Selectivity Control in Gold-Catalyzed Hydroarylation of Alkynes with Indoles: Application to Unsymmetrical Bis(indolyl)methanes.
Gold-catalyzed hydroarylation of unactivated alkynes with indoles have previously been reported to proceed with double indole addition to produce symmetrical bis(indolyl)methanes (BIMs). We demonstrate for the first time that the selectivity of the gold-catalyzed reaction can be fully switched to allow for isolation of the vinylindole products instead. Furthermore, this selective reaction can be utilized to synthesize the more difficult to access unsymmetrical BIMs from readily available starting materials.


Characterization of genetically defined sporadic and hereditary type 1 papillary renal cell carcinoma cell lines.
Renal cell carcinoma (RCC) is not a single disease but is made up of several different histologically defined subtypes that are associated with distinct genetic alterations which require subtype specific management and treatment. Papillary renal cell carcinoma (pRCC) is the second most common subtype after conventional/clear cell RCC (ccRCC), representing ~20% of cases, and is subcategorized into type 1 and type 2 pRCC. It is important for preclinical studies to have cell lines that accurately represent each specific RCC subtype. This study characterizes seven cell lines derived from both primary and metastatic sites of type 1 pRCC, including the first cell line derived from a hereditary papillary renal carcinoma (HPRC)-associated tumor. Complete or partial gain of chromosome 7 was observed in all cell lines and other common gains of chromosomes 16, 17, or 20 were seen in several cell lines. Activating mutations of MET were present in three cell lines that all demonstrated increased MET phosphorylation in response to HGF and abrogation of MET phosphorylation in response to MET inhibitors. CDKN2A loss due to mutation or gene deletion, associated with poor outcomes in type 1 pRCC patients, was observed in all cell line models. Six cell lines formed tumor xenografts in athymic nude mice and thus provide in vivo models of type 1 pRCC. These type 1 pRCC cell lines provide a comprehensive representation of the genetic alterations associated with pRCC that will give insight into the biology of this disease and be ideal preclinical models for therapeutic studies.


Accreditation of medical training in Australia and New Zealand.
The Australian Medical Council (AMC) accredits both Australian and New Zealand (NZ) medical courses and also college specialist training programmes. The common accreditation process allows mutual recognition of basic medical training and vocational training between Australia and New Zealand. The ultimate purpose of accreditation assure stakeholders including medical registration boards, health departments, students/trainees and the general community of the quality of the programs and the competence of those completing such training. AMC revised its own accreditation guidelines using the WFME standards as the model around which the new AMC standards were developed. The College Accreditation Process is similar to and builds on AMC experience in the medical school accreditation process. In conclusion, AMC accreditation has been successful in improving medical education in Australia and New Zealand and has been able to do so without the imposition of any exclusive educational model or philosophy.


Effects of oleic acid/propylene glycol on rat abdominal stratum corneum: lipid extraction and appearance of propylene glycol in the dermis measured by Fourier transform infrared/attenuated total reflectance (FT-IR/ATR) spectroscopy.
Fourie transform infrared/attenuated total reflection analysis demonstrated that the absorbance intensity of C = O stretching bands, which reflect the amounts of lipids in the stratum corneum, decreased with an increase in the duration of skin treatment with 0.15 M oleic acid/propylene glycol (PG) system, suggesting that the oleic acid/PG system induced the lipid extraction, which was followed by a reorganization of the stratum corneum structures. The spectral peaks which originated from the PG molecule were detected in dermal tissues after 30 min of treatment of the stratum corneum with the same system. This observation suggested that the reorganization of the lipid domains due to the lipid extraction by the oleic acid/PG system helped the PG molecules enter the dermal tissues. It was also suggested that an effective volume within the stratum corneum for solutes and/or solvents which could penetrate through the inter-, and/or intracellular routes could be altered in conjunction with the structural changes of the lipids.


Synthesis, stereochemical separation, and biological evaluation of selective inhibitors of human MAO-B: 1-(4-arylthiazol-2-yl)-2-(3-methylcyclohexylidene)hydrazines.
Novel 1-(4-arylthiazol-2-yl)-2-(3-methylcyclohexylidene)hydrazine derivatives have been investigated for their ability to inhibit selectively the activity of the human B isoform of monoamine oxidase. These compounds were obtained as racemates and (R)-enantiomers by a stereoconservative synthetic pattern in high yield and enantiomeric excess. The (S)-enantiomers of the most active derivatives have been separated by enantioselective HPLC. All compounds showed selective activity against hMAO-B with IC(50) ranging between 21.90 and 0.018 microM.


Long-term outcomes of a totally thoracoscopic approach for reoperative mitral valve replacement: a propensity score matched analysis.
This study aimed to summarize the perioperative and long-term outcomes of patients with previous mitral valve surgery (MVS) undergoing reoperative mitral valve replacement (MVR). Data for all reoperative mitral valve replacements (re-MVRs) with or without concomitant tricuspid surgery were analyzed from Guangdong Provincial People's Hospital between January 2013 and December 2019. Propensity score matching resulted in 30 matched pairs with improved balance after matching in baseline covariates. Perioperative data and long-term clinical outcomes were analyzed. Results are based on the matched cohorts between the two groups. The in-hospital mortality was 3.3% (two deaths) in the entire cohort and was not significantly different between the median sternotomy (MS) group and the totally thoracoscopic (TT) group. Most patients in the TT group had their tracheal intubation removed within 24 hours of surgery. The TT group had a diminished requirement for blood transfusion and a reduced 4-day postoperative chest tube drainage amount. The incidence of early major complications, including all-cause death and reoperation due to bleeding, was lower in the TT group. No significant differences were observed in the 7-year survival probability between the two groups. The encouraging results regarding the perioperative and long-term outcomes of patients who underwent a TT re-MVR show that this approach is particularly beneficial for patients requiring reoperation.


[Correlation between TCID50 and p27 antigen of avian leukosis virus subgroup J].
To study the correlation between 50% tissue-culture infective dose (TCID50) value and p27 antigen S/P value of Avian leukosis virus subgroup J and discuss their significance, chicken embryo fibroblast (CEF) cells were inoculated with Avian leukosis virus subgroup J strain NX0101 and samples were tested continuously for ten days after changing maintenance media. The correlation between TCID50 and p27 antigen S/P value of ten days were then analysized. Simultaneously, DF-1 cells were inoculated with NX0101 and passaged to 20 generations. Samples taken from 1st generation, 5th generation, 10th generation, 15th generation and 20th generation were tested for the TCID50 titer and the p27 antigen S/P value separately. A significant Pearson correlation was found between them in CEF cells (r = 0.85277; P < 0.0001) and in DF-1 cells (r = 0.93000; P = 0.0220). This study provided an important parameter for predicting TCID50 by detecting the p27 antigen S/P value.


Ocean-like water in the Jupiter-family comet 103P/Hartley 2.
For decades, the source of Earth's volatiles, especially water with a deuterium-to-hydrogen ratio (D/H) of (1.558 ± 0.001) × 10(-4), has been a subject of debate. The similarity of Earth's bulk composition to that of meteorites known as enstatite chondrites suggests a dry proto-Earth with subsequent delivery of volatiles by local accretion or impacts of asteroids or comets. Previous measurements in six comets from the Oort cloud yielded a mean D/H ratio of (2.96 ± 0.25) × 10(-4). The D/H value in carbonaceous chondrites, (1.4 ± 0.1) × 10(-4), together with dynamical simulations, led to models in which asteroids were the main source of Earth's water, with ≤10 per cent being delivered by comets. Here we report that the D/H ratio in the Jupiter-family comet 103P/Hartley 2, which originated in the Kuiper belt, is (1.61 ± 0.24) × 10(-4). This result substantially expands the reservoir of Earth ocean-like water to include some comets, and is consistent with the emerging picture of a complex dynamical evolution of the early Solar System.


Meeting report on 8th International Symposium on Platinum and Other Metal Coordination Compounds in Cancer Chemotherapy.
The platinum-based drugs, cisplatin and carboplatin, represent major agents in the chemotherapeutic treatment of a variety of types of cancer. Novel, "third-generation" agents aimed at broadening the clinical activity of this class of drug are currently undergoing clinical evaluation. These include oxaliplatin, ZD0473 and BBR3464. Clinical trials and preclinical studies are also being conducted with liposomal (SPI-077 and L-NDDP) and polymeric platinum complexes (linked to HPMA or albumin). Combination studies of cisplatin/carboplatin with other anticancer drugs such as gemcitabine and UCN-01 (7-hydroxystaurosporine) and agents designed to reduce platinum drug toxicities (e.g., BNP-7787, DIMESNA) are ongoing. Preclinically, there is interest in trans platinum complexes, terpyridine platinum(II) complexes and other metal-containing agents (ruthenium and gold).


Cloning and nucleotide sequence of a heat-stable enterotoxin gene from Vibrio cholerae non-O1 isolated from a patient with traveler's diarrhea.
We determined the nucleotide sequence of the heat-stable enterotoxin (STa) gene of the Vibrio cholerae non-O1 strain NRT36 isolated from a patient with traveler's diarrhea. The gene is chromosomally encoded and the presumed product is 78 amino acids in length, with a molecular weight of 8,814, though the genes of Escherichia coli STa(s) (STh and STp) are encoded in plasmid DNA and both products are 72 amino acids in length. The first 18 amino acids at the NH2 terminus were hydrophobic, suggesting that this region of the polypeptide acts as a signal sequence for the toxin. The last 17 amino acids at the COOH terminus were identical to those deduced from the toxin (NAG-ST) produced by V. cholerae non-O1 strain A-5 isolated from a frozen shrimp. The deduced amino acid sequence of the NAG-ST precursor had 50 and 46% homology to those of E. coli STh and STp, respectively. The hydropathy plot analysis of each predicted protein revealed similar profiles between them, suggesting that the NAG-ST precursor has structural similarity to those of E. coli STa(s).


Mechanistic model of mass-specific basal metabolic rate: evaluation in healthy young adults.
Mass-specific basal metabolic rate (mass-specific BMR), defined as the resting energy expenditure per unit body mass per day, is an important parameter in energy metabolism research. However, a mechanistic explanation for magnitude of mass-specific BMR remains lacking. The objective of the present study was to validate the applicability of a proposed mass-specific BMR model in healthy adults. A mechanistic model was developed at the organ-tissue level, mass-specific BMR = Σ(Ki × Fi), where Fi is the fraction of body mass as individual organs and tissues, and Ki is the specific resting metabolic rate of major organs and tissues. The Fi values were measured by multiple MRI scans and the Ki values were suggested by Elia in 1992. A database of healthy non-elderly non-obese adults (age 20 - 49 yrs, BMI <30 kg/m2) included 49 men and 57 women. Measured and predicted mass-specific BMR of all subjects was 21.6 ± 1.9 (mean ± SD) and 21.7 ± 1.6 kcal/kg per day, respectively. The measured mass-specific BMR was correlated with the predicted mass-specific BMR (r = 0.82, P <0.001). A Bland-Altman plot showed no significant trend (r = 0.022, P = 0.50) between the measured and predicted mass-specific BMR, versus the average of measured and predicted mass-specific BMR. In conclusion, the proposed mechanistic model was validated in non-elderly non-obese adults and can help to understand the inherent relationship between mass-specific BMR and body composition.


Analysis of the repertoire of cattle CD4(+) T cells reactive with bovine viral diarrhoea virus.
Cell-mediated immunity and CD4(+) cells in particular are important for the resolution of acute infection with non-cytopathic bovine viral diarrhoea virus (BVDV). CD4(+) T cells were shown to recognise virus-infected and non-infectious-protein-pulsed APCs, whereas CD8(+) T cells recognised only virus-infected APCs. T cell recognition was strain cross-reactive and MHC-restricted. Using native and recombinant antigens, we identified the structural glycoprotein E2 and the non-structural protein NS3 as dominant CD4(+) T cell determinants. The repertoire of CD4(+) T cell responses to E2 and NS3 was examined using inbred, homozygous cattle and overlapping synthetic peptides. The repertoire was biased toward conserved regions of NS3 and excluded the hypervariable regions of E2. The number of peptides that were recognised varied between animals but patterns could be distinguished in those animals that shared the same DRB3(*) allele. Of particular interest were: (i) a determinant that was recognised in the context of both DRB3(*) alleles (i.e. DRB3(*)2002 and DRB3(*)0701), (ii) two determinants that were juxtaposed to B cell sites, and (iii) a determinant that had structural analogy with a NS3 epitope previously described for the closely related hepatitis C virus. The minimum stimulatory sequence of the latter, NS3(397-414), was located to residues NS3(400-410).


Evaluating the efficacy of sample collection approaches and DNA metabarcoding for identifying the diversity of plants utilized by nectivorous bats.
In this study, we evaluated the efficacy of sample collection approaches and DNA metabarcoding to identify plants utilized by nectivorous bats. Samples included guano collected from beneath bat roosts and pollen-swabs from bat fur, both of which were subjected to DNA metabarcoding and visual identification of pollen (microscopy) to measure plant diversity. Our objectives were to determine whether DNA metabarcoding could detect likely food plants of nectivorous bats, whether sample types would produce different estimates of plant diversity, and to compare results of DNA metabarcoding to visual identification. Visual identification found that 99% of pollen was from Agave, which is thought to be the bats' main food source. The dominant taxon found by metabarcoding was also Agavoideae, but a broader diversity of plant species was also detected, many of which are likely "by-catch" from the broader environment. Metabarcoding outcomes differed between sample types, likely because pollen-swabs measured the plant species visited by bats and guano samples measured all items consumed in the bat's diet, even those that were not pollen or nectar. Overall, metabarcoding is a powerful, high-throughput tool to understand bat ecology and species interactions, but careful analysis of results is necessary to derive accurate ecological conclusions.


Cell-mediated amegakaryocytic thrombocytopenia associated with systemic lupus erythematosus.
We studied a patient with a rare complication of amegakaryocytic thrombocytopenia (AMT) associated with systemic lupus erythematosus (SLE). To investigate the underlying pathogenesis of AMT, the effects of peripheral blood T cells and serum on human megakaryocyte progenitor cells were studied using in vitro coculture techniques. Mononuclear bone marrow cells (2 X 10(5) from normal donors produced 33.6 +/- 8.8 (n = 10) colony-forming unit-megakaryocytes (CFU-M) in our plasma clot system. When 2 X 10(5) of the patient's T cells were added to the culture system, the number of CFU-M decreased to only 3.5 +/- 0.6/2 X 10(5) bone marrow cells. No evidence of inhibitory effects was found by the addition of the patient's serum and complement to the culture system. The T cells stored at -80 degrees C on admission were also capable of suppressing autologous CFU-M after recovery from AMT. These results indicate that in vitro suppression of CFU-M from allogenic and autologous bone marrow cells by this patient's T cells provides an explanation for the pathogenesis of AMT associated with SLE.


Stability and improvement of health after nursing home admission.
This prospective study investigated stability of residents' mental status, function (activities of daily living), and mood during the first and second week following nursing home admission. New residents (N = 647) in eight urban nursing homes were assessed three times. Mental status was measured using the Short Portable Mental Status Questionnaire, function was measured using Scaled Outcome Criteria, and mood was measured using the Mood Adjective Checklist. A repeated measures multivariate analysis of variance, controlling for admission from hospital and readmission to the nursing home, documented stable mental status during the first and second week of nursing home residence. Hygiene, grooming, dressing, and transferring improved, whereas feeding, ambulation, urination, and defecation were stable. Tired and depressed mood adjectives improved, and angry, cheerful, afraid, lonely, and alert mood adjectives were stable. Residents admitted from a hospital had lower mental status and function scores, and readmitted residents had lower urination scores.


Positive effect of granulocyte-colony stimulating factor on erythropoiesis in humans.
We studied the effects of granulocyte-colony stimulating factor (G-CSF) on human erythropoiesis in vivo. Changes in the peripheral blood were analyzed in 9 subjects; 3 healthy volunteers, 3 patients with pancytopenia and hypersplenism and 3 patients with chronic renal failure and severe anemia being treated with hemodialysis. We monitored erythropoiesis according to the number of highly fluorescent cells (HFC) present in the peripheral blood after staining with Auramine 0. These cells are relatively immature reticulocytes that contain much RNA. All subjects received recombinant human G-CSF at a daily dose of 100 micrograms/m2 administered intravenously for 3 to 5 days. Plasma erythropoietin was measured in patients receiving dialysis before and several times after its administration. The number of HFC increased significantly in all subjects. In 1 of 3 patients receiving dialysis, the plasma erythropoietin increased transiently but insignificantly. These findings show that G-CSF affects human erythropoiesis in vivo, but that the mechanism of its effect did not involve an increase in plasma erythropoietin.


The two different receptors for tumor necrosis factor mediate distinct cellular responses.
The individual roles of the murine type 1 and type 2 tumor necrosis factor (TNF) receptors (TNF-R1 and TNF-R2) were investigated utilizing (i) the strong species specificity of TNF-R2 for murine TNF compared to human TNF and (ii) agonistic rabbit polyclonal antibodies directed against the individual TNF receptors. Proliferation of mouse thymocytes and the murine cytotoxic T-cell line CT-6 is stimulated by murine TNF but not by human TNF. Consistent with this observation, polyclonal antibodies directed against TNF-R2 induced proliferation in both of these cell types, whereas polyclonal antibodies directed against TNF-R1 had no effect. In contrast, cytotoxicity in murine LM cells (which are sensitive to murine and human TNF) was induced by antibodies against TNF-R1 but not by antibodies against TNF-R2. Also, the steady-state level of manganous superoxide dismutase mRNA in the murine NIH 3T3 cell line was induced by murine TNF, human TNF, and anti-TNF-R1 but not by anti-TNF-R2. These results suggest that TNF-R2 initiates signals for the proliferation of thymocytes and cytotoxic T cells, whereas TNF-R1 initiates signals for cytotoxicity and the induction of the protective activity, manganous superoxide dismutase. The nonredundant signaling observed for the two TNF receptors cannot be explained simply by the differential expression of the two TNF receptors in the various cell types, because LM cells express on their surface higher levels of TNF-R2 than TNF-R1, and LM cells, NIH 3T3 cells, and thymus cells all express mRNA corresponding to both receptor types. It is therefore likely that the two receptors initiate distinct signaling pathways that result in the induction of different cellular responses.


Clinical outcomes, complications and fusion rates in endoscopic assisted intraforaminal lumbar interbody fusion (iLIF) versus minimally invasive transforaminal lumbar interbody fusion (MI-TLIF): systematic review and meta-analysis.
This meta-analysis aims to determine the clinical outcomes, complications, and fusion rates in endoscopic assisted intra-foraminal lumbar interbody fusion (iLIF) and minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) for lumbar degenerative diseases. The MEDLINE, Embase, and Cochrane Library databases were searched. The inclusion criteria were: five or more consecutive patients who underwent iLIF or MI-TLIF for lumbar degenerative diseases; description of the surgical technique; clinical outcome measures, complications and imaging assessment; minimum follow-up of 12 months. Surgical time, blood loss, and length of hospital stay were extracted. Mean outcome improvements were pooled and compared with minimal clinically important differences (MCID). Pooled and direct meta-analysis were evaluated. We identified 42 eligible studies. The iLIF group had significantly lower mean intra-operative blood loss, unstandardized mean difference (UMD) 110.61 mL (95%CI 70.43; 150.80; p value < 0.0001), and significantly decreased length of hospital stay (UMD 2.36; 95%CI 1.77; 2.94; p value < 0.0001). Visual analogue scale (VAS) back, VAS leg and Oswestry disability index (ODI) baseline to last follow-up mean improvements were statistically significant (p value < 0.0001), and clinically important for both groups (MCID VAS back > 1.16; MCID VAS leg > 1.36; MCID > 12.40). There was no significant difference in complication nor fusion rates between both cohorts. Interbody fusion using either iLIF or MI-TLIF leads to significant and clinically important improvements in clinical outcomes for lumbar degenerative diseases. Both procedures provide high rates of fusion at 12 months or later, without significant difference in complication rates. iLIF is associated with significantly less intraoperative blood loss and length of hospital stay. Study registration: PROSPERO international prospective register of systematic reviews: Registration No. CRD42020180980, accessible at https://www.crd.york.ac.uk/prospero/ April 2020.


Haemodynamic responses and changes of haemostatic risk factors in cold-adapted humans.
Epidemiological studies have shown an increase in acute myocardial infarctions or deaths due to myocardial infarction in colder weather; the mechanisms most likely involve increased blood levels of haemostatic risk factors, and increases in arterial blood pressure and heart rate. We studied the relationship between cold adaptation, haemostatic risk factors and haemodynamic variables. Cold adaptation was obtained by a programme of immersion of the whole body up to the neck in a water-filled bath, the temperature of which was gradually decreased from 22 degrees C to 14 degrees C, time of exposure being increased from 5 to 20 min over a period of 90 days. We studied 428 patients (44% men) and measured blood levels of fibrinogen, plasminogen activator inhibitor 1 (PAI-1), tissue plasminogen activator antigen (t-PA), plasma viscosity, von Willebrand factor, D-dimer and platelet count, both at baseline and after 90 days of daily immersion. There were significant reductions in von Willebrand factor (-3%; p < 0.001), and plasma viscosity (-3.0 s; p < 0.001), and a mild but significant increase in PAI-1 (+0.3 IU/ml; p = 0.02). The pressure rate product (systolic blood pressure x heart rate) was also significantly lower after cold adaptation (-310; p = 0.004). Cold adaptation, compared with exposure to cold weather, induces different haemodynamic responses and changes of blood levels of haemostatic risk factors.


Development and Validation of a Green Analytical Method for the Determination of Norfloxacin in Raw Material by FTIR Spectrophotometry.
Norfloxacin is a broad-spectrum antimicrobial agent, widely used in humans and animals for the treatment of urinary tract infections. It is a second-generation fluoroquinolone. Several analytical methods to analyze norfloxacin have been described in the literature. However, most of them are complex and require the use of large amounts of organic solvents. This paper describes the development and validation of a green analytical method for the determination of norfloxacin in raw material by FTIR spectrophotometry. This method does not require the use of organic solvents, minimizing waste generation in the process and its environmental impacts. The development of methods that promote the reduction, prevention, or elimination of waste generation has become highly attractive to the pharmaceutical industry because of the growing demand from civil society and government authorities for environmentally friendly products and services. The FTIR spectrophotometry method was validated according to International Conference on Harmonization guidelines, showing adequate linearity (r = 0.9936), precision, accuracy, and robustness. This validated method can be used as an environmentally friendly alternative for the quantification of norfloxacin in raw material in QC routine analysis.


Act of 15 July 1987.
The text of this Act on artificial insemination is as follows: "1. If, under the supervision of a licensed physician and with the consent of her husband, a wife is inseminated artificially with semen donated by a man not her husband, the husband is treated in law as if he were the natural father of a child thereby conceived. The husband's consent must be in writing and signed by him and his wife. The physician shall certify their signatures and the date of the insemination, and file the husband's consent with the bureau, where it shall be kept confidential and in a sealed file. The physician's failure to comply with this section shall not affect the father and child relationship. All papers and records pertaining to the insemination, whether part of the permanent record of a court or of a file held by the supervising physician or elsewhere, are subject to inspection only upon an order of the court for good cause shown. 2. The donor of semen provided to a licensed physician for use in artificial insemination of a married woman other than the donor's wife is treated in law as if he were not the natural father of a child thereby conceived."


The most difficult clinical situations: a survey of Victorian general paediatricians.
To identify which clinical situations are the most difficult to manage for general paediatricians in Victoria, Australia. Self-administered questionnaires were sent to general paediatricians in Victoria. They were asked their opinions regarding what were the most difficult and the most dangerous clinical situations with which they deal. The response rate was 64% (63 out of 98 questionnaires sent). The general paediatricians surveyed believed that behavioural, developmental and psychosocial conditions were the most difficult to deal with; conduct disorder was the most nominated clinical category (26% of respondents). The 'dangerous' cases nominated were predominately traditional medical cases. The most commonly nominated category was sepsis and shock (21% of respondents). The most difficult and dangerous clinical situations overall for general paediatricians in Victoria appear to be in the areas of sepsis, child protection, paediatric and neonatal resuscitation, depression and suicide, raised intracranial pressure, intravenous fluid management, and communication with parents and adolescents. The present survey provides useful information to help with training-programme design and it gives trainee paediatricians an idea of what experienced paediatricians find difficult. Severe behavioural, family and social difficulties, as well as neonatal and childhood resuscitation, severe sepsis, raised intracranial pressure, and intravenous fluid management were the clinical situations most frequently described as difficult.


Multiple epitopes on cartilage type II collagen are accessible for antibody binding in vivo.
Monoclonal mouse antibodies specific for the major epitopes on mouse type II collagen (CII) were biotinylated and injected into neonatal and adult mice. Anti-CII antibodies, specific for four different epitopes on the CII molecule, could be shown to bind specifically to joint surfaces in the paws of 2-day-old syngeneic DBA/1 mice after an intraperitoneal injection of 100 micrograms of biotinylated antibody. The anti-CII antibodies did not bind to cartilage from DBA/1 mice in vitro, unless the sections were pretreated with hyaluronidase or the specimens decalcified prior to freezing, showing that the epitopes are accessible in vivo but not in vitro. By analyzing the in vivo binding capacity for a number of monoclonal anti-CII antibodies which represented different IgG subclasses, it could be demonstrated that binding to the same epitopes occurred independent of IgG subclass. However, one epitope (denoted "B1") was only weakly detected, possibly due to the fact that the antibody used (CIIB1) crossreacts with type I collagen and C1q. Monoclonal anti-CII antibodies, injected into neonates or adult mice, bound specifically to most, but not all, tissues containing CII; including hyaline joint cartilage, fibrous sternal and costal cartilage, tracheal cartilage and fibrous cartilage in the spine but not to CII-containing structures in the eye. The finding that CII, while present in cartilage, is accessible for antibody binding in vivo may have important implications for the availability of CII for the immune system and for the understanding of the development of pathological autoimmunity leading to collagen-induced arthritis in mice.


The impact of paternal alcoholism and maternal social position on boys' school adjustment, pubertal maturation and sexual behavior: a test of two competing hypotheses.
Two competing hypotheses concerning the effects of stressful environments on the onset of puberty were tested using longitudinal data for a sample of boys from low socioeconomic backgrounds. Paternal alcoholism and maternal social position were used as indicators of family stress. School placement was monitored from school entry to 14 years of age. Teachers rated the boys' disruptive and anxious behaviors, while the boys reported on parenting behaviors at 10 years of age. Pubertal maturation, age of first sexual intercourse and sexual behavior were assessed between 11 and 14 years of age. The prepubertal data indicated that boys with an alcoholic father, or a mother from a low social position, were more stressed and had more behavior problems: the boys with alcoholic fathers perceived their parents as being more punitive, and as setting fewer rules concerning their behavior; those who had at least one maladjusted parent were more often placed out of an age-appropriate regular classroom, and were rated more disruptive and more anxious by their teachers. Paradoxically, the results for the onset of puberty gave support to the two rival hypotheses. Paternal alcoholism led to a delay of male pubertal onset, as suggested by the hypothesis that stress activates the hypothalamic-pituitary-adrenal axis, and inhibits the hypothalamic-pituitary-gonadal axis. However, sons of alcoholic fathers had more frequent sexual intercourse and more sexual partners, as suggested by the evolutionary theory of socialization. High maternal social position acted as a protective factor for school placement of boys with an alcoholic father. These results challenged a key hypothesis of the evolutionary theory of socialization for males. They indicated that the link between childhood family environment, behavior development, pubertal maturation and sexual promiscuity are more complex than anticipated.


Association of D-dimer levels with all-cause mortality in a healthy adult population: findings from the MOLI-SANI study.
Elevated D-dimer levels are reportedly associated with higher risk of total mortality in patients with different diseases. We investigated whether a similar association could be found in a large, apparently healthy population. A large sample of individuals (N=17,359, 47% men, age ≥ 35 years) free of clinically recognized cardiovascular and cancer disease, for whom baseline D-dimer level was available, were studied within the MOLI-SANI cohort, randomly recruited from the general adult population of Southern Italy. The cohort was followed for a median of 4.2 years (73,807 person-years). D-dimer was measured in fresh citrated plasma by an automated latex-enhanced immunoassay. Hazard ratios were calculated using three Cox-proportional hazard models. Two hundred and eighty deaths were recorded. When modeled as a continuous variable, D-dimer level at baseline showed a non-linear association with mortality, whose incidence increased only in the upper quartile of the distribution (D-dimer ≥ 221 ng/mL). Thus, the group of individuals with D-dimer <221 ng/mL (75% of the population) acted as the reference group, while the remaining individuals were subdivided in tertiles and compared with the former group. Multivariable hazard ratios for mortality were 1.06, 1.45 and 1.97, respectively (P for trend <0.0001) across the three categories of increasing D-dimer concentration. The association was slightly attenuated, but still highly significant (P for trend 0.0002), after further adjustment for white blood cell count and C-reactive protein. In conclusion, Elevated D-dimer levels were independently associated with increased risk of death from any cause in an apparently healthy adult population.


Birth order, parental health investment, and health in childhood.
We analyze the relationship between birth order, parental health investment and children's health using administrative data from Austria. We show that later-born children have better health endowments at birth. They are less likely born preterm or with a low birth weight, and less likely hospitalized for perinatal conditions. We also find significant birth order differences in parental health investment in early childhood. Later-born children are less likely to participate in preventive medical screenings and their vaccine uptake rates are lower. Our analysis indicates that these birth order differences in parental health investments are not driven by children's health endowments. Thus, we do not find evidence for compensatory behavior of parents. We discuss alternative explanations, such as the role of resource constraints. Furthermore, we show, that the initial health inequalities extend into middle childhood. Later-born children show a better health status in school health checks, they consume less medication and are less often hospitalized.


Physical Activity of Children and Adolescents in Croatia: A Global Matrix 4.0 Systematic Review of Its Prevalence and Associated Personal, Social, Environmental, and Policy Factors.
The previous review of physical activity (PA) among Croatian children and adolescents was conducted a decade ago. Therefore, the aim of this study was to summarize recent evidence on PA of Croatian children and adolescents and associated personal, social, environmental, and policy factors. Eighteen experts reviewed the available evidence and provided ratings (from the lowest grade "F" to the highest grade "A+") for the 10 Global Matrix indicators. A systematic search with 100 keywords was conducted in Hrčak, PubMed/MEDLINE, Scopus, SPORTDiscus, and Web of Science for documents published from January 01, 2012, to April 15, 2022. We also conducted internet searches and secondary analyses of data (relative frequencies) from 6 studies. After assessing 7562 references, we included 90 publications in the review and 18 studies (83.3% of medium-to-good quality) in evidence synthesis. We found a high prevalence of insufficient PA (especially among girls) and excessive screen time (especially among boys). PA participation of children and adolescents in Croatia has declined over time. The following grades were assigned to the indicators for Croatia: B- for overall PA, C- for organized sport and PA, C for active play, C- for active transportation, D+ for sedentary behavior, inconclusive for physical fitness, D+ for family and peers, B- for school, B- for community and environment, and D+ for government. Coordinated actions are needed across sectors to improve PA promotion, with a focus on increasing PA among girls, reducing sedentary screen time among boys, improving parental support for PA, and further development of national PA policies.


Molecular cloning and biochemical characterization of isoflav-3-ene synthase, a key enzyme of the biosyntheses of (+)-pisatin and coumestrol.
Most leguminous plants produce (-)-type enantiomers of pterocarpans as the phytoalexin, but pea (Pisum sativum L.) produces the opposite stereoisomer of pterocarpan, (+)-pisatin. Biosynthesis of (-)-pterocarpan skeleton is completely characterized at the molecular level, and pterocarpan synthase (PTS), a dirigent (DIR) domain-containing protein, participates in the last dehydration reaction. Similarly, isoflav-3-ene, a precursor of (+)-pisatin, is likely to be biosynthesized by the DIR-mediated dehydration reaction; however the biosynthesis is still unknown. In the present study, we screened PTS homologs based on RNA-sequence data from (+)-pisatin-producing pea seedlings and demonstrated that one of the candidates encodes isoflav-3-ene synthase (I3S). Real-time PCR analysis revealed that transcripts of I3S, in addition to other genes involved in the (+)-pisatin pathway, transiently accumulated in pea upon elicitation prior to the maximum accumulation of (+)-pisatin. I3S orthologs were also found in soybean and Lotus japonicus that are not known to accumulate (+)-pterocarpan, and the catalytic function of gene products was verified to be I3S by the in vitro enzyme assay. Incubation of the crude extract of elicited soybean cells with isoflav-3-ene yielded coumestrol, suggesting that isoflav-3-ene is a precursor of coumestrol biosynthesis in soybean.


Smoking Cessation in a Chronic Pancreatitis Population.
Smoking is a known risk factor for developing chronic pancreatitis and accelerates disease progression. Smoking cessation remains an important treatment recommendation, but little is known about its effects. This study evaluated smoking cessation in this population and its impact on quality of life. Twenty-seven smokers with chronic pancreatitis participated in a smoking cessation program incorporating the QuitWorks program and individual counseling. Their smoking cessation rates were compared with a control population (n = 200) consisting of inpatients without chronic pancreatitis who smoked. Smokers were also compared with nonsmokers (n = 25) with chronic pancreatitis in terms of quality-of-life indicators. In 27 patients, 0 had quit smoking at 6 months, 1 at 12 months, and 0 patients at 18 months. There was a 19% quit rate in the control population at the 6-month period. Smokers had a worse quality of life, higher rates of depression and anxiety, and worse coping skills than nonsmokers. Smoking cessation in the chronic pancreatitis population is extremely challenging, as shown by our 0% quit rate after 18 months. Given that smokers with chronic pancreatitis also experience a worse quality of life, it becomes even more important to stress the importance of smoking cessation in these patients.


Evaluation of the accuracy and reproducibility of a replication technique for the manufacture of electroconductive replicas for use in quantitative clinical dental wear studies.
This work sought to evaluate the accuracy and reproducibility of a replication process that formed electroconductive replicas from addition cured silicone impressions for the purposes of monitoring tooth surface loss. Replicas were constructed by painting the surface of impressions with one of three high silver content electroconductive paints [Electrocure (EC), RS Silver Paint (SP) and Electrolube (EB)] and, once dry, backing this up with a cyanoacrylate based gel material (Zapit) and die stone. For each paint an impression was recorded of a gauge block of known step height (1270 microm) and five impressions of the palatal surface of a laboratory standard maxillary central incisor were also recorded. All impressions were taken using an addition cured silicone impression material (President). The resultant electroconductive replicas were mapped using a computer controlled probe. This data was analysed to determine both the replica's step height and, using surface matching techniques, the reproducibility of the replication process. The mean step heights recorded were; EC=1268.43 (s.d.=12.09), SP=1267.09 (s.d. 1.77) and EB 1299.58 (s.d. 14.47). Both EC and SP recorded the step height to within 3 microm. In the repeat replication of the palatal surface of an upper central incisor SP maintained a greater constancy of surface topography (99.6%) that was statistically superior to both EC (P < 0.05) and EB (P < 0.01). The SP was therefore the preferred paint for this technique. Bearing this in mind the replication technique was both accurate and reproducible but vigilance, as to the selection of paint for the process, should be exercised so as not to affect the good accuracy and reproducibility of the technique.


Patient Satisfaction Surveys in the Outpatient Clinic Setting: The Variability of Response With Positively or Negatively Toned Questions.
The purpose of this study was to determine whether a patient satisfaction survey in the outpatient clinic setting using questions with either a positive or negative tone would produce consistent responses. This was a prospective study using a 20-question paper survey delivered to medical students who were asked to rate on a scale of 1 to 10 to what degree they either agree or disagree with statements regarding their most recent personal outpatient clinic health care visit (any medical specialty). The same survey was administered again through an e-mail link 1 week later. One hundred fifty (77%) students completed the 20-item survey and 53 (35%) of the participating students completed the follow-up e-mail survey. Seven of the 10 question pairs on the paper survey revealed statistically significant differences in responses based on tone, with greater values for disagreement with negatively toned questions than values representing agreement with positive-toned questions. The match rates for similar questions posed on the paper survey and then the e-mail survey 1 week later ranged between 27.8% and 56.6%. This study demonstrated that, with an outpatient health care patient satisfaction survey, disagreement with a negative-toned question was stronger than agreement with a positive-toned question. There was poor correlation between survey responses when first posed on a paper survey and then repeated on a digital survey 1 week later. These findings suggest that the wording of survey questions may affect responses and that survey answers change with time and across delivery platforms.


Complications Following Brachial Arterial Catheterization in the Surgical Intensive Care Unit.
Clinically, complication rates of brachial arterial catheterization appear to far exceed those of the radial or common femoral arteries. The study objective was to define the complication rate after brachial arterial line insertion. All patients undergoing arterial line placement to the brachial artery in the surgical intensive care units (SICUs) at our institution were retrospectively identified and included in the study (January 2016-December 2018). Demographics, complications (distal ischemia, thrombosis/dissection, brachial sheath hematoma, catheter-related sepsis, and inadvertent dislodgement), and outcomes were collected and analyzed. Over the study period, 53 patients underwent brachial arterial catheterization. Common admitting services were cardiothoracic surgery (n = 31, 58%), transplant surgery (n = 7, 13%), and neurosurgery (n = 4, 7%). The mean age was 55 ± 17 58 (24-84) years, and 58% (n = 31) were male. The hospital length of stay (LOS) was 37 ± 35 23 (1-132) days, and ICU LOS was 30 ± 27 20 (1-127) days. Mortality was 57% (n = 30). Complications of brachial arterial line placement occurred in 21 patients (40%). In summary, brachial arterial catheters were associated with high mortality and prolonged ICU length of stay. This likely reflects the critically ill nature of patients in whom conventional-site arterial line placement is not possible. Complications following brachial arterial catheterization were unacceptably high. On this basis, we recommend that the brachial artery be avoided whenever possible for arterial line placement in the SICU.


Molecular cloning and characterization of a CBF gene from Capsella bursa-pastoris.
A new CBF gene was cloned from Capsella bursa-pastoris(shepherd's purse) by rapid amplification of cDNA ends (RACE). The full-length cDNA of C. bursa-pastoris CBF gene (designated as Cbcbf) was 1034 bp long and contained a 657 bp open reading frame (ORF) encoding a putative DRE/CRT (LTRE)-binding protein of 219 amino acids. The predicted CbCBF protein was found to have a potential nuclear localization signal (NLS) in its N-terminal region followed by an AP2 DNA-binding motif and an acidic C-terminal half that might act as an activator domain. Bioinformatic analysis revealed that Cbcbf strongly resembled other CBF genes from Arabidopsis thaliana (cbf1, cbf2, cbf3) and Brassica napus (Bncbf5, Bncbf 7, Bncbf16 and Bncbf17). Subsequent cold acclimation assay showed that Cbcbf was relevant to cold acclimation. Our study implies that Cbcbf might have similar functions possessed by other CBF genes such as inducing the expression of some cold-regulated genes and increasing plants' freezing tolerance.


Guidelines for the family therapeutic approach to eating disorders.
After a brief historical overview of the literature on family therapy in eating disorders, the authors' own clinical experience is summarized in some practical guidelines: give the family therapist a central position within the team, engage the family and/or spouse as co-therapist, explore the message of the eating disorder on different levels, neutralize the symptoms outside of the family interaction, promote direct communication, facilitate the separation-individuation process, and be available for a long time. Finally some special issues are discussed: sexual and/or physical abuse in the family, broken-home situations and single-parent families, married and chronic patients.


Methodological aspects of a computer-assisted telephone interview survey of oral health.
Despite the reported benefits of computer-assisted telephone interview (CATI) methods, experiences from their use in Australian oral health surveys have not been described. This report aimed to present methodological aspects of a CATI survey conducted in the five mainland states. A response rate of 66 per cent was obtained, yielding 4050 completed interviews. Analysis revealed generally small levels of non-response bias: persons who avoided or delayed dental treatment because of cost and non-health card holders were harder to contact, while non-English speakers and persons aged 20-29 years were less likely to participate. A total of 1770 person hours of interview time was spent on the survey: 64.5 per cent of that time was spent on the telephone with an average of 10 minutes 17 seconds per call (13 minutes 37 seconds per completed call). Only seven questions had missing data for more than 1 per cent of respondents. Comprehension of questions and cooperation with the interview was rated by interviewers as 'good' or 'very good' for more than 90 per cent of respondents. The CATI method was highly efficient and yielded good quality data for the survey.


Regulation on premarital exams, 1988.
This Regulation of Shanghai, China, requires couples desiring to marry to undergo a physical check-up before marriage. The check-ups are to take place at the district and county levels. Physicians involved in the examinations must have passed proficiency requirements and must keep the records of patients secret.


Identification and Characterization of a Periplasmic α-Carbonic Anhydrase (CA) in the Gametophytes of Saccharina japonica (Phaeophyceae).
Periplasmic or external carbonic anhydrases (CAs) have been well accepted as playing a crucial role in the acquisition of dissolved inorganic carbon; however, no cytological evidence or molecular information on these enzymes has been reported in seaweeds to date. In this study, the full-length cDNA sequence coding for a putative periplasmic Sjα-CA2 was cloned from the gametophytes of Saccharina japonica, an industrial brown seaweed. It was 1,728 bp in length and included a 263-bp 5'-untranslated region (UTR), a 577-bp 3'-UTR, and an 888-bp open reading frame encoding a protein precursor consisting of 295 amino acids. The mature protein, after removal of a predicted 28-residue signal peptide, was composed of 267 amino acids with a relative molecular weight of 29.27 kDa. Multisequence alignment and phylogenetic analysis indicated that it was a member of the α-CA family. Enzyme activity assays showed that the recombinant Sjα-CA2 in Escherichia coli possessed CO2 hydration and esterase activities, thus identifying this gene Sjα-CA2 in function. Immunogold electron microscopic observations with the prepared anti-Sjα-CA2 polyclonal antibody illustrated that Sjα-CA2 was located in periplasmic space of the kelp gametophyte cells. Quantitative real-time PCR results revealed that the transcription of Sjα-CA2 was induced by elevated HCO3- levels, but it was little changed while the kelp gametophytes were subjected to elevated CO2 concentrations. This study suggests that the periplasmic Sjα-CA2 might play a role in adapting to elevated environmental levels of HCO3- by dehydration of HCO3- to generate CO2 , which could be readily taken up by S. japonica gametophytes.


Calcium salts of polyunsaturated fatty acids deliver more essential fatty acids to the lactating dairy cow.
Recent research has focused on the importance of supplying essential fatty acids to the lactating dairy cow. The addition of essential fatty acids, specifically linoleic and linolenic acid, to dairy cow diets has been investigated as a method to increase reproductive efficiency. Rumen bacteria, however, biohydrogenate polyunsaturated fatty acids (PUFA) to saturated fatty acids. This is an important issue because it can also lead to milk fat depression when unsaturated fatty acids are fed. The formation of Ca salts has previously been shown to partially protect unsaturated fatty acids from rumen biohydrogenation. The objective of this experiment was to evaluate feed intake, milk production, and milk composition of cows fed Ca salts of palm fatty acids (CS) compared with those fed Ca salts of palm fatty acids with an increased content of PUFA (CS+PUFA). Nineteen lactating Holstein cows were used in a switchback experiment to determine any differences between CS and CS+PUFA on milk production and composition. This experiment consisted of 3 consecutive periods of 14 d. Treatments were formulated to provide 450 g/d (dry matter basis) of the Ca salt supplement and were mixed with the same basal ration. Milk weights and feed intakes were recorded daily for each cow. Milk samples were collected the last 2 d of each period and analyzed for milk composition and fatty acids. Dry matter intake [28.0 vs. 27.0 kg/d; standard error of the mean (SEM) = 0.4] and milk production (44.4 vs. 44.0 kg/d; SEM = 0.7) were not different between treatments for CS and CS+PUFA, respectively. Milk fat percentage (3.34 vs. 3.22%; SEM = 0.07) and milk protein percentage (2.78 vs. 2.80%; SEM = 0.01) were not different for CS- and CS+PUFA-fed cows. Feeding CS+PUFA reduced the concentration of palmitic acid in milk fat (28.3 vs. 26.8 wt%; SEM = 0.3). Supplementation of CS+PUFA increased the linoleic acid concentration (3.96 vs. 4.61 wt%; SEM = 0.1) of milk fat, indicating that linoleic acid was partially protected from rumen biohydrogenation. Concentrations of conjugated linoleic acid were also increased (0.44 vs. 0.52 wt%; SEM = 0.02) when cows consumed CS+PUFA, indicating that some biohydrogenation did occur. Supplementing CS+PUFA did not alter milk production, milk fat percentage, or dry matter intake when compared with CS. The CS+PUFA supplement supplied more linoleic acid to the small intestine for milk fat synthesis.


Pattern of stress protein expression in human lung cell-line A549 after short- or long-term exposure to cadmium.
Exposure to cadmium is associated with the development of pulmonary damage such as emphysema and lung cancer. This metal is also a powerful inducer of stress proteins in many biologic models. The present study was undertaken to evaluate whether an overexpression of the heat shock protein (hsp)72 stress protein, which indicates repair of damaged proteins, could be a sensitive and early biomarker of environmental pollution by Cd. In comparative studies, we examined the effects of exposure to Cd (as CdCl(2)) on the growth rate of the A549 pulmonary cell line, and (by Western blot analyses) on the induction of the hsp72 stress protein and metallothioneins (MTs). CdCl(2) exposure was studied for periods of 2 hr to 1 month. For short-term exposure (2-6 hr) to Cd concentrations higher than 50 microM, an overexpression of hsp72 appeared 6 hr later, suggesting that hsp72 might be considered an early biomarker of acute exposure to Cd. For exposures lasting more than 4 days, lower doses of Cd (0.1-10 microM) similar to levels encountered in occupational exposure induced a significant increase of the hsp72 level. Because the increase of hsp72 occurs for doses that did not affect cell proliferation, our work supports the idea that its overexpression might be used as a sensitive indicator of occupational exposure to Cd. However, increased resistance to Cd appeared in A549 cells exposed for 1 month and overexpression of hsp72 disappeared simultaneously. It is possible that, in vivo, cell adaptation also occurs throughout chronic exposure to Cd, with a decrease of hsp induction as a consequence. A dose-related increase of MTs was found after 4 days of exposure to Cd concentrations ranging from 0.1 to 10 microM without change of overexpression during chronic exposure, suggesting that MT expression could be a more constant indicator of Cd pollution. Because 0.1 microM Cd (11 microg/L) induces hsp72 expression, showing the presence of damaged proteins, our work suggests that the maximum allowable biologic exposure limit should be lowered.


Kinetics of cortical bone demineralization: controlled demineralization--a new method for modifying cortical bone allografts.
We investigated the kinetics of hydrochloric acid demineralization of human cortical bone with the objective of developing a method of controlled demineralization for structural bone allografts. It is known that the demineralization of cortical bone is a diffusion rate limited process with a sharp advancing reaction front. The demineralization kinetics of human cortical bone, described as the advance of the reaction front versus immersion time, were determined by measuring extraction of bone mineral in both planar and cylindrical geometries. Mathematical models based on diffusional mass transfer were developed to predict this process. The experimental data fit well with the behavior predicted by the model. The model for planar geometry is applicable to controlled demineralization of cortical bone allografts of irregular shapes such as cortical struts. The model for cylindrical geometry is appropriate when curved surfaces are involved such as in diaphyseal bone allografts. This method of demineralization has direct application to clinical modification of cortical bone allografts to potentially enhance their osteoinductive properties.


[Problems of living-related partial liver transplantation to adult patients].
Here, we describe the clinical course of an adult patient who had living-related liver transplantation (LRLT) from a donor with Gilbert's syndrome and problems of living-related liver transplantation to adult patients. A 22-year-old woman had been diagnosed as having liver cirrhosis at the age of 5. She had undergone devascularization and transsection of the esophagus, and splenectomy for esophageal varices at the age of 8. Complications such as spontaneous bacterial peritonitis and nonspecific colitis sometimes appeared from 17 years old, and icterus and ascites had appeared on all such occasions. Such complications had frequently occurred from 21 years old. Total bilirubin was 5.5 mg/dl and direct bil. was 4.2 mg/dl. The patient and her family members were informed that LRLT might be possible, and they indicated that the patient's 57-year old father was willing to act as the donor. His liver function was examined. His hepatic function was normal except for hyperbilirubinemia (T. Bil. 2.3 mg/dl, D. Bil. 0.3 mg/dl). He was diagnosed with Gilbert's Syndrome because of an increase of unconjugated bilirubin levels during low caloric intake and nicotinic acid test. The standard liver volume for the patient was calculated to be 900 ml on the basis of body weight. Volumetric analysis with computed tomography revealed that the left lobe volume of the donor's liver was 512 ml, corresponding to 56% of the recipient standard liver volume. This proposal was submitted to the ethical committee of Tokushima University School of Medicine and was accepted. In March 28, 1995, the patient underwent LRLT with the donor's left lobe as the graft. The graft weight was 440 g and the graft corresponded to 49% of the recipient's standard liver volume. Volumetric analysis showed rapid enlargement of graft to 683 ml as early as one week after the operation. The donor has returned to work after discharge from the hospital. The recipient is well 11 months after surgery. Total bilirubin was 1.8 mg/dl and D. Bil 0.5 mg/dl. LRLT may become an option for adult recipients, if graft of more than 30% of the recipient standard liver volume is transplanted even from a donor with Gilbert's syndrome.


The role of mucin 1 in respiratory diseases.
Recent evidence has demonstrated that mucin 1 (MUC1) is involved in many pathological processes that occur in the lung. MUC1 is a transmembrane protein mainly expressed by epithelial and hematopoietic cells. It has a receptor-like structure, which can sense the external environment and activate intracellular signal transduction pathways through its cytoplasmic domain. The extracellular domain of MUC1 can be released to the external environment, thus acting as a decoy barrier to mucosal pathogens, as well as serving as a serum biomarker for the diagnosis and prognosis of several respiratory diseases such as lung cancer and interstitial lung diseases. Furthermore, bioactivated MUC1-cytoplasmic tail (CT) has been shown to act as an anti-inflammatory molecule in several airway infections and mediates the expression of anti-inflammatory genes in lung diseases such as chronic rhinosinusitis, chronic obstructive pulmonary disease and severe asthma. Bioactivated MUC1-CT has also been reported to interact with several effectors linked to cellular transformation, contributing to the progression of respiratory diseases such as lung cancer and pulmonary fibrosis. In this review, we summarise the current knowledge of MUC1 as a promising biomarker and drug target for lung disease.


Acute macular neuroretinopathy in a patient with birdshot chorioretinopathy after intravitreal triamcinolone suspension injection.
To report a case of acute macular neuroretinopathy (AMN) after intravitreal triamcinolone acetonide (TRIESENCE®) injection for cystoid macular edema secondary to birdshot chorioretinopathy. A case report. A 62-year-old female. The patient presented with acutely decreased vision and a ring scotoma around her central vision three days after intravitreal triamcinolone acetonide (TRIESENCE®) injection for cystoid macular edema in her right eye (OD) secondary to birdshot chorioretinopathy. She had undergone pars plana vitrectomy, cataract extraction, and secondary intraocular lens implantation OD three months prior to the recent injection. Best-corrected visual acuity (BCVA) was 20/1000 OD and 20/50 OS. Intraocular pressure was 21 mmHg OD and 12 mmHg OS. Fluorescein angiography demonstrated a hypofluorescent area in the perifoveal zone OD. Optical coherence tomography OD depicted hyperreflective areas in the outer nuclear layer, outer plexiform layer, and retinal pigment epithelium. We diagnosed her with AMN OD and started her on brimonidine three times a day OD. She came back a week later with resolved scotoma and her vision improved to 20/60 OD. Five weeks later, BCVA was 20/40 and Intraocular pressures (IOP) was 12 mmHg OD. Intravitreal triamcinolone injection may be a cause of AMN with cystoid macular edema (CME) and borderline-high intraocular pressure. Brimonidine may be an effective treatment for these patients in the early course of the disease.


History of aromatase: saga of an important biological mediator and therapeutic target.
Aromatase is the enzyme that catalyzes the conversion of androgens to estrogens. Initial studies of its enzymatic activity and function took place in an environment focused on estrogen as a component of the birth control pill. At an early stage, investigators recognized that inhibition of this enzyme could have major practical applications for treatment of hormone-dependent breast cancer, alterations of ovarian and endometrial function, and treatment of benign disorders such as gynecomastia. Two general approaches ultimately led to the development of potent and selective aromatase inhibitors. One targeted the enzyme using analogs of natural steroidal substrates to work out the relationships between structure and function. The other approach initially sought to block adrenal function as a treatment for breast cancer but led to the serendipitous finding that a nonsteroidal P450 steroidogenesis inhibitor, aminoglutethimide, served as a potent but nonselective aromatase inhibitor. Proof of the therapeutic concept of aromatase inhibition involved a variety of studies with aminoglutethimide and the selective steroidal inhibitor, formestane. The requirement for even more potent and selective inhibitors led to intensive molecular studies to identify the structure of aromatase, to development of high-sensitivity estrogen assays, and to "mega" clinical trials of the third-generation aromatase inhibitors, letrozole, anastrozole, and exemestane, which are now in clinical use in breast cancer. During these studies, unexpected findings led investigators to appreciate the important role of estrogens in males as well as in females and in multiple organs, particularly the bone and brain. These studies identified the important regulatory properties of aromatase acting in an autocrine, paracrine, intracrine, neurocrine, and juxtacrine fashion and the organ-specific enhancers and promoters controlling its transcription. The saga of these studies of aromatase and the ultimate utilization of inhibitors as highly effective treatments of breast cancer and for use in reproductive disorders serves as the basis for this first Endocrine Reviews history manuscript.


History of transient ischemic attack definition.
Transient ischemic attacks have been recognized as a clinical entity for well over a century. Efforts before the availability of modern imaging to establish a diagnosis of inferred ischemic stroke led to acceptance of too long a time period (>24 h) compared with the actual typical events lasting <24 min (usually 5-15 min). Revision of the time period has improved diagnostic yield and discovered many whose image-documented acute infarct is associated with a short clinical course.


Predictors of Insulin Secretion in Japanese Patients with Histopathologically-confirmed Non-alcoholic Fatty Liver Disease.
Objective The correlation between the insulin secretion levels and the risk of hepatocarcinogenesis is clinically important. The aim of the present study was to determine the effects of various clinical parameters on C-peptide (CPR) levels in patients with non-alcoholic fatty liver disease (NAFLD). Methods In this retrospective cohort study, the effects of clinical parameters on insulin resistance (HOMA-IR) and insulin secretion levels (HOMA-β and fasting CPR) were investigated. Patients A total of 244 Japanese patients with histopathologically confirmed NAFLD were evaluated. Of these, 77 underwent the meal tolerance test (MTT) to evaluate the association of various clinical parameters with the CPR levels at 120 minutes. Results A multivariate analysis identified fasting plasma glucose (FPG) (≥110 mg/dL), aspartate aminotransferase (≥1.0×ULN IU/L), and a large waist circumference as independent predictors of insulin resistance (HOMA-IR ≥2.5) or high fasting CPR levels. Significant parameters for a low insulin secretion capacity (HOMA-β <30%) were not detected, except for the parameters mentioned in the diagnostic criteria of diabetes mellitus. Regarding the MTT, the CPR levels at 120 minutes were significantly higher in patients with fibrosis stage 3-4 than in those with stage 0-2. Body composition and genetic variation did not affect the CPR levels at 120 minutes. A multivariate analysis identified fibrosis stage (3-4), hyperuricemia, FPG (≥110 mg/dL), and procollagen III peptide (>1.0 U/mL) as independent predictors of high CPR levels at 120 minutes. Conclusion The present study showed that high plasma glucose levels and severe liver fibrosis stage influence insulin secretion levels in Japanese patients with NAFLD. Conservation of delayed insulin secretion levels was confirmed in patients with severe liver fibrosis.


Nanoparticle Delivery Platforms for RNAi Therapeutics Targeting COVID-19 Disease in the Respiratory Tract.
Since December 2019, a pandemic of COVID-19 disease, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread across the globe. At present, the Food and Drug Administration (FDA) has issued emergency approval for the use of some antiviral drugs. However, these drugs still have limitations in the specific treatment of COVID-19, and as such, new treatment strategies urgently need to be developed. RNA-interference-based gene therapy provides a tractable target for antiviral treatment. Ensuring cell-specific targeted delivery is important to the success of gene therapy. The use of nanoparticles (NPs) as carriers for the delivery of small interfering RNA (siRNAs) to specific tissues or organs of the human body could play a crucial role in the specific therapy of severe respiratory infections, such as COVID-19. In this review, we describe a variety of novel nanocarriers, such as lipid NPs, star polymer NPs, and glycogen NPs, and summarize the pre-clinical/clinical progress of these nanoparticle platforms in siRNA delivery. We also discuss the application of various NP-capsulated siRNA as therapeutics for SARS-CoV-2 infection, the challenges with targeting these therapeutics to local delivery in the lung, and various inhalation devices used for therapeutic administration. We also discuss currently available animal models that are used for preclinical assessment of RNA-interference-based gene therapy. Advances in this field have the potential for antiviral treatments of COVID-19 disease and could be adapted to treat a range of respiratory diseases.


Measuring the rate of change of haemodynamic response at the onset of exercise in normal limbs and those with intermittent claudication.
Patients with claudication have an inadequate haemodynamic response to exercise. Blood flow response will not only have a magnitude, but also a rate of change. There is scope for investigating these parameters, as manipulation of the factors which control them may benefit work to improve the treatment for claudication. This work compares the responses for patients with one normal limb and one with intermittent claudication. A custom-built ergometer allows unilateral, infragenicular plantar flexion exercise, whilst common femoral artery blood flow can be measured continuously by Duplex ultrasound. This apparatus was used to measure blood flow before, at the onset of and during a 5 W square-wave exercise stimulus in 15 patients. The claudicant group had a mean steady-state gain that was approximately half that of the normal group at around 170 ml min(-1) (p < 0.001) and a response time that was much shorter (p = 0.006). A mean response time of 21.0 +/- 1.4 s was achieved in claudicant limbs compared to 31.8 +/- 2.9 s in normals. However, the average rate of change of blood flow during this response time was estimated to still be greater for the normal group, at 431.7 +/- 47.1 ml min(-2), than for the claudicant group. The differences in magnitude and rate of change of limb blood flow response to exercise in claudicants were significant and may have implications for the treatment of claudication.


CT manifestation of neutron radiotherapy-induced changes in lung.
Sixty-nine chest CT studies of 36 patients with lung cancer were obtained at various times (21 to 649 days) following completion of fast neutron radiotherapy. Multiple scans (2 to 7) were available in 16 cases. Fractionated neutron radiotherapy was delivered over four to seven weeks to a total dose of 60 to 67 Gy photon equivalent. Parenchymal change within the lung was noted in 43% by 12 weeks, in 91% between 12 and 24 weeks, and in 100% after 24 weeks. Three different patterns of lung parenchymal change were evident. Ectatic air-filled bronchi were observed in more than 50% after 24 weeks. Mediastinal shift and thoracic shrinkage were demonstrated in six and three cases, respectively. Serial CT scans revealed that lung parenchymal changes usually became stable or shrunk after 36 weeks. The possible effect of chemotherapy (mitomycin-C, vinblastin and cis-platinum), in 19 of these patients is also discussed.


Cancer and beyond: the question of survivorship.
Today, more people are surviving cancer as a result of improved treatment and early diagnosis. In Australia, the 5-year survival rate for persons diagnosed with cancer is now approaching 50%. Although there is a growing population of cancer survivors, little is known about what surviving entails. Traditionally, a survivor has been defined as one who has been disease-free for more than 5 years. However, this definition does not take into account the experience nor the process of survival and the aim of this article is to document the process of surviving cancer as reflected in the experiences of cancer survivors. Using a method of hermeneutic phenomenology (as described by van Manen), the study draws on the stories of six women, who by their definition, are surviving cancer. A discussion of themes has been structured according to the everyday experiences of living in a body and living in time. The women describe a survival process that includes: 'feeling whole again'; 'the body as the house of suspicion'; 'the future in question'; 'changes in time'; 'lucky to be alive'; and 'sharing the journey'.


Prehension synergies: effects of object geometry and prescribed torques.
We studied the coordination of forces and moments exerted by individual digits in static tasks that required balancing an external load and torque. Subjects ( n=10) stabilized a handle with an attachment that allowed for change of external torque. Thumb position and handle width systematically varied among the trials. Each subject performed 63 tasks (7 torque values x 3 thumb locations x 3 widths). Forces and moments exerted by the digit tips on the object were recorded. Although direction and magnitude of finger forces varied among subjects, each subject used a similar multidigit synergy: a single eigenvalue accounted for 95.2-98.5% of the total variance. When task parameters were varied, regular conjoint digital force changes (prehension synergies) were observed. Synergies represent preferential solutions used by the subjects to satisfy mechanical requirements of the tasks. In particular, chain effects in force adjustments to changes in the handle geometry were documented. An increased handle width induced the following effects: (a). tangential forces remained unchanged, (b). the same tangential forces produced a larger moment T (t), (c). the increased T (t) was compensated by a smaller moment of the normal forces T(n), and (d). normal finger forces were rearranged to generate a smaller moment. Torque control is a core component of prehension synergies. Observed prehension synergies are only mechanically necessitated in part. The data support a theory of hierarchical organization of prehension synergies.


Reporting guidelines for music-based interventions.
Music-based interventions are used to address a variety of problems experienced by individuals across the developmental lifespan (infants to elderly adults). In order to improve the transparency and specificity of reporting music-based interventions, a set of specific reporting guidelines is recommended. Recommendations pertain to seven different components of music-based interventions, including theory, content, delivery schedule, interventionist, treatment fidelity, setting, and unit of delivery. Recommendations are intended to support Consolidated Standards for Reporting Trials (CONSORT) and Transparent Reporting of Evaluations with Non-randomized Designs (TREND) statements for transparent reporting of interventions while taking into account the variety, complexity, and uniqueness of music-based interventions.


Electrocatalytic Hydroxylation of Sterols by Steroid C25 Dehydrogenase from Sterolibacterium denitrificans.
The electrochemically driven catalysis of the complex molybdoenzyme steroid C25 dehydrogenase (S25DH) from the β-Proteobacterium Sterolibacterium denitrificans is reported. S25DH catalyses the oxygen-independent regioselective hydroxylation of the tertiary C25 atom of sterols and also their derivatives. Cholest-4-en-3-one is a native substrate for S25DH, which produces 25-hydroxycholest-4-en-3-one as a product of catalytic turnover. Cholecalciferol (vitD3 ) is also a substrate. S25DH was immobilised on a modified gold working electrode with the co-adsorbent chitosan. The complexes ferricyanide ([Fe(CN)6 ]3- ) and ferrocenium methanol (FM+ ) are effective artificial electron acceptors from S25DH and act as mediators of electron transfer between the electrode and the enzyme. 2-Hydroxypropyl-β-cyclodextrin (HPCD) was employed as a sterol solubiliser, in addition to 2-methoxyethanol. The catalytic activity varied, depending upon the concentration of solubiliser in the reaction mixture. Parallel studies with [Fe(CN)6 ]3- as a chemical (as opposed to electrochemical) oxidant coupled to HPLC analysis show that S25DH is capable of oxidising both vitD3 and its less stable isomer, pre-vitD3 , and that the former substrate is stabilised by HPCD.


Pulmonary atresia with intact ventricular septum, right-sided aortic arch and ventriculocoronary connection--prenatal echocardiographic diagnosis.
The authors describe the prenatal echocardiographic diagnosis of a rare case of pulmonary atresia with intact ventricular septum, right-sided aortic arch, and ventriculocoronary connection in a fetus at 21 weeks gestation. The diagnosis was confirmed at autopsy.


Engagement of older adults in regional health innovation: The ECOTECH concept mapping project.
Regional health innovation ecosystems can activate collaboration and support planning, self-management and development and commercialization of innovations. We sought to understand how older adults and their caregivers can be meaningfully engaged in regional health innovation ecosystems focused on health and aging-related technology innovation. A six-phase concept mapping technique gathered data over six time points across Canada. Brainstorming conducted online and in person identified engagement ideas. Statements were sorted by similarity and rated by participants on importance and feasibility. Qualitative approaches and multidimensional scaling, hierarchical cluster analysis, descriptive statistics and t tests were used for analysis. Sixty-two unique ideas were assembled into a seven-cluster framework of priorities for engagement in regional health innovation ecosystems including public forums, co-production and partnerships, engagement, linkage and exchange, developing cultural capacity, advocacy and investment in the ecosystem. This study identified a framework of priorities for directions and strategies for older adult and caregiver engagement in regional health innovation ecosystems. Next steps include collaborations to develop regional health innovation ecosystems that actively engage older adults and their caregivers in health and aging-related technology innovation.


Elucidation of enzymes in fermentation pathways used by Clostridium thermosuccinogenes growing on inulin.
Based on the presence and absence of enzyme activities, the biochemical pathways for the fermentation of inulin by Clostridium thermosuccinogenes DSM 5809 are proposed. Activities of nine enzymes (lactate dehydrogenase, phosphoenolpyruvate carboxylase, malate dehydrogenase, fumarase, fumarate reductase, phosphotransacetylase, acetate kinase, pyruvate kinase, and alcohol dehydrogenase) were measured at four temperatures (37, 47, 58, and 70 degrees C). Each of the enzymes increased 1.5 to 2.0-fold in activity between 37 and 58 degrees C, but only lactate dehydrogenase, fumarate reductase, malate dehydrogenase, and fumarase increased at a similar rate between 58 and 70 degrees C. No acetate kinase activity was observed at 70 degrees C. Arrhenius energies were calculated for each of these nine enzymes and were in the range of 9.8 to 25.6 kcal/mol. To determine if a relationship existed between product formation and enzyme activity, serum bottle fermentations were completed at the four temperatures. Maximum yields (in moles per mole hexose unit) for succinate (0.23) and acetate (0.79) and for biomass (29.5 g/mol hexose unit) occurred at 58 degrees C, whereas the maximum yields for lactate (0.19) and hydrogen (0.25) and the lowest yields for acetate (0.03) and biomass (19.2 g/mol hexose unit) were observed at 70 degrees C. The ratio of oxidized products to reduced products changed significantly, from 0.52 to 0.65, with an increase in temperature from 58 to 70 degrees C, and there was an unexplained detection of increased reduced products (ethanol, lactate, and hydrogen) with a concomitant decrease in oxidized-product formation at the higher temperature.


Novel zwitterionic complexes arising from the coordination of an ambiphilic phosphorus-aluminum ligand to gold.
Coordination of Mes2PC(=CHPh)AltBu2 to metal chlorides has been studied. Bridging P→M-Cl→Al coordinations were observed with Rh and Pd fragments, while chloride abstraction systematically occurred with gold. The resulting zwitterionic complexes have been fully characterized and analyzed by DFT calculations.


MicroRNA-145 Aggravates Hypoxia-Induced Injury by Targeting Rac1 in H9c2 Cells.
Myocardial infarction (MI) is a leading cause of morbidity and mortality. Here, we sought to explore the potential role and underlying mechanism of miR-145 in MI. H9c2 cells were cultured under persistent hypoxia to simulate MI. The hypoxia-induced injury was assessed on the basis of cell viability, migration, invasion and apoptosis. The expression of miR-145 was evaluated by qRT-PCR and the influence of aberrantly expressed miR-145 on H9c2 cells under hypoxia was also estimated. Utilizing bioinformatics methods, the target genes of miR-145 were verified by luciferase reporter assay. Then, effects of abnormally expressed target gene on miR-145 silenced H9c2 cells were assessed. Finally, the phosphorylation levels of key kinases in the phosphatidylinositol-3-kinase (PI3K)/AKT and the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways were detected by Western blot analysis. Hypoxia remarkably lowered viability, migration and invasion but promoted cell apoptosis. Meantime, the miR-145 level was up-regulated in H9c2 cells under hypoxia. Following experiments suggested that hypoxia-induced injury was exacerbated by miR-145 overexpression while was alleviated by miR-145 silence. Rac1 was predicted and further validated to be a target gene of miR-145. The influence of miR-145 silencing on H9c2 cells under hypoxia could be reversed by down-regulation of Rac1. Additionally, the phosphorylation levels of PI3K, AKT, MAPK and ERK were all elevated in miR-145 silenced cells and these alterations were reversed by down-regulation of Rac1. miR-145 silencing could protect H9c2 cells against hypoxia-induced injury by targeting Rac1, in which PI3K/AKT and MAPK/ERK pathways might be involved.


[Dosimetric comparison of non-small cell lung cancer treatment with multi fields dynamic-MLC IMRT].
We compared the dosimetric differences between the target and surrounding tissues/organs of the 5-field and 7,9-field (Hereinafter referred to as F5, F7, F9) treatment plan in non-small cell lung cancer (NSCLC) by the dynamic intensity-modulated radiotherapy (dIMRT), to provide reference for clinical application. Using Varian planning system (Eclipse 7.3), we randomly selected 30 cases of patients who received dIMRT to study, all patients were 5, 7, 9 fixed field dynamics intensity-modulated radiotherapy plans to meet the target prescription requirements (95% dose curve enveloping 100% of the PTV), by comparing dose-volume histogram DVH evaluation, and the maximum dose D(max), the minimum dose D(min), and the mean dose D(mean), and conformal index CI of PTV,organs at risk of spinal cord the maximum dose D(max), lung V(5), V(10), V(20), V(30), heart V(30) and esophageal V(50), V(60) of F5,F7 and F9 dIMRT plans,and compare the mu of the three treatment programs. The D(max), D(min) and D(mean) values of F5's PTV are (7 203 ± 128), (5 493 ± 331), (6 900 ± 138) cGy respectively; the D(max), D(min) and D(mean) values of F7's PTV are (7 304 ± 96), (5 526 ± 296), (6 976 ± 130) cGy respectively; and the D(max), D(min) and D(mean) values of F9's PTV are (7 356 ± 54), (5 578 ± 287), (7 019 ± 56) cGy respectively. The data shows that while we increased the numbers of fields, the isodose line surrounding the target area would also promote slightly. The conformity index CI of target became better with the increase of radiation fields. The whole lung V(5) and V(10) slightly became larger with increase of fields and the V(20) showed no significant difference in three models, V(30) of double lungs slightly decreased with the increase of fields. The above date was statistically meaningless (P > 0.05). With the increase of fields esophagus V(50) were reduced by 3% and 5% respectively, V(60) of the esophagus were reduced by 6% and 11%, the average dose reduced by 5% and 10% and spinal cord D(max) decreased by 9% and 13%. In the F7 and F9, heart V5 were lower than F5 plan by 11%, 19%. The mu of them were increased with the increase of radiation fields, Treatment time of F7 and F9 plan were longer by 15% and 25%. Through comparing the three fixed dIMRT plans, we could draw a conclusion that the three multi-field intensity-modulated radiotherapy in non-small cell lung cancer can meet the clinical target volume dose requirements. If the treatment is required to protect the patient's spinal cord, esophagus and heart, we can choose 7 or 9 fields. While other ordinary patients should be treated with 5 fields plan, to shorten the treatment time and improve the biological effects of lesions, and lower mu of plans to avoid unnecessary irradiation of normal tissues.


Community-acquired pneumonia in a cohort of former injection drug users with and without human immunodeficiency virus infection: incidence, etiologies, and clinical aspects.
Although the association among bacterial pneumonia, human immunodeficiency virus (HIV) infection, and injection-drug use seems to have been well established, accurate estimates of the risk of community-acquired pneumonia among HIV-positive and HIV-negative injection-drug users (IDUs) are still needed. To estimate the incidence of pneumonia in a community of former IDUs, we followed 4,236 persons between 1991 and 1994; 1,114 (26.3%) were HIV-positive and 3,122 (73.7%) were HIV-negative. All patients were evaluated for pneumonia by standard criteria, a serum sample was obtained from each participant at least once a year, and laboratory values were monitored. Overall, 149 episodes of pneumonia occurred among HIV-positive patients and 61 among HIV-negative patients; incidence rates were 90.5 and 14.2 (per 1,000 person-years), respectively. The most common etiologic agents were Streptococcus pneumoniae, Chlamydia pneumoniae, and Haemophilus influenzae. Among the HIV-positive former IDUs, there was a 1.37-fold increase in the relative risk of pneumonia for every decrease of 100/mm3 in the CD4 cell count (95% confidence interval, 1.16-1.61). The incidence of community-acquired pneumonia was markedly higher among HIV-positive participants than among HIV-negative ones, a finding similar to that concerning the general population.


Radiofrequency energy loop primes cardiac, neuronal, and skeletal muscle differentiation in mouse embryonic stem cells: a new tool for improving tissue regeneration.
Radiofrequency (RF) waves from Wi-Fi (wireless fidelity) technologies have become ubiquitous, with Internet access spreading into homes, and public areas. The human body harbors multipotent stem cells with various grading of potentiality. Whether stem cells may be affected by Wi-Fi RF energy remains unknown. We exposed mouse embryonic stem (ES) cells to a Radio Electric Asymmetric Conveyer (REAC), an innovative device delivering Wi-Fi RF of 2.4 GHz with its conveyer electrodes immersed into the culture medium. Cell responses were investigated by real-time PCR, Western blot, and confocal microscopy. Single RF burst duration, radiated power, electric and magnetic fields, specific absorption rate, and current density in culture medium were monitored. REAC stimulation primed transcription of genes involved in cardiac (GATA4, Nkx-2.5, and prodynorphin), skeletal muscle (myoD) and neuronal (neurogenin1) commitment, while downregulating the self renewal/pluripotency-associated genes Sox2, Oct4, and Nanog. REAC exposure enhanced the expression of cardiac, skeletal, and neuronal lineage-restricted marker proteins. The number of spontaneously beating ES-derived myocardial cells was also increased. In conclusion, REAC stimulation provided a "physical milieu" optimizing stem cell expression of pluripotentiality and the attainment of three major target lineages for regenerative medicine, without using chemical agonists or vector-mediated gene delivery.


Cooperativity between S···π and Rg···π in the OCS···C6H6···Rg (Rg = He, Ne, Ar, and Kr) van der Waals complexes.
The complexes OCS···C(6)H(6), C(6)H(6)···Rg, and OCS···C(6)H(6)···Rg (Rg = He, Ne, Ar, and Kr) have been studied by means of MP2 calculations and QTAIM analyses. The optimized geometries of the title complexes have C(6v) symmetry. The intermolecular interactions in the OCS···C(6)H(6)···Rg complexes are comparatively stronger than that in the OCS···C(6)H(6) complex, which prove that the He, Ne, Ar, and Kr atoms have the ability to form weak bonds with the benzene molecule. In QTAIM studies, the π-electron density of benzene was separated from the total electron density. The molecular graphs and topological parameters of the OCS···πC(6)H(6), πC(6)H(6)···Rg, and OCS···πC(6)H(6)···Rg complexes indicate that the interactions are mainly attributed to the electron density provided by the π-bonding electrons of benzene and the top regions of the S and Rg atoms. Charge transfer is observed from the benzene molecule to SCO/Rg in the formation of the OCS···C(6)H(6), C(6)H(6)···Rg, and OCS···C(6)H(6)···Rg complexes. Molecular electrostatic potential (MEP) analyses suggest that the electrostatic energy plays a pivotal role in these intermolecular interactions.


Skin blood flow and local temperature independently modify sweat rate during passive heat stress in humans.
Sweat rate (SR) is reduced in locally cooled skin, which may result from decreased temperature and/or parallel reductions in skin blood flow. The purpose of this study was to test the hypotheses that decreased skin blood flow and decreased local temperature each independently attenuate sweating. In protocols I and II, eight subjects rested supine while wearing a water-perfused suit for the control of whole body skin and internal temperatures. While 34°C water perfused the suit, four microdialysis membranes were placed in posterior forearm skin not covered by the suit to manipulate skin blood flow using vasoactive agents. Each site was instrumented for control of local temperature and measurement of local SR (capacitance hygrometry) and skin blood flow (laser-Doppler flowmetry). In protocol I, two sites received norepinephrine to reduce skin blood flow, while two sites received Ringer solution (control). All sites were maintained at 34°C. In protocol II, all sites received 28 mM sodium nitroprusside to equalize skin blood flow between sites before local cooling to 20°C (2 sites) or maintenance at 34°C (2 sites). In both protocols, individuals were then passively heated to increase core temperature ~1°C. Both decreased skin blood flow and decreased local temperature attenuated the slope of the SR to mean body temperature relationship (2.0 ± 1.2 vs. 1.0 ± 0.7 mg·cm(-2)·min(-1)·°C(-1) for the effect of decreased skin blood flow, P = 0.01; 1.2 ± 0.9 vs. 0.07 ± 0.05 mg·cm(-2)·min(-1)·°C(-1) for the effect of decreased local temperature, P = 0.02). Furthermore, local cooling delayed the onset of sweating (mean body temperature of 37.5 ± 0.4 vs. 37.6 ± 0.4°C, P = 0.03). These data demonstrate that local cooling attenuates sweating by independent effects of decreased skin blood flow and decreased local skin temperature.


The compatibility between Shiite and Kantian approach to passive voluntary euthanasia.
Euthanasia is one of the controversial topics in current medical ethics. Among the six well-known types of euthanasia, passive voluntary euthanasia (PVE) seems to be more plausible in comparison with other types, from the moral point of view. According to the Kantian framework, ethical features come from 'reason'. Maxims are formulated as categorical imperative which has three different versions. Moreover, the second version of categorical imperative which is dubbed 'principle of ends' is associated with human dignity. It follows from this that human dignity has an indisputable role in the Kantian story. ON THE OTHER HAND, THERE ARE TWO MAIN THEOLOGICAL SCHOOLS IN ISLAMIC TRADITION WHICH ARE CALLED: Ash'arite and Mu'tazilite. Moreover, there are two main Islamic branches: Shiite and Sunni. From the theological point of view, Shiite's theoretical framework is similar to the Mu'tazilite one. According to Shiite and Mu'tazilite perspectives, moral goodness and badness can be discovered by reason, on its own. Accordingly, bioethical judgments can be made based on the very concept of human dignity rather than merely resorting to the Holy Scripture or religious jurisprudential deliberations. As far as PVE is concerned, the majority of Shiite scholars do not recognize a person's right to die voluntarily. Similarly, on the basis of Kantian ethical themes, PVE is immoral, categorically speaking. According to Shiite framework, however, PVE could be moral in some ethical contexts. In other words, in such contexts, the way in which Shiite scholars deal with PVE is more similar to Rossian ethics rather than the Kantian one.


Salivary gland epithelial cells from patients with Sjögren's syndrome induce B-lymphocyte survival and activation.
Primary Sjögren's syndrome (pSS) is characterised by chronic hyperactivation of B lymphocytes. Salivary gland epithelial cells (SGECs) could play a role in promoting B-lymphocyte activation within the target tissue. We aimed to study the interactions between SGECs from patients with pSS or controls and B lymphocytes. Patients had pSS according to 2016 European League Against Rheumatism/American College of Rheumatology criteria. Gene expression analysis of SGECs and B lymphocytes from pSS and controls isolated from salivary gland biopsies and blood was performed by RNA-seq. SGECs from pSS and controls were cocultured with B-lymphocytes sorted from healthy donor blood and were stimulated. Transwell and inhibition experiments were performed. Gene expression analysis of SGECs identified an upregulation of interferon signalling pathway and genes involved in immune responses (HLA-DRA, IL-7 and B-cell activating factor receptor) in pSS. Activation genes CD40 and CD48 were upregulated in salivary gland sorted B lymphocytes from patients with pSS. SGECs induced an increase in B-lymphocyte survival, which was higher for SGECs from patients with pSS than controls. Moreover, when stimulated with poly(I:C), SGECs from patients with pSS induced higher activation of B-lymphocytes than those from controls. This effect depended on soluble factors. Inhibition with anti-B-cell activating factor, anti-A proliferation-inducing ligand, anti-interleukin-6-R antibodies, JAK1/3 inhibitor or hydroxychloroquine had no effect, conversely to leflunomide, Bruton's tyrosine kinase (BTK) or phosphatidyl-inositol 3-kinase (PI3K) inhibitors. SGECs from patients with pSS had better ability than those from controls to induce survival and activation of B lymphocytes. Targeting a single cytokine did not inhibit this effect, whereas leflunomide, BTK or PI3K inhibitors partially decreased B-lymphocyte viability in this model. This gives indications for future therapeutic options in pSS.


Cancer-associated retinopathy in neuroendocrine carcinoma of the fallopian tube.
A 70-year-old woman developed progressive visual loss with compromised visual acuity and visual fields, cells in the anterior chamber and vitreous, attenuated retinal arterioles, and macular edema. She had undergone right oophorectomy and partial salpingectomy nearly 50 years earlier. Full-field and multifocal electroretinography showed waveforms of markedly attenuated amplitudes, findings consistent with cancer-associated retinopathy (CAR). Positron emission tomography revealed a nodule in the anterior wall of a right hydrosalpinx. Total laparoscopic hysterectomy yielded a neuroendocrine fallopian tube malignancy. She underwent partial treatment with paclitaxel and carboplatin that was aborted because of the development of herpes zoster infection. At 15 months following diagnosis, her ophthalmic status was stable. This is the first report of CAR in neuroendocrine carcinoma of the fallopian tube.


MR imaging of the acetabular labrum: variations in 200 asymptomatic hips.
The purpose of this study was to describe the MR appearance of the acetabular labrum in asymptomatic subjects and correlate the MR appearance with age and sex. We evaluated high-resolution T1-weighted spin-echo coronal MR images of one hip in each of 200 asymptomatic individuals (84 men, 116 women; mean age, 44 years old; range, 15-82 years old). The labral shapes (triangular, round, flat, or absent), the intralabral signal intensity changes, and the possible extension of the intralabral signal intensity changes to the labral surface were assessed on two sections for each subject and correlated with age and sex. Triangle was the dominant shape seen on MR imaging (66%). However, its frequency decreased significantly with age. Absence of labrum was the second most frequent pattern (14%) and increased significantly with age. Round and flat labra were found in 11% and 9% of subjects, respectively, with no significant age correlation. The frequency of homogeneous labra with low signal intensity decreased with age. Intralabral areas of high signal intensity communicating with the free surface increased with age. The large variability of the MR appearance of the labrum in asymptomatic hips must be considered when interpreting MR examinations of patients in whom labral lesions are suspected.


Interventional echocardiography: Opportunities and challenges in an emerging field.
The growth of transcatheter structural heart disease interventions has created a subspecialty of interventional imagers who focus on preprocedural planning and the periprocedural guidance of these complex cases. In particular interventional imagers who focus on periprocedural guidance have developed a specific expertise in interventional transesophageal echocardiography (iTEE). This nascent field has challenges in training, reimbursement, and occupational hazards which are unique to this field. This review encompasses the evolution of iTEE, current challenges, and future opportunities.