Comparing molnupiravir and nirmatrelvir/ritonavir efficacy and the effects on SARS-CoV-2 transmission in animal models.
Therapeutic options against SARS-CoV-2 are underutilized. Two oral drugs, molnupiravir and paxlovid (nirmatrelvir/ritonavir), have received emergency use authorization. Initial trials suggested greater efficacy of paxlovid, but recent studies indicated comparable potency in older adults. Here, we compare both drugs in two animal models; the Roborovski dwarf hamster model for severe COVID-19-like lung infection and the ferret SARS-CoV-2 transmission model. Dwarf hamsters treated with either drug survive VOC omicron infection with equivalent lung titer reduction. Viral RNA copies in the upper respiratory tract of female ferrets receiving 1.25 mg/kg molnupiravir twice-daily are not significantly reduced, but infectious titers are lowered by >2 log orders and direct-contact transmission is stopped. Female ferrets dosed with 20 or 100 mg/kg nirmatrelvir/ritonavir twice-daily show 1-2 log order reduction of viral RNA copies and infectious titers, which correlates with low nirmatrelvir exposure in nasal turbinates. Virus replication resurges towards nirmatrelvir/ritonavir treatment end and virus transmits efficiently (20 mg/kg group) or partially (100 mg/kg group). Prophylactic treatment with 20 mg/kg nirmatrelvir/ritonavir does not prevent spread from infected ferrets, but prophylactic 5 mg/kg molnupiravir or 100 mg/kg nirmatrelvir/ritonavir block productive transmission. These data confirm reports of similar efficacy in older adults and inform on possible epidemiologic benefit of antiviral treatment.


Exercise metabolism during 1 hour of treadmill walking while taking high and low doses of propranolol, metoprolol, or placebo.
Aerobic exercise and beta-blocking drugs are regularly prescribed as treatment for hypertension and as a prophylactic for patients at risk from coronary heart disease and for those recovering from an infarct. Some beta blockers, particularly non-beta 1-selective drugs, may make exercise more difficult, possibly by interfering with substrate metabolism during exercise. This study examined the effects of low and high doses of a beta 1-selective blocker, metoprolol, and a non-selective beta blocker, propranolol, on exercise metabolism. The study involved 20 healthy subjects (10 men, 10 women) who walked on a treadmill at 50% of their maximal oxygen uptake for 1 h on five occasions, separated by 7 days. On each of the five occasions they received one of the following treatments, given in random order: placebo, metoprolol 50 mg, metoprolol 100 mg, propranolol 40 mg, or propranolol 80 mg, all taken twice daily. Fat oxidation, expressed as a percentage of total energy expenditure, was significantly lower than with placebo for all of the active treatments except metoprolol 50 mg (placebo: 42.7 +/- 11.6%; metoprolol 50 mg: 38.7 +/- 14.1%, p = NS; metoprolol 100 mg: 36.3 +/- 13.7%, p = 0.05; propranolol 40 mg: 31.2 +/- 9.3%, p = 0.01; propranolol 80 mg: 29.5 +/- 10.9%, p = 0.01); and significantly lower with propranolol than with metoprolol (propranolol 40 mg: p = 0.0036; propranolol 80 mg: p = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)


Diameter of dominant leiomyoma is a possible determinant to predict coexistent endometriosis.
To identify the frequency and assess risk factors for unexpected discovery of peritoneal endometriotic implants in patients who underwent myomectomy or hysterectomy for symptomatic uterine leiomyomas. We retrospectively collected medical records of 829 patients with symptomatic leiomyomas in The University of Tokyo Hospital. All the patients underwent abdominal or laparoscopic surgeries between January 2001 and December 2010 and the presence or absence of endometriosis during surgery was analyzed. Possible determinant to predict coexistent endometriosis was statistically investigated. In total, 105 leiomyoma cases (12.7% in 829 patients) were diagnosed with endometriosis. Patients with small dominant leiomyomas were significantly complicated by peritoneal endometriotic implants (small leiomyomas were classified as < 8 cm). The patients with both diagnoses were more likely to be infertile and at age 39 years or younger than those with leiomyoma alone. Women undergoing myomectomy or hysterectomy with both endometriosis and leiomyomas have several different clinical features compared with women with only leiomyomas. The size of largest leiomyoma may provide an important clue for coexistent endometriosis. Women with substantial infertility despite a smaller leiomyomas burden may be more likely to have a surgical indication for concomitant endometriosis.


Synthesis and cytotoxicity of hydrophobic esters of podophyllotoxins.
Diverse norbornenecarboxylate esters of podophyllotoxin and its epimers and diastereoisomers have been prepared through Diels-Alder cycloaddition by treating the dienophilic acrylates of cyclolignans with cyclopentadiene. Their cytotoxicities against several cancer cell lines have been evaluated and the results compared with those found for other lignan esters. Podophyllotoxin adducts showed a one-fold increase in activity when compared to the natural product. The preparation of more hydrophobic esters, which showed less cytotoxicity, demonstrated that this activity is not primarily due to the lipophilic factor, but mainly to the spatial arrangement of the bulky moiety, which could contribute to increase the binding to the target site.


Diagnosing acute pancreatitis-Clinical and radiological characterisation of patients without threefold increase of serum lipase.
Diagnosing acute pancreatitis (AP) may be challenging in patients with acute abdominal pain but missing threefold increased serum lipase levels (Lip-). This studyaims both to characterize these patients using clinical, radiological and mortality data, and to assess the group of patients who need contrast-enhanced computed tomography (CECT). In this retrospective, IRB approved study 234 consecutive patients with AP were investigated. Inclusion criteria were single (SAP) and recurrent attacks (RAP) of AP and CECT ≥72h after onset of symptoms. Severity of AP was assessed by C-reactive protein at 48h after hospital admission and using 3 CT-based scores (CTSI, mCTSI, EPIC) by 2 observers. Mortality rates from pancreatic and non-pancreatic causes were noted with regard to lipase increase. Results were compared with paired t-test and Wilcoxon signed-rank test. 64/234 (27%) patients belonged to Lip- group and 170/234 (73%) patients were allocated to Lip+ group. Significantly more male patients (78% in Lip- vs. 63% in Lip+, p<0.05) with RAP (63% in Lip- vs. 21% in Lip+, p<0.001) were observed in the Lip- group. EPIC was significantly lower in Lip- group compared to Lip+ group (3(IQR 2-5) vs. 2(IQR 1-3), p<0.001). Mortality from pancreatic and non-pancreatic causes was comparable in Lip- and Lip+ group (pancreatic causes: 9% vs. 6%, p=0.60; nonpancreatic causes: 8% vs. 5%, p=0.58). 27% of all patients with AP presented without threefold increase of lipase levels. Thus, they would be underdiagnosed without confirming CECT, which revealed significantly lower counts of pleural effusions and ascites. Male patients with RAP were found significantly more often among the Lip- group. Hence, they would benefit the most from CECT for diagnosing AP.


The onset of heroin use and criminal behaviour: does order make a difference?
The extent to which the onset of criminality with respect to heroin use accounts for heterogeneity within a heroin-using population was investigated among 400 community and incarcerated methadone maintenance patients. Those for whom crime preceded heroin use (primary antisocials) were younger and more likely to be male than those for whom heroin use preceded crime (secondary antisocials). Primary antisocials were also more likely to have committed violent crime and to qualify for a diagnosis of antisocial personality disorder (ASPD). It is concluded that taking the order of onset of heroin use and criminality into account may reduce the risk of overdiagnosing ASPD among this population and help clarify the relationship between drug use and crime.


A single-blind, randomized, crossover study on the efficacy of icatibant for sweating-induced dermal pain (icatibant for sweating-induced dermal pain).
Severe dermal pain triggered by sweating stimuli, such as bathing, exercise, and mental stress, significantly affects patients' daily lives. The pathomechanism underlying the sweating-induced dermal pain remains poorly understood and there exists no standard treatment for such pain. This study aims to evaluate the effectiveness of icatibant as an analgesic, a bradykinin B2 receptor antagonist, in treating sweating-induced dermal pain, and to establish the role of bradykinin in pain induction. A multicenter, exploratory, crossover, single-blinded, placebo-controlled randomized, comparative study will be conducted to evaluate the efficacy of subcutaneous icatibant injection (30 mg) in treating sweating-induced dermal pain. Ten patients will be enrolled and assigned randomly in a 1:1 ratio to either the icatibant-placebo or placebo-icatibant groups. The primary endpoint is the change in the visual analog scale scores for dermal pain induced by thermal load before and after treatment with icatibant or placebo. Secondary endpoints include changes in the duration of dermal pain, blood and plasma histamine levels, serum angiotensin-converting enzyme levels, and histological evaluation of skin tissue samples at the site of dermal pain. The effectiveness of icatibant against sweating-induced dermal pain would provide clear evidence for the involvement of the bradykinin-bradykinin B2 receptor pathway in the pathogenesis of this condition. This finding may contribute to a better understanding of the underlying mechanisms of dermal pain associated with sweating stimuli and has the potential to improve patients' quality of life by suggesting potential treatment options, specifically, using drugs that inhibit bradykinin or suppress its production.


Extracellular superoxide dismutase haplotypes are associated with acute lung injury and mortality.
Extracellular superoxide dismutase (EC-SOD) is a potent antioxidant that plays an important role in controlling oxidant-mediated stress and inflammation. High levels of EC-SOD are found in the lung. Acute lung injury (ALI) frequently occurs in patients with infection, and levels of EC-SOD have been shown to modulate severity of lung injury in transgenic animal models of endotoxemia-induced ALI. An R213G single nucleotide polymorphism (SNP) has been shown to alter levels of EC-SOD and patient outcomes in chronic obstructive pulmonary disease (COPD) and ischemic heart disease. To determine genetic variation in the promoter and EC-SOD gene and to examine whether EC-SOD haplotype blocks are associated with clinical outcomes. We sequenced the EC-SOD promoter and gene to determine genetic variation and linkage disequilibrium (LD) patterns in a European American population. Two separate patient populations with infection-associated ALI were also evaluated to determine whether EC-SOD haplotypes were associated with clinical outcomes. Sequencing resulted in the identification of 28 SNPs with relatively strong LD and 1 block consisting of 4691-5321-5360-5955-5982. This specific block was shown to be protective in two separate patient populations with infection associated ALI. In particular, patients with a GCCT haplotype had a reduced risk of time on the ventilator and mortality. These results indicate that a GCCT haplotype may reduce inflammation in the lung, thereby decreasing the severity of lung injury and ultimately protecting patients from mortality associated with infection-induced ALI.


Area postrema lesions disrupt food intake induced by cerebroventricular infusions of 5-thioglucose in the rat.
The present experiment assesses the contribution of the area postrema (AP) to glucoprivic feeding in the rat. Lateral ventricular infusions of 5-thioglucose increased pelleted food intake in sham animals but not in animals with AP lesions. Drinking in response to infusion of angiotensin II into the lateral ventricle was not reduced by AP lesions. The data suggest that the AP is part of the brainstem circuitry underlying glucoprivic feeding.


Percutaneous transforaminal endoscopic discectomy for different types of lumbar disc herniation: A retrospective study.
To introduce the concept of 'nerve root as the core' and to investigate the surgical procedure and curative effect of percutaneous translaminar endoscopic discectomy (PTED) surgery in the treatment of different types of lumbar disc herniation (LDH). This retrospective study analysed the clinical data from patients with LDH that underwent single-segment PTED surgery. They were divided into three groups based on LDH location: central canal zone group, lateral recess zone group and foraminal/far lateral zone group. Different working cannula placement methods were used for the different types of LDH. All patients were followed for at least 12 months. Clinical and follow-up data were compared between the three groups. A total of 130 patients were enrolled in the study: 44 (33.8%) in the central canal zone group, 72 (55.4%) in the lateral recess zone group and 14 (10.8%) in the foraminal/far lateral zone group. All three groups of patients achieved good postoperative results. The improvements in leg pain and disability were most marked in the first postoperative month in all three groups. PTED achieved adequate decompression for different types of LDH. The concept of 'nerve root as the core' facilitated the accurate placement of the working cannula.


Characterization of the novel HLA-DRB3*02:02:23 allele by sequencing-based typing.
HLA-DRB3*02:02:23 differs from HLA-DRB3*02:02:01:02 by one nucleotide substitution in codon 218 in exon 4.


Highly efficient galvanotaxis apparatus for cleaning and concentrating rumen ciliates.
Galvanotaxis was shown to be an efficient method for cleaning and concentrating rumen ciliate protozoa whose harvesting (centrifugation of large volumes of in vitro cultures followed by repeated washing of the sediment to remove plant debris) is time consuming. We suggested the use of a new galvanotaxis apparatus (a small-capacity two-way glass stopcock) to improve cell yield in concentrating the rumen ciliate protozoa and cleaning them from impurities. Migration of the ciliates (Entodinium caudatum, Entodinium furca monolobum and Diploplastron affine) into the cathode compartment under different electric currents (0, 5, 10, and 15 mA) and intervals (5, 10, 20, and 30 min) was evaluated. The lethal current level was 20 mA. Cell yield was 9-81%, depending on ciliate species, migration time and current. The migration time significantly affected both E. caudatum and D. affine. The electric current-migration time interplay was shown to be significant in both E. caudatum and D. affine. The advantages and disadvantages of the tested apparatus were determined; the two-way glass stopcock was very convenient for both cleaning and concentrating rumen ciliate in vitro cultures by galvanotaxis.


A phase III study of adjuvant chemotherapy in advanced nasopharyngeal carcinoma patients.
To evaluate the role of adjuvant chemotherapy in locally advanced nasopharyngeal carcinoma (NPC) patients, we conducted a randomized Phase III trial comparing radiotherapy (RT) followed by adjuvant chemotherapy to RT alone in patients with advanced NPC. Between November 1994 and March 1999, 157 patients with Stage IV, M(0) (UICC/AJCC, 1992) advanced NPC disease were randomized to receive standard radiotherapy, as follows: 35-40 fractions, 1.8-2.0 Gy/fraction/day, 5 days/week, to a total dose 70-72 Gy with or without 9 weekly cycles of 24-h infusional chemotherapy (20 mg/m(2) cisplatin, 2,200 mg/m(2) 5-fluorouracil, and 120 mg/m(2) leucovorin) after RT. Of 157 patients enrolled, 154 (77 radiotherapy, 77 combined therapy) were evaluable for survival and toxicity analysis. With a median follow-up of 49.5 months, the 5-year overall survival and relapse-free survival rates were 60.5% vs. 54.5% (p = 0.5) and 49.5% vs. 54.4% (p = 0.38) for the radiotherapy-alone group and the combined radiotherapy and adjuvant chemotherapy group, respectively. The Cox regression showed that the hazard rates ratio of combined treatment to RT alone was 0.673 (p value = 0.232); the 95% confidence interval was 0.352 and 1.288, respectively. Patients who received combined treatment had a lower systemic relapse rate than radiotherapy-alone patients, according to relapse pattern analysis. The incidence of leukopenia (>or= Grade 3) occurred in 17 out of 819 (2.1%) cycles of weekly chemotherapy. No patient developed moderate to severe mucositis (>or= Grade 3). We conclude that adjuvant chemotherapy after RT for patients with advanced NPC has no benefit for overall survival or relapse-free survival.


Preparing Sr-containing nano-structures on micro-structured titanium alloy surface fabricated by additively manufacturing to enhance the anti-inflammation and osteogenesis.
The development of additive manufacturing technology has made it possible to customize joint implants. However, the fibrous tissue caused by long-term chronic inflammation delays bone regeneration. Moreover, the discovery of micro/nano-structure on the natural bone makes the study of implant surface morphology meaningful. In this study, a Sr-containing nano-structure on micro-structured titanium alloy surface was fabricated to enhanced the anti-inflammatory and osteogenic properties of implants. Ti6Al4V (TC4) alloys with micro-structured surface prepared by additive manufacturing were used as the material base model. Subsequently, spherical SrTiO3 particles were fabricated on the TC4 surfaces by hydrothermal treatment. The anti-inflammatory and osteogenic performance of smooth surface, micro-structured surface, Sr-containing nano-structured surface and Sr-containing micro/nano-structured surface were investigated. In vitro results exhibited that the macrophages cultured on micro/nano-structured surface were polarized to anti-inflammatory M2 phenotype and enhanced the expression of osteogenic growth factors. The Sr-containing micro/nano-structured surface effectively upgraded the proliferation and differentiation of SaOS-2 cells compared with other surfaces. Sr2+ and micro/nano-structure effectively enhanced the anti-inflammatory and osteogenic properties of titanium alloys. This finding suggested that the micro/nano-structured surface doped with bioactive elements is expected to broaden the horizons of biomedical materials. DATA AVAILABILITY: The raw/processed data required to reproduce these findings cannot be shared at this time as the data also forms part of an ongoing study.


Intracranial angiolipoma.
Fat containing tumours within the central nervous system are rare. The second reported case of intracranial angiolipoma is described.


Preparation of inulin-type fructooligosaccharides using fast protein liquid chromatography coupled with refractive index detection.
A fast protein liquid chromatography coupled with refractive index detection (FPLC-RID) method was firstly developed for preparation and purification of fructooligosaccharides with different degree of polymerization from burdock, Arctium lappa. After extraction with 60% ethanol and decolorization with MCI gel CHP20P, total fructooligosaccharides were purified on Bio-Gel P-2 column eluted with water at the flow rate of 0.3 ml/min, which was the optimized conditions. The obtained fructooligosaccharides with degree of polymerization of 3-9 were identified based on their methylation analysis, MS and NMR data. This method has the advantages of high automation, good recovery and easy performance, which could be used for preparation of FOS from other sources, as well as other targeted compounds without UV absorbance.


Metropolitan deconcentration: subareal in-migration and central city to ring mobility patterns among southern SMSAs.
The analysis of in-migration streams and subareal residential mobility patterns for moves made between 1965 and 1970 in SMSAs in the East South Central and South Atlantic census divisions indicates that, despite their historical contexts, these metropolitan areas now show spatial differentiation patterns similar to those of the great cities of the Northeast. The white population has increased in ring areas primarily because of in-migration rates; the black population in the central cities has increased primarily because of in-migration rates to those subareas. Little variation in these patterns across SMSA size categories was apparent.


Attitude of literate married men towards the use of aphrodisiac herbs in Ilorin, Kwara state, Nigeria.
Sexual dysfunction among men is on the increase in Nigerian societies; however, many do not seek health care; and may prefer using aphrodisiac herbs. We investigated the attitude of literate married men towards the use of aphrodisiac herbs in Ilorin, Kwara State, Nigeria. We also examined whether there would be a significant difference in the attitude of literate married men towards the use of aphrodisiac herbs based on age and educational attainment. Descriptive survey method was adopted for the study. A total of 200 literate married men were selected through simple random and purposive sampling. The participants responded to a researcher-designed questionnaire. The data were analysed using descriptive and inferential statistics at 0.05 alpha level. The attitude of literate married men was positive. There were significant differences in the attitude of literate married men towards the use of aphrodisiac herbs in Ilorin, Kwara State based on age and educational attainment. Most literate married men in Ilorin, Kwara State, Nigeria had a positive attitude towards the use of aphrodisiac herbs. Doctors and counsellors should organise community-based talk to orientate literate married men on the use of aphrodisiac herbs.


Halfway between receiving and giving: a relational analysis of doctorate-prepared nurse-scholars' first 5 years after graduation.
The longitudinal, phenomenological study described in this article is unique in exploring doctorally prepared nurses' lives during their first 5 years after graduation. Despite individual differences, there was a definite pattern in the way the 16 female participants internalized a doctoral identity. During the first year, the women asked themselves, "How big do I want my world to be?" In the second year, they were overwhelmed by trying to prove themselves because they equated doctoral identity with conducting research and scholarship. During the third year, they prioritized gradually focusing and determining the direction of their professional endeavors. In the fourth year, they "spent a lot of time creating my piece of the world." By the fifth year, they valued their accomplishments, "This is my world and I am proud of it." In between receiving and giving, most participants developed a network of colleagues who mentored them as scholars. Given that relationship and scholarly identity are linked in the nursing literature, this relational feminist analysis suggests the need for doctoral nurse educators and students to replace the single mentor-mentee model with a collegial one that allows them to mentor one another as scholars during and after doctoral studies.


QUANTIFICATION OF MITOCHONDRIAL MORPHOLOGY IN SITU.
Structural organization of mitochondria reflects their functional status and largely is an index of the cell viability. The indirect parameter to assess the functional state of mitochondria and cells is the degree of fragmentation, i. e. a ratio of long or branched mitochondrial structures to rounded mitochondria. The critical need for such evaluations requires the creation of an approach, that allows on the basis of confocal images of mitochondria stained with a fluorescent probe, to create an integral picture of the three-dimensional organization of mitochondria. In the present study, we tested three approaches to analyze the structural architecture of mitochondria under norm and fission induced by oxidative stress. We have revealed that while the most informative way of analysis is a three-dimensional reconstruction based on series of confocal images taken in Z-dimension, however, with some limitations it is plausible to use more simple algorithms of analysis, including that one that uses unitary two-dimensional images. Further improvement of these methods of image analysis will allow more comprehensive analysis of mitochondrial architecture under norm and different pathological states. It may also provide quantification of a number of mitochondrial parameters determining morpho-functional state of mitochondria primarily their absolute and relative volumes and give additional information on three-dimensional organization of mitochondriome.


[A new etiology of traveler's diarrhea in children: Cryptosporidium diarrhea].
Cryptosporidiosis is a frequent cause of Traveler's diarrhea in children. In its acute or chronic form, this diarrhea is often accompanied by dehydration and accompanying deterioration in health. Diagnosis may be reached by inspection of the stools, for parasites, utilising specific but simple procedures. The latter tests should be carried out by the laboratory in addition to the routine parasitological examination. Prognosis is good in immunocompetent children since the clinical signs spontaneously regress within about a month. The only treatment consists in symptomatic treatment of diarrhea. Spiramycin, though not constantly effective, is reserved for immunosuppressed patients.


A Randomized Controlled Trial of a Physical Activity Intervention for Self-management of Fatigue in Adolescents and Young Adults With Cancer.
Fatigue remains a persistent and troubling symptom for adolescents and young adults (AYAs) with cancer. Physical activity (PA) is recommended as a strategy for self-management of fatigue. The aim of the study was to examine a PA intervention to improve the self-management of fatigue in AYAs during chemotherapy. This randomized controlled trial enrolled AYAs (18-39 years) receiving chemotherapy. Adolescents and young adults in the intervention group received a 12-week PA intervention integrated into 5 clinic visits that included education, PA tracking, and collaboration. Physical activity was measured with an accelerometer, and participants completed measures of fatigue severity, self-efficacy for PA, and self-regulation at baseline and end of study. Forty-four AYAs completed the study. At baseline, AYAs averaged 4290 (SD, 2423) steps/day and 14.4 (SD, 20.6) minutes/day of moderate- to vigorous-intensity PA; their average Patient-Reported Outcomes Measurement Information System fatigue score was 55.0 (SD, 9.2). At end of study, there were no significant differences between groups in fatigue, self-efficacy, self-regulation, or PA, but trends in the desired direction were observed for each of the variables in the intervention group. During chemotherapy, AYAs had variable levels of PA and engaged in mostly light-intensity PA. Their average fatigue level was slightly worse than a national comparison group. Tailored interventions are needed to promote PA in AYAs as a self-management strategy for fatigue. Enhancing self-efficacy and self-regulation may be important approaches to promote PA.


The state of the excimer laser for coronary intervention in the drug-eluting stent era.
This study aims to determine how excimer laser coronary atherectomy (ELCA) performs in the drug-eluting stent (DES) era. For more than 20 years, ELCA has been used for coronary intervention. With developments in the coronary intervention field, the role of ELCA is in question. The study includes 119 patients with 124 lesions who underwent percutaneous coronary intervention (PCI) with ELCA in our institution from January 2004 to May 2011. The main indications for ELCA use were saphenous vein graft (SVG) (45 lesions), acute myocardial infarction (AMI) (7 lesions), chronic total occlusion (CTO) (32 lesions), in-stent restenosis (ISR) (15 lesions), and calcified de-novo lesions (25 lesions). High success rates were recorded for the SVG, AMI, CTO, ISR, and calcified lesion indications (91.1%, 85.7%, 93.8%, 86.7%, and 80%; respectively). ELCA related complications were reported in 10 patients (8%); four dissections, three no-reflow phenomena, two perforations, and one thrombus formation. ELCA is an alternative solution with acceptable performance in the treatment of complex coronary lesions not ideally suitable for balloon angioplasty.


Effect of inclusion complexation of meloxicam with β-cyclodextrin- and β-cyclodextrin-based nanosponges on solubility, in vitro release and stability studies.
The objective of the present work was to develop inclusion complexes of meloxicam with β-cyclodextrin- and β-cyclodextrin-based nanosponges to enhance their solubility and stability and to prolong release using different methods that included physical mixing, kneading and sonication. Particle size, zeta potential, encapsulation efficiency, stability study results, in vitro and in vivo drug release study results, FTIR, DSC and XRPD were used as characterization parameters. SEM (Scanning Electron Microscope) studies revealed that the particle sizes of the inclusion complexes of meloxicam were within the range of 350 ± 5.69-765 ± 13.29 nm. The zeta potentials were sufficiently high to obtain stable formulations. In vitro and in vivo release studies revealed the controlled release of meloxicam from the nanosponges for 24h. The interaction of the meloxicam with the nanosponges was confirmed by FTIR and DSC. A XRPD study revealed that the crystalline nature of meloxicam was changed to an amorphous form due to the complexation with the nanosponges. A stability study revealed that the meloxicam nanosponges were stable. Therefore, β-cyclodextrin-based nanosponges represent a novel approach for the controlled release of meloxicam for anti-inflammatory and analgesic effects.


Photoelastic comparison of stress induced by using stainless-steel versus nickel-titanium spreaders in vitro.
The vertical force applied to an endodontic spreader generates stress along the canal walls. Recognizing the potential for this stress may reduce the incidence of vertical root fractures. A photoelastic acrylic model was fabricated to exhibit the stress produced during obturation of curved canals using the lateral condensation technique. Twenty standardized models simulating curved canals (32 degrees) were formed within PL-2 photoelastic acrylic resin blocks. The canals were fitted with a gutta-percha point, and either a stainless-steel or nickel-titanium finger spreader was inserted. An Instron 4502 universal testing machine applied a vertical force of 20 Newtons to the spreader. Quarter wave and polarizing filters were used with backlighting to generate the fringe patterns in the models. Photographs of the resulting stress lines showed that the stainless-steel spreaders created three areas of concentrated stress. The nickel-titanium spreaders induced stress patterns spread out along the surface of the canals, thus reducing the concentration of stress and the potential for vertical root fracture.


Recycling rate - The only practical metric for a circular economy?
The paper is related to the suggestion of metrics for measuring and fostering circular economy. Besides a recycling rate based evaluation, the author recommend to include also a subsitution factor describing the share of primary resources subsituted by the establishment of a circular economy.


The modulatory effects of two bioflavonoids, quercetin and thymoquinone on the expression levels of DNA damage and repair genes in human breast, lung and prostate cancer cell lines.
The recent decade has witnessed the increasing potential of various flavonoids such as quercetin and thymoquinone in inhibiting cancer cells proliferation and growth and their therapeutic effects in various cancers. Therefore, in the current study, we aim to evaluate the expression levels of key factors of DNA damage response in human breast, lung and prostate cancer cell lines in response to treatment with quercetin and thymoquinone. MTT assay was applied to assess the effects of quercetin and thymoquinone on the viability of MCF-7, A549, and PC3 cancer cells. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to evaluate the expression levels of p53, RAD51, Ku70, XRCC1, and H2AX in treated cells. In addition, the expression rate of 8-hydroxy-deoxyguanosine (8-OH-dG) was assessed by ELISA kit. The quercetin and thymoquinone induce cytotoxicity in breast, lung, and prostate cancer cells effectively; MCF-7 cells were the most sensitive cells to quercetin with an IC50 value of 50 μM and PC3 cells were more sensitive to thymoquinone with an IC50 value of 20 μM. The expression levels of DNA damage markers, H2AX, and 8-OH-dG were significantly increased in all cancer cells treated with quercetin and thymoquinone (p < 0.05). Moreover, both flavonoids significantly decreased the expression levels of DNA repair mediators, RAD51, Ku70, XRCC1, in cell lines. P53 was also increased in MCF-7 and A549 cells. We concluded that quercetin and thymoquinone may exert their effects through modulation of DNA damage response, increasing DNA damage, and suppressing DNA repair genes.


Sensory axons induce epithelial lipid microdomain remodeling and determine the distribution of junctions in the epidermis.
Epithelial cell properties are determined by the polarized distribution of membrane lipids, the cytoskeleton, and adhesive junctions. Epithelia are often profusely innervated, but little work has addressed how neurites affect epithelial organization. We previously found that basal keratinocytes in the zebrafish epidermis enclose axons in ensheathment channels sealed by autotypic junctions. Here we characterized how axons remodel cell membranes, the cytoskeleton, and junctions in basal keratinocytes. At the apical surface of basal keratinocytes, axons organized lipid microdomains quantitatively enriched in reporters for PI(4,5)P2 and liquid-ordered (Lo) membranes. Lipid microdomains supported the formation of cadherin-enriched, F-actin protrusions, which wrapped around axons, likely initiating ensheathment. In the absence of axons, cadherin-enriched microdomains formed on basal cells but did not organize into contiguous domains. Instead, these isolated domains formed heterotypic junctions with periderm cells, a distinct epithelial cell type. Thus, axon endings dramatically remodel polarized epithelial components and regulate epidermal adhesion.


Molecular remodeling of potassium channels in fibroblasts from centenarians: a marker of longevity?
Aging is a complex process resulting from, among other, dynamic non-linear interactions between genetics and environment. Centenarians are the best example of successful aging in humans, as they escaped from, or largely postponed, major age-related diseases. Ionic fluxes changes play a key role in several patho-physiological cellular processes, but their relation to human aging is largely unexplored. In the present study we have compared patch-clamp potassium (K(+)) current recordings from dermal fibroblasts (DF) obtained from young, elderly and centenarian donors. We found that in DF from elderly donors, but not from centenarians, K(+) current amplitude is significantly smaller with respect to DF from young donors. Moreover, cell membrane capacitance of DF from elderly donors is smaller with respect to young donors and centenarians. We also observed that the voltage-gated Shaker Kv1.1 channel is expressed in higher percentage of elderly's and centenarian's DF than young's, whereas the large-conductance calcium-activated K(+) (BK(Ca)) channel β1 subunit is expressed in lower percentage of centenarian's DF than in elderly's and young's. The maintenance of "young" K(+) currents and the peculiar age-related remodeling of K(+) channel subtypes in centenarian's DF is likely associated with successful aging and might provide a predictive marker of longevity.


The origin of central pinealopetal nerve fibers in the Mongolian gerbil as demonstrated by the retrograde transport of horseradish peroxidase.
The location of perikarya and nerve fibers projecting via the habenular and posterior commissures from the brain into the pineal organ of the Mongolian gerbil was investigated by the use of the retrograde horseradish peroxidase (HRP)-tracing method. After microiontophoretic or hydraulic injection of the tracer into the superficial pineal gland via a glass micropipette, and after survival periods of 6 to 48 h, the animals were transcardially perfused and the brains processed for the histochemical demonstration of the enzyme. In the pineal stalk 15 to 20 nerve fibers, including 4 to 7 myelinated elements, were traced back to the brain. HRP-labeled perikarya were located in the medial and lateral habenular nuclei as well as in the nucleus of the posterior commissure. Few fibers projected rostrally to perikarya in the paraventricular nucleus of the hypothalamus. A striking and persistent finding was the labeling of fibers that, in the habenular area, bent laterad and continued ventral to the optic tract. These fibers originated from perikarya located in the dorsal nucleus of the lateral geniculate body. These results strongly suggest a central innervation of the pineal organ in the Mongolian gerbil originating from hypothalamic and limbic areas of the brain as well as from the optic system.


Preperitoneal pelvic packing.
Severe pelvic traumatisms are associated with elevated mortality because of the high risk of exsanguination from multiple sources of bleeding. Treatment should encompass resuscitation, bone stabilization and hemorrhage control by arterio-embolization or surgery. Pre-peritoneal packing has been described in hemodynamically unstable patients who need damage control. The surgical technique of this simple and effective procedure is fully described by the authors with some complementary useful technical advices.


The spinocerebellar ataxia 12 gene product and protein phosphatase 2A regulatory subunit Bbeta2 antagonizes neuronal survival by promoting mitochondrial fission.
The neurodegenerative disorder spinocerebellar ataxia 12 (SCA12) is caused by CAG repeat expansion in the non-coding region of the PPP2R2B gene. PPP2R2B encodes Bbeta1 and Bbeta2, alternatively spliced and neuron-specific regulatory subunits of the protein phosphatase 2A (PP2A) holoenzyme. We show here that in PC12 cells and hippocampal neurons, cell stressors induced a rapid translocation of PP2A/Bbeta2 to mitochondria to promote apoptosis. Conversely, silencing of PP2A/Bbeta2 protected hippocampal neurons against free radical-mediated, excitotoxic, and ischemic insults. Evidence is accumulating that the mitochondrial fission/fusion equilibrium is an important determinant of cell survival. Accordingly, we found that Bbeta2 expression induces mitochondrial fragmentation, whereas Bbeta2 silencing or inhibition resulted in mitochondrial elongation. Based on epistasis experiments involving Bcl2 and core components of the mitochondrial fission machinery (Fis1 and dynamin-related protein 1), mitochondrial fragmentation occurs upstream of apoptosis and is both necessary and sufficient for hippocampal neuron death. Our data provide the first example of a proapoptotic phosphatase that predisposes to neuronal death by promoting mitochondrial division and point to a possible imbalance of the mitochondrial morphogenetic equilibrium in the pathogenesis of SCA12.


Robust Differentiation of mRNA-Reprogrammed Human Induced Pluripotent Stem Cells Toward a Retinal Lineage.
The derivation of human induced pluripotent stem cells (hiPSCs) from patient-specific sources has allowed for the development of novel approaches to studies of human development and disease. However, traditional methods of generating hiPSCs involve the risks of genomic integration and potential constitutive expression of pluripotency factors and often exhibit low reprogramming efficiencies. The recent description of cellular reprogramming using synthetic mRNA molecules might eliminate these shortcomings; however, the ability of mRNA-reprogrammed hiPSCs to effectively give rise to retinal cell lineages has yet to be demonstrated. Thus, efforts were undertaken to test the ability and efficiency of mRNA-reprogrammed hiPSCs to yield retinal cell types in a directed, stepwise manner. hiPSCs were generated from human fibroblasts via mRNA reprogramming, with parallel cultures of isogenic human fibroblasts reprogrammed via retroviral delivery of reprogramming factors. New lines of mRNA-reprogrammed hiPSCs were established and were subsequently differentiated into a retinal fate using established protocols in a directed, stepwise fashion. The efficiency of retinal differentiation from these lines was compared with retroviral-derived cell lines at various stages of development. On differentiation, mRNA-reprogrammed hiPSCs were capable of robust differentiation to a retinal fate, including the derivation of photoreceptors and retinal ganglion cells, at efficiencies often equal to or greater than their retroviral-derived hiPSC counterparts. Thus, given that hiPSCs derived through mRNA-based reprogramming strategies offer numerous advantages owing to the lack of genomic integration or constitutive expression of pluripotency genes, such methods likely represent a promising new approach for retinal stem cell research, in particular, those for translational applications. In the current report, the ability to derive mRNA-reprogrammed human induced pluripotent stem cells (hiPSCs), followed by the differentiation of these cells toward a retinal lineage, including photoreceptors, retinal ganglion cells, and retinal pigment epithelium, has been demonstrated. The use of mRNA reprogramming to yield pluripotency represents a unique ability to derive pluripotent stem cells without the use of DNA vectors, ensuring the lack of genomic integration and constitutive expression. The studies reported in the present article serve to establish a more reproducible system with which to derive retinal cell types from hiPSCs through the prevention of genomic integration of delivered genes and should also eliminate the risk of constitutive expression of these genes. Such ability has important implications for the study of, and development of potential treatments for, retinal degenerative disorders and the development of novel therapeutic approaches to the treatment of these diseases.


The predictive significance of biologic risk factors for deficits in children of a high-risk population.
Two hundred forty-two high-risk children and 47 low-risk children were prospectively studied to assess the relationship between biologic risk factors that occurred during the perinatal period and the motor and cognitive deficits that were identified during the first year of life. Multiple risk factors were present in 80% of the children of the high-risk group. Provisional deficits were classified on the degree of abnormality found in a clinical and behavioral assessment that included neurological examinations, Bayley Physical and Mental Development Scales, and the Uzgiris and Hunt Scale. Provisional deficits occurred in 10% of the children of the low-risk group. High-risk children had a significantly greater incidence of provisional deficits, particularly in respect to positive deficits. In high-risk children, the probability of a deficit was 17% in those without infection or encephalopathy, 30% in those with infection, and 40% in those with encephalopathy.


Extending artificial intelligence research in the clinical domain: a theoretical perspective.
Academic research to the utilization of artificial intelligence (AI) has been proliferated over the past few years. While AI and its subsets are continuously evolving in the fields of marketing, social media and finance, its application in the daily practice of clinical care is insufficiently explored. In this systematic review, we aim to landscape various application areas of clinical care in terms of the utilization of machine learning to improve patient care. Through designing a specific smart literature review approach, we give a new insight into existing literature identified with AI technologies in the clinical domain. Our review approach focuses on strategies, algorithms, applications, results, qualities, and implications using the Latent Dirichlet Allocation topic modeling. A total of 305 unique articles were reviewed, with 115 articles selected using Latent Dirichlet Allocation topic modeling, meeting our inclusion criteria. The primary result of this approach incorporates a proposition for future research direction, abilities, and influence of AI technologies and displays the areas of disease management in clinics. This research concludes with disease administrative ramifications, limitations, and directions for future research.


Investigation of a side-chain-side-chain hydrogen bond by mutagenesis, thermodynamics, and NMR spectroscopy.
Anomalous NMR behavior of the hydroxyl proton resonance for Ser 31 has been reported for histidine-containing protein (HPr) from two microorganisms: Escherichia coli and Staphylococcus aureus. The unusual slow exchange and chemical shift exhibited by the resonance led to the proposal that the hydroxyl group is involved in a strong hydrogen bond. To test this hypothesis and to characterize the importance of such an interaction, a mutant in which Ser 31 is replaced by an alanine was generated in HPr from Escherichia coli. The activity, stability, and structure of the mutant HPr were assessed using a reconstituted assay system, analysis of solvent denaturation curves, and NMR, respectively. Substitution of Ser 31 yields a fully functional protein that is only slightly less stable (delta delta G(folding) = 0.46 +/- 0.15 kcal mol-1) than the wild type. The NMR results confirm the identity of the hydrogen bond acceptor as Asp 69 and reveal that it exists as the gauche- conformer in wild-type HPr in solution but exhibits conformational averaging in the mutant protein. The side chain of Asp 69 interacts with two main-chain amide proteins in addition to its interaction with the side chain of Ser 31 in the wild-type protein. These results indicate that removal of the serine has led to the loss of all three hydrogen bond interactions involving Asp 69, suggesting a cooperative network of interactions. A complete analysis of the thermodynamics was performed in which differences in side-chain hydrophobicity and conformational entropy between the two proteins are accounted for.(ABSTRACT TRUNCATED AT 250 WORDS)


A Machine Learning-Aided Global Diagnostic and Comparative Tool to Assess Effect of Quarantine Control in COVID-19 Spread.
We have developed a globally applicable diagnostic COVID-19 model by augmenting the classical SIR epidemiological model with a neural network module. Our model does not rely upon previous epidemics like SARS/MERS and all parameters are optimized via machine learning algorithms used on publicly available COVID-19 data. The model decomposes the contributions to the infection time series to analyze and compare the role of quarantine control policies used in highly affected regions of Europe, North America, South America, and Asia in controlling the spread of the virus. For all continents considered, our results show a generally strong correlation between strengthening of the quarantine controls as learnt by the model and actions taken by the regions' respective governments. In addition, we have hosted our quarantine diagnosis results for the top 70 affected countries worldwide, on a public platform.


A randomized comparative study of the effect of two different flow rates of carboxytherapy in the treatment of infraorbital dark circles.
Carboxytherapy is a minimally invasive, relatively safe modality that has been used for the treatment of dark circles; however, different flow rates and different injection techniques have been described in the literature. To study the effect of the flow rate on the therapeutic outcome of carboxytherapy in infraorbital dark circles. Eighty patients with infraorbital dark circles were divided into two equal groups: Group A received carboxytherapy at a flow rate of 30 ml/min, and group B received carboxytherapy at a flow rate of 60 ml/min. Patients received weekly sessions for 6 weeks, and the treatment response was evaluated 6 weeks after the last treatment session. Significant improvement of the dark circles was detected in both treatment groups. However, no significant difference in the treatment response was found when both flow rates were compared. The frequency of development of side effects was significantly higher in the group receiving CO2 at a flow rate of 60 ml/min. No significant difference in the overall post-treatment patient satisfaction between the two groups was detected. Carboxytherapy is an effective therapeutic modality for infraorbital dark circles. Lower flow rates achieve therapeutic responses similar to higher flow rates but with fewer side effects.


A hereditary double double-banded variation in the vitamin D-binding protein (GC) system analyzed by immunoblotting: duplication of the 1F and 1A2 genes?
A combination of immunoblotting and polyacrylamide gel isoelectric focusing (IEF-PAGE) was used to define a new genetic variant in the (GC) group-specific component system. This appeared to be a GC 1-type variant, and was presumed to have arisen from duplication of the GC 1F and GC 1A2 genes.


Oversight group holds RCA teams accountable.
Allow Safety Advisory Panel to review all data before closing event. Encourage RCA teams to dig deeper. Hold RCA teams accountable.


Transformation from arm joint coordinates to hand external coordinates explains non-uniform precision of hand position sense in horizontal workspace.
People perceive hand position in horizontal workspace more precisely in radial than in azimuth directions and closer to the body than farther away. Current explanations for this position sense non-uniformity include spatial asymmetry in arm proprioceptive activities and/or cortex maps, experience-dependent learning, arm posture, and others. Here we investigated contributions to this non-uniformity of a posture-dependent transformation from arm joint angles, sensed by arm proprioceptors, to hand position. We measured precision of hand position sense in a bimanual hand mirror-position matching task at four horizontal targets forming a square in front of the body in 11 blindfolded individuals. We found lower hand precision in azimuth than in radial direction, higher azimuth precision at close targets, and higher radial precision at distant targets. We then theoretically analyzed the transformation of random angle errors at shoulder and elbow into hand position random errors in a horizontal plane and obtained similar distributions of hand position errors. The predicted and experimental hand-precision ellipse orientations, but not ellipse shapes or sizes, were highly correlated and were nearly orthogonal to arm stiffness ellipse orientations reported in the literature. We concluded that the joint-to-hand coordinate transformation is responsible for the non-uniform precision of hand position sense.


The assessment of cognitive impairment in maintenance hemodialysis patients and the relationship between cognitive impairment and depressive symptoms.
Cognitive impairment and depression are common mental health problems in chronic kidney disease (CKD) patients with maintenance hemodialysis (MHD). Previous studies have proven that cognitive impairment and depression were risk factors for poor prognosis in MHD patients. However, the related factors of cognitive function and the association between cognitive impairment and depression in MHD patients are still unclear. The purpose of this study is to explore the related factors affecting the cognitive function of MHD patients and evaluate the relationship between cognitive function and depression in MHD patients. This single-center, cross-sectional study enrolled 160 MHD patients. Cognitive function and depressive symptoms were measured using Montreal Cognitive Assessment (MoCA) and Patient Health Questionnaire-9 (PHQ-9), respectively. Cognitive impairment was detected in 58.1% of 160 MHD patients. Multivariate linear regression analysis showed that age, level of education and homocysteine (HCY) were independent influencing factors of MoCA scores and the scores of attention and abstract thinking were independently correlated with PHQ-9 score after adjusting for confounding factors CONCLUSIONS: These findings indicated that age, level of education and HCY were independently associated with cognitive function, and attention and abstract thinking could independently affect depressive symptoms in MHD patients.


The indirect transfer of glass fragments to a jacket and their subsequent persistence.
Experiments were conducted to investigate a scenario sometimes encountered in casework, where a police officer has attended a scene and shortly afterwards arrested a suspect. The experiments involve the transfer of glass fragments from a surface scattered with broken glass to a hand, and then from the hand to the sleeve of a poorly retaining jacket. The persistence of the transferred fragments was studied by collecting the glass fragments as they fell off the jacket, whilst the wearer was walking on the spot. The recovery regime allowed the number and proportion of fragments picked up and transferred to the jacket from the hand to be determined, and the rate at which they were lost from the jacket to be monitored. The results show that large numbers of glass fragments can be picked up on a hand from a suitable surface. A subsequent firm grip to a poorly retaining jacket was found to transfer a significant proportion of the glass fragments from the hand to the jacket. In seven of nine tests performed, ten or more glass fragments were recovered from the jacket 60 minutes after the original contact between the hand and the broken glass. More than twenty fragments were recovered in three of these tests. Consequently, where possible and appropriate, the full circumstances of a case should be considered carefully before indirect transfer is ruled out as a possible explanation for recovered "matching" glass. This is the case even for poorly retaining clothing.


Regulation of the cholesterol side-chain cleavage cytochrome P-450 and adrenodoxin mRNAs in cultured choriocarcinoma cells.
Cytochrome P-450scc (P-450scc) catalyzes the cholesterol side-chain cleavage reaction, a rate-limiting enzymatic step for progesterone synthesis in trophoblastic and other steroidogenic cells. Adrenodoxin is the iron/sulfur protein donating electrons to P-450scc during this reaction. We examined the effects of cholera toxin (CT), an activator of adenylate cyclase, and 12-O-tetradecanoylphorbol acetate (TPA), a phorbol ester protein kinase C activator, on the levels of mRNAs encoding P-450scc and adrenodoxin in JEG-3 choriocarcinoma cells. CT induced in a concentration- and time-dependent manner P-450scc and adrenodoxin mRNA levels to 8-fold and 1.5-fold above that of control, respectively. TPA also increased P-450scc and adrenodoxin mRNA levels about 3-fold and 1.5-fold above that of control, respectively. Epidermal growth factor (EGF) was found to weakly induce P-450scc mRNA accumulation with a maximal 20% stimulation above basal levels. The effects of CT and TPA were apparently additive on both mRNAs. The protein synthesis inhibitor cycloheximide diminished basal, CT-, TPA-, and EGF-stimulated P-450scc mRNA accumulation whereas the opposite was observed for the adrenodoxin mRNA. Insulin-like growth factor I (IGF-I) appeared to have no effect on either mRNA. These data indicate that: (1) the accumulation of P-450scc and adrenodoxin mRNAs is mainly controlled by the cyclic adenosine 3',5'-monophosphate (cAMP)-dependent pathway but their stimulation by TPA- and EGF-induced signals may also play a weaker synergistic role; (2) the protein synthesis inhibitor cycloheximide inhibits basal, CT-, TPA- and EGF-stimulated P-450scc mRNA levels while it increases the expression of adrenodoxin mRNA suggesting that in the malignant trophoblasts these two enzyme mRNAs are differentially controlled.


Monitoring of hepatic artery resistance index and optimal timing of liver transplantation for biliary atresia.
Biliary atresia (BA) is diagnosed by ultrasound (US) examination of the hepatic artery and gallbladder. This study was designed to assess the usefulness of the hepatic artery resistance index (HRI) measured by Doppler ultrasonography (DUS) for prognostication of liver viability in children with BA. Seventeen patients with non-correctable BA were examined by US and DUS before and after hepatoenterostomy to evaluate hepatic artery dynamics. Dilatation of the hepatic artery was demonstrated in all 17 patients. US of the gallbladder showed hypogenesis in seven patients. Preoperatively, all 17 BA patients had an HRI of <1.0. Six of the 17 patients underwent liver transplantation. Four of the six had an HRI of >0.9, and the HRI decreased after the procedure. All patients were alive at the time of writing. Regular US examinations are helpful for diagnosis of BA and for detecting patients at high risk. A prospective study is required to determine the optimal frequency of assessment.


Using growth analysis to interpret competition between a C3 and a C4 annual under ambient and elevated CO2.
Detailed growth analysis in conjunction with information on leaf display and nitrogen uptake was used to interpret competition between Abutilon theophrasti, a C3 annual, and Amaranthus retroflexus, a C4 annual, under ambient (350 μl l-1) and two levels of elevated (500 and 700 μl l-1) CO2. Plants were grown both individually and in competition with each other. Competition caused a reduction in growth in both species, but for different reasons. In Abutilon, decreases in leaf area ratio (LAR) were responsible, whereas decreased unit leaf rate (ULR) was involved in the case of Amaranthus. Mean canopy height was lower in Amaranthus than Abutilon which may explain the low ULR of Amaranthus in competition. The decrease in LAR of Abutilon was associated with an increase in root/shoot ratio implying that Abutilon was limited by competition for below ground resources. The root/shoot ratio of Amaranthus actually decreased with competition, and Amaranthus had a much higher rate of nitrogen uptake per unit of root than did Abutilon. These latter results suggest that Amaranthus was better able to compete for below ground resources than Abutilon. Although the growth of both species was reduced by competition, generally speaking, the growth of Amaranthus was reduced to a greater extent than that of Abutilon. Regression analysis suggests that the success of Abutilon in competition was due to its larger starting capital (seed size) which gave it an early advantage over Amaranthus. Elevated CO2 had a positive effect upon biomass in Amaranthus, and to a lesser extent, Abutilon. These effects were limited to the early part of the experiment in the case of the individually grown plants, however. Only Amaranthus exhibited a significant increase in relative growth rate (RGR). In spite of the transitory effect of CO2 upon size in individually grown plants, level of CO2 did effect final biomass of competitively grown plants. Abutilon grown in competition with Amaranthus had a greater final biomass than Amaranthus at ambient CO2 levels, but this difference disappeared to a large extent at elevated CO2. The high RGR of Amaranthus at elevated CO2 levels allowed it to overcome the difference in initial size between the two species.


To what extent should older patients be included in decisions regarding their resuscitation status?
As medical technology continues to advance and we develop the expertise to keep people alive in states undreamt of even 20 years ago, there is increasing interest in the ethics of providing, or declining to provide, life-sustaining treatment. One such issue, highly contentious in clinical practice as well as in the media (and, through them, the public), is the use of do-not-attempt-resuscitation orders. The main group of patients affected by these orders is older people. This article explores some of the arguments regarding who should make the decision to implement such an order, with particular reference to older people and the unique issues they face in relation to resuscitation. The author concludes by arguing that official guidelines, while representing an ideal, are not easily applied in a typical acute setting where decisions regarding resuscitation are most commonly made, and makes suggestions as to how they may be implemented more successfully.


Release of beta-thromboglobulin during the preparation, in vitro storage and cryopreservation of platelet concentrates.
Beta-thromboglobulin is a platelet specific protein which is released from platelets during the platelet release reaction. The amount of beta-thromboglobulin released during various conditions of in vitro storage, including cryopreservation, was compared. The results suggest the measurement of beta-thromboglobulin is unlikely to be of use as a quality control assay for monitoring the in vitro viability of stored platelets.


The early evolution of neurofilamentous accumulations due to 2,5-hexanediol in the optic pathways of the rat.
Rats were given 2,5-hexanediol in their water for more than 5 weeks. The changes in the optic pathways were studied both qualitatively and quantitatively. Increase in 10-nm filaments within axons was noticeable from 10 days onwards in the superior colliculus and in the brachium of the superior colliculus. From then onwards there was a steady increase in the number of affected axons, and their gross enlargement occurred. The proportion of affected fibres in the brachia was in fact few, but all fibres were of retinotectal origin. Less than half of those in the superior colliculus that were swollen were of retinal origin. Measurement of axon diameter versus myelin sheath thickness showed gross relative thinning of the latter. Axon degeneration did not occur but there was increasing ultrastructural evidence of impairment of transport of organelles both centrifugally and centripetally as the filamentous masses accumulated.


Chemically stable fluorescent proteins for advanced microscopy.
We report the rational engineering of a remarkably stable yellow fluorescent protein (YFP), 'hyperfolder YFP' (hfYFP), that withstands chaotropic conditions that denature most biological structures within seconds, including superfolder green fluorescent protein (GFP). hfYFP contains no cysteines, is chloride insensitive and tolerates aldehyde and osmium tetroxide fixation better than common fluorescent proteins, enabling its use in expansion and electron microscopies. We solved crystal structures of hfYFP (to 1.7-Å resolution), a monomeric variant, monomeric hyperfolder YFP (1.6 Å) and an mGreenLantern mutant (1.2 Å), and then rationally engineered highly stable 405-nm-excitable GFPs, large Stokes shift (LSS) monomeric GFP (LSSmGFP) and LSSA12 from these structures. Lastly, we directly exploited the chemical stability of hfYFP and LSSmGFP by devising a fluorescence-assisted protein purification strategy enabling all steps of denaturing affinity chromatography to be visualized using ultraviolet or blue light. hfYFP and LSSmGFP represent a new generation of robustly stable fluorescent proteins developed for advanced biotechnological applications.


Effects of heparin-induced lipolytic activity on the structure of rat high-density lipoprotein.
Following its secretion into the plasma compartment, the high-density lipoprotein (HDL) is presumed to be acted upon by both soluble enzymes, such as lecithin:cholesterol acyltransferase (LCAT), and membrane-associated enzymes, such as lipoprotein lipase and hepatic lipase. Rats were injected intravenously with heparin to release membrane-associated lipolytic activities into the circulation and the collected plasma was incubated overnight at 37 degrees C in the presence or absence of an LCAT inhibitor or an inhibitor of lipoprotein lipase (1 M NaCl). It was observed that lipoprotein lipase accounted for most of the triglyceride hydrolase activity in the heparin-treated plasma, and that the heparin-releasable activities caused an increase in HDL density but no measurable change in particle size when LCAT was inhibited. Heparin treatment caused about a 60% decrease in plasma triacylglycerol during the interval between injection of heparin and blood collection. Although this caused marked compositional changes in the d less than 1.063 g/ml lipoproteins, no changes were observed in the lipid composition or apoprotein distribution in the HDL. Subsequent incubation for 18 h at 37 degrees C produced marked increases in the apoE content of HDL from heparin-treated plasma even when LCAT was inhibited. Time-course studies showed that in the presence of an LCAT inhibitor there was considerable conversion of phosphatidylcholine to lysophosphatidylcholine in heparin-treated plasma, and that this activity was diminished by 1 M NaCl, but that no phospholipolysis was observed in control plasma. By contrast, both heparin-treated and control plasma possessed substantial triglyceride hydrolase activity. The concurrent action of lipases and LCAT was observed to reduce the maximum level of cholesterol esterification which could be achieved in the absence of lipase activity. It is concluded that changes in HDL particle size are mainly attributable to LCAT, but that lipase activities, which are either free in rat plasma or releasable by heparin, play a role in restructuring the phospholipid moiety and altering the protein composition of the HDL, especially with respect to apoE, a potential ligand to cellular receptors.


Formation of C/EBP transcription factors and possible pathways for controlling their activity during learning in Helix.
Formation of a conditioned defensive reflex in the common snail is accompanied by activation of DNA-binding transcription factors of the C/EBP family. Incubation of the CNS with serotonin, which imitates the effects of conditioning, and stimulation of adenylate cyclase with forskolin also increase the efficiency with which these transcription complexes are formed. Induction of protein kinase C with phorbol ester had no stimulating effect on the formation of C/EBP factors. However, simultaneous treatment with phorbol ester and serotonin produced some increase in the cAMP-inducible effects on the activation of C/EBP transcription factors. Larger increases in the DNA-binding activity of transcription factors of the C/EBP family in response to stimulation of the cAMP-dependent pathway were seen in conditions of elevated intracellular Ca2+ concentrations (by incubation of the CNS with the calcium ionophore A23187 and forskolin). Thus, it is possible that the Ca2+ and cAMP-dependent regulatory systems converge, leading to increases in the efficiency of the formation of C/EBP transcription complexes, which may reflect the interaction of stimuli of different modalities during learning.


Comprehensive analysis of colorectal cancer-risk loci and survival outcome: A prognostic role for CDH1 variants.
Genome-wide association studies have identified common single nucleotide polymorphisms (SNPs) at 83 loci associated with colorectal cancer (CRC) risk in European populations. Because germline variation can also influence patient outcome, we studied the relationship between these SNPs and CRC survivorship. For the 83 risk loci, 10 lead SNPs were directly genotyped, 72 were imputed and 1 was not genotyped nor imputed, in 1948 unrelated patients with advanced CRC from the clinical trials COIN and COIN-B (oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab). A Cox survival model was used for each variant, and variants classified by pathway, adjusting for known prognostic factors. We imposed a Bonferroni threshold of P = 6.6 × 10-4 for multiple testing. We carried out meta-analyses of published risk SNPs associated with survival. Univariate analysis identified six SNPs associated with overall survival (OS) (P < 0.05); however, only rs9939049 in CDH1 remained significant beyond the Bonferroni threshold (Hazard Ratio [HR] 1.44, 95% Confidence Intervals [CI]: 1.21-1.71, P = 5.0 × 10-5). Fine mapping showed that rs12597188 was the most significant SNP at this locus and remained significant after adjustment for known prognostic factors beyond multiple testing thresholds (HR 1.23, 95% CI: 1.13-1.34, P = 1.9 × 10-6). rs12597188 was also associated with poor response to therapy (OR 0.61, 95% CI: 0.42-0.87, P = 6.6 × 10-3). No combinations of SNPs within pathways were more significantly associated with survival compared with single variants alone, and no other risk SNPs were associated with survival in meta-analyses. The CRC susceptibility SNP rs9939049 in CDH1 influences patient survival and warrants further evaluation as a prognostic biomarker.


Colorectal Cancer Screening in the Elderly.
Colorectal cancer (CRC) is a common and preventable malignancy, and routine CRC screening is recommended for average risk individuals between the ages of 50 and 75 years. Screening has been shown to decrease CRC incidence and mortality. Once patients are older than 75 years, the risk to benefit ratio of ongoing screening begins to shift. As comorbidities increase and life expectancy decreases, the future potential benefits of CRC prevention become less robust, and risk for screening-related complications grows. However, firm age cutoffs are not sufficient to guide these decisions, as there is substantial physiologic heterogeneity among individuals of the same age.


The effect of prostaglandin E2-induced echinocytic transformation on the potassium loss, viscosity and osmotic fragility of normal and sickle cell erythrocytes.
Prostaglandin E2 (PGE2)-induced discocyte leads to echinocytic transformation has no effect on the viscosity or osmotic fragility of normal or sickle cell erythrocytes. Membrane permeability, reflected as potassium efflux, is significantly affected in normal erythrocytes when greater than 90% of the cells are morphologically transformed to the echinocytic III stage (PGE2 concentration of 1--2x10(6) ng/ml blood). This potassium loss is significant in sickle erythrocytes when 50-70% of the cell population has been transformed (PGE2 concentration, 5x10(5) ng/ml blood). This change in membrane permeability represents one-half to one-third the flux that occurs with sickling (i.e., greater than 80% of the erythrocytes sickled).


Prevention of Infectious Mastitis by Oral Administration of Lactobacillus salivarius PS2 During Late Pregnancy.
Previous studies have shown that oral administration of lactobacilli can be an efficient approach to treat lactational infectious mastitis. In this trial, we have evaluated the potential of Lactobacillus salivarius PS2 to prevent this condition when orally administered during late pregnancy to women who had experienced infectious mastitis after previous pregnancies. In this study, 108 pregnant women were randomly assigned to one of 2 groups. Those in the probiotic group (n = 55) ingested daily 9 log10 colony-forming units of L. salivarius PS2 from approximately week 30 of pregnancy until delivery, whereas those in the placebo group (n = 53) received a placebo. The occurrence of mastitis was evaluated during the first 3 months after delivery. Globally, 44 of 108 women (41%) developed mastitis; however, the percentage of women with mastitis in the probiotic group (25% [n = 14]) was significantly lower than in the control group (57% [n = 30]). When mastitis occurred, the milk bacterial counts in the probiotic group were significantly lower than those obtained in the placebo group. Oral administration of L. salivarius PS2 during late pregnancy appears to be an efficient method to prevent infectious mastitis in a susceptible population. NCT01505361.


Quadrupole Contribution of C═O Vibrational Band in Sum Frequency Generation Spectra of Organic Carbonates.
Sum Frequency Generation (SFG) is usually governed by surface-selective signals of dipole origin, but it can also contain some bulk signals of quadrupole origin. In this work, we examined the dipole and quadrupole contributions in the C═O stretching band of organic carbonate liquids with collaboration of heterodyne SFG measurement and theoretical analysis. As a result, we found that these spectra are substantially affected by the quadrupole contribution of the bulk, which resolved the discrepancy between the experimental and computational SFG spectra.


Jaw size variation is associated with a novel craniofacial function for galanin receptor 2 in an adaptive radiation of pupfishes.
Understanding the genetic basis of novel adaptations in new species is a fundamental question in biology that also provides an opportunity to uncover new genes and regulatory networks with potential clinical relevance. Here we demonstrate a new role for galr2 in vertebrate craniofacial development using an adaptive radiation of trophic specialist pupfishes endemic to San Salvador Island in the Bahamas. We confirmed the loss of a putative Sry transcription factor binding site in the upstream region of galr2 in scale-eating pupfish and found significant spatial differences in galr2 expression among pupfish species in Meckel's cartilage and premaxilla using in situ hybridization chain reaction (HCR). We then experimentally demonstrated a novel function for Galr2 in craniofacial development and jaw elongation by exposing embryos to drugs that inhibit Galr2 activity. Galr2-inhibition reduced Meckel's cartilage length and increased chondrocyte density in both trophic specialists but not in the generalist genetic background. We propose a mechanism for jaw elongation in scale-eaters based on the reduced expression of galr2 due to the loss of a putative Sry binding site. Fewer Galr2 receptors in the scale-eater Meckel's cartilage may result in their enlarged jaw lengths as adults by limiting opportunities for a postulated Galr2 agonist to bind to these receptors during development. Our findings illustrate the growing utility of linking candidate adaptive SNPs in non-model systems with highly divergent phenotypes to novel vertebrate gene functions.


Relationship between quality of life and psychopathological profile: data from an observational study in children with ADHD.
Although ADHD significantly affects the quality of life (QoL) of patients and their families, QoL in children with ADHD has rarely been investigated in association with psychopathological profile, and the relationship remains unclear. The open-label OBSEER study evaluated the effectiveness and tolerability of Equasym XL(®), a modified-release methylphenidate, in routine care of children and adolescents (aged 6-17 years) with ADHD. At baseline, questionnaires assessing psychopathological profile (Strengths and Difficulties Questionnaire, SDQ; parental ratings) and QoL (KINDL; parent, child or adolescent versions) were completed; QoL was reassessed at final visit. We analysed the relationship between psychopathology and parent/patient-rated QoL in ADHD at baseline. Data from 721 consecutively referred children and adolescents were analysed. QoL was similarly low from parent and self-ratings and independent of severity on the SDQ subscale hyperactivity/inattention. Self-ratings indicated that additional conduct disorder was associated with further reduction in QoL. Similarly, children with high scores from parent and adolescent ratings on the SDQ subscale conduct problems had reduced QoL on some KINDL subscales. Adolescents with ADHD not receiving medication at baseline reported lower QoL than those already on medication. Results show that children and adolescents with ADHD have low QoL, independent of core symptom severity. Additional conduct problems may further impact QoL negatively, while ADHD medication use may show a trend towards improved QoL. Not all psychopathological problems associated with ADHD affect QoL similarly. As parents appear to have a less critical view of QoL compared with children's self-ratings, both parent and child ratings should be included in clinical assessments.


Exploring the role of coal consumption, solar, and wind power generation on ecological footprint: evidence from India using Fourier ADL cointegration test.
The transition to renewable energy sources has been identified as crucial to combating climate change on a global scale. India's future energy vision is becoming increasingly focused on renewable markets, particularly solar and wind power, which would improve energy efficiency and allow the country to shift from a coal-based economy to a renewable-based economy by 2030. In this context, the present study intends to investigate the impact of India's considerable investments in solar and wind power plants on mitigating environmental degradation by reducing reliance on coal-fired power. To this end, this study adopts the Fourier Autoregressive Distributive Lag (ADL) cointegration test and Fully Modified Ordinary Least Square (FMOLS) to assess the relationship between coal consumption, solar power, wind power, and ecological footprint in India using data from 1995 to 2018. The empirical results show that solar and wind power are significant and negatively related to ecological footprint, indicating that they lessen the environmental degradation. However, coal consumption is significant and positively related to ecological footprint. The study findings confirm the constructive role of solar and wind power in mitigating environmental degradation that is caused by the domination of coal-fired power generation in India, and solar and wind power are cleaner alternatives to replace coal-fired power.


Difference in clearance of intravitreal triamcinolone acetonide between vitrectomized and nonvitrectomized eyes.
To study the difference in clearance of intravitreal triamcinolone acetonide quantitatively between vitrectomized and nonvitrectomized eyes. Eighty-four eyes of 42 rabbits were divided in 2 groups: 42 right eyes underwent standard pars plana vitrectomy (vitrectomized group), and 42 left eyes were not operated on (nonvitrectomized group). All eyes received intravitreal injections with 0.1 mL (0.3 mg) of triamcinolone acetonide. Every 12 eyes were obtained by killing 6 rabbits 1, 2, 4, 7, 12, 20, or 30 days after intravitreal injection. Each eye was enucleated and immediately frozen at -70 degrees C. The frozen vitreous was prepared for measuring the concentration of triamcinolone acetonide. Triamcinolone acetonide was quantified by high-performance liquid chromatography and ultraviolet absorbance detection. After 30 days, triamcinolone acetonide was detected only in 1 eye (0.22 microg/mL) in the vitrectomized group compared with 4 of 6 eyes (0.92 +/- 1.25 microg/mL) in the nonvitrectomized group. The coefficient of logarithmic regression was -0.12 in the vitrectomized group and -0.08 in the nonvitrectomized group. Triamcinolone acetonide decreased 1.5 times more rapidly in the vitrectomized group than in the nonvitrectomized group. The half-life of triamcinolone acetonide was 1.57 days in the vitrectomized group and 2.89 days in the nonvitrectomized group. Intravitreal triamcinolone acetonide decreases more rapidly in the vitrectomized eye than in the nonvitrectomized eye. Therefore, the faster clearance of intravitreal triamcinolone acetonide must be considered when planning intravitreal injection of triamcinolone acetonide in the vitrectomized eye.


Characterization of acetylcholinesterases, and their genes, from the hemipteran species Myzus persicae (Sulzer), Aphis gossypii (Glover), Bemisia tabaci (Gennadius) and Trialeurodes vaporariorum (Westwood).
Gene sequences encoding putative acetylcholinesterases have been reported for four hemipteran insect species. Although acetylcholinesterase insensitivity occurs in insecticide-resistant populations of each of these species, no mutations were detected in the gene sequences from the resistant insects. This, coupled with a series of experiments using novel reversible inhibitors to compare the biochemical characteristics of acetylcholinesterase from a range of insect species, showed that the cloned cDNA fragments are unlikely to encode the hemipteran synaptic acetylcholinesterases, and there is likely to be a second ace locus.


A Systematic Review of the Economic Evidence for Home Support Interventions in Dementia.
Recent evidence signals the need for effective forms of home support to people with dementia and their carers. The cost-effectiveness evidence of different approaches to support is scant. To appraise economic evidence on the cost-effectiveness of home support interventions for dementia to inform future evaluation. A systematic literature review of full and partial economic evaluations was performed using the British National Health Service Economic Evaluation Database supplemented by additional references. Study characteristics and findings, including incremental cost-effectiveness ratios, when available, were summarized narratively. Study quality was appraised using the National Health Service Economic Evaluation Database critical appraisal criteria and independent ratings, agreed by two reviewers. Studies were located on a permutation matrix describing their mix of incremental costs/effects to aid decision making. Of the 151 articles retrieved, 14 studies met the inclusion criteria: 8 concerning support to people with dementia and 6 to carers. Five studies were incremental cost-utility analyses, seven were cost-effectiveness analyses, and two were cost consequences analyses. Five studies expressed incremental cost-effectiveness ratios as cost per quality-adjusted life-year (£6,696-£207,942 per quality-adjusted life-year). In four studies, interventions were dominant over usual care. Two interventions were more costly but more beneficial and were favorable against current acceptability thresholds. Occupational therapy, home-based exercise, and a carers' coping intervention emerged as cost-effective approaches for which there was better evidence. These interventions used environmental modifications, behavior management, physical activity, and emotional support as active components. More robust evidence is needed to judge the value of these and other interventions across the dementia care pathway.


Sliding movement of single actin filaments on one-headed myosin filaments.
The myosin molecule consists of two heads, each of which contains an enzymatic active site and an actin-binding site. The fundamental problem of whether the two heads function independently or cooperatively during muscle contraction has been studied by methods using an actomyosin thread, superprecipitation and chemical modification of muscle fibres. No clear conclusion has yet been reached. We have approached this question using an assay system in which sliding movements of fluorescently labelled single actin filaments along myosin filaments can be observed directly. Here, we report direct measurement of the sliding of single actin filaments along one-headed myosin filaments in which the density of heads was varied over a wide range. Our results show that cooperative interaction between the two heads of myosin is not essential for inducing the sliding movement of actin filaments.


Flicker-induced color and form: interdependencies and relation to stimulation frequency and phase.
Our understanding of human visual perception generally rests on the assumption that conscious visual states represent the interaction of spatial structures in the environment and our nervous system. This assumption is questioned by circumstances where conscious visual states can be triggered by external stimulation which is not primarily spatially defined. Here, subjective colors and forms are evoked by flickering light while the precise nature of those experiences varies over flicker frequency and phase. What's more, the occurrence of one subjective experience appears to be associated with the occurrence of others. While these data indicate that conscious visual experience may be evoked directly by particular variations in the flow of spatially unstructured light over time, it must be assumed that the systems responsible are essentially temporal in character and capable of representing a variety of visual forms and colors, coded in different frequencies or at different phases of the same processing rhythm.


Casticin induces caspase-mediated apoptosis via activation of mitochondrial pathway and upregulation of DR5 in human lung cancer cells.
To assess if casticin induces caspase-mediated apoptosis via activation of mitochondrial pathway and upregulation of DR5 in human lung cancer cells. Human non-small-cell lung carcinoma cell lines H460, A549 and H157 were cultured in vitro. The cytotoxic activities were determined using MTT assay. The apoptotic cells death was examined by flow cytometry using PI staining and DNA agarose gel electrophoresis. The activities of caspase-3, -8 and -9 were measured via ELISA. Cellular fractionation was determined by flow cytometry to assess release of cytochrome c and the mitochondrial transmembrane potential. Bcl-2/Bcl-XL/XIAP/Bid/DR5 and DR4 proteins were analyzed using western blot. The concentrations required for a 50% decrease in cell growth (IC(50)) ranged from 1.8 to 3.2 μM. Casticin induced rapid apoptosis and triggered a series of effects associated with apoptosis by way of mitochondrial pathway, including the depolarization of the mitochondrial membrane, release of cytochrome c from mitochondria, activation of procaspase-9 and -3, and increase of DNA fragments. Moreover, the pan caspase inhibitor zVAD-FMK and the caspase-3 inhibitor zDEVD-FMK suppressed casticin-induced apoptosis. In addition, casticin induced XIAP and Bcl-XL down-regulation, Bax upregulation and Bid clearage. In H157 cell line, casticin increased expression of DR5 at protein levels but not affect the expression of DR4. The pretreatment with DR5/Fc chimera protein effectively attenuated casticin-induced apoptosis in H157 cells. No correlation was found between cell sensitivity to casticin and that to p53 status, suggesting that casticin induce a p53-independent apoptosis. Our results demonstrate that casticin induces caspase-mediated apoptosis via activation of mitochondrial pathway and upregulation of DR5 in human lung cancer cells.


Expression of candidate plasticity-related gene 15 is increased following traumatic brain injury.
Candidate plasticity-related gene 15 (cpg15) is an activity-regulated gene that mediates synaptic plasticity; this study assesses the potential link between cpg15 expression levels and repair and regeneration following traumatic brain injury (TBI). We investigated the expression of cpg15 in the frontal lobe of rats subjected to TBI and sham rats, using the following methods: immunohistochemical analysis, Western blotting, and reverse transcription-polymerase chain reaction. CPG15(+) neurons were present in coronal sections of the frontal lobe at Day 1, reached the highest level around Day 14, and maintained elevated levels through Day 21. CPG15 protein and mRNA levels were noticed to increase in a similar temporal pattern. In contrast, rats in the sham group had undetectable levels of CPG15. Elevated cpg15 expression in the frontal cortex suggests its possible involvement in regenerative and reparative processes that follow TBI.


Chemistry and in vitro mutagenicity of 2-aminofluorene derivatives.
A study on the relationship between mutagenic activity and chemical reactivity of a series of 2-fluorenylamino and hydroxylamino derivatives has been carried out by assaying their ability to revert the Salmonella typhimurium strain TA98. The mutagenic potency of the fluorenamides increased with increasing availability of the amidic hydrogen for abstraction and tertiary amides were quite inactive. N-Hydroxy and N-acyloxy derivatives were directly mutagenic and increased their mutagenic activity after metabolic conversion by liver S9. N-Hydroxy-2-benzoylaminofluorene, inactive without S9, after activation was the most mutagenic. Of a pair of N-acyloxy-derivatives, N-benzoyloxy-2-acetylaminofluorene, which undergoes rearrangement of the benzoyloxy group from nitrogen to ring carbons even at room temperature, was less potent than N-acetyloxy-2-acetylamino-fluorene whose rearrangement occurs at higher temperatures. Corresponding C-1 and C-3 benzoyloxy and acetyloxy derivatives were found ineffective in this assay in agreement with previous reports on the hydroxy series. N-Chloro-2-amino-(or acetylamino)fluorene were found more active than the corresponding N-hydroxy analogs in the presence of S9, thus suggesting an alternate pathway for activation, likely a direct conversion to electrophilic species. Furthermore, in contrast with inactivity of ring hydroxy and acyloxy derivatives, 3-chloro-2-acetylaminofluorene retained mutagenic activity. Finally 2,2'-azoxyfluorene, the ultimated oxidation product of N-hydroxyaminofluorene, tested in vitro and in vivo experiments, was found completely inactive.


Immunologic work-up study for inner ear disorders: looking for a rational strategy.
For the evaluation of a patient with suspected immune-mediated inner ear disease (IMIED), an exhaustive immunologic work-up study is not recommended if financial resources are limited. Analysis of antinuclear antibodies (ANA) and the immunophenotype of peripheral blood lymphocytes (PBL) proved to be the most useful tests in our population to support the clinical diagnosis of IMIED. Owing to the lack of specific serological markers for the diagnosis of IMIED, an exhaustive immunologic work-up study for patients with suspected IMIED is usually performed. The aim of this study was to estimate the use of resources and the costs involved in the routine laboratory tests used for the diagnosis of IMIED. This was a comparative study of two groups of patients with a high suspicion of diverse clinical forms of IMIED who were subjected to different serologic test designs. The cost of the classical immunologic work-up study used for the diagnosis of IMIED (n=125) was estimated in comparison with that of a more restricted examination, based on a recently reported high-risk profile, involving the analysis of ANA and PBL (n=57). The diagnostic efficiency of the two protocols was similar. The cost of a complete immunologic work-up study was 241.77 euros and that of the limited analysis was 53.12 euros.


3D-MSCs A151 ODN-loaded exosomes are immunomodulatory and reveal a proteomic cargo that sustains wound resolution.
Non-healing wounds remain a major burden due to the lack of effective treatments. Mesenchymal stem cell-derived exosomes (MSC-Exo) have emerged as therapeutic options given their pro-regenerative and immunomodulatory features. Still, little is known on the exact mechanisms mediated by MSC-Exo. Importantly, modulation of their efficacy through 3D-physiologic cultures together with loading strategies continues underexplored. To uncover the MSC-Exo-mediated mechanism via proteomic analyses, and to use 3D-culture and loading technologies to expand MSC-Exo efficacy for cutaneous wound healing. MSC-Exo were produced in either 3D or 2D cultures (Exo3D/Exo2D) and loaded with an exogenous immunosuppressive oligodeoxynucleotide (A151 ODN). Both, loaded and naïve exosomes were characterised regarding size, morphology and the presence of specific protein markers; while IPA analyses enabled to correlate their protein content with the effects observed in vitro and in vivo. The Exo3D/Exo2D regenerative potential was evaluated in vitro by assessing keratinocyte and fibroblast mitogenicity, motogenicity, and cytokine secretion as well as using an in vivo wound splinting model. Accordingly, the modulation of inflammatory and immune responses by A151-loaded Exo3D/Exo2D was also assessed. Exo3D stimulated mitogenically and motogenically keratinocytes and fibroblasts in vitro, with upregulation of IL-1α and VEGF-α or increased secretion of TGF-β, TNF-α and IL-10. In vivo, Exo3D reduced the granulation tissue area and promoted complete re-epithelization of the wound. These observations were sustained by the proteomic profiling of the Exo3D cargo that identified wound healing-related proteins, such as TGF-β, ITGA1-3/5, IL-6, CDC151, S100A10 and Wnt5α. Moreover, when loaded with A151 ODN, Exo3D differentially mediated wound healing-related trophic factors reducing the systemic levels of IL-6 and TNF-α at the late stage of wound healing in vivo. Our results support the potential of A151-loaded Exo3D for the treatment of chronic wounds by promoting skin regeneration, while modulating the systemic levels of the pro-inflammatory cytokines.


Effects of neuromodulation on treatment of recurrent anal fissure: A systematic review.
Anal fissure is a linear tear in the distal anoderm most frequently occurring in the posterior midline. Lateral internal sphincterotomy is considered the gold standard for the treatment of this condition. To this date, several pharmacological and neuromodulatory therapies have been tried out as alternative non-invasive treatments for anal fissures, however, the efficacy of some of these methods remains to be understood. the primary aim of this study was to review available literature on neuromodulatory treatments for recurrent anal fissure as a potentially effective cure for this condition. A search was conducted among five main online databases Embase, PubMed, Web of Science, Scopus, and Scholar. All published human studies in English literature addressing neuromodulation for the treatment of recurrent anal fissure were selected. neuromodulation for the treatment of anal fissure. We chose to include all articles in which the authors stated that the procedure they performed was via neuromodulation technique, or that the described technique used in their study resembled the technique. Among a total of 3487 evaluated studies, seven represented the effects of neuro modulation on treatment of recurrent anal fissure, among which two were randomized controlled trials and the rest were prospective studies. A total of 186 patient were evaluated in these studies. The mean age of the participants was 46.97 ± 8.2. The average VAS score before intervention was 7.77 ± 2.13, which decreased to 0.31 ± 1.13 after intervention. limitations of this study include the lack of related articles, and data regarding this subject. Posterior tibial nerve stimulation (PTNS) provides rapid pain relief and fissure healing especially in short-to mid-terms with little to no complications, however, using this treatment, symptoms of anal fissure do not improve as well as LIS, especially in the long-term.


Molecular cloning of smg p21B and identification of smg p21 purified from bovine brain and human platelets as smg p21B.
We have previously purified smg p21 from bovine brain membranes and isolated its cDNA from a bovine brain cDNA library. In the present studies, we have performed extensive screening of the bovine brain cDNA library with the cloned smg p21 cDNA as a probe and isolated another cDNA encoding a protein highly homologous to smg p21. The proteins encoded by the previously and newly isolated cDNAs are designated as smg p21A and -B, respectively. Since the partial amino acid sequences determined previously from the smg p21 purified from bovine brain were identical with the common amino acid sequences between smg p21A and -B, we have further sequenced smg p21 and identified it as smg p21B. We have also further sequenced the smg p21 purified from human platelet membranes and identified it as smg p21B. Amino acid sequence analysis indicates that smg p21A is identical with the rap1A and Krev-1 proteins and smg p21B is identical with the rap1B protein.


Pan-cadherin as a high level phenotypic biomarker for prostate cancer.
High level phenotypic biomarkers such as cadherins are needed to identify individuals at risk for biologically active prostate cancer and determine which individuals with elevated prostate specific antigen or a prostate nodule are candidates for re-biopsy. Cadherins are a high level phenotypic biomarker associated with decreased cell adhesion, which is a cardinal event in carcinogenesis. Recently we reported that G-actin and tissue transglutaminase type II are potential biomarkers for prostate cancer. In this study we present cadherins as a potential third component of the biomarker profile. Prostate tissues from 38 patients with cancer and 33 controls with a 10-year prostate cancer-free followup were labeled for pan-cadherin by immunohistochemical testing. Immunoreactivity was quantified using a Pathology Workstation (Autocyte Inc., Elon College, North Carolina). Visually benign glands from controls generally expressed cadherins, whereas regions of adenocarcinoma were generally negative. On quantitative immunohistochemistry 36 of 38 prostate cancer cases expressed a lower mean percent area positive for cadherin than the 19 benign prostatic hyperplasia and 14 prostatitis cases (odds ratio 978, 95% confidence interval 45 to 21,140, relative risk 18, 95% confidence interval 5 to 67, p <0.0001). Receiver operating characteristics analysis of immunohistochemical testing data showed that an optimal threshold of 7 produced 95% sensitivity and 100% specificity. Quantitative down-regulation of cadherin expression in prostate cancer tissue sections is a strong biomarker for prostate cancer. Analysis of cadherin and other high level phenotypic biomarker expression in the premalignant field may provide additional diagnostic information to decide which patients need re-biopsy, more intensive monitoring or chemoprevention.