Dimensionality of DSM-5 PTSD symptoms: Validation of the Chinese version of the posttraumatic diagnostic scale for DSM-5 across multiple trauma samples.
The Posttraumatic Diagnostic Scale for DSM-5 (PDS-5) is an updated DSM-5 version of the PDS, a widely used measure for PTSD. The PDS-5 has recently been shown to possess sound psychometric properties and awaits cross-cultural validation. The present study aimed first, to evaluate the psychometric properties of the Chinese version of the PDS-5; second, to evaluate alternative factor models of DSM-5 PTSD symptoms with multiple trauma samples. Data were collected from five samples of Taiwanese trauma-exposed individuals (total N = 903): 138 burn injury survivors, 403 earthquake survivors, 181 trauma-exposed young adults, 91 trauma-exposed undergraduates, and 90 female domestic violence survivors. The Chinese PDS-5 possessed excellent internal consistency (α s = .94-.95) and satisfactory five-week (r = .80) and one-year temporal stability (r = 0.76). Convergent, concurrent, and discriminant validity were also established. Consistent with recent studies, confirmatory factor analyses demonstrated the best fit of a seven-factor Hybrid model, followed by a six-factor Anhedonia model across multiple trauma samples.


Circadian clock in Xenopus eye controlling retinal serotonin N-acetyltransferase.
Circadian rhythms are controlled by endogenous oscillators or clocks. These clocks exhibit a persistent period of approximately 24 h in constant conditions, a specific phase relationship to a periodic cue (zeitgeber) in the external environment, and plasticity in that the phase of the clock may be altered in response to a phase change in the zeitgeber. Although many processes exhibit circadian rhythmicity, the nature and location of endogenous clocks remain poorly defined. Recent evidence in vertebrates suggests that the mammalian suprachiasmatic nucleus and the avian pineal gland contain clocks that affect the rhythmicity of indoleamine metabolism. The vertebrate retina also exhibits a circadian rhythm of serotonin N-acetytransferase activity (NAT, EC 18.104.22.168), a key enzyme controlling melatonin synthesis, and of photoreceptor disk shedding. The latter process may be regulated by melatonin, and the immediate cellular events seem to be controlled locally within the eye. Although sustained oscillation and entrainment were not demonstrated, data suggesting that an ocular circadian clock influences disk shedding have been reported. We sought evidence for an ocular clock by studying retinal NAT activity in Xenopus eye cups maintained in culture and report here both sustained oscillation and entrainment of the in vitro system. The data indicate that in addition to the suprachiasmatic nucleus and pineal gland, the eye itself must be regarded as the locus of a circadian clock in vertebrates.


Obesity without overeating in golden hamsters.
When male golden hamsters were switched from a diet of Purina rodent chow to a calorically-dense high-fat diet or were given ad lib access to a 32% sucrose solution in addition to chow, they adjusted their food intakes rapidly (within 24 hr) and did not overeat. Nevertheless, the fat-fed hamsters tripled their rate of weight gain and nearly doubled their carcass fat content after one month on the diet. Resting oxygen consumption (animals awake but quite) was significantly lower in fat-fed animals than in chow-fed controls. Sucrose feeding had no effect on food intake, body weight gain, carcass composition or oxygen consumption. Thus, whereas rats exhibit dietary obesity in spite of increases in energy expenditure (diet-induced thermogenesis), fat-fed hamsters seem to become obese because of decreases in energy expenditure. However, although actual energy expenditure is reduced, fat-fed hamsters exhibit an enhanced thermogenic capacity. Interscapular brown adipose tissue mass, protein content, and DNA content as well as norepinephrine-stimulated oxygen consumption were all significantly elevated in fat-fed hamsters. The significance of these concurrent diet-induced decreases in energy expenditure and increases in thermogenic capacity is not clear, but they could be of some value in preparing the hamster for winter.


Cell therapy for full-thickness wounds: are fetal dermal cells a potential source?
The application of autologous dermal fibroblasts has been shown to improve burn wound healing. However, a major hurdle is the availability of sufficient healthy skin as a cell source. We investigated fetal dermal cells as an alternative source for cell-based therapy for skin regeneration. Human (hFF), porcine fetal (pFF) or autologous dermal fibroblasts (AF) were seeded in a collagen-elastin substitute (Novomaix, NVM), which was applied in combination with an autologous split thickness skin graft (STSG) to evaluate the effects of these cells on wound healing in a porcine excisional wound model. Transplantation of wounds with NVM+hFF showed an increased influx of inflammatory cells (e.g., neutrophils, macrophages, CD4(+) and CD8(+) lymphocytes) compared to STSG, acellular NVM (Acell-NVM) and NVM+AF at post-surgery days 7 and/or 14. Wounds treated with NVM+pFF presented only an increase in CD8(+) lymphocyte influx. Furthermore, reduced alpha-smooth muscle actin (αSMA) expression in wound areas and reduced contraction of the wounds was observed with NVM+AF compared to Acell-NVM. Xenogeneic transplantation of NVM+hFF increased αSMA expression in wounds compared to NVM+AF. An improved scar quality was observed for wounds treated with NVM+AF compared to Acell-NVM, NVM+hFF and NVM+pFF at day 56. In conclusion, application of autologous fibroblasts improved the overall outcome of wound healing in comparison to fetal dermal cells and Acell-NVM, whereas application of fetal dermal fibroblasts in NVM did not improve wound healing of full-thickness wounds in a porcine model. Although human fetal dermal cells demonstrated an increased immune response, this did not seem to affect scar quality.


Bone morphogenetic protein signaling in nephron progenitor cells.
Bone morphogenetic protein (BMP) signaling plays an essential role in many aspects of kidney development, and is a major determinant of outcome in kidney injury. BMP treatment is also an essential component of protocols for differentiation of nephron progenitors from pluripotent stem cells. This review discusses the role of BMP signaling to nephron progenitor cells in each of these contexts.


Embracing Change: An International Survey Study on the Beliefs and Attitudes of Pediatric Rheumatologists Towards Biosimilars.
Biosimilars have been adopted by clinicians more slowly than anticipated in the post-marketing phase. We aimed to reveal the perceptions and attitudes of pediatric rheumatologists towards biosimilars and the obstacles to biosimilar therapy. A web-based survey designed to determine the knowledge, experience, and perceptions of pediatric rheumatologists about biosimilars was electronically mailed to the participants between April and August 2021. Responses were collected anonymously and subsequently analyzed. A total of 114 pediatric rheumatologists including fellows (32.4%), specialists (29.8%), and seniors (37.7%) responded to the questionnaire. According to the data, 75 (65.8%) physicians had already prescribed at least one biosimilar. The vast majority of participants were aware of the potential cost savings of biosimilars (84, 73.3%). Participants who felt insufficiently informed were 41.8%, 67.6%, and 83.7% among seniors, specialists, and fellows, respectively. In pediatric rheumatology, the scarcity of clinical trials and real-life data (64%) and inadequate information about tolerance to the biosimilars and related side effects in children (49.1%) were the most common barriers expressed by prescribers. Nearly half (45%) of the pediatric rheumatologists preferred to prescribe biosimilars in the treatment of biologic-naive cases. However, most (93%) were reluctant to switch a reference molecule to a biosimilar while the patient was doing well under the originator medicine. This survey provided insights into the concerns about prescribing biosimilars among pediatric rheumatologists. In the field of pediatric rheumatology, further education about biosimilars and real-life experiences is required to better inform about treatment options in children.


Sex differences and reversal of brain asymmetry by testosterone in chickens.
The study examined the effect of testosterone on the asymmetry of visual discrimination performance of young chicks. Two-week-old chicks were tested on the pebble floor visual discrimination task. Male chicks were found to have brain asymmetry for visual discrimination learning, since chicks tested binocularly, or tested monocularly using their right eye system, have superior learning performance compared to chicks tested monocularly using their left eye system. Control female chicks were not found to have brain asymmetry. Testosterone treatment (12.5 mg of testosterone oenanthate on day 2 posthatch) reversed the pattern of brain asymmetry observed in control males but not females. In addition, asymmetry of visual discrimination learning is demonstrated in both male and female chicks after unilateral intracranial treatment with monosodium glutamate.


Radioembolization: Is Prophylactic Embolization of Hepaticoenteric Arteries Necessary? A Systematic Review.
To study the effectiveness of prophylactic embolization of hepaticoenteric arteries to prevent gastrointestinal complications during radioembolization. A PubMed, Embase and Cochrane literature search was performed. We included studies assessing both a group of patients with and without embolization. Our search revealed 1401 articles of which title and abstract were screened. Finally, eight studies were included investigating 1237 patients. Of these patients, 456 received embolization of one or more arteries. No difference was seen in the incidence of gastrointestinal complications in patients with prophylactic embolization of the gastroduodenal artery (GDA), right gastric artery (RGA), cystic artery (CA) or hepatic falciform artery (HFA) compared to patients without embolization. Few complications were reported when microspheres were injected distal to the origin of these arteries or when reversed flow of the GDA was present. A high risk of confounding by indication was present because of the non-randomized nature of the included studies. It is advisable to restrict embolization to those hepaticoenteric arteries that originate distally or close to the injection site of microspheres. There is no conclusive evidence that embolization of hepaticoenteric arteries influences the risk of complications.


Copability, coping, and learning as focal concepts in the evaluation of computerised diabetes disease management.
Within diabetes care, the majority of health decisions are in the hands of the patient. Therefore, the concepts of disease management and self-care represent inescapable challenges for both patient and healthcare professionals, entailing a considerable amount of learning. Thus, a computerised diabetes disease management systems (CDDM) is to be seen not merely as tools for the medical treatment, but also as pedagogical tools to enhance patient competence. The unfortunate lack of success for most knowledge-based systems might be related to the problem of finding an adequate way of evaluating the systems from their development through the implementation phase to the daily clinical practice. The following presents the initial methodological considerations for evaluating the usefulness of a CDDM system called DiasNet, which is being implemented as a learning tool for patients. The evaluation of usefulness of a CDDM, we claim, entails clinical assessment taking into account the challenges and pitfalls in diabetes disease management. Drawing on activity theory, we suggest the concept of copability as a supplement to 'usability' and 'utility' when determining 'usefulness'. We maintain that it is necessary to ask how well the user copes with the new situation using the system. As ways to measure copability of DiasNet the concepts of coping and learning are discussed, as well as ways this methodology might inform systems development, implementation, and daily clinical practice.


Metal artifacts and artifact reduction of neurovascular coils in photon-counting detector CT versus energy-integrating detector CT - in vitro comparison of a standard brain imaging protocol.
Photon-counting detector computed tomography (PCD-CT) is a promising new technique for CT imaging. The aim of the present study was the in vitro comparison of coil-related artifacts in PCD-CT and conventional energy-integrating detector CT (EID-CT) using a comparable standard brain imaging protocol before and after metal artifact reduction (MAR). A nidus-shaped rubber latex, resembling an aneurysm of the cerebral arteries, was filled with neurovascular platinum coils and inserted into a brain imaging phantom. Image acquisition and reconstruction were repeatedly performed for PCD-CT and EID-CT (n = 10, respectively) using a standard brain imaging protocol. Moreover, linear interpolation MAR was performed for PCD-CT and EID-CT images. The degree of artifacts was analyzed quantitatively (standard deviation in a donut-shaped region of interest) and qualitatively (5-point scale analysis). Quantitative and qualitative analysis demonstrated a lower degree of metal artifacts in the EID-CT images compared to the total-energy PCD-CT images (e.g., 82.99 ± 7.89 Hounsfield units (HU) versus 90.35 ± 6.28 HU; p < 0.001) with no qualitative difference between the high-energy bin PCD-CT images and the EID-CT images (4.18 ± 0.37 and 3.70 ± 0.64; p = 0.575). After MAR, artifacts were more profoundly reduced in the PCD-CT images compared to the EID-CT images in both analyses (e.g., 2.35 ± 0.43 and 3.18 ± 0.34; p < 0.001). PCD-CT in combination with MAR have the potential to provide an improved option for reduction of coil-related artifacts in cerebral imaging in this in vitro study. • Photon-counting detector CT produces more artifacts compared to energy-integrating detector CT without metal artifact reduction in cerebral in vitro imaging after neurovascular coil-embolization. • Spectral information of PCD-CT provides the potential for new post-processing techniques, since the coil-related artifacts were lower in PCD-CT images compared to EID-CT images after linear interpolation metal artifact reduction in this in vitro study.


The association between personal measurements of environmental exposure to particulates and heart rate variability.
Epidemiologic evidence indicates that airborne particulates are associated with mortality risk, predominately from heart disease. This may occur through changes in the cardiac autonomic nervous system, witnessed by changes in heart rate variability. This short-term longitudinal study used continuous personal particulate matter measurements to examine the effects of exposure to particulate matter less than 2.5 microm in diameter (PM2.5) on heart rate and rate variability in 20 relatively young, healthy male workers. Continuous exposure and cardiac monitoring were performed on each subject on a nonwork day. The 5-minute standard deviation of the normal-to-normal interval was used as the main measure of heart rate variability. Mixed-effects regression models estimate an average 1.4% (95% confidence limits = -2.1, -0.6) decrease in the 5-minute standard deviation of the normal-to-normal interval for each 100 microg/m3 increase in the 3-hour PM2.5 moving average, and small increases in heart rate, after adjustment for potential confounding factors. Predicted effects of exposure were greatest using the 3-hour averaging interval for PM2.5 and decreased in magnitude using shorter and longer intervals. These results reveal an association between cardiac autonomic function and environmental PM2.5 exposure. These observed associations may result from decreased vagal or increased sympathetic tone.


Antihypertensive effect of various doses of hydrochlorothiazide and its relation to the plasma level of the drug.
Nine previously untreated hypertensive patients (WHO Stage I and II) were given hydrochlorothiazide (hct) 12.5, 25, 50 and 75 mg for two weeks after an initial four week period of placebo treatment. Blood pressure recordings were made casually and after 30 min rest in lying, sitting and standing positions. Plasma concentrations of the drug were measured by GLC. A significant decrease in BP was seen during treatment with hct 12.5 mg except in the casual standing position. Doubling of the dose twice produced very little further decrease in BP. The mean steady state concentration was 111 ng.ml-1 during treatment with hct 75 mg. A linear relationship was found between the plasma concentration of hct at 0 and 5 h and the various dose level of hct. No relation was found between plasma concentration and reduction in blood pressure.


Prematurity, subclinical intraamniotic infection, and fetal biophysical parameters: is there a correlation?
This prospective study was undertaken to examine the effects of subclinical intraamniotic infection on fetal behavioral patterns. Amniotic fluid was obtained from four groups of patients (n = 99): group 1, patients with preterm premature rupture of the fetal membranes (PPROM) without infection; group 2, patients with PPROM and infection; group 3, patients with preterm labor (PTL) and without infection; and group 4, patients with PTL and infection. Fetal biophysical profiles were obtained on admission to the labor suite. Amniotic fluid was analyzed for the presence of microorganisms and endotoxin to confirm intraamniotic infection; cytokines interleukin (IL)-1beta, IL-6, and IL-8 were also assayed. We found no association between low scores for biophysical parameters and subclinical infection in patients with PPROM or PTL. We could not demonstrate that upon a patient's admission to the labor hall absent fetal breathing and absent fetal movement, as well as reactivity, correlate with subclinical intraamniotic infection. Elevated cytokines, i.e. IL-1beta, IL-6, and IL-8 were associated with subclinical chorioamnionitis.


Competition assays between ESBL-producing E. coli and K. pneumoniae isolates collected from Lebanese elderly: An additional cost on fitness.
The dissemination of Multi Drug Resistant Organisms (MDROs) is one of the major public health problems addressed nowadays. High fecal carriage rates of MDR Enterobacteriaceae were reported from Lebanese nursing homes. Studies have shown that the acquisition of resistance genes by bacteria might confer a fitness cost detected as a decrease in the frequency of these bacteria as compared to sensitive isolates. In this study, the competitive growth of MDR Enterobacteriaceae isolated from elderly is assessed. Sensitive and ESBL-producing Escherichia coli and Klebsiella pneumoniae isolates were identified. Inter-species in-vitro competition assays were conducted in different combinations. ESBL-producing K. pneumoniae presented a fitness cost when competing against sensitive E. coli. On the other hand, resistant E. coli only showed a fitness cost when growing in presence of two sensitive K. pneumoniae isolates. These results suggest that ESBL-production genes in E. coli and K. pneumoniae may confer a fitness cost that leads to the decrease in frequency of these bacteria in interspecies competitions. Culturing bacteria in a medium with more diverse isolates can provide better insights into bacterial competition and resistance dynamics, which can be exploited in the search for alternative therapeutic approaches towards the colonization of resistant bacteria.


Repeated injection of GBR 12909, but not cocaine or WIN 35,065-2, into the ventral tegmental area induces behavioral sensitization.
A role for the mesolimbic dopamine system in the development of behavioral sensitization to psychostimulants, such as cocaine and amphetamine, is well established. Previous reports have suggested that the ventral tegmental area (VTA) is involved in the initiation of, while the nucleus accumbens is in involved in the expression of behavioral sensitization. This hypothesis is supported in part, by studies which demonstrated that behavioral sensitization could be induced by repeated intra-VTA, but not intra-accumbal, administration of amphetamine. The present studies were designed to determine whether repeated intra-VTA cocaine would similarly induce behavioral sensitization. Rats receiving four daily injections of cocaine (1.5, 5 or 15 nmol/side) into the VTA did not show a sensitized behavioral response when challenged with cocaine (15 mg/kg, ip) 1 week later. In contrast to this, repeated injection of the specific dopamine reuptake inhibitor, GBR 12909 (15 nmol/side) produced behavioral sensitization to a challenge injection of cocaine. Repeated injections of the cocaine analog WIN 35,065-2 did not induce behavioral sensitization to cocaine, suggesting that the local anesthetic properties of cocaine were not responsible for the inability of intra-VTA cocaine to induce sensitization. In summary, the data suggest that sensitization to cocaine may involve mechanisms different from amphetamine.


Serum YKL-40 as a marker of disease activity and stricture formation in patients with Crohn's disease.
YKL-40 is secreted by macrophages and neutrophils and is a growth factor for vascular endothelial cells and fibroblasts. Elevated serum levels of YKL-40 have been reported in patients with various inflammatory conditions and ongoing fibrosis. The aim of this study was to investigate the relationship between serum concentrations of YKL-40 and disease activity, acute phase reactants, and the presence of strictures in patients with Crohn's disease (CD). We studied the serum concentrations of YKL-40 in 41 patients with CD, in which 12 had an endoscopically- or radiologically-proven stricture formation. Forty-six age- and sex-matched healthy volunteers served as controls and a multivariate regression analysis was performed to find out the independent predictors of intestinal strictures and clinical activity. The serum YKL-40 concentrations in the patients were significantly higher than that in the healthy controls (105.69 +/- 88.08 ng/mL [range 20.23-333.57]vs 44.92 +/- 24.89 ng/mL [range 18.31-113.43], P = 0.000) and patients with a stricture formation had significantly higher YKL-40 levels than those without strictures (167.50 +/- 119.30 ng/mL [range 23.62-333.57]vs 80.12 +/- 56.38 ng/mL [range 20.23-259.19], P = 0.003). Significant correlations were noted between YKL-40 levels and clinical activity (r = 0.681; P = 0.000) and the presence of intestinal strictures (r = 0.457; P = 0.003). The multivariate regression analysis found the serum YKL-40 levels to be an independent predictor of intestinal strictures (P = 0.001) and clinical activity (P = 0.001). Patients with CD, particularly those with a stricture formation, have significantly higher levels of YKL-40. YKL-40 seems to be a useful marker of disease activity as well as stricture formation in patients with CD.


Biological evaluation of substance P antagonists.
Five undeca- and six C-terminal heptapeptide substance P (SP) analogues were tested for their capacity to block the contractile effect of SP on the guinea-pig isolated taenia coli. They had one feature in common, namely substitutions in positions 7 and 9 in the SP molecule. In the majority of analogues D-tryptophan was used for these substitutions. All analogues tested were found to be competitive antagonists to exogenous SP and to be capable of blocking the electrically induced non-cholinergic, non-adrenergic neuronal contraction of the taenia. Of the undecapeptides, (D-Arg1, D-Pro2, D-Trp7,9, Leu11) SP and (D-Arg1, D-Trp7,9, Leu11) SP (Spantide) had the highest pA2 value, 7.1-7.2, and the lowest IC50 value, 10(-6) M. The pA2 values of the heptapeptides were generally lower. Three of the most potent antagonists were tested for specificity and found to block the smooth muscle contraction induced by SP, physalaemin, eledoisin and bombesin but not that induced by bradykinin, carbachol, 5-hydroxytryptamine, histamine, prostaglandins and vasopressin. The SP antagonists were also tested for spasmogenic effect on the taenia and for their capacity to release histamine from rat isolated peritoneal mast cells. The spasmogenic activity displayed by most of the SP antagonists tested is likely to be related to their ability to release histamine since the contractile response was reduced by mepyramine, a histamine H1-receptor antagonist. (D-Arg1, D-Trp7,9, Leu11) SP was notable for combining a high antagonistic potency with a weak spasmogenic effect (and poor histamine releasing effect).


Safety of third dose of COVID-19 vaccination in frail patients: Results from the prospective Italian VAX4FRAIL study.
Despite people with impaired immune competence due to an underlying disease or ongoing therapy, hereinafter frail patients, are (likely to be) the first to be vaccinated, they were usually excluded from clinical trials. To report adverse reactions of frail patients after receipt of the third dose (booster) administered after completion of a two-dose mRNA vaccination and to compare with those reported after the receipt of the first two doses. A multicenter, observational, prospective study aimed at evaluating both the safety profile and the immune response of Pfizer-BioNTech or Moderna vaccines in frail patients. National Project on Vaccines, COVID-19 and Frail Patients (VAX4FRAIL). People consenting and included in the VAX4FRAIL trial. A series of three doses of COVID-19 mRNA vaccination from the same manufacturer. Evaluation of a self-assessment questionnaire addressing a predefined list of eight symptoms on a five-item Likert scale. Symptoms were classified as severe if the patient rated them as severe or overwhelming. Among 320 VAX4FRAIL participants diagnosed/treated for hematological malignancies (N=105; 32.8%), solid tumors (N=48; 15.0%), immune-rheumatological diseases (N=60; 18.8%), neurological diseases (N=107; 33.4%), and receiving the booster dose, 70.3% reported at least one loco-regional or systemic reactions. Adverse events were mostly mild or moderate, none being life-threatening. Only six of the 320 (1.9%) patients had their treatment postponed due to the vaccine. The safety profile of the booster compared to previously administered two doses showed a stable prevalence of patients with one or more adverse events (73.5%, 79.7% and 73.9% respectively), and a slightly increment of patients with one or more severe adverse events (13.4%, 13.9% and 19.2% respectively). The booster of the mRNA COVID-19 vaccine was safely administered in the largest prospective cohort of frail patients reported so far. VAX4FRAIL will continue to monitor the safety of additional vaccine doses, especially systemic adverse events that can be easily prevented to avoid interruption of continuity of care. https://clinicaltrials.gov/ct2/show/NCT04848493, identifier NCT04848493.


Globin RNA precursor molecules: biosynthesis and process in erythroid cells.
Hybridization of labeled RNA with excess amounts of DNA complementary to globin mRNA, in conjunction with a pulse-chase technique, were used to investigate the biosynthetic pathway of globin mRNA in erythroid cells. Three species of molecules sharing common sequences with globin mRNA were detected in the nuclei of these cells, two of which are larger than the cytoplasmic globin mRNA. One species was approximately 7 times larger than globin mRNA ("27S"), and the other ("15S") was only about twice the size of cytoplasmic globin mRNA. The largest species lacked poly(A) sequences, while the others contained poly(A), After chase, the large RNA species gradually disappeared ( 1/2 = 5 min), while the cytoplasmic 10S species accumulated. From these results a model is proposed describing the biosynthetic pathway of globin RNA transcription: an early transcription product is the large molecule "27S" (approximately 5000 nucleotides long) which is then cleaved into a smaller species "15S" (approximately 1500 nucleotides). This intermediate precursor is then clipped, presumably at the 5' end, and finally converted to the exported "10S" molecule (approximately 750 nucleotides) which accumulates in the cytoplasm.


Intravenous Ethanol Administration and Operant Self-Administration Alter Extracellular Norepinephrine Concentration in the Mesocorticolimbic Systems of Male Long Evans Rats.
Norepinephrine has been suggested to regulate ethanol (EtOH)-related behaviors, but little is known about the effects of EtOH on norepinephrine release in mesocortical and mesolimbic brain areas that are targets of EtOH actions. We used in vivo microdialysis to examine the effects of EtOH on extracellular norepinephrine concentrations in mesocorticolimbic brain regions of male Long Evans rats. We determined the effects of intravenous infusion of saline or EtOH in the medial prefrontal cortex (mPFC) and the basal forebrain. We also measured dialysate norepinephrine concentrations during operant self-administration of EtOH in the mPFC. Intravenous infusion (1 or 0.25 ml/min) of 1.0 g/kg EtOH stimulated an increase in dialysate norepinephrine in mPFC and in basal forebrain. In the basal forebrain, an infusion of 0.5 g/kg EtOH did not stimulate dialysate norepinephrine concentrations. In both regions, saline infusions did not increase dialysate norepinephrine concentrations. In the behavioral experiment, 1 week of experience with operant self-administration of sweetened EtOH resulted in an apparent reduction in basal dialysate norepinephrine concentrations in the mPFC relative to the sucrose control. Dialysate norepinephrine increased during the transfer from home cage to the operant chamber in all groups. We conclude that acute EtOH stimulates both the locus coeruleus (which projects to the mPFC) and the nucleus tractus solitarius (which projects to the basal forebrain) noradrenergic neurons. Additionally, limited EtOH self-administration experience alters dialysate norepinephrine in the mPFC in a manner consistent with a decrease in tonic norepinephrine release. Further studies are necessary to elucidate the mechanisms by which EtOH exerts these variable effects.


Adherence to the Mediterranean lifestyle pattern is associated with favorable weight loss outcomes: the MedWeight study.
Individual lifestyle targets have been associated with weight loss outcomes, yet few studies have examined associations of one's total lifestyle with weight loss maintenance. We aimed to examine the relationship between lifestyle patterns and weight loss outcomes in weight loss maintainers and regainers. We hypothesized that higher adherence to a broader healthy lifestyle favors maintenance (over regain). This is a cross-sectional analysis of 470 adults (62% women) with a history of overweight/obesity and significant weight loss 12 months before study entry. Participants were classified as maintainers (current weight ≤90% maximum weight) or regainers. They were asked to fill in a series of questionnaires on demographics and lifestyle habits (dietary intake and eating behaviors through two 24-hour recalls, physical activity, and sleep). A total Mediterranean Lifestyle Index (total-MLI, range 0-13) was generated by summing up ratings in the lifestyle domain quartiles (diet quality, physical activity, and sleep habits) and dietary behaviors (seasonal food and vegetable intake, intake of traditional foods, responsibility for food preparation, conviviality). Maintainers scored higher in the total-MLI than regainers (6.93 ± 2.31 vs 5.78 ± 2.49, P < .001). Adherence to the total-MLI was associated with 28% higher odds for weight loss maintenance (per unit increment) in linear analyses. Being in the highest total-MLI quartile was associated with 5.27 (95% CI, 2.77-10.02) odds for maintenance. Higher adherence to a comprehensive Mediterranean lifestyle pattern was associated with higher odds for weight loss maintenance. Our findings suggest that even modest shifts toward a healthier living may contribute to favorable weight loss outcomes.


Relationships between physical activity, healthy eating and cortical thickness in children and young adults.
Prior neuroimaging studies have shown associations between healthy lifestyle factors and cortical thickness; however, results on the direction of this association have been inconsistent. While the majority of studies were performed in older adults within specific weight status categories, little has been reported in younger populations with a range of adiposity, including groups with healthy-weight, overweight, and obesity. Here we investigated relationships between indices of physical activity (PA) and healthy eating with cortical thickness in children and youth/young adults and examined whether these relationships differed by weight status and age groups. Study participants included 119 youth/young adults and 159 children. We hypothesized that greater levels of PA and/or healthy eating index (HEI) composite scores would be positively associated with cortical thickness, and that this association would differ in overweight or obese groups versus normal weight groups, as well as youth/young adults vs. child cohorts. Overall PA (minutes/day) was assessed using 24-hour PA recalls. HEI was calculated to assess diet quality. A structural MRI was performed, and FreeSurfer 6.0 was used to assess cortical thickness in 68 regions of interest (ROI). Mixed effects modeling was performed to investigate associations of PA or HEI with cortical thickness. FDR corrections were applied for multiple ROIs. PA was positively associated with cortical thickness in the caudal middle frontal cortex (FDR adjusted p = 0.042) and cuneus cortex (FDR adjusted p = 0.017) after controlling for sex, age group, and weight status. When stratified by age, in youth/young adults, higher time spent in PA was associated with greater cortical thickness in the frontal, temporal, parietal and occipital cortex, after adjusting for sex and weight group (FDR adjusted ps < 0.05). No significant associations between PA and cortical thickness were observed in children. No significant associations between PA and cortical thickness were observed when stratified by weight group. No significant associations between HEI and cortical thickness were observed. These results indicate that higher time spent in PA is associated with greater cortical thickness, a relationship that appears to be stronger during youth/young adulthood and may be related to more favorable brain health outcomes.


Does exposure to chronic stress influence blood pressure in rats?
The principal aim of this study was to determine whether prolonged chronic footshock stress can evoke sustained changes in blood pressure in rats and to elucidate possible underlying neurochemical mechanisms as mediated by the sympathoadrenal system. Adult male Wistar rats instrumented for telemetric recording of arterial pressure, heart rate and locomotor activity were subjected to six weeks of inescapable unpredictable electrical footshocks (FS+) or were exposed to shock chambers but were not shocked (FS-). Compared to FS- animals, FS+ animals had significantly reduced body weight gain (by 30%), locomotor activity (by 25%) and social interaction time (by 30%)--symptoms commonly induced by chronic stress and depression in humans. These changes were associated with small, but significant increases in systolic blood pressure (by 7%) and pulse pressure (by 11%) in FS+ rats relative to FS- rats. We have also found neurochemical alterations in sympathoadrenal pathways (that lasted for at least one week post-stress) including about 2-3 fold increases in the levels of tyrosine hydroxylase phosphorylation in the sympathetic ganglia and adrenal gland and a 1.8-fold increase in the expression of the Angiotensin II receptor type 1 protein in the adrenal gland of FS+ rats relative to FS- rats. We conclude that uncontrollable and unpredictable footshock stress can lead to elevation in systolic blood pressure when applied for an extended period of time (six weeks) in Wistar rats, and that these changes could be mediated by stress-induced modifications in sympathoadrenal pathways.


DNA binding of some chiral metallointercalators derived from 9,10-phenanthrenediamine.
A study of the interaction with calf thymus DNA is described of a novel set of chiral ternary complex cations of general form [Ru(N(4)-tet)(phdi)](2+) (where N(4)-tet is the chiral linear tetradentate R(*)R(*)-picchxn or R(*)-picchxnMe(2)). Individual equilibrium binding constants (K(B)) have been determined from spectroscopic titrations employing the hypochromism induced in the visible absorbance of the cations on interaction with the nucleic acid. These demonstrate both stereo- and enantioselectivity in the binding interactions. These K(B) data, together with induced circular dichroism and DNA thermal denaturation results, are all indicative of selective intercalation of the bidentate components of the cations into the nucleobase stack of the duplex. Supportive evidence for a secondary binding mode for the picchxn complexes is provided by the different mutagenicity profiles obtained for related cations.


Retroviral endostatin gene transfer inhibits growth of human lung cancer in a murine orthotopic xenotransplant model.
The administration of endostatin, a potent anti-angiogenic agent, will be required for extended periods of time as a cancer treatment. The aim of the present study was to induce endogenous endostatin secretion in a continuous fashion, based on retroviral gene transfer. The tumor response was evaluated in an orthotopic murine tumor model of human lung cancer. Human non-small-cell lung cancer cells (KNS 62) were retrovirally transduced with the human endostatin gene. An orthotopic murine xenotransplant model was used to investigate tumor growth, metastases and survival. After 4 weeks of subcutaneous growth, endostatin expression was measured by immunoblot analysis in tumor lysates. The growth of the subcutaneous tumors was significantly delayed, and orthotopic tumor growth and pleural metastases were significantly reduced in endostatin-transduced KNS 62 tumors. Prolongation of survival subsequent to orthotopic tumor induction was demonstrated. Strong endostatin expression was found in subcutaneous tumors after 4 weeks. Retroviral transduction of the human endostatin gene is capable of achieving long-term endostatin expression. Endostatin transduction provides significant anti-tumor effects with regard to local tumor growth, metastases and survival.


[Elastic traction for correctly situating rotated teeth in patients with cleft palate].
In 15 patients with cleft palate rubber traction was used on 20 rotated permanent incisors placing the traction bands between clasps made of composites on the teeth and orthodontic devices. The method was suitable for correction of the position of rotated incisors in these children.


Human Somatic Stem Cell Neural Differentiation Potential.
Human somatic stem cells can be identified and isolated from different types of tissues and are grouped here based on their developmental maturation and ability to undergo neural differentiation. The first group will represent afterbirth somatic tissues, which are perinatal stem cells including placental blood and tissue, amniotic fluid and tissue, and umbilical cord blood- and umbilical cord tissue-derived cells. The second group of cells discussed in this chapter is the adult stem cells, generally those in a transient period of development, thus placing them in the special position of transitioning from the perinatal to young somatic tissue, and they include the menstrual blood-, the peripheral blood-, and the bone marrow-derived stem cells.


Human levator veli palatini muscle: a novel source of mesenchymal stromal cells for use in the rehabilitation of patients with congenital craniofacial malformations.
Bone reconstruction in congenital craniofacial differences, which affect about 2-3% of newborns, has long been the focus of intensive research in the field of bone tissue engineering. The possibility of using mesenchymal stromal cells in regenerative medicine protocols has opened a new field of investigation aimed at finding optimal sources of multipotent cells that can be isolated via non-invasive procedures. In this study, we analyzed whether levator veli palatini muscle fragments, which can be readily obtained in non-invasive manner during palatoplasty in cleft palate patients, represent a novel source of MSCs with osteogenic potential. We obtained levator veli palatini muscle fragments (3-5 mm3), during surgical repair of cleft palate in 5 unrelated patients. Mesenchymal stromal cells were isolated from the muscle using a pre-plating technique and other standard practices. The multipotent nature of the isolated stromal cells was demonstrated via flow cytometry analysis and by induction along osteogenic, adipogenic, and chondrogenic differentiation pathways. To demonstrate the osteogenic potential of these cells in vivo, they were used to reconstruct a critical-sized full-thickness calvarial defect model in immunocompetent rats. Flow cytometry analysis showed that the isolated stromal cells were positive for mesenchymal stem cell antigens (CD29, CD44, CD73, CD90, and CD105) and negative for hematopoietic (CD34 and CD45) or endothelial cell markers (CD31). The cells successfully underwent osteogenic, chondrogenic, and adipogenic cell differentiation under appropriate cell culture conditions. Calvarial defects treated with CellCeram™ scaffolds seeded with the isolated levator veli palatini muscle cells showed greater bone healing compared to defects treated with acellular scaffolds. Cells derived from levator veli palatini muscle have phenotypic characteristics similar to other mesenchymal stromal cells, both in vitro and in vivo. Our findings suggest that these cells may have clinical relevance in the surgical rehabilitation of patients with cleft palate and other craniofacial anomalies characterized by significant bone deficit.


Lithium protects dopaminergic cells from rotenone toxicity via autophagy enhancement.
Previous studies have indicated that enhancement of autophagy lysosome pathway may be beneficial for Parkinson's disease (PD), in which aberrant accumulation of aggregated/misfolded proteins and mitochondrial dysfunction are considered as crucial pathogenesis. Recently, a number of studies have suggested the neuroprotective effects of lithium in models of several neurodegenerative diseases including PD. However, the exact mechanisms underlying this neuroprotection remain unclear. In our study, rotenone-exposed SH-SY5Y cells were used as an in vitro parkinsonian model to assess the autophagy-enhancing effect of lithium and the underlying mechanisms were further investigated. Similar to the common used autophagy enhancer rapamycin (Rap, 0.2 μM), lithium (LiCl, 10 mM) significantly recovered the shrinkage of SH-SY5Y cells, and alleviated rotenone-induced cell apoptosis, mitochondrial membrane potential reduction and reactive oxygen species accumulation. Furthermore, the protective effects induced by LiCl were partially blocked by the co-treatment of autophagy inhibitors such as 3-methyladenine (3-MA, 10 mM) or chloroquine (CHL, 10 μM). Moreover, 3-MA or Chl suppressed LiCl-induced autophagy in the immunoblot assay. In addition, the co-localization of LC3 and mitochondria and the preservation of mitochondrial function within LiCl-treated cells were observed, confirming that the damaged mitochondria were cleared through autophagy (mitophagy). These findings suggested that lithium exerted neuroprotection against rotenone-induced injuries partially through the autophagy pathway. Pharmacologically induction of autophagy by lithium may represent a novel therapeutic strategy as a disease-modifier in PD.


Fingerprint visualization enhancement by deposition of columnar thin films and fluorescent dye treatment.
Enhanced visualization of latent fingerprints on two non-porous surfaces, smooth glass slides and highly reflecting rough aluminum sheets, is obtained by depositing columnar thin films (CTFs) of calcium fluoride (CaF2) and silica (SiO2) by physical vapor deposition at large oblique angles. Due to the vapor flux getting shadowed by the physical residues in the fingerprints, the CTFs are deposited only on the upraised ridges, resulting in highly enhancing the visibility of the fingerprint. The visualization of these fingerprints with deposited CTFs is further enhanced by subsequently treating them with a fluorescent dye and fluorescence imaging. A specific amino-acid reagent (1,2-indanedione) and non-specific laser dye (Rhodamine 6G), both allowed enhanced visualization of the CTFs grown on the fingerprints, due to the localization and entrenchment of the dye within the CTF regions.


Effects of aging on the fraction distribution and bioavailability of selenium in three different soils.
Aging refers to the processes by which the mobility and bioavailability of metals in soil decline with time. Although long-term aging is a key process that needs to be considered in risk assessment of metals, few investigations has been attempted to determine whether and how residence time influences the selenium (Se) fractions and bioavailability in soil. In this study, the fractions of Se in soils was evaluated, and bioavailability were assessed by measuring Se concentration in pak choi (Brassica chinensis L.). Results showed that the change of soil available Se in all tested soils divided into two phases: rapid decrease at the initial time (42 d) and slow decline thereafter. The second-order equation could describe the decrease processes of available Se in tested soils during the entire incubation time (R(2) > 0.99), while parabolic diffusion equation had less goodness of fit. Those results indicated that Se aging was controlled not only by diffusion process but also by other processes such as nucleation/precipitation, adsorption/desorption with soil component, occlusion by organic matter and reduction reaction. Soil available Se fractions tended to transform to more stable fractions during aging. The changes of Se concentration in pak choi were consistent with the variation in soil available Se content. In addition, 21 d could be reference for the time of Se aging reaching stabilization in krasnozems and fluvo-aquic soil, and 30 d for black soil. Results could provide theoretical basis to formulate environmental quality criterion and choose the equilibrium time before implementing a pot experiment in Se-spiked soils.


Ictal Asystole Induced by Right Posterior Quadrant Epilepsy: Report of a Radically Treated Case.
Ictal asystole (IA) and ictal bradycardia (IB) are mainly seen with temporal or frontal lobe epilepsy. Many patients with these conditions undergo cardiac pacemaker therapy but not epilepsy surgery. We report the case of a 15-year-old boy with IA and IB secondary to right posterior quadrant epilepsy (PoQE) who underwent right posterior quadrant disconnection, but not cardiac pacemaker implantation. He has remained free from daily epileptic seizures, IA, and IB for more than 6 months postoperatively. This is the first report of a radically treated case with IA and IB caused by PoQE. Both temporofrontal lobe epilepsy and PoQE caused the IA and IB. Because a cardiac pacemaker only addresses arrhythmia, not epileptic seizures, radical treatment for both epilepsy and arrhythmia may be warranted for patients with medically intractable epilepsy.


Dynamic consensus of linear multi-agent system using self-triggered distributed model predictive control.
This article discusses self-triggering algorithm using distributed model predictive control (DMPC) to achieve dynamic consensus in linear multi-agent systems (MASs). The iterative computations and communications required at each time step in traditional consensus algorithms cause escalation of the energy consumption and shorten the life span of the MAS. An attempt to solve this problem is made by proposing a sequential self-triggering consensus algorithm, where each agent computes its own triggering instants. A Laguerre based DMPC design is adopted that notably reduces the computational complexity of conventional DMPC. The proposed self-triggered DMPC algorithm optimizes the control input and triggering interval while guaranteeing the dynamic consensus of the agents. By virtue of the Laguerre function based control architecture, the additional computations owing to the self-triggered algorithm do not impose stress on the controller; yet reduce the load on communication resources. The equality constraint on the terminal state of the agents is utilized along with Lyapunov criteria to establish the closed loop stability of the MAS. The proposed scheme achieves a considerable drop in controller design computations as well as data transmissions among agents, and the same is established by comparing these traits of existing schemes while achieving comparable performance. The proposed algorithm is verified through simulation of platoon configuration of vehicles, each of which is modeled as a linear multi-input multi-output (MIMO) system.


Nonisotopic detection of microRNA using digoxigenin labeled RNA probes.
MicroRNAs (miRNAs) are an important class of endogenously derived, small approximately 22 nucleotide noncoding regulatory RNAs that have recently become implicated in development, cell regulation and cancers of various tissues. Here we report a nonisotopic Northern analysis method for miRNA detection using 3'-digoxigenin (DIG)-labeled RNA oligo probes. Northern blot analysis was performed using miRNA or total RNA fractions extracted from human leukemic cell lines, and blots were hybridized with either 32P- or DIG-labeled RNA probe for miR-181, miR-155 or miR-16. A labeled probe for U6 small nuclear RNA served as an internal control. The use of DIG-labeled RNA probes was equally sensitive compared to 32P-labeled probes in detecting miRNA quantities as low as 50 ng. The ability to use nonisotopic methods and yet obtain sensitive and reliable results offers an advantage to investigators who prefer to avoid isotopes.


Inhibition of bone resorption in vitro by serine-esterase inhibitors.
The effect of two synthetic serine esterase inhibitors, N-alpha-dansyl(p-guanidino)phenylalaninepiperidine hydrochloride (I 2581) and D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (D-Phe-Pro-Arg-CH2Cl), on bone resorption in organ cultured mouse calvaria from neonatal mice has been examined. Mineral mobilization was assessed by analyzing the release of 45Ca, stable calcium (Ca2+) and inorganic phosphate (Pi). Organic matrix degradation was studied by analyzing the release of 3H from [3H]proline-labelled bones, and by quantifying the amounts of hydroxyproline in bone after culture. It was found that I 2581, at and above 30 mumol/l, dose-dependently inhibited 45Ca release induced by thrombin, parathyroid hormone (PTH), prostaglandin E2 and 1-alpha-hydroxyvitamin D-3. I 2581 (50 mumol/l) inhibited PTH-stimulated release of 3H from [3H]proline-labelled bones, and this effect was reversible after withdrawal of I 2581. I 2581 (50 mumol/l) inhibited the release of Ca2+, Pi, beta-glucuronidase and beta-N-acetylglucosaminidase in bones stimulated by PTH and 1-alpha-hydroxyvitamin D-3, without affecting the release of lactate dehydrogenase. In parallel, I 2581 decreased PTH and 1-alpha-hydroxyvitamin D-3 induced reduction of hydroxyproline levels in bones after culture. I 2581 (50 mumol/l) did not affect the basal release of 45Ca, Ca2+, beta-glucuronidase and beta-N-acetylglucosaminidase, nor the basal amounts of hydroxyproline in bones after culture. D-Phe-Pro-Arg-CH2Cl (100 mumol/l) significantly inhibited PTH- and PGE2-induced release of 45Ca without affecting basal release of radioactive calcium. These data indicate that activation of serine proteinase(s) may be a necessary step in the mechanism of action of several stimulators of bone resorption.


Effect of toluene extraction on Biomer surface: I. ESCA, ATR/FTIR, contact angle analysis and biological properties.
Biomer is a poly(ether-urethane-urea) block copolymer widely used as biomedical devices. Extraction process of this polymer has purified its surface of low molecular weight polyurethane chains and Santowhite Powder additive. ESCA and ATR/FTIR have suggested a homogenization of the polymer by enrichment of the first layers with poly(aminomethacrylate) additive after extraction. Therefore, the surface of the extracted Biomer exhibits a different wettability and biological response. The treatment causes a significant decrease in fibronectin adsorption and induces a reduction in Staphylococcus aureus adhesion.


Simultaneous determination of benzodiazepines in whole blood or serum by HPLC/DAD with a semi-micro column.
A simple and sensitive high performance liquid chromatographic (HPLC) method using a semi-micro column, C8 reversed-phase column (3 mm i.d.) and a low flow rate 0.3 ml/min was developed and validated for the determination of five frequently prescribed benzodiazepines: clonazepam, diazepam, flunitrazepam, midazolam and oxazepam. Quantification was performed at 220 nm with methylclonazepam as internal standard. The method involved a simple extraction from alkalinized blood (1 ml) into 1-chlorobutane and provided excellent sensitivity, recovery, accuracy and reproducibility for benzodiazepines in therapeutic or toxic concentrations.


Failure of cerebral hemodynamic selection in general or of specific positron emission tomography methodology?: Carotid Occlusion Surgery Study (COSS).
The Carotid Occlusion Surgery Study (COSS) was an improvement over the Extracranial-Intracranial Bypass Study, which did not utilize physiological selection. To assess possible reasons for early closure of the COSS trial, we reviewed COSS methods used to identify high-risk patients and compared results with separate quantitative data. Increased oxygen extraction fraction (OEF) by positron emission tomography is a gold standard for ischemia, but the specific thresholds and equivalency of the semiquantitative OEF ratio utilized in COSS and quantitative OEF are at issue. The semiquantitative hemispheric OEF ratio used in COSS did not identify the same group of patients as did quantitative OEF using a threshold of 50%. The failure of COSS is likely caused by a failure of the semiquantitative, hemispheric OEF ratio method rather than by the selection for bypass based on hemodynamic compromise.


Viscoelastic analysis of high molecular weight, alkali-denatured DNA from mouse 3T3 cells.
Alkaline lysates of mouse 3T3 cells showed viscoelastic properties characteristic of very large molecules of single-stranded DNA. The viscoelastic retardation time and the sensitivity to low doses of nitrogen mustard and of X-irradiation suggest a molecular weight in excess of 10-10 daltons. Contact-inhibited cells yielded larger single strands than actively growing cells.


Acidic tumor microenvironment-activatable fluorescent diagnostic probe for the rapid identification and resection of human tumors via spraying.
A fluorescent diagnostic probe for real-time intraoperative image-guided tumor resection can significantly improve the efficiency and quality of oncological therapy, but their development is challenging. Herein, a novel fluorescent diagnostic probe called HLTC based on β-carboline was designed and synthesized. HLTC was found to show a ∼10-fold enhancement of fluorescence quantum field with pH from 7.4 to 4.0, indicating its imaging potential in acid environment which is a typical hallmark of the tumor microenvironment (TME). Following fluorescence microscopy imaging showed HLTC could emit specific signals in cancer cells and sections, by both one-photon excitation and two-photon excitation. Importantly, HLTC enabled the precise and rapid delineation of both transplanted tumor and clinical tumor tissues within several minutes of simple topical spray. The tumor-to-background ratio (TBR) was up to 10.2 ± 1.0 at clinical liver cancer tissues and 9.9 ± 0.3 at clinical colon cancer tissues, allowing precise tumor margin identification and the effective guidance of surgical tumor resection. Furthermore, CCK8 assay, pharmacokinetic evaluation, blood analysis and H&E staining were performed, which verified high biocompatibility and biosafety of HLTC at working concentration. These results reveal the exciting potential of this small-molecule fluorescent diagnostic probe for real-time fluorescence-based navigation during surgical tumor resection.


Characterisation of a synthetic diamond detector for end-to-end dosimetry in stereotactic body radiotherapy and radiosurgery.
Synthetic diamond detectors offer real time measurement of dose in radiotherapy applications which require high spatial resolution. Additional considerations and corrections are required for measurements where the diamond detector is orientated at various angles to the incident beam. This study investigated diamond detectors for end-to-end testing of Stereotactic Body Radiotherapy (SBRT) and Stereotactic Radiosurgery (SRS) in the context of dosimetry audits. Seven individual diamond detectors were investigated and compared with respect to warm up stability, dose-rate dependence, linearity, detector shadowing, energy response, cross-calibration, angular dependence and positional sensitivity in SBRT and SRS. Large variation in the cross calibration factors was found between the seven individual detectors. For each detector, the energy dependence in the cross calibration factor was on average <0.6% across the beam qualities investigated (Co-60 Gamma Knife, and MV beams with TPR20,10 0.684-0.733). The angular corrections for individual fields were up to 5%, and varied with field size. However, the average angular dependence for all fields in a typical SRS treatment delivery was <1%. The overall measurement uncertainty was 3.6% and 3.1% (2σ) for an SRS and SBRT treatment plan respectively. Synthetic diamond detectors were found to be reliable and robust for end-to-end dosimetry in SBRT and SRS applications. Orientation of the detector relative to the beam axis is an important consideration, as significant corrections are required for angular dependence.


Experimental testing of reciprocal effects of nutrition and parasitism in wild black capuchin monkeys.
Nutritional stress may predispose individuals to infection, which in turn can have further detrimental effects on physical condition, thus creating an opportunity for reciprocal effects between nutrition and parasitism. Little experimental investigation has been conducted on this "vicious circle" hypothesis in wild animals, especially under natural conditions. We evaluated the reciprocal effects of nutritional status and parasitism using an experimental approach in two groups of wild black capuchin monkeys (Sapajus nigritus). Across two consecutive winters, we collected faecal samples from identified capuchins to determine presence and load of gastrointestinal helminthes, and measured individual body mass as a proxy of physical condition. Food availability was manipulated by provisioning monkeys with bananas, and parasite burdens by applying antiparasitic drugs to selected individuals. We found no effect of antiparasitic drugs on physical condition, but parasite loads decreased in response to high levels of food availability. Our results represent the first experimental evidence that the nutritional status may drive parasite dynamics in a primate.


[Report on the clinical findings, the treatment, and the course of a case of hemangiofibroma of the adnexa (author's transl)].
The case of a hemangiofibroma of the right adnexa with locally infiltrative growth is described. The complete operative removal was not possible. A local recurrence was stopped from progressing by ligation of the most important arteries feeding the tumor. Progressive growth was stopped for two years and the patient wihch was an invalid became ambulatory following the operation.


Balloon compression as treatment for refractory vaginal hemorrhage.
Severe vaginal hemorrhage is a rare presenting condition but serious life threat in the emergency department (ED). Initial management has historically been limited to vaginal packing, fluid resuscitation, and emergency surgical intervention. An alternative approach to therapy is presented that can be effectively deployed in the ED. In the present case, balloon compression of the vaginal mucosa was successful in arresting life-threatening hemorrhage. The patient survived subsequent hemodynamic stabilization and surgical intervention and was ultimately discharged home.


Immunoglobulin expression in diploid and polyploid interspecies hybrid of Xenopus: evidence for allelic exclusion.
The expression of species-specific surface IgM was studied in various Xenopus species hybrids. Whether the hybrids are diploid or polyploid, a lymphocyte does not produce all of the immunoglobulins (Ig) encloded by the Ig genes present in its genome. This suggests that the selection pressure to make a lymphocyte synthesize only one antibody is high and that allelic exclusion already existed in the ancestors of amphibians which appeared 300 million years ago. The apparent lack of cells producing multiple Ig in polyploid hybrids having more than one pair of functional Ig genes suggests that if a stochastic model for allelic exclusion is correct, the frequency of multiple successful rearrangements has to be very low, resulting in a huge waste of lymphocyte precursors. Given the particularity of frog development it is argued that this is not likely to be the case.


Human circulating and tissue-resident memory CD8+ T cells.
Our current knowledge of human memory CD8+ T cells is derived largely from studies of the intravascular space. However, emerging data are starting to challenge some of the dogmas based on this work, suggesting that a conceptual revision may be necessary. In this review, we provide a brief history of the field and summarize the biology of circulating and tissue-resident memory CD8+ T cells, which are ultimately responsible for effective immune surveillance. We also incorporate recent findings into a biologically integrated model of human memory CD8+ T cell differentiation. Finally, we address how future innovative human studies could improve our understanding of anatomically localized CD8+ T cells to inform the development of more effective immunotherapies and vaccines, the need for which has been emphasized by the global struggle to contain severe acute respiratory syndrome coronavirus 2.


The absolute stereochemistry of protoxylogranatin A - a new protolimonoid from the seeds of Chinese mangrove Xylocarpus granatum.
A new protolimonoid, named protoxylogranatin A, has been isolated from the seeds of a Chinese mangrove Xylocarpus granatum. Its structure was elucidated on the basis of modern spectroscopic data. The absolute configuration was determined by the application of the modified Mosher MTPA ester method. The first complete assignments of (1)H and (13)C NMR spectral data for this protolimonoid were achieved by means of 2D NMR techniques, including (1)H-(1)H COSY, HSQC, HMBC and NOESY spectra.


In vivo biochemical indices of nephrotoxicity of platinum analogs tetraplatin, CHIP, and cisplatin in the Fischer 344 rat.
In vivo biochemical indices of nephrotoxicity were investigated in Fischer 344 rats treated with a new platinum analog, tetraplatin [tetrachloro(dl-trans)1,2-diaminocyclohexane platinum(IV), NSC-363812], in comparison with rats receiving equimolar dosages of cisplatin and CHIP [cis-dichloro,trans-dihydroxybis-isopropylamine platinum(IV), NSC-256927]. The goals of this study were to assess the comparative nephrotoxicities and to determine which battery of tests might be useful for the assessment of platinum analog-induced nephrotoxicity in future clinical investigations of these drugs. An iv bolus injection of 6.7, 13.3, 26.7, and 53.3 mumol/kg of each drug in saline was administered and assessment of biochemical parameters was conducted for 15 days postinjection. A combination of urinary enzyme and protein excretion rates along with blood urea nitrogen (BUN) determinations was used to assess the nephrotoxicity of these compounds. At equimolar dosages, tetraplatin appeared to be less nephrotoxic than cisplatin, and CHIP was not nephrotoxic. At all dosages tested, cisplatin increased the rate of urinary excretion of protein, lactate dehydrogenase (LDH), and N-acetylglucosaminidase (NAG) between Days 1 and 5. Tetraplatin did not affect these parameters until the 13.3 mumol/kg dosage. Cisplatin had little effect on the excretion rates of the brush border enzymes alkaline phosphatase and maltase, whereas tetraplatin caused an initial elevation with delayed onset of peak excretion rates at 8 days postinjection. Changes in BUN were not evident until after the 13.3 mumol/kg dosage of cisplatin and the 26.7 mumol/kg dosage of tetraplatin. BUN was useful for ranking the relative toxicities of the three compounds tested, but was not as sensitive in detecting the onset of injury that correlated with early histopathological changes. Tetraplatin appeared to be less nephrotoxic than cisplatin on an equimolar basis and the specific manifestations of its toxicity were different from those observed with cisplatin. Urinary excretion rates for LDH, NAG, and protein proved to be sensitive indicators of platinum analog-induced nephrotoxicity. These indices, combined with BUN determinations and functional assessments, facilitated comparisons of the nephrotoxicity induced by cisplatin and tetraplatin in rats.


Pastoral wildfires in the Mediterranean: understanding their linkages to land cover patterns in managed landscapes.
The pastoral use of fire to regenerate rangelands is a major cause of wildfires in many Mediterranean countries. Despite producing important environmental impacts, this phenomenon has hardly ever been studied separately from other wildfire ignition causes. As extensive livestock breeding relies on the available pasture resources, we hypothesised that a higher rate of pastoral wildfire ignitions could be associated with land cover patterns, as these reflect the spatial arrangement of human activities in managed landscapes. To investigate these patterns, we studied landscape structure and the pastoral wildfires recorded between 1988 and 2000 in 24 Nature Park landscapes in Andalusia (Spain). The CORINE Land Cover map was reclassified according to five levels of grazing use and landscape metrics were calculated. Neural networks were developed to model the relationship between landscape metrics and pastoral wildfires, obtaining a set of significant variables which are discussed in the frame of land and livestock management in the region. We conclude that pastoral wildfire ignitions are more likely in landscapes where the pattern of being dominated by a matrix composed of several large patches of low to moderate grazing use, and having abundant small and elongated patches of higher grazing use, is more extreme. This pattern could be reflecting the persistence of numerous small livestock farms within an increasingly abandoned agrarian landscape. To prevent pastoral wildfires, land management could attempt to enlarge and merge those small patches of higher grazing use, reducing the amount of interface and their intermixture with the surrounding poorer pasture resources.


'The principles of a future pharmacology': Johann Christian Reil (1759-1813) and his role in the development of clinical pharmacology.
Johann Christian Reil was an eighteenth-century German physician and clinical academic with wide interests. These included building the scientific foundations of modern medical practice. In 1799, he published a work specifically calling for a scientific approach to pharmacology in medical practice. In this paper, I aim to present the key parts of that work for the first time in English translation. Reil's 1799 work was translated into English and evaluated against current standards of practice in clinical pharmacology to highlight his 'modern' approach to our subject. Reil defines pharmacology and presents a series of eight rules or principles that should be followed by those wishing to evaluate drugs in humans. These rules highlight the need for scientific rigour, including the use of multiple controlled experiments, and call for the introduction of a specialized vocabulary to facilitate the exchange of ideas between pharmacological researchers. Although rarely mentioned in the pharmacological literature today, Reil's work in the late eighteenth century is an important precursor of our modern approach to the evaluation and testing of drugs in clinical practice. This English translation of the key sections of his work may now allow others to properly evaluate his contribution.


The omniscient placenta: Metabolic and epigenetic regulation of fetal programming.
Fetal development could be considered a sensitive period wherein exogenous insults and changes to the maternal milieu can have long-term impacts on developmental programming. The placenta provides the fetus with protection and necessary nutrients for growth, and responds to maternal cues and changes in nutrient signaling through multiple epigenetic mechanisms. The X-linked enzyme O-linked-N-acetylglucosamine transferase (OGT) acts as a nutrient sensor that modifies numerous proteins to alter various cellular signals, including major epigenetic processes. This review describes epigenetic alterations in the placenta in response to insults during pregnancy, the potential links of OGT as a nutrient sensor to placental epigenetics, and the implications of placental epigenetics in long-term neurodevelopmental programming. We describe the role of placental OGT in the sex-specific programming of hypothalamic-pituitary-adrenal (HPA) axis programming deficits by early prenatal stress as an example of how placental signaling can have long-term effects on neurodevelopment.


Modelling Duchenne muscular dystrophy in vitro with newly generated, blood cell-derived induced pluripotent stem cell line ORIONi003-A.
Here, we present newly derived in vitro model for modeling Duchenne muscular dystrophy. Our new cell line was derived by reprogramming of peripheral blood mononuclear cells (isolated from blood from pediatric patient) with Sendai virus encoding Yamanaka factors. Derived iPS cells are capable to differentiate in vitro into three germ layers as verified by immunocytochemistry. When differentiated in special medium, our iPSc formed spontaneously beating cardiomyocytes. As cardiomyopathy is the main clinical complication in patients with Duchenne muscular dystrophy, the cell line bearing the dystrophin gene mutation might be of interest to the research community.


PP2Acα positively regulates the termination of liver regeneration in mice through the AKT/GSK3β/Cyclin D1 pathway.
Liver injury triggers a highly organized and ordered liver regeneration (LR) process. Once regeneration is complete, a stop signal ensures that the regenerated liver is an appropriate functional size. The inhibitors and stop signals that regulate LR are unknown, and only limited information is available about these mechanisms. A 70% partial hepatectomy (PH) was performed in hepatocyte-specific PP2Acα-deleted (PP2Acα(-/-)) and control (PP2Acα(+/+)) mice. LR was estimated by liver weight, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and cell proliferation, and the related cellular signals were analyzed. We found that the catalytic subunit of PP2A was markedly upregulated during the late stage of LR. PP2Acα(-/-) mice showed prolonged LR termination, an increased liver size compared to the original mass and lower levels of serum ALT and AST compared with control mice. In these mice, cyclin D1 protein levels, but not mRNA levels, were increased. Mechanistically, AKT activated by the loss of PP2Acα inhibited glycogen synthase kinase 3β (GSK3β) activity, which led to the accumulation of cyclin D1 protein and accelerated hepatocyte proliferation at the termination stage. Treatment with the PI3K inhibitor wortmannin at the termination stage was sufficient to inhibit cyclin D1 accumulation and hepatocyte proliferation. PP2Acα plays an essential role in the proper termination of LR via the AKT/GSK3β/Cyclin D1 pathway. Our findings enrich the understanding of the molecular mechanism that controls the termination of LR and provides a potential therapeutic target for treating liver injury.


Loss of heterozygosity on chromosome 13q: suggestion of a candidate tumor suppressor gene in sporadic breast cancer.
In order to corroborate the assumption that a candidate tumor suppressor gene is located on chromosome 13q21-22 between D13S1313 and D13S162, we examined loss of heterozygosity of six microsatellite markers in this region in 98 sporadic breast tumors. Our data demonstrate that loss of heterozygosity at 13q21-22 is not solely caused by genetic changes in BRCA2, but is also attributable to another gene in this region. There is strong indication of a new tumor suppressor gene located between D13S1313 and D13S162, most probably adjacent to D13S1308, which could play a role in sporadic breast cancer.


VarGenius-HZD Allows Accurate Detection of Rare Homozygous or Hemizygous Deletions in Targeted Sequencing Leveraging Breadth of Coverage.
Homozygous deletions (HDs) may be the cause of rare diseases and cancer, and their discovery in targeted sequencing is a challenging task. Different tools have been developed to disentangle HD discovery but a sensitive caller is still lacking. We present VarGenius-HZD, a sensitive and scalable algorithm that leverages breadth-of-coverage for the detection of rare homozygous and hemizygous single-exon deletions (HDs). To assess its effectiveness, we detected both real and synthetic rare HDs in fifty exomes from the 1000 Genomes Project obtaining higher sensitivity in comparison with state-of-the-art algorithms that each missed at least one event. We then applied our tool on targeted sequencing data from patients with Inherited Retinal Dystrophies and solved five cases that still lacked a genetic diagnosis. We provide VarGenius-HZD either stand-alone or integrated within our recently developed software, enabling the automated selection of samples using the internal database. Hence, it could be extremely useful for both diagnostic and research purposes.


Theoretical study of switching characteristics of molecular tweezers based on bis(Zn-salphen).
A series of novel tweezers based on bis(Zn-salphen) complex is theoretically studied. Density functional theory (DFT) method is used to investigate the switchable properties of terpy/bis(Zn-salphen) complex (1, terpy=2,2':6',2″-terpyridine) and Br-phtpy/bis(Zn-salphen) complex (2, Br-phtpy=4'-bromophenyl-2,2':6',2″-terpyridine). In this study, the free tweezers 1 and 2 can be converted from a "W" open form to a "U" closed form upon Ru(III) coordination. The switching performances were characterized by 1H NMR and absorption spectra. DFT calculations were carried out using a B3LYP-D3 functional and def2-SVP basis set for all atoms. 1H NMR spectra showed that terpyridine protons had an obvious upfield shift during complexation with RuCl3. The absorption spectrum was observed in the closed tweezers with a significant red shift and a decreased oscillator strength. In addition, the tweezers were reopened by introducing molecule pyrazine in the "U"-shaped conformation to form a host-guest system. The recognition ability of two Zn-salphen complexes was studied by geometrical optimization and absorption spectra.


Labelling halophilic Archaea using 13C and 15N stable isotopes: a potential tool to investigate haloarchaea consumption by metazoans.
The use of stable isotope (SI) labelling and tracing of live diets is currently considered one of the most comprehensive tools to detect their uptake and assimilation by aquatic organisms. These techniques are indeed widely used in nutritional studies to follow the fate of specific microbial dietary components, unraveling trophic interactions. Nevertheless, to the current date our understanding of aquatic trophic relationships has yet to include a whole domain of life, the Archaea. The aim of the present research was, therefore, to describe a halophilic Archaea (haloarchaea) labelling procedure, using the SI 13C and 15N, to enable the application of SI tracing in future studies of haloarchaea consumption by aquatic metazoans. To this end, three 13C enriched carbon sources and two 15N enriched nitrogen sources were tested as potential labels to enrich cells of three haloarchaea strains when supplemented to the culture medium. Our overall results indicate 13C-glycerol as the most effective carbon source to achieve an efficient 13C enrichment in haloarchaea cells, with Δδ13C values above 5000‰ in all tested haloarchaea strains. As for 15N enriched nitrogen sources, both (15NH4)2SO4 and 15NH4Cl seem to be readily assimilated, also resulting in efficient 15N enrichment in haloarchaea cells, with Δδ15N values higher than 20,000‰. We believe that the proposed methodology will allow for the use of SI labelled haloarchaea biomass in feeding tests, potentially providing unambiguous confirmation of the assimilation of haloarchaea biomass by aquatic metazoans.


Pasteurella multocida CMP-sialic acid synthetase and mutants of Neisseria meningitidis CMP-sialic acid synthetase with improved substrate promiscuity.
Cytidine 5'-monophosphate (CMP)-sialic acid synthetases (CSSs) catalyze the formation of CMP-sialic acid from CTP and sialic acid, a key step for sialyltransferase-catalyzed biosynthesis of sialic acid-containing oligosaccharides and glycoconjugates. More than 50 different sialic acid forms have been identified in nature. To facilitate the enzymatic synthesis of sialosides with diverse naturally occurring sialic acid forms and their non-natural derivatives, CMP-sialic acid synthetases with promiscuous substrate specificity are needed. Herein we report the cloning, characterization, and substrate specificity studies of a new CSS from Pasteurella multocida strain P-1059 (PmCSS) and a CSS from Haemophillus ducreyi (HdCSS). Based on protein sequence alignment and substrate specificity studies of these two CSSs and a Neisseria meningitidis CSS (NmCSS), as well as crystal structure modeling and analysis of NmCSS, NmCSS mutants (NmCSS_S81R and NmCSS_Q163A) with improved substrate promiscuity were generated. The strategy of combining substrate specificity studies of enzymes from different sources and protein crystal structure studies can be a general approach for designing enzyme mutants with improved activity and substrate promiscuity.


Hearing impairment in WBN/Kob rats with spontaneous diabetes mellitus.
The inner ear of spontaneously diabetic WBN/Kob rats was functionally and morphologically examined in order to elucidate the relationship between diabetes mellitus and hearing impairment. At 3 months of age, WBN/Kob rats were non-diabetic, and their hearing function was normal. At 6-7 months of age, they showed decreased glucose tolerance and an increasing tendency toward urinary excretion of glucose without high plasma concentration of glucose, and were therefore judged to be pre-diabetic. They also displayed a significant elevation of hearing threshold in the auditory brainstem response, but showed little morphological and histochemical changes in the inner ear. At 12-13 months of age, they were spontaneously diabetic and showed a more apparent elevation of hearing threshold in auditory brainstem response than that in pre-diabetic animals. In addition, they displayed a marked decrease in the number of spiral ganglion cells and oedematous changes in the stria vascularis. The stria vascularis also showed a decrease in the intensity of staining with some lectins, i.e., wheat germ agglutinin, succinylated wheat germ agglutinin, Soranum tuberosum lectin, and concanavalin A. In conclusion, hearing impairment is induced by diabetes in the WBN/Kob rats first as an elevation of hearing threshold along with glucose intolerance; secondly, as a decrease in the number of spiral ganglion cells; and thirdly, as oedematous change of the stria vascularis with decreased intensity of lectin staining.


Synthesis of a fully protected glycooctaosyl serine isolated from blood group A human ovarian mucin.
N-(9-Fluorenylmethoxycarbonyl)-O-([O-(2-acetamido-3,4,6-tri-O-acet yl-2- deoxy-alpha-D-galactopyranosyl)-(1-->3)-O-[(2,3,4-tri-O-benzyl-alpha-L- fucopyranosyl)-(1-->2)]-O-(4,6-di-O-acetyl-beta-D-galactopyranosyl)- (1-->3)-O-(3,6-di-O-benzyl-2-deoxy-2-phthalimido-beta-D-glucopyranosyl)- (1-->6)]-O-[(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-alpha-D- galactopyranosyl)-(1-->3)-O-[(2,3,4-tri-O-benzyl-alpha-L-fucopyranosyl)- (1-->2)]-O-(4,6-di-O-acetyl-beta-D-galactopyranosyl)-(1-->3)]-2- acetamido-2-deoxy-alpha-D-galactopyranosyl)-(1-->3)-L-serine allyl ester, a protected glycosylserine identified as a blood group A mucin-type determinant, was synthesized for the first time in an efficient and stereocontrolled manner. Ethyl O-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy- alpha-D-galactopyranosyl-(1-->3)-O-[(2,3,4-tri-O-benzyl-alpha-L- fucopyranosyl)-(1-->2)]-O-(4,6-di-O-acetyl-beta-D-galactopyranosyl)- (1-->3)-3,6-di-O-benzyl-2-deoxy-2-phthalimido-1-thio-beta-D-glucopyranos ide and N-(9-fluorenylmethoxycarbonyl)-O-[O-(2-acetamido-3,4,6-tri-O-acety l-2- deoxy-alpha-D-galactopyranosyl)-(1-->3)-O-[(2,3,4-tri-O-benzyl-alpha-L- fucopyranosyl)-(1-->2)]-O-(4,6-di-O-acetyl-beta-D-galactopyranosyl)- (1-->3)-2-acetamido-2-deoxy-alpha-D-galactopyranosyl]-(1-->3)-L-serine allyl ester were the key intermediates for the crucial glycosylation to afford the title compound.


Factors associated with low birth weight at term: a population-based linkage study of the 100 million Brazilian cohort.
Factors associated with low birth weight at term (TLBW), a proxy for intrauterine growth restriction (IUGR), are not well-elucidated in socioeconomically vulnerable populations. This study aimed to identify the factors associated with TLBW in impoverished Brazilian women. Records in the 100 Million Brazilian Cohort database were linked to those in the National System of Information on Live Births (SINASC) to obtain obstetric, maternal, birth and socioeconomic data between 2001 and 2015. Multivariate logistic regression was performed to investigate associations between variables of exposure and TLBW. Of 8,768,930 term live births analyzed, 3.7% presented TLBW. The highest odds of TLBW were associated with female newborns (OR: 1.49; 95% CI: 1.47-1.50), whose mothers were black (OR: 1.20; 95% CI: 1.18-1.22), had a low educational level (OR: 1.57; 95% CI: 1.53-1.62), were aged ≥35 years (OR: 1.44; 95% CI: 1.43-1.46), had a low number of prenatal care visits (OR: 2.48; 95% CI: 2.42-2.54) and were primiparous (OR: 1.62; 95% CI: 1.60-1.64). Lower odds of TLBW were found among infants whose mothers lived in the North, Northeast and Center-West regions of Brazil compared to those in the South. Multiple aspects were associated with TLBW, highlighting the need to comprehensively examine the mechanisms underlying these factors, especially in more vulnerable Brazilian populations, in order to contribute to the elaboration of health policies and promote better conditions of life for poor and extremely poor mothers and children.


In vitro susceptibility of Pityrosporum ovale (Malassezia furfur) to human androgenic steroids.
Cells of Pityrosporum ovale that colonize human pilosebaceous units are constantly exposed to cutaneous androgenic steroids. The aim of our study was to find out whether P. ovale is susceptible to these hormones. Three strains of P. ovale were grown in vitro in the presence of various concentrations of testosterone, dehydroepiandrosterone, androstenedione, androstanedione, 5-alpha-dihydrotestosterone and progesterone (10, 100, and 1000 micrograms/ml; agar dilution assays). In addition, three strains of Candida albicans were also exposed to equal concentrations of the same androgens. As a result, all P. ovale strains were suppressed by 1000 micrograms/ml androstenedione, which was the strongest inhibitor. The other androgenic steroids also significantly reduced P. ovale growth at different concentrations, depending on the hormone used and the strain tested. Progesterone was inhibitory at the highest concentration for one P. ovale strain only. Candida albicans was not affected by any of the androgens. These findings demonstrate an in vitro susceptibility of P. ovale to high concentrations of human androgenic steroids. A relevance of this interaction for the in vivo fungus-host relation is not apparent.


Management of pregnancy in cystic fibrosis.
With recent therapeutic advances in care, people with cystic fibrosis (CF) are living longer and healthier lives. Development of the cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies has led to improved function of the CFTR protein resulting in improved lung function, decreased rates of pulmonary exacerbations and improved nutritional status for the majority of people with CF. Given improved quality and quantity of life, more people with CF are considering becoming pregnant than ever before. Since the first reported pregnancy in a woman with CF in 1960, the management of pregnancy in CF has been of increased interest and is an active field of research. In this review, we aim to discuss the management of pregnancy in CF. We discuss the optimisation of preconception health, management of maintenance CF therapies, and use of CFTR modulators during pregnancy and lactation. We also describe the management of pulmonary exacerbations during pregnancy as well as the unique management of pregnancy in a post-transplant patient with CF. To describe considerations for optimisation of preconception health.To describe the management of chronic CF therapies including CFTR modulators during pregnancy and lactation.To describe treatment of an acute pulmonary exacerbation during pregnancy.To describe the management of pregnancy in individuals with CF following organ transplantation.


[Clinico-statistical considerations on a sample of school-age population in the Province of Trieste. I. Period of eruption of the lst molars and change in permanent incisors].
The phenomenon relating to the period of change of the incisors and eruption of the first permanent molar were studied in a group of 343 Trieste school children. Both deciduous and permanent teeth were examined. The results were processed on a computer and are presented in graph form.


Monogenic mouse models of social dysfunction: implications for autism.
Autism is a pervasive disorder characterized by a complex symptomatology, based principally on social dysfunction. The disorder has a highly complex, largely genetic etiology, involving an impressive variety of genes, the precise contributions of which still remain to be determined. For this reason, a reductionist approach to the study of autism has been proposed, employing monogenic animal models of social dysfunction, either by targeting a candidate gene, or by mimicking a single-gene disorder characterized by autistic symptoms. In the present review, we discuss this monogenic approach by comparing examples of each strategy: the mu opioid receptor knock-out (KO) mouse line, which targets the opioid system (known to be involved in the control of social behaviors); and the Fmr1-KO mouse, a model for Fragile X syndrome (a neurodevelopmental syndrome that includes autistic symptoms). The autistic-relevant behavioral phenotypes of the mu-opioid and Fmr1-KO mouse lines are described here, summarizing previous work by our research group and others, but also providing novel experimental evidence. Relevant factors influencing the validity of the two models, such as sex differences and age at testing, are also addressed, permitting an extensive evaluation of the advantages and limits of monogenic mouse models for autism.


Human papillomavirus. Subclinical and atypical manifestations.
Subclinical HPV infections, together with latent infections, are probably the most likely outcome after exposure to HPV. Subclinical infection is associated with symptoms such as burning, fissuring, and dyspareunia in some patients. Only these patients should be offered treatment. Diagnosing and treating asymptomatic HPV infection cannot be recommended until better knowledge about the infectious potential of the infection in that phase is obtained. Recently, results have been presented showing a median duration of HPV infection of only 8 months, and after 24 months, only 9% of the women studied continued to be infected. This provides the possibility to reassure patients with HPV infection that it is most likely a transient infection, and one should not worry unduly. In light of this knowledge, it seems unwise to diagnose an asymptomatic infection for which no effective treatment is available and for which the natural history and consequences remain unclear; however, if these lesions were found to have the potential to transmit HPV, the patient should be so counseled.


Cobalt Metal-Organic Framework Based on Two Dinuclear Secondary Building Units for Electrocatalytic Oxygen Evolution.
The synthesis of a new microporous metal-organic framework (MOF) based on two secondary building units, with dinuclear cobalt centers, has been developed. The employment of a well-defined cobalt cluster results in an unusual topology of the Co2-MOF, where one of the cobalt centers has three open coordination positions, which has no precedent in MOF materials based on cobalt. Adsorption isotherms have revealed that Co2-MOF is in the range of best CO2 adsorbents among the carbon materials, with very high CO2/CH4 selectivity. On the other hand, dispersion of Co2-MOF in an alcoholic solution of Nafion gives rise to a composite (Co2-MOF@Nafion) with great resistance to hydrolysis in aqueous media and good adherence to graphite electrodes. In fact, it exhibits high electrocatalytic activity and robustness for the oxygen evolution reaction (OER), with a turnover frequency number value superior to those reported for similar electrocatalysts. Overall, this work has provided the basis for the rational design of new cobalt OER catalysts and related materials employing well-defined metal clusters as directing agents of the MOF structure.


Prevalence and risk factors of mixed Mycobacterium tuberculosis complex infections in China.
Mixed infections have been considered as a potential obstacle for tuberculosis treatment and control. To date, few studies have been done to determine the rate of mixed infections of Mycobacterium tuberculosis in China. In this study, we used the standard 24-loci MIRU-VNTR method to genotype the representative M. tuberculosis isolates from the national drug-resistant survey conducted in China. A total of 3248 M. tuberculosis complex (MTBC) strains had complete 24-loci MIRU-VNTR results and available for the analyses. Overall, MIRU-VNTR typing identified 115 (3.5%) isolates as being mixed MTBC infections in China. Statistical analysis revealed that mixed infections were significantly more likely to occur in men than women. Compared with the percentage of mixed infection from patients aged 45-56 years, the percentages of mixed infections were higher among patients aged 25-44 years [OR (95% CI): 1.844(1.129-3.014)] and old patients [older than 65 years OR (95% CI): 1.908(1.097-3.319)]. In addition, significantly higher frequencies of hemoptysis (P = 0.022) and chest pain (P = 0.012) were observed among mixed infections, using patients infected with a single strain as a reference. In conclusion, this study has provided the first comprehensive understanding of mixed MTBC infections in China, which will be essential to generate the effective TB control strategies.


Accumulation of proline in a submerged aquatic halophyte, Ruppia L.
Osmoregulation in the aquatic halophyte Ruppia was examined as part of a wider study of mechanisms of salt tolerance within the genus. The tissue fluids of the three species R. megacarpa Mason, R. polycarpa Mason and R. tuberosa Davis and Tomlinson, were always hypertonic to the surrounding water. The organic solute proline was accumulated, possibly as a mechanism to counteract the effects of high external salinities. Proline content increased with the salinity of the habitat in all three species. In general proline content increased while plant growth was active and declined later in the growing season. If the assumptions that proline is confined to the cytoplasm and that the cytoplasm comprises 10% of the cell volume are made for these submerged aquatic plants, proline is estimated to generate a solute concentration in this compartment equivalent to up to 50% of the total solute concentration of the external habitat.


Naïve to memory T-cell differentiation during homeostasis-driven proliferation.
During homeostasis-driven T-cell proliferation, naïve T cells stably acquire the cell surface markers and functional properties of antigen-induced memory T cells. Thus, in T-cell-deficient individuals, homeostasis-driven T-cell proliferation appears to restore only the memory T-cell compartment, whereas the reconstitution of the naïve T-cell compartment depends on de novo T-cell development in the thymus.


High salt exacerbates programmed hypertension in maternal fructose-fed male offspring.
Consumption of food and drinks containing high fructose (HF), which is associated with hypertension, is increasing steeply. Moreover, increased salt intake significantly increases hypertension risk. We examined whether maternal HF and postnatal high salt (HS) intake had synergistic effects on blood pressure (BP) elevation in adult offspring and determined the underlying mechanisms. Pregnant Sprague-Dawley rats received regular chow or chow supplemented with 60% fructose during the entire pregnancy and lactation periods. Half of the male offspring received 1% NaCl in drinking water from weaning to 3 months of age. Male offspring were assigned to 4 groups (control, HF, HS, and HF + HS) and were sacrificed at 12 weeks of age. Offspring in HF and HS groups developed hypertension, indicating that HF and HS synergistically increased BP. Postnatal HS intake increased Ace expression and decreased Agtr1b and Mas1 expression in the kidneys. Renal mRNA levels of Ace and Agtr1a were significantly higher in HF + HS group than in control group. Renal levels of Na-K-2Cl cotransporter, type 3 sodium hydrogen exchanger, and Na(+)/Cl(-) cotransporter were higher in HS and HF + HS groups than in control group. Postnatal HS intake exacerbated prenatal HF-induced programmed hypertension. HF and HS induced programmed hypertension by differentially inducing renin-angiotensin system and sodium transporters in the kidneys. Better understanding of the effect of the relationship between HF and HS on hypertension development will help prevent hypertension in mothers and children exposed to HF and HS.


p.E66Q mutation in the GLA gene is associated with a high risk of cerebral small-vessel occlusion in elderly Japanese males.
GLA is the causative gene of Fabry disease, an X-linked lysosomal storage disorder resulting from α-galactosidase A (α-GAL) deficiency. Stroke is an important manifestation of Fabry disease, and recent epidemiological studies have indicated that up to 4.9% of young male cryptogenic stroke patients have GLA mutations. To determine the importance of GLA mutations in the general stroke population, the frequency of GLA mutations in Japanese male ischaemic stroke (IS) patients with various risk factors and ages was measured. A total of 475 male IS patients (mean age 69.7 ± 12.5 years), were enrolled in this study. A blood sample was obtained to produce blood spots for measurement of α-GAL activity. Blood samples with decreased enzymatic activity were reassayed and the entire GLA gene was analyzed by direct DNA sequencing if α-Gal A activity was consistently low. α-Gal A activity was decreased in 10 men, five of whom (1.1%) had the GLA gene mutation, p.E66Q. All IS patients with p.E66Q mutation had substantial residual α-Gal A activity, in contrast to patients with classic-type Fabry disease. Clinically, all patients with p.E66Q mutation were > 50 years old and had multiple small-vessel occlusions (lacunar infarctions). Statistical analysis using Fisher's exact test showed the allele frequency of GLA p.E66Q in patients with small-vessel occlusion to be significantly higher than that in the general Japanese population [odds ratio (OR) = 3.34, P = 0.025). GLA p.E66Q mutation is a genetic risk factor for cerebral small-vessel occlusion in elderly Japanese males.


NY-ESO-1 is a ubiquitous immunotherapeutic target antigen for patients with myxoid/round cell liposarcoma.
Myxoid/round cell liposarcoma (MRCL) is the second most common liposarcoma subtype, accounting for >33% of liposarcomas and approximately 10% of all soft tissue sarcomas. Although MRCL is a chemosensitive subtype, patients with metastatic disease have a poor outcome. NY-ESO-1 is a cancer-testis antigen (also known as cancer germ cell antigen) that has been successfully targeted in vaccine trials and in adoptive T-cell therapy trials for the treatment of several solid tumors. The authors investigated the feasibility of targeting NY-ESO-1 in patients with MRCL by evaluating the prevalence of NY-ESO-1 expression in tumors using immunohistochemistry and quantitative reverse transcriptase-polymerase chain reaction analysis. NY-ESO-1-specific tumor recognition by NY-ESO-1-specific T-cells also was analyzed using a chromium release assay. A search of the University of Washington Sarcoma Tissue Bank identified paraffin-embedded tumor samples from 25 patients with MRCL. NY-ESO-1 expression was observed in every MRCL tumor assessed (100%); in 18 tumors (72%), staining was homogenous. In all but 2 tumors, staining was sufficiently robust (2+) that such patients would be eligible for clinical trials of NY-ESO-1-directed therapy. By using NY-ESO-1 specific, CD8-positive T-cells, the in vitro sensitivity of myxoid liposarcoma cell lines to antigen-specific lysis was demonstrated. The current results establish NY-ESO-1 as an important target antigen for the treatment of patients with MRCL.


Conjugated microporous polymers with azide groups: a new strategy for postsynthetic fluoride functionalization and effectively enhanced CO2 adsorption properties.
A series of conjugated microporous polymers (CMPs) have been synthesized based on zinc-porphyrin building blocks. Azide groups incorporated within the pores of the CMPs were subjected to alkyne click conditions via a facile, one-step quantitative procedure, the resultant porous frameworks exhibited enhanced CO2 sorption properties.