Distant survival for patients undergoing surgery using volatile versus IV anesthesia for hepatocellular carcinoma with portal vein tumor thrombus: a retrospective study.
Whether anesthesia type is associated with the surgical outcome of Hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) remains to be determined. This study aims to investigate the impact of volatile inhalational anesthesia (INHA) versus total IV anesthesia (TIVA) on the survival outcomes in HCC patients with PVTT. A cohort of in-patients whom were diagnosed of HCC with PVTT in Eastern Hepatobiliary Surgery Hospital, Shanghai, China, from January 1, 2008 to December 24, 2012 were identified. Surgical patients receiving the INHA and TIVA were screened out. The overall survival (OS), recurrence-free survival (RFS) and several postoperative adverse events were compared according to anesthesia types. A total of 1513 patients were included in this study. After exclusions are applied, 263 patients remain in the INHA group and 208 in the TIVA group. Patients receiving INHA have a lower 5-year overall survival rate than that of patients receiving TIVA [12.6% (95% CI, 9.0 to 17.3) vs. 17.7% (95% CI, 11.3 to 20.8), P = 0.024]. Results of multivariable Cox-regression analysis also identify that INHA anesthesia is significantly associated with mortality and cancer recurrence after surgery compare to TIVA, with HR (95%CI) of 1.303 (1.065, 1.595) and 1.265 (1.040, 1.539), respectively. Subgroup analysis suggested that in more severe cancer patients, the worse outcome related to INHA might be more significant. This retrospective analysis identifies that TIVA is associated with better outcomes compared with INHA. Future prospective studies clinical and translational studies are required to verify this difference and investigate underlying pathophysiology.


Fluorescent core-shell silica nanoparticles as tunable precursors: towards encoding and multifunctional nano-probes.
Core-shell silica nanoparticles comprised of a RuBpy doped silica core and a Pas-DTPA doped silica shell were synthesized and post-functionalized with an encoding fluorescence combination and multiplex imaging function.


Population size as a major determinant of mating system and population genetic differentiation in a narrow endemic chasmophyte.
Mating system is one of the major determinants of intra- and interspecific genetic structure, but may vary within and between plant populations. Our study model included all known populations of Moehringia tommasinii (Caryophyllaceae), a narrow endemic plant inhabiting rock crevices in the northwestern Adriatic, and some populations of co-occurring and widespread M. muscosa, an ecologically divergent relative with an overlapping flowering period. We performed reciprocal crosses within and between taxa and used molecular markers to assess the extent of gene flow within and between populations and taxa. Using coefficient of inbreeding, population size, seed weight, pollen-to-ovule ratio, and flower display size, we also looked for evidence of a selfing syndrome. A surprisingly high variation in mating systems was observed among populations of M. tommasinii. These populations exhibited genetic structuring, with their size positively correlated with both seed weight and pollen production. Although a selfing syndrome could not be confirmed as the majority of selfing resulted from allogamous treatments, the occurrence of selfing was notable. In the presence of M. muscosa, at a site where both species coexist closely, a distinct pattern of fruit production was observed in M. tommasinii following various pollination treatments. Molecular and morphometric data provided evidence of hybridization followed by local extinction at this site. Population size proved to be the most important factor affecting the mating system in genetically structured populations of M. tommasinii. Lighter seeds and lower pollen production observed in populations with pronounced selfing do not provide enough evidence for the selfing syndrome. Detected gene flow between M. tommasinii and the sympatric M. muscosa suggested weak reproductive barriers between the taxa, which could pose a conservation problems for the former species. Hybridization leading to local extinction may also resulted in floral polymorphism and disruption of mating patterns of M. tommasinii.


A Novel Nanoemulsion-Based Method to Produce Ultrasmall, Water-Dispersible Nanoparticles from Chitosan, Surface Modified with Cell-Penetrating Peptide for Oral Delivery of Proteins and Peptides [Retraction].
[This retracts the article DOI: 10.2147/IJN.S116063.].


Experimental investigations in hamsters and rabbits with DNA extracted from human uterine tumors.
Experimental inoculation of a DNA preparation extracted from a fragment of non-irradiated human uterine cervix carcinoma was followed by the appearance of neoplasia in four hamsters and of lymphosarcoma in one rabbit. Similar DNA preparations obtained from three cases of irradiated human uterine cervix carcinoma and from a human uterine fibroma proved to have no biological activity.


Correlations between the genetic control of natural and oxazolone-induced antibody production.
Nonimmune sera of inbred and H-2 congenic mouse strains contain natural antibodies of the IgM type reacting with 4-(ethoxymethylene)-2-phenyloxazolin-5-one (oxazolone). The genetic regulation of the level of natural and induced antibodies to oxazolone was compared. High natural antibody-producing ability was inherited recessively, while high oxazolone-induced IgM antibody formation was dominant in F1 animals. Studies on nude mice demonstrated that T cells do not affect the natural antibody level, but were required for induced antibody production. Breeding studies and linkage analysis revealed multigenic control and a significant role of allotype-linked genes in both cases. Furthermore, the influence of H-2 linked genes on induced primary IgM antibody production was demonstrated.


Understanding of RF Cloud Interference Measurement and Modeling.
Importance of spectrum regulation and management was first revealed on May of 1985 after the release of unlicensed ISM bands resulting in emergence of Wi-Fi, Bluetooth and many other wireless technologies that has affected our daily lives by enabling the emergence of the smart world and IoT era. Today, the idea of a liberated spectrum is circulating around, which can potentially direct wireless networking industry into another revolution by enabling a new paradigm in intelligent spectrum regulation and management. The RF signal radiated from IoT devices as well as other wireless technologies create an RF cloud causing co- and cross-interference to each other. Lack of a science and technology for understanding, measurement, and modeling of the RF cloud interference in near real-time results in inefficient utilization of the precious spectrum, a unique natural resource shared among all wireless devices of the universe in frequency, time, and space. Near real time forecasting of the RF cloud interference is essential to pursue the path to the optimal utilization of spectrum and a liberated spectrum management. This paper presents a historical perspective on the evolution of spectrum regulation and management, explains the diversified meanings of interference for different sectors of the wireless industry, and presents a path for implementing a theoretical foundation for interference monitoring and forecasting to enable the emergence of a liberated spectrum industry and a new paradigm in spectrum management and regulations.


Assessment of the environmental fate and effects of azilsartan, a selective antagonist of angiotensin II type 1.
In this paper the results of a thorough evaluation of the environmental fate and effects of azilsartan are presented. Azilsartan medoxomil is administered as a pro-drug for the treatment of patients with essential hypertension. The pro-drug is converted by hydrolysis to the active pharmaceutical ingredient azilsartan. Laboratory tests to evaluate the environmental fate and effects of azilsartan medoxomil were conducted with azilsartan and performed in accordance with OECD test guidelines. The predicted environmental concentration (PEC) in surface water was estimated at 0.32 μg L(-1) (above the action limit of 0.01 μg L(-1)), triggering a Phase II assessment. Azilsartan is not readily biodegradable. Results of the water sediment study demonstrated significant shifting of azilsartan metabolites to sediment. Based on the equilibrium partitioning method, metabolites are unlikely to pose a risk to sediment-dwelling organisms. Ratios of the predicted environmental concentrations (PECs) to the predicted-no-effect concentrations (PNECs) did not exceed the relevant triggers, and the risk to aquatic, sewage treatment plant (STP), groundwater and sediment compartments was concluded acceptable. A terrestrial assessment was not triggered. Azilsartan poses an acceptable risk to the environment.


Regulation of dietary fiber on intestinal microorganisms and its effects on animal health.
The animal gut harbors diverse microbes that play an essential role in the well-being of their host. Specific diets, such as those rich in dietary fiber, are vital in disease prevention and treatment because they affect intestinal flora and have a positive impact on the metabolism, immunity, and intestinal function of the host. Dietary fiber can provide energy to colonic epithelial cells, regulate the structure and metabolism of intestinal flora, promote the production of intestinal mucosa, stimulate intestinal motility, improve glycemic and lipid responses, and regulate the digestion and absorption of nutrients, which is mainly attributed to short-chain fatty acids (SCFA), which is the metabolite of dietary fiber. By binding with G protein-coupled receptors (including GPR41, GPR43 and GPR109A) and inhibiting the activity of histone deacetylases, SCFA regulate appetite and glucolipid metabolism, promote the function of the intestinal barrier, alleviate oxidative stress, suppress inflammation, and maintain immune system homeostasis. This paper reviews the physicochemical properties of dietary fiber, the interaction between dietary fiber and intestinal microorganisms, the role of dietary fiber in maintaining intestinal health, and the function of SCFA, the metabolite of dietary fiber, in inhibiting inflammation. Furthermore, we consider the effects of dietary fiber on the intestinal health of pigs, the reproduction and lactation performance of sows, and the growth performance and meat quality of pigs.


Assessment of the percentages of maximum static pressure in the anal canal for postoperative continence in patients with imperforate anus.
The maximum static pressure in the anal canal was measured using an open-tip manometric method with a continuous infusion system. The values obtained from 49 postoperative patients with imperforate anus were expressed as a percentage of those values obtained from 108 aged-matched controls. The value was observed to be 50 per cent or more in those patients with translevator type, showing normal defecation, 30-50 per cent in those with supralevator type, showing normal defecation or constipation, and 30 per cent or less in those with supralevator type, showing incontinence, and 30 per cent or less in those who had undergone surgery on the anal area at another hospital and required re-operation at our department, showing normal continence or incontinence.


The acute radiation syndrome. A memorial to William Michael Court-Brown.
The pattern of symptoms in 189 patients irradiated with a large single dose to one half of the body are described. Radiation sickness developed in 83 and 39% of upper half-body irradiation and lower half-body irradiation treatments respectively and the incidence is not reduced by sedatives or anti-emetics. Following treatment there is a latent period up to 90 min before a phase of acute upset and nausea and vomiting starts. This phase persists for about 6h with an average of six bouts of vomiting and is then followed by recovery.


A parent-child conjoint psychological intervention for children in maintenance phase of acute lymphoblastic leukemia: Feasibility and preliminary outcomes from a randomized control pilot trial.
To develop and test a brief Composite Intervention Module for Pre-adolescents with Acute Lymphoblastic Leukemia (CIMPALL). Single-center randomized controlled design. A tertiary care center of national importance PARTICIPANTS: A total of 36 children with acute lymphoblastic leukemia in the maintenance phase of the treatment. A five-session (540 min) brief, multidomain, audiovisually aided, therapist-facilitated conjoint intervention module for children with cancer and their parents. Standardized psychological tools for children including CBCL, CPSS (Child Posttraumatic Stress Disorder Symptoms Scale), PedsQol (Pediatric Quality of Life), and NIMHANS (National Institute of Mental Health and Neurosciences) neuropsychological battery and parents including PTSD CC (Posttraumatic Stress Disorder Civilian Checklist), CHIP (Coping Health Inventory for Parents), CBS (Caregiver Burden Scale), and SRQ (Self-Reporting Questionnaire). A total of 36 patients were randomized to an experimental or a control group. Over 80% agreement was observed on indices of expert evaluation; 100% of participants found the sessions to be helpful, useful, appropriate in terms of time, duration, and place, and interventionist. The participation rate in the sessions was 94% and the study flow was smooth; 97.3% eligible candidates agreed to participate. Furthermore, 100% agreement on performance of activities was observed and the attrition rate was 5.26%. This pilot study presents the CIMPALL, which to the best of our knowledge is the first of its kind in India. The data suggest that the CIMPALL intervention is feasibly delivered by a clinical psychologist and that the CIMPALL intervention has an impact on important psychosocial variables for children with acute lymphoblastic leukemia and their parents.


Full recovery after 45 min of open cardiac massage for penetrating trauma: Resuscitation guided by end tidal CO2 and permissive hypotension.
We present a rare case of a patient who sustained a gunshot wound to the abdomen, injuring the aorta, IVC and right common iliac vein. After initially obtaining return of spontaneous circulation (ROSC) en route to the hospital, the patient again lost cardiac activity in the operating room during exploratory laparotomy. Resuscitative thoracotomy was performed and open cardiac massage was maintained for approximately 45 min while vessel injuries were repaired. During cardiac massage, end tidal CO2 was maintained between 15 and 31 mm Hg with 100% oxygen saturation and the patient received on-going transfusion of recycled whole blood and blood component therapy. Permissive hypotension was maintained to facilitate rapid repair of major vessels. Return of spontaneous circulation was achieved with a single 30 joule defibrillation. The patient was discharged home on hospital day 11, neurologically intact. This is the first report of survival after 45 min of open cardiac massage with aortic cross clamping, indicating that end tidal CO2 may act as an indicator of adequate end organ perfusion during protracted periods of hypotension.


Role of verbal representations in testing recognition of naturalistic sounds.
This paper reports two experiments concerned with verbal representation in the test stage of recognition memory for naturalistic sounds. In Study I 10 subjects produced verbal description to 50 sounds and after a 7-day delay 5 subjects reviewed self-produced verbal descriptions while 5 did not prior to testing for recognition. Review of descriptions increased recognition to 94.4% compared to 88.5% for those with no review. In Study II 16 subjects produced verbal descripitions to 50 naturalistic sounds. After a 7-day delay all subjects reviewed descriptionss of one-half of the items which were "targets" and 8 subjects reviewed description of 25 "non-targeted" items. The latter condition produced interference, observed as a significant decrement in recognition from 90.3% to 86.5%.


Robot-assisted Radical Prostatectomy Using Single-port Perineal Approach: Technique and Single-surgeon Matched-paired Comparative Outcomes.
Radical perineal prostatectomy (RPP) has been revived with the advent of single-port (SP) robotic surgery. However, its interest and precise role need to be evaluated and better defined. To describe in detail the technique of SP-RPP and compare initial perioperative outcomes with those of multiport robot-assisted transperitoneal radical prostatectomy (MP-RARP). From October 2018 to June 2020, perioperative data of 26 consecutive patients who underwent SP-RPP for localized prostate cancer (PCa) in a single institution were prospectively entered into an institutional review board-approved database. Data of 86 consecutive patients treated from September 2017 to September 2018 with MP-RARP by the same surgeon, before the beginning of the SP experience, were used as comparators. SP-RPP was performed using the SP robotic platform (Intuitive Surgical, Sunnyvale, CA, USA) according to the technique described in the supplementary video. Demographics, and intra- and postoperative data were analyzed in a matched-paired design with a 1:1 ratio on the following factors: age at surgery, prostate-specific antigen level, preoperative Gleason score, and history of abdominal surgery. After matching, baseline characteristics were comparable except for the rate of prior laparotomy, which was higher in the SP-RPP group (52% vs 8%, p < 0.001). In the SP-RPP group, 84% of the patients had a high risk and an unfavorable intermediate risk of positive surgical margins (PSMs) versus 57% in the MP-RARP group (p = 0.03). While the rate of nonlimited PSMs (ie, >3 mm) was higher in the SP-RPP group (38.5% vs 7.7%, p < 0.01), the number of patients with biochemical recurrence at 1 yr was comparable between SP-RPP and MP-RARP (1 vs 3, p = 0.3). SP-RPP is a complex procedure for patients with a complex surgical history and high-risk localized PCa with limited alternative therapeutic options. Our study suggests that patients with high-risk localized prostate cancer and limited treatment options due to a complex abdominal surgical history (ie, frozen pelvis) may be suitable candidates for single-port radical perineal prostatectomy.


A fluorescent cholesterol analogue for observation of free cholesterol in the plasma membrane of live cells.
Free cholesterol in mammalian cells resides mostly in the plasma membrane, where it plays an important role in cellular homeostasis. We synthesized a new fluorescent cholesterol analogue that retained an intact alkyl chain and the sterane backbone of cholesterol. The hydroxyl group of cholesterol was converted into an amino group that was covalently linked to the fluorophore tetramethylrhodamine to retain the ability to form hydrogen bonds with adjacent molecules. Incubating live MDCK (Madin-Darby canine kidney) cells with our fluorescent cholesterol analogue resulted in the generation of intense signals that were detected by microscopy at the plasma membrane. Incubation with the analogue exerted minimal, if any, influence on cell growth, indicating that it could serve as a useful tool for analyzing free cholesterol at the plasma membrane.


Axon fiber orientation as the source of T1 relaxation anisotropy in white matter: A study on corpus callosum in vivo and ex vivo.
Recent studies indicate that T1 in white matter (WM) is influenced by fiber orientation in B0 . The purpose of the study was to investigate the interrelationships between axon fiber orientation in corpus callosum (CC) and T1 relaxation time in humans in vivo as well as in rat brain ex vivo. Volunteers were scanned for relaxometric and diffusion MRI at 3 T and 7 T. Angular T1 plots from WM were computed using fractional anisotropy and fiber-to-field-angle maps. T1 and fiber-to-field angle were measured in five sections of CC to estimate the effects of inherently varying fiber orientations on T1 within the same tracts in vivo. Ex vivo rat-brain preparation encompassing posterior CC was rotated in B0 and T1 , and diffusion MRI images acquired at 9.4 T. T1 angular plots were determined at several rotation angles in B0 . Angular T1 plots from global WM provided reference for estimated fiber orientation-linked T1 changes within CC. In anterior midbody of CC in vivo, where small axons are dominantly present, a shift in axon orientation is accompanied by a change in T1 , matching that estimated from WM T1 data. In CC, where large and giant axons are numerous, the measured T1 change is about 2-fold greater than the estimated one. Ex vivo rotation of the same midsagittal CC region of interest produced angular T1 plots at 9.4 T, matching those observed at 7 T in vivo. These data causally link axon fiber orientation in B0 to the T1 relaxation anisotropy in WM.


Effects of mycophenolate mofetil on cutaneous lupus erythematosus in (NZB × NZW) F1 mice.
Few studies have evaluated the effects and precise molecular mechanism of mycophenolate mofetil (MMF) in the treatment of human cutaneous lupus erythematosus (CLE). Our findings shed light on the therapeutic effects of MMF in a UVB-induced NZB × NZW (NZBW) F1 CLE mouse model. Continuous MMF treatment (60 mg/kg/day) was administered up to Day 50 from the beginning of UVB induction (Day 0; 20 weeks old), as the pathologic features of CLE are present after 50 days. The therapeutic effects of MMF treatment in NZBW lupus mice were examined by comparing histopathological changes, lupus band test (deposition of immune complexes at the dermal-epidermal junction) and colocalization of autoantibodies with a dermal autoantigen Dsg3, and by evaluating the associations of local matrix metalloprotease activities. MMF improved survival in the NZBW lupus mice from 35.7% to 81.8%. The proteinuria, blood urea nitrogen, and interleukin 6 levels were significantly reduced after MMF treatment. The dermal lymphocytic infiltration, deposition of immune complexes at the dermal-epidermal junction, colocalized autoantibodies with Dsg3, and epidermal matrix metalloprotease activity were also attenuated in MMF-treated NZBW F1 mice. The results confirmed that MMF could substantially attenuate skin damage due to CLE in the NZBW F1 mouse model.


[Tissue compatiblity of stomatologic materials in cell cultures].
The paper contains results of investigations on the suitability of cell cultures for biological testing of soluble substances from dental cements and their components. The preparation of the specimens as well as the elution process are described. Furthermore the culture system of cell populations in vitro and representative biological parameters are reported.


VE-CADHERIN is expressed transiently in early ISL1+ cardiovascular progenitor cells and facilitates cardiac differentiation.
Adherens junctions (AJs) provide adhesive properties through cadherins and associated cytoplasmic catenins and participate in morphogenetic processes. We examined AJs formed between ISL1+ cardiovascular progenitor cells during differentiation of embryonic stem cells (ESCs) in vitro and in mouse embryogenesis in vivo. We found that, in addition to N-CADHERIN, a percentage of ISL1+ cells transiently formed vascular endothelial (VE)-CADHERIN-mediated AJs during in vitro differentiation on days 4 and 5, and the same pattern was observed in vivo. Fluorescence-activated cell sorting (FACS) analysis extended morphological data showing that VE-CADHERIN+/ISL1+ cells constitute a significant percentage of cardiac progenitors on days 4 and 5. The VE-CADHERIN+/ISL1+ cell population represented one-third of the emerging FLK1+/PDGFRa+ cardiac progenitor cells (CPCs) for a restricted time window (days 4-6). Ablation of VE-CADHERIN during ESC differentiation results in severe inhibition of cardiac differentiation. Disruption of all classic cadherins in the VE-CADHERIN+ population via a cadherin dominant-negative mutant's expression resulted in a dramatic decrease in the ISL1+ population and inhibition of cardiac differentiation.


Follow-up in patients with localised primary cutaneous melanoma.
Follow-up services for patients with localised cutaneous melanoma are widely discussed but there is no international consensus. Our aim was to discuss frequency and duration of follow-up, type of health professional involved, optimum intensity of routine investigation, and patients' satisfaction with follow-up. Searches of the published work were directed at publications between January, 1985, and February, 2004 on recurrences, subsequent primary melanoma, routine tests, and patients' satisfaction. In a selection of 72 articles, 2142 (6.6%) recurrences were reported, 62% of which were detected by the patients themselves. 2.6% of patients developed a subsequent primary melanoma. Most investigators do not support high-intensity routine follow-up investigations. Of the various follow-up investigations requested by physicians, only medical history and physical examination seem to be cost effective. Lymph-node sonography seems to be a promising method for detection, although survival benefit remains to be proven. Patients were found to be anxious about follow-up visits, although other research showed that provision of information to patients was much appreciated. Published work on the follow-up of patients with cutaneous melanoma has mainly been retrospective and descriptive. Recommendations can be given with only a low grade of evidence. For meaningful guidelines to be developed, prospective, high-quality methodological research is needed.


Radiosensitivity of fibroblasts obtained from a café-au-lait spot and normal-appearing skin of a patient with neurofibromatosis (NF-6).
Fibroblast cells derived from a café-au-lait spot and normal-appearing skin of a neurofibromatosis (NF-6) patient were studied for radiosensitivity in comparison with two normal cell lines used as "controls." No difference in radiosensitivity was observed between the patient's cell lines and the controls using acute gamma-irradiation. However, a markedly increased radiosensitivity of the fibroblasts obtained from the patient's skin of normal appearance was demonstrated after chronic gamma-irradiation. The cells from the café-au-lait spot showed intermediate sensitivity to chronic irradiation as compared with the control cell lines and the fibroblasts derived from the normal skin of the patient. These results showed the usefulness of chronic irradiation in detecting increased cellular radiosensitivity which may result from a unique DNA repair defect in an NF patient. We suggest that enhanced genetic changes in radiosensitive NF patients may lead to formation of café-au-lait lesions and certain tumors. Such a transformation may be associated with production of radiotolerant cells.


A preliminary study of angiographic classification and its correlation to treatment of central arteriovenous malformation in the jaw.
To elaborate on the classification of central arteriovenous malformations (AVMs) in the jaw based on angioarchitecture and to evaluate the correlation of this classification with treatment options. X-ray films and digital subtraction angiograms (DSA) of 25 cases with AVMs in the jaw were retrospectively reviewed to evaluate the appearance of bone resorption, feeding arteries, nidus of the malformations, and draining veins. Based on the findings a classification of angioarchitecture was recommended. Furthermore, the treatment results of these cases were reviewed to assess the correlation of this classification system with treatment options. The angiographic pictures of 25 cases with central AVMs could be divided into 5 types: Type I (n = 5) had diffused microarteriovenous fistulas (AVFs); type II (n = 8) had 1 large venous pouch with all the feeding arteries draining into it; type III (n = 7) had a large venous pouch as well as diffused microAVFs (I+II); type IV (n = 2) had multiple venous pouches; and type V (n = 3) had multiple venous pouches and diffused microAVFs (I + IV). The angioarchitecture corresponded well to the x-ray appearance in all cases except 1 (96%). With respect to the treatment outcomes, type II, III, and IV AVMs gained clinical cure in 100% of the cases, whereas type I and type V AVMs obtained clinical cure only in 60% and 33.3% of the cases, respectively. Central AVMs in the jaw contained variant patterns of angioarchitecture and could be divided into 5 types. This angiographic classification was helpful for decision making about appropriate therapy.


Sonodynamically-induced apoptosis, necrosis, and active oxygen generation by mono-l-aspartyl chlorin e6.
In this study, we investigated the induction of apoptosis by ultrasound in the presence of a photochemically active chlorin, mono-l-aspartyl chlorin e6 (NPe6). HL-60 cells were exposed to ultrasound for up to 3 min in the presence and absence of NPe6, and the induction of apoptosis was examined by analyzing cell morphology, DNA fragmentation, and caspase-3 activity. Cells treated with 80 microM NPe6 and ultrasound clearly showed membrane blebbing and cell shrinkage, whereas significant morphologic changes were not observed in cells exposed to either ultrasound alone, at the same intensity, or NPe6 alone. Also, DNA ladder formation and caspase-3 activation were observed in cells treated with both ultrasound and NPe6 but not in cells treated with ultrasound or NPe6 alone. In addition, NPe6 substantially enhanced nitroxide generation by ultrasound in the same acoustical arrangement. Sonodynamically-induced apoptosis, caspase-3 activation, and nitroxide generation were significantly suppressed by histidine. These results suggest that the combination of ultrasound and NPe6 sonochemically induces apoptosis as well as necrosis in HL-60 cells. They further suggest that some ultrasonically-generated active species, deactivatable by histidine, are the major mediators to induce the observed apoptosis.


Urea kinetics: effect of severely restricted dietary intakes on urea hydrolysis.
Urea kinetics (urea-N production-P, excretion-E, hydrolysis-H, recycling-R and retention-S) were measured in 7 healthy adults consuming a standard diet compared with 4 fasted for 24 and/or 96 h, using primed/intermittent doses of [(15)N (15)N]-urea and mass spectrometry. Standard values were P = 196, E = 132, H = 65, R = 13 and S = 51, mgN/kg/day. After 24 h fasting all urea kinetics were reduced, and P and H were significantly reduced compared with the standard diet (p < 0.01 and < 0.05 respectively). After 96 h fasting, urea kinetics returned to standard values (P = 187, E = 136, H = 51, R =13 and S = 38, mgN/kg/day), although nitrogen intake was significantly lower (p < 0.001). Relative urea excretion (E/P) was 67%, standard diet, and 75% after fasting. Consequently H/P was slightly reduced from 33 to 25%. S/P was 26%, standard diet, 15% after 24 h and 20% after 96 h fasting, suggesting increased urea-N retention with prolonged fasting. These results imply a slight temporary shift towards increased nitrogen excretion at 24 h and subsequent return to the kinetics of the fed state after 96 h. Urea-N retention increases with prolonged fasting.


Effects of CP-060S, a novel cardioprotective drug, on cardiac function and myocardial oxygen consumption.
1. We examined the effects of CP-060S on cardiac function and myocardial oxygen consumption (MVO2) in anesthetized dogs. 2. CP-060S (10-300 microg/kg i.v.) decreased heart rate, increased aortic flow and decreased mean blood pressure in a dose-dependent manner. The PR interval was significantly prolonged by administration of CP-060S (300 microg/kg i.v.). 3. CP-060S (10-300 microg/kg i.v.) increased coronary blood flow in a dose-dependent manner. Left ventricular end-diastolic pressure and maximal first derivative of left ventricular pressure were not significantly affected. 4. CP-060S (10-300 microg/kg i.v.) increased coronary sinus blood flow and decreased arteriovenous oxygen difference and MVO2 in a dose-dependent manner. 5. The effects of CP-060S on cardiac function and MVO2 are qualitatively similar to those of diltiazem, a typical Ca2+ antagonist.


Characterization by deletion mutagenesis in vitro of the promoter region of ompF, a positively regulated gene of Escherichia coli.
The ompF gene codes for a major outer membrane protein whose expression is positively regulated by the ompR and envZ genes. Two sets of promoter deletions, upstream deletions and downstream deletions, were generated in vitro, and the promoter function was studied by connecting them with the tet genes. One of the hybrid genes thus constructed had a functioning ompF-tet hybrid promoter. The 107 base-pair fragment was found to be functioning as the ompF promoter, 90 nucleotides upstream and 17 nucleotides downstream of the mRNA start site that was also determined in this study. The start site was preceded by a convenient Pribnow box. Although the sequence at the -35 region had a low degree of homology to the consensus sequence, analyses of the hybrid promoter suggested that this region is involved in the promoter function in relation to the Pribnow box. They also indicated that the domain responsible for regulation by the ompR gene is located within the -35 region and its upstream region.


An illusory transformation in a model of optic flow processing.
We present results from computer simulations of a biologically plausible model of heading detection in the visual motion pathway of higher mammals. These simulations are closely related to a recently discovered visual illusion in optic flow processing in humans. The model reproduces the results described for humans and suggests a possible explanation, namely that humans interpret the illusory stimuli in terms of egomotion. It provides further indication that the visual system makes use of visual information to cope with eye movement effects in dealing with optic flow.


Congenital toxoplasmosis from an HIV-infected woman as a result of reactivation.
Congenital toxoplasmosis usually results from acquired infection in non-immune pregnant women. However, severely HIV-infected women with a latent Toxoplasma infection can transmit the parasite as a result of reactivation. We report a case of toxoplasmic reactivation in an HIV-infected woman with moderate immunosuppression resulting in a severe congenital toxoplasmosis.


Role of cigarette sensory cues in modifying puffing topography.
Human puffing topography promotes tobacco dependence by ensuring nicotine delivery, but the factors that determine puffing behavior are not well explained by existing models. Chemosensory cues generated by variations in cigarette product design features may serve as conditioned cues to allow the smoker to optimize nicotine delivery by adjusting puffing topography. Internal tobacco industry research documents were reviewed to understand the influence of sensory cues on puffing topography, and to examine how the tobacco industry has designed cigarettes, including modified risk tobacco products (MRTPs), to enhance puffing behavior to optimize nicotine delivery and product acceptability. Relevant internal tobacco industry documents were identified using systematic searching with key search terms and phrases, and then snowball sampling method was applied to establish further search terms. Modern cigarettes are designed by cigarette manufacturers to provide sensory characteristics that not only maintain appeal, but provide cues which inform puffing intensity. Alterations in the chemosensory cues provided in tobacco smoke play an important role in modifying smoking behavior independently of the central effects of nicotine. An associative learning model is proposed to explain the influence of chemosensory cues on variation in puffing topography. These cues are delivered via tobacco smoke and are moderated by design features and additives used in cigarettes. The implications for regulation of design features of modified risk tobacco products, which may act to promote intensive puffing while lowering risk perceptions, are discussed.


Azathioprine: a guide for the management of dermatology patients.
Azathioprine, a prodrug of 6-mercaptopurine, was developed over four decades ago. Since its development, azathioprine has been shown to have antileukemic, anti-inflammatory, and immunosuppressive properties. Hence, the reason azathioprine is used in multiple medical specialties. In the dermatology field, it is used as an immunosuppressant and corticosteroid-sparing agent for the treatment of several cutaneous diseases. In this article, the present authors review the following aspects relating to azathioprine: history, pharmacokinetics, significance of thiopurine methyltransferase, side effects, contraindications, therapeutic uses, and recommended evaluation and monitoring for patients initiating azathioprine.


The Non-medical Switch from Reference Adalimumab to Biosimilar Adalimumab is Highly Successful in a Large Cohort of Patients with Stable Inflammatory Rheumatic Joint Diseases: A Real-Life Observational Study.
The adalimumab biosimilar (ADAbio) Amgevita® has a similar efficacy and safety profile as the adalimumab reference (ADA) Humira®. We studied the clinical consequences of a non-medical switch from ADA to ADAbio in adult patients with mainly established rheumatoid arthritis (RA), psoriatic arthritis (PsA), and spondyloarthritis (SpA). Patients that received treatment with ADA for at least three months were switched to ADAbio. Data was collected retrospectively from 1 year before the switch up to 6 months after. A total of 603 patients were switched from ADA to ADAbio (switch group). During a 1-year follow-up, over 93% of all patients underwent a successful transition in terms of disease activity and safety from ADA to biosimilar, supporting the bioequivalence of both drugs in patients with stable inflammatory rheumatic joint diseases. Forty patients (6.6%) switched back to ADA (re-switch group). There were no objective changes in disease activity score in 28 joints using C-reactive protein (DAS28-CRP), or adverse effects before and after the switch between both groups. In line with earlier reports, the transition to ADAbio went successful in the majority of patients with stable inflammatory rheumatic joint diseases. Patient-reported symptoms without objective signs that indicate a flare of disease activity after the switch to ADAbio are probably explained by nocebo effects. A pre-emptive approach to counteract nocebo effects and stimulate placebo response may have a positive impact on health outcomes for patients and preserve the economic benefits of cost savings that can be achieved by prescribing a biosimilar instead of the reference drug.


Intraosseous Arteriovenous Malformations in the Extremities Managed with Coils and Absolute Ethanol Treatment.
The extremity intraosseous arteriovenous malformations (AVMs) are rare high flow vascular lesions for which the treatment remains challenging. The aim of the study wasto assess treatment methods, interim results, and complications of coils and absolute ethanol in managing extremity intraosseous AVMs via direct puncture approach. From 2009 to 2017, 12 patients (mean age, 27.5 years; range, 3-54 years) with extremity intraosseous AVMs underwent staged coils and absolute ethanol treatment via the direct puncture approach. All patients were symptomatic before the procedure as per the Schobinger staging system. The mechanical detachable coils and undetachable coils were used first followed by the injection of absolute ethanol used as a sclerosant agent via a direct puncture approach. Follow-up evaluation (6 to 72 months; mean, 23.5 months), including imaging and symptoms and signs, was performed in all patients. Twenty-seven absolute alcohol procedures were performed for patients with intravascular sclerosis (range: 1-3, mean: 2) with one procedure required per patient (n = 2), 2 per patient (n = 5), or 3 per patient (n = 5). The average stretched length of the total coils per patient was 843.33 cm. The amount of absolute ethanol used ranged from 10 mL to 45 mL (mean, 25.69 mL) in a single session. Nine of twelve patients (75%) exhibited complete responses, and 3 patients (25%) exhibited partial responses. One patient experienced minor complication of transient motor nerve injury and completely recovered half a month later. No major complications occurred. The study provides strong evidence, suggesting that direct puncture and coils with absolute ethanol approach is an effective and safe treatment in patients with extremity intraosseous AVMs, yielding minor complications and good results.


On the natural history of Plummer's disease.
Plummer's disease (autonomous goiter) presents a spectrum of forms, raging from solitary autonomous thyroid nodules to numerous small autonomous areas, and from unequivocal to servere hyperthyroidism. Progression is often very slow, but data on long-term follow up are scare, contradictory and limited to solitary nodules. We re-examined 58 untreated patients on one or more occasions. Follow-up time ranged from 1 to 12 years (average 4 years). There were gross clinical or scintigraphic changes in 13 patients. Three included six euthyroidal patients who became (mildly) hyperthyroid, one with a change from single to numerous "hot spots," and one in which the radionuclide disappeared in one of two separate autonomous areas. Minor changes were seen in 14 patients. Changes occurred irrespective of the scintigraphic pattern. In contrast, progression was very rapid in two of 300 other patients with the disease, leading to fatal thyrotoxic crisis withing three months in one. In another patient, transient hyperthyroidism was documented after excessive iodine administration. It is concluded that patients may be left untreated as long as serious complaints and clinical suspicion of associated malignancy are absent.


A rapid latex agglutination assay for the detection of penicillin-binding protein 2'.
A simple and rapid slide latex agglutination assay was developed to detect penicillin-binding protein 2' (PBP2') from isolates of staphylococi. PBP2' present in the membranes of methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant coagulase negative staphylococci (MRCNS) was rapidly extracted by alkaline treatment and, by combining with a slide agglutination reaction using latex particles sensitized with monoclonal antibodies raised against it, PBP2' could be detected from a single loopful of cells taken from agar plates not containing beta-lactum antibiotics within 15 min. In a study of clinical isolates previously characterized as either MRSA or methicillin-susceptible Staphylococcus aureus (MSSA) by antibiotic susceptibility testing, 231 specimens of 232 MRSA were PBP2' positive by latex agglutination, and the 87 specimens of MSSA were all negative. One specimen identified as MRSA by susceptibility testing but PBP2' negative by latex agglutination was confirmed as mecA gene negative by PCR. This simple and rapid slide latex reagent should be useful in clinical diagnostics.


Indirect measurement of the carotid arterial pressure from vibrocardiographic signal: Calibration of the waveform and comparison with photoplethysmographic signal.
The detection of arterial Blood Pressure waveform provides important information about the subject health status. Laser Doppler Vibrometry (LDV) is a non-contact technique with high sensitivity able to detect mechanical movements of the arterial wall; several previous studies have shown that LDV is able to characterize cardiac activity. Photoplethysmogram (PPG) quantifies the digital volume artery pulse, which has been demonstrated to be closely related to the pressure signal measured by an arterial tonometer. In this paper, an indirect measurement of carotid arterial pressure by means of LDV is presented. Moreover, a comparison between LDV and PPG is conducted in order to estimate the time interval between opening and closing of the aortic valve, that is the Left Ventricular Ejection Time (LVET). Results show an average reduction of around 20% of the systolic pressure derived from LDV signal measured over the carotid artery with respect to the systolic pressure measured at brachial level (i.e. peripheral pressure value). Finally, the comparison between LDV and PPG in the estimation of LVET shows a mean percentage deviation <;10%. So, in conclusion, it can be stated that LDV technique has the potential of providing a displacement waveform that, adequately calibrated, can furnish significant information about pressure waveform.


Multi-step prediction of carbon emissions based on a secondary decomposition framework coupled with stacking ensemble strategy.
Accurate prediction of carbon emissions is vital to achieving carbon neutrality, which is one of the major goals of the global effort to protect the ecological environment. However, due to the high complexity and volatility of carbon emission time series, it is hard to forecast carbon emissions effectively. This research offers a novel decomposition-ensemble framework for multi-step prediction of short-term carbon emissions. The proposed framework involves three main steps: (i) data decomposition. A secondary decomposition method, which is a combination of empirical wavelet transform (EWT) and variational modal decomposition (VMD), is used to process the original data. (ii) Prediction and selection: ten models are used to forecast the processed data. Then, neighborhood mutual information (NMI) is used to select suitable sub-models from candidate models. (iii) Stacking ensemble: the stacking ensemble learning method is innovatively introduced to integrate the selected sub-models and output the final prediction results. For illustration and verification, the carbon emissions of three representative EU countries are used as our sample data. The empirical results show that the proposed framework is superior to other benchmark models in predictions 1, 15, and 30 steps ahead, with the mean absolute percentage error (MAPE) of the proposed framework being as low as 5.4475% in Italy dataset, 7.3159% in France dataset, and 8.6821% in Germany dataset.


Memories of childhood sexual abuse: a survey of young adults.
To explore the prevalence of, characteristics of, and factors associated with forgetting of childhood sexual abuse memories in a large non-clinical sample (N = 1712). Using an anonymous survey, we asked respondents about (a) the nature and severity of their childhood abuse; (b) the continuity of their abuse memories; and (c) their experiences with others suggesting to them that they might have been abused. A substantial minority of victims in our sample reported having temporarily forgotten their childhood sexual abuse. Forgetting was largely unassociated with victim or abuse characteristics. Compared to individuals who always remembered their abuse, however, individuals who temporarily forgot were more likely to report that someone had suggested to them that they might have experienced abuse. Those who received such suggestions were particularly likely to suspect that they may have experienced childhood sexual abuse that they do not yet remember. Forgetting may be less common than implied by earlier estimates from clinical samples, yet it is not uncommon. Also, a sizable minority of the population is wondering whether they have experienced unremembered abuse, and these suspicions are linked to having encountered suggestions from others. We discuss the implications of these findings for understanding the phenomenon sometimes labeled repression.


A 1,2,3-Triazole Derivative of Quinazoline Exhibits Antitumor Activity by Tethering RNF168 to SQSTM1/P62.
Quinazoline and its derivatives have drawn much attention in the development of potential antitumor agents. Here, we synthesized a series of 1,2,3-triazole derivatives of quinazoline at the C6 position and evaluated for their cytotoxic activity in various human cancer cell lines. We found that compound 5a was the most cytotoxic to HCT-116 cells (IC50, 0.36 μM). Target profiling found that 5a directly binds to both the autophagy-associated protein SQSTM1/P62 and the E3 ligase RNF168, promoting their interaction. Consistently, 5a treatment induces a decrease in RNF168-mediated H2A ubiquitination and compromises homologous recombination-mediated DNA repair, thus increasing the sensitivity of HCT-116 to X-ray radiation. Moreover, 5a suppressed xenografted tumor growth in mice in a dose-dependent manner. Taken together, the 1,2,3-triazole derivative of quinazoline 5a may serve as a novel compound for tumor therapy based on its role in promoting a P62/RNF168 interaction.


Infectious risk of add-on leflunomide or tacrolimus versus TNF inhibitors among patients with rheumatoid arthritis receiving background methotrexate: A population-based cohort study.
To compare infectious risk between leflunomide versus TNF inhibitors (TNFi), and between tacrolimus versus TNFi among rheumatoid arthritis (RA) patients receiving methotrexate (MTX). Using Korea National Health Insurance Service database, we conducted a cohort study on RA patients initiating TNFi, leflunomide, or tacrolimus. The primary outcome was any serious infections defined as a composite endpoint of serious bacterial, opportunistic, and herpes zoster infections. Secondary outcomes were individual components of the primary outcome. Propensity-score fine-stratification (PSS) and weighting were applied to adjust for confounding. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models comparing leflunomide versus TNFi, and tacrolimus versus TNFi. Among 72,516 RA patients receiving MTX, we identified 3,336 TNFi initiators, 11,122 leflunomide initiators, and 5,136 tacrolimus initiators. Two study cohorts were 10,992 leflunomide initiators PSS-weighted on 1,623 TNFi initiators and 5,126 tacrolimus initiators PSS-weighted on 2,521 TNFi initiators. The incidence rate per 100 person-years of herpes zoster infection (3.70-4.27) was beyond 3-times that of serious bacterial infection (1.12-1.36), but opportunistic infection was relatively rare (0.11-0.23). The PSS-weighted HR [95% CI] for any serious infection was 1.03 [0.89-1.22] comparing leflunomide versus TNFi, and 0.91 [0.77-1.08] comparing tacrolimus versus TNFi. Analyses on the secondary outcomes showed consistent results. In this nation-wide cohort study, we did not find a significant difference in the risk of serious infections (i.e., serious bacterial, opportunistic, and herpes zoster infections) between leflunomide versus TNFi, and between tacrolimus versus TNFi among RA patients receiving background MTX.


Optimal vaccination policies for an SIR model with limited resources.
The purpose of the paper is to use analytical method and optimization tool to suggest a vaccination program intensity for a basic SIR epidemic model with limited resources for vaccination. We show that there are two different scenarios for optimal vaccination strategies, and obtain analytical solutions for the optimal control problem that minimizes the total cost of disease under the assumption of daily vaccine supply being limited. These solutions and their corresponding optimal control policies are derived explicitly in terms of initial conditions, model parameters and resources for vaccination. With sufficient resources, the optimal control strategy is the normal Bang-Bang control. However, with limited resources, the optimal control strategy requires to switch to time-variant vaccination.


Pericruciate intra-articular lateral meniscal cyst without meniscal tear.
A case of intra-articular pericruciate type of meniscal cyst from anterior horn of lateral meniscus without associated meniscal tear is reported with review of literature. To our knowledge such association has not been reported earlier.


Chemical constituents from the colombian medicinal plant Niphogeton ternata.
Two coumarins and one polyacetylene, 5-0-(3-chloro-2-hydroxy-3-methylbutyl)-8-methoxypsoralen (1), 2',3'-dihydro-jatamansin (2), and 10-chloro-1-heptadecene-4,6-diyne-3,8,9-triol (3), along with 15 known compounds (4-18), were isolated from the methanol extract of Niphogeton ternata. Their structures were elucidated by spectroscopy.


Pharmacokinetics of oral nifedipine: relevance of the distribution phase.
Pharmacokinetics of oral Nifedipine was studied in 12 Mexican young healthy volunteers, six men and six women, who received a 10 mg capsule. Plasma levels were determined by a nifedipine specific HPLC assay. Experimental data were fitted and pharmacokinetic parameters were calculated using an open two compartment model. No statistically significant difference was detected between men and women, thus both sexes were considered as a single population. Nifedipine plasma levels rose rapidly (ka = 8.46 +/- 1.96 h-1) reaching a maximum concentration of 145 +/- 23 ng/ml in 0.61 +/- 0.07 h. Plasma levels then decayed with a distribution phase (alpha = 1.98 +/- 0.40 h-1, t1/2 alpha = 0.46 +/- 0.06 h) and a terminal elimination phase (beta = 0.17 +/- 0.03 h-1, t1/2 beta = 4.98 +/- 0.55 h). AUC was 384 +/- 41 ng h/ml. Values of AUC and t1/2 beta were higher than those reported by other authors. Differences in the AUC could be due to ethnic origin, environmental factors or nutritional habits. Ten subjects presented plasma concentration-time curves in which the distribution phase was clearly distinguishable, having a ka/alpha relationship higher than 1.5. For the other two subjects, the distribution phase was not apparent and ka/alpha was lower than 1.5. The results show that an adequate characterization of the distribution phase is required if one pretends to use pharmacokinetic data for dosage regimen design.


Posture during head turning in pre-term infants: a longitudinal study of 15 low-risk infants of 32-36 weeks of conceptional age.
As part of a longitudinal study of spontaneous behaviour from 32-36 weeks of conceptional age, body posture was studied during spontaneous head movements in 15 low-risk pre-term infants. At the moment of an active head position in the midline, the most frequently observed posture was a symmetrical one in which the arms were fully flexed and the legs partly extended. With regard to the arm position no clearly developmental trend was noted. With regard to the leg position an increase of the partly flexed position of the limbs related to conceptional age was found. The observed postures during activity in our study showed a cephalocaudal acquisition of flexor tone. A symmetrical posture, when the head is in the midline, may be a sign of normality in pre-term infants.


MicroRNA profiling as a novel diagnostic tool for identification of patients with inflammatory and/or virally induced cardiomyopathies.
MicroRNAs (miRNAs) might be used as prospective biomarkers for the identification of unexplained heart failure caused by a viral and/or inflammatory process. The aim of this study was to identify and to evaluate prognostic miRNAs in serum of patients with inflammatory heart diseases diagnosed by endomyocardial biopsies. After TaqMan® OpenArray® screening of 754 unique circulating miRNAs in serum of biopsy-proven patients [184 patients with inflammatory and/or virally induced myocardial diseases (DCMi), 25 patients with dilated cardiomyopathy (DCM), and 25 healthy donors], we identified seven miRNAs of interest (P < 0.05). These data have been verified by single qRT-PCR assays in other biopsy-proven patients (159 patients with viral and/or inflammatory myocardial diseases, 46 patients with DCM, and 60 healthy donors). The expression of let-7f, miR-197, miR-223, miR-93, and miR-379 allowed us to differentiate between patients with a virus and/or inflammation and healthy donors (P < 0.05) with the specificity over 93%. Based on the expression of miR-21 and miR-30a-5p, we could sort out patients with DCM from all other study groups (P < 0.05) with the specificity over 95%. This miRNA profile provides for the first time a new non-invasive diagnostic perspective to identify patients with intramyocardial inflammation and/or viral persistence only from single serum sample, independently of prescribed therapy and time of symptoms onset. It allows the early finding of those patients relevant for myocardial biopsy for exact diagnosis and further proscription of causal aetiology-driven specific treatment.


N-linked glycoprotein synthesis and transport during G1 are necessary for astrocytic proliferation.
The proliferation of astrocytes, purified by a selective detachment technique from mixed glial primary cultures derived from newborn rat cerebrum, was studied. The cells were synchronized by first inducing a quiescent state by removing fetal calf serum (FCS) from the culture medium for 2 days; reversal of the quiescent state by return of serum to the culture medium caused a marked increase in DNA synthesis 12-24 hr later. 2-Deoxyglucose, an inhibitor of dolichol-linked oligosaccharide and thereby N-linked glycoprotein biosynthesis, prevented not only an increase in glycoprotein biosynthesis in G1 phase of the cell cycle but also the burst of DNA synthesis that followed during S phase. Addition of mannose to the culture medium prevented the inhibitions by deoxyglucose of both glycoprotein and DNA syntheses. These data indicated an obligatory relationship in astrocytes between dolichol-linked glycoprotein synthesis and DNA synthesis. To determine whether transport of the newly synthesized glycoproteins to the plasma membrane for incorporation therein or for secretion were necessary for DNA synthesis and astrocytic proliferation, we studied cells treated with monensin, an ionophore for monovalent cations, and an inhibitor of intracellular transport of glycoproteins. The presence of monensin in the first 12 hr after repletion of serum to synchronized astrocytes prevented progression to the S phase and cell proliferation; addition of monensin after the first 12 hr, at the onset of the S phase, had no effect on progression through S phase. Lectin-staining methods combined with fluorescence microscopy demonstrated in monensin-treated cells failure of intracellular glycoproteins to be transported to the plasma membrane.(ABSTRACT TRUNCATED AT 250 WORDS)


Association methods in human genetics.
Genetic association studies are increasingly used in the search for susceptibility variants for human traits. While many of the statistical tools available for such studies are well established, the field is advancing rapidly, as biological and technological developments allow investigators to generate vast amounts of detailed genetic data. This chapter gives an overview of the statistical evaluation of genetic data in both unrelated individuals and families. A brief introduction to fundamental population genetics concepts is followed by detailed examinations of measures of linkage disequilibrium and single-marker and haplotype association tests. Emphasis is given to the historical development of family-based tests to provide the context for more recent advancements. The chapter concludes with a discussion of design strategies for genetic association studies with dense genotyping of hundreds or thousands of markers, such as those planned for follow up of a linkage-candidate region or genome-wide association studies.


1H-pyrrole-2,5-dione-based small molecule-induced generation of mesenchymal stem cell-derived functional endothelial cells that facilitate rapid endothelialization after vascular injury.
Despite the success of interventional processes such as drug-eluting stents, complete prevention of restenosis is still hindered by impaired or delayed endothelialization or both. Here, we report that 1H-pyrrole-2,5-dione-based small molecule-generated mesenchymal stem cell-derived functional endothelial cells (MDFECs) facilitated rapid transmural coverage of injured blood vessels. Small molecules that induced CD31 expression were screened by principal component analysis (PCA). Rat mesenchymal stem cells (MSCs) were treated with selected small molecules for up to 16 days, and the expression levels of CD90 and CD31 were examined by immunocytochemistry. In vitro functional assays of MDFECs, including tube formation assays and nitric oxide production assays, were performed. After MDFECs (intravenous, 3×10(6) cells per animal) were injected into balloon-injured rats, neointima formation was monitored for up to 21 days. The endothelial coverage of denuded blood vessels was evaluated by Evans Blue staining. The functionality of repaired blood vessels was evaluated by measuring vasorelaxation and hemodynamic changes. Additionally, derivatives of the selected small molecules were examined for their ability to induce endothelial markers. PCA indicated that 3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione effectively induced MDFECs. MDFECs inhibited the neointima formation of denuded blood vessels by facilitating more rapid endothelialization. Further examination indicated that derivatives with a 1H-pyrrole-2,5-dione moiety are important for initiating the endothelial cell differentiation of MSCs. Small molecules with 1H-pyrrole-2,5-dione as a core structure have great potential to improve the efficacy of MSC-based cell therapy for vascular diseases, such as atherosclerosis and restenosis.


Thermal stability of extracted lignin from novel millet husk crop residue.
Recent alarming tones regarding the environment and energy crises have resulted in an emergent need for the utilization of bio-based materials. The current study aims to experimentally investigate the thermal kinetics and pyrolysis behavior of lignin extracted from novel barnyard millet husk (L-BMH) and finger millet husk (L-FMH) crop residue. The characterization techniques FTIR, SEM, XRD, and EDX were employed. TGA was performed to assess the thermal, pyrolysis, and kinetic behavior using Friedman kinetic model. The average lignin yield was obtained as 16.25 % (L-FMH) and 21.31 % (L-BMH). The average activation energy (Ea) was recorded as 179.91-227.67 kJ mol-1 for L-FMH while 158.50-274.46 kJ mol-1 for L-BMH in the conversion range of 0.2-0.8. The higher heating value (HHV) was found to be 19.80 ± 0.09 MJ kg-1 (L-FMH) and 19.65 ± 0.03 MJ kg-1 (L-BMH). The results create a possibility for the valorization of extracted lignin as a potential bio-based flame retardant in polymer composites.


Bacterial sulfite-oxidizing enzymes.
Enzymes belonging to the Sulfite Oxidase (SO) enzyme family are found in virtually all forms of life, and are especially abundant in prokaryotes as shown by analysis of available genome data. Despite this fact, only a limited number of bacterial SO family enzymes has been characterized in detail to date, and these appear to be involved in very different metabolic processes such as energy generation from sulfur compounds, host colonization, sulfite detoxification and organosulfonate degradation. The few characterized bacterial SO family enzymes also show an intriguing range of structural conformations, including monomeric, dimeric and heterodimeric enzymes with varying numbers and types of redox centres. Some of the bacterial enzymes even catalyze novel reactions such as dimethylsulfoxide reduction that previously had been thought not to be catalyzed by SO family enzymes. Classification of the SO family enzymes based on the structure of their Mo domain clearly shows that three distinct groups of enzymes belong to this family, and that almost all SOEs characterized to date are representatives of the same group. The widespread occurrence and obvious structural and functional plasticity of the bacterial SO family enzymes make this an exciting field for further study, in particular the unraveling of the metabolic roles of the three enzyme groups, some of which appear to be associated almost exclusively with pathogenic microorganisms.


Effects of Asn-33 glycosylation on the thermostability of Thermomyces lanuginosus lipase.
The study was to examine whether glycosylation could improve the thermostability of recombinant Thermomyces lanuginosus lipase (Tll) expressed in Pichia pastoris. The Tll gene was synthesized and transformed into Pichia pastoris GS115.The recombinant Tll protein was expressed and purified, and its glycosylation site was identified by LCMS/MS as Asn-33. Two nonglycosylated mutants were constructed and the variant proteins were also expressed and purified. Effects of temperature on activities of the wild-type Tll and variants were analysed. The glycosylated Tll exhibited better thermostability than nonglycosylated variants. Our experiments have demonstrated the improvement of Tll thermostability by Asn-33 glycosylation. This work has deepened our understanding in the mechanism of Tll thermostability and will guide us to directional improvement of lipases and even other industrial enzymes.


Coordinated Health Care Interventions for Childhood Asthma Gaps in Outcomes (CHICAGO) plan.
Evidence-based strategies to improve outcomes in minority children with uncontrolled asthma discharged from the emergency department (ED) are needed. This multicenter pragmatic clinical trial was designed to compare an ED-only intervention (decision support tool), an ED-only intervention and home visits by community health workers for 6 months (ED-plus-home), and enhanced usual care (UC). Children aged 5 to 11 years with uncontrolled asthma were enrolled. The change over 6 months in the Patient-Reported Outcomes Measurement Information System Asthma Impact Scale score in children and Satisfaction with Participation in Social Roles score in caregivers were the primary outcomes. The secondary outcomes included guideline-recommended ED discharge care and self-management. Recruitment was significantly lower than expected (373 vs 640 expected). Of the 373 children (64% Black and 31% Latino children), only 63% completed the 6-month follow-up visit. In multivariable analyses that accounted for missing data, the adjusted odds ratios and 98% CIs for differences in Asthma Impact Scores or caregivers' Satisfaction with Participation in Social Roles scores were not significant. However, guideline-recommended ED discharge care was significantly improved in the intervention groups versus in the UC group, and self-management behaviors were significantly improved in the ED-plus-home group versus in the ED-only and UC groups. The ED-based interventions did not significantly improve the primary clinical outcomes, although the study was likely underpowered. Although guideline-recommended ED discharge care and self-management did improve, their effect on clinical outcomes needs further study.


Reduction of plasma 1,5-anhydroglucitol (1-deoxyglucose) concentration in diabetic patients.
The plasma concentration of 1,5-anhydro-D-glucitol(AG)(1-deoxyglucose) is known to decrease in diabetic patients. In order to evaluate the usefulness of this polyol as a diabetic marker, we examined the specificity of the plasma AG reduction in various diseases: the plasma AG level was determined in 108 newly diagnosed diabetic patients, 229 normal subjects and 200 patients with various other disorders. The mean plasma AG concentration in diabetes mellitus was 1.9 +/- 1.8 micrograms/ml (mean +/- SD), which was definitely lower than that in healthy subjects and patients with other diseases including some metabolic and hormonal diseases (mean value range: 13.4-28.3 micrograms/ml). Only the "malignancies" group showed statistically different mean values from that in normal subjects; however, these values were much higher than those of diabetic patients. The AG concentration seemed to be relatively low in some severe by uraemic patients, but is likely to be little influenced by the glomerular filtration rate. Upon adjustment for sex and age, AG concentration was not found to be correlated with the degree of obesity in both healthy subjects and diabetic patients. The plasma AG concentration showed a tendency to be higher in healthy males than in healthy females in all age-matched groups; however, statistically significant differences were not seen. Also, no significant influence of age was observed.


The temporal expression of amyloid precursor protein mRNA in vitro in dissociated hippocampal neuron cultures.
The subunit protein of the neurofibrillary tangle, the core protein of the neuritic plaque, and the amyloid of the cerebrovasculature in Alzheimer disease and normal aging is a unique 42-amino acid protein (amyloid beta-protein), suggesting a common origin for these pathological entities. However, the expression of the amyloid precursor protein mRNA (APP mRNA) from which the amyloid beta-protein is derived varies between specific neuronal populations. To determine the conditions under which neuronal synthesis of amyloid beta-protein might contribute to the formation of these structures, we have studied the temporal pattern of APP mRNA expression in developing fetal rabbit hippocampal neurons in vitro. Using in situ hybridization with a biotinylated riboprobe transcribed from a cDNA which includes the region encoding the amyloid beta-protein, we have observed a developmentally specific pattern of APP mRNA hybridization during neuronal maturation in vitro.


Intrahepatic cholestasis of pregnancy in twin pregnancies.
To clarify whether the increase in estrogen levels occurring during twin pregnancies (TP) is associated with a greater risk of developing intrahepatic cholestasis of pregnancy (ICP), we followed up 62 consecutive patients with TP and compared them with single pregnancies delivered in our hospital during 1 year. The prevalence of ICP was significantly higher in twin than in single pregnancies (20.9% versus 4.7%, respectively; P less than 0.001). Urinary estriol excretion was also significantly higher in twin compared to single pregnancies, although no quantitative differences were detected in TP with or without ICP. In multiparous patients with a proband TP affected by ICP, the disease recurred only in further TP, emphasizing the important role that estrogens seem to play in the pathogenesis of ICP. In contrast, in multiparous patients with a proband single pregnancy affected by ICP, the disease occurred in 70.5% of their other single pregnancies, suggesting the presence of a metabolic predisposition in these cases. However, in both groups of multiparous women a notable number of single pregnancies were not affected by the disease, supporting the postulate that the pathogenesis of ICP is multifactorial and that some as yet unidentified environmental factor needs to be present in order to develop the disease and also to modulate its expressivity.


Pretreatment of rats with increased bioavailable berberine attenuates cerebral ischemia-reperfusion injury via down regulation of adenosine-5'monophosphate kinase activity.
Berberine (BBR) exhibits multiple beneficial biological effects. However, poor bioavailability of BBR has limited its clinical application. We previously demonstrated that solid dispersion of BBR with sodium caprate (HGSD) remarkably improves its bioavailability. We examined whether this increased bioavailability of BBR could protect the brain from ischemia-reperfusion (IR) induced injury. Rats treated with HGSD, SC and saline for 7 days then subjected to cerebral ischemia reperfusion by middle cerebral artery occlusion for 2h followed 12h reperfusion. Neurological deficit scores, infarct size, SOD, MDA and NO levels were examined. P-AMPK, Bax, cleaved-Caspase-3 in brain was determined. To further probe for the mechanism of beneficial effect of HGSD, PC12 cells were incubated with serum from control or HGSD pretreated animals, incubated with 300μM H2O2 to induce apoptosis. Caspase-3 activity and cell apoptosis was evaluated. HGSD pretreatment significantly attenuated neurological deficit scores, reduced infarct size, increased SOD and decreased MDA and NO after cerebral IR injury compared to controls. Meanwhile, HGSD pretreatment significantly reduced expression of p-AMPK, Bax, cleaved-Caspase-3 after cerebral IR injury. Sodium caprate (100mg/kg/d) pretreatment alone did not exhibit any of these beneficial effects. PC12 cell apoptosis was attenuated when cells were cultured with HGSD serum compared to control. The presence of AMPK activator (AICAR) attenuated whereas AMPK inhibitor (Compound C) augmented the protective effect of HGSD serum on PC12 cell apoptosis.The results indicate that HGSD-pretreatment of rats protects the brain from ischemia-reperfusion injury and the mechanism is due to its anti-apoptotic effect mediated by decreased activation of AMPK.


Nucleation and growth of calcium phosphate on amine-, carboxyl- and hydroxyl-silane self-assembled monolayers.
Upon implantation, calcium phosphate (Ca-P) surfaces form on materials that are bone bioactive. In this study, the evolving surface characteristics associated with calcium phosphate precipitation are modeled using self-assembled monolayers (SAMs), in a one-step nucleation process. SAMs were used to create amine (-NH2), carboxyl (-COOH) and hydroxyl (-OH) functionalized surfaces by grafting 3-aminopropyltriethoxysilane, 3-triethoxysilylpropyl succinic anhydride and glycidoxypropyl tri-methoxysilane, respectively, onto oxidized silicon wafers. The SAM surfaces were characterized using ellipsometry to establish the presence of grafted molecules. On the surfaces incubated in simulated physiological fluids for 7 days, the thickness of Ca-P layer grew slowly over the first few hours, increasing strongly between 1 and 5 days and then slowed down again. FTIR showed the dependence of calcium phosphate morphology on the type of surface groups, with stronger P-O bands seen on the OH-terminated surface. SEM analysis showed dispersed Ca-P precipitates on the -COOH and -OH terminated surfaces after 1 day immersion. After 7 days, all SAM surfaces were covered with uniformly dispersed and denser Ca-P precipitates. The underlying Ca-P layer showed cracks on the -NH2-terminated surface. Rutherford backscattering spectrometry (RBS) data analysis confirmed that Ca/P ratio is in excellent agreement with the theoretical value of 1.67 for hydroxyapatite. X-ray diffraction (XRD) analysis also showed evidence of apatite formation on all the surfaces, with stronger evidence on the -OH-terminated surface. Highly porous Ca-P precipitates were observed on the SAM surfaces portrayed by the AFM scans with nanoscale RMS roughness. Thus, using highly controlled surface chemistry, under physiological conditions, in vitro, this study demonstrates that a hydroxylated surface enhances Ca-P nucleation and growth relative to other surfaces, thereby supporting the concept of its beneficial effect on bone tissue formation and growth.


Diabetes prevention and the role of risk factor reduction in the Medicare population.
Medicare is keenly aware of the secular changes in weight gain and of the nearly parallel increases in both the incidence and prevalence of type 2 diabetes throughout the U.S. population. The Medicare population, however, differs from the population at large because of its advanced age and frequency of comorbid conditions and/or disability. These factors affect life span as well as participation in and potential benefit from lifestyle modification and risk-factor reduction activities. Further, macrovascular disease is the greatest burden for older beneficiaries with diabetes, and its risks may antedate the appearance of hyperglycemia. Both diabetes prevention and treatment must be considered in this context. Medicare benefits focus on reduction of cardiovascular risk and mitigation of more temporally immediate complications of weight gain and glucose elevation. These preventive services and interventions are described.


Fentanyl for epidural intravascular test dose in obstetrics.
Although dizziness and drowsiness may be produced with either intravenous or epidural fentanyl, their occurrence after an intravenous injection is more rapid and relatively more pronounced. The purpose of this study was to determine whether or not the difference between routes of administration would be a reliable method of detecting an accidental intravascular injection. In part 1, using a double-blinded protocol, we prospectively assessed in laboring women the incidence of dizziness, drowsiness, or both associated with intravenous fentanyl (100 micrograms). In random order, subjects received two peripheral intravenous injections: 2 ml of fentanyl and 2 ml of saline, separated by a 3-minute observation period. In group 1 (18/18) and group 2 (22/22), all subjects reported a response to intravenous fentanyl within the one-minute assessment. In part 2, we evaluated in laboring patients the frequency of dizziness, drowsiness, or both to epidural fentanyl (100 micrograms). The study design was identical to part 1; however, the subjects received 2 ml of fentanyl and 2 ml of saline via a functional epidural catheter. In group 3 (1/18) and group 4 (1/22), one subject reported a response to epidural fentanyl within the 3-minute observation period. Overall, the responses to intravenous fentanyl (40/40) occurred in a remarkably more consistent fashion when compared to epidural fentanyl (2/40). Thus, the results suggest that in laboring patients, intravenous fentanyl produces predictable and easily detectable changes that may be useful in identifying an epidural catheter unintentionally placed intravascularly.


Phasic alterations in dopamine metabolites following continuous administration of amphetamine.
Rats were treated with slow-release (+)-amphetamine pellets for 7 days and then sacrificed at various times following pellet removal. Pellet-treated animals had decreased dopamine levels in caudate but not nucleus accumbens, with no recovery even 30 days after pellet removal. In both caudate and accumbens the levels of 3,4-dihydroxyphenylacetic acid and homovanillic acid were decreased at the time of pellet removal, then increased shortly after pellet removal, and were again decreased at 10 and 30 days after pellet removal. These fluctuations may reflect cyclical alterations in dopamine receptors following continuous amphetamine.


PFAS and Phthalate/DINCH Exposure in Association with Age at Menarche in Teenagers of the HBM4EU Aligned Studies.
Early puberty has been found to be associated with adverse health outcomes such as metabolic and cardiovascular diseases and hormone-dependent cancers. The decrease in age at menarche observed during the past decades has been linked to an increased exposure to endocrine-disrupting compounds (EDCs). Evidence for the association between PFAS and phthalate exposure and menarche onset, however, is inconsistent. We studied the association between PFAS and phthalate/DINCH exposure and age at menarche using data of 514 teenagers (12 to 18 years) from four aligned studies of the Human Biomonitoring for Europe initiative (HBM4EU): Riksmaten Adolescents 2016-2017 (Sweden), PCB cohort (follow-up; Slovakia), GerES V-sub (Germany), and FLEHS IV (Belgium). PFAS concentrations were measured in blood, and phthalate/DINCH concentrations in urine. We assessed the role of each individual pollutant within the context of the others, by using different multi-pollutant approaches, adjusting for age, age- and sex-standardized body mass index z-score and household educational level. Exposure to di(2-ethylhexyl) phthalate (DEHP), especially mono(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP), was associated with an earlier age at menarche, with estimates per interquartile fold change in 5OH-MEHP ranging from -0.34 to -0.12 years in the different models. Findings from this study indicated associations between age at menarche and some specific EDCs at concentrations detected in the general European population, but due to the study design (menarche onset preceded the chemical measurements), caution is needed in the interpretation of causality.


A new insight into sex-specific non-coding RNAs and networks in response to SARS-CoV-2.
SARS-CoV-2 is the RNA virus responsible for COVID-19, the prognosis of which has been found to be slightly worse in men. The present study aimed to analyze the expression of different mRNAs and their regulatory molecules (miRNAs and lncRNAs) to consider the potential existence of sex-specific expression patterns and COVID-19 susceptibility using bioinformatics analysis. The binding sites of all human mature miRNA sequences on the SARS-CoV-2 genome nucleotide sequence were predicted by the miRanda tool. Sequencing data was excavated using the Galaxy web server from GSE157103, and the output of feature counts was analyzed using DEseq2 packages to obtain differentially expressed genes (DEGs). Gene set enrichment analysis (GSEA) and DEG annotation analyses were performed using the ToppGene and Metascape tools. Using the RNA Interactome Database, we predicted interactions between differentially expressed lncRNAs and differentially expressed mRNAs. Finally, their networks were constructed with top miRNAs. We identified 11 miRNAs with three to five binding sites on the SARS-COVID-2 genome reference. MiR-29c-3p, miR-21-3p, and miR-6838-5p occupied four binding sites, and miR-29a-3p had five binding sites on the SARS-CoV-2 genome. Moreover, miR-29a-3p, and miR-29c-3p were the top miRNAs targeting DEGs. The expression levels of miRNAs (125, 181b, 130a, 29a, b, c, 212, 181a, 133a) changed in males with COVID-19, in whom they regulated ACE2 expression and affected the immune response by affecting phagosomes, complement activation, and cell-matrix adhesion. Our results indicated that XIST lncRNA was up-regulated, and TTTY14, TTTY10, and ZFY-AS1 lncRN as were down-regulated in both ICU and non-ICU men with COVID-19. Dysregulation of noncoding-RNAs has critical effects on the pathophysiology of men with COVID-19, which is why they may be used as biomarkers and therapeutic agents. Overall, our results indicated that the miR-29 family target regulation patterns and might become promising biomarkers for severity and survival outcome in men with COVID-19.


Water-Soluble Fluorescent Probes for Selective Recognition of Lysine and Its Application in an Object Carry-and-Release System.
A water-soluble fluorescent probe PEG-TPA-5' was synthesized, which shows an excellent selectivity to detect Lys in aqueous phase. An object carry-and-release system is established by applying PEG-TPA-5' as carrier and Lys as chemical stimulating source.


The development of scientific communication skills: a qualitative study of the perceptions of trainees and their mentors.
Scientific communication, both written and oral, is the cornerstone of success in biomedical research, yet formal instruction is rarely provided. Trainees with little exposure to standard academic English may find developing scientific communication skills challenging. In this exploratory, hypothesis-generating qualitative study, the authors examined the process by which mentored junior researchers learn scientific communication skills, their feelings about the challenges, and their mentor's role in the process. In 2010, the authors conducted semistructured focus groups and interviews to explore research trainees' and faculty mentors' perceptions and practices regarding scientific communication skills development, as part of the development phase of a larger quantitative study. The facilitator took detailed notes and verified their accuracy with participants during the sessions; a second member of the research team observed and verified the recorded notes. Three coders performed a thematic analysis, and the other authors reviewed it. Forty-three trainees and 50 mentors participated. Trainees and mentors had diverging views on the role of mentoring in fostering communication skills development. Trainees expressed varying levels of self-confidence but considerable angst. Mentors felt that most trainees have low self-confidence. Trainees expressed interest in learning scientific communication skills, but mentors reported that some trainees were insufficiently motivated and seemed resistant to guidance. Both groups agreed that trainees found mentors' feedback difficult to accept. The degree of distress, dissatisfaction, and lack of mutual understanding between mentors and trainees was striking. These themes have important implications for best practices and resource development.


Few-Shot Learning Geometric Ensemble for Multi-label Classification of Chest X-Rays.
This paper aims to identify uncommon cardiothoracic diseases and patterns on chest X-ray images. Training a machine learning model to classify rare diseases with multi-label indications is challenging without sufficient labeled training samples. Our model leverages the information from common diseases and adapts to perform on less common mentions. We propose to use multi-label few-shot learning (FSL) schemes including neighborhood component analysis loss, generating additional samples using distribution calibration and fine-tuning based on multi-label classification loss. We utilize the fact that the widely adopted nearest neighbor-based FSL schemes like ProtoNet are Voronoi diagrams in feature space. In our method, the Voronoi diagrams in the features space generated from multi-label schemes are combined into our geometric DeepVoro Multi-label ensemble. The improved performance in multi-label few-shot classification using the multi-label ensemble is demonstrated in our experiments (The code is publicly available at https://github.com/Saurabh7/Few-shot-learning-multilabel-cxray).


Including Internet insurance as part of a hospital computer network security plan.
Cyber attacks on a hospital's computer network is a new crime to be reckoned with. Should your hospital consider internet insurance? The author explains this new phenomenon and presents a risk assessment for determining network vulnerabilities.


Constitutive Expression of Hif2α Confers Acute O2 Sensitivity to Carotid Body Glomus Cells.
Acute oxygen (O2) sensing and adaptation to hypoxia are essential for physiological homeostasis. The prototypical acute O2 sensing organ is the carotid body, which contains chemosensory glomus cells expressing O2-sensitive K+ channels. Inhibition of these channels during hypoxia leads to cell depolarization, transmitter release, and activation of afferent sensory fibers terminating in the brain stem respiratory and autonomic centers. Focusing on recent data, here we discuss the special sensitivity of glomus cell mitochondria to changes in O2 tension due to Hif2α-dependent expression of several atypical mitochondrial electron transport chain subunits and enzymes. These are responsible for an accelerated oxidative metabolism and the strict dependence of mitochondrial complex IV activity on O2 availability. We report that ablation of Epas1 (the gene coding Hif2α) causes a selective downregulation of the atypical mitochondrial genes and a strong inhibition of glomus cell acute responsiveness to hypoxia. Our observations indicate that Hif2α expression is required for the characteristic metabolic profile of glomus cells and provide a mechanistic explanation for the acute O2 regulation of breathing.


A novel prospective descriptive analysis of nausea and vomiting among patients receiving gastrointestinal radiation therapy.
Nausea and vomiting are common side effects from radiotherapy that can interfere with gastrointestinal (GI) cancer patients' quality of life (QOL). This study described the subjective experience of patients with radiation-induced nausea and vomiting (RINV) and its relation to QOL. Forty-eight patients treated with abdominal radiotherapy alone or with concomitant chemoradiotherapy were followed in a prospective study. All episodes of nausea, vomiting, and antiemetic use were recorded daily for the treatment period and the week following completion of therapy. QOL was assessed weekly using the Functional Living Index-Emesis QOL Tool (FLIE) and the EORTC QLQ-C30 core questionnaire (C30). In total, 351 episodes of nausea severity, duration, onset time, and 154 outcomes of vomiting onset times and contents were documented. The median nausea severity experienced per episode was 5 (on a scale from 1 to 10), and the most common durations of nausea were 30 min or less and constant nausea all day and night. The most common location of nausea was the abdomen. Longer nausea duration, great nausea severities, and the location of nausea experienced had significant adverse relationships to multiple QOL items on both the FLIE and the C30. In addition, the onset timing and number of vomiting episodes were related to the majority of all FLIE and QOL scores. Patient's subjective experiences of RINV directly correlated to the worsening of QOL outcomes. The identification and amelioration of these RINV experiences could improve QOL.


Developmental constraints versus flexibility in morphological evolution.
Evolutionary developmental biology has encouraged a change of research emphasis from the sorting of phenotypic variation by natural selection to the production of that variation through development. Some morphologies are more readily generated than others, and developmental mechanisms can limit or channel evolutionary change. Such biases determine how readily populations are able to respond to selection, and have been postulated to explain stasis in morphological evolution and unexplored morphologies. There has been much discussion about evolutionary constraints but empirical data testing them directly are sparse. The spectacular diversity in butterfly wing patterns is suggestive of how little constrained morphological evolution can be. However, for wing patterns involving serial repeats of the same element, developmental properties suggest that some directions of evolutionary change might be restricted. Here we show that despite the developmental coupling between different eyespots in the butterfly Bicyclus anynana, there is great potential for independent changes. This flexibility is consistent with the diversity of wing patterns across species and argues for a dominant role of natural selection, rather than internal constraints, in shaping existing variation.


The human islet amyloid polypeptide in protein misfolding disorders: Mechanisms of aggregation and interaction with biomembranes.
Human islet amyloid polypeptide (hIAPP), otherwise known as amylin, is a 37-residue peptide hormone which is reported to be a common factor in protein misfolding disorders such as type-2 diabetes mellitus, Alzheimer's disease and Parkinson's disease, due to deposition of insoluble hIAPP amyloid in the pancreas and brain. Multiple studies point to the importance of the peptide's interaction with biological membranes and the cytotoxicity of hIAPP species. Here, we discuss the aggregation pathways of hIAPP amyloid fibril formation and focus on the complex interplay between membrane-mediated assembly of hIAPP and the associated mechanisms of membrane damage caused by the peptide species. Mitochondrial membranes, which are unique in their lipid composition, are proposed as prime targets for the early intracellular formation of hIAPP toxic entities. We suggest that future studies should include more physiologically-relevant and in-cell studies to allow a more accurate model of in vivo interactions. Finally, we underscore an urgent need for developing effective therapeutic strategies aimed at hindering hIAPP-phospholipid interactions.


Use of common spatial patterns for early detection of Parkinson's disease.
One of the most common diseases that affects human brain is Parkinson's disease. Detection of Parkinson's disease (PD) poses a serious challenge. Robust methods for feature extraction allowing separation between the electroencephalograms (EEG) of healthy subjects and PD patients are required. We used the EEG records of healthy subjects and PD patients which were subject to auditory tasks. We used the common spatial patterns (CSP) and Laplacian mask as methods to allow robust selection and extraction of features. We used the derived CSP whitening matrix to determine those channels that are the most promising in the terms of differentiating between EEGs of healthy controls and of PD patients. Using the selection of features calculated using the CSP we managed to obtain the classification accuracy of 85% when classifying EEG records belonging to groups of controls or PD patients. Using the features calculated using the Laplacian operator we obtained the classification accuracy of 90%. Diagnosing the PD in early stages using EEG is possible. The CSP proved to be a promising technique to detect informative channels and to separate between the groups. Use of the combination of features calculated using the Laplacian offers good separability between the two groups.


pH-Dependent nanostructure based on isoquinoline-cyclodextrin conjugate for thrombosis therapy.
The modification of 3S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (THIQA) with β-cyclodextrin (β-CD) provides an oral antithrombotic agent, 6-(3'S-isoquinoline-3'-carboxylaminoethylamino)-6-deoxy-β-CD (THIQA-β-CD). In aqueous solution THIQA-β-CD undergoes intermolecular inclusion complexation and forms pH-dependent nanostructures. The morphological feature of THIQA-β-CD is a nanocloud consisting of numerous particles that are 5 nm-6 nm in diameter at pH 3.0. The nanocloud switches to a nanorod ranging from 100 nm to 385 nm in length at pH 7.2, then to nanowires of 50 nm to 530 nm in length at pH 10.1. THIQA-β-CD, which has unusual nanostructures, offers enhanced stability in blood. Inhibition of thrombin-induced platelet aggregation in vitro and demonstrated antithrombotic efficacy in vivo. This investigation demonstrated that the modification of THIQA with β-CD is a promising approach for clinical therapy of thrombus disease. The pH-dependent nanostructures of conjugate provide the desired in vivo antithrombotic activity and in vitro stability in blood. This study a demonstrates that the modification of 3S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (THIQA) with beta-cyclodextrin, which leads to pH dependent nanostructure formation, is a promising approach for clinical therapy of thrombotic disease.


Flap revascularization in patients following immediate reconstruction using an autologous free dermal fat graft for breast cancer: a report of two cases.
It has been reported that use of the free dermal fat graft (FDFG) technique produces a good cosmetic outcome for breast cancer. An FDFG is harvested from the lower abdomen as a columnar-shaped specimen and implanted into the defect of the breast after a partial mastectomy as a volume replacement technique. In this report, two patients who underwent breast-conserving surgery with immediate reconstruction using an autologous FDFG are described in order to show the difference in status between one case with and one without blood flow in the graft. To assess the benefit of this technique using FDFGs, their cosmetic satisfaction was evaluated using a questionnaire, graft shrinkage was measured by CT, and blood flow was assessed using contrast-enhanced ultrasound (CEUS). Both patients scored 10 of 12 points on the questionnaire. After 2 years, shrinkage of the grafts was 21.6 and 25.2 %, respectively. Although one patient had no blood flow in the center of the graft, the other had blood flow from the pectoralis major muscle to the center of the graft. While satisfaction and graft shrinkage were similar in the two patients, one case showed blood flow and had a somewhat softer graft than the other. The graft status was maintained with a good cosmetic outcome for 3 years after breast-conserving surgery with immediate reconstruction using an autologous FDFG, despite mild shrinkage and hardness of the graft. It is notable that blood flow was observed into the graft on CEUS, and more distinct perfusion was seen in the softer graft case after more than 3 years.


Anti-inflammatory dietary pattern is associated with handgrip strength decline: a prospective cohort study.
Skeletal muscle strength decline is strongly associated with inflammation. While previous research has confirmed that diet can modulate chronic inflammation, little is known about the relationship between an anti-inflammatory dietary pattern and muscle strength. The aim of this study was to investigate the association between an anti-inflammatory dietary pattern and handgrip strength decline in a large-scale adult population. During a median follow-up period of 3 years, this prospective cohort study was carried out between 2013 and 2018 and included 2840 participants (60.2% men). Dietary intake was assessed using a validated food frequency questionnaire at baseline, and handgrip strength was measured annually with a handheld digital dynamometer. The dietary inflammatory potential score was calculated using white blood cell count and hypersensitive C-reactive protein as inflammatory markers, and was determined using reduced rank regression and stepwise linear regression. Multivariable linear regression models were used to estimate the association between the dietary inflammatory potential score and the annualized change in handgrip strength and weight-adjusted handgrip strength. After adjusting for multiple confounding factors, significant associations between the dietary inflammatory potential score and the annualized change in handgrip strength and weight-adjusted handgrip strength in women, with values of - 0.8322 kg (95% confidence interval [CI] - 1.6405, - 0.0238; P < 0.0408) and - 0.0171 kg/kg (95% CI - 0.0310, - 0.0032; P < 0.0158), respectively. However, no significant differences were observed between the dietary inflammatory potential score and the annualized change in handgrip strength and weight-adjusted handgrip strength in men, with values of 0.1578 kg (95% CI - 0.6107, 0.9261; P < 0.6874) and - 0.0014 kg/kg (95% CI - 0.0115, 0.0088; P < 0.7933), respectively. Our findings suggest that consuming an anti-inflammatory dietary pattern could be a protective strategy against the decline in skeletal muscle strength in women.


Antitumor effect of CPT-11, a new derivative of camptothecin, against pleiotropic drug-resistant tumors in vitro and in vivo.
CPT-11, a new derivative of camptothecin, was effective against tumor cells, especially vincristine (VCR)-and adriamycin (ADM)-resistant P388 leukemia, compared to either VCR or ADM. The drug showed superior chemotherapeutic effects over VCR and ADM in sensitive P388 leukemia-bearing mice, and was also effective in VCR- and ADM-resistant P388 leukemia-bearing mice. These latter survival advantages with CPT-11 were almost equal to those obtained by CPT-11 against sensitive P388 leukemia. CPT-11 was found to be effective against human tumor cells, especially various pleiotropically drug-resistant human tumor lines, compared to VCR and ADM. CPT-11 should be considered for further development as a new chemotherapeutic agent potentially effective against pleiotropically drug-resistant tumors.