The facilitatory effects of hyperbaric oxygen treatment on membrane bone wound healing in a rat calvarial defect model.
We examined the effect of hyperbaric oxygen (HBO2) treatment on bone wound healing in a rat calvarial defect. Critical-sized defects were created in the calvaria of adult Wistar rats. The animals were divided into four groups--HBO2, normobaric oxygen, hyperbaric air, and no treatment. Treatments were performed five days a week, for two weeks. Micro-computerized tomography and histological analysis were used to evaluate the bone defects. Regenerated bone areas were calculated as the percentage of new bone in the cross-sectional area of defect. The new bone cross-sectional area was significantly greater in the HBO2 group than in the other groups. There were no significant differences in the numbers of nucleated cells in the new bone areas. Although new bone volume per defect volume was significantly greater in the HBO2 group than in the other groups, no significant differences in bone mineral density in the new bone area were observed. These findings indicate the facilitatory role of HBO2 treatment on bone wound healing in the rat calvarial bone defect, and it does not appear to have any negative effects on bone maturity. We propose that HBO2 treatment would be useful in promoting bone regeneration following injury in the orofacial region.


[A simple method for high-resolution banding of chromosomes and its application to diagnosis of birth defects].
A simple method for obtaining high-resolution banding patterns on elongated chromosomes is devised as follows: Peripheral lymphocytes cultured for 3 days with phytohemagglutinin were exposed to 10 micrograms/ml ethidium bromide for 2 hours and with 0.02 micrograms/ml colcemid for 1 hour prior to harvesting. After preparation by steam-dry method, high-resolution G-bands were obtained by Giemsa staining following exposure to hydrogen peroxide and trypsin treatment. 19 cases of the Prader-Willi syndrome, 3 cases of the aniridia-Wilms' tumor syndrome, 2 cases of the Langer-Giedion syndrome, 2 cases of retinoblastoma and 6 cases with multiple congenital anomalies whose diagnosis was not made by routine chromosome analysis were examined by this method. 18 of the 19 cases of the Prader-Willi syndrome had a deletion of 15q11.2. 2 of the 3 cases of the aniridia-Wilms' tumor syndrome had a deletion of 11p13 and the other had a balanced insertion with a breakpoint at 11p13. The 2 cases of the Langer-Giedion syndrome had a deletion of 8q23.3-24.13. One of retinoblastoma had a deletion of 13q14 and the other had a balanced reciprocal X/13 translocation with breakpoints at Xp11.21 and 13q12.3. The last 6 cases had subtle chromosomal aberrations: 46, XX, del (5) (q15q22), 46, XX, del (13) (q32.3), 46, XX, inv dup (6) (p25p21.3), 46, XX, -5, +der (5), t (3; 5) (p23; p13) mat, 46, XX, -5, +der (5), t (5; 9) (p13.3p21) mat, and 46, XX, -4, +der (4), t (4; 16) (p15.2; p13.1) pat. The simple method for high-resolution banding of chromosomes is useful for diagnosis of many kinds of birth defects.


Delusional Jealousy (Othello Syndrome) in 67 Patients with Parkinson's Disease.
Othello syndrome (OS) is a type of paranoid delusional jealousy, characterized by the false absolute certainty of the infidelity of a partner. Because OS has infrequently occurred in patients with Parkinson's disease (PD), the characteristics of OS in PD remain unclear. We reviewed the clinical characteristics of this syndrome in PD. We reviewed 67 patients who had PD with OS. OS was more common in men (45 patients) than in women (22 patients), and it frequently occurred in middle-aged patients. Until the onset of OS, the duration of PD (range, 2-19.8 years) and the duration of treatment with PD medications (range, 2 months to 18.5 years) varied. At the onset of OS, cognition was preserved in most patients. 42 of 47 patients had other psychiatric disorders in addition to OS, and 5 patients had isolated OS. Persecutory or other paranoid delusions developed in 34 patients with OS. OS was associated with PD medication in 25 of 26 patients, especially in patients, used the dopamine agonists. The dose of the PD medication associated with OS was decreased or these drugs were withdrawn to facilitate the treatment of OS. In most patients, OS disappeared or the severity of OS was reduced. OS is infrequent in patients with PD, but is likely to be easily detected because OS is commonly accompanied by persistent paranoid and sexual delusions. When clinicians encounter such patients, the withdrawal or reduction of dopamine agonists should be attempted, and if necessary, additional treatment with clozapine is recommended.


[Biocompatibility of silicon containing micro-arc oxidation coated magnesium alloy ZK60 with osteoblasts cultured in vitro].
To research in vitro biocompatibility of silicon containing micro-arc oxidation (MAO) coated magnesium alloy ZK60 with osteoblasts. The surface microstructure of silicon containing MAO coated magnesium alloy ZK60 was observed by a scanning electron microscopy (SEM), and chemical composition of the coating surface was determined by energy dispersive spectrum analysis. The experiments were divided into 4 groups: silicon containing MAO coated magnesium alloy ZK60 group (group A), uncoated magnesium alloy ZK60 group (group B), titanium alloy group (group C), and negative control group (group D). Extracts were prepared respectively with the surface area to extraction medium ratio (1.25 cm(2)/mL) according to ISO 10993-12 standard in groups A, B, and C, and were used to culture osteoblasts MC3T3-E1. The a-MEM medium supplemented with 10% fetal bovine serum was used as negative control in group D. The cell morphology was observed by inverted phase contrast microscopy. MTT assay was used to determine the cell viability. The activity of alkaline phosphatase (ALP) was detected. Cell attachment morphology on the surface of different samples was observed by SEM. The capability of protein adsorption of the coating surface was assayed, then DAPI and calcein-AM/ethidium homodimer 1 (calcein-AM/EthD-1) staining were carried out to observe cell adhesion and growth status. The surface characterization showed a rough and porous layer with major composition of Mg, O, and Si on the surface of silicon containing MAO coated magnesium alloy ZK60 by SEM. After cultured with the extract, cells grew well and presented good shape in all groups by inverted phase contrast microscopy, group A was even better than the other groups. At 5 days, MTT assay showed that group A presented a higher cell proliferation than the other groups (P < 0.05). Osteoblasts in groups A and C presented a better cell extension than group B under SEM, and group A exhibited better cell adhesion and affinity. Protein adsorption in group A [ (152.7 +/- 6.3) microg/mL] was significantly higher than that of group B [(96.3 +/-3.9) microg/mL] and group C [ (96.1 +/-8.7) microg/mL] (P < 0.05). At each time point, the adherent cells on the sample surface of group A were significantly more than those of groups B and C (P < 0.05). The calcein-AM/EthD-1 staining showed that groups A and C presented better cell adhesion and growth status than group B. The ALP activities in groups A and B were 15.55 +/-0.29 and 13.75 +/-0.44 respectively, which were significantly higher than those in group C (10.43 +/-0.79) and group D (10.73 +/-0.47) (P < 0.05), and group A was significantly higher than group B (P < 0.05). The silicon containing MAO coated magnesium alloy ZK60 has obvious promoting effects on the proliferation, adhesion, and differentiation of osteoblasts, showing a good biocompatibility, so it might be an ideal surface modification method on magnesium alloys.


Treatment of adult growth hormone deficiency: who, why and how? A review.
Adult growth hormone deficiency (AGHD) is nowadays recognized as a distinct clinical entity and replacement therapy has become a standard practice. Reflecting on the accumulated evidence, questions nevertheless arise. Should all AGHD patients be treated? What dose of GH should be given and for how long? What are the real long-term benefits, in particular regarding life expectancy? if the diagnosis of severe GHD is firmly established and if there is no contra-indication (such as an active cancer or uncontrolled diabetes), it is worthwile initiating GH replacement therapy. Treatment can indeed correct the abnormal body composition, improve various adverse cardiovascular parameters and risk factors, increase muscle strength and bone mineral density and, although to a variable degree, improve the patient's quality of life and psychological well-being. Treatment should be started with very low doses to avoid side-effects related to fluid retention and should then be gradually titrated against IGF-I values, clinical response and individual tolerance.There is unfortunately no confirmed predictive factor for the overall therapeutic response in a given individual. Thus, the decision to whether or not pursue the therapy will depend on the ratio of perceived and expected benefits over cost and risks of treatment, as well as on the persistent motivation of the patient.


Involvement of the TGFβ1/Smad2/MMP3 signaling pathway in SB431542-induced inhibition of cell invasion in multiple myeloma RPMI 8226 cells.
Multiple myeloma (MM) is a malignancy characterized by plasma cell hyperplasia. The majority of patients with MM suffer from mortality due to tumor recurrence and metastasis, which has become an emerging clinical problem. Transforming growth factor β1 (TGFβ1) has been implicated in tumor metastasis; however, its role in RPMI 8226 cells remains to be elucidated. In the present study, RPMI 8226 cells were treated with various concentrations of SB431542, a TGFβ1 inhibitor, for 12, 24 and 48 h. RPMI 8226 cells were transfected with lentiviral-TGFβ1 vectors to overexpress TGFβ1. Cell proliferation rate was subsequently determined by cell-counting kit-8 assay and cell invasion was assessed by Transwell assay. Expression of TGFβ1, SMAD family member 2 (Smad2) and matrix metallopeptidase 3 (MMP3) were analyzed by western blotting. The results demonstrated that cell proliferation and invasion of RPMI 8226 cells was significantly inhibited by SB431542 (P<0.05). SB431542 was able to significantly downregulate the expression of TGFβ1, phosphorylated (p)-Smad2 and MMP3; however, the overexpression of TGFβ1 significantly upregulated the expression of TGFβ1, p-Smad2 and MMP3. In conclusion, SB431542 reduced cell invasion in RPMI 8226 cells, and this effect may be mediated via the TGFβ1/Smad2/MMP3 signaling pathway.


Effects of mercury vapor inhalation on reactive oxygen species and antioxidant enzymes in rat brain and kidney are minimal.
Metals are known to induce the formation of reactive oxygen species (ROS) that initiate oxidative stress, an important mechanism of cell injury. The brain is particularly sensitive to oxidative attack because of its high level of unsaturated lipids and high rate of oxidative metabolism. The objective of this study was to determine if elemental mercury (Hg(0)) vapor inhalation increases ROS production and affects activities or levels of antioxidant-related biomolecules in the rat brain and kidney. Adult female Sprague-Dawley rats were exposed for 2 h per day for 11 consecutive days to Hg(0) vapor (1, 2, and 4 mg Hg(0) m(-3)). Brain regions (frontal cortex, cerebellum, brain stem) and kidney were assayed for total Hg, ROS and glutathione (GSH) levels, and for enzyme activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD). Marked exposure-related increases (2500-5600-fold) in total Hg were detected in the brain regions and in kidney. A statistically significant increase in ROS production (ca. 30% above controls) was observed only in the cortex of rats exposed to 1 mg m(-3) Hg vapor, but no significant changes were apparent at other exposures. Although a trend towards increasing ROS production was observed in the kidney, these effects were not statistically significant. Mercury vapor exposure had no significant effects on GSH levels or GPx activity in the three brain regions, however, statistically significant decreases in GSH and GPx activity were detected in the kidneys of rats exposed to 2 mg m(-3). Mercury exposure did not cause significant effects on SOD activity in the brain or kidney. The data indicate that oxidative stress and changes in GSH and activities of antioxidant enzymes do not play a major role in Hg(0) vapor toxicity in brain and kidney.


Different ways to treat subtrochanteric fractures with the Medoff sliding plate.
Thirty-two consecutive subtrochanteric fractures in 32 patients were stabilized using the Medoff sliding plate and were followed up prospectively for 1 year. Two patients died during the first postoperative year. Twenty-nine of the remaining 30 (97%) fractures united by 1-year followup. Two types of plate dynamization schema were used: uniaxial (17 patients) and biaxial (15 patients). With uniaxial dynamization, plate sliding averaged 12 mm along the femoral shaft without medialization of the femoral shaft. With biaxial dynamization along the femoral shaft and the neck, plate sliding averaged 11 mm and screw in barrel sliding averaged 9 mm; medialization of the femoral shaft ranged from 0% to 35% of the femoral shaft diameter. Three fractures treated with uniaxial dynamization had migration of the lag screw within the femoral head; all three fractures united without additional screw migration after secondary or staged biaxial plate dynamization.


[Endotracheal dystopia of thyroid tissue].
Endotracheal ectopic thyroid tissue is rare. It can cause gradual obstruction of the tracheal lumen culminating in sudden dyspnoea. The diagnosis is relatively easy to make with the aid of a laryngeal mirror, by endoscopy, or by x-rays. However, it is most important to take the clinical picture into consideration. It is thought that the ectopic tissue arises from splitting of the thyroid gland during the descent in the embryonal stage. Treatment consists of removal via a tracheofissure. The tracheal mucous membrane must be treated with special care to prevent cicatricial stenosis of the trachea.


Fiber type-specific muscle glycogen sparing due to carbohydrate intake before and during exercise.
The effect of carbohydrate intake before and during exercise on muscle glycogen content was investigated. According to a randomized crossover study design, eight young healthy volunteers (n = 8) participated in two experimental sessions with an interval of 3 wk. In each session subjects performed 2 h of constant-load bicycle exercise ( approximately 75% maximal oxygen uptake). On one occasion (CHO), they received carbohydrates before ( approximately 150 g) and during (1 g.kg body weight(-1).h(-1)) exercise. On the other occasion they exercised after an overnight fast (F). Fiber type-specific relative glycogen content was determined by periodic acid Schiff staining combined with immunofluorescence in needle biopsies from the vastus lateralis muscle before and immediately after exercise. Preexercise glycogen content was higher in type IIa fibers [9.1 +/- 1 x 10(-2) optical density (OD)/microm(2)] than in type I fibers (8.0 +/- 1 x 10(-2) OD/microm(2); P < 0.0001). Type IIa fiber glycogen content decreased during F from 9.6 +/- 1 x 10(-2) OD/microm(2) to 4.5 +/- 1 x 10(-2) OD/microm(2) (P = 0.001), but it did not significantly change during CHO (P = 0.29). Conversely, in type I fibers during CHO and F the exercise bout decreased glycogen content to the same degree. We conclude that the combination of carbohydrate intake both before and during moderate- to high-intensity endurance exercise results in glycogen sparing in type IIa muscle fibers.


The characterization of the whey proteins of guinea-pig milk. The isolation and properties of alpha-lactalbumin.
1. The whey proteins of guinea-pig milk were examined by electrophoresis on paper, cellulose acetate, starch gel and polyacrylamide gel. 2. Two major proteins were detected, one of which was identified as blood serum albumin. 3. The major whey protein was isolated by CM-cellulose chromatography and on columns of Sephadex G-100. 4. The amino acid composition of the protein, taken in conjunction with its other properties, indicated that the major whey protein in guinea-pig milk is homologous with cow alpha-lactalbumin and that beta-lactoglobulin is absent from guinea-pig milk. 5. Guinea-pig alpha-lactalbumin, which was obtained crystalline, had mol.wt. 15800, N-terminal lysine and C-terminal glutamine.


The tert-butylsulfinamide lynchpin in transition-metal-mediated multiscaffold library synthesis.
A unified synthetic approach to diverse polycyclic scaffolds has been developed using transition-metal-mediated cycloaddition and cyclization reactions of enynes and diynes. The tert-butylsulfinamide group has been identified as a particularly versatile lynchpin in these reactions, with a reactivity profile uniquely suited for efficient, stereoselective substrate synthesis and downstream transformations. This approach provides 10 distinct, functionalized scaffold classes related to common core structures in alkaloid and terpenoid natural products.


Compassion fatigue and moral sensitivity in midwives in COVID-19.
The Covid-19 pandemic has impacted compassion fatigue and the mental health of health care providers, particularly midwives and nurses. Although there are studies involving health workers such as nurses and physicians affected by the pandemic's compassion fatigue, few studies include midwives. The present study seeks to investigate the effects of compassion fatigue experienced by midwives working under intense stress during the third wave of the COVID-19 pandemic on the level of moral sensitivity. This is a descriptive-correlation study. The statistical population consisted of all the midwives in Türkiye hospitals in 2021. This cross-sectional study was collected through a questionnaire using convenience sampling. Three hundred and ten midwives working in different units of the country participated in the study. Approval from the researcher's university Institutional Review Board for ethical review was obtained with the code of IRB 20/510. The average age of the midwives is 34.29 ± 8.39. It has been noticed that 43.5% of the midwives work in public hospitals and 38.1% in family health and community health centers. Midwives' mean MR-CS score is 67.11 ± 25.13, secondary trauma sub-dimension average 15.77 ± 6.23, and occupational burnout sub-dimension 40.69 ± 16.35. The mean moral sensitivity questionnaire score is determined as 93.86 ± 19.51. It has been observed that the working style and working time are effective on compassion fatigue. In the linear regression model, 98% of compassion fatigue was explained. Age, secondary trauma, and occupational burnout sub-dimensions affect the model. Working year, working style, second trauma, age, and occupational burnout parameters may help explain some of the links between midwives' symptoms of compassion fatigue. The pandemic affects the compassion fatigue of midwives. It is crucial to provide social support to midwives and health workers to prevent compassion fatigue and examine and control groups at risk in mental health.


[Case of visceral varicella-zoster virus infection after autologous peripheral blood stem cell transplantation in which severe abdominal pain preceded the skin rash].
We report a 54-year-old man who developed visceral varicella-zoster virus (VZV) infection after autologous peripheral blood stem cell transplantation (auto-PBSCT) without using immunosuppressive agents for multiple myeloma. He suffered from severe abdominal pain 2 months after auto-PBSCT, and morphine chloride was needed to control it. Since the characteristic skin rash of VZV infection appeared over his entire body on the seventh hospital day, aciclovir was immediately started with favorable results. It is extremely difficult to diagnose VZV infection when severe abdominal pain proceeds and the eruptions characteristic of VZV infections are absent. This may also result in devastating delays in effective antiviral treatment. The increase in fat density around the celiac trunk and the root of the superior mesenteric artery on computed tomography shown in this case may has contributed to the correct diagnosis of visceral VZV infection.


Endophenotype best practices.
This review examines the current state of electrophysiological endophenotype research and recommends best practices that are based on knowledge gleaned from the last decade of molecular genetic research with complex traits. Endophenotype research is being oversold for its potential to help discover psychopathology relevant genes using the types of small samples feasible for electrophysiological research. This is largely because the genetic architecture of endophenotypes appears to be very much like that of behavioral traits and disorders: they are complex, influenced by many variants (e.g., tens of thousands) within many genes, each contributing a very small effect. Out of over 40 electrophysiological endophenotypes covered by our review, only resting heart, a measure that has received scant advocacy as an endophenotype, emerges as an electrophysiological variable with verified associations with molecular genetic variants. To move the field forward, investigations designed to discover novel variants associated with endophenotypes will need extremely large samples best obtained by forming consortia and sharing data obtained from genome wide arrays. In addition, endophenotype research can benefit from successful molecular genetic studies of psychopathology by examining the degree to which these verified psychopathology-relevant variants are also associated with an endophenotype, and by using knowledge about the functional significance of these variants to generate new endophenotypes. Even without molecular genetic associations, endophenotypes still have value in studying the development of disorders in unaffected individuals at high genetic risk, constructing animal models, and gaining insight into neural mechanisms that are relevant to clinical disorder.


TaZFP1, a C2H2 type-ZFP gene of T. aestivum, mediates salt stress tolerance of plants by modulating diverse stress-defensive physiological processes.
Salt stress suppresses plant growth, development, and crop productivity. In this study, we characterized the role of TaZFP1, a C2H2 type-zinc finger protein family member of T. aestivum, in salt stress tolerance. TaZFP1 possesses a conserved C2H2 motif (CX2-4CX12HX3-5H) shared by plant ZFP proteins, translocates to the nucleus after endoplasmic reticulum (ER) assortment, and displays a ZF 3-D structure similar to its eukaryote homologs. The transcripts of TaZFP1 were upregulated during salt stress condition and this effect was restored under normal conditions. Compared to wild type (WT), the transgenic lines of TaZFP1 overexpression or knockdown displayed improved phenotypes, biomass, photosynthesis parameters (Pn, ΨPSII, and NPQ), osmolytes contents (i.e. proline and soluble sugar), and enhanced antioxidant enzyme (AE) activity following salt stress treatment. A set of genes associated with proline synthesis (i.e., NtP5CS1 and NtP5CS2) and encoding AEs (i.e., NtSOD2, NtCAT1, and NtPOD4) were upregulated in the salt-challenged transgenic lines of TaZFP1 expression. Additionally, the transgenic lines exhibited similar stomata movement patterns and leaf water retention properties under salinity conditions compared to those induced by exogenous abscisic acid (ABA) treatment, suggesting that the TaZFP1-mediated salt response is dependent on the ABA signaling. High throughput RNAseq analysis revealed significant alteration of gene transcription in transgenic lines upon salt stress. Among them, the differentially expressed genes (DEGs) represented by the gene ontology (GO) terms were associated with organic acid, carboxylic acid, carbohydrate, and coenzyme as well as organonitrogen compounds, translation, peptide metabolism, and peptide biosynthesis. A set of upregulated DEGs were found to be thylakoid- and photosystem-associated, which is consistent with the TaZFP1-mediated improvement in photosynthesis in salt-stressed transgenic lines. Our investigation indicated that the TaZFP1-mediated salt tolerance is ascribed to the regulation of gene functions related to photosynthesis, osmolytes metabolism and ROS homeostasis mediated by ABA signaling.


Ventilation of the deep Gulf of Mexico and potential insights to the Atlantic Meridional Overturning Circulation.
Ventilation in the deep Gulf of Mexico (GoM), its connection to the North Atlantic, and its susceptibility to changes of the Atlantic Meridional Overturning Circulation are investigated by combining observations of radiocarbon and volume transport with a Coupled Model Intercomparison Project phase 6 (CMIP6) General Circulation Model (GCM) ensemble output. Radiocarbon data and multiannual volume transport through the Yucatan Channel suggest deep water residence times ~100 years for the GoM. Comparisons to previous radiocarbon observations suggest that the deep GoM has aged in the recent past, consistent with observed raising temperatures and the CMIP6 GCM simulations. The distribution of radiocarbon indicates a time frame of ~160 years between North Atlantic convection and complete ventilation of the deep GoM. This suggests that aging and warming of GoM deep waters were initiated in the North Atlantic before ~1890 consistent with reported rapid and persistent AMOC weakening since the Little Ice Age.


Transgenerational inheritance of neurobehavioral and physiological deficits from developmental exposure to benzo[a]pyrene in zebrafish.
Benzo[a]pyrene (B[a]P) is a well-known genotoxic polycylic aromatic compound whose toxicity is dependent on signaling via the aryl hydrocarbon receptor (AHR). It is unclear to what extent detrimental effects of B[a]P exposures might impact future generations and whether transgenerational effects might be AHR-dependent. This study examined the effects of developmental B[a]P exposure on 3 generations of zebrafish. Zebrafish embryos were exposed from 6 to 120h post fertilization (hpf) to 5 and 10μM B[a]P and raised in chemical-free water until adulthood (F0). Two generations were raised from F0 fish to evaluate transgenerational inheritance. Morphological, physiological and neurobehavioral parameters were measured at two life stages. Juveniles of the F0 and F2 exhibited hyper locomotor activity, decreased heartbeat and mitochondrial function. B[a]P exposure during development resulted in decreased global DNA methylation levels and generally reduced expression of DNA methyltransferases in wild type zebrafish, with the latter effect largely reversed in an AHR2-null background. Adults from the F0 B[a]P exposed lineage displayed social anxiety-like behavior. Adults in the F2 transgeneration manifested gender-specific increased body mass index (BMI), increased oxygen consumption and hyper-avoidance behavior. Exposure to benzo[a]pyrene during development resulted in transgenerational inheritance of neurobehavioral and physiological deficiencies. Indirect evidence suggested the potential for an AHR2-dependent epigenetic route.


Experimental evidence for the protective effects of coffee against liver fibrosis in SD rats.
Coffee is one of the most commonly consumed beverages worldwide. Accumulating clinical evidence has shown an inverse relationship between coffee and liver cirrhosis. We investigated the protective effect of coffee against liver fibrosis and underlying molecular mechanisms using a dimethylnitrosamine (DMN)-induced liver fibrosis model. Coffee administration significantly prevented the deterioration of body weight, organ weight, and serum biochemistry by DMN treatment. Histopathological examination revealed that necrosis/inflammation and fibrotic septa decreased significantly in coffee-treated rats compared to those treated with DMN and water. Coffee administration also significantly inhibited the accumulation of hydroxyproline (P < 0.001) and the production of malondialdehyde (P < 0.05), as well as stellate cell activation caused by DMN injection. Coffee protected the depletion of glutathione, superoxide dismutase, and catalase in liver tissue. In addition, coffee treatment inhibited the gene expression of inducible nitric oxide synthase, transforming growth factor (TGF)-beta, tumor necrosis factor-alpha, interleukin-1, and platelet-derived growth factor (PDGF)-beta in liver tissues, and lowered the concentration of TGF-beta and PDGF-beta in liver. Coffee inhibited NO production by macrophages. Coffee exerts protective effects against liver fibrosis via antioxidant action and the suppression of fibrogenic cytokines, TGF-beta and PDGF-beta.


Microfluidics in the eye: a review of glaucoma implants from an engineering perspective.
Glaucoma is a progressive optic neuropathy in the eye, which is a leading cause of irreversible blindness worldwide and currently affects over 70 million individuals. Clinically, intraocular pressure (IOP) reduction is the only proven treatment to halt the progression of glaucoma. Microfluidic devices such as glaucoma drainage devices (GDDs) and minimally invasive glaucoma surgery (MIGS) devices are routinely used by ophthalmologists to manage elevated IOP, by creating an artificial pathway for the over-accumulated aqueous humor (AH) in a glaucomatous eye, when the natural pathways are severely blocked. Herein, a detailed modelling and analysis of both the natural microfluidic pathways of the AH in the eye and artificial microfluidic pathways formed additionally by the various glaucoma implants are conducted to provide an insight into the causes of the IOP abnormality and the improvement schemes of current implant designs. The mechanisms of representative glaucoma implants have been critically reviewed from the perspective of microfluidics, and we have categorized the current implants into four groups according to the targeted drainage sites of the AH, namely Schlemm's canal, suprachoroidal space, subconjunctival space, and ocular surface. In addition, we propose to divide the development and evolution of glaucoma implant designs into three technological waves, which include microtube (1st), microvalve (2nd) and microsystem (3rd). With the emerging trends of minimal invasiveness and artificial intelligence in the development of medical implants, we envision that a comprehensive glaucoma treatment microsystem is on the horizon, which is featured with active and wireless control of IOP, real-time continuous monitoring of IOP and aqueous rate, etc. The current review could potentially cast light on the unmatched needs, challenges, and future directions of the microfluidic structural and functional designs of glaucoma implants, which would enable an enhanced safety profile, reduced complications, increased efficacy of lowering IOP and reduced IOP fluctuations, closed-loop and on-demand control of IOP, etc.


Hospital coronavirus disease 2019 (COVID-19) public health reporting: Lessons from validation of an automated surveillance tool to facilitate data collection.
A comparison of computer-extracted and facility-reported counts of hospitalized coronavirus disease 2019 (COVID-19) patients for public health reporting at 36 hospitals revealed 42% of days with matching counts between the data sources. Miscategorization of suspect cases was a primary driver of discordance. Clear reporting definitions and data validation facilitate emerging disease surveillance.


Evaluation of ovarian function and metabolic factors in women affected by polycystic ovary syndrome after treatment with D-Chiro-Inositol.
To evaluate the effects of D-Chiro-Inositol in women affected by polycystic ovary syndrome (PCOS). We enrolled 48 patients, with homogeneous bio-physical characteristics, affected by PCOS and menstrual irregularities. These patients underwent treatment with 1 gr of D-Chiro-Inositol/die plus 400 mcg of Folic Acid/die orally for 6 months. We analyzed pre-treatment and post-treatment BMI, Systolic and Diastolic blood pressure, Ferriman-Gallwey score, Cremoncini score, serum LH, LH/FSH ratio, total and free testosterone, DHEA-S, Δ-4-androstenedione, SHBG, prolactin, glucose/IRI ratio, HOMA index, and resumption of regular menstrual cycles. We evidenced a statistically significant reduction of systolic blood pressure, Ferriman-Gallwey score, LH, LH/FSH ratio, total Testosterone, free Testosterone, ∆-4-Androstenedione, Prolactin, and HOMA Index; in the same patients, we noticed a statistically significant increase of SHBG and Glycemia/IRI ratio. Moreover, we observed statistically significant (62.5%; p < 0.05) post-treatment menstrual cycle regularization. D-Chiro-Inositol is effective in improving ovarian function and metabolism of patients affected by PCOS.


Modeling Endoplasmic Reticulum Network Maintenance in a Plant Cell.
The endoplasmic reticulum (ER) in plant cells forms a highly dynamic network of complex geometry. ER network morphology and dynamics are influenced by a number of biophysical processes, including filament/tubule tension, viscous forces, Brownian diffusion, and interactions with many other organelles and cytoskeletal elements. Previous studies have indicated that ER networks can be thought of as constrained minimal-length networks acted on by a variety of forces that perturb and/or remodel the network. Here, we study two specific biophysical processes involved in remodeling. One is the dynamic relaxation process involving a combination of tubule tension and viscous forces. The other is the rapid creation of cross-connection tubules by direct or indirect interactions with cytoskeletal elements. These processes are able to remodel the ER network: the first reduces network length and complexity whereas the second increases both. Using live cell imaging of ER network dynamics in tobacco leaf epidermal cells, we examine these processes on ER network dynamics. Away from regions of cytoplasmic streaming, we suggest that the dynamic network structure is a balance between the two processes, and we build an integrative model of the two processes for network remodeling. This model produces quantitatively similar ER networks to those observed in experiments. We use the model to explore the effect of parameter variation on statistical properties of the ER network.


Technical Considerations in the Freezing, Low-Temperature Storage and Thawing of Stem Cells for Cellular Therapies.
The commercial and clinical development of cellular therapy products will invariably require cryopreservation and frozen storage of cellular starting materials, intermediates and/or final product. Optimising cryopreservation is as important as optimisation of the cell culture process in obtaining maximum yield and a consistent end-product. Suboptimal cryopreservation can lead not only to batch-to-batch variation, lowered cellular functionality and reduced cell yield, but also to the potential selection of subpopulations with genetic or epigenetic characteristics divergent from the original cell line. Regulatory requirements also impact on cryopreservation as these will require a robust and reproducible approach to the freezing, storage and thawing of the product. This requires attention to all aspects of the application of low temperatures: from the choice of freezing container and cryoprotectant, the cooling rate employed and its mode of de-livery, the correct handling of the frozen material during storage and transportation, to the eventual thawing of the product by the end-user. Each of these influences all of the others to a greater or lesser extent and none should be ignored. This paper seeks to provide practical insights and alternative solutions to the technical challenges faced during cryopreservation of cells for use in cellular therapies.


Rapid and Cost-Efficient Detection of RET Rearrangements in a Large Consecutive Series of Lung Carcinomas.
RET-kinase-activating gene rearrangements occur in approximately 1-2% of non-small-cell lung carcinomas (NSCLCs). Their reliable detection requires next-generation sequencing (NGS), while conventional methods, such as immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) or variant-specific PCR, have significant limitations. We developed an assay that compares the level of RNA transcripts corresponding to 5'- and 3'-end portions of the RET gene; this test relies on the fact that RET translocations result in the upregulation of the kinase domain of the gene and, therefore, the 5'/3'-end expression imbalance. The present study included 16,106 consecutive NSCLC patients, 14,449 (89.7%) of whom passed cDNA quality control. The 5'/3'-end unbalanced RET expression was observed in 184 (1.3%) tumors, 169 of which had a sufficient amount of material for the identification of translocation variants. Variant-specific PCR revealed RET rearrangements in 155/169 (91.7%) tumors. RNA quality was sufficient for RNA-based NGS in 10 cases, 8 of which carried exceptionally rare or novel (HOOK1::RET and ZC3H7A::RET) RET translocations. We also applied variant-specific PCR for eight common RET rearrangements in 4680 tumors, which emerged negative upon the 5'/3'-end unbalanced expression test; 33 (0.7%) of these NSCLCs showed RET fusion. While the combination of the analysis of 5'/3'-end RET expression imbalance and variant-specific PCR allowed identification of RET translocations in approximately 2% of consecutive NSCLCs, this estimate approached 120/2361 (5.1%) in EGFR/KRAS/ALK/ROS1/BRAF/MET-negative carcinomas. RET-rearranged tumors obtained from females, but not males, had a decreased level of expression of thymidylate synthase (p < 0.00001), which is a known predictive marker of the efficacy of pemetrexed. The results of our study provide a viable alternative for RET testing in facilities that do not have access to NGS due to cost or technical limitations.


The global problem of child maltreatment: Perspectives on mechanisms of influence and illness presentation.
Child abuse and neglect negatively impact both neurological and psychological development. Patterns of abuse are learned and repeated in families. Adverse childhood experiences are a risk factor for psychopathology later in life, including borderline personality disorder (BPD). BPD is prevalent in clinical populations in the United States, but its prevalence has not been well-documented in most other parts of the world. The aim of this paper is to explore the impact of culture upon the intergenerational transmission of childhood maltreatment and the clinical presentation of abused children. To facilitate this exploration, we will consider the cases of four adolescent girls in unique socioeconomic and cultural settings around the world: Liberia, El Salvador, India, and a Congolese immigrant in France. Each of these girls endorsed some features of BPD, but only two met full criteria. In societies in which externalizing behaviors are not acceptable, children may internalize their distress or separate from their families. Defining BPD in terms of internal experience makes it more difficult to identify, but it would allow for the inclusion of cases in which symptoms may manifest differently while the underlying problem is similar.


Enhanced amygdala responses to emotional versus neutral schematic facial expressions.
Human facial emotional expressions are complex. This may confound studies examining brain responses to these stimuli in control and clinical populations. However, several lines of evidence suggest that a few elementary facial features convey the gist of emotional expressions. Using fMRI, we assessed brain responses to line drawings of emotionally valenced (i.e. angry and happy) and neutral faces in healthy human subjects. Significantly increased fMRI signal was found in the amygdala, hippocampus and prefrontal cortex in response to emotional vs neutral schematic faces. Although direct comparisons of schematic and human faces will be needed, these initial results suggest that schematic faces may be useful for studying brain responses to emotional stimuli because of their simplicity relative to human faces.


Management of Obstructive Sleep Apnea in Commercial Motor Vehicle Operators: Recommendations of the AASM Sleep and Transportation Safety Awareness Task Force.
The American Academy of Sleep Medicine Sleep and Transportation Safety Awareness Task Force responded to the Federal Motor Carrier Safety Administration and Federal Railroad Administration Advance Notice of Proposed Rulemaking and request for public comments regarding the evaluation of safety-sensitive personnel for moderate-to-severe obstructive sleep apnea (OSA). The following document represents this response. The most salient points provided in our comments are that (1) moderate-to-severe OSA is common among commercial motor vehicle operators (CMVOs) and contributes to an increased risk of crashes; (2) objective screening methods are available and preferred for identifying at-risk drivers, with the most commonly used indicator being body mass index; (3) treatment in the form of continuous positive airway pressure (CPAP) is effective and reduces crashes; (4) CPAP is economically viable; (5) guidelines are available to assist medical examiners in determining whether CMVOs with moderate-to-severe OSA should continue to work without restrictions, with conditional certification, or be disqualified from operating commercial motor vehicles.


Radiation hybrid maps of the D-genome of Aegilops tauschii and their application in sequence assembly of large and complex plant genomes.
The large and complex genome of bread wheat (Triticum aestivum L., ~17 Gb) requires high resolution genome maps with saturated marker scaffolds to anchor and orient BAC contigs/ sequence scaffolds for whole genome assembly. Radiation hybrid (RH) mapping has proven to be an excellent tool for the development of such maps for it offers much higher and more uniform marker resolution across the length of the chromosome compared to genetic mapping and does not require marker polymorphism per se, as it is based on presence (retention) vs. absence (deletion) marker assay. In this study, a 178 line RH panel was genotyped with SSRs and DArT markers to develop the first high resolution RH maps of the entire D-genome of Ae. tauschii accession AL8/78. To confirm map order accuracy, the AL8/78-RH maps were compared with:1) a DArT consensus genetic map constructed using more than 100 bi-parental populations, 2) a RH map of the D-genome of reference hexaploid wheat 'Chinese Spring', and 3) two SNP-based genetic maps, one with anchored D-genome BAC contigs and another with anchored D-genome sequence scaffolds. Using marker sequences, the RH maps were also anchored with a BAC contig based physical map and draft sequence of the D-genome of Ae. tauschii. A total of 609 markers were mapped to 503 unique positions on the seven D-genome chromosomes, with a total map length of 14,706.7 cR. The average distance between any two marker loci was 29.2 cR which corresponds to 2.1 cM or 9.8 Mb. The average mapping resolution across the D-genome was estimated to be 0.34 Mb (Mb/cR) or 0.07 cM (cM/cR). The RH maps showed almost perfect agreement with several published maps with regard to chromosome assignments of markers. The mean rank correlations between the position of markers on AL8/78 maps and the four published maps, ranged from 0.75 to 0.92, suggesting a good agreement in marker order. With 609 mapped markers, a total of 2481 deletions for the whole D-genome were detected with an average deletion size of 42.0 Mb. A total of 520 markers were anchored to 216 Ae. tauschii sequence scaffolds, 116 of which were not anchored earlier to the D-genome. This study reports the development of first high resolution RH maps for the D-genome of Ae. tauschii accession AL8/78, which were then used for the anchoring of unassigned sequence scaffolds. This study demonstrates how RH mapping, which offered high and uniform resolution across the length of the chromosome, can facilitate the complete sequence assembly of the large and complex plant genomes.


AICA riboside improves myocardial ischemia in coronary microembolization in dogs.
This study was undertaken to examine whether 5-amino-4-imidazolecarboxamide (AICA) riboside (acadesine), which augments adenosine release in ischemic myocardium, further attenuates ischemic injury after acute coronary microembolization. The left anterior descending coronary artery was cannulated and perfused with blood from the left carotid artery in 46 dogs, and coronary blood flow (CBF) of the perfused area was measured. In 12 dogs, 15-microns microspheres (5.0 x 10(4)/ml) were injected repeatedly until CBF approached zero. Changes in CBF, fractional shortening, lactate extraction ratio, and adenosine release were measured with and without administration of AICA riboside. In the control group (n = 7), CBF increased to 154 +/- 11 ml.100 g-1.min-1 at 16-30% of total coronary embolization, and adenosine release was 6.1 +/- 1.0 nmol.100 g-1.min-1. Administration of AICA riboside (n = 5) enhanced coronary hyperemia (187 +/- 8 ml.100 g-1.min-1, P < 0.05), adenosine release (11.9 +/- 0.9 nmol.100 g-1.min-1, P < 0.001), and myocardial adenosine content (0.434 +/- 0.069 vs. 0.118 +/- 0.019 nmol/mg wet wt, P < 0.01) and attenuated decreases in fractional shortening and lactate extraction ratio. AICA riboside preserved myocardial tissue ATP content of the embolized area. The administrations of 8-phenyltheophylline (n = 12) and alpha,beta-methyleneadenosine 5'-diphosphate (n = 10) abolished the beneficial effects of AICA riboside. Furthermore, AICA riboside increased ectosolic and cytosolic 5'-nucleotidase activity of the embolized myocardium (n = 12). Thus we conclude that AICA riboside attenuates contractile and metabolic dysfunction by enhancing adenosine release via activation of ectosolic 5'-nucleotidase and inducing local hyperemia in acute coronary microembolization.


Expression patterns of the transcription factors Fezf1, Fezf2, and Bcl11b in the olfactory organs of turtle embryos.
Many tetrapod vertebrates have two distinct olfactory organs, the olfactory epithelium (OE) and vomeronasal organ (VNO). In turtles, the olfactory organ consists of two types of sensory epithelia, the upper chamber epithelium (UCE; corresponding to the OE) and the lower chamber epithelium (LCE; corresponding to the VNO). In many turtle species, the UCE contains ciliated olfactory receptor cells (ORCs) and the LCE contains microvillous ORCs. To date, several transcription factors involved in the development of the OE and VNO have been identified in mammals. Fez family zinc-finger protein 1 and 2 (Fezf1 and 2) are expressed in the OE and VNO, respectively, of mouse embryos, and are involved in the development and maintenance of ORCs. B-cell lymphoma/leukemia 11B (Bcl11b) is expressed in the mouse embryo OE except the dorsomedial parts of the nasal cavity, and regulates the expression of odorant receptors in the ORCs. In this study, we examined the expression of Fezf1, Fezf2, and Bcl11b in the olfactory organs of embryos in three turtle species, Pelodiscus sinensis, Trachemys scripta elegans, and Centrochelys sulcata, to evaluate their involvement in the development of reptile olfactory organs. In all three turtle species, Bcl11b was expressed in the UCE, Fezf2 in the LCE, and Fezf1 in both the UCE and LCE. These results imply that the roles of the transcription factors Fezf1, Fezf2, and Bcl11b in olfactory organ development are conserved among mammals and turtles.


Prevalence of aortic aneurysms in the Twin Cities metropolitan area, 1979-84.
The discharge summaries for Minneapolis-St. Paul metropolitan area residents hospitalized during 1979-84 were reviewed for diagnoses of aortic aneurysms. Annual age-specific and age-adjusted sex-specific hospital discharge diagnosis rates were calculated for all aortic aneurysms, dissecting aortic aneurysms, thoracic aortic aneurysms (nondissecting), and abdominal aortic aneurysms (nondissecting). For each aortic aneurysm type, hospital discharge diagnosis rates were found to increase with age for both men and women. Abdominal aortic aneurysms were the most common type reported (age-adjusted annual rates for men varied between 40.6 and 49.3 per 100,000 population; for women, between 6.8 and 12.0 per 100,000 population). Men were noted to have higher rates for each aneurysm type. An increasing temporal trend was observed for all aortic aneurysms and abdominal aortic aneurysms among men. These findings are reviewed in light of recent data on mortality from aortic aneurysms in the United States.


The panmixia paradigm of eastern Pacific olive ridley turtles revised: consequences for their conservation and evolutionary biology.
Previous studies of the olive ridley Lepidochelys olivacea population structure in the tropical eastern Pacific have indicated the existence of a single panmictic population ranging from Costa Rica to Mexico. This information has been used to design specific management measures to conserve primary nesting beaches in Mexico. However, little is known about olive ridleys in the Baja California Peninsula, their northernmost reproductive limit, where recent observations have shown differences in nesting female behaviour and size of hatchlings relative to other continental rookeries. We used mtDNA control region sequences from 137 turtles from five continental and four peninsular nesting sites to determine whether such differences correspond to a genetic distinction of Baja California olive ridleys or to phenotypic plasticity associated with the extreme environmental nesting conditions of this region. We found that genetic diversity in peninsular turtles was significantly lower than in continental nesting colonies. Analysis of molecular variance revealed a significant population structure (Phi ST = 0.048, P = 0.006) with the inclusion of peninsular samples. Our results: (i) suggest that the observed phenotypic variation may be associated with genetic differentiation and reproductive isolation; (ii) support the recent colonization of the eastern Pacific by Lepidochelys; (iii) reveal genetic signatures of historical expansion and colonization events; and (iv) significantly challenge the notion of a single genetic and conservation unit of olive ridleys in the eastern Pacific. We conclude that conservation measures for olive ridleys in Mexico should be revised to grant peninsular beaches special attention.


Electronic absorption spectrum of triacetylene cation for astronomical considerations.
The A(2)Πg ← X(2)Πu electronic transition (4800-6000 Å) of triacetylene cation was measured in an ion trap, where the vibrational and rotational degrees of freedom were equilibrated to 25 K. The rotational profile of the origin band is predicted by a collisional-radiative rate model under conditions expected in diffuse interstellar clouds. Variation in the density of the surrounding gas, rotational temperature, and velocity dispersion are taken into account.


Understanding Competition of Polyalcohol Dehydration Reactions in Hot Water.
Dehydration of biomass-derived polyalcohols has recently drawn attention in green chemistry as a prototype of selective reactions controllable in hot water or hot carbonated water, without any use of organic solvents or metal catalysts. Here, we report a free-energy analysis based on first-principles metadynamics and blue-moon ensemble simulations to understand the mechanism of competing intramolecular dehydration reactions of 1,2,5-pentanetriol in hot acidic water. The simulations consistently predict that the most dominant mechanism is the proton-assisted SN2 process, where the protonation of the hydroxyl group by water and the C-O bond breaking and formation occur in a single step. However the free-energy barriers are different between the reaction paths: those leading to five-membered ether products, tetrahydrofurfuryl alcohol (THFA), are few kcal/mol lower than those leading to six-membered ether products, 3-hydroxytetrahydropyran (3-HTHP). A slight difference is seen in the timing of the protonation of the hydroxyl group of THFA and 3-HTHP on their reaction pathways. The detailed mechanism found from the simulations shows how the reaction paths are selective in hot water and why the reaction rates are accelerated in acidic environments, thus giving a clear explanation of experimental findings for a broad class of competing dehydration processes of polyalcohols.


Recommendations for patient involvement in health technology assessment in Central and Eastern European countries.
Meaningful patient involvement in health technology assessment (HTA) is essential in ensuring that the interests of the affected patient population, their families, and the general public are accurately reflected in coverage and reimbursement decisions. Central and Eastern European (CEE) countries are generally at less advanced stages of implementing HTA, which is particularly true for patient involvement activities. As part of the Horizon2020 HTx project, this research aimed to form recommendations for critical barriers to patient involvement in HTA in CEE countries. Built on previous research findings on potential barriers, a prioritisation survey was conducted online with CEE stakeholders. Recommendations for prioritised barriers were formed through a face-to-face workshop by CEE stakeholders and HTx experts. A total of 105 stakeholders from 13 CEE countries completed the prioritisation survey and identified 12 of the 22 potential barriers as highly important. The workshop had 36 participants representing 9 CEE countries, and 5 Western European countries coming together to discuss solutions in order to form recommendations based on best practices, real-life experience, and transferability aspects. Stakeholder groups involved in both phases included HTA organisation representatives, payers, patients, caregivers, patient organisation representatives, patient experts, health care providers, academic and non-academic researchers, health care consultants and health technology manufacturers/providers. As a result, 12 recommendations were formed specified to the CEE region's context, but potentially useful for a broader geographic audience. In this paper, we present 12 recommendations for meaningful, systematic, and sustainable patient involvement in HTA in CEE countries. Our hope is that engaging more than a hundred CEE stakeholders in the study helped to spread awareness of the importance and potential of patient involvement and that the resulting recommendations provide tangible steps for the way forward. Future studies shall focus on country-specific case studies of the implemented recommendations.


Diversity in genetic in vivo methods for protein-protein interaction studies: from the yeast two-hybrid system to the mammalian split-luciferase system.
The yeast two-hybrid system pioneered the field of in vivo protein-protein interaction methods and undisputedly gave rise to a palette of ingenious techniques that are constantly pushing further the limits of the original method. Sensitivity and selectivity have improved because of various technical tricks and experimental designs. Here we present an exhaustive overview of the genetic approaches available to study in vivo binary protein interactions, based on two-hybrid and protein fragment complementation assays. These methods have been engineered and employed successfully in microorganisms such as Saccharomyces cerevisiae and Escherichia coli, but also in higher eukaryotes. From single binary pairwise interactions to whole-genome interactome mapping, the self-reassembly concept has been employed widely. Innovative studies report the use of proteins such as ubiquitin, dihydrofolate reductase, and adenylate cyclase as reconstituted reporters. Protein fragment complementation assays have extended the possibilities in protein-protein interaction studies, with technologies that enable spatial and temporal analyses of protein complexes. In addition, one-hybrid and three-hybrid systems have broadened the types of interactions that can be studied and the findings that can be obtained. Applications of these technologies are discussed, together with the advantages and limitations of the available assays.


Dopamine responsiveness to drugs of abuse: A shell-core investigation in the nucleus accumbens of the mouse.
The existence of subterritories within the nucleus accumbens has now been widely supported by histochemical, neurochemical, electrophysiological, as well as morphological and ultrastructural studies and suggest specific afferent and efferent systems involved in different behavioral aspects. Microdialysis studies in the rat have consistently shown that most drugs of abuse increase extracellular dopamine levels preferentially in the shell subregion of the nucleus accumbens. The study of the relative roles of NAc subregions may considerably help our understanding of the neurobiological basis of drug addiction. Accordingly, the aim of the present work was to extend the outcome of rat studies to the mouse species. Five major drugs of abuse were systemically and acutely administered to mice with a microdialysis probe implanted in either the shell or the core. A statistical comparison was performed on data transformed as percentage values of baseline dopamine vs. logarithmic values with baseline dopamine as a covariate. Results show a significant increase in dopamine levels in both the shell and core subregions following cocaine, amphetamine, nicotine, ethanol, and morphine treatments. A difference between shell and core after cocaine, nicotine, and morphine was evident when data were analyzed as percent values of baseline. However, such a shell-core dichotomy became no longer significant when ANOVA was applied on the statistically more appropriate logarithmic transformation of data with baseline as a covariate. The significant baseline differences among groups of mice (dopamine levels in the shell significantly lower compared with dopamine levels in the core) may have compromised, at least in part, the statistical procedure usually applied in microdialysis studies. These findings suggest that a careful evaluation of the data is required when subtle changes in extracellular levels of DA are measured.


Design and characterization of an enclosed coaxial carbon nanotube speaker.
Automotive mufflers are heavy, large, and loud at low frequencies. Carbon nanotube (CNT) speakers are solid-state, lightweight, flexible, and capable of handling high temperatures. This makes them suitable as loudspeakers in active exhaust noise cancellation applications. A coaxial CNT speaker designed for active noise control in an exhaust system is developed. Test results for resistance, in-pipe axial sound pressure level, and efficiency are presented. The maximum in-pipe sound pressure level was above 120 dB (re 20 μPa) using 105 W of electrical power. The maximum power efficiency was 0.008%. The weight, dimensions, and sound pressure level of the speaker show promise for active exhaust noise cancellation applications.


The Effect of Intravenous Dexmedetomidine Compared to Propofol on Patients Hemodynamics as a Sedative in Brachial Plexus Block: A Comparative Study.
The quest for an ideal sedative during regional anesthesia is on. Although propofol has been accepted as a sedative intraoperatively, it can be associated with troublesome hemodynamic changes. Dexmedetomidine is a new alpha 2 agonist used widely for sedation. In this study, we tried to compare equivalent doses of dexmedetomidine infusion with propofol with emphasis on their effect on the hemodynamics. Prospective, single-blinded randomized controlled trial. In a single blinded study, 60 American Society of Anesthesiologists (ASA) I and II patients scheduled for forearm surgeries under brachial plexus block were randomized to receive either propofol (Group I) or dexmedetomidine (Group II) infusion. Ultrasound-guided supraclavicular brachial plexus block was given in all the patients. After confirming adequate motor and sensory blockade, they were administered an initial loading dose of the drug over 10 min followed by a maintenance dose till the end of the surgery. The rate of infusion was titrated to maintain Ramsay sedation score of 2-4. Intraoperative hemodynamic and respiratory effects were documented along with surgeon and patient satisfaction. Any adverse effect such as hypotension, bradycardia, nausea, and vomiting was also noted. The data collected were evaluated using Stata version 10. P < 0.05 was considered statistically significant. Heart rate decreased significantly in Group II (dexmedetomidine) while mean arterial pressure decreased significantly in Group I (propofol). There was no increase in the incidence of bradycardia or hypotension in either groups. Patient satisfaction score was significantly greater in Group II (dexmedetomidine) while surgeon satisfaction score was similar in both the groups. Dexmedetomidine at equivalent doses of propofol has a similar hemodynamic and respiratory effect, similar surgeon's satisfaction score, higher patient's satisfaction score, and no significant side effects in ASA I/II patients. Thus, dexmedetomidine may prove to be a valuable alternative to propofol for sedation in patients undergoing upper limb surgeries in brachial plexus block.


Production of virus-like particles of porcine circovirus 2 in baculovirus expression system and its application for antibody detection.
Porcine circovirus 2 (PCV-2) is one of the pathogens that leads to a growing and persistent threat in pigs. Thus, the development of serological detection methods for PCV-2 is of great necessity for clinical diagnosis as well as epidemiological investigations. This study aimed to establish an indirect enzyme-linked immunosorbent assay (ELISA) to examine antibodies against PCV-2 based on virus-like particles (VLPs). Recombinant PCV-2 Cap protein was expressed in the baculovirus-insect cells system and PCV-2 VLPs were observed over transmission electron microscopy (TEM). The PCV-2 VLPs were shown to have good immunogenicity in mice and stimulated a high level of PCV-2 antibody titers. Using PCV-2 VLPs as coating antigen, the indirect ELISA can detect PCV-2 antibodies in animals with diagnostic sensitivity and specificity of 98.33% and 93.33% compared to immunofluorescence assay (IFA), respectively. The intra- and inter-assay coefficient variations (CVs) were < 10% in a batch, and < 15% in different batches, indicating good repeatability. There was no cross-reaction of this ELISA with antibodies against other porcine viruses. A total of 170 serum samples collected from different pig farms in China were tested for PCV-2 antibodies, and 151 (88.8%) samples were PCV-2 antibody positive. Our findings suggest that this ELISA was rapid, specific, and reproducible and can be used for large-scale serological investigations of PCV-2 antibodies in pigs.


Interdependence between Zn and Cu serum concentrations and serum immunoglobulins (IgA, IgM, IgG) in liver diseases.
The object of this study was to find out, by means of statistical-mathematical methods, whether the serum concentrations of Zn and Cu had a role in the interrelation among immunoglobulins IgA, IgM, IgG in four groups of subjects with various forms of liver diseases. It was found that the correlation structure between IgA, IgM, IgG and the serum concentration of Zn or Cu were different in the four types of diseases studied, and also that of these two metal ions, Zn was the most important, influencing the interdependence between the immunoglobulins in the active forms of disease.


[Nutritional rehabilitation of undernourished and nutritionally at-risk children admitted to a supplementary food program in Mogi das Cruzes, São Paulo, Brazil].
This study aimed to evaluate the nutritional rehabilitation of undernourished children admitted to a program entitled Incentives to Fight Nutritional Deficiencies (ICCN) in Mogi das Cruzes, São Paulo, Brazil. The study included 724 children (6 to 24 months old) from July 1999 to July 2001. The indices used to evaluate baseline nutritional status were weight-for-age, weight-for-length, and length-for-age, defining normal as z score > or = -1, at-risk as > or = -2 and < -1, moderate malnutrition as < -2 and > -3, and severe malnutrition as < or = -3. Nutritional evolution was evaluated using the length-for-age index, and the results were analyzed considering the average z score variation at the end of the 12-month program. After 12 months, nutritional status had improved in all categories, while the best results were in children with more intense baseline nutritional deficiency. Gains in length were 1.12, 0.82, 0.57, and 0.45 z scores for the severe and moderate malnutrition, nutritional risk, and normal categories, respectively. The ICCN in Mogi das Cruzes thus demonstrated effective nutritional improvement for program beneficiaries.


Decreased serum testosterone response to gonadotropin-releasing hormone in male offspring of diabetic female rats.
A study was designed to examine the testicular function of male offspring rats produced by diabetic dams. A marked decrease in testosterone response to exogenous administration of gonadotropin-releasing hormone (GnRH) was found in male offspring of female rats made diabetic by administration of streptozotocin during early pregnancy. Control rats responded to GnRH with a marked increase in serum testosterone within 4-h postinjection. Male offspring of diabetic female rats demonstrated an unexpected decrease in serum testosterone in response to GnRH when compared with saline-injected rats. The results suggest that a defect in Leydig cell function may occur in the male offspring of diabetic female rats. However, a decreased release of pituitary LH in response to exogenous GnRH stimulation cannot be excluded as a cause of the lower testosterone values.


Self-assembled cGAMP-STINGΔTM signaling complex as a bioinspired platform for cGAMP delivery.
The stimulator of interferon (IFN) genes (STING) pathway constitutes a highly important part of immune responses against various cancers and infections. Consequently, administration of STING agonists such as cyclic GMP-AMP (cGAMP) has been identified as a promising approach to target these diseases. In cancer cells, STING signaling is frequently impaired by epigenetic silencing of STING; hence, conventional delivery of only its agonist cGAMP may be insufficient to trigger STING signaling. In this work, while expression of STING lacking the transmembrane (TM) domain is known to be unresponsive to STING agonists and is dominant negative when coexpressed with the full-length STING inside cells, we observed that the recombinant TM-deficient STING protein complexed with cGAMP could effectively trigger STING signaling when delivered in vitro and in vivo, including in STING-deficient cell lines. Thus, this bioinspired method using TM-deficient STING may present a universally applicable platform for cGAMP delivery.


Awareness of wearing an accelerometer does not affect physical activity in youth.
This study aimed to investigate whether awareness of being monitored by an accelerometer has an effect on physical activity in young people. Eighty healthy participants aged 10-18 years were randomized between blinded and nonblinded groups. The blinded participants were informed that we were testing the reliability of a new device for body posture assessment and these participants did not receive any information about physical activity. In contrast, the nonblinded participants were informed that the device was an accelerometer that assessed physical activity levels and patterns. The participants were instructed to wear the accelerometer for 4 consecutive days (2 school days and 2 school-free days). Missing data led to the exclusion of 2 participants assigned to the blinded group. When data from the blinded group were compared with these from the nonblinded group, no differences were found in the duration of any of the following items: (i) wearing the accelerometer, (ii) total physical activity, (iii) sedentary activity, and (iv) moderate-to-vigorous activity. Our study shows that the awareness of wearing an accelerometer has no influence on physical activity patterns in young people. This study improves the understanding of physical activity assessment and underlines the objectivity of this method. NCT02844101 (retrospectively registered at July 13th 2016).


Enalapril in the treatment of congestive heart failure.
Congestive heart failure (CHF) is a complex clinical syndrome affecting 1% of the U.S. population. The basic dysfunction, a lack of sufficient blood flow to the periphery, triggers reflex neurohumoral mechanisms that cause systemic vasoconstriction and sodium and water retention as the body attempts to protect vital organs. This, in turn, results in additional work for the failing heart and further deterioration. Vasodilators, in general, and angiotensin converting enzyme (ACE) inhibitors, in particular, interrupt this pathophysiology and improve hemodynamics. Enalapril, a long-acting ACE inhibitor, has been demonstrated to improve New York Heart Association (NYHA) functional class, pulmonary capillary wedge pressure, cardiac index, maximum oxygen uptake, and exercise tolerance in CHF patients. Data from a recent trial provide evidence that a group of patients with severe CHF who were treated with enalapril showed reduced heart size, reduced need for other heart-failure medication, and reduced mortality.


A Novel Approach to the Management of Margin-positive DCIS in Nipple-sparing Mastectomy.
Nipple-sparing mastectomy (NSM) is gaining acceptance as an oncologically sound and cosmetically superior mastectomy technique. Debate exists over the management of positive margins near the nipple-areola complex. This case report presents a novel approach to the management of margin-positive ductal carcinoma in situ in NSM. A 50-year-old white female with invasive ductal carcinoma underwent NSM. Intraoperative pathology indicated the presence of DCIS-positive retroareolar margins. Revision through a direct vertical nipple incision allowed for adequate surgical revision and pathologic evaluation of the retroareolar breast tissue while maintaining the nipple-areola skin and primary mastectomy incision. This novel approach ensures negative margins, allows superior cosmetic outcome, and improves patient autonomy in decision making. The technique may translate to NSM patients with positive retroareolar margins or false-negative margins.


Differential, partial and total electron impact ionization cross sections for SF(6).
Single and double differential ionization cross sections for the production of ions resulting from dissociative, single and double ionization of SF(6) by electron impact have been calculated using a semiempirical formulation based on the Jain-Khare approach. In addition, triple differential cross sections have been obtained for some of the doubly charged fragment ions at an incident electron energy of 100, 150, and 200 eV, respectively, and a fixed scattering angle of 30 degrees. As no previous data seem to exist for differential cross sections we have derived from these differential cross sections corresponding partial and total ionization cross sections from threshold up to 900 eV and compared those with the available theoretical and experimental data.


21st Lenna Frances Cooper memorial lecture: nutrition research by and about women.
Physiologists, chemists, and a few physicians, virtually all men, carried out the early research in human nutrition. Nutrition emerged as a "woman's field" of study and practice during a period when women's attempts to enter traditionally male-dominated fields of science were being resisted and frustrated. Nutrition benefited as a result, because it was given the attention of outstanding women scholars denied opportunities in their own fields. Women were the principal investigators of the nutrition concerns of women and children, for reasons of access and gentility . Analysis of historical and contemporary contributions by and about women suggests a gender difference between investigators' concerns: Men explore problems; women study needs.


Improving awareness of patient safety in a peer-led pilot educational programme for undergraduate medical students.
Patient safety is becoming an important but under-emphasised topic in medical education. Despite high-profile recommendations, it has not yet been ingrained in the medical undergraduate curriculum. We designed and evaluated an educational intervention on patient safety to pre-clinical undergraduate medical students, devised and run entirely by medical students in their clinical years. The aim was to raise awareness of patient safety, and provide the opportunity to practice specific skills useful as medical students and junior doctors. We designed a two hour seminar consisting of a brief lecture on the principles of patient safety, followed by a carousel of interactive activities in small groups. Attendance was voluntary. The effects were evaluated by questionnaires addressing satisfaction, attitudes and self-efficacy completed before, after and six months following the seminar. A total of 86 students attended, with a reserve list of interested students in place. A total of 92% completed the pre- and post-evaluation, of whom 100% enjoyed the seminar, 99% recommended other students to take part and 92% thought it should be a mandatory part of the curriculum. A total of 64% completed follow-up questionnaires at six months and showed significant maintenance of skills taught. Student tutors can deliver effective and engaging teaching on patient safety and should be utilised as part of the existing medical curriculum. Patient safety should be taught at medical schools using interactive methodologies to promote interest.


Bedtime administration of antihypertensive medication can reduce morning blood pressure surges in hypertensive patients: a systematic review and meta-analysis.
The risk of cardiovascular and cerebrovascular events is the highest during the first several hours post-awakening in patients with hypertension. This is largely due to surges in morning blood pressure (BP). The current meta-analysis explored whether morning BP is affected by the timing of antihypertensive drug administration. Four medical databases were searched for clinical trials that examined the relationship between the timing of antihypertensive drug administration and morning BP levels. This meta-analysis compared morning BP surges in patients administered medication at bedtime versus patients administered medication during the day. The random effects model demonstrated that bedtime administration of antihypertensive drugs reduced morning systolic blood pressure (SBP) by 1.17 mmHg [with 95% confidence interval (CI): -2.47 to 0.37; P=0.08), and reduced morning diastolic blood pressure (DBP) by 0.95 mmHg (95% CI: -2.03 to 0.13; P=0.08), compared with patients who were administered medication during the daytime hours. However, the results did not demonstrate statistical significance. There was strong heterogeneity in both morning SBP (I2 =77.9% >50%, and Q test >0.1) and morning DBP results (I2 =77.9% >50%, and Q test >0.1). The funnel plots showed no publication bias in this study. Studies have shown that a 1 mmHg change was sufficient to reduce the risk of cardiovascular-related deaths by 2.1%. Therefore, changing the time of taking antihypertensive medications may significantly reduce cardiovascular-associated mortality. There were certain limitations to this meta-analysis. First, the heterogeneity of the meta-analysis was strong, with undefined reasons. Second, the sample size was relatively small, and future studies involving larger cohorts are warranted to further assess the effects of bedtime antihypertensive medication on minimizing morning BP surges.


Rolling resistance of casters increases significantly after two years of simulated use.
Manual wheelchair propulsion is associated with upper limb pain and injury, and clinical guidelines recommend minimizing propulsive force to lower health risks. One of the strategies to reduce propulsive force is by minimizing rolling resistance (RR). Product testing studies suggest that RR of casters is affected by wear and tear which could have implications on the health risk of wheelchair users. The study will investigate the relationship between caster RR and environmental exposure using standard testing protocols. RR of ten casters representing a range of diameters for different models of wheelchairs were measured before and after environmental exposure that includes corrosion, shock and abrasion simulating two years of community use. Four casters exhibited failures during durability testing, one catastrophically. Increases to RR after corrosion, shock and abrasion exposure were statistically significant using mixed-effects modeling, and four casters had increased RR greater than 20%. Many of the casters evaluated exhibited increased RR forces and failure after environmental exposure. Improved caster design and use of corrosion resistant materials may reduce these failures. In addition, modification of the provision process could include replacement casters to reduce failures and avoid breakdowns that leave manual wheelchair users stranded or injured.


Electroacupuncture Inhibits Pain Memory and Related Anxiety-Like Behaviors by Blockading the GABAB Receptor Function in the Midcingulate Cortex.
Pain memory is commonly considered an underlying cause of chronic pain and is also responsible for a range of anxiety. Electroacupuncture (EA) has been shown to ameliorate pain memories and exert anti-anxiety effects. Previous research has indicated that GABAergic neurons and/or GABA receptors (GABARs) in the midcingulate cortex (MCC) have potential associations with chronic pain and anxiety. However, there is no known empirical research that has specifically studied the effects of EA on the GABAergic system in the MCC. Here, we used cross-injection of carrageenan to establish the pain memory rats model. Immunofluorescence were used to detect the excitability of GABAergic neurons within MCC. Von Frey filament, elevated zero maze, and open field tests were used to measure mechanical allodynia and anxiety-like behaviors, combined with chemogenetic and pharmacologic technologies. Finally, this study provides evidence that pain memories contribute to generalized negative emotions and that downregulating the activity of GABAergic neurons within MCC could block pain memories and reverse anxiety emotion. Specifically, GABABR is involved in pain memory and related anxiety-like behaviors. Activation of GABAergic neurons in the MCC did not reverse the effects of EA on pain memories and related anxiety-like behaviors, whereas these effects could be reversed by a GABABR agonist. These findings highlight the functional significance of GABABR in the EA-mediated attenuation of pain memories and related anxiety-like behaviors in rats.


Screening for signatures of selection of Tianzhu white yak using genome-wide re-sequencing.
The Tianzhu white yak, a domestic yak indigenous to the Qilian Mountains, migrated inland from the Qinghai-Tibet Plateau. Specific ecological and long-term artificial selection influenced the evolution of its pure white coat and physiological characteristics. Therefore, it is not only a natural population that represents a genomic selective region of environmental adaptability but is also an animal model for studying the pigmentation of the yak coat. A total of 24 261 829 variants, including 22 445 252 SNPs, were obtained from 29 yaks by genome-wide re-sequencing. According to the results of a selective sweep analysis of Tianzhu white yak in comparison to Tibetan yaks, nine candidate genes under selection in Tianzhu white yak were identified by combining π, Tajima's D, πA/πB and FST statistics, with threshold standards of 5%. These genes include PDCD1, NUP210, ABCG8, NEU4, LOC102287650, D2HGDH, COL4A1, RTP5 and HDAC11. Five of the nine genes were classified into 12 molecular signaling pathways, and most of these signaling pathways are involved in environmental information processing, organismal systems and metabolism. A majority of these genes has not been implicated in previous studies of yak coat color and high-altitude animals. Our findings are helpful not only for explaining the molecular mechanism of yak coat pigmentation but also for exploring the genetic changes in Tianzhu white yak due to environmental adaptation.


Review and Assessment of Medicinal Safety Data of Orally Used Echinacea Preparations.
Echinacea purpurea, Echinacea angustifoli and Echinacea pallida are frequently used as medicinal plants. Besides asking for evidence on their efficacy, there is an increasing interest for safety data. This review systematically presents the available literature on drug interactions, contraindications, adverse events, duration of use, and safety of use in pregnant and nursing women, and assesses the safety profile of corresponding Echinacea preparations. It is noteworthy that all safety data reported are as product specific as the pharmacological or efficacy data are. In pharmacokinetic herb-drug interaction studies performed in vivo, no significant inhibitions of human CYP2D6 and CYP3A4 isoforms have been found after the administration of standardized E. purpurea preparations. However, contradictory results exist in studies using liver microsomes. Adverse events reported during clinical trials following administration of Echinacea spp. mono-preparations were generally mild and mostly without causality. Due to published long term studies with continuous ingestion of different Echinacea preparations up to 6 month with no reported toxicological concerns, Echinacea can be recommended also for long-term use. Moreover, the contraindications in cases of autoimmune diseases and immune-suppression are questionable, since lipophilic Echinacea preparations containing alkamides suppress cellular immune responses, and beneficial effects in autoimmunity were reported. The same applies for the use during pregnancy. Although there has been some impact reported on embryonic angiogenesis in mice, no association with an increased risk for major or minor malformations during organogenesis was found in a literature review. Altogether, the different evaluated Echinacea preparations are well-tolerated herbal medicines in the management in children and adults alike.


13C- and 15N-Isotope Analysis of Desphenylchloridazon by Liquid Chromatography-Isotope-Ratio Mass Spectrometry and Derivatization Gas Chromatography-Isotope-Ratio Mass Spectrometry.
The widespread application of herbicides impacts surface water and groundwater. Metabolites (e.g., desphenylchloridazon from chloridazon) may be persistent and even more polar than the parent herbicide, which increases the risk of groundwater contamination. When parent herbicides are still applied, metabolites are constantly formed and may also be degraded. Evaluating their degradation on the basis of concentration measurements is, therefore, difficult. This study presents compound-specific stable-isotope analysis (CSIA) of nitrogen- and carbon-isotope ratios at natural abundances as an alternative analytical approach to track the origin, formation, and degradation of desphenylchloridazon (DPC), the major degradation product of the herbicide chloridazon. Methods were developed and validated for carbon- and nitrogen-isotope analysis (δ13C and δ15N) of DPC by liquid chromatography-isotope-ratio mass spectrometry (LC-IRMS) and derivatization gas chromatography-IRMS (GC-IRMS), respectively. Injecting standards directly onto an Atlantis LC-column resulted in reproducible δ13C-isotope analysis (standard deviation <0.5‰) by LC-IRMS with a limit of precise analysis of 996 ng of DPC on-column. Accurate and reproducible δ15N analysis with a standard deviation of <0.4‰ was achieved by GC-IRMS after derivatization of >100 ng of DPC with 160-fold excess of (trimethylsilyl)diazomethane. Application of the method to environmental-seepage water indicated that newly formed DPC could be distinguished from "old" DPC by the different isotopic signatures of the two DPC sources.


Sports knee injuries - assessment and management.
Sports knee injuries present commonly in the general practice setting. A good understanding of the anatomy and biomechanics of the knee assists accurate diagnosis of acute knee injuries. This article describes the assessment and management of sports knee injuries in the general practice setting. When a patient presents with a sporting knee injury, a detailed history can help narrow down the nature of the injury. Examination can be difficult in the acute setting and may need to be repeated 3 or more days after the injury. Fractures can usually be excluded with plain X-rays; where indicated MRI or CT scan will usually confirm the diagnosis. Management aims are to manage pain, minimise knee swelling, maintain range of movement and quadriceps activation, and arrange appropriate referral. Medial collateral ligament, posterior cruciate ligament and some small meniscal injuries can usually be managed conservatively. Most meniscal injuries, anterior cruciate ligament and lateral collateral ligament injuries require surgical management. Physiotherapy is an integral part of the management of knee injuries in both the conservative and surgical settings.


Morphology of root canal cross-sections of resected roots of first and second lower molars.
Precise preparation of the root canal ostium with a view to hermetical closing with retrograde root filling is an important prognostic factor determining the success of the procedure of tooth resection. Root canals interconnected with a narrow isthmus may cause problems both in endodontic treatment and in retrograde filling. The aim of this work is the research of the transverse cross-section of root canals of first and second lower molars on the resection model. The research encompasses 100 randomly selected molar teeth: 50 first and 50 second lower molars. The tooth root apexes were cut 3 mm below the apex and examined under an electron microscope, special attention being paid to the shape of root canal cross-sections. In the group of first molar teeth, in 20% the presence of an isthmus between canals in the proximal roots was observed; in the group of second molar teeth an isthmus between the canals of proximal roots occurred in 18% of the cases. It seems that the relatively high percentage (20%-18%) of the occurrence of an isthmus, 3 mm below the root apex, between two elongated transverse cross-section proximal root canals of first and second molars should encourage particular caution in the retrograde filling of the above-mentioned canals during the procedure of resection.


Learning by heart: cultural patterns in the faunal processing sequence during the middle pleistocene.
Social learning, as an information acquisition process, enables intergenerational transmission and the stabilisation of cultural forms, generating and sustaining behavioural traditions within human groups. Archaeologically, such social processes might become observable by identifying repetitions in the record that result from the execution of standardised actions. From a zooarchaeological perspective, the processing and consumption of carcasses may be used to identify these types of phenomena at the sites. To investigate this idea, several faunal assemblages from Bolomor Cave (Valencia, Spain, MIS 9-5e) and Gran Dolina TD10-1 (Burgos, Spain, MIS 9) were analysed. The data show that some butchery activities exhibit variability as a result of multiple conditioning factors and, therefore, the identification of cultural patterns through the resulting cut-marks presents additional difficulties. However, other activities, such as marrow removal by means of intentional breakage, seem to reflect standardised actions unrelated to the physical characteristics of the bones. The statistical tests we applied show no correlation between the less dense areas of the bones and the location of impacts. Comparison of our experimental series with the archaeological samples indicates a counter-intuitive selection of the preferred locus of impact, especially marked in the case of Bolomor IV. This fact supports the view that bone breakage was executed counter-intuitively and repetitively on specific sections because it may have been part of an acquired behavioural repertoire. These reiterations differ between levels and sites, suggesting the possible existence of cultural identities or behavioural predispositions dependant on groups. On this basis, the study of patterns could significantly contribute to the identification of occupational strategies and organisation of the hominids in a territory. In this study, we use faunal data in identifying the mechanics of intergenerational information transmission within Middle Pleistocene human communities and provide new ideas for the investigation of occupational dynamics from a zooarchaeological approach.


Brain metastases in adenocarcinoma of the lung: frequency, risk groups, and prognosis.
A consecutive group of 259 patients with inoperable adenocarcinoma of the lung (ACL) were observed to define risk groups for and frequency of brain metastases together with prognosis. All patients received chemotherapy in a three-armed randomized trial. Brain metastases were diagnosed in 25 patients before protocol entry and in 37 during treatment. Brain autopsy was performed in 87 patients and was positive in 38 (44%). Eleven of these (29%) were not diagnosed clinically. Patients younger than 60 years had a somewhat higher overall frequency of brain metastases than older patients. Patients with initial performance status above 60% and patients responding to chemotherapy had higher risk for developing brain metastasis during treatment than other patients, probably because of the increasing cumulated risk for this complication with prolonged survival. Median survival after onset of brain metastases was 73 days and survival was significantly shorter for these patients than for patients without this complication at days 0, 90, 180, and 365 after protocol entry. Thus, brain metastases is a frequent complication in ACL and the frequency increases with prolonged survival. Survival after development of brain metastases is short and it is questionable whether the inclusion of this subgroup of ACL patients into experimental cytostatic treatments is justified.


Dehydration predicts longitudinal decline in cognitive functioning and well-being among older adults.
Adequate hydration is essential for health, with even mild forms of dehydration often having negative effects on cognition and well-being. Despite evidence of higher risk for dehydration among older adults, links between dehydration and cognitive or well-being outcomes have not been established in old age. In this study, we used longitudinal data from the Berlin Aging Study II (age range 60-89) to investigate whether trajectories of cognitive functioning (digit symbol, N = 1,111) and well-being (Diener satisfaction with life, N = 1,066; Socio-Economic Panel Study life satisfaction, N = 1,067; and Lawton morale, N = 1,067) are associated with objective dehydration (osmolarity; 33% dehydrated). Our results revealed that higher dehydration was associated with steeper decline in cognitive functioning and well-being over time, and lower well-being among those with higher body mass index. These associations were independent of sociodemographic and physical health characteristics. Our findings highlight the importance of adequate hydration for preserved cognition and well-being across old age. We discuss potential mechanisms and consider practical implications arising from our results. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Repairing the basic defect in cystic fibrosis - one approach is not enough.
Cystic fibrosis has attracted much attention in recent years due to significant advances in the pharmacological targeting of the basic defect underlying this recessive disorder: the deficient functional expression of mutant cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels at the apical membrane of epithelial cells. However, increasing evidence points to the reduced efficacy of single treatments, thus reinforcing the need to combine several therapeutic strategies to effectively target the multiple basic defect(s). Protein-repair therapies that use potentiators (activating membrane-located CFTR) or correctors (promoting the relocation of intracellular-retained trafficking mutants of CFTR) in frequent mutations such as F508del and G551D have been put forward and made their way to the clinic with moderate to good efficiency. However, alternative (or additional) approaches targeting the membrane stability of mutant proteins, or correcting the cellular phenotype through a direct effect upon other ion channels (affecting the overall electrolyte transport or simply promoting alternative chloride transport) or targeting less frequent mutations (splicing variants, for example), have been proposed and tested in the field of cystic fibrosis (CF). Here, we cover the different strategies that rely on novel findings concerning the CFTR interactome and signalosome through which it might be possible to further influence the cellular trafficking and post-translational modification machinery (to increase rescued CFTR abundance and membrane stability). We also highlight the new data on strategies aiming at the regulation of sodium absorption or to increase chloride transport through alternative channels. The development and implementation of these complementary approaches will pave the way to combinatorial therapeutic strategies with increased benefit to CF patients.


Effects of Carbohydrate Source on Genetic Competence in Streptococcus mutans.
The capacity to internalize and catabolize carbohydrates is essential for dental caries pathogens to persist and cause disease. The expression of many virulence-related attributes by Streptococcus mutans, an organism strongly associated with human dental caries, is influenced by the peptide signaling pathways that control genetic competence. Here, we demonstrate a relationship between the efficiency of competence signaling and carbohydrate source. A significant increase in the activity of the promoters for comX, comS, and comYA after exposure to competence-stimulating peptide (CSP) was observed in cells growing on fructose, maltose, sucrose, or trehalose as the primary carbohydrate source, compared to cells growing on glucose. However, only cells grown in the presence of trehalose or sucrose displayed a significant increase in transformation frequency. Notably, even low concentrations of these carbohydrates in the presence of excess glucose could enhance the expression of comX, encoding a sigma factor needed for competence, and the effects on competence were dependent on the cognate sugar:phosphotransferase permease for each carbohydrate. Using green fluorescent protein (GFP) reporter fusions, we observed that growth in fructose or trehalose resulted in a greater proportion of the population activating expression of comX and comS, encoding the precursor of comX-inducing peptide (XIP), after addition of CSP, than growth in glucose. Thus, the source of carbohydrate significantly impacts the stochastic behaviors that regulate subpopulation responses to CSP, which can induce competence in S. mutans The signaling pathways that regulate development of genetic competence in Streptococcus mutans are intimately intertwined with the pathogenic potential of the organism, impacting biofilm formation, stress tolerance, and expression of known virulence determinants. Induction of the gene for the master regulator of competence, ComX, by competence-stimulating peptide (CSP) occurs in a subpopulation of cells. Here, we show that certain carbohydrates that are common in the human diet enhance the ability of CSP to activate transcription of comX and that a subset of these carbohydrates stimulates progression to the competent state. The cognate sugar:phosphotransferase permeases for each sugar are needed for these effects. Interestingly, single-cell analysis shows that the carbohydrates that increase com gene expression do so by enhancing the proportion of cells that respond to CSP. A mathematical model is developed to explain how carbohydrates modulate bistable behavior in the system via the ComRS pathway and ComX stability.


TIDB: a comprehensive database of trained immunity.
Trained immunity is a newly emerging concept that defines the ability of the innate immune system to form immune memory and provide long-lasting protection against previously encountered antigens. Accumulating evidence reveals that trained immunity not only has broad benefits to host defense but is also harmful to the host in chronic inflammatory diseases. However, all trained immunity-related information is scattered in the literature and thus is difficult to access. Here, we describe Trained Immunity DataBase (TIDB), a comprehensive database that provides well-studied trained immunity-related genes from human, rat and mouse as well as the related literature evidence. Moreover, TIDB also provides three modules to analyze the function of the trained-immunity-related genes of interest, including Reactome pathway over-representation analysis, Gene Ontology enrichment analysis and protein-protein interaction subnetwork reconstruction. We believe TIDB will help developing valuable strategies for vaccine design and immune-mediated disease therapy. Database URL: http://www.ieom-tm.com/tidb.