUS-guided iodine-125 (125I) seed localisation was 60%. Across the four studies that evaluated preoperative CEUS-guided SLN biopsy, pooled sensitivity for identification of nodal metastases was 54% (95% confidence interval [CI]: 47-61) and pooled specificity 100% (95% CI: 99-100). CEUS is a promising technique for preoperative staging of the axilla. CEUS-guided core biopsy has the potential to identify nodal metastases in over half (54%) of patients with normal axillary B-mode ultrasound. CEUS-guided identification and localisation of the SLN may offer a viable alternative to standard lymphatic mapping using isotope and blue dye; however, further prospective studies with larger samples are warranted.


Congenital anterior urethral diverticulum in a young man: A case report and review of the literature.
Congenital anterior urethral diverticulum is a rare entity that can occur at any age but exceptionally in adults. Its diagnosis is suspected clinically by obstructive symptoms of the lower urinary tract most often associated with a penoscrotal ball. Its management consists of a diverticulectomy associated or not with a urethroplasty depending on the size of the diverticulum. We discuss through a case report the clinical and therapeutic aspects of this rare entity.


Attenuation of iron-binding proteins in ARPE-19 cells reduces their resistance to oxidative stress.
Oxidative stress-related damage to retinal pigment epithelial (RPE) cells is an important feature in the development of age-related macular degeneration. Iron-catalysed intralysosomal production of hydroxyl radicals is considered a major pathogenic factor, leading to lipofuscin formation with ensuing depressed cellular autophagic capacity, lysosomal membrane permeabilization and apoptosis. Previously, we have shown that cultured immortalized human RPE (ARPE-19) cells are extremely resistant to exposure to bolus doses of hydrogen peroxide and contain considerable amounts of the iron-binding proteins metallothionein (MT), heat-shock protein 70 (HSP70) and ferritin (FT). According to previous findings, autophagy of these proteins depresses lysosomal redox-active iron. The aim of this study was to investigate whether up- or downregulation of these proteins would affect the resistance of ARPE-19 cells to oxidative stress. The sensitivity of ARPE-19 cells to H2 O2 exposure was tested following upregulation of MT, HSP70 and/or FT by pretreatment with ZnSO4 , heat shock or FeCl3 , as well as siRNA-mediated downregulation of the same proteins. Upregulation of MT, HSP70 and FT did not improve survival following exposure to H2 O2 . This was interpreted as existence of an already maximal protection. Combined siRNA-mediated attenuation of both FT chains (H and L), or simultaneous downregulation of all three proteins, made the cells significantly more susceptible to oxidative stress confirming the importance of iron-binding proteins. The findings support our hypothesis that the oxidative stress resistance exhibited by RPE cells may be explained by a high autophagic influx of iron-binding proteins that would keep levels of redox-active lysosomal iron low.


Determinants of breast self-examination performance among Iranian women: an application of the health belief model.
Breast cancer is one of the most common cancers among women. Screening behavior rates are low in the world. Therefore, the purpose of the current study was to investigate breast self-examination (BSE) rate and the relationships of Health Belief Model (HBM) constructs for predicting BSE. Path analysis was used to examine both one-way direct and indirect effects of HBM factors on BSE in this population (N = 382). Data were collected by a part of Champion's HBM Scale (CHBMS) and a self-administered questionnaire. The results showed that 7.6% of the participants reported performing BSE regularly. The final model provided a good fit to the data, with 13 variables explaining 62% of the variance in BSE. Perceived self-efficacy was intermediate construct between modifying factors and HBM constructs. Also, perceived self-efficacy and perceived benefits were the most highly related to BSE. The results suggest that HBM is a useful framework for identifying factors influencing the use of BSE in Iranian women.


Rationale and design of a UK database for a rare cancer type: the GEM Registry for gastrointestinal stromal tumours.
Despite advances in the management of and changes in clinical practice, little is known about the epidemiology, patterns of care and outcomes of gastrointestinal stromal tumour (GIST) patients in the UK. Patient registries are receiving increasing attention as they can provide important information on clinical practice and patient outcomes. The rationale and study design of the GIST Epidemiology and Management (GEM) Registry, which forms part of the routine clinical practice for GISTs in several UK centres, are described. The GEM Registry is a secure web-based registry system designed around a Microsoft Access core using SQL interface. Demographic, surgical, histopathological and clinical data will be captured including treatment outcomes and survival. The registry was piloted in six centres and following further fine tuning of the data sets, ethical committee submission and approval was completed. The GEM National Registry is the first of its kind to be implemented in rare cancers in UK. The registry is being rolled out initially in selected centres with the aim to expand to other centres. The first publication reporting analyses of the central data set is anticipated for the summer of 2013. GEM Registry will enable us to obtain a clear picture of incidence/prevalence of GISTS in UK. Clinicians will be able to review the prognostic and predictive value of variables in a large prospective data set. The data can be used for planning the delivery and improving the quality of care. This information is likely to inform clinical practice and, in years to come, guide the development and implementation of clinical trials for novel tyrosine kinase inhibitors. The results will not only benefit the GIST community, but also serve as a basis for the study of other rare tumour types.


Addition of parenteral cefoxitin to regimen of oral antibiotics for elective colorectal operations. A randomized prospective study.
The efficacy of cefoxitin, a perioperative parenteral antibiotic, combined with mechanical bowel preparation and oral antibiotics to prevent wound infections and other septic complications in patients undergoing elective colorectal operations, was examined in a prospective randomized study. All 197 patients who completed the study received mechanical bowel preparation and oral neomycin/erythromycin base. In addition a perioperative parenteral antibiotic was given in three divided doses to 101 patients. The other 96 patients received no parenteral antibiotics. The overall incidence of intra-abdominal septic complications was 7.3% (7 of 96) in the control group (no cefoxitin) and 5% (5 of 101) in the treatment group (cefoxitin). This difference was not statistically significant. The incidence of abdominal wound infection was 14.6% in the control group and 5% in the treatment group, a statistically significant difference (p = 0.02). The addition of perioperative parenteral cefoxitin greatly reduced the incidence of wound infections in patients undergoing elective colorectal operations who had been prepared with mechanical bowel cleansing and oral antimicrobial agents.


Anatomy and function of scrotal ligament.
The anatomy of the scrotal ligament has been studied in 22 cadavers by dissection and histologic examination. The ligament could be identified in 20 cadavers. It binds the scrotal skin firmly to the tunica vaginalis at the lower testicular pole. The embryonic nature of the ligament is discussed. It synchronizes the crematerico-dartos action under normal and varied temperatures. Absence of the ligament results in disordered testicular thermoregulation and may be a factor in the genesis of subfertility; the mechanisms involved are discussed. The difference between the aligamentous testicle and the high scrotal undescended testicle is discussed.


Attenuation of Adverse Effects of Aging on Skeletal Muscle by Regular Exercise and Nutritional Support.
Beginning early in midlife, natural/primary aging is inevitably associated with a progressive reduction in muscle mass and function. This process can progress with aging to a substantial loss of strength, particularly in the lower extremities, reducing mobility. This condition, commonly referred to as sarcopenia, can result in frailty, reducing one's ability to live independently. This article reviews the underlying biological process contributing to the development of sarcopenia and the roles of regular exercise and nutritional support for attenuating aging-associated muscle loss as well as risk and management of sarcopenia and associated frailty.


Randomised trial of neonatal hypoglycaemia prevention with oral dextrose gel (hPOD): study protocol.
Neonatal hypoglycaemia is common, affecting up to 15% of newborn babies and 50% of those with risk factors (preterm, infant of a diabetic, high or low birthweight). Hypoglycaemia can cause brain damage and death, and babies born at risk have an increased risk of developmental delay in later life. Treatment of hypoglycaemia usually involves additional feeding, often with infant formula, and admission to Neonatal Intensive Care for intravenous dextrose. This can be costly and inhibit the establishment of breast feeding. Prevention of neonatal hypoglycaemia would be desirable, but there are currently no strategies, beyond early feeding, for prevention of neonatal hypoglycaemia. Buccal dextrose gel is safe and effective in treatment of hypoglycaemia. The aim of this trial is to determine whether 40% dextrose gel given to babies at risk prevents neonatal hypoglycaemia and hence reduces admission to Neonatal Intensive Care. Randomised, multicentre, placebo controlled trial. Babies at risk of hypoglycaemia (preterm, infant of a diabetic, small or large), less than 1 h old, with no apparent indication for Neonatal Intensive Care Unit admission and mother intends to breastfeed. Trial entry & randomisation: Eligible babies of consenting parents will be allocated by online randomisation to the dextrose gel group or placebo group, using a study number and corresponding trial intervention pack. Babies will receive a single dose of 0.5 ml/kg study gel at 1 h after birth; either 40% dextrose gel (200 mg/kg) or 2% hydroxymethylcellulose placebo. Gel will be massaged into the buccal mucosal and followed by a breast feed. Primary study outcome: Admission to Neonatal Intensive Care. 2,129 babies are required to detect a decrease in admission to Neonatal Intensive Care from 10-6% (two-sided alpha 0.05, 90% power, 5% drop-out rate). This study will investigate whether admission to Neonatal Intensive Care can be prevented by prophylactic oral dextrose gel; a simple, cheap and painless intervention that requires no special expertise or equipment and hence is applicable in almost any birth setting. Australian New Zealand Clinical Trials Registry--ACTRN 12614001263684.


A mutation in the 5' untranslated region of the human alpha-galactosidase A gene in high-activity variants inhibits specific protein binding.
Recently, normal individuals were identified who had high levels of plasma alpha-galactosidase A activity and a G to A transition in the 5' untranslated (5' UT) region of the alpha-galactosidase A gene. Electrophoretic mobility shift assays revealed that the wild-type sequence at the site of this mutation complexed with specific nuclear proteins. A standard NF-kappa B site competed with the 5' UT site for formation of these DNA-protein complexes. Complex formation was inhibited by the transition mutation. Therefore, the wild-type site might down-modulate expression of the alpha-galactosidase A gene from this 5' untranslated region, which includes a previously described protein-binding site for another family of sequence-specific DNA-binding proteins, methylated DNA-binding protein.


Neural correlates of mystical experience.
Mystical experiences, or subjectively believed encounters with a supernatural world, are widely reported across cultures and throughout human history. Previous theories speculate that executive brain functions underpin mystical experiences. To evaluate causal hypotheses, structural studies of brain lesion are required. Previous studies suffer from small samples or do not have valid measures of cognitive functioning prior to injury. We investigated mystical experience among participants from the Vietnam Head Injury Study and compared those who suffered penetrating traumatic brain injury (pTBI; n=116) with matched healthy controls (HC; n=32). Voxel-based lesion-symptom mapping analysis showed that lesions to frontal and temporal brain regions were linked with greater mystical experiences. Such regions included the dorsolateral prefrontal cortex (dlPFC) and middle/superior temporal cortex (TC). In a confirmatory analysis, we grouped pTBI patients by lesion location and compared mysticism experiences with the HC group. The dlPFC group presented markedly increased mysticism. Notably, longitudinal analysis of pre-injury data (correlating with general intelligence and executive performance) excludes explanations from individual differences. Our findings support previous speculation linking executive brain functions to mystical experiences, and reveal that executive functioning (dlPFC) causally contributes to the down-regulation of mystical experiences.


Thoracoscopic Transmitral Myectomy for an Anatomically Complex Case With Midventricular Obstruction.
A 51-year-old man was diagnosed with hypertrophic obstructive cardiomyopathy with left ventricular outflow tract obstruction at the subaortic and midventricular level combined with mitral systolic anterior motion and systolic anterior motion-related mitral regurgitation. The mildly thickened basal and nonthickened midventricular anteroseptum combined with the predominantly hypertrophic basal and midventricular inferoseptum made this case anatomically complex. Thoracoscopic transmitral myectomy plus fibrillation radiofrequency ablation were conducted to eliminate those lesions. The patient was discharged successfully and showed an improved hemodynamic and functional status at the 3-month follow-up.


Coevolution of pierid butterflies and their cruciferous foodplants : V. Habitat selection, community structure and speciation.
Early models of hostplant exploitation by phytophagous insects suffer from unwarranted assumptions and may not be generally applicable. Wordmodels of the co-evolutionary approach may assume unwarranted evolutionary stability in 'strategic' explanations, whilst mathematical models derived from earlier optimal-diet studies are unrealistic and unwieldy. A simple arithmetic model synthesises these two approaches, using the two parameters of foodplant suitability and availability. Hostplant use by the butterfly Anthocharis cardamines, previously thought to be maladaptively polyphagous, is shown to be optimal under prevailing conditions of short search time. The predictions of the model for hostplant use and community structure of butterflies and other phytophagous insects are tested and, in large part, corroborated. Monophagy and monophagic forms of oligophagy are shown to be favoured by: long adult lifespan; low search costs to females; search images (Whether visual or olfactory); batch-laying of eggs; high differential in foodplant suitability.


Knowledge of novel coronavirus disease (COVID-19) among dental surgeons of Nepal: a nationwide study.
COVID-19 is an emerging respiratory disease caused by a novel coronavirus. There is not much evidence assessing the knowledge of dental surgeons regarding COVID-19. This study was conducted to assess the knowledge of COVID-19 among dental surgeons of Nepal. A web-based cross-sectional study was conducted among registered dental surgeons of Nepal. Ethical approval was obtained. Consent was taken, and knowledge on COVID-19 was assessed via a pre-tested structured questionnaire using Google form. The form was emailed to the participants. Descriptive analysis was performed using frequency, percentage, median and inter-quartile range. Man-Whitney test and Kruskal-Wallis tests were carried out to see the difference in knowledge score. P-value < 0.05 was considered statistically significant. Total 227 dental surgeons responded to the questionnaire (male: 46.4%; female: 53.7%). Almost two-third ( 65.2% ) of the respondents were B.D.S. (Bachelor of Dental Surgery) graduates. Only 29.1% worked in the government hospitals. 17.6% were currently involved in COVID-19 management. Of the participants, 87.7% knew about the condition of the requirement of Personal Protective Equipment (PPE) but only 29.1% could correctly answer the framed question for PPE. The median knowledge score calculated was 14.0 (8.0-18.0). The bivariate analysis showed a statistically significant difference in knowledge score among the age group ≥30 years and < 30 years (p = 0.013); M.D.S. (Master of Dental Surgery) graduate and B.D.S. graduate (0.041); dental surgeons of government healthcare facilities and other healthcare facilities (p < 0.001); dental surgeons of COVID-19 centers and non-COVID-19 centers (0.002). The dental surgeons of Nepal have a good knowledge of COVID-19, and they can be utilized for assisting in the management of COVID-19 cases in Nepal.


Direct carbon-carbon bond formation via reductive soft enolization: a kinetically controlled syn-aldol addition of α-halo thioesters and enolizable aldehydes.
The direct addition of enolizable aldehydes and α-halo thioesters to produce β-hydroxy thioesters enabled by reductive soft enolization is reported. The transformation is operationally simple and efficient and has the unusual feature of giving high syn-selectivity, which is the opposite of that produced for (thio)esters under conventional conditions. Moreover, excellent diastereoselectivity results when a chiral nonracemic α-hydroxy aldehyde derivative is used.


History of medical physics.
Medical physics began with the development of safe handling of radium, such as protecting medical personnel from radiation when radium radiation is used to treat cancer. By the end of World War II, the field of medical physics had expanded to the development of safe and reliable treatments for cancer with radiation and quantification of radiation dose, which is called dosimetry that is required to evaluate the therapeutic effect. The rapid development of nuclear technology during World War II made it possible to use large amounts of radioisotopes (RI) produced in nuclear reactors, and the medical use of RI gave birth to clinical nuclear medicine. Since knowledge and skills in radiation measurement and RI handling were required for the development and clinical use of its equipment, nuclear medicine physics was added to medical physics after the war. The invention of computed tomography (CT) in 1972 had a great impact on clinical medicine, while the development of magnetic resonance imaging (MRI) began around that time. As a result, the development of CT and MRI, as well as the study of their image characteristics, which had not necessarily been regarded as the field of medical physics before, was added to that field as radiation diagnostic physics. This review outlines the history of developments in medical physics, and touches on the first medical physicists in Europe and the United States. It also briefly explains the beginning of medical physics and the world-class medical physics achievements in Japan.


Trendspotting in the Protein Data Bank.
The Protein Data Bank (PDB) was established in 1971 as a repository for the three dimensional structures of biological macromolecules. Since then, more than 85000 biological macromolecule structures have been determined and made available in the PDB archive. Through analysis of the corpus of data, it is possible to identify trends that can be used to inform us abou the future of structural biology and to plan the best ways to improve the management of the ever-growing amount of PDB data.


Weekly paclitaxel for a patient with advanced gastric cancer.
A 56-year-old woman diagnosed with gastric cancer was admitted to our hospital for operation on May 15, 2001. The operation was performed on May 23. The tumor formed a large mass from the antrum to the head of the pancreas, and cancer cells were detected in the ascitic fluid microscopically. During the operation, resection was impossible, and so 100 mg of cisplatin (CDDP) was infused into the abdominal cavity. After the operation, she experienced continuous nausea and there was a discharge of 1200-1600 ml of digestive fluid per day from her nasogastric tube. On July 17, a new regimen, of 4-week courses of chemotherapy, with weekly administrations of 65 mg/m2 of paclitaxel, along with premedication for 3 weeks, followed by 1 week of rest, was started. After the first of these 4-week courses, the discharge from her nasogastric tube decreased to 200-600 ml per day, and the tube was removed 78 days after insertion. Oral intake of food increased smoothly, and she was discharged on September 14. After another, short, hospitalization, she was discharged on October 20, and she has been coming to our outpatient clinic once a week. After paclitaxel was started, gastric fiberscopy and computed tomography (CT) scan showed reduction of the tumor. Of special note was the disappearance of a scitic fluid after two courses, rated as a "partial response" (Japanese classification). There was a decrease in hemoglobin, but neither leukocytopenia nor a decrease in platelets was found. Neuropathy was slight and no treatment was needed. Now, after 1 year, 11 courses of chemotherapy have been administered at the outpatient clinic. These results suggest weekly administration of paclitaxel to be a promising treatment for advanced gastric cancer with peritoneal dissemination. The therapeutic efficacy should be confirmed by further clinical trials.


A preliminary study to design a floating treatment wetland for remediating acid mine drainage-impacted water using vetiver grass (Chrysopogon zizanioides).
Acid mine drainage (AMD) is extremely acidic, sulfate-rich effluent from abandoned or active mine sites that also contain elevated levels of heavy metals. Untreated AMD can contaminate surface and groundwater and pose severe ecological risk. Both active and passive methods have been developed for AMD treatment consisting of abiotic and biological techniques. Abiotic techniques are expensive and can create large amounts of secondary wastes. Passive biological treatment mainly consists of aerobic or anaerobic constructed wetlands. While aerobic wetlands are economical, they are not effective if the pH of the AMD is < 5. Anaerobic wetlands use organic-rich substrates to provide carbon source to iron- and sulfate-reducing bacteria. The efficiency of these systems declines overtime and requires continuous maintenance. Our objective is to develop an alternative, low-cost, and sustainable floating wetland treatment (FWT) system for AMD for the abandoned Tab-Simco coal mining site in Illinois using vetiver grass (Chrysopogon zizanioides). Tab-Simco AMD is highly acidic, with mean pH value of 2.64, and contains high levels of sulfate and metals. A greenhouse study was performed for a 30-day period in order to screen and optimize the necessary parameters to design a FWT system. Water quality and plant growth parameters were continuously monitored. Results show significant SO42- removal, resulting in increased pH, particularly at higher planting densities. Vetiver also helped in metal removal; high amounts of Fe, Zn, and Cu were removed, with relatively lower amounts of Pb, Al, and Ni. Iron plaque formation on the root was observed, which increased metal stabilization in root and lowered root to shoot metal translocation. Vetiver was tolerant of AMD, showing minimal change in biomass and plant growth. Results obtained are encouraging, and a large scale mesocosm study is now in progress, as the next step to develop the vetiver-based system for AMD treatment.


Peripheral neuropathy in severe COVID-19 resolved with therapeutic plasma exchange.
Peripheral neuropathies including Guillain-Barré syndrome may be linked to life-threatening COVID-19. Plasma exchange is a safe rescue therapy in severe COVID-19 with associated neurological manifestations and thromboinflammation.


Correlation Between Doppler Echocardiography and Right Heart Catheterisation-Derived Systolic and Mean Pulmonary Artery Pressures: Determinants of Discrepancies Between the Two Methods.
There is still controversy about whether transthoracic echocardiography (TTE) can provide reliable estimations of pulmonary artery pressures (PAP). The primary endpoint of this study was to evaluate the correlation between TTE and right heart catheterisation (RHC) in estimating systolic (SPAP) and mean (MPAP) pulmonary artery pressures. Between January 2011 and December 2018, 141 consecutive patients (average age 63.6±11.5 years; 84 women) with suspected or confirmed pulmonary hypertension (PH) were enrolled into this retrospective observational monocentric study. All patients underwent TTE and, within 3 hours, RHC. The correlation between TTE and RHC in estimating both SPAP and MPAP was retrospectively determined. Seventeen (17) of the patients were excluded due to insufficient TTE signal quality. Of the remaining 124 patients, 18 had no PH. There was moderate correlation between both SPAP and MPAP estimated by TTE and those assessed by RHC (r=0.65 and r=0.60, respectively). Bland-Altman analysis revealed a bias of -11.9 mmHg (with the 95% limits of agreement ranging -45.4 to +21.5 mmHg) for SPAP estimation and -4.6 mmHg (with the 95% limits of agreement ranging -27.9 to +18.8 mmHg) for MPAP estimation, suggesting a general overestimation of PAP by TTE. The main factors responsible for discrepancies between TTE and RHC were: female gender, arrhythmic cardiac electrical activity, systemic arterial hypertension, and diuretic treatment. Transthoracic echocardiography frequently overestimated PAP in comparison with RHC, especially in hypertensive women with arrhythmias and under diuretic treatment.


The use of a conventional tissue culture plate as an optically accessible perfusion chamber for in situ assays and for long-term cultivation of mammalian cells.
An alternative culture system has been developed based on a conventional tissue culture plate (3.5 cm diameter) which is changed into a closed perfusion chamber. The system can easily be scaled up from one to several chambers. The shape and the size of the area of cell growth may be designed to individual experimental demands. The whole culture chamber is optically accessible, so cell growth and morphology can be evaluated by light microscopy. Furthermore the cellular physiology can be characterised by any fluorimetric assay using a bottom type fluorescence reader. A peristaltic pump sustains a constant medium flow through the chamber thus creating true homeostasis. The use of HPLC-valves and connectors allows the switching between different media or assay solutions. Thus it is possible to perform in situ assays also measuring transient effects. A protocol for vitality tests using calcein-AM is worked out for an adherent cell line and for a suspension cell line. The lower detection limits are 7 × 10(2) cells cm(-2) for the adherent cells and 5 × 10(4) cells mL(-1) for the suspension cells. The upper limits are 1-2 × 10(5) cells cm(-2) respectively 8 × 10(6) cells mL(-1).