Assay, purification and characterization of a recombinant malaria circumsporozoite fusion protein by high-performance liquid chromatography.
The immunodominant repeat region of the malaria circumsporozoite protein from Plasmodium falciparum was purified from a recombinant Escherichia coli to study as a potential subunit vaccine. The recombinant protein, R32Leu-Arg, is composed of 32 tetrapeptide repeat sequences from the circumsporozoite protein (R32) linked to the dipeptide, Leu-Arg. R32Leu-Arg was purified by a series of precipitation steps including temperature, ammonium sulfate, and acid pH treatments; followed by reversed-phase high-performance liquid chromatography (RP-HPLC). An automated RP-HPLC assay was developed to measure the R32Leu-Arg concentration during both fermentation and purification. This assay was used in a variety of applications including measurement of production levels of the antigen during fermentation, evaluation of the protein purification process, quantitation of protein recovery, and as one criterion of protein purity. With minimal changes, the assay conditions were easily adapted to the semi-preparative level to produce 200 mg of purified product. The purified product was characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis; amino acid composition; and analytical size-exclusion and RP-HPLC.


Correlation analysis of the transcriptome of growing leaves with mature leaf parameters in a maize RIL population.
To sustain the global requirements for food and renewable resources, unraveling the molecular networks underlying plant growth is becoming pivotal. Although several approaches to identify genes and networks involved in final organ size have been proven successful, our understanding remains fragmentary. Here, we assessed variation in 103 lines of the Zea mays B73xH99 RIL population for a set of final leaf size and whole shoot traits at the seedling stage, complemented with measurements capturing growth dynamics, and cellular measurements. Most traits correlated well with the size of the division zone, implying that the molecular basis of final leaf size is already defined in dividing cells of growing leaves. Therefore, we searched for association between the transcriptional variation in dividing cells of the growing leaf and final leaf size and seedling biomass, allowing us to identify genes and processes correlated with the specific traits. A number of these genes have a known function in leaf development. Additionally, we illustrated that two independent mechanisms contribute to final leaf size, maximal growth rate and the duration of growth. Untangling complex traits such as leaf size by applying in-depth phenotyping allows us to define the relative contributions of the components and their mutual associations, facilitating dissection of the biological processes and regulatory networks underneath.


An online cross-sectional survey of community pharmacists to assess information needs for evidence-based self-medication counselling.
Community pharmacists play an important role in healthcare. They are frequently visited by patients to receive advice on self-medication products. Little research has been conducted to investigate pharmacists' information needs for evidence-based self-medication counselling. To assess community pharmacists' information needs in five predefined areas: general and specific individual needs, quality needs, utilisation needs, implication needs, and access needs for evidence based self-medication counselling. After ethical approval, we conducted an exploratory, semi-quantitative, cross-sectional online survey. Members of three different chambers of pharmacists in Germany were invited to participate anonymously in the survey. They gave informed consent and received no incentive for their participation. Quantitative outcome: Frequency of relevance / importance of items within predefined information needs areas, except for access needs. Qualitative outcome: Open-text responses concerning all information needs. We analysed data from a total of 823 participants who completed the survey. General and specific information such as dosage (74.2% [611/823]) and when to refer to a physician (64.6% [532/823]) as well as an over-the-counter product's effectiveness according to medical guidelines (71.4% [588/823]) were rated as very important. Participants reported to prefer digital information sources (50.5% [416/823] strongly agreed), especially in the form of an easily accessible database (61.6% [507/823] strongly agreed) that contains regularly updated, manufacturer-independent, critically appraised, concise information. Community pharmacists expressed distinct information needs for evidence-based self-medication counselling. Further information services on essential evidence-based pharmacy knowledge may be necessary to support implementation.


Clinical application of large channel endoscopic decompression in posterior cervical spine disorders.
We investigated the clinical value of posterior percutaneous endoscopic decompression (PED) for single-segment cervical spondylotic myelopathy (CSM) and cervical spondylotic radiculopathy (CSR). Clinical data from February 2016 to March 2018 were collected for 32 patients with single-segment CSM or CSR who underwent posterior cervical percutaneous large channel endoscopic decompression and completed a regular follow-up exam at 12 months after surgery. Patient data included: age (range 30-81 years and mean of 49.5 years) and surgical information (operation time, bleeding volume, hospital stay, complications, etc.). The Japan Orthopedic Association (JOA) score and pain visual analog scale (VAS) were used to evaluate the surgical outcome for each patient. Cervical spine radiographs were used to evaluate cervical curvature (Cervical spondylotic angle (CSA), C2-7 Cobb angle) and CT and MRI were used to assess the extent of laminectomy and nerve root decompression. The JOA score, VAS score, cervical curvature were analyzed statistically, and the clinical outcome was evaluated using modified Macnab criteria at the last patient follow-up exam. The JOA and VAS scores were compared before and after surgery (1 day Pre-op; 3 days, 3 months and 12 months Post-op). The differences were statistically significant (P < 0.05). There were significant differences in cervical curvature (C2-7 Cobb angle) between the time points (1 day Pre-op; 3 days, 3 months and 12 months Post-op), but the differences were no statistically significant in CSA angle (P < 0.05) The operation time range was 45-110 min (mean 68.6 ± 23.8 min); the intraoperative blood loss range was 20-85 ml (mean28 ± 14.8 ml), and the hospital stay was 3-8 days (mean4.5 days). At the last follow-up, the clinical efficacy was evaluated using modified Macnab criteria. The results were excellent in 18 cases, good in 11 cases, and fair in 3 cases. The combined excellent and good rate was 93.75%. Postoperative CT and MRI showed that the compression of the spinal cord or nerve roots was completely relieved. Endoscopic decompression of posterior cervical vertebral disorders is a safe, effective, and minimally invasive surgical procedure with rapid recovery times. This procedure warrants additional research and clinical application.


Cancer protective effects of plums: A systematic review.
Plums is one of the most cultivated stone fruits due to its fast growing popularity. It has various traditionally recognized health benefits. There are two main commercial types of plums: the European plum (Prunus domestica) and the Japanese plum (Prunus salicina), each having many varieties. Researchers are gathering further evidence of pharmacological effects for plums by scientifically studying its anti-inflammatory, antioxidant properties. A systematic review analysing the literature related to the effects of plums on prevention and treatment of cancer is warranted. This is the first review examining the cancer-related effects of plums. Antioxidation properties of the active constituents of plum were also compared. Scopus, Google Scholar, PubMed, Medxriv and Cochrane Library databases, from their date of inception until July 2021 were utilized. The risk of bias was assessed using CONSORT checklist. A total of 6639 studies were screened and eventually only 54 studies were included. Full-text review of included studies revealed that plum extracts were rich in antioxidants. Overall, most of the studies that fulfilled the eligibility criteria were in vitro and a few clinical studies involving in vivo work. Therefore, it would be beneficial to perform more studies on animals or humans, to confirm that the result obtained from these in vitro studies are able to be extrapolated in a wider range of applications. Further clinical and in vivo studies are warranted to validate plums as a functional food for treatment and prevention of cancer.


Cell- and tissue-specific expression of a 34,000-molecular-weight peptide growth factor in humans.
A 34,000-dalton peptide growth factor that we originally identified in human placental trophoblasts and in certain carcinomas was shown to be expressed in several normal human tissues. A highly specific antibody to the trophoblast-derived growth factor was used in an immunoperoxidase staining technique to identify the immunoreactive peptide in tissue sections. Immunoreactivity was seen in the adrenal cortex, Leydig cells of the testes, and follicular cells of the thyroid. In addition, strong staining was seen in the ducts and terminal ductules of the pancreas, in glandular epithelium of the prostate, in the chief cells of the stomach, and in the columnar epithelium of the trachea and bronchus of the lung. Certain tissues were negative for the peptide, including the adrenal medulla, liver, esophagus, small intestine, colon, bladder, lymph node, spleen, bone marrow, and thymus. Thus, the expression of the peptide depends on cell lineage and the state of differentiation; tissues of hematopoietic lineage are devoid of the 34,000-dalton peptide, whereas some of the major hormone-secreting tissues that are under pituitary control show the highest immunoreactivity.


Lethal septicemia caused by calcified cavo-tricuspid thrombus. Case report on a patient with atrial shunt.
With the introduction of one way calibrated shunt systems, made of silicon rubber, an efficient treatment of hydrocephalus seemed to be possible. The mortality rate decreased rapidly for example for non-communicating hydrocephalus from 80 to 20%. However, other complications appeared, such as shunt infections, shunt malfunctions and even severe thromboembolic complications and septic shock. This report presents one patient with shunt-treated normal pressure hydrocephalus who developed pulmonary emboli, mural calcified atrial thrombus with involvement of the tricuspid valve and shunt infection with lethal septic shock. Despite of an aggressive treatment, he died of multiple organ system failure.


A membrane protein from IFN-beta-treated Daudi cells causes a cessation in cell growth.
An interferon-induced 17 kDa protein has been partially purified from the membranes of interferon-beta-treated Daudi cells. A fraction containing the 17 kDa protein purified 200 fold causes an inhibition of growth of Daudi, Namalva and Hela cells. The same fraction purified from the membranes of untreated cells causes no inhibition of cell growth. This interferon-beta-induced protein is located on the exterior of Daudi cells for it can be labeled with [125I] iodine catalyzed by lactoperoxidase. These results suggest that interferons induce a cell surface protein whose role is to cause an inhibition of cell growth.


Identification of a 1.1-Mb region for a carcass weight QTL onbovine Chromosome 14.
We previously mapped a quantitative trait locus for carcass weight, designated Carcass Weight-1 (CW-1), to bovine Chromosome 14 using a purebred Wagyu pedigree based on progeny design analysis. To refine the critical region within 8.1 cM flanked by microsatellites BMS1941 and INRA094, we constructed a bacterial artificial chromosome (BAC) contig composed of 60 tiled BAC clones and prepared a high-density physical map including 80 microsatellites, of which 55 were developed in this study. We conducted linkage disequilibrium (LD) mapping in the CW-1 region with 47 microsatellites using paternal half-sib pedigrees whose sires exhibited homozygous CW-1 Q alleles in the region. The LD mapping study significantly narrowed the CW-1 locus to the 1.1-Mb region between microsatellites DIK7012 and DIK7020. Finally, we surveyed the 1.1-Mb-region genotypes of 1700 steers from 11 bulls having -/-, Q/-, or Q/Q alleles in the region, and we examined the effect of the CW-1 Q allele on carcass weight. The presence of the first Q increased carcass weight by 23.6 kg (95% confidence interval [CI], 17.6-29.5 kg), and the second Q increased carcass weight an additional 15.2 kg (95% CI, 10.7-19.7 kg). These results indicate the presence of a gene responsible for carcass weight within the 1.1-Mb region.


Electric-field-enhanced collection of laser-ablated materials onto a solvent bridge for electrospray ionization mass spectrometry.
Ambient imaging mass spectrometry methods are critically dependent on the ability to efficiently collect all substances from a well-defined area of the sample. Improvements in this area are critical and enabling. Methods for the efficient collection of laser-ablated materials directly into a solvent, for immediate transport to an ion source, have been explored using the application of electric fields. Electric-field-enhanced collection of laser-ablated materials has been demonstrated. Demonstrated increases in collection efficiency are as large as two orders of magnitude, in particular for hydrated biological materials, such as living bacterial colonies. This was achieved by applying approximately 1 kV between the sample and the receiving solvent surface. Electric-field-enhanced collection of laser-ablated materials holds great promise for ambient sampling and imaging mass spectrometry with rapid and direct interfacing to ionization sources, such as electrospray.


The effectiveness of community-based visual screening and utility of adjunctive diagnostic aids in the early detection of oral cancer.
A systematic review of community-based oral cancer screening programmes published between 1966 and March 2002 was undertaken. Data relating to study design, sampling and characteristics of the study group, interventions, and reported outcomes and diagnostic value of visual screening or adjunctive diagnostic aids were abstracted from 36 articles meeting inclusion and exclusion criteria. From these reports, there is insufficient evidence to demonstrate the effectiveness of community-based oral cancer visual screening in enhancing the early detection of oral cancer, due to small effect size. While the evidence is fair to support use of toluidine blue as an aid in diagnosis of oral cancer, there is insufficient evidence to determine whether the use of this or other adjunctive techniques will increase the detection of oral malignancies in community screening programmes. Targeted clinical examination of high-risk individuals may be more effective than mass screening in facilitating early detection of oral cancers.


Organoid and microfluidics-based platforms for drug screening in COVID-19.
Proposing efficient prophylactic and therapeutic strategies for coronavirus 2019 (COVID-19) requires precise knowledge of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis. An array of platforms, including organoids and microfluidic devices, have provided a basis for studies of SARS-CoV-2. Here, we summarize available models as well as novel drug screening approaches, from simple to more advanced platforms. Notably, organoids and microfluidic devices offer promising perspectives for the clinical translation of basic science, such as screening therapeutics candidates. Overall, modifying these advanced micro and macro 3D platforms for disease modeling and combining them with recent advances in drug screening has significant potential for the discovery of novel potent drugs against COVID-19.


Biological and photochemical degradation rates of diethylenetriaminepentaacetic acid (DTPA) in the presence and absence of Fe(III).
The environmental fate of ethylenediaminetetraacetic acid (EDTA) has been extensively studied, while much less is known about the environmental behaviour of diethylenetriaminepentaacetic acid (DTPA). In this study, it was confirmed that DTPA is persistent toward biodegradation. The biodegradability of DTPA was investigated in the absence and in the presence of Fe(III) by using CO2 evolution test and Manometric respirometry test. The CO2 evolution and oxygen uptake of iron-free (DTPA was added as free acid) and Fe(III)DTPA were less than in inoculum blank. Possible inhibitor effect was analysed by testing biodegradation of sodium benzoate with and without iron-free or Fe(III)DTPA in the Manometric respirometry test. Only slight inhibition was observed when DTPA was added as free acid. Photodegradation of iron-free DTPA and Fe(III)-DTPA complex was studied by using sunlight and UV radiation at the range 315-400 nm emitted by black light lamps. The results indicate that DTPA added as free acid degrades photochemically in humic lake water. Fe(III)DTPA was shown to be very photolabile in humic lake water in the summer; the photochemical half-life was below one hour. Photodegradation products were identified by the mass spectrometric technique (GC-MS). It was shown that photodegradation of Fe(III)DTPA does not result in total mineralization of the compound. Diethylenetriaminetetraacetic acid, diethylenetriaminetriacetic acid, ethylenediaminetriacetic acid, N,N'- and/or N,N-ethylenediaminediacetic acid, iminodiacetate, ethylenediaminemonoacetic acid and glycine were identified as photodegradation products of Fe(III)DTPA. Based on these observations, we propose a photodegradation pathway for Fe(III)DTPA.


Characterization of effector memory CD8+ T cells in the synovial fluid of rheumatoid arthritis.
Little is known about the cellular characteristics of CD8(+) T cells in rheumatoid arthritis (RA). We addressed this by investigating whether the frequency of the CD8(+) T cell subsets and their phenotypic characteristics are altered in the peripheral blood and synovial fluid (SF) from patients with RA. In this study, CD8(+) T cells, mainly CD45RA(-) effector memory (EM) CD8(+) T cells, were increased significantly in the SF, but not in the peripheral blood from RA patients, compared with healthy controls. The synovial EM CD8(+) T cells were activated phenotypes with high levels of CD80, CD86, and PD-1, and had a proliferating signature in vivo upon Ki-67 staining, whereas the Fas-positive cells were prone to apoptosis. In addition, EM CD8(+) T cells in the SF were less cytotoxic, as they expressed less perforin and granzyme B. In particular, the proportions of synovial fluid mononuclear cells that were CCR4(+)CD8(+) T cells and IL-4-producing CD8(+) T cells (i.e., Tc2 cells) were significantly higher than those in peripheral blood mononuclear cells of patients with RA and healthy controls. In addition, the number of IL-10-producing CD8(+) suppressor T (Ts) cells increased significantly in the SF of RA patients. Especially, CD8(+) T cells were inversely correlated with disease activity. These findings strongly suggest that EM CD8(+) T cells in the SF are increased, likely because of inflammation, and they may be involved in modulating inflammation, thereby affecting the development and progression of RA.


Intracellular ROS scavenging and antioxidant regulation of WL15 from cysteine and glycine-rich protein 2 demonstrated in zebrafish in vivo model.
Antioxidant peptides are naturally present in food, especially in fishes, and are considered to contain rich source of various bioactive compounds that are structurally heterogeneous. This study aims to identify and characterize the antioxidant property of the WL15 peptide, derived from Cysteine and glycine-rich protein 2 (CSRP2) identified from the transcriptome of a freshwater food fish, Channa striatus. C. striatus is already studied to contain high levels of amino acids and fatty acids, besides traditionally known for its pharmacological benefits in the Southeast Asian region. In our study, in vitro analysis of WL15 peptide exhibited strong free radical scavenging activity in 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS), superoxide anion radical and hydrogen peroxide (H2O2) scavenging assay. Further, to evaluate the cytotoxicity and dose-response, the Human dermal fibroblast (HDF) cells were used. Results showed that the treatment of HDF cells with varying concentrations (10, 20, 30, 40 and 50 μM) of WL15 peptide was not cytotoxic. However, the treatment concentrations showed enhanced antioxidant properties by significantly inhibiting the levels of free radicals. For in vivo assessment, we have used zebrafish larvae for evaluating the developmental toxicity and for determining the antioxidant property of the WL15 peptide. Zebrafish embryos were treated with the WL15 peptide from 4 h of post-fertilization (hpf) to 96 hpf covering the embryo-larval developmental period. At the end of the exposure period, the larvae were exposed to H2O2 (1 mM) for inducing generic oxidative stress. The exposure of WL15 peptide during the embryo-larval period showed no developmental toxicity even in higher concentrations of the peptide. Besides, the WL15 peptide considerably decreased the intracellular reactive oxygen species (ROS) levels induced by H2O2 exposure. WL15 peptide also inhibited the H2O2-induced caspase 3-dependent apoptotic response in zebrafish larvae was observed using the whole-mount immunofluorescence staining. Overall results from our study showed that the pre-treatment of WL15 (50 μM) in the H2O2-exposed zebrafish larvae, attenuated the expression of activated caspase 3 expressions, reduced Malondialdehyde (MDA) levels, and enhanced antioxidant enzymes, including superoxide dismutase (SOD) and catalase (CAT). The gene expression of antioxidant enzymes such as glutathione S-transferase (GST), glutathione peroxide (GPx) and γ-glutamyl cysteine synthetase (GCS) was found to be upregulated. In conclusion, it can be conceived that pre-treatment with WL15 could mitigate H2O2-induced oxidative injury by elevating the activity and expression of antioxidant enzymes, thereby decreasing MDA levels and cellular apoptosis by enhancing the antioxidant response, demonstrated by the in vitro and in vivo experiments.


The distribution of pulmonary shadowing in farmer's lung.
Reports of the radiological features in farmer's lung are inconsistent. We have reviewed clinical and radiological findings in eight patients with farmer's lung in the acute and sub-acute phases. In the acute phase the main feature is transient widespread diffuse shadowing of air space consolidation. In the sub-acute phase, the predominant feature is fine nodular shadowing tending to involve either the upper half or upper two-thirds of the lungs with relative sparing of the basal segments. This is in accordance with both the pathophysiological behaviour of the inhaled particulate antigen and the subsequent distribution of pulmonary changes in chronic farmer's lung.


Accumulation of cadmium and copper by the terrestrial snail Arianta arbustorum L.: kinetics and budgets.
Specimens of the terrestrial gastropod Arianta arbustorum were fed on cadmium- or copper-enriched agar plates with the aim of performing an input/output analysis and of studying the distribution of these metals in several organs of the snails. After a feeding period of 20 days about 45% of cadmium were lost. 36% accumulated in the hepatopancreas, where a cadmium concentration of more than 500 μg/g was measured. The efficiency of cadmium assimilation decreased from about 90% at the beginning to about 55% after 20 days. Copper was distributed more evenly than cadmium, but the main site of copper storage seemed to be the foot/mantle tissues, where 49% of the ingested copper were found. The efficiency of copper assimilation always exceeded 95%. The patterns of distribution and assimilation of copper and cadmium are discussed in relation to differences in the cytological and biochemical detoxification mechanisms which exist for these metals in molluscs.


A preliminary study of clinical assessment of left unilateral spatial neglect using a head mounted display system (HMD) in rehabilitation engineering technology.
Unilateral spatial neglect (USN) is a common syndrome in which a patient fails to report or respond to stimulation from the side of space opposite a brain lesion, where these symptoms are not due to primary sensory or motor deficits. The purpose of this study was to analyze an evaluation process system of USN in various visual fields using HMD in order to understand more accurately any faults of USN operating in the object-centred co-ordinates. Eight stroke patients participated in this study and they had Left USN in clinical test, and right hemisphere damage was checked by CT scan. Assessments of USN were performed the BIT common clinical test (the line and the stars cancellation tests) and special tests the zoom-in condition (ZI) condition and the zoom-out condition (ZO) condition. The subjects were first evaluated by the common clinical test without HMD and then two spatial tests with HMD. Moreover, we used a video-recording for all tests to analyze each subject's movements. For the line cancellation test under the common condition, the mean percentage of the correct answers at the left side in the test paper was 94.4%. In the ZI condition, the left side was 61.8.% and the right side was 92.4.%. In the ZO condition, the left side was 79.9% and the right side was 91.7.%. There were significant differences among the three conditions. The results of the stars cancellation test also showed the same tendency as the line bisection test. The results showed that the assessment of USN using a technique of HMD system may indicate the disability of USN more than the common clinical tests. Moreover, it might be hypothesized that the three dimensional for USN test may be more related to various damage and occurrence of USN than only the two dimensional test.


The influence of xanthines on the contractile responses of PGF2 alpha and PGD2 in human parenchymal strips.
Prostaglandins (PGs) F2 alpha and D2 are bronchoconstrictor agents which are released under allergic conditions such as asthma. The efficacy and potency of PGF2 alpha and PGD2 differ in some tissues. We compared the effects of these two PGs in sensitized human parenchymal strips. In six experiments, PGF2 alpha 0.1 and 0.3 microM produced greater contractions than PGD2 at the same concentrations. There were no significant differences between the contractions from the two PGs at concentrations of 0.01, 0.03, 1.0-10 microM and the two PGs appeared to be equipotent. We studied the effects of the anti-asthmatic drug theophylline, and its analogue enprofylline, on the contraction caused by these PGs. Theophylline 100 microM caused no change to the cumulative concentration response curves. However, enprofylline 100 microM reduced the PGF2 alpha-induced contractions.


gamma-Aminobutyric acid and gastric acid secretion: a physiologic role?
The purpose of this study was to examine the effect of endogenous brain GABA levels or GABAergic tone on gastric acid secretion. Experiments were performed with Sprague-Dawley rats under urethane anesthesia. Continuous acid secretion was measured in vivo using a gastric luminal perfusion system. Initial experiments studied the effects on basal acid secretion of (aminooxy)acetic acid (AOAA), a substance which increases brain GABA levels, and flumazenil, a substance which decreases central GABAergic neurotransmission. After basal acid secretion was measured for 30 min, AOAA (15 mg/kg), flumazenil (10 mg/kg), or saline was given by intravenous infusion and acid secretion was measured for 120 min. There was no significant difference in acid secretion between groups (n = 8/group). A second series of experiments measured the effects of AOAA, flumazenil, or saline on gastric secretion during submaximal stimulation by bethanechol (180 micrograms/kg/hr) in normal and vagotomized rats. Total acid secretions (mean +/- SE) after saline, AOAA, or flumazenil were 78.7 +/- 11.8, 51.0 +/- 5.9, and 109.3 +/- 1.5 mumole/90 min, respectively (P less than 0.01). In vagotomized rats, there were no significant differences in rates of acid secretion between groups. In summary, GABAergic tone did not effect basal acid secretion in anesthetized rats. However, during submaximal acid secretion, acid secretion decreased when brain GABA levels increased, and acid secretion increased when GABAergic neurotransmission was inhibited. We conclude that endogenous brain GABA levels may effect gastric acid secretion in rats, perhaps via inhibition of central-vagal tone.


The Fusarium toxin deoxynivalenol (DON) modulates the LPS induced acute phase reaction in pigs.
The systemic effects of the Fusarium toxin deoxynivalenol (DON) and of bacterial lipopolysaccharides (LPS) were studied in male castrated pigs (40.4 ± 3.7 kg) infused intravenously with either DON or LPS alone (100 μg DON/kg/h, 7.5 μg/LPS/kg/h), or together (100 μg DON plus 7.5 μg/LPS/kg/h). The Control group received a saline infusion (n=6/treatment, 24h observation period). An additional DON infusion did not exacerbate the clinical signs observed in LPS-infused pigs. For example, rectal temperature climaxed after 4h (40.4 ± 0.2°C) and 5h (40.1 ± 0.3°C), in the LPS and LPS+DON group, respectively. Saline and DON alone did not induce an acute phase reaction as indicated by unaltered plasma levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) while LPS caused a significant rise of both cytokines. TNF-alpha plasma peak concentrations were significantly higher in the LPS compared to the DON+LPS group (94.3 ± 17.2 ng/mL vs. 79.2 ± 15.7 ng/mL) while IL-6 climaxed earlier in the latter group (3h p.i. vs. 2h p.i.). From the tested clinical-chemical plasma characteristics the total bilirubin concentration and the ASAT activity were strongly elevated by the LPS infusion and additionally increased and decreased by DON, respectively. In conclusion, the LPS-induced effects were only marginally modified by DON.


Use of formamide increases the number of detectable inputs to polyneuronally innervated mammalian skeletal muscle.
We evaluated the extent of polyneuronal innervation in neonatal rat lateral gastrocnemius muscle with intracellular recording techniques using both formamide and d-tubocurarine as paralytic agents. We detected more polyneuronal innervation during the first postnatal week using formamide than d-tubocurarine. Both the average number of inputs per muscle cell and the percentage of polyinnervated cells were greater when formamide, rather than d-tubocurarine, was used to diminish muscle contraction. The difference in the extent of polyneuronal innervation detected using the two methods declines during the first postnatal week and the number of inputs observed with formamide during the second postnatal week does not differ from that seen with d-tubocurarine.


Metabolic regulation is important for spermatogenesis.
Male factor infertility is increasing in developed countries, and several factors linked to lifestyle have been shown to negatively affect spermatogenesis. Sertoli cells are pivotal to spermatogenesis, providing nutritional support to germ cells throughout their development. Sertoli cells display atypical features in their cellular metabolism; they can metabolize various substrates, preferentially glucose, the majority of which is converted to lactate and not oxidized via the tricarboxylic acid cycle. Why Sertoli cells preferentially export lactate for germ cells is not entirely understood. However, lactate is utilized as the main energy substrate by developing germ cells and has an antiapoptotic effect on these cells. Several biochemical mechanisms contribute to the modulation of lactate secretion by Sertoli cells. These include the transport of glucose through the plasma membrane, mediated by glucose transporters; the interconversion of pyruvate to lactate by lactate dehydrogenase; and the release of lactate mediated by monocarboxylate transporters. Several factors that modulate Sertoli cell metabolism have been identified, including sex steroid hormones, which are crucial for maintenance of energy homeostasis, influencing the metabolic balance of the whole body. In fact, energy status is essential for normal reproductive function, since the reproductive axis has the capacity to respond to metabolic cues.


Dose- and time-response studies of sodium o-phenylphenate urinary bladder carcinogenicity in rats.
Dose- and time-response studies of urinary bladder carcinogenesis due to orally administered sodium o-phenylphenate (OPP-Na) were performed using 5-week-old male Fischer 344 rats given diets containing 0 (control), 2500, 5000, 10,000, 15,000 or 20,000 ppm OPP-Na for 104 weeks and fed basal diets until 112 weeks (experiment 1). In addition, rats received diets containing 20,000 ppm OPP-Na for 0 (control), 12, 24, 52 or 104 weeks and were killed at week 112 (experiment 2). In experiment 1, the transitional cell carcinoma (TCC) was the major tumor type in the urinary bladder, and the dose-response curve was steep with many tumors occurring at the high doses of 15,000 and 20,000 ppm. The virtually safe dose at a risk level of 10(-6) for TCCs and papillomas was estimated to be 144 ppm by the Weibull model, a high value similar to that for sodium saccharin. In experiment 2, a few TCCs developed after 24 weeks of treatment, but the time-response curve was also steep with the majority of lesions occurring after longer exposure periods. Based on the observed steepness in dose- and time-responses, any implied cancer risk of OPP-Na at the low doses of interest to man must be considered to be very small.


The combined CXCR1/CXCR2 antagonist CXCL8(3-74)K11R/G31P blocks neutrophil infiltration, pyrexia, and pulmonary vascular pathology in endotoxemic animals.
CXC chemokine receptor 2 (CXCR2) antagonism alone can reduce neutrophil infiltration of some inflammatory sites, but the CXCR1 and CXCR2 critically regulate neutrophil responses to Glu-Leu-Arg-CXC chemokines. Herein, we assessed a combined CXCR1/CXCR2 antagonist, CXC chemokine ligand 8(3-74) [CXCL8(3-74)]K11R/G31P, for its ability to blunt neutrophil-influx and ancillary pathology in severe endotoxemia. Guinea pigs challenged via the airways with Escherichia coli lipopolysaccharide (LPS; 5 microg/kg) were given CXCL8(3-74)K11R/G31P (subcutaneously) before or after the onset of symptoms. The airways of the LPS-challenged animals contained high levels of endogenous pyrogens interleukin (IL)-1 and tumor necrosis factor (TNF) at 2-4 h, and the animals developed pyrexia, which peaked at approximately 6 h; strong pulmonary, neutrophilic inflammation; and marked pleural hemorrhagic consolidation, as assessed at approximately 15 h. CXCL8(3-74)K11R/G31P treatment before LPS challenge reduced lung pleural hemorrhagic consolidation and airway neutrophilia by >90% and essentially abrogated the IL-1, TNF, and fever responses. When given 3 or 6 h after LPS, CXCL8(3-74)K11R/G31P reduced pulmonary neutrophilia by up to 85% and pleural hemorrhagic consolidation by 50-85%. The 3-h treatment reduced the 6- to 24-h fever response to background. Delays of 6 or 9 h in beginning treatment had significant effects on the fever decay curve, but only the 6-h treatment had a significant effect on the 24-h fever. These results indicate that combined CXCR1/CXCR2 antagonism can have significant therapeutic effects on pulmonary inflammation and hemorrhage, as well as pyrexia in endotoxemic animals.


Dissolution of [²²⁶Ra]BaSO₄ and partial separation of ²²⁶Ra from radium/barium sulfate: A new treatment method for NORM waste from petroleum industry.
Complete dissolution of [(226)Ra]BaSO4 precipitate was successfully performed using NaNO2 as a reducing agent in acidic solution at room temperature. Results showed a significant effect of acid and NaNO2 concentrations and temperature on the dissolution efficiency. The method was successfully used for separation of radium from NORM scale samples from the petroleum industry; sufficient volume reduction of NORM waste was achieved. The obtained (226)Ra solution was purified using two separation methods. The dissolution method can be of great interest in the development of radiochemical analysis of radium isotopes.


Change in salt appetite due to rehydration level in rats.
Thermally dehydrated rats were given a choice of tap water and saline (0.9% or 1.8% NaCl), and the change in the salinity of their choice during rehydration was measured up to 15 hr. The rats consumed more water than saline for about 2 hr after the start of fluid replacement (about 55 mEq/l), while they consumed more saline than tap water (about 120 mEq/l) thereafter. Urine output and urinary Na output were only about 20% of their intake during the initial 4 hr of rehydration, while after 4 hr the output became almost equal with the intake. The change in salt intake occurred when about 90% of Na loss and 60% of fluid loss was regained. The results indicate that rats choose dilute salt solution to lower plasma osmolality during the initial period of the rehydration and then regain body fluid isotonically. Urine volume and urinary Na output increased only after volume repletion. Thus, osmoregulation with salt appetite has priority over fluid volume regulation in restitution from thermal dehydration.


Expression of Ras-related C3 botulinum toxin substrate 1 (RAC1) in human cholesteatoma.
Ras-related C3 botulinum toxin substrate 1 (RAC1) is a 21-kDa signaling G protein that functions as a pleiotropic regulator of many cellular processes including epithelial differentiation. RAC1 activates the nicotinamide adenine dinucleotide phosphate oxidase complex which promotes formation of reactive oxygen species and degradation enzymes. RAC1 has been associated with rapid epithelial differentiation and invasive properties in human cholesteatoma. This study aimed to identify the presence of RAC1 in human cholesteatoma and analyze its functional role as a regulator of proteolysis and overgrowth. Tissue samples from human cholesteatoma and normal postaural skin were obtained from patients during otologic surgery for cholesteatoma. The expression of RAC1 mRNA was quantified by real-time RT-PCR, and localization of RAC1 expression was confirmed using immunohistochemical staining. Expression of RAC1 mRNA in the epithelium of cholesteatoma was significantly elevated 2.94 fold on average, compared with normal control skin. RAC1 expression in the suprabasal and basal layer of cholesteatoma epithelium was stronger than normal control skin. Our results suggest that RAC1 can be associated with rapid epithelial differentiation and invasive properties of human cholesteatoma.


Interaction of paired cortical and peripheral nerve stimulation on human motor neurons.
This paper contrasts responses in the soleus muscle of normal human subjects to two major inputs: the tibial nerve (TN) and the corticospinal tract. Paired transcranial magnetic stimulation (TMS) of the motor cortex at intervals of 10-25 ms strongly facilitated the motor evoked potential (MEP) produced by the second stimulus. In contrast, paired TN stimulation produced a depression of the reflex response to the second stimulus. Direct activation of the pyramidal tract did not facilitate a second response, suggesting that the MEP facilitation observed using paired TMS occurred in the cortex. A TN stimulus also depressed a subsequent MEP. Since the TN stimulus depressed both inputs, the mechanism is probably post-synaptic, such as afterhyperpolarization of motor neurons. Presynaptic mechanisms, such as homosynaptic depression, would only affect the pathway used as a conditioning stimulus. When TN and TMS pulses were paired, the largest facilitation occurred when TMS preceded TN by about 5 ms, which is optimal for summation of the two pathways at the level of the spinal motor neurons. A later, smaller facilitation occurred when a single TN stimulus preceded TMS by 50-60 ms, an interval that allows enough time for the sensory afferent input to reach the sensory cortex and be relayed to the motor cortex. Other work indicates that repetitively pairing nerve stimuli and TMS at these intervals, known as paired associative stimulation, produces long-term increases in the MEP and may be useful in strengthening residual pathways after damage to the central nervous system.


Migration Health: Highlights from Inaugural International Society of Travel Medicine (ISTM) Conference on Migration Health.
International migration is a global phenomenon that is growing in scope, complexity and impact. The inaugural International Society of Travel Medicine (ISTM) International Conference on Migration Health provided a forum to discuss scientific evidence on the broad issues relevant to migration health. This review summarises the key health issues, with a focus on infectious diseases, current effective strategies and future considerations presented at this forum and in the recent literature. Migrants face health disparities for both communicable and non-communicable diseases. Their heightened infectious disease risks, compared to host populations, are related to pre-migration exposures, the circumstances of the migration journey and the receptivity and access to health services in their receiving countries. While the prevalence of infectious diseases identified through screening programmes are generally low, delays in diagnosis and treatment for a range of treatable infectious diseases result in higher morbidity and mortality among migrants. Barriers to care in host countries occur at the patient, provider and health systems levels. Coordinated and inclusive health services, healthcare systems and health policies, responsive to patient diversity reduce these barriers. Structural barriers to healthcare provision impede equitable care to migrants and refugees. Public health and medical professionals have a role in advocating for policy reforms.


Possible Protective Effect of Omalizumab on Lung Function Decline in Patients Experiencing Asthma Exacerbations.
Frequent exacerbations are associated with greater FEV1 decline in patients with asthma. The effect of omalizumab versus placebo on lung function in patients experiencing asthma exacerbations has not been previously examined. To evaluate the relationship between postbaseline (treatment phase) exacerbation status and lung function decline in children, adolescents, and adults treated with omalizumab versus placebo using data from 3 pediatric and adolescent/adult studies. Changes in percent predicted FEV1 (ppFEV1) and FEV1 by treatment (omalizumab/placebo) and postbaseline exacerbation status (exacerbators/nonexacerbators) were assessed in patients aged 6 to 11 years (IA05, n = 576) and 12 to 75 years (EXTRA/INNOVATE pooled, n = 1202). Pediatric patients were examined at treatment weeks 12, 24, 28, 40, and 52, and adolescent/adult data at weeks 4, 12, 20, and 28. Omalizumab-treated patients experienced larger increases in ppFEV1 and FEV1 compared with placebo-treated patients in the pediatric and pooled adolescent/adult populations. The response was observed in pediatric exacerbators, with significantly larger increases in ppFEV1 and FEV1 at week 12 (mean difference [95% CI], 4.11% [0.93%-7.30%], P = .011 for ppFEV1; 80 [10-140] mL, P = .017 for FEV1) and week 28 (mean difference [95% CI], 3.65% [0.11%-7.19%], P = .043 for ppFEV1; 100 [30-170] mL, P = .007 for FEV1). In the adolescent/adult population, both exacerbators and nonexacerbators derived similar benefit with omalizumab compared with placebo. Findings from this post hoc analysis suggest that omalizumab may confer some protection against lung function decline among patients who experienced exacerbations during treatment.


Does measurement of the hepatic artery velocity improve the sonographic diagnosis of cholangitis?
To determine the frequency of elevated peak systolic proper hepatic artery velocity (HAV) in patients with acute cholangitis and to determine the diagnostic performance of this metric relative to existing criteria. Between 9/2016 and 11/2017, 107 patients clinically suspected to have cholangitis were referred for an abdominal ultrasound. Of these, 56 patients had HAV measurements and were included in the final analysis. Clinical and imaging features, including HAV, HAV resistive index (RI), portal vein velocity (PVV), biliary dilation, and presence of an obstructive etiology were extracted. The diagnostic performance of HAV was compared to the existing available clinical criteria (Charcot's triad and 2018 Tokyo Guidelines). Elevated HAV was defined as HAV > 100 cm/s. Presence of cholangitis was determined by the discharge summary following medical workup and admission or observation. 32% had cholangitis while 68% did not. Average HAV for patients with cholangitis was 152 ± 54 cm/s versus 91 ± 44 cm/s for those without (p < 0.0001; t test). The HAV was elevated in 83% of patients with cholangitis. When considered in isolation, an elevated HAV had a high negative predictive value (90%), was more accurate (77%; 95% confidence interval 64-87%) than Charcot's triad (73%; 60-83%), and had similar accuracy compared to 2018 Tokyo Guidelines (79%; 66-88%). Substitution of conventional imaging criteria with elevated HAV in the 2018 Tokyo Guidelines yielded the highest overall accuracy of 84% (72-92%). HAV is elevated in the majority of patients with cholangitis. Substitution of an elevated HAV for conventional sonographic criteria is more accurate than existing clinical criteria in identifying patients with cholangitis.


Progesterone and fluoxetine treatments of postpartum depressive-like behavior in rat model.
Research studies have indicated that alterations in plasma progesterone levels might be associated with the hippocampal synaptic plasticity of postpartum depressive-like behavior. Herein, we assess both progesterone and fluoxetine effects in adult female Sprague-Dawley rats with postpartum depressive-like behavior. Depressive-like behavior of postpartum rats was established using chronic ultra-mild stress (CUMS) method for 1 week from gestation day 15. Postpartum rats that showed depressive-like behavior were treated with either progesterone (subcutaneously, 0.5 mg/kg) from gestation day 17 to gestation day 22 or fluoxetine (by gavage, 10 mg/kg/day) for 4 weeks after birth. Open field and sucrose preference tests were conducted at the start, week 2 and week 4 postpartum. Golgi staining, immunofluorescence and Western blot analyses of rats' hippocampi were conducted on week 4 postpartum. Results showed CUMS increases depressive-like behavior, however, treatment with progesterone and fluoxetine improves this behavior. Both progesterone and fluoxetine treatments increase the numbers of dendritic spines pyramidal neurons in the CA3 region of the hippocampus as well as protein expression levels of microtubule-associated protein 2 (MAP-2) and synaptophysin (SYP). CUMS-induced decrement of MAP-2 and SYP protein expressions can be prevented by treatment with progesterone in advanced pregnant stage and fluoxetine in the postpartum period.


The relationship between body mass index and unintended pregnancy: results from the 2002 National Survey of Family Growth.
The study was conducted to characterize the relationship between body mass index (BMI) and unintended pregnancy, contraceptive use patterns, and perceived fertility. This study employed a cross-sectional, nationally representative database (2002 National Survey of Family Growth). Unintended pregnancy was compared among BMI groups [normal (<25 m/kg(2)), overweight (25-30 m/kg(2)) and obese (>30 m/kg(2))]. Analyses also evaluated the association between demographic, socioeconomic, behavioral and health-related variables and BMI. Multiple logistic regression with adjustment for sampling design was used to measure associations of interest. BMI data were available from 6690 nonpregnant women. Of these, 3600 (53.6%) were normal weight, 1643 (25%) were overweight and 1447 (21.4%) were obese. Compared to women with normal BMIs, the risk of unintended pregnancy in the last 5 years did not differ among overweight [adjusted OR 0.95 (95% CI 0.77-1.17)] or obese [adjusted OR 0.87 (95% CI 0.70-1.09)] women. There were no differences in contraceptive use patterns or perceived fertility among BMI groups. Data from the 2002 NSFG do not support an association between obesity and unintended pregnancy.


Umbilical signs of peritoneal tuberculosis in children.
To report the observation of involvement of the umbilicus with alteration of its morphology in association with peritoneal tuberculosis. This is a retrospective observational case series of abdominal tuberculosis (ATB) in children, treated in the department of pediatric surgery of a tertiary-care children's hospital in the period from January 2004 through April 2010. Out of a total of 38 cases of ATB in children, 22(57.9%) were of the peritoneal type, 14(36.8%) were of the intestinal type, and 2(5.3%) involved the mesenteric lymph nodes. Of the patients manifesting with peritoneal tuberculosis, 11 cases (50%) had involvement of the umbilicus with changes in the umbilical shape and appearance. In seven cases the umbilicus was found retracted and transversely oriented (a slit-like "smiling" appearance) with loss of the umbilical hollow. In two cases there was puckering of the umbilicus. Other findings included umbilical erythema with inflammation in one patient and a fecal fistula at the umbilicus in another patient. While seven cases responded to treatment with antituberculous therapy (ATT), four cases underwent surgery (two laparotomy and two laparoscopy). Findings were similar in all four patients, consisting of adhered dilated bowel loops studded with tubercles which also covered the parietal peritoneum and the falciform ligament. All four cases responded to postoperative ATT. Morphological changes of the umbilicus can provide an additional clue to the diagnosis of peritoneal tuberculosis in children.


A comparative biomechanical study for complex tibial plateau fractures: nailing and compression bolts versus modern and traditional plating.
To compare the biomechanical properties of a newly proposed technique, utilizing intramedullary nailing and compression bolts, for the osteosynthesis of intra-articular proximal tibial fractures with meta-diaphyseal comminution, with modern and conventional plating techniques. Fifteen left tibia 4th generation composite Sawbones models (in 3 groups of 5 for each technique) with identically reproduced type VI Schatzker tibial plateau fractures, including meta-diaphyseal dissociation, were used. Three different techniques of osteosynthesis were tested: (a) a new technique that combines intramedullary nailing and compression bolts, (b) internal fixation with a single lateral locking plate and (c) internal fixation with dual buttress plating technique. The model-device constructs were successively subjected to 500N, 1000N and 1500N load levels with five cycles applied at each level on both articular compartments and a final load cycle to failure. Four parameters were recorded for each technique: the average reversible or irreversible displacement in vertical subsidence, the horizontal diastasis of the intra-articular fracture, the average passive construct stiffness and the load to failure. The new intramedullary nailing technique provided rigid intra-articular osteosynthesis being statistically similar to dual buttress plating for subsidence at medium and higher load levels. At the same time the proposed technique provided statistically equivalent stiffness values to the single lateral locking plate incarnating the rational of biologic fixation. Average load to failure was 1611N for single lateral locking plates, 2197N for intramedullary nailing and 4579N for dual buttress plating. The single lateral locking plate technique had the worse results in interfragmentary displacement while dual buttress plating was superior in stiffness from the other 2 techniques. The mode of failure differed between techniques, with collapse of medial plateau occurring exclusively in the single lateral locking plates group. The proposed new technique of intramedullary nailing and compression bolts demonstrates a flexural behaviour similar to single lateral locking plates, which complies with the terms and benefits of biological fixation, while at the same time maintains a rigid intra-articular stability similar to the stiff dual buttressing plating technique.


Tubulin inhibitory activity of a novel colchicine-binding compounds based on a dinaphthospiropyranran scaffold.
Spiropyrans have been investigated for their thermo- and photochromic characteristics, but their biotherapeutic properties have not been addressed. We report anti-proliferative properties of a novel dinaphthospiropyran analogue (1). The compound 1 was synthesized by a simple and expedient method using a one-pot acid-catalyzed aldol condensation of 2-hydroxy-1-naphthaldehyde with 4-piperidone followed by an acetalization reaction. Compound 1 was submitted to anticancer drug screen in the National Cancer Institute's panel of 60 human tumor cell lines. The average concentration of 1 to inhibit 50% cell growth was 5.4 ± 0.23 µM. All cell lines responded at almost the same concentration, suggesting that the action of 1 is not selective for cancer of origin. COMPARE analysis of dose-response data revealed interaction with tubulin as the possible mechanism of action of 1. At molecular level, 1 induced tubulin reorganization in colon cancer HCT-116 cells. Under cell-free conditions, the efficacy of 1 to inhibit tubulin polymerization was comparable to that of paclitaxel and vinblastine. Molecular docking showed that compound 1 binds to the colchicine-binding site of tubulin. We conclude that dinaphthospiropyrans present a novel scaffold for the development of tubulin inhibitors.


Purifying selection shapes the coincident SNP distribution of primate coding sequences.
Genome-wide analysis has observed an excess of coincident single nucleotide polymorphisms (coSNPs) at human-chimpanzee orthologous positions, and suggested that this is due to cryptic variation in the mutation rate. While this phenomenon primarily corresponds with non-coding coSNPs, the situation in coding sequences remains unclear. Here we calculate the observed-to-expected ratio of coSNPs (coSNPO/E) to estimate the prevalence of human-chimpanzee coSNPs, and show that the excess of coSNPs is also present in coding regions. Intriguingly, coSNPO/E is much higher at zero-fold than at nonzero-fold degenerate sites; such a difference is due to an elevation of coSNPO/E at zero-fold degenerate sites, rather than a reduction at nonzero-fold degenerate ones. These trends are independent of chimpanzee subpopulation, population size, or sequencing techniques; and hold in broad generality across primates. We find that this discrepancy cannot fully explained by sequence contexts, shared ancestral polymorphisms, SNP density, and recombination rate, and that coSNPO/E in coding sequences is significantly influenced by purifying selection. We also show that selection and mutation rate affect coSNPO/E independently, and coSNPs tend to be less damaging and more correlated with human diseases than non-coSNPs. These suggest that coSNPs may represent a "signature" during primate protein evolution.


Rapid qualitative identification and quantitative analysis of Flos Mume based on Fourier transform near infrared spectroscopy.
Flos Mume, an ancient Chinese plant, is widely used for food and medicine. There are numerous varieties of Flos Mume, whose main active components are chlorogenic acid, hyperoside and isoquercitrin. Currently, Flos Mume varieties are mainly distinguished by physical appearance and they have not been scientifically indexed for identification. Fourier transform near infrared spectroscopy (FT-NIR) is a technique that when combined with chemometrics, determines internal components of samples and classifies them. Here, to distinguish between different Flos Mume varieties, we used a qualitative identification model based on FT-NIR. Various model parameters indicated its stability and high predictive performance. We developed a rapid, non-destructive method of simultaneously analyzing 8 components but found that only neochlorogenic acid, chlorogenic acid, rutin, hyperoside, and isoquercitrin have application value. Other components were excluded due to low concentration and poor prediction. Chemometric analysis found that chlorogenic acid become an ingredient which is quite different in the different categories. The content of chlorogenic acid were the highest among these components. Different varieties of Flos Mume were distinguished based on chlorogenic acid content, indicating that chlorogenic acid has potential to become a key indicator for application in quality evaluation. The established FT-NIR model for chlorogenic acid detection had excellent predictive capacity. FT-NIR was the first time applied to Flos Mume and our findings offer theoretical reference for the rapid identification and quantitative analysis of Flos Mume based on FT-NIR. Flos Mume could be evaluated for quality quickly and easily by means of FT-NIR spectroscopy.


High-Suspicion Subcentimeter Thyroid Nodules: Cost Effectiveness of Active Surveillance versus Fine Needle Aspiration.
To compare the cost-benefit of active surveillance (AS) against immediate fine needle aspiration (FNA) of sonographically suspicious subcentimeter thyroid nodules. A Markov model was constructed to compare the cost-benefit of 3 strategies from the point of discovery until death: (a) Surveillance of all nodules, (b) Surveillance of nodules with positive cytology, and (c) Surgery of nodules with positive cytology. The reference case was a 40-year-old woman with a sonographically suspicious subcentimeter thyroid nodule. Transition probabilities, costs, and health state utilities were derived from the literature. Sensitivity analyses were performed to evaluate model uncertainty. Willingness-to-pay threshold was set at $100,000/quality-adjusted life year. Surveillance of nodules with positive cytology dominated in the reference scenario and was cost-beneficial over Surveillance of all nodules, independent of the utility of AS. Surveillance of all nodules was cost-beneficial only at a life expectancy of <2.6 years or surveillance duration of <4 years. While current guidelines recommend AS of sonographically suspicious subcentimeter nodules, the results of this study suggest that immediate FNA (Surveillance of nodules with positive cytology) is more cost-beneficial than AS (Surveillance of all nodules). Patients with positive cytology on FNA may subsequently opt for AS (Surveillance of nodules with positive cytology) or surgery (Surgery of nodules with positive cytology) according to their level of comfort (ie, utility) with AS.


Protein drift-diffusion dynamics and phase separation in curved cell membranes and dendritic spines: Hybrid discrete-continuum methods.
We develop methods for investigating protein drift-diffusion dynamics in heterogeneous cell membranes and the roles played by geometry, diffusion, chemical kinetics, and phase separation. Our hybrid stochastic numerical methods combine discrete particle descriptions with continuum-level models for tracking the individual protein drift-diffusion dynamics when coupled to continuum fields. We show how our approaches can be used to investigate phenomena motivated by protein kinetics within dendritic spines. The spine geometry is hypothesized to play an important biological role regulating synaptic strength, protein kinetics, and self-assembly of clusters. We perform simulation studies for model spine geometries varying the neck size to investigate how phase-separation and protein organization is influenced by different shapes. We also show how our methods can be used to study the roles of geometry in reaction-diffusion systems including Turing instabilities. Our methods provide general approaches for investigating protein kinetics and drift-diffusion dynamics within curved membrane structures.


A taxonomy of generic clinical questions: classification study.
To develop a taxonomy of doctors' questions about patient care that could be used to help answer such questions. Use of 295 questions asked by Oregon primary care doctors to modify previously developed taxonomy of 1101 clinical questions asked by Iowa family doctors. Primary care practices in Iowa and Oregon. Random samples of 103 Iowa family doctors and 49 Oregon primary care doctors. Consensus among seven investigators on a meaningful taxonomy of generic questions; interrater reliability among 11 individuals who used the taxonomy to classify a random sample of 100 questions: 50 from Iowa and 50 from Oregon. The revised taxonomy, which comprised 64 generic question types, was used to classify 1396 clinical questions. The three commonest generic types were "What is the drug of choice for condition x?" (150 questions, 11%); "What is the cause of symptom x?" (115 questions, 8%); and "What test is indicated in situation x?" (112 questions, 8%). The mean interrater reliability among 11 coders was moderate (kappa=0.53, agreement 55%). Clinical questions in primary care can be categorised into a limited number of generic types. A moderate degree of interrater reliability was achieved with the taxonomy developed in this study. The taxonomy may enhance our understanding of doctors' information needs and improve our ability to meet those needs.


Preliminary results on the postmortem measurement of 3-beta-hydroxybutyrate in liver homogenates.
The concentrations of 3-beta-hydroxybutyrate (3HB) in blood and two liver samples were retrospectively examined in a series of medicolegal autopsies. These cases included diabetic ketoacidosis, nondiabetic individuals presenting moderate to severe decompositional changes and nondiabetic medicolegal cases privy of decompositional changes. 3HB concentrations in liver sample homogenates correlate well with blood values in all examined groups. Additionally, decompositional changes were not associated with increases in blood and liver 3HB levels. These results suggest that 3HB can be reliably measured in liver homogenates when blood is not available at autopsy. Furthermore, they suggest that metabolic disturbances potentially leading or contributing to death may be objectified through liver 3HB determination even in decomposed bodies.


Comparative biochemical studies of ATPases in cells from patients with the T8993G or T8993C mitochondrial DNA mutations.
We performed comparative biochemical studies in cultured fibroblast mitochondria from patients with the T8993G or the T8993C point mutations in the ATPase 6 gene of mitochondrial DNA. We found that ATP production was much more severely decreased in cells from patients with the T8993G mutation than in those from patients with the T8993C mutation. Kinetic studies suggest that both mutations affect only the F0 sector of the mitochondrial ATPase complex. We conclude that these two mutations, which result in the substitution of different amino acids at the same site of the ATPase, result in an enzyme with different biochemical characteristics.


Experience and strategy for the molecular testing of Duchenne muscular dystrophy.
Mutations in the dystrophin gene result in both Duchenne and Becker muscular dystrophies (DMD and BMD). Approximately two-thirds of the affected patients have large deletions or duplications. Using the multiplex polymerase chain reaction and Southern blotting techniques, the detection of these larger mutations is relatively straightforward. Detection of the point mutations in the remaining one-third of the patients has been challenging, mainly due to the large gene size and lack of hotspots or prevalent mutations. However, with the addition of some of the newer molecular screening methods, it is becoming more feasible for clinical laboratories to test for point mutations in the larger genes like dystrophin. Here we review the clinical features, describe the mutation distributions, evaluate current molecular strategies, and illustrate how the genetic findings have impacted the current clinical diagnostics of Duchenne and Becker muscular dystrophies.


Stimulation of tyrosine aminotransferase activity by dl-alpha-methyltryptophan.
DL-alpha-Methyltryptophan (alphaMeTrp), a synthetic analogue of tryptophan, has been found to be a potent inducer of hepatic tyrosine aminotransferase activity in the adrenalectomized rat. alphaMeTrp is inactive in vitro. Unlike the action of other known inducers (tryptophan, hydrocortisone, adenosine cyclic 3:5-monophosphate, and glucagon), maximal stimulation of enzyme activity occurs only 16 to 30 hours after alphaMeTrp administration and the activity is still elevated at 96 hours. Only the L isomer of alphaMeTrp is active, and addition of a hydroxyl group to position 5 of the indole ring renders an inactive compound. The induction can be prevented by actinomycin D or cycloheximide but not galactosamine. Administration of alphaMeTrp together with hydrocortisone produced an additive stimulation of enzyme activity. alphaMeTrp given along with glucagon or adenosine cyclic 3:5-monophosphate caused a further but not additive increase in enzyme activity. Tryptophan given along with alphaMeTrp promoted no extra stimulation whatsoever. These data indicate that alphaMeTrp and tryptophan may act via a common pathway which in part requires RNA synthesis. Other enzymes, namely alanine and aspartate aminotransferase, ornithine aminotransferase, ornithine carbamoyltransferase, serine dehydratase, and histidine ammonialyase, were not affected by treatment of rats with alphaMeTrp.


Organizational manipulation of gonadal hormones and systemic morphine analgesia in female rats: effects of adult ovariectomy and estradiol replacement.
Previous research has indicated the importance of sex in mediating the larger magnitude of mu-opioid receptor agonist-induced analgesia in male relative to female rodents. Whereas manipulations involving the adult activational effects of gonadal hormones minimally alter these analgesic sex differences, manipulations involving neonatal organizational effects of gonadal hormones have previously been shown to profoundly affect morphine analgesia. Thus, adult male rats neonatally castrated on the first day after birth displayed reductions in morphine analgesia relative to sham-operated males, and adult female rats neonatally treated with testosterone propionate on the first day after birth displayed enhancements in morphine analgesia relative to vehicle-treated females. Because neonatal androgenization in female rats produces an anovulatory syndrome that could change their adult hormonal milieu, the present study examined whether adult ovariectomy altered the magnitude of systemic morphine analgesia (1-5 mg/kg) in neonatal androgenized female rats relative to neonatal vehicle-treated female rats as well as gonadal steroid hormone replacement with estradiol benzoate. Intact male rats displayed significantly greater magnitudes and potencies (2- to 2.3-fold leftward shift) of systemic morphine analgesia than female rats treated neonatally with either vehicle (1-5 mg/kg) or testosterone (1.7-5 mg/kg). In turn, neonatal androgenized female rats displayed significantly greater magnitudes of systemic morphine (1, 5 mg/kg) analgesia than vehicle-treated female rats accompanied by a smaller 20% leftward shift in potency. Adult ovariectomy minimally affected morphine analgesia in neonatal vehicle-treated females, while significantly reducing the magnitude (1 mg/kg), but not the potency of morphine analgesia in neonatal androgenized female rats. Estradiol replacement therapy significantly increased the magnitude of morphine analgesia in both groups at some doses, but only changed the potency (20-30%) in females treated neonatally with vehicle. Taken together, these data suggest a limited organizational-activational gonadal hormone interaction in the mediation of systemic morphine analgesia in female rats.


Perceived technology use, attitudes, and barriers among primary care nurses.
In primary healthcare, health information technology has the potential to facilitate the delivery of healthcare services by improving quality of care, efficiency and patient safety. However, little is known about the uptake and technology acceptance among primary healthcare nurses. The aim of this study was to describe health information technology acceptance and use among primary healthcare nurses. Primary healthcare centres in the Western Cape. A quantitative descriptive survey was conducted with a sample of 160 nurses working in primary healthcare for more than 6 months, using a self-administered questionnaire based on the technology acceptance model constructs. Eighteen primary healthcare centres were randomly selected with a sample of 160 using nonprobability purposive sampling. Ninety-three (58.1%) respondents completed the survey. Three-quarters of the respondents reported positive attitudes, positive perceptions of usefulness and ease of use towards the use of health information technology. Barriers of access and training were reported by 75%, with around half the respondents reporting poor computer and information accessing skills. Health information technology use was varied, with high ratings for seeking and using and low ratings of ability to use health information technology for patient administration and management. Health information technology use was predicted by perceptions of ease of use. This research presents a mixed picture of acceptance of technology among primary healthcare nurses and highlights the lack of access to computers and Internet in these settings. This study contributes to the field of technology acceptance among primary healthcare nurses.


E-C coupling and contractile characteristics of mechanically skinned single fibres from young rats during rapid growth and maturation.
The postnatal growth of rats involves a developmental phase (0 to approximately 3 weeks), a rapid growth phase ( approximately 3 to approximately 10 weeks), and a slower maturation phase ( approximately 10 weeks+). In this study, we investigated the age-related changes in excitation-contraction (E-C) coupling characteristics of mammalian skeletal muscle, during rapid growth (4-10 weeks) and maturation (10-21 weeks) phases, using single, mechanically skinned fibres from rat extensor digitorum longus (EDL) muscle. Fibres from rats aged 4 and 8 weeks produced lower maximum T-system depolarization-induced force responses and fewer T-system depolarization-induced force responses to 75% run-down than those produced by fibres from rats aged 10 weeks and older. The sensitivity of the contractile apparatus to Ca(2+) in fibres from 4-week rats was significantly higher than that in fibres from 10-week rats; however, the maximum Ca(2+)-activated force per skinned fibre cross-sectional area (specific force) developed by fibres from 4-week rats was on average approximately 44% lower than the values obtained for all the other age groups. In agreement with the age difference in specific force, the MHC content of EDL muscles from 4-week rats was approximately 29% lower than that of 10-week rats. Thus, mechanically skinned fibres from rats undergoing rapid growth are less responsive to T-system depolarization and maximal Ca(2+) activation than fibres from rats at the later stage of maturation or adult rats. These results suggest that during the rapid growth phase in rats, the structure and function of elements involved in E-C coupling in fast-twitch skeletal muscle continue to undergo significant changes.


Gold-Nanocluster-Assisted Nanotransfer Printing Method for Metasurface Hologram Fabrication.
Given the development of nano/microscale patterning techniques, efforts are being made to use them for fabricating metasurfaces. In particular, by using abrupt phase discontinuities, it is possible to generate holographic images from two-dimensional nanoscale-patterned metasurfaces. However, the fabrication of metasurface holograms is hindered by the high costs and long fabrication time involved, because the process requires expensive equipment such as that for electron-beam lithography. Therefore, it is difficult to realize metasurface holograms in a fast and repetitive manner. In this study, we propose a method for fabricating metasurface holograms based on the nanotransfer printing of the desired nanoscale patterns, which is assisted by Au nanoclusters, while controlling the bonding energy based on the shape of the deposited Au layer. Robust covalent bonds are formed between the Si of the adhesive used and the O of the SiO2 layer in order to transfer the deposited Au onto the transparent substrate quickly. It was found that the fabricated metasurface hologram coincides with the one designed by computer-generated holography. The proposed method should lead to a significant breakthrough in the fabrication of holograms based on different types of metasurfaces at a low cost in a fast, repetitive manner with various metals.


Anesthetics inhibit membrane receptor coupling to the Gq/11 heterotrimeric G protein in airway smooth muscle.
Some anesthetics relax airway smooth muscle in part by inhibiting acetylcholine-induced increases in Ca2+ sensitivity, an effect associated with inhibition of guanosine nucleotide exchange at the alpha subunit of the Gq/11 (Galphaq/11) heterotrimeric G protein. This study tested the hypothesis that these anesthetic effects are not unique to the muscarinic receptor but are a general property of the heptahelical receptors that increase Ca2+ sensitivity in airway smooth muscle. Anesthetic effects on agonist-induced increases in Ca2+ sensitivity were measured in porcine airway smooth muscle strips permeabilized with S. aureus alpha-toxin. Anesthetic effects on basal (without agonist stimulation) and agonist-promoted Galphaq/11 guanosine nucleotide exchange were determined in crude membranes prepared from porcine airway smooth muscle. The nonhydrolyzable, radioactive form of guanosine 5'-triphosphate was used as the reporter for nucleotide exchange at Galphaq/11. Acetylcholine, endothelin-1, and histamine caused a concentration-dependent increase in Ca2+ sensitivity. Halothane (0.67 +/- 0.07 mM) and hexanol (10 mM) significantly inhibited the increase in Ca2+ sensitivity induced by each agonist. Each agonist also caused a time- and concentration-dependent increase in Galphaq/11 nucleotide exchange. Neither anesthetic had an effect on basal Galphaq/11 nucleotide exchange, whereas halothane and hexanol significantly inhibited the increase in Galphaq/11 nucleotide exchange promoted by each agonist. These data suggest that inhibition of agonist-promoted guanosine nucleotide exchange at Galphaq/11 by some anesthetics may be a general property of heptahelical receptors involved cellular processes mediated by Galphaq/11, including muscarinic, endothelin-1, and histamine receptor activation of Ca2+ sensitivity.


What is new in cancer-associated fibroblast biomarkers?
The tumor microenvironment is one of the important drivers of tumor development. Cancer-associated fibroblasts (CAFs) are a major component of the tumor stroma and actively participate in tumor development, invasion, metastasis, drug resistance, and other biological behaviors. CAFs are a highly heterogeneous group of cells, a reflection of the diversity of their origin, biomarkers, and functions. The diversity of CAF origin determines the complexity of CAF biomarkers, and CAF subpopulations expressing different biomarkers may play contrasting roles in tumor progression. In this review, we provide an overview of these emerging CAF biomarkers and the biological functions that they suggest, which may give a better understanding of the relationship between CAFs and tumor cells and be of great significance for breakthroughs in precision targeted therapy for tumors. Video Abstract.


Control of cryopreservation procedures on blood vessels using fiber x-ray diffraction.
We sought to determine variations in fiber organization at the molecular level using x-ray diffraction analyses on human blood vessel specimens after cryopreservation processes. Diffractometric profiles were performed on aortic and carotid cryopreserved-thawed vessel samples (CVS) versus the same fresh vessel samples (FVS). X-ray diffraction was performed on vascular tissues from 17 cadaveric donors after informed consent. Measurements utilized a Seifert Scintag PAD-II powder diffractometer with CuK(a) radiation; lambda = 1.5418 A. Scans were evaluated in the 5 degrees to 60 degrees range in theta -2theta mode, in the 5 degrees to 60 degrees range in 2-theta, with steps 0.1 degrees and 10 seconds per step. Ten aortic and 8 carotid diffractometric profiles were analyzed, using differential planimetric surfaces measured under x-ray diffraction curve. Diffractographic profiles were analyzed according to intervals based upon the ages of the donors. An ordering profile coefficient (OPC) was obtained as the quotient between the differential planimetric surface (DPS) of FVS versus CVS vessel ordering diffraction. There was a decreased ordering profile according to age: older donors showed less ordering than younger ones. Clear peaks at d-spacing of 2.86 A and 2.15 A (2-theta = 31.3 degrees and 42.0 degrees , respectively) were always confirmed despite the different profiles of samples. OPC showed a higher ordering profile among the CVS than FVS: 70% aortas and 62.5% carotids. The cryopreserved-thawed procedure does not damage the fibrillar organization of vessels.


Validity of the diagnosis of pre-eclampsia in the Medical Birth Registry of Norway.
Evaluating the validity of pre-eclampsia registration in the Medical Birth Registry of Norway (MBRN) according to both broader and restricted disease definitions. Retrospective nested cohort study. Multicenter study. In this study, two cohorts of women with pre-eclamptic pregnancies registered in the MBRN were selected. Study group 1 contained 966 pregnancies from 1967 to 2002. Concomitant participation in the Nord-Trøndelag Health Study 2 was required. Study group 2 comprised 1138 pregnancies recorded in 1967-2005, examined as a pre-eclampsia biobank was established. Diagnostic criteria vary. The broader criteria for pre-eclampsia, used by the MBRN, are one measurement of hypertension and proteinuria (Criterion A). Criteria used internationally today require two measurements of hypertension and proteinuria (Criterion B). The diagnostic validities in Study groups 1 and 2 were judged against medical records according to Criterion A and B, respectively. Positive predictive value (PPV) and trend analyses. The diagnosis was confirmed in 88.3% of pregnancies in Study group 1, and in 63.6% in Study group 2. PPV was high for Study group 1 throughout the period. For Study group 2, results improved significantly after 1986. This study ascertains high PPV of pre-eclampsia in the MBRN using broader traditional criteria, although the PPV decreases through assessment using restricted modern criteria. This illustrates how inclusion of direct measurements may improve registration of complex disorders defined by changing diagnostic criteria.


Effects of potassium on blood pressure regulation.
Short-term changes (1 week) of potassium intake had no effect on elevated or normal blood pressure of 18 subjects. Potassium supplementation (100 mmol KCl/day) for 8 weeks caused a fall in blood pressure in 16 patients with mild hypertension. After cessation of potassium supplementation, blood pressure returned to "prepotassium" levels. In healthy volunteers, high potassium intake for 1 week resulted in a marked increase in intraleukocytic concentration of potassium. No change was observed in mean arterial pressure, cardiac index, or total peripheral resistance. The hemodynamic response to an intravenous infusion of ouabain was reduced during high potassium intake. Baroreceptor sensitivity rose during high potassium intake as demonstrated by the infusion of norepinephrine.


CCM molecular screening in a diagnosis context: novel unclassified variants leading to abnormal splicing and importance of large deletions.
Loss of function mutations in CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10 gene are identified in about 95 % of familial cases of cerebral cavernous malformations and 2/3 of sporadic cases with multiple lesions. In this study, 279 consecutive index patients referred for either genetic counseling or for diagnosis of cerebral hemorrhage of unknown etiology were analyzed for the three cerebral cavernous malformations (CCM) genes by direct sequencing and quantitative studies, to characterize in more detail the mutation spectrum associated with cerebral cavernous malformations and to optimize CCM gene screening. Analysis of the cDNA was performed when possible to detect the consequences of the genomic variations. A pathogenic mutation was identified in 122 patients. CCM1 was mutated in 80 patients (65 %), CCM2 in 23 (19 %), and CCM3 in 19 (16 %). One hundred patients harbored a loss of function point mutation (82 %) and 22 had a large deletion (18 %). Novel unclassified variants were detected in the patients among whom six led to a splicing defect. The causality of three missense variants that did not modify the splicing could not be established. These findings expand the CCM mutation spectrum and highlight the importance of screening the three CCM genes with both direct sequencing and a quantitative method. In addition, six new unclassified variants were shown to be deleterious because they led to a splicing defect. This underlines the necessity of the cDNA analysis when an unknown variant is detected.


Prevalence and Antimicrobial Resistance Profile of Diarrheagenic Escherichia coli from Fomites in Rural Households in South Africa.
Diarrheagenic Escherichia coli (DEC) pathotypes are the leading cause of mortality and morbidity in South Asia and sub-Saharan Africa. Daily interaction between people contributes to the spreading of Escherichia coli (E. coli), and fomites are a common source of community-acquired bacterial infections. The spread of bacterial infectious diseases from inanimate objects to the surrounding environment and humans is a serious problem for public health, safety, and development. This study aimed to determine the prevalence and antibiotic resistance of diarrheagenic E. coli found in toilets and kitchen cloths in the Vhembe district, South Africa. One hundred and five samples were cultured to isolate E. coli: thirty-five samples were kitchen cloths and seventy-five samples were toilet swabs. Biochemical tests, API20E, and the VITEK®-2 automated system were used to identify E. coli. Pathotypes of E. coli were characterised using Multiplex Polymerase Chain Reaction (mPCR). Nine amplified gene fragments were sequenced using partial sequencing. A total of eight antibiotics were used for the antibiotic susceptibility testing of E. coli isolates using the Kirby-Bauer disc diffusion method. Among the collected samples, 47% were positive for E. coli. DEC prevalence was high (81%), with ETEC (51%) harboring lt and st genes being the most dominant pathotype found on both kitchen cloths and toilet surfaces. Diarrheagenic E. coli pathotypes were more prevalent in the kitchen cloths (79.6%) compared with the toilet surfaces. Notably, hybrid pathotypes were detected in 44.2% of the isolates, showcasing the co-existence of multiple pathotypes within a single E. coli strain. The antibiotic resistance testing of E. coli isolates from kitchen cloths and toilets showed high resistance to ampicillin (100%) and amoxicillin (100%). Only E. coli isolates with hybrid pathotypes were found to be resistant to more than three antibiotics. This study emphasizes the significance of fomites as potential sources of bacterial contamination in rural settings. The results highlight the importance of implementing proactive measures to improve hygiene practices and antibiotic stewardship in these communities. These measures are essential for reducing the impact of DEC infections and antibiotic resistance, ultimately safeguarding public health.


No association between the use of Bti for mosquito control and the dynamics of non-target aquatic invertebrates in French coastal and continental wetlands.
The environmental safety of Bacillus thuringiensis subsp. israelensis (Bti) is still controversial, mainly because most of the previous field studies on its undesired effects were spatially limited and did not address the relationship between community similarity and application time and frequency. No general statement can therefore be drawn on the usage conditions of Bti that insure protection of non-target organisms. The present study was conducted in eight sites distributed over the main geographical sectors where mosquito control is implemented in mainland France and Corsica. Changes in non-target aquatic invertebrates were followed at elapsed time after repeated applications of two Bti formulations (VectoBac® WDG or 12AS) up to four consecutive years. We examined the influence of both larvicide treatments and environmental variables on community dynamics and dissimilarity between treated and control areas. As it can be argued that chironomids are the most vulnerable group of non-target invertebrates, we scrutinised potential Bti-related effects on the dynamics of their community. The use of VectoBac® WDG and 12AS in coastal and continental wetlands had no immediate or long-term detectable effect on the taxonomic structure and taxa abundance of non-target aquatic invertebrate communities, including chironomids. This applied to the main habitats where mosquito larvae occur, regardless of their geographic location. Flooding, whose frequency and duration depend on local meteorological and hydrological conditions, was identified as the main environmental driver of invertebrate community dynamics. Our findings add support to the environmental safety of currently available Bti formulations when following recommended application rates and best mosquito control practices.


Unexpected features of acute T lymphoblastic lymphomas in Notch1IC transgenic rats.
Dysregulated Notch signaling accounts for the majority of acute T lymphoblastic leukemia/lymphoma (T-ALL) cases in humans. Here, we characterize lymphomas from Notch1IC transgenic rats, which develop T-ALL shortly after weaning, and show that they display a number of previously undocumented features. Starting from monoclonal thymic tumors, the CD4(+)CD8alphaalpha(+) lymphoma cells infiltrate the bone marrow and then spread to secondary lymphoid and non-lymphoid organs. However, major hallmarks of T-ALL cells in other murine models and human patients, such as constitutive NF-kappaB activity and increased levels of anti-apoptotic proteins, are remarkably absent in Notch1IC lymphomas. In contrast, CD30, a classic marker of Hodgkin lymphomas, is overexpressed in these tumors. Intriguingly, enforced Notch1 signaling up-regulates expression of Notch3, which has also been implicated in the pathogenesis of T-ALL. By blocking endogenous Notch signaling, we could demonstrate that Notch1IC is sufficient to induce sustained preTCR expression in transgenic thymocytes but not for their progression to the double-positive stage. This suggests that other Notch activities may also contribute to the phenotype of the transgenic rats. In summary, we anticipate this new animal model will help to further elucidate the role of Notch1 in the pathogenesis of T-ALL.


Ultrastructure of Kolmer's crystalloid in the pinealocytes of the common spiny mouse (Acomys cahirinus dimidiatus).
Light- and electron-microscopical observations revealed a rod-like inclusion body in the pinealocytes of the common spiny mouse (Acomys cahirinus dimidiatus). Ultrastructurally, the body is composed of a varying number of tubes whose wall consists of thin filaments aligned in helical arrangement. The inner and outer surface of the wall is covered with ribosome-like granules. Based on a morphological analysis it is concluded that the body described in the present investigation is identical with Kolmer's crystalloid of horizontal cells in the human and primate retina.


Phylogenic analysis and forensic genetic characterization of Guizhou Miao tribes from 58 microareas via autosomal STR.
Genetic polymorphism of 17 autosomal short tandem repeat (STR) loci, included in the PowerPlex®18D amplification kit, were analyzed in Miao tribes from 58 different sampling microareas (N = 5255) of Guizhou as well as two cities (N = 151) of Hunan, China. Allele frequencies and forensic efficiency parameters were calculated. Moreover, comprehensive population genetic comparisons among 91 nationwide populations and 174 Asian populations were conducted based on raw genotype data and allele frequency data, respectively. Our results of forensic efficiency parameters showed that the panel was a robust tool in forensic individual identification and paternity cases for this population. Genetic affinities were observed among most of the Miao tribes revealed by multidimensional scaling plot, principal component analysis, and neighboring-joining tree. The genetic distance between Miao tribes and Han nationalities were varies by different geographical positions. Some of the Miao tribes were genetically closer to the Hmong-Mien populations living in southeastern contiguous regions and even the Indochina. The result coincided with the migration or reverse migration routes for Miao nationality in modern history. This study of the Miao tribes from plenty of microareas in Guizhou would be useful in reconstructing the population history and establishing a more comprehensive forensic reference database.


Lifetime prevalence and correlates of syncope in five ancestry groups. The HELIUS study.
To explore the lifetime prevalence and correlates of syncope in the general population. Through stratified random sampling, we included 14,937 White-European, Asian, Turkish, Moroccan, and West-African ancestry adults (18-70 y) in the cross-sectional Healthy Life in an Urban Setting (HELIUS) population study. We assessed syncope history by ancestry, and the potential correlates body mass index (BMI), systolic/diastolic blood pressure (SBP/DBP), resting plasma activity of creatine kinase (CK), the ATP-generating enzyme that facilitates cardiovascular contractility and sodium retention, and in a subgroup, supine cardiac contractility (dP/dt), cardiac output (CO) and systemic vascular resistance (SVR). Mean age of the participants (39% men) was 43.3 y (SD12.9). Lifetime prevalence of syncope in women/men was respectively (%), White-European 42/24; Asian 34/19; Moroccan 32/16; Turkish 30/17; and West-African 20/14. Mean age at first syncope was 24 y (SD13). Participants with syncope history had lower SBP, DBP, BMI, CK, and modestly lower dP/dt and CO, but not SVR. In multivariable regression analysis, male sex (OR 0.52 [0.48 to 0.57]), West-African ancestry (0.59 [0.54 to 0.65]), and CK (0.56 [0.46 to 0.69]/log CK increase) were negatively associated with syncope. This study indicates that West-African ancestry, male sex, and high activity of the pressor enzyme CK are associated with lower syncope prevalence. These findings may inform further studies on the hemodynamics of syncope.


Alternative water supply solutions: China's South-to-North-water-diversion in Jinan.
Inter-basin water transfers are intended to have a positive impact on the development of a region, but are always accompanied by huge energy consumption. The feasibility and effectiveness of water transfer projects have not yet been clearly evaluated, especially in the light of their energy consumption and effects on social development. This paper develops a method that combines life cycle approach and system dynamic model to reveal the effectiveness of different water supply alternatives (transferred water, reclaimed wastewater and rainwater harvesting) when they are all constrained to consume equal energy. This approach is applied to the case of Jinan city in Shandong province, China, the main water-receiving city on the Eastern Route of the South-to-North Water Transfer Project (ER-SNWTP). The results show that in normal years, Jinan's reclaimed water and rainwater harvesting supply are effective replacements for transferred water under the constraints of equal energy consumption and capital costs; even in dry years these two alternatives still play an important role. The results of this study indicate the relative effectiveness of reclaimed water and rainwater harvesting in supplying urban water while conserving energy and capital.


Effects of melanocyte-stimulating hormone (MSH) and melatonin on passive avoidance and on an emotional response.
The present experiment investigated the opposite effects of synthetic alpha-MSH and Melatonin on acquisition and extinction of a passive avoidance response (PAR) and on emotionality, as indexed by defecation, in the PA box. It was found that intraperitoneal (IP) administration of alpha-MSH delayed extinction and increased defecation responses whereas IP administration of Melatonin facilitated extinction of the PAR and decreased defecation. The present experiment confirmed MSH-Melatonin opposition on memory and on the defecation response.


Clinical characteristics and management of immune checkpoint inhibitor-related pneumonitis: A single-institution retrospective study.
The increasing application of immune checkpoint inhibitors (ICIs) will cause more checkpoint inhibitor-related pneumonitis (CIP), which is a common cause of ICI-related death. The clinical management of CIP needs further optimization. Patients who were managed at Peking Union Medical College Hospital (PUMCH) between February 2017 and December 2019 with a diagnosis of CIP were retrospectively analyzed. Clinical data including clinical manifestations, radiologic data, laboratory and bronchoscopy results, treatments, and outcomes were collected and analyzed. The Mann-Whitney test was used to compare patients with and without co-infections. In total, 48 CIP cases in 42 patients were analyzed. The median time from the first dose of ICI to the onset of CIP was 1.9 months (range: 0.1-13.7). Grade 3-4 (G3-4) accounted for 30 cases (71.4%). The most common symptoms were cough (88.1%) and dyspnea (78.6%). The median starting dose of equivalent prednisone (EP) was 55 mg (range: 30-200) for all patients. The median total duration of glucocorticosteroids (GCS) treatment was 42.5 days (range: 15-89). Three patients (7.14%) died because of infection. A higher starting dose and longer duration of GCS (≥30 mg/day; p = 0.001) were associated with opportunistic infection. Chest computed tomography (CT) showed diverse and asymmetrical lesions. Twelve patients were re-challenged, and six patients developed recurrent CIP. The clinical and imaging manifestations of CIP are various, and differential diagnosis of exclusion is essential. GCS at 1-2 mg/kg is feasible to treat CIP, but the duration of GCS ≥30 mg/day should be used with caution, given the high risk of acquired infections. Re-challenges of ICI are feasible, but the recurrence of CIP needs to be closely monitored.


Radiation therapy of tumors of the brainstem and midbrain in children: experience of the Joint Center for Radiation Therapy and Children's Hospital Medical Center (1971-1981).
Between 1971 and 1981, 79 previously untreated children with proven or presumed gliomas of the brainstem or midbrain were seen and treated at the Joint Center for Radiation Therapy and Children's Hospital Medical Center in Boston. Twenty-seven patients had tumors of the thalamus and midbrain (Group I) and 52 had lesions of the pons or medulla (Group II). Overall 5- and 10-year survivals were 50% and 41% respectively. Eighty percent of deaths occurred within 2 years of treatment. Eighty-six percent of the children (69/79) had clinical improvement or stabilization of disease after treatment. Group I patients had a 5-year survival of 73% which was significantly greater than that of Group II patients (38%) (p = 0.007). Children who presented with hypothalamic tumors in association with a diencephalic syndrome or other growth abnormality appeared to have had a better prognosis with 6/6 (100%) surviving without evidence of disease. Age at presentation was not correlated with prognosis. Of 10 children less than 3 years of age at presentation and treatment, 6 are alive (60%) at 2, 3, 7, 9, 10, and 12 years after treatment. The functional results in this group have been good--all six are leading apparently normal lives in regular schools with minor or no apparent neurologic deficits. Although these children will require long term follow-up to determine whether cures have actually been achieved, it appears that the majority achieve some benefit, that a significant proportion enjoy long term survival, and that very young children may be treated successfully with minimal radiation-induced neurologic sequela.


Alterations in the stages of continuous amphetamine intoxication produced by lesions of locus coeruleus and substantia nigra.
1. Slow-release silicone pellets containing d-amphetamine base were implanted subcutaneously in rats 20 days following radio-frequency lesions of the locus coeruleus (LC), substantia nigra (SN), or control operations. 2. LC-lesioned rats exhibited enhanced motor stereotypies soon after implantation, while SN-lesioned animals showed increased locomotion but decreased stereotypy and anorexia. 3. The later behavioral stages of continuous amphetamine intoxication were attenuated in both lesioned groups as controls then entered the most intense stereotypy, showed the greatest withdrawal to the burrows, and maximally exhibited the increase in socially disruptive behaviors which appear following four days of constant amphetamine intoxication. 4. The integrity of both dopaminergic and noradrenergic systems was necessary for the full expression of the late stages of this animal model of amphetamine psychosis.