Synthesis of Two-Dimensional C-C Bonded Truxene-Based Covalent Organic Frameworks by Irreversible Brønsted Acid-Catalyzed Aldol Cyclotrimerization.
The synthesis of new C-C bonded two-dimensional (2D) covalent organic frameworks (COFs) is highly desirable. Here, a simple but effective synthetic strategy has been developed using an irreversible Brønsted acid-catalyzed aldol cyclotrimerization reaction by virtue of truxene as a linkage. Nonolefin C-C bonded 2D truxene-based covalent organic frameworks (Tru-COFs) were constructed by polymerization of 1,3,5-triindanonebenzene (TDB). The structure formation was confirmed by wide-angle X-ray scattering, Fourier-transform infrared spectroscopy, and solid-state 13C CP/MAS NMR. The results showed that the Tru-COFs were porous (645 m2/g) and chemically stable. Benzyl methylene in conjugated Tru-COFs more effectively produced photoinduced radicals than the model truxene compound. Due to the radical photoresponsiveness, Tru-COFs were efficient catalysts for photocatalytic oxidation of sulfides. We expect that this will provide a new synthetic methodology to obtain C-C bonded functional 2D COFs.


Promoting effect of truncal vagotomy on pancreatic carcinogenesis initiated with N-nitrosobis(2-oxopropyl)amine in Syrian golden hamsters.
The effect of truncal vagotomy (TV) on pancreatic carcinogenesis initiated with N-nitrosobis(2-oxopropyl)amine (BOP) was investigated in 81 female Syrian golden hamsters. The animals were divided into four groups according to the treatment, groups 1 and 2 serving as non-initiated controls receiving a single s.c. injection of 0.9% NaCl followed by either a sham operation or TV respectively, at week 2. Groups 3 and 4 were given a single s.c. injection of 70 mg/kg body wt of BOP before the sham operation or TV. All hamsters were killed at week 24, and the pancreas, liver and gall bladder tissues were examined histologically. While TV itself caused no significant change in pancreatic weight, the incidence of pancreatic carcinomas in hamsters from group 4 was 48.4%, significantly higher than the 16.7% evident in hamsters from group 3 (P less than 0.05). GLC analysis of the bile acid composition of gall bladder bile from hamsters not receiving carcinogen 1 and 4 months after TV revealed significantly decreased secondary bile acids. The results thus indicated that changes in bile acid composition may be involved in enhancement of BOP-initiated pancreatic carcinogenesis in hamsters by TV.


An evaluation of exogenous application of protoporphyrin IX and its dimethyl ester as a photodynamic diagnostic agent in poorly differentiated human nasopharyngeal carcinoma.
5-Aminolevulinic acid and its esterified analogues have been under much investigation to enhance the endogenous production of protoporphyrin IX (PpIX) in tumor cells. However, in this work, we studied the in vitro and in vivo efficacy of exogenously administered PpIX and its esterified analogue, PpIX dimethyl ester (PME), in poorly differentiated human nasopharyngeal carcinoma (NPC/CNE-2) as a photodynamic diagnostic (PDD) agent. NPC/CNE-2 at its earliest time, 1 h after incubation with PME in in vitro studies, has exhibited 64% (P <0.01) higher tumor to normal cell (T/N) fluorescence ratio than with PpIX. In an in vivo mouse xenograft model, comparable photosensitizer concentration in tumor after intravenous administration was observed at 1-3 h time points, but at 9 h, PME had 31% (P=0.05) greater concentration in tumor compared with PpIX. In addition, by constituting PME and PpIX in different topical gel composites, of which, PME gel composition of 8:2 Plasdone and Gantrez resulted in the highest T/N ratio at 6 h after application (34%; P <0.05) in comparison with other gel composites. Evaluation of PME and PpIX constituted in the delivery vehicles investigated showed comparable selectivity for tumor at 1-3 h, thus neither photosensitizer is more efficient than the other for PDD at the early time points; however, beyond 6 h, PME had higher selectivity for tumor compared with PpIX. Thus, further investigation is warranted to improve the drug delivery vehicle for greater tumor selectivity at a shorter incubation time.


Dietary Intakes of Elite 14- to 19-Year-Old English Academy Rugby Players During a Pre-Season Training Period.
Good nutrition is essential for the physical development of adolescent athletes, however data on dietary intakes of adolescent rugby players are lacking. This study quantified and evaluated dietary intake in 87 elite male English academy rugby league (RL) and rugby union (RU) players by age (under 16 (U16) and under 19 (U19) years old) and code (RL and RU). Relationships of intakes with body mass and composition (sum of 8 skinfolds) were also investigated. Using 4-day diet and physical activity diaries, dietary intake was compared with adolescent sports nutrition recommendations and the UK national food guide. Dietary intake did not differ by code, whereas U19s consumed greater energy (3366 ± 658 vs. 2995 ± 774 kcal·day-1), protein (207 ± 49 vs. 150 ± 53 g·day-1) and fluid (4221 ± 1323 vs. 3137 ± 1015 ml·day-1) than U16s. U19s consumed a better quality diet than U16s (greater intakes of fruit and vegetables; 4.4 ± 1.9 vs. 2.8 ± 1.5 servings·day-1; nondairy proteins; 3.9 ± 1.1 vs. 2.9 ± 1.1 servings·day-1) and less fats and sugars (2.0 ± 1. vs. 3.6 ± 2.1 servings·day-1). Protein intake vs. body mass was moderate (r = .46, p < .001), and other relationships were weak. The findings of this study suggest adolescent rugby players consume adequate dietary intakes in relation to current guidelines for energy, macronutrient and fluid intake. Players should improve the quality of their diet by replacing intakes from the fats and sugars food group with healthier choices, while maintaining current energy, and macronutrient intakes.


Risky sexual practice and associated factors among people living with HIV/AIDS receiving antiretroviral therapy in Ethiopia: Systematic review and meta-analysis.
The risky sexual behavior of people living with HIV/AIDS (PLWHA) may impose a risk of transmitting the disease to their partners and increase Human Immunodeficiency Virus (HIV) co-infection. This systematic review and meta-analysis aimed to determine the pooled prevalence of risky sexual behavior and associated factors among PLWHA receiving [Antiretroviral Therapy (ART)] in Ethiopia. To identify both published and unpublished research articles, systematic searches were performed in PubMed, HINARI, Medline, Science Direct, and Google Scholar databases. The review was carried out following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline. Cross-sectional studies reporting the prevalence of risky sexual practice and its associated factors among PLWHA receiving ART in Ethiopia were included. Two authors independently extracted all necessary data using a standardized data extraction format prepared in Microsoft Excel and exported to STATA version 14 statistical software for further analyses. The Cochrane Q test statistics and I2 test were used to assess the heterogeneity of the studies. Since the included studies exhibited considerable heterogeneity, the random-effects meta-analysis model was computed to estimate the pooled prevalence of risky sexual practice which was determined by dividing the total number of PLWHA with risky sexual practice practices by the total number of PLWHA on ART in the study and multiplied by 100. Furthermore, pooled odds ratio (OR) with 95% confidence interval (CI) was determined for the association between determinant factors and risky sexual practice. In this study, 2351 articles were identified from different databases, and fifteen articles were selected for final systematic review and meta-analysis. In Ethiopia, the pooled prevalence of risky sexual practices was 43.56% (95% confidence interval (CI):35.51, 51.62). Discussion about safe sex with sexual partner/s [AOR = 0.26, 95% CI: 0.08, 0.92] and having multiple sexual partners [AOR = 1.90, 95% CI: 0.53, 6.84] were factors significantly associated with risky sexual practice in Ethiopia. A significant proportion of respondents engaged in risky sexual practices. Multiple sexual partners and a lack of discussion about safe sex are linked to a higher prevalence of the risky sexual practice in Ethiopia. It is critical to raise awareness about safe sexual practices during health education and counselling services and to encourage clients to freely discuss safer sex practices with their sexual partner/s at their antiretroviral therapy (ART) appointments as part of their follow-up care. The protocol for this systematic review and meta-analysis was registered at PROSPERO (record ID = CRD42021274600, 25 September 2021).


Plasma membrane ultrastructural differences between the exponential and stationary phases of Saccharomyces cerevisiae as revealed by freeze-etching.
Ultrastructural changes in the plasma membrane of Saccharomyces cerevisiae during the exponential and stationary growth phases were studied by freeze-etching. In the exponential phase, plasma membrane-intercalated particles were distributed randomly. In the stationary phase, several areas of the plasma membrane showed a hexagonal arrangement of particles; these areas appeared to increase with the age of the culture. The polarity of the particles also changed partially: the E-face of the plasma membrane was only sparsely embedded with particles in exponential phase cells, but relatively densely embedded in stationary phase cells. Invaginations of the plasma membrane on the P-face were devoid of particles during both growth phases. Invaginations of the E-face were sparsely embedded with particles in exponential phase cells, but densely embedded with particles in stationary phase cells.


Ocular chlamydiales infections of western barred bandicoots (Perameles bougainville) in Western Australia.
The western barred bandicoot (Perameles bougainville) is an endangered species, free ranging on only two islands off the coast of Western Australia (Dorre and Bernier Islands). Conservation efforts are currently directed at reintroducing these marsupials into predator-proof enclosures and habitats in historical distribution ranges on the mainland in the southwest of Western Australia and in South Australia. In September 2000, 19 western barred bandicoots were captured on Bernier Island for translocation, and 11 of these had evidence of at least one of the following eye conditions: corneal opacity, conjunctivitis, ocular discharge, and blepharitis. Five bandicoots were examined, and conjunctival and cloacal swabs were collected. Polymerase chain reaction for Chlamydiales was positive in four bandicoots. Four Chlamydiales types were identified by gene sequencing, including a strain of Chlamydia pecorum different from strains previously found in koalas and several new Chlamydiales genotypes. The bandicoots responded excellently to treatment with oxytetracyline weekly for 6 wk, and topical oxytetracycline and neomycin were administered topically to both eyes s.i.d. for 4 mo.


The plasma membrane of growing root hairs is composed of zones of local differentiation.
Growing root hairs of cress (Lepidium sativum L.) were investigated using freeze-fracture and electron-microscopic techniques. Three zones of differentiation could be detected: the tip zone, the zone of vacuolation and the foot zone. Corresponding to these zones, the plasmatic fracture face of the plasma membrane showed areas of pronounced differentiation with respect to the distribution and frequency of intramembranous particles (IMPs). The tip zone was characterized by an irregular fracture plane caused by a large number of blisters which were more or less free of IMPs. These blisters coincided in size and shape with Golgi vesicles accumulated in the ground cytoplasm near the very tip. Outside these blisters, IMPs were randomly distributed. The surrounding cell wall was very thin and mainly composed of amorphous material. The plasma membrane of the vacuolation zone often revealed areas of hexagonally ordered particles (HOPS). Such patterns of particles were observed in chemically fixed and unfixed root hairs with a maximum surface density of 1200 HOPS per area. Mostly, however, 15-50 HOPS per area were found. The number of such areas increased with increasing distance from the tip up to five areas per μm(2). Additionally, imprints of large cellulose microfibrils could be detected in unfixed material; they were mainly parallel to the root-hair axis and sometimes ended in areas of HOPS. However, HOPS were observed only in approximately 60% of the root hairs. Otherwise, large areas free of IMPs were interspersed between areas of randomly distributed IMPs. The particle frequency was relatively low and varied greatly in the tip as well as in the vacuolation zone, that is, from 1200 to 2000 IMPs μm(-2). Finally, the plasma membrane of the foot zone showed a very constant number of approx. 2000 IMPs μm(-2). These particles were mainly distinct and randomly distributed. In this zone, HOPS were never observed in spite of the fact that the cell wall was composed of numerous parallel-running cellulose microfibrils. Since membrane material is mainly incorporated in the tip zone where IMPs are statistically distributed, the results indicate that the plasma membrane of the outgrowing part of the root-hair cells is characterized by a high lateral mobility of its components. Furthermore, they indicate that specifically arranged particles are involved in the synthesis of cellulose microfibrils. These areas of HOPS seem to be locally restricted and - or limited with respect to their lifetime.


Mouth Washing Impaired SARS-CoV-2 Detection in Saliva.
A previous study demonstrated the performance of the Salivette® (SARSTEDT, Numbrecht, Germany) as a homogeneous saliva collection system to diagnose COVID-19 by RT-qPCR, notably for symptomatic and asymptomatic patients. However, for convalescent patients, the corroboration of molecular detection of SARS-CoV-2 in paired nasopharyngeal swabs (NPS) and saliva samples was unsatisfactory. The aim of the present work was to assess the concordance level of SARS-CoV-2 detection between paired sampling of NPSs and saliva collected with Salivette® at two time points, with ten days of interval. A total of 319 paired samples from 145 outpatients (OP) and 51 healthcare workers (HW) were collected. Unfortunately, at day ten, 73 individuals were lost to follow-up, explaining some kinetic missing data. Due to significant waiting rates at hospitals, most of the patients ate and/or drank while waiting for their turn. Consequently, mouth washing was systematically proposed prior to saliva collection. None of the HW were diagnosed as SARS-CoV-2 positive using NPS or saliva specimens at both time points (n = 95) by RT-qPCR. The virus was detected in 56.3% (n = 126/224) of the NPS samples from OP, but solely 26.8% (n = 60/224) of the paired saliva specimens. The detection of the internal cellular control, the human RNase P, in more than 98% of the saliva samples, underlined that the low sensitivity of saliva specimens (45.2%) for SARS-CoV-2 detection was not attributed to an improper saliva sample storing or RNA extraction. This work revealed that mouth washing decreased viral load of buccal cavity conducting to impairment of SARS-CoV-2 detection. Viral loads in saliva neo-produced appeared insufficient for molecular detection of SARS-CoV-2. At the time when saliva tests could be a rapid, simple and non-invasive strategy to assess large scale schoolchildren in France, the determination of the performance of saliva collection becomes imperative to standardize procedures.


Adverse drug reactions and safety considerations of NSAIDs: clinical analysis.
NSAIDs are the most frequently used drugs for treatment, in Europe and the United States, accounting for approximately 5% of all prescriptions. Moreover, the use of NSAIDs is increasing because these constitute the first-line drug therapy for a wide range of rheumatic conditions. This increase is in part the result of the increasing population of elderly patients, who constitute the group of patients with greatest demand for these agents. There are many types of NSAIDs that vary in potency, action and potential side effects. Thus various efforts have been made to determine the safety considerations including adverse drug effects, duration of drug therapy, drug interactions, precautions and other drugs applied to reduce side effects. Researchers have introduced some novel techniques to diagnose NSAIDs related adverse effects on the gastrointestinal mucosa. The researchers dealing with the development of drug delivery system for these drugs should aim at designing a therapeutically efficacious dosage form with reduced side/adverse effects. Thus an effort has been made in this review to deal with the safety parameters of various NSAIDs with a special emphasis on preclinical and clinical safety analysis and various attempts to minimize the side effects by structural modification or by drug delivery system.


Effects of dietary forage level and monensin on lactation performance, digestibility and fecal excretion of nutrients, and efficiency of feed nitrogen utilization of Holstein dairy cows.
Two experiments (Exp. 1 and 2) were conducted using a 4 x 4 Latin square design with 2 replications (n = 8) to evaluate effects of feeding Holstein dairy cows a total mixed ration containing 50 or 60% of ration dry matter (DM) from forages with or without supplementation of monensin. In Exp. 1, alfalfa silage (AS) was used as the major forage (55% forage DM), and corn silage (CS; 45% forage DM) was used to make up the rest of the forage portion of diets (55AS:45CS). In Exp. 2, CS was used as the major forage (70% forage DM) and alfalfa hay (AH; 30% forage DM) was used to make up the rest of the forage portion of diets (70CS:30AH). Experimental diets were arranged in a 2 x 2 factorial with 50 or 60% ration DM from forages and monensin supplemented at 0 or 300 mg/cow daily. In Exp. 1 (55AS:45CS), feeding 60% forage diets decreased DM intake (DMI; 27.3 vs. 29.6 kg/d) but maintained the same levels of milk (45.8 vs. 47.0 kg/d) compared with 50% forage diets. The efficiency of converting feed to milk or 3.5% fat-corrected milk was greater for cows fed 60% compared with 50% forage diets (1.7 vs. 1.6 kg milk or 3.5% fat-corrected milk/kg of DMI, respectively). Increasing dietary forage level from 50 to 60% of ration DM increased milk fat percentage (3.4 to 3.5%); however, adding monensin to the 60% forage diet inhibited the increase in milk fat percentage. Feeding 60% forage diets decreased feed cost, but this decrease ($0.5/head per day) in feed cost did not affect income over feed cost. Feeding 60% forage diets decreased fecal excretion of DM (10.6 to 9.6 kg/d) and nitrogen (N; 354 to 324 g/d) and improved apparent digestibility of neutral detergent fiber from 43 to 49% and apparent efficiency of feed N utilization from 32.3 to 35.9% compared with 50% forage diets. In Exp. 2 (70CS:30AH), feeding 60% forage diets decreased DMI from 29.6 to 28.2 kg but maintained the same level of milk (41.1 vs. 40.8 kg/d) and therefore increased the efficiency of converting feed to milk (1.46 vs. 1.38 kg milk/kg DMI) compared with 50% forage diets. Daily feed cost for feeding 60% forage diets was $0.3/head lower than for the 50% forage diets. Fecal excretion of DM (10.3 vs. 11.5 kg/d) was lower and fecal excretion of N (299 vs. 328 g/d) tended to be lower for 60% compared with 50% forage diets. Results from these 2 experiments suggest that a 60% forage diet consisting of either AS or CS as the major forage can be fed to high producing Holstein dairy cows without affecting milk production while improving or maintaining the efficiency of converting feed to milk and the apparent efficiency of utilization of feed N. Cows receiving a 60% forage diet had a similar or improved digestibility of nutrients with a similar or reduced fecal excretion of nutrients. Effects of monensin under the conditions of the current experiments were minimal.


The effects of dual-tasks on intrusive memories following analogue trauma.
Patients with post-traumatic stress disorder frequently and involuntarily experience intrusions, which are strongly linked to the trauma hotspot. Voluntary memory characteristics (i.e., vividness and unpleasantness) of this hotspot can be reduced by performing a dual-task, such as making horizontal eye movements, which is frequently used in Eye Movement Desensitization and Reprocessing. We tested whether such dual-task interventions would also reduce involuntary memory (i.e., intrusions). Moreover, we examined if changes in hotspot vividness and unpleasantness predicted intrusion frequency. Additionally, we examined whether the effects were dependent on dual-task modality. We tested this in three experiments. Participants watched a trauma film and performed one of the interventions 10-min post-film (1) Recall + Eye movements, (2) Recall + Counting, or (3) No-Task Control. Before and after the intervention, participants rated the hotspot vividness and unpleasantness. They recorded intrusive memories about the film in a diary for a week. Unexpectedly, we found that hotspot vividness and unpleasantness ratings were not affected by the intervention. However, the prolonged (experiment 2), but not standard (experiment 1), dual-task interventions resulted in a lower number of intrusions, regardless of modality. However, this effect was not replicated in experiment 3. We discuss potential explanations and present suggestions for future research.


Corticotropin-releasing factor and urocortin differentially modulate rat Purkinje cell dendritic outgrowth and differentiation in vitro.
The precise outgrowth and arborization of dendrites is crucial for their function as integrators of signals relayed from axons and, hence, the functioning of the brain. Proper dendritic differentiation is particularly resonant for Purkinje cells as the intrinsic activity of this cell-type is governed by functionally distinct regions of its dendritic tree. Activity-dependent mechanisms, driven by electrical signaling and trophic factors, account for the most active period of dendritogenesis. An as yet unexplored trophic modulator of Purkinje cell dendritic development is corticotropin-releasing factor (CRF) and family member, urocortin, both of which are localized in climbing fibers. Here, we use rat organotypic cerebellar slice cultures to investigate the roles of CRF and urocortin on Purkinje cell dendritic development. Intermittent exposure (12 h per day for 10 days in vitro) of CRF and urocortin induced significantly more dendritic outgrowth (45% and 70%, respectively) and elongation (25% and 15%, respectively) compared with untreated cells. Conversely, constant exposure to CRF and urocortin significantly inhibited dendritic outgrowth. The trophic effects of CRF and urocortin are mediated by the protein kinase A and mitogen-activating protein kinase pathways. The study shows unequivocally that CRF and urocortin are potent regulators of dendritic development. However, their stimulatory or inhibitory effects are dependent upon the degree of expression of these peptides. Furthermore, the effects of CRF and urocortin on neuronal differentiation and re-modeling may provide a cellular basis for pathologies such as major depression, which show perturbations in the expression of these stress peptides.


A case of hemangiosarcoma in thyroid with severe anemia due to bone marrow metastasis.
A 56-year-old woman presented with rapidly enlarging thyroid mass and deep anemia. There was no history of gastrointestinal bleeding, and endoscopic examinations of the gastrointestinal system were normal. Fine needle aspiration cytology from the thyroid nodule was suspicious. After blood transfusion, total thyroidectomy was performed. Postoperative histopathological examination of the specimen revealed hemangiosarcoma of the thyroid. After establishment of the diagnosis chemotherapy was started. But hemoglobin values decreased again and hepatosplenomegaly developed at the second month of surgery. Bone marrow aspiration cytology which was performed demonstrated the same tumoral cells infiltrating bone marrow. The patient died at 12th week after surgery. Thyroid hemangiosarcoma can metastasize to the bone marrow and anemia may be an indicator of the advanced disease. In the differential diagnosis of the anemia, bone marrow metastasis and bone marrow biopsy should be considered in suspected cases.


Parenting after stroke: a systematic review.
Background Stroke is a leading cause of disability in the United States, resulting in physical, cognitive, and emotional impairments. One in ten strokes occur in adults younger than 50 years of age and the incidence has increased approximately 44% from 2000 to 2010. Young adult survivors have specific needs related to their developmental stage including childcare responsibilities. Despite the high value placed on parenting by society, parenting is currently not assessed at any stage of stroke rehabilitation. Objective To determine the state of the science on parenting after stroke Methods A literature search of multiple electronic databases was conducted from 1964 to February 2018. Select key words were adapted for use in each database. Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines were followed. Results One thousand two hundred and forty-one articles were identified from electronic databases. After deduplication, abstract/title review, and full-text review, ten studies were included. Nine of the studies were qualitative and one was a retrospective cohort study. Survivors in all but one of the qualitative studies reported limitations in parenting tasks after stroke. Changes in social relationships and participation as a parent in other life domains as a result of stroke were also described by survivors. Conclusion Findings from this systematic review of the perspectives of stroke survivors actively parenting suggest that residual stroke impairments lead to both activity limitations and participation restrictions. However, the literature available on parenting after stroke is limited and there is a significant opportunity to advance this area of stroke research.


Runoff prediction using rainfall data from microwave links: Tabor case study.
Rainfall spatio-temporal distribution is of great concern for rainfall-runoff modellers. Standard rainfall observations are, however, often scarce and/or expensive to obtain. Thus, rainfall observations from non-traditional sensors such as commercial microwave links (CMLs) represent a promising alternative. In this paper, rainfall observations from a municipal rain gauge (RG) monitoring network were complemented by CMLs and used as an input to a standard urban drainage model operated by the water utility of the Tabor agglomeration (CZ). Two rainfall datasets were used for runoff predictions: (i) the municipal RG network, i.e. the observation layout used by the water utility, and (ii) CMLs adjusted by the municipal RGs. The performance was evaluated in terms of runoff volumes and hydrograph shapes. The use of CMLs did not lead to distinctively better predictions in terms of runoff volumes; however, CMLs outperformed RGs used alone when reproducing a hydrograph's dynamics (peak discharges, Nash-Sutcliffe coefficient and hydrograph's rising limb timing). This finding is promising for number of urban drainage tasks working with dynamics of the flow. Moreover, CML data can be obtained from a telecommunication operator's data cloud at virtually no cost. That makes their use attractive for cities unable to improve their monitoring infrastructure for economic or organizational reasons.


Physical exercise, mental health problems, and suicide attempts in university students.
Physical inactivity and mental health problems are both major public health concerns worldwide. Although several studies have demonstrated the health benefits of regular physical exercise, few epidemiological studies have investigated the nature of the association between different aspects of physical exercise and mental health, and little is known regarding the possible link to suicidality. To examine the association between frequency, intensity, and duration of physical exercise and mental health problems, and to explore whether low levels of physical activity is related to self-harm and suicide attempts among college and university students. We employed data from the SHoT2018-study, a national health survey for higher education in Norway, in which 50,054 students aged 18-35 years participated. Physical exercise was assessed with three questions (frequency, intensity, and duration). Mental health problems were assessed with both a screening tool assessing psychological distress (Hopkins Symptom Checklist-25; HSCL-25) and self-reported depressive disorder (using a pre-defined list of conditions). Suicide attempts and self-harm were assessed with two items from the Adult Psychiatric Morbidity Survey. Physical exercise was negatively associated with all measures of mental health problems and suicidality in a dose-response manner. The strongest effect-sizes were observed for frequency of physical exercise. Women with low levels of physical activity had a near three-fold increased odds of both scoring high on the HSCL-25, and self-reported depression, compared to women exercising almost every day. Even stronger effect-sizes were observed for men (ORs ranging from 3.5 to 4.8). Also, physical exercise duration and intensity were significantly associated with mental health problems, but with generally smaller ORs. Similarly, graded associations were also observed when examining the link to self-harm and suicide attempts (ORs ranging from 1.9 to 2.5). Given the demonstrated dose-response association between inactivity and both poor mental health, self-harm, and suicidal attempt, there is a need to facilitate college students to become more physically active. This is a shared responsibility that resides both on a political level and on the post-secondary institutions. The cross-sectional nature of the study means that one should be careful to draw firm conclusion about the direction of causality.


The mTOR inhibitor sirolimus suppresses renal, hepatic, and cardiac tissue cellular respiration.
The purpose of this in vitro study was to develop a useful biomarker (e.g., cellular respiration, or mitochondrial O2 consumption) for measuring activities of mTOR inhibitors. It measured the effects of commonly used immunosuppressants (sirolimus - rapamycin, tacrolimus, and cyclosporine) on cellular respiration in target tissues (kidney, liver, and heart) from C57BL/6 mice. The mammalian target of rapamycin (mTOR), a serine/threonine kinase that supports nutrient-dependent cell growth and survival, is known to control energy conversion processes within the mitochondria. Consistently, inhibitors of mTOR (e.g., rapamycin, also known as sirolimus or Rapamune®) have been shown to impair mitochondrial function. Inhibitors of the calcium-dependent serine/threonine phosphatase calcineurin (e.g., tacrolimus and cyclosporine), on the other hand, strictly prevent lymphokine production leading to a reduced T-cell function. Sirolimus (10 μM) inhibited renal (22%, p = 0.002), hepatic (39%, p < 0.001), and cardiac (42%, p = 0.005) cellular respiration. Tacrolimus and cyclosporine had no or minimum effects on cellular respiration in these tissues. Thus, these results clearly demonstrate that impaired cellular respiration (bioenergetics) is a sensitive biomarker of the immunosuppressants that target mTOR.


Clinical pharmacology of beta 3-adrenoceptors.
1. An atypical non beta 1/beta 2-adrenoceptor (AR) subtype (beta 3-AR) has been identified which is selectively stimulated by a group of ligands which mediate lipolytic and thermic responses in brown and white adipose tissue. 2. Molecular studies have shown that beta 3-AR in man are mainly expressed in visceral adipocytes, and to a lesser extent in gall-bladder and colon. In vitro studies with beta 3-AR agonists have shown activity at other sites including skeletal muscle and myocardium. 3. Regulation of beta 3-AR may differ from beta 1/beta 2-AR subtypes in that continuous agonist exposure does not result in receptor down-regulation. 4. A polymorphism of the human beta 3-AR gene (Trp64Arg) has been identified which is associated with obesity, insulin resistance and an earlier onset of non-insulin-dependent diabetes mellitus (NIDDM). Studies are required to establish whether expression of the mutant gene results in altered metabolic responses to beta 3-AR stimulation in man. 5. There is accumulating evidence to support a therapeutic role of beta 3-AR agonists in NIDDM because of anti-obesity and anti-diabetic activity, as a consequence of thermogenic effects as well as increased insulin sensitivity and glucose tolerance. 6. Selectivity studies with BRL35135 and isoprenaline in humans have demonstrated a beta 3-AR mediated component to thermogenesis which is dissociated from beta 1/beta 2-mediated effects on carbohydrate and fat metabolism. Similar studies have suggested a functional beta 3-AR mediating cardiac but not airway responses in humans. An evaluation of beta 3-AR agonists in irritable bowel syndrome may be warranted in view of colonic antimotility properties in vitro.


Deleterious Consequences of UDP-Galactopyranose Mutase Inhibition for Nematodes.
Parasitic nematodes pose a serious threat to agriculture, livestock, and human health. Increasing resistance to antiparasitic agents underscores the need to replenish our anthelmintic arsenal. The nonpathogenic Caenorhabditis elegans, which serves as an effective model of parasitic helminths, has been used to search for new anthelmintic leads. We previously reported small-molecule inhibitors of the essential C. elegans protein UDP-galactopyranose mutase (UGM or Glf). This enzyme is required for the generation of galactofuranose (Galf)-containing glycans and is needed in nematodes for proper cuticle formation. Though our first-generation inhibitors were effective in vitro, they elicited no phenotypic effects. These findings are consistent with the known difficulty of targeting nematodes. C. elegans is recalcitrant to pharmacological modulation; typically, less than 0.02% of small molecules elicit a phenotypic effect, even at 40 μM. We postulated that the lack of activity of the UGM inhibitors was due to their carboxylic acid group, which can be exploited by nematodes for detoxification. We therefore tested whether replacement of the carboxylate with an N-acylsulfonamide surrogate would result in active compounds. UGM inhibitors with the carboxylate mimetic can phenocopy the deleterious consequences of UGM depletion in C. elegans. These findings support the use of UGM inhibitors as anthelmintic agents. They also outline a strategy to render small-molecule carboxylates more effective against nematodes.


Biochanin A partially restores the activity of ofloxacin and ciprofloxacin against topoisomerase IV mutation-associated fluoroquinolone-resistant Ureaplasma species.
This study aims to investigate the synergistic antimicrobial activity of four phytoalexins in combination with fluoroquinolones against Ureaplasma spp., a genus of cell wall-free bacteria that are intrinsically resistant to many available antibiotics, making treatment inherently difficult. A total of 22 958 urogenital tract specimens were assessed for Ureaplasma spp. identification and antimicrobial susceptibility. From these, 31 epidemiologically unrelated strains were randomly selected for antimicrobial susceptibility testing to determine the minimum inhibitory concentration (MIC) of four fluoroquinolones and the corresponding quinolone resistance-determining regions (QRDRs). Synergistic effects between fluoroquinolones and four phytoalexins (reserpine, piperine, carvacrol and biochanin A) were evaluated by fractional inhibitory concentration indices (FICIs). Analysis of the QRDRs suggested a vital role for the mutation of Ser-83→Leu in ParC in fluoroquinolone-resistant strains, and the occurrence of mutations in QRDRs showed significant associations with the breakpoint of levofloxacin. Moreover, diverse synergistic effects of the four phytoalexins with ofloxacin or ciprofloxacin were observed and biochanin A was able to enhance the antimicrobial activity of fluoroquinolones significantly. This is the first report of the antimicrobial activity of biochanin A in combination with fluoroquinolones against a pathogenic mycoplasma, and opens up the possibility of using components of biochanin A as a promising therapeutic option for treating antibiotic-resistant Ureaplasma spp. infections.


The oral core vocabulary of typically developing English-speaking school-aged children: implications for AAC practice.
This study analyzes the core vocabulary used by typically developing school-aged English-speaking children in the United States while participating in a variety of school activities. The language of typically developing children, some of whom spoke English as a second language was recorded, transcribed and analyzed to identify the most frequently used words across samples. An inventory of oral core vocabulary of typically developing school-aged children resulted from this analysis. This inventory can be used as a source list for vocabulary selection for school-aged children with AAC needs. Implications for vocabulary selection are discussed.


Studies of the ethylation of rat liver transfer ribonucleic acid after administration of L-ethionine.
1. The ethylated nucleosides present in tRNA isolated from the livers of rats treated with 0.5g of l-ethionine/kg body wt. were investigated. Evidence that this tRNA contained N(2)-ethylguanine, N(2)N(2)-diethylguanine, N(2)-ethyl-N(2)-methylguanine, 7-ethylguanine, two ethylated pyrimidines and ethylated ribose groups was obtained. 2. Ethylation of bacterial tRNA was catalysed by extracts containing tRNA methylases prepared from rat liver by using S-adenosyl-l-ethionine as an ethyl donor, but the rate of ethylation was 20 times less than the rate of methylation with S-adenosyl-l-methionine as a methyl donor. 3. The principal product of such ethylation in vitro was N(2)-ethylguanine and traces of the other ethylated guanines and pyrimidines found in tRNA isolated from rats treated with ethionine in vivo were also found. 1-Ethyladenine was not formed, although 1-methyl-adenine is a major product of methylation of bacterial tRNA by these extracts, and 1-ethyladenine was not present in the rat liver tRNA isolated from ethionine-treated animals. 4. After injection of actinomycin D (15mg/kg body wt.) or l-methionine (1.0g/kg body wt.) before the ethionine, ethylation of tRNA was diminished by about 80% but not completely abolished. Administration of 1-aminocyclopentanecarboxylic acid (2.5g/kg body wt.) to inhibit the formation of S-adenosyl-l-ethionine inhibited ethylation of tRNA by 44%. 5. These results suggest that not all of the ethylation of tRNA that occurs in the livers of rats treated with ethionine is mediated by the action of tRNA methylases acting with S-adenosyl-l-ethionine as a substrate, but that this pathway does occur and accounts for a major part of the observed ethylation. 6. The results are discussed with reference to ethionine-induced hepatocarcinogenesis.


Note: Multi-pass Thomson scattering measurement on the TST-2 spherical tokamak.
In multi-pass Thomson scattering (TS) scheme, a laser pulse makes multiple round trips through the plasma, and the effective laser energy is enhanced, and we can increase the signal-to-noise ratio as a result. We have developed a coaxial optical cavity in which a laser pulse is confined, and we performed TS measurements using the coaxial cavity in tokamak plasmas for the first time. In the optical cavity, the laser energy attenuation was approximately 30% in each round trip, and we achieved a photon number gain of about 3 compared with that obtained in the first round trip. In addition, the temperature measurement accuracy was improved by accumulating the first three round trip waveforms.


Influence of Cone Beam Computed Tomography Settings on Implant Artifact Production: Zirconia and Titanium.
This in vitro study assessed the artifact production related to titanium and zirconia implants in cone beam computed tomography (CBCT) and compared the effect of different protocol settings on image quality for both materials. A titanium implant and a zirconia implant were placed in a dry mandible. CBCT scans were obtained separately for each implant using the ProMax 3D (Planmeca) unit; 20 protocols were tested with varying kilovoltage (70 to 90 kVp) and resolution (high and low), and with and without a metal artifact reduction tool. Standard deviation and contrast-noise ratio were calculated in regions of interest adjacent and distant to the implant. The zirconia produced more artifacts and its images were more affected by the different protocols than titanium. High kVps and an activated metal artifact reduction tool decreased the standard deviation values related to both implants. Activation of the metal artifact reduction tool also increased contrast-noise ratio values for both implants, whereas increasing kVp improved them only on titanium images. The standard deviation and contrast-noise ratio were not affected by resolution. The zirconia implant generated more image artifacts than the titanium implant. Increasing kVp and the metal artifact reduction tool are efficient in decreasing the CBCT artifacts for both implants, whereas resolution does not affect their production.


An Intervention in Congruence for End-of-Life Treatment Preference: A Randomized Trial.
There is a gap in family knowledge of their adolescents' end-of-life (EOL) treatment preferences. We tested the efficacy of Family Centered Advance Care Planning for Teens with Cancer (FACE-TC) pediatric advance care planning (to increase congruence in EOL treatment preferences. Adolescents with cancer/family dyads were randomized into a clinical trial from July 2016 to April 2019 at a 2:1 ratio: intervention (n = 83); control (n = 43) to either 3 weekly sessions of FACE-TC (Lyon Advance Care Planning Survey; Next Steps: Respecting Choices Interview; Five Wishes, advance directive) or treatment as usual (TAU). Statement of Treatment Preferences measured congruence. Adolescents' (n = 126) mean age was 16.9 years; 57% were female and 79% were White. FACE-TC dyads had greater overall agreement than TAU: high 34% vs 2%, moderate 52% vs 45%, low 14% vs 52%, and P < .0001. Significantly greater odds of congruence were found for FACE-TC dyads than TAU for 3 of 4 disease-specific scenarios: for example, "a long hospitalization with low chance of survival," 78% (57 of 73) vs 45% (19 of 42); odds ratio, 4.31 (95% confidence interval, 1.89-9.82). FACE-TC families were more likely to agree to stop some treatments. Intervention adolescents, 67% (48 of 73), wanted their families to do what is best at the time, whereas fewer TAU adolescents, 43% (18 of 42), gave families this leeway (P = .01). High-quality pediatric advance care planning enabled families to know their adolescents' EOL treatment preferences.


Optoacoustic properties of Doxorubicin - A pilot study.
Doxorubicin (DOX) is a widely used chemotherapeutic anticancer drug. Its intrinsic fluorescence properties enable investigation of tumor response, drug distribution and metabolism. First phantom studies in vitro showed optoacoustic property of DOX. We therefore aimed to further investigate the optoacoustic properties of DOX in biological tissue in order to explore its potential as theranostic agent. We analysed doxorubicin hydrochloride (Dox·HCl) and liposomal encapsulated doxorubicin hydrochloride (Dox·Lipo), two common drugs for anti-cancer treatment in clinical medicine. Optoacoustic measurements revealed a strong signal of both doxorubicin substrates at 488 nm excitation wavelength. Post mortem analysis of intra-tumoral injections of DOX revealed a detectable optoacoustic signal even at three days after the injection. We thereby demonstrate the general feasibility of doxorubicin detection in biological tissue by means of optoacoustic tomography, which could be applied for high resolution imaging at mesoscopic depths dictated by effective penetration of visible light into the biological tissues.


Analysis of Sleep Quality and TCM Constitution Characteristics in 258 Outpatients: A Cross-Sectional Study Based on Outpatient Cases.
To explore the correlation between traditional Chinese medicine (TCM) constitutions and insomnia by studying the distribution characteristics of different TCM constitutions in an outpatient insomnia population. From November 2020 to March 2021, 258 patients in the outpatient department of the Traditional Medicine Department of Tongren Hospital were interviewed using some questionnaires (Athens Insomnia Scale and constitution of traditional Chinese medicine), and correlation analysis was conducted. The participants consisted of 152 (58.91%) insomniacs and 106 (41.09%) noninsomniacs. The top four biased constitutions of the insomniac population (the same patient may have two or more constitutions simultaneously), as determined from the proportions of constitutions in ascending order, are as follows: Qi deficiency constitution, 95 cases (62.50%); Yang deficiency constitution, 85 cases (45.95%); blood stasis, 70 cases (37.84%); and qi stagnation, 65 cases (35.14%). The results of the Spearman correlation analysis showed that the standard scores of qi deficiency, Yang deficiency, blood stasis, and Qi stagnation were positively correlated with the total score of AIS (P < 0.05). Insomnia is correlated and the TCM constitution bias, Qi deficiency, Yang deficiency, blood stasis, and Qi stagnation exhibiting the highest correlation.


Evaluation of neuropsychological domain scores and postural stability following cerebral concussion in sports.
With increasing knowledge and research about concussion, there have been few objective studies that have used neuropsychological domain scores and postural stability to assess concussion. To evaluate the recovery curve of athletes who incur sport-related concussion from repeated serial testing of neuropsychological and posturography testing. A prospective epidemiological model was used for the course of the study. Division I intercollegiate athletics. Athletes participating in football, soccer, basketball, softball, and cheerleading. Neuropsychological scores and posturography measures were obtained preseason and serially at day 1, day 2, day 3, and day 10 postconcussion. Control participants were tested at the same intervals. Neuropsychological scores were converted to standards score and then into domains of attention, learning, speed of information processing, concentration, memory, and verbal fluency. Analysis of covariance with the baseline test as the covariate was used to analyze the data with univariate post hoc tests performed. Significant group differences were found for self reported symptoms (P = 0.001), speed of information processing (P = 0.005), mean stability (P = 0.002), and vestibular function (P = 0.003) between injured and control participants. A group, by day, planned comparison found that speed of information processing and composite balance measures demonstrated significant differences through day 10 postinjury, while symptoms and the vestibular ratio remained significant only through day 3. The concussion recovery curve demonstrated short-term neuropsychological and posturography deficits following injury. A comprehensive approach to concussion management should be used to assess the injury and make return-to-play decisions.


Eating attitudes in an adolescent schoolgirl population.
One thousand five hundred and fourteen Auckland school girls in the age range 13 to 17 were given an eating attitudes test. Fourteen percent of this large population produced a score on that test of greater than 30 which has been claimed to be indicative of potential eating disorder. We view this incidence with alarm and make commentary on the social process of coupling the thin feminine body ideal with success.


The association of physical activity before and after lymphoma diagnosis with survival outcomes.
The impact of physical activity (PA) on lymphoma survival is not known. The association of PA and change in PA with overall (OS), lymphoma-specific (LSS) and event-free (EFS) survival was evaluated in a prospective cohort of newly diagnosed lymphoma patients (2002-2012). We calculated Leisure Score Indexes (mLSI) from the self-reported usual adult PA (baseline) and at 3-years post-diagnosis (FU3), grouping patients by active vs insufficiently active by the American Cancer Society PA guidelines. Associations of PA with survival were assessed using hazard ratios (HRs) and 95% confidence intervals (CI) from Cox models stratified by lymphoma subtype, adjusted for age, sex, baseline BMI, and comorbidity score with change scores further adjusted for baseline PA. Three thousand sixty participants were evaluable at baseline and 1371 at FU3. Active patients had superior survival from baseline [HR (CI): OS 0.82 (0.72-0.94); LSS 0.74 (0.61-0.90); EFS 0.92 (0.82-1.02)] and FU3 [HR (CI): OS 0.64 (0.46-0.88); LSS 0.32 (0.18-0.59); EFS 0.82 (0.61-1.10)] compared to insufficiently active. An increase in mLSI from baseline to FU3 (vs stable mLSI) was associated with superior OS (HR = 0.70, CI 0.49-1.00) and LSS (HR = 0.49, CI 0.26-0.94).The continuous change in mLSI at FU3 was significantly associated with OS, LSS and EFS; maintained across subgroups and appeared linear. Higher PA among lymphoma patients at diagnosis and 3 years is significantly associated with OS, LSS, and EFS. Increasing PA after diagnosis is significantly associated with improved OS and LSS supporting an important role for PA in lymphoma survivorship and the need for intervention trials.


The role of FGF-2/HGF and fibronectin matrix on pleomorphic adenoma myoepithelial cell morphology and immunophenotype: an in vitro study.
Myoepithelial cells play a central role in glandular tumors, regulating the progression of in situ to invasive neoplasias, with the tumor microenvironment being shown to be involved in both initiation and progression. This study aimed to analyze the in vitro effects of fibroblast growth factor-2 (FGF-2) and hepatocyte growth factor (HGF) in myoepithelial cells under the influence of the fibronectin matrix extracellular protein. Benign myoepithelial cells were obtained from pleomorphic adenoma and cultured on a fibronectin substratum. FGF-2 and HGF were supplemented at different concentrations and time intervals, in order to evaluate cell proliferation, morphology and immunophenotype. Individually, FGF-2 and HGF supplementation did not alter myoepithelial cell proliferation, morphology or immunophenotype. The fibronectin substratum provoked an increase in cell proliferation and immunopositivity for α-smooth muscle actin and FGF-2. The myoepithelial cell morphology changed when the fibronectin substratum and FGF-2 acted together, highlighting the importance of the fibronectin extracellular matrix protein on the behavior of these cells.


High-throughput ultra-performance liquid chromatography-mass spectrometry characterization of metabolites guided by a bioinformatics program.
Metabolite profiling in biomarker discovery research requires new data preprocessing approaches to correlate specific metabolites to their biological origin. Mass spectrometry-based metabolomics often results in the observation of hundreds to thousands of features that are differentially regulated in biosamples. Extracting biomedical information from large metabolomic datasets by multivariate data analysis is of considerable complexity. Therefore, more efficient and optimized metabolomics data processing technologies are needed to improve MS applications in biomarker discovery. Here we use a sensitive ultra-performance LC-ESI/quadrupole-TOF high-definition mass spectrometry (UPLC-ESI-Q-TOF-MS) approach, in negative ion mode, to characterize metabolites. XCMS online analysis was used which incorporates novel nonlinear retention time alignment, matched filtration, peak detection, and peak matching. XCMS software can facilitate prioritization of the data and greatly increases the probability of identifying metabolites causally related to the phenotype of interest. 26 urinary differential metabolites contributing to the complete separation of HCC patients from matched healthy controls were identified involving the key metabolic pathways including tyrosine metabolism, glutathione metabolism, phenylalanine metabolism, ascorbate and aldarate metabolism, and arginine and proline metabolism. It demonstrates that high-throughput UPLC-ESI-Q-TOF-MS metabonomics combined with the proposed bioinformatic approach (based on XCMS) are pivotal to elucidate the developing biomarkers and physiological mechanism of disease in a clinical setting.


The relationship between serum CXCL16 level and carotid vulnerable plaque in patients with ischemic stroke.
We investigated the relationship between the serum macrophage chemokine ligand 16 (CXCL16) levels and the vulnerable carotid plaque in patients with ischemic stroke. We successively selected 118 cases of patients with an initial diagnosis of acute ischemic stroke (time of onset < 72 h), recorded risk factors, including gender, age, family history, smoking, body mass index, blood glucose levels, blood lipid levels, average systolic pressure and diastolic blood pressure (DBP) and homocysteine levels. ELISA was used to detect the levels of serum CXCL16. GE-3000 color Doppler ultrasound diagnostic instrument was applied for the detection of the cervical artery (including a bilateral common carotid artery, internal carotid artery and external carotid artery) intima-media thickness (IMT), plaque number, size, nature (stable and vulnerable) and luminal stenosis rate. Delica EMS-9EBx2P type transcranial Doppler ultrasound (TCD) was used to detect micro-arterial micro-embolic signals (MES). Stroke, according to etiologic type, was divided into large artery atherosclerosis (LAA), small artery occlusion (SAA) and others. Serum CXCL16 levels were not significantly correlated with sex, age, family history, smoking, BMI, blood glucose levels, blood lipid levels, mean systolic blood pressure, diastolic blood pressure, and homocysteine levels. Serum CXCL16 levels increased with an increase of IMT, plaque area and lumen stenosis rate. Serum CXCL16 levels of vulnerable plaques were significantly higher than those of stable plaques; differences were statistically significant (p<0.05). It has nothing to do with the number of atherosclerotic plaques. The levels of serum CXCL16 in MES positive group were significantly higher than that in MES negative group; differences were statistically significant (p<0.05). The serum CXCL16 levels of LAA patients were significantly higher than that of SAA and other types of patients; differences were statistically significant (p<0.05). The levels of serum CXCL16 are not related to high-risk factors for acute stroke and closely related to characteristics of atherosclerotic plaque, micro-embolic signals and stroke subtypes.


The identification of novel structural compound classes exhibiting high affinity for neuronal nicotinic acetylcholine receptors and analgesic efficacy in preclinical models of pain.
Neuronal nicotinic acetylcholine receptors represent a new and potentially useful target for the development of novel non-opioid, non-NSAID (nonsteroidal antiinflammatory drug) analgesic agents. A variety of nicotinic acetylcholine receptor agonists such as nicotine, epibatidine and the azetidinyl ether, (R)-5-(2-azetidinylmethoxy-2-chloropyridine (ABT-594) possesses significant efficacy in preclinical models of pain. A preponderance of evidence suggests that nicotinic acetylcholine receptor agonists produce their analgesic effects predominantly via activation of descending inhibitory pain pathways originating in the key brainstem regions of the nucleus raphe magnus, dorsal raphe, and locus coeruleus, and that alpha4-containing nicotinic acetylcholine receptor subunits mediate these effects. Although these studies may provide a pharmacological target for the development of nicotinic acetylcholine receptor analgesics, the rational design of selective ligands based on the protein structure of the binding site is hampered by insufficient structural information. Using an approach based upon homology to known high-affinity ligands for the alpha4beta2 binding site, a four-point model is proposed which defines distance and directionality parameters common to this set of nicotinic acetylcholine receptor ligands.


A neural network with asymmetric basis functions for feature extraction of ECG P waves.
In this work a simple neural network with asymmetric basis functions is proposed as a feature extractor for P waves in electrocardiographic signals (ECG). The neural network is trained using the classical backward-error-propagation algorithm. The performance of the proposed network was tested using actual ECG signals and compared with other types of neural feature extractors.


Association between Sex, CD4 Cell Counts, Antiretroviral Medications, and Olfactory and Gustatory Functions of HIV-Infected Adults.
Objective To investigate the olfactory and gustatory functions of human immunodeficiency virus (HIV)-infected adults in Ibadan, Nigeria. Study Design A cross-sectional study of olfactory and gustatory functions of HIV-infected adults between March 2015 and December 2015. Setting Tertiary health institution. Subjects and Methods A structured questionnaire was administered to participants to obtain relevant sociodemographic and clinical information. Participants' nadir and most recent CD4 cell count and viral loads were obtained from their medical records. Participants' body mass indices were determined, and each subjectively rated their olfactory and gustatory performances. Objective olfactory and gustatory functions were determined using validated "Sniffin' Sticks" and "Taste Strips" impregnated with 4 different concentrations of sucrose, quinine hydrochloride, sodium chloride, and citric acid. Results In total, 135 HIV-infected adults, comprising 41 (30.4%) men and 94 (69.6%) women, were evaluated. Their ages ranged from 20 to 70 years, mean 43.4 ± 10.4 years. Participants were on highly active antiretroviral therapy for a mean duration of 75.8 ± 36.9 months. The proportions of male participants in HIV stages 1, 2, and 3 were 18 (43.9%), 19 (46.3%), and 4 (9.8%), respectively, while female participants were 46 (48.9%), 41 (43.6%), and 7 (7.4%), respectively. Participants' mean olfactory threshold, discrimination, identification, and TDI scores were 8.0 ± 4.9, 9.9 ± 4.7, 8.8 ± 4.5, and 26.7 ± 11.1, respectively, while total taste score was 25.1 ± 5.7. Conclusion HIV-infected adults have tendency to develop hyposmia and hypogeusia. These are worse with advanced stage of HIV infection.


Direct measurement of high-energy phosphate compounds in patients with neuromuscular disease.
Several neuromuscular disorders are associated with reductions in intramuscular adenosine triphosphate (ATP) and/or phosphocreatine (PCr). These alterations have been primarily characterized using (31)P-magnetic resonance spectroscopy ((31)P-MRS). We prospectively measured total creatine, PCr, and ATP in muscle biopsies from 81 patients: normal controls (n = 33), mitochondrial cytopathy (n = 8), neuropathic (n = 3), dystrophy/congenital myopathies (n = 7), inflammatory myopathy (n = 12), and miscellaneous myopathies (n = 18) using direct biochemical analysis. Intramuscular concentrations of PCr and ATP were lower for the dystrophy/congenital myopathy, inflammatory myopathy, and mitochondrial disease patients with ragged red fiber (RRF) as compared with normal controls (P < 0.05). Total creatine was lower for the dystrophy/congenital myopathy group as compared with the normal control group (P < 0.05). These values compare favorably to results from other studies using (31)P-MRS and provide external validation for the values obtained using that method. Given the reductions in high-energy phosphate compounds in these patients, there is the potential for therapeutic intervention with creatine monohydrate supplementation.


A potential bat adenovirus-based oncolytic virus targeting canine cancers.
Although a canine adenovirus (CAdV)-based oncolytic virus (OV) candidate targeting canine tumors has been reported, its oncolytic effect could be attenuated by CAdV vaccine-induced neutralizing antibodies in dog patients. To circumvent this issue, we focused on the bat adenovirus (BtAdV) strain, which was previously isolated from healthy microbats. We previously showed that this virus replicated efficiently in canine cell lines and did not serologically cross-react with CAdVs, suggesting that it may offer the possibility of an OV candidate for canine tumors. Here, we tested the growth properties and cytotoxicity of the BtAdV Mm32 strain in a panel of canine tumor cells and found that its characteristics were equivalent to those of CAdVs. To produce an Mm32 construct with enhanced tumor specificity, we established a novel reverse genetics system for BtAdV based on bacterial artificial chromosomes, and generated a recombinant virus, Mm32-E1Ap + cTERTp, by inserting a tumor-specific canine telomerase reverse transcriptase promoter into its E1A regulatory region. The growth and cytotoxicity of this recombinant were superior to those of wild-type Mm32 in canine tumor cells, unlike in normal canine cells. These data suggest that Mm32-E1Ap + cTERTp could be a promising OV for alternative canine cancer therapies.


[Experience of treatment of an acute hematogenic osteomyelitis in children].
The results of treatment of 215 patients with an acute gematogenic osteomyelitis (AGO) aged from newborn to 15 years were analyzed. The main principles and methods of the AGO treatment, elaborated and introduced in the clinic, were suggested. The osteotomy method with introduction of two drains for the affection focus sanation in the senior age children was proposed. Complications had occurred in 13% of patients, transition into chronic form was noted in 8%.


Invasion of erythrocytes by malaria parasites: a cellular and molecular overview.
Studies on the morphology, cell biology, and immunology of invasion have characterized events that are now being studied at the molecular level. The initial events of invasion are receptor-specific. A determinant associated with Duffy blood group antigens is involved in the invasion of human erythrocytes by P. knowlesi and P. vivax. The Duffy Fya antigen has recently been identified and further characterization of its role in reception and invasion should now be possible. P. falciparum utilizes erythrocyte ligands that differ from those of P. knowlesi and P. vivax. Sialic acid and a trypsin-sensitive erythrocyte membrane component are important for invasion by P. falciparum parasites. There is evidence that at least two ligands are involved in invasion. For P. knowlesi there is a ligand for attachment, common to both Duffy-negative and Duffy-positive human erythrocytes, and a second ligand for invasion, which is found only on Duffy-positive human erythrocytes. P. vivax also appears to utilize two ligands, a Duffy-associated ligand and a ligand specific for reticulocytes. P. falciparum binds to sialic acid-dependent and sialic acid-independent trypsin-sensitive ligands. P. falciparum merozoites require erythrocyte sialic acid to varying degrees in order to invade; this indicates heterogeneity of the receptor mechanism. Monoclonal antibodies and recombinant DNA technology have greatly facilitated the identification, isolation, and characterization of proteins that may be involved in invasion. Molecules that may have invasion-related functions include those whose antibodies block invasion, those that bind to erythrocyte ligands important for invasion, those that appear on the merozoite surface, and those that appear to be inserted into the erythrocyte membrane at the time of invasion. It has not been possible to identify a definite function for any of the molecules identified thus far. No monoclonal or polyclonal monospecific antibody has been identified that reacts specifically over the surface of the apical region of the merozoite where junction formation occurs. Identification of molecules responsible for apical attachment and junction formation will be important for our understanding of invasion. In terms of vaccine development, it is not yet known whether any of the molecules discussed here will prove to be effective immunogens. It is clear from the data obtained with the 140-kd protein of P. knowlesi that antigenic variation poses a potential problem for vaccine development. As the molecular events responsible for invasion become better understood, novel ways may be devised to interfere with the process and prevent the disease.


Mammary carcinoma with osteoclast-like giant cells: a case report.
Mammary carcinoma with osteoclast-like giant cells is rare, and comprises less that 2% of breast carcinoma cases. Herein, we present a case of a 45-year-old woman who underwent breast lumpectomy and sentinel lymph node biopsy for a solitary well defined breast tumor. Histological examination revealed an invasive tumor composed of ducts, small nests and cribriform formations intermixed with a prominent osteoclast like giant cell component. The background stroma is hemorrhagic with conspicuous hemosiderin deposition. The paper will outline the clinico-pathologic characteristic features of this uncommon subtype as well as the current understanding on the pathogenesis of the osteoclast-like giant cells. The invasive carcinoma and the osteoclast-like giant cells staining patterns using immunohistochemical stains for estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, receptor activator of nuclear-kB, RANK ligand, and matrix metalloproteinase 1 are reported.


Delineation of the interaction domains of Agrobacterium tumefaciens VirB7 and VirB9 by use of the yeast two-hybrid assay.
The Agrobacterium tumefaciens VirB proteins are postulated to form a transport pore for the transfer of T-DNA. Formation of the transport pore will involve interactions among the VirB proteins. A powerful genetic method to study protein-protein interaction is the yeast two-hybrid assay. To test whether this method can be used to study interactions among the VirB membrane proteins, we studied the interaction of VirB7 and VirB9 in yeast. We recently demonstrated that VirB7 and VirB9 form a protein complex linked by a disulfide bond between cysteine 24 of VirB7 and cysteine 262 of VirB9 (L. Anderson, A. Hertzel, and A. Das, Proc. Natl. Acad. Sci. USA 93:8889-8894, 1996). We now demonstrate that VirB7 and VirB9 interact in yeast, and this interaction does not require the cysteine residues essential for the disulfide linkage. By using defined segments in fusion constructions, we mapped the VirB7 interaction domain of VirB9 to residues 173 to 275. In tumor formation assays, both virB7C24S and virB9C262S expressed from a multicopy plasmid complemented the respective deletion mutation, indicating that the cysteine residues may not be essential for DNA transfer.


Characterization of multiblock copolymers by chromatographic techniques.
Multiblock copolymers (MBC) composed of blocks of poly(1,4-dioxanone) (PPDO) and poly(e-caprolactone) (PCL) were investigated in order to gain information on the extend of chemical heterogeneity of the samples. A gradient chromatographic method was established allowing separation of purely PPDO- from purely PCL-containing chains. Application of the gradient to MBC made of PPDO- and PCL-diols connected by trimethylhexamethylene diisocyanate (TMDI) resulted in two well separated peaks which were analyzed by means of FTIR, 1H-NMR and pyrolysis GC-MS. It was shown that the first peak was composed to a large extent of PPDO and only lower amounts of PCL were incorporated. Conversely, the second peak consisted predominantly of PCL with only a minor fraction of PPDO. Thus, the MBCs having PPDO and PCL segments show an unexpected broad chemical heterogeneity.


A comparative study of materials assembled from recombinant K31 and K81 and extracted human hair keratins.
Natural biopolymers have found success in tissue engineering and regenerative medicine applications. Their intrinsic biocompatibility and biological activity make them well suited for biomaterials development. Specifically, keratin-based biomaterials have demonstrated utility in regenerative medicine applications including bone regeneration, wound healing, and nerve regeneration. However, studies of structure-function relationships in keratin biomaterials have been hindered by the lack of homogeneous preparations of materials extracted and isolated from natural sources such as wool and hair fibers. Here we present a side-by-side comparison of natural and recombinant human hair keratin proteins K31 and K81. When combined, the recombinant proteins (i.e. rhK31 and rhK81) assemble into characteristic intermediate filament-like fibers. Coatings made from natural and recombinant dimers were compared side-by-side and investigated for coating characteristics and cell adhesion. In comparison to control substrates, the recombinant keratin materials show a higher propensity for inducing involucrin and hence, maturation in terms of potential skin cell differentiation.


On the modelling and testing of a laboratory-scale Foucault pendulum as a precursor for the design of a high-performance measurement instrument.
An integrated study is presented on the dynamic modelling and experimental testing of a mid-length Foucault pendulum with the aim of confirming insights from the literature on the reliable operation of this device and setting markers for future research in which the pendulum may be used for the measurement of relativistic effects due to terrestrial gravity. A tractable nonlinear mathematical model is derived for the dynamics of a practical laboratory Foucault pendulum and its performance with and without parametric excitation, and with coupling to long-axis torsion is investigated numerically for different geographical locations. An experimental pendulum is also tested, with and without parametric excitation, and it is shown that the model closely predicts the general precessional performance of the pendulum, for the case of applied parametric excitation of the length, when responding to the Newtonian rotation of the Earth. Many of the principal inherent performance limitations of Foucault pendulums from the literature have been confirmed and a general prescription for design is evolved, placing the beneficial effect of principal parametric resonance of this inherently nonlinear system in a central mitigating position, along with other assistive means of response moderation such as excitational phase control through electromagnetic pushing, enclosure, and the minimization of seismic and EMC noise. It is also shown, through a supporting analysis and calculation, that although the terrestrial measurement of the Lense-Thirring (LT) precession by means of a Foucault pendulum is certainly still within the realms of possibility, there remains a very challenging increase in resolution capability required, in the order of 2 × 109 to be sure of reliable detection, notwithstanding the removal of extraneous motions and interferences. This study sets the scene for a further investigation in the very near future in which these challenges are to be met, so that a new assault can be made on the terrestrial measurement of LT precession.


Escherichia coli phenylalanyl-tRNA synthetase operon: characterization of mutations isolated on multicopy plasmids.
Plasmid pB1 carries the genes for threonyl-tRNA synthetase, phenylalanyl-tRNA synthetase, and translation initiation factor IF3. Strains carrying this plasmid overproduce phenylalanyl-tRNA synthetase about 100-fold. Spontaneous mutant plasmids were obtained which no longer caused the overproduction of the enzyme. Three classes of mutations were found. (i) Deletion mutations were found, some of which had the interesting property of fusing different genes together, e.g., putting phenylalanyl-tRNA synthetase under the control of the threonyl-tRNA synthetase promoter. (ii) Insertion mutations were found; one insertion in particular was studied. This insertion is located in front of the structural gene for phenylalanyl-tRNA synthetase and is shown to interrupt a cis-acting regulatory region. (iii) Mutations that showed no major change in DNA structure were found. One of these mutations is apparently purely structural, as it produces a small subunit of phenylalanyl-tRNA synthetase with a reduced molecular weight. This protein is less stable than the wild-type enzyme. These mutations represent useful tools to investigate how the phenylalanyl-tRNA synthetase operon is regulated.


Usual Nutrient Intake Distribution and Prevalence of Inadequacy among Australian Children 0-24 Months: Findings from the Australian Feeding Infants and Toddlers Study (OzFITS) 2021.
(1) Background: Breastmilk provides all the nutrition an infant requires between 0−6 months. After that, complementary foods are needed to meet the child's increasing energy and nutrient requirements. Inadequate energy and nutrient intake may lead to growth faltering, impaired neurodevelopment, and increased disease risk. While the importance of early life nutrition is well recognized, there are few investigations assessing the nutritional adequacy of Australian children <24 months. Here, we describe usual energy and nutrient intake distributions, including the prevalence of inadequate intakes and exceeding the upper limit (UL), in a national sample of Australian children 6− 24 months and infants < six months who had commenced solids and/or formula. (2) Methods: Dietary intakes were assessed using a one-day food record for 976 children with a repeat one-day record in a random subset. (3) Results: Based on the Nutrient Reference Values for Australia and New Zealand, children's intakes were above the Adequate Intake or Estimated Average Requirement for most nutrients. Exceptions were iron and zinc where the prevalence of inadequacy was estimated to be 90% and 20%, respectively, for infants aged 6−11.9 months. Low iron intake was also observed in one quarter of toddlers 12−24 months. On average, children consumed 10% more energy than predicted based on Estimated Energy Requirements, and ~10% were classified as overweight based on their weight for length. One third of toddlers exceeded the tolerable upper limit for sodium and consumed > 1000 mg/day. Of the children under six months, 18% and 43% exceeded the UL for vitamin A (retinol) and zinc. (4) Conclusions: Compared to nutrient reference values, diets were sufficient for most nutrients; however, iron was a limiting nutrient for infants aged 6−11.9 months and toddlers 12−24 months potentially putting them at risk for iron deficiency. Excessive sodium intake among toddlers is a concern as this may increase the risk for hypertension.


Role of laparoscopy in the management of adrenal malignancies.
The role of laparoscopic approach for the treatment of malignant adrenal diseases is still controversial. The aim of this study was to verify the results of laparoscopic adrenalectomy (LA) in the management of adrenal malignancies. The medical records of all the patients who underwent laparoscopic procedures for adrenal diseases and in whom malignancy was demonstrated at final histology were reviewed. Nine patients were included (three malignant pheochromocytomas, four adrenocortical carcinomas, and two adrenal metastases). At a mean follow-up of 23.0 months, all but two patients were alive. One patient died for metastatic disease and the other one for unrelated causes. One patient operated on for an adrenocortical carcinoma developed a pelvic recurrence. One patient operated on for a malignant pheochromocytoma developed multiple intra-abdominal recurrences. No other case of recurrence was observed. The results of this study demonstrate that LA can have a role also in case of adrenal malignancies. Conversion to open surgery is mandatory in case of local invasion and when the dissection cannot be as accurate as in conventional operations. A preliminary laparoscopic exploration can be planned in case of suspected malignant lesions to confirm the diagnosis and to evaluate their operability.


Unmyelinated preganglionic fibers in frog ventral roots.
It has been suggested that the preganglionic visceral fibers in the frog are unmyelinated. To obtain further evidence for this suggestion: (1) the percentages of unmyelinated fibers and the myelinated fiber histograms were done for all frog ventral roots, (2) the number of unmyelinated fibers were counted on either side of a chronic section of the seventh ventral root and (3) compound action potentials were obtained for roots 7-10. The results are that slightly more than 80% of the unmyelinated fibers in the seventh ventral root arise in the spinal cord and are presumably unmyelinated preganglionic efferents. Furthermore, a C fiber volley could be followed from the seventh ventral root into caudal parts of the sympathetic chain. Thus this data provides confirmation for the idea that many frog preganglionic fibers are unmyelinated. This study also shows that 24% of the ventral root axons in the frog are unmyelinated and that, on the basis of percentages of unmyelinated fibers and myelinated fiber histograms, there are five categories of frog ventral roots.


Multimodal biomedical imaging with asymmetric single-walled carbon nanotube/iron oxide nanoparticle complexes.
Magnetic iron oxide nanoparticles and near-infrared (NIR) fluorescent single-walled carbon nanotubes (SWNT) form heterostructured complexes that can be utilized as multimodal bioimaging agents. Fe catalyst-grown SWNT were individually dispersed in aqueous solution via encapsulation by oligonucleotides with the sequence d(GT)15, and enriched using a 0.5 T magnetic array. The resulting nanotube complexes show distinct NIR fluorescence, Raman scattering, and visible/NIR absorbance features, corresponding to the various nanotube species. AFM and cryo-TEM images show DNA-encapsulated complexes composed of a approximately 3 nm particle attached to a carbon nanotube on one end. X-ray diffraction (XRD) and superconducting quantum interference device (SQUID) measurements reveal that the nanoparticles are primarily Fe2O3 and superparamagnetic. The Fe2O3 particle-enriched nanotube solution has a magnetic particle content of approximately 35 wt %, a magnetization saturation of approximately 56 emu/g, and a magnetic relaxation time scale ratio (T1/T2) of approximately 12. These complexes have a longer spin-spin relaxation time (T2 approximately 164 ms) than typical ferromagnetic particles due to the smaller size of their magnetic component while still retaining SWNT optical signatures. Macrophage cells that engulf the DNA-wrapped complexes were imaged using magnetic resonance imaging (MRI) and NIR mapping, demonstrating that these multifunctional nanostructures could potentially be useful in multimodal biomedical imaging.


Morbidity and mortality in rheumatoid arthritis patients with prolonged therapy-induced lymphopenia: twelve-year outcomes.
To assess immunologically relevant outcomes in a cohort of rheumatoid arthritis (RA) patients with prolonged therapy-induced lymphopenia. Morbidity (infection or malignancy) and mortality were assessed in 53 RA patients who were treated with the lymphocytotoxic monoclonal antibody alemtuzumab between 1991 and 1994. Data were obtained by interview, medical record review, and Office for National Statistics mortality monitoring. Lymphocyte subsets were enumerated by flow cytometry. A retrospective, matched-cohort study of mortality was performed with 102 control subjects selected from the European League Against Rheumatism database of patients with rheumatic disorders. Lymphopenia persisted in the patients: median CD3+CD4+, CD3+CD8+, CD19+, and CD56+ lymphocyte counts measured at a median followup of 11.8 years from the first administration of alemtuzumab were 0.50 x 10(9)/liter, 0.26 x 10(9)/liter, 0.11 x 10(9)/liter, and 0.09 x 10(9)/liter, respectively. Twenty-seven of 51 cases and 46 of 101 controls with available data had died, yielding a mortality rate ratio of 1.20 (95% confidence interval 0.72-1.98). Causes of death were similar to those that would be expected in a hospital-based RA cohort. No opportunistic infections were noted, and only 3 infections were documented following 36 elective orthopedic procedures. Despite continued lymphopenia 11.8 years after therapy, our patient cohort did not exhibit excess mortality or unusual infection-related morbidity, and surgery was well tolerated. These data should be reassuring for clinicians and patients who are considering lymphocytotoxic or other immunomodulatory therapy for RA.


COVID-19 Exposure Assessment Tool (CEAT): Exposure quantification based on ventilation, infection prevalence, group characteristics, and behavior.
The coronavirus disease 2019 (COVID-19) Exposure Assessment Tool (CEAT) allows users to compare respiratory relative risk to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for various scenarios, providing understanding of how combinations of protective measures affect risk. CEAT incorporates mechanistic, stochastic, and epidemiological factors including the (i) emission rate of virus, (ii) viral aerosol degradation and removal, (iii) duration of activity/exposure, (iv) inhalation rates, (v) ventilation rates (indoors/outdoors), (vi) volume of indoor space, (vii) filtration, (viii) mask use and effectiveness, (ix) distance between people (taking into account both near-field and far-field effects of proximity), (x) group size, (xi) current infection rates by variant, (xii) prevalence of infection and immunity in the community, (xiii) vaccination rates, and (xiv) implementation of COVID-19 testing procedures. CEAT applied to published studies of COVID-19 transmission events demonstrates the model's accuracy. We also show how health and safety professionals at NASA Ames Research Center used CEAT to manage potential risks posed by SARS-CoV-2 exposures.


Vascularised endosteal bone tissue in armoured sauropod dinosaurs.
The presence of well-vascularised, endosteal bone in the medullary region of long bones of nonavian dinosaurs has been invoked as being homologous to medullary bone, a specialised bone tissue formed during ovulation in birds. However, similar bone tissues can result as a pathological response in modern birds and in nonavian dinosaurs, and has also been reported in an immature nonavian dinosaur. Here we report on the occurrence of well-vascularised endosteally formed bone tissue in three skeletal elements of armoured titanosaur sauropods from the Upper Cretaceous of Argentina: i) within the medullary cavity of a metatarsal, ii) inside a pneumatic cavity of a posterior caudal vertebra, iii) in intra-trabecular spaces in an osteoderm. We show that considering the criteria of location, origin (or development), and histology, these endosteally derived tissues in the saltasaurine titanosaurs could be described as either medullary bone or pathological bone. Furthermore, we show that similar endosteally formed well-vascularised bone tissue is fairly widely distributed among nondinosaurian Archosauriformes, and are not restricted to long bones, but can occur in the axial, and dermal skeleton. We propose that independent evidence is required to verify whether vascularised endosteal bone tissues in extinct archosaurs are pathological or reproductive in nature.


Late-onset hypogonadism: current concepts and controversies of pathogenesis, diagnosis and treatment.
Although suppressed serum testosterone (T) is common in ageing men, only a small proportion of them develop the genuine syndrome of low T associated with diffuse sexual (e.g., erectile dysfunction), physical (e.g. loss of vigor and frailty) and psychological (e.g., depression) symptoms. This syndrome carries many names, including male menopause or climacterium, andropause and partial androgen deficiency of the ageing male (PADAM). Late-onset hypogonadism (LOH) describes it best and is therefore generally preferred. The decrease of T in LOH is often marginal, and hypogonadism can be either due to primary testicular failure (low T, high luteinizing hormone (LH)) or secondary to a hypothalamic-pituitary failure (low T, low or inappropriately normal LH). The latter form is more common and it is usually associated with overweight/obesity or chronic diseases (e.g., type 2 diabetes mellitus, the metabolic syndrome, cardiovascular and chronic obstructive pulmonary disease, and frailty). A problem with the diagnosis of LOH is that often the symptoms (in 20%-40% of unselected men) and low circulating T (in 20% of men >70 years of age) do not coincide in the same individual. The European Male Ageing Study (EMAS) has recently defined the strict diagnostic criteria for LOH to include the simultaneous presence of reproducibly low serum T (total T <11 nmol l-1 and free T <220 pmol l-1 ) and three sexual symptoms (erectile dysfunction, and reduced frequency of sexual thoughts and morning erections). By these criteria, only 2% of 40- to 80-year-old men have LOH. In particular obesity, but also impaired general health, are more common causes of low T than chronological age per se. Evidence-based information whether, and how, LOH should be treated is sparse. The most logical approach is lifestyle modification, weight reduction and good treatment of comorbid diseases. T replacement is widely used for the treatment, but evidence-based information about its real benefi ts and short- and long-term risks, is not yet available. In this review, we will summarize the current concepts and controversies in the pathogenesis, diagnosis and treatment of LOH.


Robust multipoint identical-by-descent mapping for affected relative pairs.
The genetic mapping of complex traits has been challenging and has required new statistical methods that are robust to misspecified models. Liang et al. proposed a robust multipoint method that can be used to simultaneously estimate, on the basis of sib-pair linkage data, both the position of a trait locus on a chromosome and its effect on disease status. The advantage of their method is that it does not require specification of an underlying genetic model, so estimation of the position of a trait locus on a specified chromosome and of its standard error is robust to a wide variety of genetic mechanisms. If multiple loci influence the trait, the method models the marginal effect of a locus on a specified chromosome. The main critical assumption is that there is only one trait locus on the chromosome of interest. We extend this method to different types of affected relative pairs (ARPs) by two approaches. One approach is to estimate the position of a trait locus yet allow unconstrained trait-locus effects across different types of ARPs. This robust approach allows for differences in sharing alleles identical-by-descent across different types of ARPs. Some examples for which an unconstrained model would apply are differences due to secular changes in diagnostic methods that can change the frequency of phenocopies among different types of relative pairs, environmental factors that modify the genetic effect, epistasis, and variation in marker-information content. However, this unconstrained model requires a parameter for each type of relative pair. To reduce the number of parameters, we propose a second approach that models the marginal effect of a susceptibility locus. This constrained model is robust for a trait caused by either a single locus or by multiple loci without epistasis. To evaluate the adequacy of the constrained model, we developed a robust score statistic. These methods are applied to a prostate cancer-linkage study, which emphasizes their potential advantages and limitations.


Imaging Acute and Chronic Pain in the Human Brainstem and Spinal Cord.
While acute pain serves as a protective mechanism designed to warn an individual of potential or actual damaging stimuli, chronic pain provides no benefit and is now considered a disease in its own right. Since the advent of human brain imaging techniques, many investigations that have explored the central representation of acute and chronic pain have focused on changes in higher order brain regions. In contrast, far fewer have explored brainstem and spinal cord function, mainly due to significant technical difficulties. In this review, we present some of the recent human brain imaging studies that have specifically explored brainstem and spinal cord function during acute noxious stimuli and in individuals with chronic pain. We focus particularly on investigations that explore changes in areas that receive nociceptor afferents and compare humans and experimental animal data in an attempt to describe both microscopic and macroscopic changes associated with acute and chronic pain.


Use of antiarrhythmic drugs in elderly patients.
Human aging is a global issue with important implications for current and future incidence and prevalence of health conditions and disability. Cardiac arrhythmias, including atrial fibrillation, sudden cardiac death, and bradycardia requiring pacemaker placement, all increase exponentially after the age of 60. It is important to distinguish between the normal, physiological consequences of aging on cardiac electrophysiology and the abnormal, pathological alterations. The age-related cardiac changes include ventricular hypertrophy, senile amyloidosis, cardiac valvular degenerative changes and annular calcification, fibrous infiltration of the conduction system, and loss of natural pacemaker cells and these changes could have a profound effect on the development of arrhythmias. The age-related cardiac electrophysiological changes include up- and down-regulation of specific ion channel expression and intracellular Ca(2+) overload which promote the development of cardiac arrhythmias. As ion channels are the substrates of antiarrhythmic drugs, it follows that the pharmacokinetics and pharmacodynamics of these drugs will also change with age. Aging alters the absorption, distribution, metabolism, and elimination of antiarrhythmic drugs, so liver and kidney function must be monitored to avoid potential adverse drug effects, and antiarrhythmic dosing may need to be adjusted for age. Elderly patients are also more susceptible to the side effects of many antiarrhythmics, including bradycardia, orthostatic hypotension, urinary retention, and falls. Moreover, the choice of antiarrhythmic drugs in the elderly patient is frequently complicated by the presence of co-morbid conditions and by polypharmacy, and the astute physician must pay careful attention to potential drug-drug interactions. Finally, it is important to remember that the use of antiarrhythmic drugs in elderly patients must be individualized and tailored to each patient's physiology, disease processes, and medication regimen.


Vascular endothelial growth factor-induced in vitro angiogenesis and plasminogen activator expression are dependent on endogenous basic fibroblast growth factor.
Induction of in vitro angiogenesis and upregulation of urokinase- and tissue type-plasminogen activator (uPA, tPA) expression are two hallmarks of vascular endothelial growth factor (VEGF) activity on cultured endothelial cells. We report here that neutralizing antibodies to basic fibroblast growth factor (bFGF) inhibit VEGF-induced in vitro angiogenesis in bovine microvascular endothelial (BME) cells. Analysis of VEGF receptor-2 (VEGFR-2) expression revealed no alteration in VEGFR-2 mRNA or total protein in anti-bFGF antibody-treated BME or bovine aortic endothelial (BAE) cells. Ethidium bromide/agarose gel electrophoresis on the cytosolic fraction of BME cells revealed a basal level of fragmented DNA that was increased by anti-bFGF antibodies to an extent not exceeding that observed in parallel cultures incubated with concentrations of transforming growth factor-ss1 that increase VEGF-induced in vitro angiogenesis. In both BME and BAE cells, antibodies to bFGF also decreased basal levels of cell-associated uPA activity, and completely blocked the VEGF-mediated increase in uPA and tPA expression observed in parallel cultures incubated with VEGF alone. In contrast, PA inhibitor-1 expression was strongly upregulated in BME and BAE cells incubated with antibodies to bFGF, either alone or in combination with VEGF. These findings demonstrate that: (1) VEGF-induced in vitro angiogenesis and PA expression are dependent on endogenous bFGF, (2) that this phenomenon is not mediated by a decrease in VEGFR-2 expression and that apoptosis does not necessarily correlate with inhibition of invasion, and (3) that inhibition of endogenous bFGF in VEGF-treated cells results in a net antiproteolytic (and possibly also anti-adherent) effect, which could account in part for the inhibitory effect of the anti-bFGF antibodies. These findings point to a novel and unsuspected role for endogenous bFGF in regulating VEGF-induced in vitro angiogenesis.


Antioxidant properties of dried plum ingredients in raw and precooked pork sausage.
Raw pork sausages with no antioxidant (control), 3% or 6% dried plum puree (DP), 3% or 6% dried plum and apple puree (DPA), or 0.02% butylated hydroxytoluene and butylated hydroxyanisole (BHA/BHT) were (1) stored raw in chubs at 4 degrees C (RR) and evaluated weekly over 28 d, (2) cooked as patties, vacuum packaged, and stored at 4 degrees C (PR) for weekly evaluation over 28 d, or (3) cooked, vacuum packaged, and stored at -20 degrees C (PF) and evaluated monthly over 90 d. DP at 3% or 6% levels was as effective as BHA/BHT for retarding lipid oxidation in PR sausage patties. Likewise, DP at 3% was equally as effective in PF patties, but DP at 6% was even more effective (lower TBARS values) than BHA/BHT for retarding oxidative rancidity. All treatments decreased the fat and increased moisture content of raw sausages but only 6% DP reduced cooking yields. Inclusion of 6% DP decreased internal redness while both 6% DP and DPA increased yellowness of raw sausage. Trained panel sensory evaluations indicated that DP enhanced sweet taste, decreased salt and bitter tastes, and masked cooked pork/brothy, cooked pork fat, spicy/peppery, and sage flavors. In general, warmed-over flavor notes were not affected by storage treatments. Overall, pork sausage with 3% DP or DPA was as acceptable to consumers as the control or those patties with BHA/BHT, but patties with 6% of either plum product were less desirable. Inclusion of 3% DP was effective as a natural antioxidant for suppressing lipid oxidation in precooked pork sausage patties.


History of blood pressure measurement in newborns and infants.
The development of methods for measuring blood pressure (BP) in newborns and small children has a rich history. Methods for BP measuring in adults had to be adapted to this age group. For measuring BP in direct invasive way, a suitable approach had to be found to access the arterial circulation through the umbilical and later radialis artery. Currently, results obtained from direct invasive BP measurement are considered the "gold standard". The development of non-invasive methods for BP measuring in newborns and children began with the use of von Basch's sphygmomanometer (1880). In 1899, Gustav Gärtner constructed the device, which was the basis for the flush method. After the discovery of the palpation and auscultation methods, these methods were also used for BP measurement in newborns and children, however, the BP values obtained in these ways were typically underestimated using excessively wide cuffs. From the auscultation method, methods utilizing ultrasound and infrasound to detect arterial wall movement and blood flow were later developed. The oscillometric method for BP measurement was introduced by E. J. Marey so early as in 1876. In 1912, P. Balard used the oscillometric technique to measure blood pressure in a large group of newborns. Through different types of oscillometers using various methods for detecting vascular oscillations (such as xylol method, impedance and volume plethysmography, etc.), the development has continued to assessment of vascular oscillations by modern sensor technology and software. For continuous non-invasive blood pressure measurement, the volume-clamp method, first described by Jan Peňáz in 1968, was developed. After modification for use in newborns, application of the cuff to the wrist instead of the finger, it is primarily used in clinical physiological studies to evaluate beat-to-beat BP and heart rate pressure variability, such as in the determination of the baroreflex sensitivity.


Principal protocols for the processing of cultured meat.
The purpose of this study was to establish a basic principal procedure for the processing of cultured meat. The first stage involved isolating satellite cells from the desired muscle of an animal using enzymatic digestion (i.e., by using proteases, collagenases, and pronases). The second stage involved culturing the isolated muscle satellite cells in a growth medium containing fetal bovine serum and penicillin/streptomycin with growth factors for an optimal period of time. The second stage involved a basic method for the isolated muscle cells to proliferate while sub-culturing to further induce differentiation in gelatin-coated culture dishes with the general culture medium. The third stage involved the induction of differentiation of muscle satellite cells or formation of myotubes using myogenic medium. Lastly, the fourth stage involved the identification of cell differentiation or myotube formation (myogenesis) using fluorescent dyes. Moreover, the principle of these protocols can be applied to perform primary culture of animal cells. This study will assist beginners with the technical aspects of culturing meat (isolation, cultivation, and differentiation of muscle satellite cells as well as identification of myotube formation for myogenesis).