Caerulein stimulates pancreatic secretory response in conscious newborn rats.
The aim of our study was to measure age-dependent, caerulein-stimulated pancreatic enzyme secretion of conscious CFY suckling rats without pancreatic duct cannulation. Pancreatic secretory response was expressed as the decrease in specific enzyme (trypsin, amylase) activity compared to saline-injected control. The study was performed in three phases. In 10-d-old conscious newborn rats, single 1 and 3 micrograms/kg sc doses of caerulein induced significant decreases in specific trypsin (42 and 47%) and amylase (34 and 33%) activity 15 min after the caerulein injection; the same doses injected at 0 and 30 min evoked a similar decrease 90 min after the first injection. The 0.5 microgram/kg dose was ineffective. In 10-d-old anesthetized rats, the 90-min-decrease in total pancreatic trypsin activity, induced by graded doses (1,3,10, and 30 micrograms/kg) of caerulein, was compared to the 90-min output of trypsin in their bile-pancreatic juice. Each of the applied doses induced significant change in the total trypsin activity both in the pancreas (-33-57%) and juice (+21 +/- 49%) and its decrease in the gland corresponded quantitatively well (r = 0.52; p less than 0.01) to the increase in the simultaneous 90-min trypsin output. The age- and dose-dependent pancreatic response of 3-, 5-, 10-, and 20-d-old conscious rats was investigated under the effect of 1,3,10, and 30 micrograms/kg sc doses of caerulein injected at 0 and 30 min. In 3-d-old rats, the 10 and 30 micrograms/kg and in 20-d-old rats, the 1 and 3 micrograms/kg doses were effective, whereas in 5- and 10-d-old rats each caerulein dose applied evoked a significant decrease in pancreatic-specific trypsin activity. The pancreas of newborn rats is in vivo less sensitive to caerulein between postnatal d 3 and 10 than in already weaned rats.


Energy band structure of multistream quantum electron system.
In this paper, using the quantum multistream model, we develop a method to study the electronic band structure of plasmonic excitations in streaming electron gas with arbitrary degree of degeneracy. The multifluid quantum hydrodynamic model is used to obtain N-coupled pseudoforce differential equation system from which the energy band structure of plasmonic excitations is calculated. It is shown that inevitable appearance of energy bands separated by gaps can be due to discrete velocity filaments and their electrostatic mode coupling in the electron gas. Current model also provides an alternative description of collisionless damping and phase mixing, i.e., collective scattering phenomenon within the energy band gaps due to mode coupling between wave-like and particle-like oscillations. The quantum multistream model is further generalized to include virtual streams which is used to calculate the electronic band structure of one-dimensional plasmonic crystals. It is remarked that, unlike the empty lattice approximation in free electron model, energy band gaps exist in plasmon excitations due to the collective electrostatic interactions between electrons. It is also shown that the plasmonic band gap size at first Brillouin zone boundary maximizes at the reciprocal lattice vector, G, close to metallic densities. Furthermore, the electron-lattice binding and electron-phonon coupling strength effects on the electronic band structure are discussed. It is remarked that inevitable formation of energy band structure is a general characteristics of various electromagnetically and gravitationally coupled quantum multistream systems.


Ultrastructural features of Borrelia garinii in naturally infected voles, Clethrionomys rufocanus, with special reference to the relationship with peripheral nerves.
The ultrastructural features of Borrelia garinii found in the ear tissues of the vole, Clethrionomys rufocanus, are described. The spirochetes were observed in the interstitium of connective tissue or in contact with fibroblasts and were occasionally situated in the endoneurium of the peripheral nerves. The spirochetes did not injure or enter into the fibroblasts or Schwann cells. The cytotoxicity and migration of the spirochetes are also discussed.


Changes in services for students with learning disabilities in U.S. and Canadian medical schools, 1991 to 1997.
To determine the changes between 1991 and 1997 in the admission policies of and services offered by U.S. and Canadian medical schools to students with learning disabilities. Between June 1 and August 31, 1997, the author surveyed 144 medical schools in the United States and Canada regarding their services and programs for learning-disabled medical students. The questionnaire was the same one as used in a 1991 study. Of the medical schools contacted, 106 responded (one Canadian school sent a letter but did not complete the questionnaire). Ninety-four of 96 U.S. schools and seven of the remaining nine Canadian schools said that they accept students with learning disabilities. All of the respondents that accept such students claimed to make some academic accommodations. Most indicated that they would administer non-standard (e.g., untimed) licensing examinations, and many reported that their affiliated postgraduate medical training programs would also make appropriate accommodations for students with learning disabilities. When compared with the results from the 1991 survey, the new data suggest that medical schools have improved their services for learning-disabled students in response to the Americans with Disabilities Act.


Sex differences in the uptake of orthodontic services among adolescents in the United States.
The purpose of this study was to test whether girls are treated orthodontically for milder occlusal issues than are boys, thus accounting for the greater uptake of orthodontic services among girls compared with boys. The dental aesthetic index (DAI) was used to score the severity of esthetic occlusal issues in 357 white adolescents. Half of the subjects were from private practices; the others were from a university specialty clinic. Average DAI scores were statistically significantly lower (milder) in girls than boys in both venues; this confirms the assumption that the actual uptake of services is greater in girls because of heightened concern for their esthetic occlusal issues. Average DAI scores predictably were higher in the teaching setting because of selection for more complex cases, but the sex difference was still evident statistically. There was no association between DAI score and age at the start of treatment among these adolescents. Spacing and incisor irregularity showed the greatest sex differences among the DAI variables, possibly because girls are more attuned to these esthetic issues. These results complement studies that have recorded adolescents' perceptions of orthodontic need. The actual uptake of orthodontic treatment is greater in girls because they (and their parents) seek treatment for milder occlusal issues.


A continuum for using placebo interventions in regional anesthesia and analgesia studies.
The anesthesiologist Henry K. Beecher is commonly associated with his crusade for informed consent for research. Less recognized is his contribution to the development of principles of randomized controlled trials through his emphasis on surgery as placebo to minimize bias. This article reviews Beecher's contribution and how it should be applied to modern studies of perioperative analgesia.


Effects of amino-terminus truncation in human cytochrome P450IID6 on its insertion into the endoplasmic reticulum membrane of Saccharomyces cerevisiae.
A truncated form of cytochrome P450IID6 deprived of 22 NH2-terminal amino acids residues (P450IID6 delta 1-22) was found in both the cytosol and the microsomal fraction of the yeast, Saccharomyces cerevisiae. A reduced CO difference spectrum of this form was characterized by the absence of absorption at 448 nm and weak absorption at 420 nm. Another peculiarity of P450IID6 delta 1-22 expression was its reduced content in the yeast cells compared to that of P450IID6, with the intracellular levels of the corresponding mRNAs being the same. We suggest that the deleted form of P450IID6, i.e. lacking 22 NH2-terminal amino acid residues, is not inserted properly in the endoplasmic reticulum membrane: it does not take up the proper conformation to enable normal heme binding and is degraded in the yeast cells.


Effects of dichlorvos (DDVP) inhalation on the activity of acetylcholinesterase in the bronchial tissue of rats.
The experiments presented here deal with the effects of the inhalation of dichlorvos [dimethyl-(2,2 dichlorvinyl)-phosphate, DDVP] vapor on acetylcholinesterase (ACHE) activity in rat bronchial tissue. Exposure to DDVP concentrations of 0.8 and 1.8 micrograms/l for 3 days reduced ACHE activity in the bronchial tissue (62.8 +/- 0.8 and 51.6 +/- 1.6% of the control), but did not elicit any changes in blood ACHE activity (101 +/- 4.5% of the control each). Higher concentrations (4.3 micrograms/l) induced a decline in ACHE activity also in the blood (38.2 +/- 1.1% of the control). In the histochemical preparations used to demonstrate ACHE activity in bronchial tissue (thiolacetic acid method), a staining of the bronchial glands and smooth muscles characteristic of the enzyme activity was strongly reduced after exposure of the animals to even the lowest dose applied (0.2 microgram/l). The question of whether localized inhibition of ACHE in the bronchial tissue might cause increases in airway resistance due to activation of a broncho-bronchial reflex is discussed. This efferent cholinergic mechanism has been found to be at least partly responsible for maintenance of bronchospasm and hypersecretion in chronic obstructive diseases of the respiratory system.


Expectations of survivors towards disaster nurses in Indonesia: A qualitative study.
This study aims to explore the expectations of survivors towards disaster nurses. The study used qualitative content analysis. Data were collected in 2017 through three focus group discussions with 21 survivors and in-depth interviews with three community leaders; the respondents had experienced one of the following events: a) an earthquake in Padang 2009, b) a volcanic eruption in Yogyakarta 2010, and c) flooding in Jakarta 2014. Four themes represented survivors' expectations of what nurses can do in responding to a disaster, including: a) provision of direct nursing care, b) provision of information of health service access, c) provision of resources through cross-sector coordination, and d) disaster preparedness activities for the community. This study suggests the importance of disaster nurses having the competency to update information regarding healthcare access, particularly the utilization of health insurance and providing culturally competent care to the survivors. Disaster nurses are also expected to be able to train the community and families about preparedness-related activities. Besides, these disaster nurses should improve their competency in disaster risk reduction. More broadly, such nurses should have the ability to advocate and coordinate with the local government and other stakeholders regarding access to healthcare services and continuous rapid assessment, so that survivors receive immediate and appropriate treatment.


Fruits of Tetrapterys (Malpighiaceae) from the Oligocene of Hungary and Slovenia.
Propeller-like winged fruits of Tetrapterys harpyiarum Unger from the Oligocene of Sotzka, Budapest, Eger-Vécsey valley, and a new occurrence at Eger-Kiseged, were reinvestigated and compared in detail with extant species of Tetrapterys (Malpighiaceae) and with other dicotyledonous genera with four winged fruits. T. harpyiarum fruits are bilaterally symmetrical, consisting of a globose nut surrounded by four elongate wings with parallel venation. Tetrapterys is now distributed only in tropical America and this implies that there was an opportunity for Tetrapterys to spread between the Partethys region and the New World during the Tertiary.


Association between coffee consumption and risk of hypertension.
The longitudinal relationship between coffee use and hypertension is not well known. Aim. We did a prospective study to investigate if there is a temporal relationship between coffee consumption and development of sustained hypertension. We assessed 1107 white subjects with elevated blood pressure who were followed up for 6.4 years. Coffee intake and other life-style factors were ascertained from regularly administered questionnaires. Incident physician-diagnosed hypertension was the outcome measure. During the follow-up, 561 subjects developed sustained hypertension, whereas 546 subjects did not meet the criteria for treatment. Coffee drinkers developed sustained hypertension more frequently than abstainers (53.1% versus 43.9%, P = 0.007). The incidence of hypertension did not differ between moderate and heavy coffee drinkers. Kaplan-Meier analysis confirmed that sustained hypertension was developed more frequently by coffee drinkers compared with nondrinkers (P<0.001). The adjusted relative risk of hypertension was greater in both categories of coffee drinking than in abstainers (hazard ratio, 95% confidence limit (CL) = 1.24, 1.06-1.44). The risk of hypertension associated with coffee drinking increased gradually with increasing level of alcohol use (adjusted P for interaction = 0.005). In subjects screened for stage 1 hypertension a nonlinear association was found between coffee consumption and development of sustained hypertension.


A phase response curve for circannual rhythm in the varied carpet beetle Anthrenus verbasci.
We know that entrainment, a stable phase relationship with an environmental cycle, must be established for a biological clock to function properly. Phase response curves (PRCs), which are plots of phase shifts that result as a function of the phase of a stimulus, have been created to examine the mode of entrainment. In circadian rhythms, single-light pulse PRCs have been obtained by giving a light pulse to various phases of a free-running rhythm under continuous darkness. This successfully explains the entrainment to light-dark cycles. Some organisms show circannual rhythms. In some of these, changes in photoperiod entrain the circannual rhythms. However, no single-pulse PRCs have been created. Here we show the PRC to a long-day pulse superimposed for 4 weeks over constant short days in the circannual pupation rhythm in the varied carpet beetle Anthrenus verbasci. Because the shape of that PRC closely resembles that of the Type 0 PRC with large phase shifts in circadian rhythms, we suggest that an oscillator having a common feature in the phase response with the circadian clock, produces a circannual rhythm.


Case report: two novel VPS13B mutations in a Chinese family with Cohen syndrome and hyperlinear palms.
Cohen syndrome (CS) is an uncommon developmental disease with evident clinical heterogeneity. VPS13B is the only gene responsible for CS. Only few sporadic cases of CS have been reported in China. A Chinese family with two offspring-patients affected by developmental delay and intellectual disability was investigated in this study. Exome sequencing was performed, and compound heterozygous mutations in VPS13B were segregated for family members with autosomal recessive disorder. Splicing mutation c.3666 + 1G > T (exon 24) and nonsense mutation c. 9844 A > T:p.K3282X (exon 54) were novel. We revisited the family and learned that both patients are affected by microcephaly, developmental delay, neutropenia, and myopia and have a friendly disposition, all of which are consistent with CS phenotypes. We also found that both patients have hyperlinear palms, which their parents do not have. VPS13B mutations reported among the Chinese population were reviewed accordingly. This study presents two novel VPS13B mutations in CS. The identification of hyperlinear palms in a family affected by CS expands the phenotype spectrum of CS.


Discovery of quinazoline HPK1 inhibitors with high cellular potency.
Hematopoietic progenitor kinase 1 (HPK1) is regarded as a highly validated target in pre-clinical immune oncology. HPK1 has been described as regulating multiple critical signaling pathway in both adaptive and innate cells. In support of this role, HPK1 KO T cells show enhanced sensitivity to TCR activation and HPK1 KO mice display enhanced anti-tumor activity. Taken together, inhibition of HPK1 has the potential to induce enhanced anti-tumor immune response. Herein, we described the discovery of highly potent HPK1 inhibitors starting form a weak HTS hit. Using a structure-based drug design, HPK1 inhibitors exhibiting excellent cellular single-digit nanomolar potency in both proximal (pSLP76) and distal (IL-2) biomarkers along with sustained elevation of IL-2 cytokine secretion were discovered.


Computed tomography imaging for subclinical leaflet thrombosis following surgical and transcatheter aortic valve replacement.
Subclinical leaflet thrombosis (LT) may occur following surgical and transcatheter aortic valve replacement. Computed tomography (CT) has become an established imaging modality to diagnose subclinical LT following bioprosthetic aortic valve replacement. Even so, there is a limited (but growing) experience in utilizing CT imaging for this indication. This review emphasizes a systematic approach to acquiring and analysing CT imaging for subclinical LT, highlighting evidence surrounding clinical sequelae of subclinical LT and anti-thrombotic implications following diagnosis.


Aeromonas veronii cellulitis, bacteremia, and sepsis in a patient with liver cirrhosis and end-stage renal disease following a minor abrasion with exposure to pond water: A case report and literature review.
Aeromonads are a well-known cause of gastrointestinal illness in humans; however, extra-intestinal infections due to Aeromonas spp. have been increasingly reported. Severe infection and septic shock due to Aeromonas spp. is rare, though the risk is greater for immunocompromised individuals. Patients with liver cirrhosis have been noted to be at especially high risk for severe infection due to Aeromonas spp. Several cases of septicemia due to A. hydrophila have been reported in the literature. We report a rare case of A. veronii septicemia in a patient with known liver cirrhosis and end-stage renal disease following a minor abrasion with exposure to pond water. The patient's history fostered clinical suspicion of Aeromonas infection and tailored early diagnosis and treatment.


An area function method for calculating the apparent elimination rate constant of a metabolite.
A simple method for determination of the apparent elimination rate constant of a metabolite (km) has been developed. This procedure requires calculation of area intervals under the plasma concentration-time curves of the parent drug and its derived metabolite. The method has been evaluated and compared with the Chan moment method using both errorless and errant data. The approach is accurate for various ratios of elimination rate constants of drug and metabolite, allows several values of km to be averaged, but works best using data prior to the metabolite tmax.


Zinc, the pancreas, and diabetes: insights from rodent studies and future directions.
Molecular and cellular studies have demonstrated several roles for zinc (Zn) in insulin production and the consequent actions of insulin on metabolism. Clinical and epidemiological studies suggest that reduced Zn status is associated with diabetes. Investigations of Zn in rodent models of diabetes have provided a valuable link for understanding the molecular, cellular, clinical and epidemiological observations in the context of inter-organ metabolism and the metabolic disturbances of diabetes. This review highlights some of the current knowledge and future research directions for the role of Zn in the pancreas and diabetes based on rodent studies and experimental manipulations of Zn. Overall, Zn supplementation is effective for preventing or ameliorating diabetes in several rodent models of Type 1 and Type 2 diabetes. Studies with chemically-induced Type 1 diabetes indicate that the protective effects of Zn involve antioxidant mechanisms whether it is Zn alone (as an antioxidant), Zn induction of metallothionein or Zn inhibition of redox-sensitive transcription factors. Further studies are needed to identify the mechanism(s) for Zn protection in Type 2 diabetes, including pancreatic and peripheral effects. Experimental manipulations of Zn status in rodent models of diabetes provide a valuable approach to explore mechanisms for the protective effects of Zn; however, long term clinical studies establishing safety (lack of toxicity) and efficacy are required before any recommendations can be made for people with diabetes.


VATS pericardiotomy for patients with known malignancy and pericardial effusion: survival and prognosis of positive cytology and metastatic involvement of the pericardium: a case control study.
Pericardiotomy for cancer patients with effusion can alleviate symptoms, but with unclear effect on long term survival. Our experience with VATS technique has produced some long-term survivors. A retrospective review of 62 VATS pericardiotomy for pericardial effusion in patients with known malignancy. Kaplan-Meier survival curves and Log-Rank tests were used for analysis. The mean age was 54.8+/-14.3 years (ranging from 19 to 79). The mean hospital stay was 8.7+/-5.5 days. The median survival was 6.75 months (range 1 month-10 years). Overall one-year survival was 44.2%, 3-year survival 17.6%, and 5-year survival 10% after drainage of pericardial effusion. The mean survival in cytology negative patients (n=21) was 13.4+/-0.98 months, compared to 4.89+/-0.9 months in cytology positive patients (n=27) (p=0.0175). The 5-year survival in cytology negative patients was 19.6%, while none of the patients with positive cytology were alive after 36 months. The mean survival in patients with no evidence of metastatic disease on the pericardium (n=28) was 12.8+/-0.9 months, compared to patients with metastatic disease of the pericardium (n=22) 4.66+/-0.8 months (p=0.026). VATS Pericardiotomy can provide effective long-term drainage in patients with symptomatic pericardial effusion. Positive cytology and metastatic involvement of the pericardium are predictive of worse survival. Survival greater than 5 years can be expected in 19% and 17% of patients with negative fluid cytology and negative metastatic disease of the pericardium, respectively.


Metabotropic glutamate receptor 5 knockout rescues obesity phenotype in a mouse model of Huntington's disease.
Obesity represents a global health problem and is characterized by metabolic dysfunctions and a low-grade chronic inflammatory state, which can increase the risk of comorbidities, such as atherosclerosis, diabetes and insulin resistance. Here we tested the hypothesis that the genetic deletion of metabotropic glutamate receptor 5 (mGluR5) may rescue metabolic and inflammatory features present in BACHD mice, a mouse model of Huntington's disease (HD) with an obese phenotype. For that, we crossed BACHD and mGluR5 knockout mice (mGluR5-/-) in order to obtain the following groups: Wild type (WT), mGluR5-/-, BACHD and BACHD/mGluR5-/- (double mutant mice). Our results showed that the double mutant mice present decreased body weight as compared to BACHD mice in all tested ages and reduced visceral adiposity as compared to BACHD at 6 months of age. Additionally, 12-month-old double mutant mice present increased adipose tissue levels of adiponectin, decreased leptin levels, and increased IL-10/TNF ratio as compared to BACHD mice. Taken together, our preliminary data propose that the absence of mGluR5 reduce weight gain and visceral adiposity in BACHD mice, along with a decrease in the inflammatory state in the visceral adipose tissue (VAT), which may indicate that mGluR5 may play a role in adiposity modulation.


[Protecting mice from fatal Bordetella bronchiseptica infection by immunization with recombinant pertactin antigens].
We evaluated the efficacy of the recombinant pertactin (PRN)-specific active or passive immunization against Bordetella bronchiseptica (Bb) in an aerosol challenge model established by using BALB/c mice. Mice, immunized subcutaneously with two doses of purified glutathione S-transferase (GST)-PRN protein mixed with an equal volume of Freund's adjuvant, produced robust PRN-specific IgG antibody activity. All 20 mice vaccinated with GST-PRN protein survived aerosol challenge with three times the 50% lethal dose (LD50) of virulent Bb HH0809 compared with 3 of 20 GST protein-treated controls and 4 of 20 PBS-treated controls that survived. Furthermore, we observed complete protection against intraperitoneal challenge with ten times the LD50 of virulent HH0809 strain in mice that were injected intraperitoneally with 0.5 ml rabbit anti-GST-PRN serum. No survivors were observed in mice that received either rabbit anti-GST serum or PBS alone. The recombinant PRN protein had strong immunogenicity against Bb infection.


Perception of eye contact, self-referential thinking and age.
Increased thinking about one's self has been proposed to widen the gaze cone, that is, the range of gaze deviations that an observer judges as looking directly at them (eye contact). This study investigated the effects of a self-referential thinking manipulation and demographic factors on the gaze cone. In a preregistered experiment (N = 200), the self-referential thinking manipulation, as compared to a control manipulation, did not influence the gaze cone, or the use of first-person pronouns in a manipulation check measuring self-referential processing. This may indicate a failure of the manipulation and participants' lack of effort. However, participants' age was significantly correlated with both measures: older people had wider gaze cones and used more self-referring pronouns. A second experiment (N = 300) further examined the effect of the manipulation and demographic factors on self-referential processing, and the results were replicated. These findings may reflect age-related self-reference and positivity effects.


Cytotoxic-induced ovarian failure in Hodgkin's disease. II. Effects on sexual function.
Chemotheraphy for Hodgkin's disease produces ovarian failure in young women. The consequences of this are emotional distress, sexual dysfunction, and the disruption of families and friendships. These previously unappreciated side effects of cytotoxic therapy had developed in 25 of 41 patients, among whom we conducted a retrospective study.


Two monoclonal antibodies to two different epitopes of human growth hormone form a precipitin line when counterdiffused as soluble immune complexes.
We have tested whether soluble immune complexes obtained by mixing human growth hormone (hGH) with one anti-hGH monoclonal antibody (MAb) can form a precipitin line when diffused against another MAb in a polyethylene glycol containing gel. By testing seven anti-hGH MAbs one against the other in this assay, we have found that 10 pairs of MAbs out of the 21 possible combinations formed a line. Apparently, the first MAb formed soluble hGH dimers that were linked by the second MAb into precipitating linear complexes. Since each precipitin line was formed by the cooperative reaction of two MAbs, this sequential reaction of MAbs may be used in methods for the positive selection of MAbs that are suitable for two-site immunoassays.


Enhanced reducing equivalent generation for 1,3-propanediol production through cofermentation of glycerol and xylose by Klebsiella pneumoniae.
1,3-Propanediol (1,3-PD) biosynthesis plays a key role in NADH consumption to regulate the intracellular reducing equivalent balance of Klebsiella pneumoniae. This study aimed to increase reducing equivalent for enhancing 1,3-PD production through cofermentation of glycerol and xylose. Adding xylose as cosubstrate resulted in more reducing equivalent generation and higher cell growth. In batch fermentation under microaerobic condition, the 1,3-PD concentration, conversion from glycerol, and biomass (OD(600)) relative to cofermentation were increased significantly by 9.1%, 20%, and 15.8%, respectively. The reducing equivalent (NADH) was increased by 1-3 mg/g (cell dry weight) compared with that from glycerol alone. Furthermore, 2,3-butannediol was also doubly produced as major byproduct. In fed-batch fermentation with xylose as cosubstrate, the final 1,3-PD concentration, conversion from glycerol, and productivity were improved evidently from 60.78 to 67.21 g/l, 0.52 to 0.63 mol/mol, and 1.64 to 1.82 g/l/h, respectively.


Fluence to local skin absorbed dose and dose equivalent conversion coefficients for monoenergetic positrons using Monte-Carlo code MCNP6.
Conversion coefficients fluence to local skin equivalent dose, as introduced in ICRP Publication 116, 2010, are calculated for positrons of energies ranging from 10 keV to 10 MeV using the code MCNP6. Fluence to dose equivalent conversion coefficients H'(0.07,0°)/Φ are calculated for positrons of energy ranging between 20 keV and 10 MeV. A comparison between operational dose quantity H'(0.07,0°) and the Local-Skin equivalent Dose shows an overall good agreement between these two quantities, except between 60 keV and 100 keV.


Long-term toxicity assessment of soils in a recovered area affected by a mining spill.
Residual pollution in the Guadiamar Green Corridor still remains after Aználcollar mine spill in 1998. The polluted areas are identified by the absence of vegetation, soil acidic pH and high concentrations of As, Pb, Zn and Cu. Soil toxicity was assessed by lettuce root elongation and induced soil respiration bioassays. In bare soils, total As and Pb concentrations and water-extractable levels for As, Zn and Cu exceeded the toxicity guidelines. Pollutants responsible for toxicity were different depending on the tested organism, with arsenic being most toxic for lettuce and the metal mixture to soil respiration. Soil properties, such as pH or organic carbon content, are key factors to control metal availability and toxicity in the area. According to our results, there is a risk of pollution to living organisms and the soil quality criteria established in the area should be revised to reduce the risk of toxicity.


Unilateral Embolization of the Internal Iliac Artery for Endovascular Aortic Repair Does Not Induce Gluteal Muscle Atrophy.
To investigate the effect of unilateral internal iliac artery (IIA) embolization for endovascular aortic repair (EVAR) on gluteal muscle size. We assessed the gluteal muscle size in 111 consecutive patients who underwent elective EVAR with unilateral IIA embolization (n = 31) or without IIA embolization (n = 80) for abdominal aortic and/or iliac artery aneurysm. The cross-sectional area (CSA) of the gluteus maximus (Gmax) and gluteus medius/minimus (Gmed/min) was measured on computed tomography preoperatively, 6 months postoperatively, and final follow-up. Mean changes in the Gmax and Gmed/min CSA were evaluated using a mixed model analysis of variance. In the patients with embolization, both the Gmax and Gmed/min CSA significantly decreased over time on the embolization and nonembolization sides (P < 0.001); however, embolization did not affect the changes in the Gmax CSA (P = 0.64) and Gmed/min CSA (P = 0.99). In the patients with embolization and those without embolization, both the Gmax and Gmed/min CSA significantly decreased over time (P < 0.001); however, embolization did not affect the changes in the Gmax CSA (P = 0.76) and Gmed/min CSA (P = 0.11). Unilateral IIA embolization was not associated with gluteal muscle atrophy after EVAR. Pre-emptive unilateral IIA embolization for EVAR seems to be an acceptable procedure in terms of maintenance of gluteal muscle size.


Clinical implication of tissue carcinoembryonic antigen expression in association with serum carcinoembryonic antigen in colorectal cancer.
This study aimed to evaluate the prognostic significance of carcinoembryonic antigen (CEA) expression in tumor tissues of patients with colorectal cancer (CRC). The cohort included 7,412 patients with CRC from January 2010 to December 2015. Survival outcomes were assessed based on tissue CEA (t-CEA) patterns and intensities. Three-year (76.7% versus 81.3%) and 5-year (71.7% versus 77.6%, p < 0.001) disease-free survival (DFS) rates were significantly (p < 0.001) poorer in patients with a diffuse-cytoplasmic pattern than an apicoluminal pattern. Three-year (79% versus 86.6%) and 5-year (74.6% versus 84.7%) DFS rates were also significantly (p < 0.001) poorer in patients with high than low t-CEA intensity. Three-year (84.6% versus 88.4%) and 5-year (77.3% versus 82.6%) overall survival (OS) rates were significantly (p < 0.001) poorer in patients with diffuse-cytoplasmic than apicoluminal pattern of CEA expression, and both 3-year (86.7% versus 91.2%) and 5-year (80.1% versus 87.7%) OS rates were significantly (p < 0.001) poorer in patients with high than low t-CEA intensity. Multivariate analyses showed that high-intensity t-CEA was independently associated with DFS (p = 0.02; hazard ratio [HR] = 1.233) and OS (p = 0.032; HR = 1.228). Therefore, high-intensity t-CEA is a significant prognostic factor in CRC, independent of serum CEA (s-CEA), and can complement s-CEA in predicting survival outcomes after CRC resection.


Long-term survival of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis as isolates and in nasopharyngeal specimens in frozen STGG storage medium.
We evaluated survival in WHO-recommended STGG storage medium of bacteria causing respiratory-tract infection. Streptococcus pneumoniae and Moraxella catarrhalis survived as single and mixed isolates stored at -70°C for 12.5 years, but Haemophilus influenzae less than 4 years. All the bacteria survived in the nasopharyngeal specimens at -70°C for 11 years.


To what extent do community members' personal health beliefs and experiences impact what they consider to be important for their community-at-large?
Health assessments are used to prioritize community-level health concerns, but the role of individuals' health concerns and experiences is unknown. We sought to understand to what extent community health assessments reflect health concerns of the community-at-large versus a representation of the participants sampled. We conducted a health assessment survey in 30 rural African American churches (n = 412). Multivariable logistic regression produced odds ratios examining associations between personal health concern (this health concern is important to me), personal health experience (I have been diagnosed with this health issue) and community health priorities (this health concern is important to the community) for 20 health issues. Respondents reported significant associations for 19/20 health conditions between personal health concern and the ranking of that concern as a community priority (all P < 0.05). Inconsistent associations were seen between personal health experience of a specific health condition and the ranking of that condition as a community priority. Personal health concerns reported by individuals in a study sample may impact prioritization of community health initiatives. Further research should examine how personal health concerns are formed.


Ru(II)-Catalyzed Chemoselective C(sp3)-H Monoarylation of 8-Methyl Quinolines with Arylboronic Acids.
The transition-metal-promoted C-H activation has become an efficient as well as atom-economic methodology for the synthesis of a wide array of organic molecules, but the cost of the metal catalyst and selectivity remain the major challenges. Herein, the first [Cl2Ru(p-cymene)]2-catalyzed direct monoarylation of unactivated C(sp3)-H bonds of 8-methyl quinolines with arylboronic acids to synthesize diarylmethane compounds is presented. The transformation shows a broad substrate scope with high chemoselectivity for the synthesis of 8-benzyl quinolines. In the preliminary mechanistic studies, control experiments, deuterium labeling experiments, and kinetic studies have been performed.


PUF60 promotes glioblastoma progression through regulation of EGFR stability.
PUF60 (Poly (U) binding splicing factor 60 kDa), a nucleic acid-binding protein, has been shown to regulate transcription and links to tumorigenesis in various cancers. However, its biological role and function in glioblastoma remain unknown. In this study, we found that PUF60 is highly expressed in glioblastoma and correlated with poor prognosis. Furthermore, PUF60 knockdown significantly decreased the proliferation of glioblastoma cells in vitro and in vivo. Mechanistically, PUF60 could reduce the ubiquitination level of EGFR by transcriptionally regulating STUB1, an E3 ubiquitin ligase of EGFR, which lead to the activation of the EGFR-AKT pathway. Collectively, our study reveals the oncogenic role of PUF60 in glioblastoma and provides a potential therapeutic target for glioblastoma treatment.


New optical paper sensor for in situ measurement of hydrogen sulphide in waters and atmospheres.
A novel and low-cost colorimetric sensor for the determination of hydrogen sulphide in environmental samples has been developed. This sensor is based on the immobilization of the reagent N,N-Dimethyl-p-phenylenediamine and FeCl3 in paper support, in which the H2S is adsorbed in order to give rise to the formation of methylene blue as reaction product. The sensor has been applied to determine H2S in water and air samples. Two different sampling systems for H2S caption from the air have been assayed: active and passive sampling. The analytical properties of the different systems have been obtained and compared. The analytical signals, corresponding to the methylene blue, have been obtained measuring the absorbance by conventional reflectance diffuse or using different algorithms for quantifying color intensity. The results obtained with both measurement procedures were comparable, with a detection limit of 1.11 and 1.12mLm(-3) for air samples (active and passive), and 0.5mgL(-1) for water samples. The developed sensor provides good accuracy and precision (RSD<12%) and simplifies significantly the analytical measurements because it avoids the need of preparing derivatization reagents, sample handling and allows in situ measurements. The reaction product obtained is highly stable in this support and no provide any blank signal. Under the optimal conditions, the proposed method exhibit excellent visual sensitivity for the naked eye procedure, making the detection of H2S possible.


Posterior atlantoaxial internal fixation using Harms technique assisted by 3D-based navigation robot for treatment of atlantoaxial instability.
To evaluate the accuracy of screw placement using the TiRobot surgical robot in the Harms procedure and to assess the clinical outcomes of this technique. This retrospective study included 21 patients with atlantoaxial instability treated by posterior atlantoaxial internal fixation (Harms procedure) using the TiRobot surgical robot between March 2016 and June 2021. The precision of screw placement, perioperative parameters and clinical outcomes were recorded. Screw placement was assessed based on intraoperative guiding pin accuracy measurements on intraoperative C-arm cone-beam computed tomography (CT) images using overlay technology and the incidence of screw encroachment identified on CT images. Among the 21 patients, the mean age was 44.8 years, and the causes of atlantoaxial instability were os odontoideum (n = 11), rheumatoid arthritis (n = 2), unknown pathogenesis (n = 3), and type II odontoid fracture (n = 5). A total of 82 screws were inserted with robotic assistance. From intraoperative guiding pin accuracy measurements, the average translational and angular deviations were 1.52 ± 0.35 mm (range 1.14-2.25 mm) and 2.25° ± 0.45° (range 1.73°-3.20º), respectively. Screw placement was graded as A for 80.5% of screws, B for 15.9%, and C for 3.7%. No complications related to screw misplacement were observed. After the 1-year follow-up, all patients with a neurological deficit experienced neurological improvement based on Nurick Myelopathy Scale scores, and all patients with preoperative neck pain reported improvement based on Visual Analog Scale scores. Posterior atlantoaxial internal fixation using the Harms technique assisted by a 3D-based navigation robot is safe, accurate, and effective for treating atlantoaxial instability.


Negative impact of computed tomography-based low skeletal muscle mass on swallowing recovery in patients with post-stroke dysphagia.
Dysphagia due to stroke has a high prevalence, and evaluating the swallowing function of dysphagia and promoting oral intake is essential in patients with stroke. The psoas muscle mass index(cm2/height2(m2)), calculated by the psoas muscle area at the L3 level via abdominal computed tomography (CT), can predict the development of dysphagia. However, knowledge about the impact of CT-based skeletal muscle mass on swallowing recovery, remains unknown. Therefore, we investigated whether CT-based low skeletal muscle mass impacted swallowing recovery. A retrospective cohort study was conducted on patients with post-stroke dysphagia who underwent acute treatments along with a videofluoroscopic swallowing study(VFSS). Swallowing recovery was identified as the improvement of the Functional Oral Intake Scale (FOIS) from the time of VFSS to discharge(observational period: ObPd). The psoas muscle mass index's cut-off values for low skeletal muscle mass were 3.74 cm2/m2 and 2.29 cm2/m2 for men and women respectively. There were 53 subjects (36 male, median age 73.9). The median during the ObPd was 26 days, and the median days from onset to admission and admission to VFSS were 0 and 18, respectively. Sixteen patients had low skeletal muscle mass. The median improvement of FOIS during the ObPd was 2, and the median length of hospital stay was 51 days. In the stepwise multiple linear regression analysis for the improvement of FOIS during the ObPd, low skeletal muscle mass (β - 0.245; 95% confidence interval - 2.248 to - 0.127; p = 0.029) was a significant factor, even adjusted for serum albumin at admission, disturbance of consciousness at VFSS, FOIS at VFSS, and aspiration during VFSS. CT-based low skeletal muscle mass negatively impacted swallowing recovery during the ObPd in patients with post-stroke dysphagia.


Somatic mutations in facial skin from countries of contrasting skin cancer risk.
The incidence of keratinocyte cancer (basal cell and squamous cell carcinomas of the skin) is 17-fold lower in Singapore than the UK1-3, despite Singapore receiving 2-3 times more ultraviolet (UV) radiation4,5. Aging skin contains somatic mutant clones from which such cancers develop6,7. We hypothesized that differences in keratinocyte cancer incidence may be reflected in the normal skin mutational landscape. Here we show that, compared to Singapore, aging facial skin from populations in the UK has a fourfold greater mutational burden, a predominant UV mutational signature, increased copy number aberrations and increased mutant TP53 selection. These features are shared by keratinocyte cancers from high-incidence and low-incidence populations8-13. In Singaporean skin, most mutations result from cell-intrinsic processes; mutant NOTCH1 and NOTCH2 are more strongly selected than in the UK. Aging skin in a high-incidence country has multiple features convergent with cancer that are not found in a low-risk country. These differences may reflect germline variation in UV-protective genes.


Medications for attention-deficit/hyperactivity disorder in individuals with or without coexisting autism spectrum disorder: analysis of data from the Swedish prescribed drug register.
Clinical studies found that medication for attention-deficit/hyperactivity disorder (ADHD) is effective in coexisting autism spectrum disorder (ASD), but current research is based on small clinical studies mainly performed on children or adolescents. We here use register data to examine if individuals with ADHD and coexisting ASD present differences in the prescribing patterns of ADHD medication when compared to individuals with pure ADHD. Data with information on filled prescriptions and diagnoses was retrieved from the Swedish Prescribed Drug Register and the National Patient Register. We identified 34,374 individuals with pure ADHD and 5012 individuals with ADHD and coexisting ASD, aged between 3 and 80 years. The first treatment episode with ADHD medications (≥ 2 filled prescriptions within 90 days) and daily doses of methylphenidate during a 3-year period was measured. Odds ratios (ORs) were calculated for the likelihood of being prescribed ADHD medication in individuals with and without ASD and Wilcoxon rank-sum test was used to compare group differences in dose per day. Individuals with ADHD and coexisting ASD were less likely to start continuous treatment with ADHD medication (ADHD 80.5%; ADHD with ASD 76.2%; OR, 0.80; 95% confidence interval, 0.75-0.86), were less likely to be prescribed methylphenidate, and were more commonly prescribed second line treatments such as dexamphetamine, amphetamine, or modafinil. No group difference was observed for atomoxetine. In adults with ADHD and coexisting ASD, methylphenidate was prescribed in lower daily doses over three years as compared to individuals with pure ADHD. The findings indicate that there are differences in the medical treatment of individuals with or without ASD. If these differences are due to different medication responses in ASD or due to other factors such as clinicians' perceptions of medication effects in patients with ASD, needs to be further studied.


Dosimetric considerations of water-based bolus for irradiation of extremities.
The dosimetry of high-energy photon beams in the treatment of superficial lesions occurring in extremities was examined. Large parallel-opposed fields with different photon beam energies were used. The extremity was immersed in water contained in a commercially available plastic wastebasket. The water bolus serves to even out the surface irregularities of the extremities and to remove the skin sparing effect. A polystyrene block was placed at the floor of the wastebasket to ensure that the extremity was encompassed in the radiation fields. The photon beam energies considered were 4 MV, 6 MV, 10 MV, and 24 MV. The results show that the dose distributions are more homogeneous with higher photon beam energies. The isodose lines are more constricted at mid-plane for low energy photon beams. Higher energy photon beams, 10 MV and up would be preferable for the treatment of superficial lesions of the extremities immersed in water bolus contained in a typical wastebasket size.


Delayed Calcineurin Inhibitor Introduction Without Antibody Induction in Liver Transplantation Is Safe and Helps Preserve Kidney Function.
Acute kidney injury (AKI) is common after liver transplantation and affects outcome after liver transplantation. Antibody induction is commonly used to reduce dose and/or to delay introduction of calcineurin inhibitor (CNI) but is very expensive. We propose a modified immunosuppressive protocol that delays administration of CNI for 48 to 72 hours without antibody induction. This study evaluates the results of our new protocol. A retrospective case-control study was performed. Study patients had induction with steroid and mycophenolate mofetil without antibody induction, and CNI administration was delayed for 48 to 72 hours. Control patients received CNI and steroid induction without antibody induction, and CNI was continued posttransplant. AKI was defined as an increase in serum creatinine level of at least 1.5 times the pretransplant baseline within the first postoperative week. Sixty liver transplant recipients from 2013 to 2015 were included in this study (30 in the delayed CNI group and 30 in the control group). The patient characteristics and intraoperative factors were comparable in both groups. AKI developed in 11 patients in the study group and in 20 patients in the control group (37% vs 66.7%; P = .02). There was no acute rejection observed in the first month in either group. We have demonstrated that delayed CNI introduction without antibody induction is safe and helps preserve kidney function. Antibody induction can be omitted safely in a delayed CNI introduction protocol to reduce the cost of liver transplantation without increasing the risk of acute rejection.


Hydralazine-induced vasodilation involves opening of high conductance Ca2+-activated K+ channels.
The purpose of this study was to investigate whether high conductance Ca2+-activated K+ channels (BK(Ca)) are mediating the vasodilator action of hydralazine. In isolated porcine coronary arteries, hydralazine (1-300 microM), like the K+ channel opener levcromakalim, preferentially relaxed contractions induced by K+ (20 mM) compared with K+ (80 mM). In addition, concentration-relaxation curves for hydralazine (pD2 = 5.38 +/- 0.06; Emax = 85.9 +/- 3.6%) were shifted 10-fold to the right by the BK(Ca) blockers tetraethylammonium (1 mM) and iberiotoxin (0.1 microM). In contrast, nimodipine (a Ca2+-entry blocker), relaxed contractions induced by K+ (20 mM) and K+ (80 mM) equally and nimodipine-induced relaxations were neither antagonized by tetraethylammonium nor by iberiotoxin. In isolated perfused rat hearts, hydralazine (1 microM) increased coronary flow by 28.8 +/- 2.7%. Iberiotoxin (0.1 microM) suppressed this response by 82% (P < 0.05). In conscious, chronically catheterized rats the hypotensive response to hydralazine (0.6 mg kg(-1) min(-1)) was significantly reduced by 41% during infusion of iberiotoxin (0.1 mg kg(-1)). It is concluded, that opening of BK(Ca) takes part in the mechanism whereby hydralazine produces vasodilation.


Unipolar depression with racing thoughts: a bipolar spectrum disorder?
Major depressive disorder (MDD) with racing/crowded thoughts is understudied. Kraepelin classified 'depression with flight of ideas' in the mixed states of his manic-depressive insanity. The aim of the study was to test whether MDD with racing/crowded thoughts was close to bipolar disorders. Consecutive 379 bipolar-II disorder (BP-II) and 271 MDD depressed outpatients were interviewed using the Structured Clinical Interview for DSM-IV, the Hypomania Interview Guide, and the Family History Screen, by a senior psychiatrist in a private practice. Intra-depression hypomanic symptoms were systematically assessed. Mixed depression was defined as a major depressive episode (MDE) plus three or more intra-MDE hypomanic symptoms. MDD with racing/crowded thoughts was compared to MDD without racing/crowded thoughts on classic bipolar validators (young onset age, many recurrences, atypical and mixed depression, bipolar family history). Frequency of MDD with racing/crowded thoughts was 56.4%. MDD with racing/crowded thoughts, versus MDD without racing/crowded thoughts, had significantly lower age at onset, more MDE severity, more psychotic, melancholic, atypical, and mixed depressions, and more bipolar family history. Of the intra-MDE hypomanic symptoms, irritability, psychomotor agitation and distractibility were significantly more common in MDD with racing/crowded thoughts. Compared to BP-II on bipolar validators, validators were less common in MDD with racing/crowded thoughts. MDD with racing/crowded thoughts seemed to be a severe variant of MDD. MDD with racing/crowded thoughts versus MDD without racing/crowded thoughts, and versus BP-II, had significant differences on bipolar validators, suggesting that it may lie along a continuum linking MDD without racing/crowded thoughts and BP-II.


Society of Interventional Radiology Clinical Practice Guideline for Inferior Vena Cava Filters in the Treatment of Patients with Venous Thromboembolic Disease: Developed in collaboration with the American College of Cardiology, American College of Chest Physicians, American College of Surgeons Committee on Trauma, American Heart Association, Society for Vascular Surgery, and Society for Vascular Medicine.
To provide evidence-based recommendations on the use of inferior vena cava (IVC) filters in the treatment of patients with or at substantial risk of venous thromboembolic disease. A multidisciplinary expert panel developed key questions to address in the guideline, and a systematic review of the literature was conducted. Evidence was graded based on a standard methodology, which was used to inform the development of recommendations. The systematic review identified a total of 34 studies that provided the evidence base for the guideline. The expert panel agreed on 18 recommendations. Although the evidence on the use of IVC filters in patients with or at risk of venous thromboembolic disease varies in strength and quality, the panel provides recommendations for the use of IVC filters in a variety of clinical scenarios. Additional research is needed to optimize care for this patient population.


Alignment of targeted temperature management treatment with patients' mortality risk for out-of-hospital cardiac arrest.
To examine whether TTM treatment was aligned with predicted mortality risk in patients with resuscitated OHCA during a period when it was a class I guideline-recommended therapy. Within the Cardiac Arrest Registry to Enhance Survival for OHCA, we identified adult patients with OHCA who survived to hospital admission and were presumed eligible for TTM. Multivariable models were constructed using pre-hospital variables to predict in-hospital death in patients with shockable and non-shockable rhythms. Within each rhythm category, we divided patients into deciles of predicted mortality risk and examined TTM treatment rates across deciles. From 2013-2019, there were 25,882 successfully resuscitated patients with shockable rhythms and 43,414 patients with non-shockable rhythms presumed eligible for TTM. Of patients with shockable rhythms, predicted in-hospital mortality ranged from 16%-78% in deciles 1-10. TTM treatment increased from 44% in decile 1 to 59% in decile 10 (P for trend < 0.001), but over a third of patients in deciles 4-9 were not treated with TTM. Of patients with non-shockable rhythms, predicted mortality ranged from 48%-95% in deciles 1-10. Although TTM treatment rates increased from 36% in decile 1 to 43% in decile 10 (P for trend 0.003), TTM treatment rates were agnostic to mortality risk (44% to 47%) from decile 2-9. TTM treatment patterns were not well-aligned with patients' mortality risk during a period when it was a guideline-recommended treatment for OHCA. Identifying strategies to better align guideline-recommended treatments with patients' mortality risk is critical for efforts to improve OHCA survival.


New molecular marker for phylogenetic reconstruction of black yeast-like fungi (Chaetothyriales) with hypothetical EIF2AK2 kinase gene.
In eukaryotes, phosphorylation of the α-subunit of eIF2 is a mechanism to adjust cellular gene expression profiles in response to specific signals. The eIF2α kinases are a group of serine-threonine kinases that perform important functions in response to infection, proteotoxicity, and nutrient scavenging. The conserved nature of eIF2α kinases among fungi makes them potential evolutionary markers, which may contribute to deeper understanding of taxonomy and evolution. To date, only few studies are available of eIF2α kinases in black yeasts, which are members of Chaetothyriales containing potential agents of a gamut of major human diseases, such as chromoblastomycosis, phaeohyphomycosis and mycetoma. To establish the phylogenetic validity of sequences of eIF2α kinases hypothetical genes, we compared these genes between members of different classes of fungi, including black yeasts and allies, aiming at evaluation of the phylogeny of this group using an alternative molecular marker, compared to standard ribosomal genes. Trees generated with eIF2α kinase sequences of fungi were compared with those generated by ribosomal internal transcribed spacers (ITS rDNA) sequences from the same species. Sequences used were obtained from the protein Non-redundant database of NCBI, were aligned using CLUSTALX v1.8 and alignments were analyzed with RAxML v8.2.9 on the CIPRES Science Gateway portal. The trees generated had similar topologies, demonstrating that eIF2α kinases hypothetical gene sequences present a coherent reflection of evolution among fungi, compared to trees reconstructed by the use of ribosomal sequences. Our preliminary findings with a limited dataset strongly suggest that the evolution of kinases among black yeasts follows a similar path as revealed by ribosomal data, which underlines the validity of current taxonomy of black yeasts and relatives.


A diagnostic accuracy study on an innovative auto-edge detection technique for identifying simulated implant fractures on radiographic images.
Implant fracture is a rare but devastating complication of treatment in partially or fully edentulous patients which requires prompt diagnosis. Nevertheless, studies on defining the most accurate technique for the detection of implant fractures are lacking. In the present study, the Canny edge detection algorithm was applied on multiple radiographic modalities including parallel periapical (PPA), oblique periapical (OPA), and cone beam CT (CBCT) with and without metal artifact reduction (MAR) to examine its accuracy for diagnosis of simulated implant fractures. Radiographs were taken from 24 intact implants and 24 implants with artificially created fractures. Images were evaluated in their original and Canny formats. The accuracy of each radiograph was assessed by comparison with a reference standard of direct observation of the implant. The greatest area under the receiver operating characteristic curve belonged to Canny CBCT with MAR (0.958), followed by original CBCT with MAR (0.917), original CBCT without MAR = Canny CBCT without MAR = Canny OPA (0.875), Canny PPA (0.833), original PPA = original OPA (0.792), respectively. The Canny edge detection algorithm is suggested as an innovative method for accurate diagnosis of clinically suspected implant fractures on CBCT and periapical radiographies.


How many genomics targets can a portfolio afford?
The pharmaceutical industry can look back at a history of successful innovations. Although genomics technologies have provided drug discovery pipelines with a plethora of new potential drug targets, solid target validation is crucial to avoiding high attrition rates. Biomarkers for patient stratification and approaches for personalized medicine will further help to reduce the risk associated with new targets. To achieve an overall risk balance, portfolios have to be supplemented with precedented targets, me-too approaches and line extensions of existing drugs. However, capitalizing on genomics investments and working on unprecedented targets is essential for a continuous stream of innovative drugs.


Pharmacokinetics and pharmacodynamics of pravastatin in children with familial hypercholesterolemia.
Pravastatin is a widely used statin in adults, but its pharmacokinetics in children is not known. Our aim was to determine the single-dose pharmacokinetics and the lipid-lowering effect and safety of short-term administration of pravastatin in children. Twenty children (age range, 4.9-15.6 years) with heterozygous familial hypercholesterolemia ingested a single dose of 10 mg pravastatin. Plasma concentrations of pravastatin were measured for up to 10 hours. The patients then took 10 mg pravastatin orally once daily for 8 weeks. The concentration of serum lipids and safety laboratory parameters were measured before and after 8 weeks of treatment. The mean peak plasma concentration (C(max)) of pravastatin was 15.7 ng/mL (range, 1.6-55.0 ng/mL), and the mean time to reach C(max) was 1.4 hours (range, 0.5-4 hours). The mean elimination half-life of pravastatin was 1.6 hours (range, 0.85-4.2 hours). The area under the plasma concentration-time curve of pravastatin ranged from 5.7 to 58.9 ng. h/mL (mean value, 26.6 ng. h/mL). By 8 weeks of treatment, the serum concentration of total cholesterol had decreased 18% (P <.0001); low-density lipoprotein cholesterol, 21% (P <.0001); and triglycerides, 18% (not significant, P =.18). The concentration of high-density lipoprotein cholesterol had increased 8% (not significant, P =.13). Few transient adverse events occurred. No increases in serum alanine aminotransferase, creatine kinase, or creatinine level were observed. The pharmacokinetic and pharmacodynamic profile of pravastatin in children is similar to that reported for adults. In the short term, the daily dose of 10 mg pravastatin was well tolerated and moderately effective in decreasing the serum cholesterol concentration. However, further studies are needed on the long-term safety and efficacy of pravastatin in children.


An aqueous extract of Prunella vulgaris L. ameliorates cadmium-induced bone loss by promoting osteogenic differentiation in female rats.
Cadmium (Cd) causes bone loss, concerning inhibiting osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Prunella vulgaris L. (PV) has the potential for promoting osteogenic differentiation, but its influence on Cd-induced bone loss is unclear. This study investigated the effect of PV aqueous extract (PVE) on Cd-induced bone loss and its underlying mechanisms. Eight-week-old female SD rats were randomly assigned into four groups and treated for 16 weeks: Control, Cd (50 mg/L of Cd chloride), Cd + PV Low (125 mg/kg bw of PVE), and Cd + PV High (250 mg/kg bw of PVE). PV ameliorated femoral bone loss in Cd-treated rats manifested as increases in bone mineral density, bone volume, trabecular thickness, number, and area, and decreases in trabecular separation. Compared with Cd group, PV-treatment groups had higher serum levels of bone formation markers (ALP, BGP). Additionally, in PV-treatment groups, expressions of bone formation markers (Osterix, Runx2) and molecules involved in osteogenic differentiation signal pathway BMP/Smad (BMP4, Smad1/5/9) in the tibia of rats and isolated rat primary BMSCs were upregulated. These results suggest that PV alleviates Cd-induced bone loss by promoting osteogenic differentiation, which is likely associated with BMP/Smad pathway.


In the company of wolves: the physical, social, and psychological benefits of dog ownership.
The increase in aging populations has implications for the provision of health and social services. A preventative approach is taken to address this problem by examining a mechanism that can enhance physical health and reduce minor ailments. Participants in 10 focus groups discussed physical, psychological, and social benefits associated with human-dog interactions. Interaction between humans and dogs is a mechanism that can enhance the physical and psychological health of elderly citizens and promote a social support network between dog owners. In turn, dependence and impact on health and social services are alleviated. The social and community consequences of promoting dog ownership in the elderly are addressed, and it is concluded that the benefits of dog ownership should be promoted among the elderly and acknowledged by relevant agencies.


Computerized optimization of 125I implants in brain tumors.
A computer program for treatment planning for the interstitial radiotherapy of brain tumors with 125I stereotactic implants is presented. To minimize brain traumatization only 1-3 catheters loaded with several seeds are implanted. It is possible to position the catheters very accurately due to CT guided stereotactic techniques. Precise treatment planning is necessary because of the high dose gradient of the radiation field. Two planning methods are available: conventional planning with interactive optimization of source configurations and an automatic optimization procedure. The goal of optimization is to identify source parameters (catheter positions and seed activities) for which a prescribed dose at the target surface is approximated as closely as possible.


[Systems approach to the development of equipment provision for roentgenological research].
A systemic approach to the X-ray out fits allowed 3 levels of the roentgen-diagnostic process to be singled out, viz. the lower with the data the data "normally--anormality", the medium, with a tentative conclusion and the highest, with an authentic diagnosis at the output end. The levels may be characterized by formulas reflecting the number of inputs, processes (methods) and outputs. The optimal roentgenological facilities should be in keeping with the diagnostic levels formulas. The prospects for improving the facilities involve a systemic approach to the development of equipment and an integration on this basis of the investigation methods, both horizontally (within the framework of roentgenology) and vertically (outside roentgenology).


Toxicity of chlorophenols to Pseudokirchneriella subcapitata under air-tight test environment.
A closed-system algal toxicity test with no headspace was applied to evaluate the toxicity of chlorophenols to Pseudokirchneriella subcapitata. The dissolved oxygen production and the growth rate based on cell density were the response endpoints. Phenol and seven chlorophenols were tested using the above test technique. Median effective concentrations (EC50) range from 0.004 to 25.93 mg/l (based on DO production) and 0.0134 to 20.90 mg/l (based on growth rate). No-observed-effect concentration (NOEC) is within the range of 0.001-8.19 mg/l. In general, growth rate is a more sensitive response endpoint than the oxygen production, except for the case of pentachlorophenol. However, the differences in sensitivity between the two parameters were marginal. Furthermore, quantitative structure-activity relationships (QSAR's) based on the n-octanol/water partition coefficient (log P) and the acid dissociation constant (pK(a)) values were established with R(2) ranged from 0.90 to 0.96. From literature data also based on P. subcapitata, the new test method is 1.65-108 times more sensitive than the conventional algal batch tests. A completely different relative-sensitivity relationship among various aquatic organisms was thus observed. The results of this study indicate that the toxicity data of volatile organic chemicals derived by conventional algal toxicity tests may severely underestimate the impact of these toxicants. Our results show that alga is very sensitive to chlorophenols compared to other aquatic organisms such as the luminescent bacteria (the Microtox test), Daphnia magna, and rainbow trout.


Systematic review of outcomes after intersphincteric resection for low rectal cancer.
For a select group of patients proctectomy with intersphincteric resection (ISR) for low rectal cancer may be a viable alternative to abdominoperineal resection, with good oncological outcomes while preserving sphincter function. The purpose of this systematic review was to evaluate the current evidence regarding oncological outcomes, morbidity and mortality, and functional outcomes after ISR for low rectal cancer. A systematic review of the literature was undertaken to evaluate evidence regarding oncological outcomes, morbidity and mortality after ISR for low rectal cancer. Three major databases (PubMed, MEDLINE and the Cochrane Library) were searched. The review included all original articles reporting outcomes after ISR, published in English, from January 1950 to March 2011. Eighty-four studies were identified. After applying inclusion and exclusion criteria, 14 studies involving 1289 patients were included (mean age 59.5 years, 67.0 per cent men). R0 resection was achieved by ISR in 97.0 per cent. The operative mortality rate was 0.8 per cent and the cumulative morbidity rate 25.8 per cent. Median follow-up was 56 (range 1-227) months. The mean local recurrence rate was 6.7 (range 0-23) per cent. Mean 5-year overall and disease-free survival rates were 86.3 and 78.6 per cent respectively. Functional outcome was reported in eight studies; among these, the mean number of bowel motions in a 24-h period was 2.7. Oncological outcomes after ISR for low rectal cancer are acceptable, with diverse, often imperfect functional results. These data will aid the clinician when counselling patients considering an ISR for management of low rectal cancer.


Comparison of noninvasive blood pressure measurements in patients with atrial fibrillation.
Limited research is available on the accuracy of automatic blood pressure (BP) measurement devices in patients with irregular rhythms. The purpose of this study was to examine the agreement between different methods for noninvasive BP measurement in patients with atrial fibrillation. In a convenience sample of hospitalized patients with atrial fibrillation, a method-comparison study design was used to examine the agreement between 2 noninvasive devices for BP measurement (manual, automated). Blood pressure was obtained sequentially, with each device following manufacturer's directions and American Heart Association guidelines for BP determination and with BP order determined by random assignment. Heart rate and rhythm were determined from a continuous electrocardiographic monitoring. Heart rate was also recorded from the automated BP device. Differences and limits of agreement between the automated and reference standard (manual) BP devices were calculated and graphed according to the Bland-Altman method. Student t test was used to test differences in BP obtained with the 2 devices, as well as heart rate differences between the electrocardiographic monitor and automated BP device. The level of significance for all tests was set at 0.05. 53 participants were observed. Bland-Altman analysis found a bias plus/minus precision of -0.91 +/- 11.4 mm Hg for systolic BP and 3.3 +/- 6.9 mm Hg for diastolic BP. A significant difference was found for the diastolic BP obtained with the automated device and with that of the manual device (t52 = 3.51, P = .0009) and for heart rate differences between the automated BP device and the cardiac monitor (t52 = 2.4, P = .0217). This study confirms that in the presence of irregular cardiac rhythms, diastolic BP and heart rate cannot reliably be measured with an automated BP device.


On the phenomenology of auditory verbal hallucinations in affective and non-affective psychosis.
Phenomenological comparisons of auditory verbal hallucinations (AVHs) in affective versus non-affective psychosis have not been adequately documented. The current study aimed to: a) comprehensively describe AVH phenomenology by diagnosis and mood state, b) investigate significant predictors of voice-related distress and functional impairment, and c) conduct qualitative thematic analysis of participants' experiences. Participants were diagnosed with: a) bipolar disorder (n = 31), b) major depressive disorder (n = 34), c) schizophrenia (n = 50), or d) schizoaffective disorder (n = 26). Current voice-hearers were also subdivided into prevailing mood states: a) euthymic (n = 23), b) depressed (n = 51), or c) mania-mixed (n = 12). An in-depth, semi-structured interview was conducted, accompanied by mixed-methods analyses. Of the 34 AVH characteristics, significant group differences across diagnoses were identified only for frequency, number of voices, form of address, perceived location, level of conviction, beliefs regarding origin, and functional interference. Random forests modelling (RFM) showed experienced distress and functional interference were best predicted by discrete AVH variables. Qualitative thematic analysis revealed first-order themes: a) content, b) form, c) function, and d) non-voice. There were more similarities than differences in the phenomenology of AVHs across diagnoses, yet significant predictors of voice-related distress and functional impairment differed across affective and non-affective psychosis. This has important nosological and therapeutic applications.


Lowering of body temperature affects human platelet functions and norepinephrine release.
The effect of lowering body temperature on plasma epinephrine, norepinephrine, and platelet density distribution and volume was studied in a placebo-controlled double-blind study. Lowering of body core temperature was induced by either exposure to a cold environment at a temperature of 5 degrees C (CT) or by a single dose of the 5-HT1A agonist ipsapirone (IPS). A third group exposed to an ambient temperature of 28 degrees C was given placebo (PLAC). All of the three groups were investigated in a climate chamber. In the CT group the density distribution of blood platelet subpopulations was shifted to an increase in less dense platelets that were more sensitive towards aggregation-inducing agents. The mean platelet volume in this subpopulation was decreased. Epinephrine was not affected, whereas the increase of norepinephrine was correlated with an increase of platelets that were more sensitive to aggregation-inducing agents in the CT group but not in the PLAC and IPS groups.


Editorial Commentary: Indications for Lateral Extra-Articular Tenodesis in Primary Anterior Cruciate Ligament Reconstruction.
Lateral extra-articular tenodesis and other anterolateral procedures improve patient outcomes when combined with anterior cruciate ligament reconstruction. Failure rates are >50% lower in young patients at high risk of reinjury. We defined patients at high risk as those aged 14 to 25 years with 2 or more factors of the following criteria: 1) returning to contact pivoting sport, 2) high-grade anterolateral rotatory laxity, as measured by pivot shift test (grade 2 or higher), and 3) generalized ligamentous laxity (Beighton score greater than 4) or knee hyperextension recurvatum of greater than 10°. Other indications may include Segond fracture, chronic anterior cruciate ligament lesion, radiographic lateral femoral notch sign, and lateral coronal plane laxity. A clearer understanding of indications determined by a comprehensive clinical assessment and risk stratification is needed. As indications continue to be "stretched," we need to better understand the role of lateral extra-articular tenodesis and when to employ it in our practice.


Disentangling perceptual and motor components in inhibition of return.
Following an abrupt onset of a peripheral stimulus (a cue), the response to a visual target is faster when the target appears at the cued position than when it appears at other positions. However, if the stimulus onset asynchrony (SOA) is longer than approximately 300 ms, the response to the target is slower at the cued position than that at other positions. This phenomenon of a longer response time to cued targets is called "inhibition of return" (IOR). Previous hypotheses propose contributions of both response inhibition and attentional inhibition at cued position to IOR, and suggest that responding to the cue can eliminate the component of response inhibition. The current study uses tasks either executing or withholding response to the cue to investigate the relative contributions of response and attention components to IOR. A condition with bilateral display of the cue is also chosen as a control condition, and eight different SOAs between 1,000 and 2,750 ms are tested. Compared to the control condition, response delay to the target at a cued position is eliminated by responding to the cue, and a response advantage to the target at an uncued position is not affected by responding to the cue. Furthermore, both response delay at a cued position and response advantage at an uncued position decrease with SOA in the time window tested in these experiments. The results reported here indicate a dominant response inhibition at a cued position and a primary attentional allocation at an uncued position for IOR. Nonsignificant perceptual/attentional suppression at a cued position is argued to be a benefit for visual detection in a changing world.


Epigenetic regulation of extracellular-superoxide dismutase in human monocytes.
Extracellular-superoxide dismutase (EC-SOD) is a major SOD isozyme mainly present in the vascular wall and plays an important role in normal redox homeostasis. We previously showed the significant reduction or induction of EC-SOD during human monocytic U937 or THP-1 cell differentiation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), respectively; however, its cell-specific expression and regulation have not been fully elucidated. It has been reported that epigenetic factors, such as DNA methylation and histone modification, are involved in several kinds of gene regulation. In this study, we investigated the involvement of epigenetic factors in EC-SOD expression and determined high levels of DNA methylation within promoter and coding regions of EC-SOD in THP-1 cells compared to those in U937 cells. Moreover, treatment with a DNA methyltransferase inhibitor, 5-azacytidine, significantly induced the expression of EC-SOD in THP-1 cells, indicating the importance of DNA methylation in the suppression of EC-SOD expression; however, the DNA methylation status did not change during THP-1 cell differentiation induced by TPA. On the other hand, we detected histone H3 and H4 acetylation during differentiation. Further, pretreatment with histone acetyltransferase inhibitors, CPTH2 or garcinol, significantly suppressed the TPA-inducible EC-SOD expression. We also determined the epigenetic suppression of EC-SOD in peripheral blood mononuclear cells. Treatment with granulocyte macrophage colony-stimulating factor (GM-CSF)/granulocyte-CSF induced that expression. Overall, these findings provide novel evidence that cell-specific and TPA-inducible EC-SOD expression are regulated by DNA methylation and histone H3 and H4 acetylation in human monocytic cells.


Excretion kinetics of the rubber anti-oxidant N-isopropyl-N'-phenyl-p-phenylendiamine (IPPD).
Sixteen rubber vulcanizers using IPPD as anti-oxidant were monitored for the presence of the parent compound in the urine during two consecutive working weeks using HPLC for analysis. At least two components in the excretion kinetics could be demonstrated: a fast one, as end-shift urinary concentrations significantly exceeded before-shift ones, and a less rapid one, as before-shift values at the end of the week significantly differed from those determined at the beginning. A skin absorption experiment was also performed. It demonstrated three components in the excretion kinetics, with apparent half-times of approximately 3, 7 and 24 h. Excretion ceased 7 d after skin exposure.


The effect of differentiation inducers on the sensitivity of two myeloid cell lines to natural killer (NK) cell-mediated lysis.
The effects of differentiation inducers on the sensitivity of two human myeloid cell lines, K562 and HL-60, to natural killer (NK) cell lysis were examined. K562 cells treated with 12-O-tetradecanoyl phorbol-13-acetate (TPA) and HL-60 cells treated with either TPA or dimethylsulfoxide (DMSO) not only became less sensitive NK targets, but also became less competitive in cold target inhibition experiments. Target binding cell assays revealed that TPA-treated target cells bound fewer NK effector cells than did untreated targets. TPA treatment renders K562 and HL-60 target cells more susceptible to hypotonic lysis, indicating that the decreased NK sensitivity is not due to altered osmotic fragility. The observed reduction in sensitivity to NK lysis was not apparently mediated by interferon (IFN) released by the target cells, as neither alpha nor gamma IFN were detected in culture supernatants. Furthermore, the effects of TPA were additive to the known protective effect of IFN on NK target cells. In contrast to the parent line, a subclone of HL-60 resistant to chemically induced differentiation did not become a less sensitive target after exposure to TPA. These observations with myeloid and erythroid target cells imply that the reduced killing of the TPA-treated cells was secondary to impaired recognition of the target by the effector, and that the state of cellular differentiation is a major determinant of susceptibility to NK cell-mediated lysis.


[Role of computerized tomography and ultrasonic diagnosis in adrenal neoplasms with an adipose matrix].
Ten cases of adrenal lipomatous tumors discovered incidentally with ultrasounds (US) and computed tomography (CT) during examinations for the staging of malignant tumors are reported. Transparietal bioptic approach and surgery revealed three histologic diagnosis: non-functioning adenomas, lipomas and myelolipomas. Those findings confirmed that adrenal tumours with low density are mainly benign; but in neoplastic patients biopsy and surgery are still mandatory.


Serological evidence for the co-circulation of multiple dengue virus serotypes in Singapore.
We did a seroepidemiological study to determine the circulating dengue virus serotypes and the extent to which the Singapore population has been exposed to multiple dengue virus serotypes, using the plaque reduction neutralization assay (PRNT). Of 164 enrolled subjects aged between 18-30 years, 49 subjects (29.8%) were PRNT positive for at least one dengue serotype. The seroprevalence was 39 (23.8%) for dengue virus serotype 1, 37 (22.6%) for type 2, 43 (26.2%) for type 3, and 30 (18.3%) for type 4. Of the 49 subjects with PRNT-positive dengue virus results, 28 (57.1%) were positive to all four virus serotypes, seven (14.3%) to three serotypes, two (4%) to two serotypes, and 12 (24.5%) to a single serotype. All four dengue virus serotypes circulate in Singapore, and a substantial proportion of the adult population in Singapore had exposure to more than one dengue virus serotype. In spite of multiple circulating types, the rate of dengue haemorrhagic fever is low in Singapore.


The relationship between COVID-19 and HLA in kidney transplant recipients, an evaluation of predictive and prognostic factors.
The purpose of this study was to determine the predictive and prognostic factors for COVID-19 infection and its relationship with human leukocyte antigen (HLA) in kidney transplant recipients. Three hundred fifty kidney transplant recipients were included in the study. Recipients were divided into two groups: COVID-19(+) (n = 100) and control (n = 250). The relationships between HLA frequencies, COVID-19 infection, and prognostic factors (age, donor type, immunosuppression protocol, etc.) were then evaluated. Logistic regression analysis, heatmap, and decision tree methods were used to determine predictive and prognostic factors. The study was performed retrospectively. Advanced age and deceased transplantation emerged as predictive of SARS-CoV-2 infection, while the presence of HLA-A*11, the HLA match ratio, and high-dose tacrolimus were identified as prognostic factors in kidney transplant recipients. HLA-A10, HLA-B*13, HLA-B22, and HLA-B*55 were shown to be associated with SARS-CoV-2 infection at univariate analysis, and HLA-B*57, HLA-DRB1*11, and HLA-DRB1*13 at logistic regression analysis. HLA-A10, HLA-B*13, HLA-B*55, HLA-B*57, HLA-DRB1*11, and HLA-DRB1*13 were identified for the first time in the literature associated with SARS-CoV-2 infection in kidney transplant recipients.


Role of cathepsin D in the degradation of human serum albumin by peritoneal macrophages and veiled cells in antigen presentation.
Murine peritoneal macrophages (PMO) and veiled cells (VC) isolated from the thoracic duct of irradiated lymphadenectomized (MNLX) mice presented intact human serum albumin (HSA) to stimulated T lymphocytes, but VC were not as effective as PMO in presenting the antigen. Pepstatin A significantly inhibited the presentation of HSA by VC. Lysates prepared from PMO degraded [125I]HSA at pH 4.0 to peptides as demonstrated by SDS-polyacrylamide-gel electrophoresis and autoradiography. Degradation was inhibited by pepstatin A, suggesting that cathepsin D might be responsible for processing the antigen. In contrast, lysates prepared from VC did not degrade [125I]HSA. The localization of cathepsin D, by light microscopy, was examined on cytospins of PMO and VC by means of a peroxidase antiperoxidase technique (PAP). Cathepsin D was found in vacuoles in the cytoplasm of PMO and, in some cases, appeared to be bound to some areas of the cell surface, but the enzyme could not be detected in VC.


A fish oil diet minimizes hepatic reperfusion injury in the low-flow, reflow liver perfusion model.
In this study, the effects of fish oil treatment on hepatic reperfusion injury in a low-flow, reflow perfusion model were investigated. Rats were fed powdered diets containing either 5% corn or 5% encapsulated fish oil for 13 to 15 days. Average daily food intake in both control and fish oil groups was about 20 g per rat, and weight gain averaged 9 g/rat/d. Livers were perfused at flow rates around 1 muL/g/min for 75 minutes, which caused cells in pericentral regions to become anoxic because of insufficient delivery of oxygen. When normal flow rates (about 4 mL/g/min) were restored for 40 minutes, reperfusion injury occurred. Upon reflow, lactate dehydrogenase (LDH) release increased from basal levels around 1 to 50 IU/g/h in livers from control rats, whereas fish oil treatment minimized values to 16 IU/g/h Rates of bile production reached 23 muL/g/h during reperfusion in livers from controls and 38 muL/g/h in the fish oil-treated group. Oxygen uptake was about 110 mumol/g/h during the reperfusion period in livers from both groups. Malondialdehyde (MDA), an end product of lipid peroxidation, was released into the effluent perfusate at rates around 80 nmol/g/h during reperfusion in controls, and values were not affected by fish oil treatment, Portal pressure, an indicator of hepatic microcirculation, increased from basal levels of 3 to 10.5 cm H2O during reperfusion in controls, but was only elevated to 8.3 cm H2O in the fish oil-treated group. In addition, Trypan Blue distribution time, another indicator of hepatic microcirculation, was reduced significantly by 44% by fish oil treatment.(ABSTRACT TRUNCATED AT 250 WORDS)


Chemoreception for fat: do rats sense triglycerides directly?
Rats given a choice between fluid containing 0.1-0.5% triglyceride oil and the same fluid without oil, generally preferred the fluid containing oil. Several experiments indicate that this preference is based on the detection of impurities rather than triglycerides per se. Rats preferred crude triolein to a greater degree than they did highly purified triolein or corn oil. Rats did not show any preference for or aversion to tristearin, a fat that does not decompose as readily as triolein. Rats that have been trained to avoid a dilute suspension of triolein, also avoided an aqueous extract of triolein. Since rats that had been trained to avoid triolein oil also avoided corn oil, it seems likely that different oils may possess similar impurities. Since training rats to avoid mineral oil did not reduce preference for triolein, these substances may have different flavors. It is proposed that rats use fat decomposition products to detect the presence of fats in foods.


The evaluation of the safety and efficacy of intravenously administered allogeneic multilineage-differentiating stress-enduring cells in a swine hepatectomy model.
Multilineage-differentiating stress-enduring (Muse) cells are non-tumorigenic endogenous pluripotent-like cells residing in the bone marrow that exert a tissue reparative effect by replacing damaged/apoptotic cells through spontaneous differentiation into tissue-constituent cells. Post-hepatectomy liver failure (PHLF) is a potentially fatal complication. The main purpose of this study was to evaluate the safety and efficiency of allogeneic Muse cell administration via the portal vein in a swine model of PHLF. Swine Muse cells, collected from swine bone marrow-mesenchymal stem cells (MSCs) as SSEA-3(+) cells, were examined for their characteristics. Then, 1 × 107 allogeneic-Muse cells and allogeneic-MSCs and vehicle were injected via the portal vein in a 70% hepatectomy swine model. Swine Muse cells exhibited characteristics comparable to previously reported human Muse cells. Compared to the MSC and vehicle groups, the Muse group showed specific homing of the administered cells into the liver, resulting in improvements in the control of hyperbilirubinemia (P = 0.04), prothrombin international normalized ratio (P = 0.05), and suppression of focal necrosis (P = 0.04). Integrated Muse cells differentiated spontaneously into hepatocyte marker-positive cells. Allogeneic Muse cell administration may provide a reparative effect and functional recovery in a 70% hepatectomy swine model and thus may contribute to the treatment of PHLF.


Forced Out-Migration from Hill Regions and Return Migration During the Pandemic: Evidence from Uttarakhand.
This paper deals with out-migration which has been a common phenomenon in the hill regions and is closely related to their socio-economic and cultural patterns. In particular, male-specific out-migration has been a sustained tradition from the hill districts of Uttarakhand. The people have been migrating not just for seeking diverse avenues of employment, but also for accessing better educational and health opportunities. As per 2011 Census, the overall population growth rate in the state was 1.7% with huge differentials in the hill and plain districts. Hill districts witnessed one-fourth growth (0.7%) of the population compared to that of plain districts (2.8%) suggestive of huge out-migration from these (hill) districts of the state. The important thing to note is that the nature and patterns of out-migration have now paved the way from long-term to permanent out-migration. Also, the lack of employment opportunities is creating distress out-migration to destinations within or outside the state, which has become a major cause of concern. The COVID-19 pandemic has impacted the most short-term migrants who returned to their villages in desperation resulting in despondency and distress. In this context, the paper explores the factors of distress migration by analysing the data from a quick survey of 323 return migrants carried out in June 2020 to understand their employment and livelihood profile, reasons for their return to native places, coping mechanism and future plans. The findings reveal that due to lack of livelihood opportunities in their place of origin, most of them would eventually like to return to their destination places in the future to eke out their living. From a policy point of view, enhancing the economic base and livelihood opportunities by focusing on niche activities with improved provisioning of educational and health infrastructure and services can eventually help restrict out-migration from Uttarakhand.


Comparison of O-RADS, GI-RADS, and IOTA simple rules regarding malignancy rate, validity, and reliability for diagnosis of adnexal masses.
The American College of Radiology (ACR) recently published the ovarian-adnexal reporting and data system (O-RADS) to provide guidelines to physicians who interpret ultrasound (US) examinations of adnexal masses (AM). This study aimed to compare the O-RADS with two other well-established US classification systems for diagnosis of AM. This retrospective multicenter study between May 2016 and December 2019 assessed consecutive women with AM detected by the US. Five experienced consultant radiologists independently categorized each AM according to O-RADS, gynecologic imaging reporting and data system (GI-RADS), and international ovarian tumor analysis (IOTA) simple rules. Pathology and adequate follow-up were used as reference standards for calculating the validity of three US classification systems for diagnosis of AM. Kappa statistics were used to assess the inter-reviewer agreement (IRA). A total of 609 women (mean age, 48 ± 13.7 years; range, 18-72 years) with 647 AM were included. Of the 647 AM, 178 were malignant and 469 were benign. Malignancy rates were comparable to recommended rates by previous literature in O-RADS and IOTA, but higher in GI-RADS. O-RADS had significantly higher sensitivity for malignancy than GI-RAD and IOTA (p = 0.003 and 0.0007, respectively), but non-significant slightly lower specificity (p > 0.05). O-RADS, GI-RADS, and IOTA showed similar overall IRA (κ = 0.77, 0.69, and 0.63, respectively) with a tendency toward higher IRA with O-RADS than with GI-RADS and IOTA. O-RADS compares favorably with GI-RADS and IOTA. O-RADS had higher sensitivity than GI-RADS and IOTA simple rules with relatively similar specificity and reliability. • The malignancy rates were comparable to recommended rates by previous literature in O-RADS and IOTA, but higher in GI-RADS. • The O-RADS had significantly higher sensitivity for malignancy than GI-RADS and IOTA (96.8% vs 92.7% and 92.1%; p = 0.003 and 0.0007, respectively), but non-significant slightly lower specificity (92.8% vs 93.6% and 93.2%, respectively; p > 0.05). • The O-RADS, GI-RADS, and IOTA showed similar overall inter-reviewer agreement (IRA) (κ = 0.77, 0.69, and 0.63, respectively), with a tendency toward higher IRA with O-RADS than with GI-RADS and IOTA.


Treatment of chronic thoracic duct fistula with the sternocleidomastoid muscle flap.
Thoracic duct fistula is a rare but potentially serious complication of head and neck surgery. The fistulae can be difficult to treat, and several techniques, both operative and nonoperative, are advocated. We present a simple technique for the treatment of chronic thoracic duct fistula where other procedures have failed. After identification and ligation of the duct, the area is covered with the clavicular head of the sternocleidomastoid muscle.


Validation of in vivo assessment of facial soft-tissue volume changes and clinical application in midfacial distraction: a technical report.
The purpose of this study was to validate the assessment of visible volume changes of the facial soft tissue with an optical three-dimensional sensor and to introduce new parameters for the evaluation of the soft-tissue shape achieved from three-dimensional data of selected cases of midfacial distraction. Images of a truncated cone of known volume were assessed repeatedly with an optical three-dimensional sensor based on phase-measuring triangulation to calculate the volume. Two cubic centimeters of anesthetic solution was injected into the right malar region of 10 volunteers who gave their informed consent. Three-dimensional images were assessed before and immediately after the injections for the assessment of the visible volume change. In five patients who underwent midfacial distraction after a high quadrangular Le Fort I osteotomy, three-dimensional scans were acquired before and 6 and 24 months after the operation. The visible soft-tissue volume change in the malar-midfacial area and the mean distance of the accommodation vector that transformed the preoperative into the postoperative surface were calculated. The volume of the truncated cone was 235.26 +/- 1.01 cc, revealing a measurement uncertainty of 0.4 percent. The injections of anesthetic solution into the malar area resulted in an average visible volume change of 2.06 +/- 0.06 cc. The measurement uncertainty was 3 percent. In the five patients, the average distance of maxillary advancement was 6.7 +/- 2.3 mm after 6 months and 5.4 +/- 3.0 mm after 2 years. It was accompanied by a mean visible volume increase of 8.92 +/- 5.95 cc on the right side and 9.54 +/- 4.39 cc on the left side after 6 months and 3.54 +/- 3.70 cc and 4.80 +/- 3.47 cc, respectively, after 2 years. The mean distance of the accommodation vector was 4.41 +/- 1.94 mm on the right side and 4.74 +/- 1.32 mm on the left side after 6 months and 1.62 +/- 1.96 mm and 2.16 +/- 1.52 mm, respectively, after 2 years. The assessment of visible volume changes by optical three-dimensional images can be carried out with considerable accuracy. The determination of volume changes and accompanying accommodation vectors completes the cephalometric analysis during the follow-up of patients undergoing midfacial distraction. The new parameters will help to assess normative soft-tissue data on the basis of three-dimensional imaging with a view to an improved three-dimensional prediction of the operative outcome of orthognathic surgery.


Total synthesis of fentanyl.
Fentanyl of a potent anilidopiperidine analgesic has been synthesized from a simple phenylethylamine by four step sequence. The key part of this synthesis involves an efficient construction of phenylethylpiperidone skeleton via aminomethano desilyltion-cyclization followed by Swern oxidation.


Synthesis of cysteinylphenol, cysteaminylphenol, and related compounds, and in vivo evaluation of antimelanoma effect.
Phenolic and catecholic compounds were synthesized, by combination with cysteine or cysteamine through thioether bond, and their antimelanoma and melanocytotoxic effects were evaluated. Among nine compounds tested, 4-S-cysteaminylphenol (CAP) resulted in an increase in the life span (% ILS) of melanoma-bearing mice and in the growth inhibition (% GI) of melanoma tissue. 4-S-Cysteinylphenol (CP) and its methyl ester form also showed some increase in % GI. The 2-S-isomers of CP and CAP and diphenolic derivatives of CP did not show any significant antimelanoma effect. In addition, the s.c. injection of 4-S-CAP and 4-S-CP, in particular 4-S-CAP, caused the depigmentation of black hair which was manifested by loss of functioning melanocytes, as seen under light microscopy. The 4-S-CAP appears to provide a basis for development of a new class of antimelanoma and melanocytotoxic agents that are more stable than catecholic compounds, which have been most widely utilized as a source of rational chemotherapy for malignant melanoma.