Onychomycosis in the elderly.
Onychomycosis is found more frequently in the elderly, and in more males than females. Onychomycosis of the toes is usually caused by dermatophytes, most commonly Trichophyton rubrum and T. mentagrophytes. The most common clinical presentations are distal and lateral subungual onychomycosis (which usually affects the great/first toe) and white superficial onychomycosis (which generally involves the third/fourth toes). Only about 50% of all abnormal-appearing nails are due to onychomycosis. In the remainder, trauma to the nail, psoriasis and conditions such as lichen planus should be considered in the differential diagnosis. Therefore, the clinical impression of onychomycosis should be confirmed by mycological examination, whenever possible. The management of onychomycosis may include no therapy, palliative treatment with mechanical or chemical debridement, topical antifungal therapy, oral antifungal agents or a combination of treatment modalities. In the US, the only new oral agents approved for treatment of onychomycosis are terbinafine and itraconazole. Fluconazole is approved for onychomycosis in some other countries. Ciclopirox nail lacquer has recently been approved in the US for the treatment of onychomycosis. In some other countries topical agents such as amorolfine are also used. Griseofulvin and ketoconazole are no longer preferred for the treatment of onychomycosis. The new oral antifungal agents are effective and well tolerated in the elderly. Patient selection should be based on the history (including systems review and medication record), examination and baseline monitoring, if indicated. Laboratory monitoring during therapy for onychomycosis varies among physicians. A combination of removal of the diseased nail plate or local measures and oral antifungal therapy may be optimal in certain instances, e.g. when lateral onychomycosis or dermatophytoma are present. For dermatophyte toe onychomycosis the recommended duration of therapy with terbinafine is 250 mg/day for 12 weeks. For itraconazole (pulse) the regimen is 200 mg twice daily for 1 week on, 3 weeks off, repeated for 3 consecutive pulses and with fluconazole the regimen is 150 to 300 mg once weekly given for a usual range of 6 to 12 months or until the nail plate has grown out. In some instances, if extra therapy is required, one suggestion is that 4 weeks of terbinafine or an extra pulse of itraconazole are given between months 6 and 9 from the start of therapy. Once cure has been achieved, it is important to counsel patients on the strategies of reducing recurrence of disease.


Effects of carnitine and its congeners on eicosanoid discharge from rat cells: implications for release of TNFalpha.
THE acyl carrier coenzyme A (CoA) is involved in fatty acid metabolism. The carnitine/CoA ratio is of particular importance in regulating the transport of long-chain fatty acids into mitochondria for oxidation. Also CoA has a role in the formation and breakdown of products from both the cyclooxygenase and lipoxygenase pathways of the precursor arachidonic acid. In the present study the effect of 4 days feeding of 300 mg/kg/day of L-carnitine, acetyl Lcarnitine and propionyl L-carnitine on the basal and calcium ionophore (A23187) stimulated release of arachidonic acid metabolites from rat carrageenin elicited peritoneal cells was investigated. There were two series of experiments carried out. In the first, the harvested peritoneal cell population consisted of less than 90% macrophages and additional polymorphonuclear (PMN) leucocytes. The basal release of prostaglandin E(2) (PGE(2)), 6-ketoprostaglandin F(1alpha) (6-keto-PGF(1alpha)) and leukotriene B(4) (LTB(4)) was stimulated by all treatments. The A23187 stimulated release of 6-keto-PGF(1alpha) and LTB(4) was increased by all three compounds. The 6-keto-PGF(1alpha):TxB(2) and 6-keto-PGF(1alpha):LTB(4) ratios were increased by carnitine treatment. These results suggested that carnitine could modify the macrophage component of an inflammatory site in vivo. In the second series of experiments the harvested cell population was highly purified (>95% macrophages) and none of the compounds fed to the rats caused a change of either eicosanoid or TNFalpha formation. Moreover the 6-keto-PGF(1alpha):TxB(2) and 6-keto-PGF(1alpha):LTB(4) ratios were not enhanced by any of the compounds tested. It is conceivable that in the first series the increased ratios 6-keto-PGF(1alpha):TxB(2) and 6-keto-PGF(1alpha):LTB(4) reflected the effect of carnitine or its congeners on PMN leucocytes rather than on macrophages.


Intracellular calcium and the relationship to contractility in an avian model of heart failure.
Global contractile heart failure was induced in turkey poults by furazolidone feeding (700 ppm). Abnormal calcium regulation appears to be a key factor in the pathophysiology of heart failure, but the cellular mechanisms contributing to changes in calcium fluxes have not been clearly defined. Isolated ventricular myocytes from non-failing and failing hearts were therefore used to determine whether the whole heart and ventricular muscle contractile dysfunctions were realized at the single cell level. Whole cell current- and voltage-clamp techniques were used to evaluate action potential configurations and L-type calcium currents, respectively. Intracellular calcium transients were evaluated in isolated myocytes with fura-2 and in isolated left ventricular muscles using aequorin. Action potential durations were prolonged in failing myocytes, which correspond to slowed cytosolic calcium clearing. Calcium current-voltage relationships were normal in failing myocytes; preliminary evidence suggests that depressed transient outward potassium currents contribute to prolonged action potential durations. The number of calcium channels (as measured by radioligand binding) were also similar in non-failing and failing hearts. Isolated ventricular muscles from failing hearts had enhanced inotropic responses, in a dose-dependent fashion, to a calcium channel agonist (Bay K 8644). These data suggest that changes in intracellular calcium mobilization kinetics and longer calcium-myofilament interaction may be able to compensate for contractile failure. We conclude that the relationship between calcium current density and sarcoplasmic reticulum calcium release is a dynamic process that may be altered in the setting of heart failure at higher contraction rates.


Comprehensive phylogenomic analyses re-write the evolution of parasitism within cynipoid wasps.
Parasitoidism, a specialized life strategy in which a parasite eventually kills its host, is frequently found within the insect order Hymenoptera (wasps, ants and bees). A parasitoid lifestyle is one of two dominant life strategies within the hymenopteran superfamily Cynipoidea, with the other being an unusual plant-feeding behavior known as galling. Less commonly, cynipoid wasps exhibit inquilinism, a strategy where some species have adapted to usurp other species' galls instead of inducing their own. Using a phylogenomic data set of ultraconserved elements from nearly all lineages of Cynipoidea, we here generate a robust phylogenetic framework and timescale to understand cynipoid systematics and the evolution of these life histories. Our reconstructed evolutionary history for Cynipoidea differs considerably from previous hypotheses. Rooting our analyses with non-cynipoid outgroups, the Paraulacini, a group of inquilines, emerged as sister-group to the rest of Cynipoidea, rendering the gall wasp family Cynipidae paraphyletic. The families Ibaliidae and Liopteridae, long considered archaic and early-branching parasitoid lineages, were found nested well within the Cynipoidea as sister-group to the parasitoid Figitidae. Cynipoidea originated in the early Jurassic around 190 Ma. Either inquilinism or parasitoidism is suggested as the ancestral and dominant strategy throughout the early evolution of cynipoids, depending on whether a simple (three states: parasitoidism, inquilinism and galling) or more complex (seven states: parasitoidism, inquilinism and galling split by host use) model is employed. Our study has significant impact on understanding cynipoid evolution and highlights the importance of adequate outgroup sampling. We discuss the evolutionary timescale of the superfamily in relation to their insect hosts and host plants, and outline how phytophagous galling behavior may have evolved from entomophagous, parasitoid cynipoids. Our study has established the framework for further physiological and comparative genomic work between gall-making, inquiline and parasitoid lineages, which could also have significant implications for the evolution of diverse life histories in other Hymenoptera.


Cilostazol attenuates hepatic stellate cell activation and protects mice against carbon tetrachloride-induced liver fibrosis.
Liver fibrosis is a common pathway leading to cirrhosis. Cilostazol, a clinically available oral phosphodiesterase-3 inhibitor, has been shown to have antifibrotic potential in experimental non-alcoholic fatty liver disease. However, the detailed mechanisms of the antifibrotic effect and its efficacy in a different experimental model remain elusive. Male C57BL/6J mice were assigned to five groups: mice fed a normal diet (groups 1 and 2); 0.1% or 0.3% cilostazol-containing diet (groups 3 and 4, respectively); and 0.125% clopidogrel-containing diet (group 5). Two weeks after feeding, groups 2-5 were intraperitoneally administered carbon tetrachloride (CCl4 ) twice a week for 6 weeks, while group 1 was treated with the vehicle alone. To investigate the effects of cilostazol on hepatic cells, in vitro studies were conducted using primary hepatic stellate cells (HSC), Kupffer cells and hepatocytes with cilostazol supplementation. Sirius red staining revealed that groups 3 and 4 exhibited a lesser fibrotic area (2.49 ± 0.43% and 2.31 ± 0.30%, respectively) than group 2 (3.17 ± 0.67%, P < 0.05 and P < 0.001, respectively). In vitro studies showed cilostazol dose-dependently suppressed HSC activation (assessed by morphological change, cell proliferation, and the expression of HSC activation markers), suggesting the therapeutic effect of cilostazol is mediated by its direct action on HSC. Cilostazol could alleviate CCl4 -induced hepatic fibrogenesis in vivo, presumably due, at least partly, to its direct effect to suppress HSC activation. Given its clinical availability and safety, it may be a novel therapeutic intervention for chronic liver diseases.


Edge-mediated skyrmion chain and its collective dynamics in a confined geometry.
The emergence of a topologically nontrivial vortex-like magnetic structure, the magnetic skyrmion, has launched new concepts for memory devices. Extensive studies have theoretically demonstrated the ability to encode information bits by using a chain of skyrmions in one-dimensional nanostripes. Here, we report experimental observation of the skyrmion chain in FeGe nanostripes by using high-resolution Lorentz transmission electron microscopy. Under an applied magnetic field, we observe that the helical ground states with distorted edge spins evolve into individual skyrmions, which assemble in the form of a chain at low field and move collectively into the interior of the nanostripes at elevated fields. Such a skyrmion chain survives even when the width of the nanostripe is much larger than the size of single skyrmion. This discovery demonstrates a way of skyrmion formation through the edge effect, and might, in the long term, shed light on potential applications.


Quality and sensory milk traits of goats grazing Caatinga or confined receiving either corn or spineless cactus-based diets in the Brazilian semiarid environment.
This study aimed to evaluate the yield, physical-chemical properties, fatty acid (FA) profile, and sensory traits of goat milk under different nutritional strategies in a Brazilian semiarid environment. Eighteen lactating crossbred dairy goats were distributed in a completely randomized design with three nutritional strategies: Caatinga strategy (1.5% of body weight with a concentrate supplementation), Corn-based confined strategy, and Spineless Cactus confined strategy. Daily milk yield was recorded, and milk samples were collected from all animals. Goats fed the spineless cactus-based diet presented a higher milk yield than goats feed the other strategies. Moreover, milk from goats fed with a spineless Cactus confined strategy presented higher saturated FA (SFA), and a lower proportion of cis- monounsaturated FA, trans-monounsaturated FA, and c9,t11-18:2 than milk from goats feed the other strategies. Milk from goats in the pasture system presented the highest proportions of 18:2n-6, 18:3n-3, and thus of polyunsaturated FA, when compared with milk from confined goats. We assume that milk from goats grazing in Caatinga pastures presents more benefits to human health due to the positive effects of this diet on the milk's fat content and FA profile, and this feeding strategy also results in a better sensory evaluation that may increase the acceptability of goat milk by consumers. All nutritional strategies evaluated herein and adopted in the semiarid region of Brazil are recommended for maintaining the yield, physical-chemical properties, and acceptability of milk goats.


Transcription of the maxicircle kinetoplast DNA of Leishmania tarentolae.
Numerous transcripts of the 30 kilobase maxicircle component of the kinetoplast DNA of Leishmania Tarentolae have been analyzed by the Northern blotting method. The transcripts range in size from 1.8 to 0.1 kb. RNAs arising from the cloned 6.6 kb region containing the presumptive miniribosomal RNA genes were shown to be transcribed in the direction 12 S to 9 S on the same strand. A preliminary transcriptional map was constructed and related to the distribution of AT-rich regions of the maxicircle DNA molecule.


Understanding the Patient Experience of Home-Based Pulmonary Rehabilitation with Health Coaching for COPD: A Qualitative Interview Study.
We recently reported on a randomized trial of home-based pulmonary rehabilitation (PR) for chronic obstructive pulmonary disease (COPD) that showed improvement in all domains of quality of life, accelerometry-measured physical activity, and self-management. In this current study, we used a theoretical framework to help us gain an in-depth understanding of how patients experience complex, multi-component programs to help uncover factors related to behavior change and to inform program scale-up in other populations. The parent trial was conducted with COPD patients receiving care at an academic medical center and a community health system in the upper Midwest. The 12-week PR intervention included 3 daily video-guided exercises, activity monitors, and weekly telephonic health coaching. Trial participants were eligible to participate in an individual phone interview about their experience if they completed the intervention within the prior 12 months.. Analysis of verbatim transcripts followed an inductive thematic approach followed by deductive categorization and interpretation using a theoretical model: the Capability, Opportunity, Motivation-Behavior (COM-B) model developed for linking intervention functions to aspects of behavioral change. Among 32 eligible program participants,32 were approached, and 15 completed interviews between October 19, 2021, and January 13, 2022. The COM-B model and recommendations for program improvement were observed in the primary findings. Participants' feedback highlighted how the health coaching bolstered skills and confidence among individuals with the poorest function at program enrollment and how improved physical function and mood led to motivation. It also highlighted the roles of technology and telephonic support in a home-based program. Suggestions for improvement included providing exercise variations.


[Serological and molecular markers of HCV infection in Polish blood donors].
The algorithms of blood donor screening for HCV and verification of the results of screening tests are presented. Currently blood donors in Poland are tested for anti-HCV and those with no antibodies are screened using molecular biology methods for HCV RNA.


Technical note: fluoride pre-treatment effects on microleakage of a resin bonding agent.
This pilot study reports the effect of fluoride pre-treatment of dentin and enamel on microleakage of a resin bonding agent. Pairs of circular class V cavities involving 50% enamel and 50% cementum were cut in 12 extracted third molars. Each tooth contained a control and a treatment cavity (matched-pair design). A stannous fluoride solution (0.717% SnF2, Gel-Kam, Scherer Laboratories, Dallas, TX) was applied to the entire treatment preparation of each tooth. A dentin resin bonding system (Scotchbond 2 with Scotchprep, a dentin primer, 3M Dental Products Div., St. Paul, MN) was applied per manufacturer's instructions. Silux resin (3M) was placed over the resin bonding agent, light-cured, and finished. The teeth were subjected to 500 temperature cycles between 5 and 55 degrees C. A silver nitrate staining technique was used for evaluation of microleakage. The mean leakage for the control was 2235 +/- 1146 microns, and 2105 +/- 1052 microns for the fluoride treatment sites. It is concluded, from this pilot study with small sample size, that pre-treatment with fluoride of dentin and enamel prior to the placement of a resin bonding agent produced no significant change in microleakage (Student's t test for paired samples, p = 0.6492).


Incidence and factors associated with early pregnancy losses in Simmental dairy cows.
It has been suggested that management system, milk yield, parity, body condition score and ambient temperature can significantly influence the rate of early pregnancy loss in dairy cattle. The objectives of this study were to establish the extent and patterns of early pregnancy loss from days 32 to 86 of gestation, and to check relationships between management system, milk yield, ambient temperature (quartile), body condition score, bull and parity on the early pregnancy loss rate for Simmental dairy cattle in Croatia. Animals were housed in two dairy farms with two different management systems (pasture based-group A, n=435 and intensive-group B, n=425) with a total of 151 heifers and 709 cows. Overall pregnancy losses were recorded in 67 (7.79%) animals, with late embryonic losses in 30 (44.77%) and early fetal losses in 37 (55.23%) animals (P>0.05). Early pregnancy losses were twofold higher in group B when compared to the group A (P<0.05). More than the half of pregnancy losses were recorded during the III quartile (P<0.05). There was no significant relationship between the paternal bull and pregnancy loss rate. Low body condition score (BCS 2-3) was associated with the highest, while BCS 3.25-4 showed the lowest pregnancy loss rate (P<0.05). The pregnancy loss rate increased in parallel with parity and milk yield increase.


Modified precordial lead ECG SafOne on electrocardiography recordings.
Adaptability in precordial lead placement is one of the sources of electrocardiography inaccuracy. The present experimental study aimed to investigate the modified precordial lead ECG SafOne on electrocardiography recordings. Fourteen subjects were selected using purposive sampling. All the artefacts that emerged in the ECG recording results from the subjects using both the modified precordial lead ECG SafOne and precordial lead standard ECG were measured and identified. Data were analysed using a t test to examine the difference in the artefacts from all ECG recordings. The electrocardiography recordings of males aged 21-25 years using modified precordial lead ECG SafOne showed that out of 168 precordial leads from 14 subjects, two indicated artefact images in lead II (1.19%) and three in lead III (1.79%). The statistical test showed no significant difference in terms of artefacts that emerged in the electrocardiography recording results from both standard ECG and modified precordial lead ECG SafOne (p = 0.096). The modified precordial lead ECG SafOne showed no significant effect on ECG recordings related to artefacts. Additionally, the precordial lead ECG SafOne had no substantial difference in the presence of artefacts compared to the standard ECG. Therefore, ECG SafOne was usable as an ECG precordial lead for electrocardiography recording.


Developing CHCA/PPD as a novel matrix for enhanced matrix-assisted laser desorption/ionization-mass spectrometry imaging for analysis of antibiotics in grass carp tissues.
Antibiotics have important medical value, but they need to be monitored when used as veterinary drugs. We report α-cyano-4-hydroxycinnamic acid/p-phenylenediamine (CHCA/PPD) hybrid as a novel matrix for enhanced matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) in situ the spatial distribution of antibiotic drugs in grass carp tissues. We have used MALDI-TOF-MSI in positive ion mode for the analysis of quinolones and sulfonamides in grass carps. A novel CHCA/PPD matrix was prepared and applied using a simple method to improve the analysis. Compared with the traditional matrix, CHCA/PPD significantly improved the detection intensity of quinolones and sulfonamides with better sensitivity (17.20%-94.30%) and reproducibility. For demonstration, this novel matrix was successfully applied to visualize enrofloxacin (ENR) in grass carp tissues, with the entire abundance differences clearly observed based on MALDI-MSI. The concentration levels in different tissues were determined, with a calibration curve of 10-2000 μg/ml (R2 > 0.993). This study was the first to introduce CHCA/PPD as a novel matrix, and the classical acid-base mixing was used to improve the ionization effect of the traditional matrix CHCA in MALDI. Based on CHCA/PPD, MALDI-MSI detected ENR in different grass carp tissues for the first time and realized the spatial distribution and concentration detection.


Pathways to delinquent and sex offending behavior: The role of childhood adversity and environmental context in a treatment sample of male adolescents.
Exposure to greater Adverse Childhood Experiences (ACEs) has been associated with increased likelihood of general and sex offending behaviors. However, few studies consider both the impact of varied ACE exposures and other early experiences on pathways to offending behaviors in adolescents who have engaged in sexually abusive behaviors. The purpose of this study was to examine the impact of ACEs and sexual boundary problems within the home on the development of delinquent and sexually abusive behavior. Data were collected from archival records of male adolescents (N = 285) who had received treatment for sexually abusive behavior at a youth facility. This study investigated the effects of individual adverse experiences on delinquent nonsexual and sexually abusive behaviors through structural equation modeling. Structural equation modeling revealed a three-factor model for ACEs. Direction and significance of paths between ACEs and the onset, persistence, and nature of maladaptive behaviors differed. Household dysfunction was related to an earlier onset (β = 1.19, p = 0.013) and more persistent nonsexual delinquent offending (β = 1.05, p = 0.048) and contact sexual offending (β = 1.19, p = 0.010). Conversely, sexual abuse and exposure to sexual boundary problems were associated with an earlier onset of sexually abusive behavior (β = -1.08, p = 0.038) as well as indicators of adolescent-onset (β = -1.30, p = 0.002), less persistent (β = -1.53, p = 0.001), and nonviolent (β = -1.89, p = 0.001) delinquency. Findings suggest variations in ACE exposures differentially influence the onset, severity, and persistence of delinquent and sexually abusive behaviors among these youths.


Double plication for spring-mediated in-continuity intestinal lengthening in a porcine model.
Short bowel syndrome is a condition with substantial morbidity and mortality, yet definitive therapies are lacking. Distraction enterogenesis uses mechanical force to "grow" new intestine. In this study, we examined whether intestinal plication can be used to safely achieve spring-mediated intestinal lengthening in a functioning segment of jejunum in its native position. A total of 12 juvenile, miniature Yucatan pigs underwent laparotomy to place either compressed springs or expanded springs within a segment of jejunum (n = 6 per group). The springs were secured within the jejunum by performing intestinal plication to narrow the intestinal lumen around the spring. After 3 weeks, the jejunum was retrieved and examined for lengthening and for histologic changes. There were no intraoperative or postoperative complications, and the pigs tolerated their diets and gained weight. Segments of jejunum containing expanded springs showed no significant change in length over the 3 weeks. In contrast, jejunum containing compressed springs showed nearly a 3-fold increase in length (P < .001). Histology of the retrieved jejunum showed a significant increase in thickness of the muscularis propria and in crypt depth relative to normal jejunum. Intestinal plication is effective in securing endoluminal springs to lengthen the jejunum. This approach is a clinically relevant model because it allows for normal GI function and growth of animals during intestinal lengthening, which may be useful in lengthening intestine in patients with short bowel syndrome.


Accumulation of pigment granules in lacrymal gland epithelium in practolol-treated beagle dogs.
A 6-month oral toxicity test of practolol was carried out in beagle dogs as a reference control for a newly developed beta blocker. No significant drug-induced changes were detected in any animals by various ophthalmological examinations such as ERG, tear flow, lysozymal activity in tears, etc. However, an unusual pathological change was detected in the lacrymal gland of all five dogs treated with practolol and not in control animals. Macroscopically, the lacrymal glands assumed a blackish brown to deep black colour on both the outside and the cut surface. Microscopically, fine, dark-brown pigment granules were present in the apical and supra-nuclear portion of the cytoplasm of predominantly serosal type epithelial cells. These pigments reacted positively to Schmorl's method for lipofuscin, but gave a negative PAS reaction for polysaccharide, Prussian blue for iron and Ziehl-Neelsen method for ceroid pigment. They were detected as membrane-bound electron-dense bodies by electron microscopy. Similar pigments were also deposited in the cytoplasm of the apocrine sweat gland. Although the mechanism of the accumulation of these granules is far from clear, concentration of practolol in the lacrymal gland is considered to be very closely related to the presence of these granules. A possible mechanism for ocular toxicity by practolol, involving this change, is discussed.


Endogenous neurotoxins from tryptophan.
In most tissues, including brain, a major proportion of the tryptophan which is not used for protein synthesis is metabolised along the kynurenine pathway. Long regarded as the route by which many mammals generate adequate amounts of the essential co-factor nicotinamide adenine dinucleotide, two components of the pathway are now known to have marked effects on neurones. Quinolinic acid is an agonist at the N-methyl-D-aspartate sensitive subtype of glutamate receptors in the brain, while kynurenic acid is an antagonist and, thus, a potential neuroprotectant. A third kynurenine, 3-hydroxykynurenine, is involved in the generation of free radicals which can also damage neurones. Quinolinic acid is increasingly implicated in neurodegenerative disorders, most especially the AIDS-dementia complex and Huntington's disease, while kynurenic acid has become a standard for the identification of glutamate-releasing synapses, and has been used as the parent for several groups of compounds now being developed as drugs for the treatment of epilepsy and stroke.


Model evaluation of rapid 4-dimensional lung tomosynthesis.
This is an investigation of a lung motion digital tomosynthesis (DTS) model using combined stationary detector and stationary cold cathode x-ray sources at projection acquisition rates that exceed the present norms. The intent is to reduce anatomical uncertainties from artifacts inherent in thoracic 4-dimensional computed tomography (CT). Parameters necessary to perform rapid lung 4-dimensional DTS were studied using a conventional radiographic system with linear motion of the x-ray source and a simple hypothetical hardware performance model. Hypothetical rapid imaging parameters of sweep duration, projections per second, pulse duration, and tube current (mA) were derived on the basis of 0.5 mm and 1 mm motion captures per phase, 10 and 15 breaths per minute (bpm), 10 to 40 mm breathing amplitude, and 2 signal-to-noise ratio (SNR) levels. Anterior-posterior and lateral projection images of a normal size anthropomorphic thorax phantom with iodine contrast inserts were collected and reconstructed with an algebraic algorithm to study the effects of reduced x-ray output associated with field emission cold cathodes composed of carbon nanotubes or metal Spindt-type. Radiographic projections were collected at 3 SNR levels that were set at standard clinical DTS milliampere-seconds (mAs) and reduced corresponding to 50% and 25% standard DTS mAs to simulate a reduced x-ray output. The DTS SNR of the inserts was superior in all reconstructions at clinical mAs versus automatic exposure-control radiographs and superior in 3 of 4 at the 50% and 25% mAs levels. The most demanding performance parameters corresponding to 40 mm amplitude, 15 bpm, 0.5 mm motion capture limit, and 61 projections were sweep duration (10.4 msec), projection rate (5862 projections per second), pulse duration (0.161 msec), current 189 mA anterior-posterior, and 653 mA lateral. Feasibility depends on the output performance of stationary cold cathode hardware being developed for DTS. Present image receptor technology can accommodate frame acquisition rates.


Quality of life of family caregivers 5 years after a relative's cancer diagnosis: follow-up of the national quality of life survey for caregivers.
Although cancer has been considered as a chronic disease for those diagnosed, the long-term impact of cancer on the family caregivers' quality of life (QOL) remains unknown. Thus, the current study aimed: (a) to characterize family caregivers of cancer survivors, (b) to describe the multidimensional aspects of QOL of family caregivers of cancer survivors, and (c) to identify demographic and caregiving experience factors that may play significant roles in the caregivers' QOL around 5 years after the relative's initial diagnosis. Methods. A total of 1218 caregivers participated in the 5-year follow-up nationwide QOL Survey for Caregivers. Demographics and caregiving experiences were measured 2 years post-diagnosis of their relative's cancer. Multidimensional aspects of QOL were assessed, including mental and physical health, psychological adjustment, and spirituality at 5 years post-diagnosis. Three groups of caregivers were identified: former caregivers due to the recipients being in remission, former caregivers whose recipients were deceased, and current caregivers. Current caregivers reported worst levels of QOL. Bereaved caregivers reported lower levels of psychological and spiritual adjustment than former caregivers whose recipients were in remission. In addition, caregivers' age and stress were consistent predictors of QOL across three caregiver groups at 5 years post-diagnosis. The findings help to increase evidence-based awareness of the long-term impact of cancer on the family caregivers' QOL. Findings also have implications for developing programs, whereby family caregivers in the various phases of caregivership will benefit by improving their QOL.


Effect of diets on growth, digestibility, carcass and meat quality characteristics of four rabbit breeds.
The current study was conducted to evaluate three diets using four rabbit breeds. A total of 320 male weaned rabbits representing four breeds named V-line, Saudi-1, Saudi-2 and Saudi-3 were randomly distributed into three comparable dietary treatments. Three levels of indigenous feedstuffs (IFS) of 42.5%, 65% or 87.5% (alfalfa hay, barley and wheat bran) were substituted for the same levels of non-indigenous feedstuffs in the diet (corn grain, soybean, molasses, and limestone) to form three diets named D1, D2 and D3, respectively. These dietary treatments were used to evaluate post-weaning growth performance, feed intake, feed conversion, carcass and lean composition, and nutrients digestibility in four rabbit breeds. Partial replacement of IFS with non-indigenous feedstuffs attained significant increase in growth performance. The diet containing 87.5% IFS led to significant increase in daily weight gains by 8.4, 4.0, 8.1, 6.2 and 6.7 g at age intervals of 5-6, 7-8, 9-10, 10-11 and 11-12 weeks compared to the control diet, respectively. The diet containing 87.5% IFS showed a significant reduction in feed conversion ratio compared to control diet during the experimental periods. The diet containing 65% IFS showed significant increases in pre-slaughter weight (112 g) and hot carcass weight (89 g), while dressing percent, offal weight and percent, and non-carcass weights and percentages (head, fur, legs + tail, viscera) were not significantly different. The diet containing 87.5% IFS gave an increase of 1.1%, 6.4%, 8.8%, 17.9%, 7.4%, and 19.6% in digestibility coefficients of organic matter (OM), crude protein (CP), neutral detergent fibre (NFD), acid detergent fiber (ADF), hemi-cellulose (HC) and cellulose (C) compared to control diet, respectively. Feed intakes were moderate and ranged from 69 to 124 g for V-line, 77 to 128 g for Saudi-1, 79 to 130 g for Saudi-2, and 76 to 119 g for Saudi-3 along with moderate ratios of feed conversion ranging from 2.65 to 3.80, 2.45 to 3.90, 2.46 to 3.79 and 2.63 to 3.65, respectively. Pre-slaughter weight, hot carcass weight, and offal weight were in favour of Saudi-2 rabbits compared to the other groups. Both Saudi-1 and Saudi-2 rabbits were slightly higher than Saudi-3 in weights and percentages of head, fur, viscera and legs + tail. Lean and bone weights and percentages and meat to bone ratio in Saudi-2 carcasses were slightly higher than those recorded in the other groups, while moisture, DM, CP, EE and ash contents in the lean have shown little differences between groups. Rabbits of Saudi-1 were ranked the first in digestibility coefficients of OM, CP, NDF, ADF, HC, C and cell count compared to other groups. Rabbits of Saudi-2 fed diet containing 87.5% IFS recorded the heaviest body weights and gains since this class showed considerable deviations in body weights of 345, 341, 269, 307, 321, 345 and 347 g at 6, 7, 8, 9, 10, 11 and 12 weeks of age, respectively, in comparison with the lightest class. Both Saudi-2 and Saudi-3 rabbits fed the diet containing 87.5% IFS had favourable estimates of feed conversions ranging from 2.1 to 3.4, while rabbits of Saudi-1 fed the diet containing 87.5% IFS recorded the best digestibility coefficients.


The influence of some promising fused azaisocytosine-containing congeners on zebrafish (Danio rerio) embryos/larvae and their antihaemolytic, antitumour and antiviral activities.
The present study was aimed at broadening the profile of toxicity and biological activity of promising fused azaisocytosine-containing congeners (I-VI) possessing medical applicability and important pharmacokinetic properties. For this purpose, the in vivo zebrafish test was applied for evaluating embryotoxic effects of test compounds, whereas the ex vivo model of oxidatively-stressed rat erythrocytes was developed for assessing their antihaemolytic activities. Additionally, the MTT-based assays suitable for assessing cytotoxic and antiviral activities of I-VI were employed. The influence of compounds I-VI on zebrafish embryos/larvae was carefully investigated in relation to lack or presence of various substituents at the phenyl moiety. The least embryotoxic proved to be the parent compound (I) and its para-methyl (II) and ortho-chloro (III) derivatives. Simultaneously, they revealed the minimum embryotoxic concentrations higher than that of aciclovir, what makes them safer than this pharmaceutic. Moreover, most of test compounds showed protective effects (better or comparable to that of ascorbic acid) on oxidatively-stressed erythrocytes. All the investigated compounds were effective at inhibiting the growth of human solid tumours of pharynx (FaDu) and tongue (SCC-25). The majority of molecules showed good selectivity indices. The most selective proved to be II showing in normal Vero cells over a 5-fold and an almost 3-fold decreased cytotoxicity relative to that in tumour SCC-25 and FaDu cells, respectively. Additionally, a 3,4-dichloro derivative (VI) was shown to possess concentration-dependent inhibitory effects on the replication of Herpes simplex virus type 1 and simultaneously at active concentrations was found to be nontoxic for normal Vero cells.


Probing the chemoprevention potential of the antidepressant fluoxetine combined with epigallocatechin gallate or kaempferol in rats with induced early stage colon carcinogenesis.
The enhanced chemopreventive action against 1,2 Dimethylhydrazine (DMH)-induced preneoplastic lesion in rats could be achieved via simultaneous administration of the antidepressant fluoxetine (FLX) with two natural polyphenolic compounds viz., kaempferol (KMP) and/or epigallocatechin-gallate (EGCG). The obtained results revealed that single FLX pre-treatment possess a significant apoptotic effect by increasing the activity of serum and colon tissue caspase 3. It also attenuated the DMH driven increase in, colon tissue MDA, NO, PCNA and COX-2 expression as well as serum and colon tissue β-catenin, with a decrease in the multiplicity of ACF and number of MPLs. The combination of FLX with either KMP or EGCG improved the antioxidant, anti-inflammatory and antiproliferating activities but with higher apoptotic activity in case of KMP. Eventually, histopathological assessment of colon tissues exposed that while sole pre-treatment can improve DMH-induced hyperplasia with only moderate inflammatory infiltration, tissues from the combined pre-treatment regimens groups exhibited almost a normal colonic architecture with slight submucosal edema. The study proved that single FLX administration prior to DMH exerts a chemopreventive effect and that the investigated combined pre-treatment regimens demonstrated more potent chemopreventive and antiproliferative actions.


Lethal and sublethal effects of chlorantraniliprole on the migratory moths Agrotis ipsilon and A. segetum: New perspectives for pest management strategies.
Agrotis ipsilon and A. segetum are major migratory pests of many crops in China, and frequent regional outbreaks cause severe yield losses. Use of food attractants is one of the most promising control methods against adult lepidoptera, notably through the attract-and-kill strategy. Chlorantraniliprole's acute toxicity and sublethal effects on both moths were evaluated. Chlorantraniliprole showed high activity against both adults of both species, with LC20 and LC50 values of 0.08 and 0.21 mg L-1 (A. ipsilon), and 0.14 and 0.51 mg L-1 (A. segetum). The fecundity, effective oviposition rate, and egg hatching rate of both species in dual-sex exposure treatments were all significantly reduced compared with the control, and the population growth coefficients in the LC50 ♀ × LC50 ♂ treatments were only 0.32% (A. ipsilon) and 3.35% (A. segetum) that of the control. Furthermore, the flight distance was significantly suppressed from 6.67 km (control) to 0.01 km (LC50 ) for A. ipsilon, and from 7.39 km (control) to 0.78 km (LC50 ) for A. segetum. The proportions of robust- and medium-flight individuals of A. ipsilon and A. segetum in exposure treatments were greatly reduced. Low lethal concentration exposures to chlorantraniliprole can drastically reduce the reproduction and flight performance of A. ipsilon and A. segetum, while inhibiting the production of offspring, suggesting chlorantraniliprole would be an excellent compound for use in combination with food attractants. Chlorantraniliprole has good potential for management of the two long-range migratory pests tested using an attract-and-kill strategy. © 2022 Society of Chemical Industry.


PARP inhibitor resistance: the underlying mechanisms and clinical implications.
Due to the DNA repair defect, BRCA1/2 deficient tumor cells are more sensitive to PARP inhibitors (PARPi) through the mechanism of synthetic lethality. At present, several PAPRi targeting poly (ADP-ribose) polymerase (PARP) have been approved for ovarian cancer and breast cancer indications. However, PARPi resistance is ubiquitous in clinic. More than 40% BRCA1/2-deficient patients fail to respond to PARPi. In addition, lots of patients acquire PARPi resistance with prolonged oral administration of PARPi. Homologous recombination repair deficient (HRD), as an essential prerequisite of synthetic lethality, plays a vital role in killing tumor cells. Therefore, Homologous recombination repair restoration (HRR) becomes the predominant reason of PARPi resistance. Recently, it was reported that DNA replication fork protection also contributed to PARPi resistance in BRCA1/2-deficient cells and patients. Moreover, various factors, such as reversion mutations, epigenetic modification, restoration of ADP-ribosylation (PARylation) and pharmacological alteration lead to PARPi resistance as well. In this review, we reviewed the underlying mechanisms of PARP inhibitor resistance in detail and summarized the potential strategies to overcome PARPi resistance and increase PARPi sensitivity.


A methodology for identifying workers exposed to asbestos since 1940.
This paper describes a method to identify individual workplaces and to determine the number of employees at those workplaces who have had substantial exposure to asbestos. A total of 486,400 individuals are estimated to have had substantial exposure to asbestos in New Jersey since the start of World War II, including 102,700 individuals from 16 manufacturing plants, 376,200 from eight shipyards, and 7,500 insulators.


Plasma Electrochemistry for Carbon-Carbon Bond Formation via Pinacol Coupling.
The formation of carbon-carbon bonds by pinacol coupling of aldehydes and ketones requires a large negative reduction potential, often realized with a stoichiometric reducing reagent. Here, we use solvated electrons generated via a plasma-liquid process. Parametric studies with methyl-4-formylbenzoate reveal that selectivity over the competing reduction to the alcohol requires careful control over mass transport. The generality is demonstrated with benzaldehydes, benzyl ketones, and furfural. A reaction-diffusion model explains the observed kinetics, and ab initio calculations provide insight into the mechanism. This study opens the possibility of a metal-free, electrically-powered, sustainable method for reductive organic reactions.


New cloning and expression vector derived from Escherichia coli plasmid pIGWZ12; a potential vector for a two-plasmid expression system.
We constructed pIGPZ, a new cloning and expression vector derived from Escherichia coli plasmid pIGWZ12::Kan. pIGPZ contains a kanamycin resistance marker, a multiple-cloning-site (MCS) region, and a promoter for constitutive expression of cloned genes. pIGPZ has the same high level of stability as the original plasmid, even in the absence of antibiotic selection. Furthermore, we show that pIGPZ is compatible with ColE1-based plasmids and a pSC101-like plasmid. All the characteristic elements of theta-replicating plasmids were found in the pIGPZ putative origin of replication. Finally, we demonstrate that pIGPZ can be used in a double-plasmid expression system by co-expressing UBP1 protease from pIGPZ with ubi-interferon alpha (IFNA13; GenBank Accession No. NM_006900.3) or ubi-human growth hormone (ubi-hGH; patent No. WO 2005/066208 A2) cloned in another plasmid. In this system, both ubi-interferon alpha and ubi-human growth hormone were deubiquitinated efficiently in E. coli cells.


[Therapeutic effectiveness of gamma-globulin on experimental burns].
Experiments on rabbits were made to examine excretory-absorption liver function and the blood kallikrein-kinin system after thermal burn and treatment with gamma-globulin immune to burn skin toxin. Immunotherapy leads to a more rapid and effective recovery of the functional indicators in the burnt animals than in burns without or with the treatment by nonimmune preparations. It was demonstrated that specific detoxification plays an important role in multiple modality treatment of burn disease.


Role and mechanism of action of leucine-rich repeat kinase 1 in bone.
Leucine-rich repeat kinase 1 (LRRK1) plays a critical role in regulating cytoskeletal organization, osteoclast activity, and bone resorption with little effect on bone formation parameters. Deficiency of Lrrk1 in mice causes a severe osteopetrosis in the metaphysis of the long bones and vertebrae bones, which makes LRRK1 an attractive alternative drug target for the treatment of osteoporosis and other high-turnover bone diseases. This review summarizes recent advances on the functions of the Lrrk1-related family members, Lrrk1 deficiency-induced skeletal phenotypes, LRRK1 structure-function, potential biological substrates and interacting proteins, and the mechanisms of LRRK1 action in osteoclasts.


Effect of enhanced nutrition services with community-based nutrition services on the diet quality of young children in Ethiopia.
Poor diet quality related to inadequate complementary feeding is a major public health problem in low and middle-income countries including Ethiopia. Low dietary diversity has been linked to negative health outcomes in children. To provide a package of interventions to close nutritional gaps through agriculture, the Sustainable Undernutrition Reduction in Ethiopia (SURE) programme was set up as a multi-sectoral initiative and the results of combined effects of community-based and enhanced nutrition services, compared to community-based alone, on diet diversity and diet quality of complementary feeding of young children are presented. The study used pre- and post-intervention design. Baseline (n = 4980) data were collected from May to July 2016, and follow-up (n = 2419) data from December 2020 to January 2021. From 51 intervention districts having the SURE programme, 36 intervention districts were randomly selected for baseline and 31 for the follow-up survey. The primary outcome was diet quality: minimum dietary diversity (MDD), minimum meal frequency (MMF) and minimum acceptable diet (MAD). Comparing endline to baseline over the 4.5-year intervention, the use of standard community-based nutrition services of growth monitoring and promotion increased (16%-46%), as did enhanced nutrition services of infant and young child feeding counselling, and agricultural advising (62%-77%). Women involved in home gardening significantly increased (73%-93%); however, household production of food decreased yet consumption of most own-grown foods increased. Importantly, MAD and MDD increased four-fold. The SURE intervention programme was associated with improvements in complementary feeding and diet quality through enhanced nutrition services. This suggests programmes targeted at nutrition-sensitive practices can improve child feeding in young children.


Dynamic stereotactic radiosurgery.
Two radiosurgical procedures using a stereotactic frame and a linear accelerator X ray beam with a circular field diameter between 0.5 and 3 cm are presented. One technique is based on a single plane rotation (single plane radiosurgery) whereas the other uses simultaneous and continuous motions of both the gantry (approximately 360 degrees) and couch (approximately 180 degrees) during the radiosurgical procedure (dynamic radiosurgery). The dose, typically a few thousand cGy, is prescribed to the 90% isodose line which just covers the target volume. The dose fall-off outside the spherical target volume is considerably sharper for the dynamic rotation than for the single plane rotation, and is comparable to the dose fall-off obtained with the two presently known dedicated radiosurgical techniques: one based on focused cobalt beams and the other on proton beams. The dose fall-off in the dynamic radiosurgery discussed here is also comparable to that of previously described linear accelerator based multiple converging are techniques, making the dynamic radiosurgery an attractive alternative to presently known radiosurgical procedures. The radiation beam parameters are discussed and the stereotactic frame described. The dose distributions for both radiosurgical techniques are calculated in a single plane and then corrected for the attenuation effects in the stereotactic frame (approximately 2%) and for the effects of the dynamic rotation (approximately 2%). The skin doses are 0.7% and 2%, and the lens doses, if the beam passes through the eyes, are 2.5% and 3.5% for the dynamic rotation and single plane rotation, respectively. The scatter and leakage dose for the radiosurgical procedures is typically 0.2% to the patient's thyroid, 0.06% to the breast, and 0.02% to the gonads.


Obstetric dimensions of the female pelvis are less integrated than locomotor dimensions and show protective scaling patterns: Implications for the obstetrical dilemma.
The "obstetrical dilemma" hypothesis assumes that the modern human female pelvis serves two discrete functions: obstetrics and locomotion. We investigate whether these differing functions create observable patterns of morphological covariation and whether those patterns differ by height, weight, and age. This allows evaluation of evidence for canalization and phenotypic plasticity relevant to obstetric and locomotor function among a living female population. Landmarks (N = 86) were collected and inter-landmark distances were calculated (N = 36) on the pelvis and proximal femur of CT scans of living women aged 20 to 90 years (M = 93) receiving a routine CT scan. Partial least squares and relative SD of eigenvalues analyses were used to evaluate integration overall and within locomotor and obstetric modules, respectively. Ordinary Least Squared regression was used to evaluate scaling relationships between inter-landmark distances and height, weight, and age. The obstetric pelvis was significantly less internally integrated than the locomotor pelvis. Many obstetric measurements were constrained in absolute terms relative to height; shorter women had relatively larger birth canal dimensions, and several key obstetric dimensions showed relative freedom from height. Lower weight women had some relatively larger obstetric and locomotor dimensions. Regarding age, younger women showed a few relatively larger outlet dimensions. This study suggests that the obstetric pelvis and the locomotor pelvis function are morphologically distinct, with the obstetric pelvis showing relatively greater flexibility. These relationships between relative constraints support the hypothesis that the modern female pelvis shows evidence of both canalization and phenotypic plasticity in obstetric and locomotor structures.


Spatio-temporal assessment of land use land cover based on trajectories and cellular automata Markov modelling and its impact on land surface temperature of Lahore district Pakistan.
This research aims to assess the urban growth and impact on land surface temperature (LST) of Lahore, the second biggest city in Pakistan. In this research, various geographical information system (GIS) and remote sensing (RS) techniques (maximum likelihood classification (MLC)) LST, and different normalized satellite indices have been implemented to analyse the spatio-temporal trends of Lahore city; by using Landsat for 1990, 2004, and 2018. The development of integrated use of RS and GIS and combined cellular automata-Markov models has provided new means of assessing changes in land use and land cover and has enabled the projection of trajectories into the future. Results indicate that the built-up area and bare area increased from 15,541 (27%) to 23,024 km2 (40%) and 5756 km2 (10%) to 13,814 km2 (24%). Meanwhile, water area and vegetation were decreased from 2302 km2 (4%) to 1151 km2 (2%) and 33,961 km2 (59%) to 19,571 km2 (34%) respectively. Under this urbanization, the LST of the city was also got affected. In 1990, the mean LST of most of the area was between 14 and 28 ℃, which rose to 22-28 ℃ in 2004 and 34 to 36 ℃ in 2018. Because of the shift of vegetation and built-up land, the surface reflectance and roughness of each land use land cover (LULC) class are different. The analysis established a direct correlation between Normalized Difference Water Index (NDWI), Normalized Difference Vegetation Index (NDVI) with LST and an indirect correlation among Soil Adjusted Vegetation Index (SAVI), Normalized Difference Built-up Index (NDBI), and Built-up Index (BI) with LST. The results are important for the planning and development department since they may be used to guarantee the sustainable utilization of land resources for future urbanization expansion projects.


The genetic architecture of host response reveals the importance of arbuscular mycorrhizae to maize cultivation.
Arbuscular mycorrhizal fungi (AMF) are ubiquitous in cultivated soils, forming symbiotic relationships with the roots of major crop species. Studies in controlled conditions have demonstrated the potential of AMF to enhance the growth of host plants. However, it is difficult to estimate the actual benefit in the field, not least because of the lack of suitable AMF-free controls. Here we implement a novel strategy using the selective incorporation of AMF-resistance into a genetic mapping population to evaluate maize response to AMF. We found AMF to account for about one-third of the grain production in a medium input field, as well as to affect the relative performance of different plant genotypes. Characterization of the genetic architecture of the host response indicated a trade-off between mycorrhizal dependence and benefit. We identified several QTL linked to host benefit, supporting the feasibility of breeding crops to maximize profit from symbiosis with AMF.


Apolipoprotein B detected in the plasma of a patient with homozygous hypobetalipoproteinaemia: implications for aetiology.
A hypobetalipoproteinaemic kindred is described in which the proband manifested the clinical and biochemical features of the homozygous state. Unlike the apparent complete absence of apolipoprotein B in the plasma of the five cases of homozygous hypobetalipoproteinaemia reported so far, we were able to demonstrate minute quantities of this protein (approximately 0.025% of normal) in the plasma of the proband. This finding suggests that the disorder may not result from a structural gene defect but may rather reflect a failure of secretion.


Magnetic resonance imaging of the cervix during pregnancy: effect of gestational age and prior vaginal birth.
To investigate how gestational age and prior vaginal birth affect cervical anatomy on magnetic resonance imaging during pregnancy. Magnetic resonance images of the cervix were obtained in consecutive patients referred for a suspected fetal abnormality. We used an image processing protocol to measure cervical dimensions, orientation, and signal intensity. We determined how outcome variables were affected by gestational age and prior vaginal birth. Adequate images were obtained in 53 of 57 patients at 17 to 36 weeks. As gestational age increased by 12 weeks, the mean cross-sectional area of the cervical canal and cervical stroma increased 31% (95% confidence interval 0% to 73%) and 31% (95% confidence interval 11% to 55%), respectively. The normalized signal intensity of the stroma increased from 0.83 (95% confidence interval 0.81 to 0.85) at 20 weeks to 0.91 (95% confidence interval 0.88 to 0.94) at 32 weeks. None of the outcome variables were affected by prior vaginal birth. Magnetic resonance imaging revealed that cross-sectional area and signal intensity of the cervical stroma increase with increasing gestational age.


The rat P450 IID subfamily: complete sequences of four closely linked genes and evidence that gene conversions maintained sequence homogeneity at the heme-binding region of the cytochrome P450 active site.
Four genes in the P450 IID gene subfamily were isolated from Sprague-Dawley rat lambda EMBL 3 and Charon 4A genomic libraries and completely sequenced. Their transcription start sites were determined by primer extension analysis. The four genes designated IID2, IID3, IID4, and IID5 span 4036, 4371, 4678, and 4567 bp, respectively, and are closely linked head to tail on a 60-kb segment of DNA. All IID genes contained nine exons, and interestingly, the IID2, IID3, and IID4 genes possessed an atypical GC5' splice junction in intron 2. All four genes are transcribed, however, IID4 mRNA is produced at a level of less than one-tenth of those of IID2, IID3, and IID5. The exonic regions of these genes displayed from 79 to 84% sequence similarties. Several regions of extremely high nucleotide similarity were found within the introns, exons, and in the flanking regions of the four genes. These localized areas of high nucleotide similarities are the result of former gene conversion events. Of interest was the finding that the most highly similar region of all IID genes that was maintained by gene conversion covers portions of the eighth and ninth exons and the eighth intron. The ninth exon codes for a region of the P450 protein that is well conserved among all P450 gene families and in all species and that is associated with the noncovalently bound heme iron at the enzyme's active site. These data indicate that gene conversions have maintained sequence homogeneity within a critical region of the four P450 IID proteins.


A Geospatial Model to Identify Areas Associated with Late- Stage Breast Cancer: A Spatial Epidemiology Approach.
The aim of this study was to show how a geospatial model can be used to identify areas with a higher probability for late-stage breast cancer (BC) diagnoses. Our study considered an ecological design. Clinical records at a tertiary care hospital were reviewed in order to obtain the place of residence and stage of the disease, which was classified as early (0-IIA) and late (IIB-IV) and whose diagnoses were made during the 2013-2017 period. Then, they were geolocated to identify the distribution and spatial trend. Subsequently, the pattern of location, i.e. scattered, random and concentrated, was statistically assessed and a geospatial model was elaborated to determine the probability of late diagnoses in the state of Jalisco, Mexico. There were 1 954 (N) geolocated BC diagnoses: 58.3% were late. During the five-year period, a southwest-northeast trend was identified, nearly 9.5% of the surface of Jalisco, where 6 out of 10 (n= 751) late- stage diagnoses were concentrated. A concentrated and statistically significant pattern was identified in the southern, central and northern Pacific area of Jalisco, where the geospatial model delimited the places with the highest probability of late clinical stages (p <0.05). The geographical differences associated with the late diagnoses of BC suggest it is necessary to adapt and focus the strategies for early detection as an alternative to create a major impact on the population. Reproducible analysis tools were used in other contexts where geolocation data are available to complement public policies and strategies aimed to control BC.


The aryl hydrocarbon receptor (AhR) pathway as a regulatory pathway for cell adhesion and matrix metabolism.
The aryl hydrocarbon receptor (AhR) is an orphan receptor in the basic helix-loop-helix PAS family of transcriptional regulators. Although the endogenous regulator of this pathway has not been identified, the AhR is known to bind and be activated by a variety of compounds ranging from environmental contaminants to flavanoids. The function of this receptor is still unclear; however, animal models indicate that the AhR is important for normal development. One hypothesis is that the AhR senses cellular stress and initiates the cellular response by altering gene expression and inhibiting cell cycle progression and that activation of the AhR by exogenous environmental chemicals results in the dysregulation of this normal function. In this review we will examine the role of the AhR in the regulation of genes and proteins involved in cell adhesion and matrix remodeling, and discuss the implications of these changes in development and disease. In addition, we will discuss evidence suggesting that the AhR pathway is responsive to changes in matrix composition as well as cell-cell and cell-matrix interactions.


Hydrogel beads based on carboxymethyl cassava starch/alginate enriched with MgFe2O4 nanoparticles for controlling drug release.
Implementing novel oral drug delivery systems with controlled drug release behavior is valuable in cancer therapy. Herein, a green synthetic approach based on the sol-gel technique was adopted to prepare MgFe2O4 nanoparticles at different calcination temperatures using citric acid as a chelating/combustion agent. In this context, pH-responsive and magnetic carboxymethyl starch/alginate hydrogel beads (CMCS-SA) containing the MgFe2O4 nanoparticles were developed as potential drug carriers for the anticancer drug (Doxorubicin, Dox) release in simulated gastrointestinal fluids. Furthermore, in vitro release behaviors validated that these beads illustrated excellent stability in the simulated stomach liquids. In contrast, the data in simulated intestinal fluids showed sustained release of Dox because of their pH-sensitive swelling characteristics. Notably, applying an external magnetic field (EMF) could accelerate drug release from the beads. The in vitro release of drugs from gel beads was mainly accomplished by a combination of diffusion, swelling and erosion. Moreover, the cell cytotoxicity test and laser confocal results showed no harmful effects on normal cells (3T3) but were significant cytotoxic to colon cancer cell lines (HCT116) by drug-loaded hydrogel beads. Therefore, the prepared gel beads could be qualified as latent platforms for controlling the release of anticancer drugs in cancer treatment.


A novel role of FKN/CX3CR1 in promoting osteogenic transformation of VSMCs and atherosclerotic calcification.
Fractalkine (FKN) and its specific receptor CX3CR1 play a critical role in the pathogenesis of atherosclerosis including recruitment of vascular cells and the development of inflammation. However, its contribution to regulating the development of atherosclerotic calcification has not been well documented. Osteogenic transformation of vascular smooth muscle cells (VSMCs) is critical in the development of calcification in atherosclerotic lesions. In this study, for the first time, we evaluated the effect of FKN/CX3CR1 on the progression of VSMCs calcification and defined molecular signaling that is operative in the FKN/CX3CR1-induced osteogenic transformation of VSMCs. We found that high-fat diet induced atherosclerotic calcification in vivo was markedly inhibited in the Apolipoprotein E (ApoE) and CX3CR1 deficient (ApoE-/-/CX3CR1-/-) mice compared with their control littermates. FKN and CX3CR1 were both expressed in VSMCs and up-regulated by oxidized low-density lipoprotein (ox-LDL). FKN/CX3CR1 promoted the expression of osteogenic markers, including osteopontin (OPN), bone morphogenetic protein (BMP)-2 and alkaline phosphatase (ALP) and decreased VSMCs markers, including smooth muscle (SM) α-actin and SM22-α in a dose-dependent manner. The essential role of FKN/CX3CR1 in VSMCs calcification was further confirmed by lentivirus-mediated knockdown or overexpression of CX3CR1 blocked or accelerated osteogenic transformation of VSMCs. This response was associated with reciprocal up- and down-regulation of osteogenic factor, runt-related transcription factor 2 (RUNX2), transcription factors in osteoclast differentiation, receptor activator of nuclear factor-κB (RANK), RANK ligand (RNAKL) and osteoprotegerin (OPG), respectively. Inhibition of FKN/CX3CR1-activated Jak2/Stat3 signaling by the Jak/Stat inhibitor AG490 blocked osteogenic transformation of VSMCs and RUNX2 induction concurrently. Taken together, our data uncovered novel roles of FKN/CX3CR1 in promoting VSMC osteogenic transformation and atherosclerotic calcification by activating RUNX2 through Jak2/Stat3 signaling pathway and suppressing OPG. Our findings suggest that targeting FKN/CX3CR1 may provide new strategies for the prevention and treatment of atherosclerotic calcification.


Ambulatory electrocardiographic monitoring: can we predict sudden death?
Cardiac arrhythmias can be accurately detected and quantified using ambulatory electrocardiographic monitoring. From a review of major studies, it appears that the presence of advanced ventricular arrhythmias identifies a subset of patients with coronary heart disease who are at a relatively higher risk for sudden death than are those patients without such arrhythmias. Left ventricular dysfunction is an independent and additive risk factor for subsequent development of sudden cardiac death. The presence of high grade ventricular arrhythmias appears to increase the risk for sudden death in patients with hypertrophic and dilated cardiomyopathy. Ambulatory monitoring can be used to identify a subset of patients with coronary disease or cardiomyopathy who are at increased risk for sudden cardiac death. Because of the relatively low overall incidence of sudden cardiac death in such patients, and the low sensitivity and specificity for accurately classifying patients, the practical applicability of this technique to large population subgroups is limited.


Autonomic nervous system activity in primary Raynaud's phenomenon: Heart rate variability, plasma catecholamines and [123 I]MIBG heart scintigraphy.
Primary Raynaud's phenomenon (pRP) is characterized by an exaggerated response to cold, resulting in the whitening typically of the fingers and toes. The patients are generally perceived as healthy individuals with a benign condition. However, the condition has been associated with increased cardiovascular mortality and changes in autonomic nervous system activity. This study aimed to investigate whether pRP is associated with pervasive changes in autonomic nervous activity. The hypothesis was that patients with pRP have increased sympathetic nervous activity. The autonomic nervous activity of 22 patients with pRP was investigated by means of heart rate variability (HRV) and the plasma catecholamine response to head-up tilt and compared with 22 age- and gender-matched controls. In addition, the patients were examined with a [123 I]metaiodobenzylguanidine heart scintigraphy and compared with an external control group. The plasma norepinephrine response to head-up tilt was significantly lower in the patient group than in the control group. Similarly, the heart scintigraphy revealed a lower heart-to-mediastinum ratio in the patient group than in the control group. HRV analysis did not reveal significant differences between the groups. The findings of the study showed that the autonomic nervous activity of patients with pRP was altered compared with the activity of healthy individuals. This was observed both during rest and after positional stress, but the findings did not uniformly concur with our initial hypothesis.


The influence of essential oils on the process of wound healing: a review of the current evidence.
This paper reports on a literature review of evidence on the influence of essential oils on wound healing and their potential application in clinical practice. It focuses mainly on tea tree, lavender, chamomile, thyme and ocimum oils.


Dietary Weight Loss, Exercise, and Inflammation in Older Adults with Overweight or Obesity and Cardiometabolic Disease.
This study aimed to examine exercise modality during weight loss on change in inflammation among older adults with overweight or obesity and cardiometabolic disease. A total of 222 older adults with a mean (SD) age of 66.9 (4.7) years and a mean (SD) BMI of 33.5 (3.5) kg/m2 were randomized to weight loss (WL; n = 68), WL plus aerobic training (WL + AT; n = 79), or WL plus resistance training (WL + RT; n = 75) for 18 months. C-reactive protein (CRP) and interleukin-6 were measured at baseline, 6 months, and 18 months. All groups lost significant weight from baseline to 18 months, with average adjusted changes of -5.5% for WL, -9.0% for WL + AT, and -10.1% for WL + RT. WL + RT and WL + AT lost significantly more weight than WL (P < 0.05). At 18 months, CRP values in WL + RT were significantly lower than WL (2.25 pg/mL vs. 3.38 pg/mL; P = 0.004). The only difference in interleukin-6 was that at 18 months, WL + RT was lower than WL + AT (2.32 pg/mL vs. 2.75 pg/mL; P = 0.03). The addition of RT during WL was more effective at reducing levels of CRP than WL. Although results were in the expected direction, there was no difference in CRP between WL and WL + AT.


Perinephric Transplant Myelolipoma: A Case Report of a Rare Entity.
Myelolipomas are benign tumors usually found in adrenal glands. They can also be found extra-adrenally, either in 1 or multiple locations. Perinephric transplant myelolipoma has rarely been reported in the English literature. There's only been 1 instance of such a case reported in a kidney transplant patient, which was found on the explanted kidney. We report a case involving an asymptomatic patient with an ill-defined perinephric transplant mass. The mass was then identified as myelolipoma on biopsy. The patient was then managed conservatively with serial imaging and laboratory testing. At the time of our report, the patient continues to have stable renal function and is doing well 24 months after the mass was first identified. We report the first case of perinephric transplant myelolipoma in a patient with ongoing stable renal allograft function. Based on our case report, we recommended that conservative management with serial imaging and routine testing be considered for patients with perinephric transplant myelolipoma.


Reliable and mobile all-fiber modular optical tweezers.
Miniaturization and integration of optical tweezers are attractive. Optical fiber-based trapping systems allow optical traps to be realized in miniature systems, but the optical traps in these systems lack reliability or mobility. Here, we present the all-fiber modular optical tweezers (AFMOTs), in which an optical trap can be reliably created and freely moved on a sample substrate. Two inclined optical fibers are permanently fixed to a common board, rendering a modular system where fiber alignments are maintained over months. The freely movable optical trap allows particles to be trapped in their native locations. As a demonstration, we applied AFMOTs to trap and deform freely floating individual cells. By the cell mechanical responses, we differentiated the nontumorigenic breast epithelial cell line (MCF10A) from its cancerous PTEN mutants (MCF10 PTEN-/-). To further expand the functionalities, three modalities of AFMOTs are demonstrated by changing the types of fibers for both the optical trap creation and particle position detection. As a miniature and modular system that creates a reliable and mobile optical trap, AFMOTs can find potential applications ranging from point-of-care diagnostics to education, as well as helping transition the optical trapping technology from the research lab to the field.


[Permanent endocardial pacing. Experience on 1678 patients. (De Gasperis Cardiology Center--Ente Ospedaliero Niguarda--Milano) (author's transl)].
The Authors report on eleven years and six months experience with permanent endocardial pacing in the treatment of various conduction disturbances. This experience relates to 1678 patients, 3617 pacers were used. The age of the patients ranges from 60 to 80 (70%), 30% referring to the remaining decades, minimum 14--maximum 94. Fixed rate pacers were used in 31% of cases, QRS synchronous or QRS inhibited pacers were used in 69%. Average life of the pacers varies from 25 to 29 months; the average life of fixed rate pacer is higher. Complications and causes of failures, among which electrode dislodgement is the most relevant and frequent, as well as the relative therapeutical treatments, are described. Early mortality is about 1% and late mortality 20%; the survival rate calculated altogether after 11 years and 6 months treatment with implantable pervenous pacing is about 16%.


Sheep fed with banana leaf hay reduce ruminal protozoa population.
A ciliate protozoa suppression can reduce methane production increasing the energy efficiency utilization by ruminants. The physicochemical characteristics of rumen fluid and the profile of the rumen protozoa populations were evaluated for sheep fed banana leaf hay in replacement of the Cynodon dactylon cv. vaqueiro hay. A total of 30 male sheep were raised in intensive system during 15 days of adaptation and 63 days of experimental period. The animals were distributed in a completely randomized design that included six replicates of five treatments with replacement levels (0, 25, 50, 75, and 100%) of the grass vaquero for the banana leaf hay. Samples of fluid were collected directly from the rumen with sterile catheters. Color, odor, viscosity, and the methylene blue reduction potential (MBRP) were evaluated and pH estimated using a digital potentiometer. After decimal dilutions, counts of genus protozoa were performed in Sedgewick Rafter chambers. The averages of pH, MBRP, color, odor, and viscosity were not influenced by the inclusion of the banana leaf hay. However, the total number of protozoa and Entodinium spp. population significantly decreased at 75 and 100% inclusions of banana leaf hay as roughage.


Clinical Implementation of Platelet- and Extracellular Vesicle-Rich Product Preparation Protocols.
Extracellular vesicles (EVs) are considered essential mediators of regenerative roles of autologous platelet- and extracellular vesicle-rich plasma (PVRP) and platelet- and extracellular vesicle-rich gel (PVRG). PVRP and PVRG are novel blood-derived products gaining attraction in regenerative medicine. However, despite their reported good efficacy, their preparation protocols are too time-consuming. Moreover, patient-tailored preparation protocols are desired to optimize platelet and EV count in PVRP and PVRG. This article presents the clinical implementation of one-step, patient-tailored erythrocyte sedimentation rate (ESR)-based, PVRP and PVRG preparation protocols through the presentation of three cases: (1) large chronic tympanic membrane (TM) perforation, (2) osteoradionecrosis of the lateral skull base, and (3) cerebrospinal fluid (CSF) leak in the sphenoid sinus. These were treated with PVRP and PVRG, prepared according to our preclinically constructed mathematical sedimentation model of cells and EVs based on the patient's ESR. (1) TM healed completely after the treatment with 3.6 mL of PVRP and PVRG (high platelet and EV protocol). The speech discrimination score and air conduction pure tone average improved from 75% to 95% and from 65 to 25 dB, respectively. (2) The osteoradionecrotic surface area decreased from 46 to 18 cm2, and infection was eradicated after six applications of 13-65 mL of PVRG ("half-volume" protocol). (3) No CSF leak recurrence was detected after surgical closure with 30 mL of PVRG postoperatively. Reproducible preparation protocols proved effective, safe, fast, and straightforward enough for the surgical staff to prepare PVRP and PVRG intraoperatively. To alleviate preparation, a calculator is provided. This pilot study presents a sound basis for further studies, which are needed to assess the therapeutic effect of PVRP and PVRG. Impact statement We introduce a clinical implementation of a patient-tailored, erythrocyte sedimentation rate-based platelet- and extracellular vesicle-rich plasma (PVRP) and gel (PVRG) preparation protocol based on a mathematical model. Products proved beneficial in wound healing and were, to our knowledge, used for the first time in the treatment of osteoradionecrosis of the lateral skull base. Furthermore, this reproducible preparation protocol is fast and straightforward to implement in clinical practice. A calculator is provided to alleviate PVRP and PVRG preparation for various clinical scenarios.


Blood-brain barrier mechanisms involved in brain calcium and potassium homeostasis.
This study examined the potential roles of the plasma membrane Ca2+-ATPase (PMCA) at the blood-CSF and blood-brain barriers in brain Ca2+ homeostasis and blood-brain barrier Na+/K+-ATPase subunits in brain K+ homeostasis. During dietary-induced hypo- and hypercalcemia (0.59+/-0.06 and 1.58+/-0.12 mM [Ca2+]) there was no significant change in choroid plexus PMCA (Western Blots) compared to normocalcemic rats (plasma [Ca2+]: 1.06+/-0.11 mM). In contrast, PMCA in cerebral microvessels isolated from hypocalcemic rats was 150% greater than that in controls (p<0.001). Comparison of the alpha3 subunit of Na+/K+-ATPase from cerebral microvessels isolated from hypo-, normo- and hyperkalemic rats (2.3+/-0.1, 3.9+/-0.1 and 7. 2+/-0.6 mM [K+]) showed a 75% reduction in the amount of this isoform during hyperkalemia. None of the other Na+/K+-ATPase isoforms varied with plasma [K+]. These results suggest that both PMCA and the alpha3 subunit of Na+/K+-ATPase at the blood-brain barrier play a role in maintaining a constant brain microenvironment during fluctuations in plasma composition.


The markers of inflammation and endothelial dysfunction in correlation with glycated haemoglobin are present in type 2 diabetes mellitus patients but not in their relatives.
The aim of this study is to test several biomarkers of inflammation, of endothelial dysfunction, glycated haemoglobin, and their reflection in arterial dilatation, in patients with type 2 diabetes mellitus and in their relatives, in order to demonstrate if relatives present markers as a form of precocious indicators of diabetes mellitus. Individuals between 30 and 55 years of age and without clinical arterial disease were divided in three groups: type 2 diabetes mellitus patients without complications (12 men and 18 women); first degree relatives of type 2 diabetes mellitus (14 men and 20 women); and control individuals (9 men and 16 women). Body composition was measured with a bioelectrical impedance analyzer and endothelial function with an eco-Doppler device. We determined glucose, insulin, C-peptide, glycated haemoglobin, fibrinogen, E-selectin, P-selectin, soluble intercellular cell adhesion molecule-1 (ICAM-1), soluble vascular cell adhesion molecule-1 (VCAM-1), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), C-reactive protein (CRP) in plasma. We also studied endothelium independent dilatation and endothelium dependent dilatation. ICAM-1 and VCAM-1 were significantly higher in the diabetic group (237.5+/-43.4 and 692.5+/-168.6 ng/l) than in controls (197.4+/-51.2 and 573.5+/-121.1 ng/l, p=0.011 and 0.013, respectively), but were not higher in the family group (224.5+/-45.2 and 599.8+/-150.4 ng/l). CRP was higher in the diabetic group (3.35+/-3.27 mg/l) than in the other groups (1.28+/-1.29 and 1.61+/-1.54 mg/l, p=0.002) and correlated with glycated haemoglobin. The non-endothelium mediated dilatation was lesser in the diabetic group than in the family group (17.3+/-6.1 vs. 24+/-8, p=0.029) and controls. In conclusion patients with uncomplicated type 2 diabetes, but not their relatives, have biochemical markers of sub-clinical inflammation in relationship with glycated haemoglobin and dysfunction of the endothelial cells markers. In these patients endothelium independent dilatation is more affected than endothelium dependent dilatation.


Comprehensive genomic profile of Chinese lung cancer patients and mutation characteristics of individuals resistant to icotinib/gefitinib.
Lung cancer is the leading causes of cancer-related death worldwide. Precise treatment based on next-generation sequencing technology has shown advantages in the diagnosis and treatment of lung cancer. This cohort study included 371 lung cancer patients. The lung cancer subtype was related to the smoking status and sex of the patients. The most common mutated genes were TP53 (62%), EGFR (55%), and KRAS (11%). The mutation frequencies of EGFR, TP53, PIK3CA, NFE2L2, KMT2D, FGFR1, CCND1, and CDKN2A were significantly different between lung adenocarcinoma and lung squamous cell carcinoma. We identified the age-associated mutations in ALK, ERBB2, KMT2D, RBM10, NRAS, NF1, PIK3CA, MET, PBRM1, LRP2, and CDKN2B; smoking-associated mutations in CDKN2A, FAT1, FGFR1, NFE2L2, CCNE1, CCND1, SMARCA4, KEAP1, KMT2C, and STK11; tumor stage-associated mutations in ARFRP1, AURKA, and CBFB; and sex-associated mutations in EGFR. Tumor mutational burden (TMB) is associated with tumor subtype, age, sex, and smoking status. TMB-associated mutations included CDKN2A, LRP1B, LRP2, TP53, and EGFR. EGFR amplification was commonly detected in patients with acquired lcotinib/gefitinib resistance. DNMT3A and NOTCH4 mutations may be associated with the benefit of icotinib/gefitinib treatment.


Optically-induced changes in tonic vergence and AC/A ratio in normal monkeys and monkeys with lesions of the flocculus and ventral paraflocculus.
Monkeys wore either base-out prisms to promote changes in tonic vergence or periscopic spectacles to promote changes in the coupling between accommodation and vergence. Eye movements were recorded using the magnetic search coil technique and the monkeys were rewarded for accurate fixation. Two normal monkeys and two monkeys which had previously received lesions of the flocculus and ventral paraflocculus were studied. After 30 min of prism viewing the two normal monkeys had elevated phoria--increased by approximately 50% of the prism stimulus. The two lesioned monkeys also had phoria increases of a similar size after prism viewing. The effect of duration of prism viewing on the magnitude and time course of phoria elevation was studied in one normal monkey. The initial magnitude of phoria elevation and the time constant of relaxation of phoria both increased as the duration of prism exposure varied from 5 s to 30 min. Initial phoria increased approximately in proportion to the logarithm of duration of prism exposure whereas the time constant of phoria relaxation increased linearly with duration. In the same normal monkey it was shown that increasing vergence by means of accommodative-vergence did not induce phoria changes. The effect of periscopic spectacle viewing was studied in all four monkeys. After 30 min of periscopic spectacle viewing all four monkeys had a higher AC/A ratio. The magnitude of the changes was (paradoxically) greater in the two lesioned monkeys than in the one normal monkey studied fully.(ABSTRACT TRUNCATED AT 250 WORDS)


[3H] GBR 12935 binding to the dopamine uptake site in post-mortem brain tissue in schizophrenia.
Specific [3H] GBR 12935 binding was performed on striatal tissue (caudate nucleus) obtained post-mortem from brains of schizophrenic patients and matched controls. Scatchard analysis of left and right hemisphere caudate tissue was performed on each individual subject. Kd and Bmax values were obtained by linear regression analysis of Scatchard plots. The results indicated no change in either the density or the affinity of the dopamine uptake site between schizophrenics and controls. Comparison of left and right hemisphere data also failed to demonstrate any asymmetry in the populations of dopamine uptake sites in both groups studied. The results do not support the hypothesis of a functional alteration of presynaptic dopamine systems in the caudate nucleus in schizophrenia.


hERG1 and CA IX expression are associated with disease recurrence in surgically resected clear cell renal carcinoma.
In search of novel prognostic biomarkers for clear cell renal carcinoma (ccRCC), we analysed the expression of several proteins related to angiogenesis and hypoxia. A monocentric study on 30 consecutive surgical samples from surgically-treated ccRCC patients with a 10-year follow up was performed. The following proteins were analysed by immunohistochemistry: Vascular Endothelial Growth Factor- A (VEGF-A), Platelet-Derived Growth Factor β Receptor (PDGFRβ), VEGF-receptor 1 (Flt1), VEGF-receptor 2 (KDR), Glucose Transporter 1 (GLUT1), Carbonic anhydrase IX (CA-IX) and the hERG1 potassium channel. Data were analysed in conjunction with the clinico-pathological characteristics of the patients and follow up. All the proteins were expressed in the samples, with statistically significant associations of VEGF-A with PDGFRβ and Flt1 and hERG1 with CA IX. Notably, hERG1 and CAIX co-immunoprecipitated in primary ccRCC samples and survival analysis showed that the positivity for hERG1 and CA IX had a negative impact on Recurrence Free Survival (RFS) at the univariate analysis. At the multivariate analysis only hERG1 maintained its statistically significant negative impact. hERG1 expression can be exploited to predict recurrence in surgically-treated ccRCC patients. hERG1 channels form a multiprotein complex with the pH regulator CA IX in primary ccRCC samples their potential use as therapeutic target might be suggested.


Correlated intramolecular motions and diffuse X-ray scattering in lysozyme.
Correlated motions of protein atoms are of biological significance in processes involving ligand binding, conformational change and information transmission. X-ray scattering patterns from protein crystals contain diffuse scattering that originates from correlated displacements of atoms. Here we present experimental data on diffuse X-ray scattering from lysozyme crystals. We show that the diffuse scattering is similar in form to scattering derived from molecular dynamics simulation and normal mode analysis of the isolated protein, the normal modes giving the closest agreement with experiment.


A definition of catheter-related infection.
There is controversy about the definitions of catheter-related infection. The term "infection" implies a physiological reaction by the patient to a pathogenic microorganism. However, the organism has no pathognomonic infectious reaction to a colonised catheter, with the exception of a local exit-site infection. Therefore, suggestions have been made that the definition of catheter-related infection should be based solely on the degree of bacterial colonisation, i.e. the number of colony forming units recovered from the catheter. Although this method does not define catheter-related infections in the strict sense, the approach may be useful for comparing various studies carried out on this topic. However, various methods are used to analyse intraluminal and/or extraluminal colonisation, and comparison of data across studies is difficult. Ideally studies addressing this issue should use a combination of different methods to analyse catheter colonisation. On the basis of microbiological semi-quantitative or quantitative analysis of bacterial colonisation, an attempt should be made to correlate the clinical symptoms of infection to these culture results in order to define useful cutoff values.


High resolution microarray CGH and MLPA analysis for improved genotype/phenotype evaluation of two childhood genetic disorder cases: ring chromosome 19 and partial duplication 2q.
A detailed analysis of the constitutional chromosomal changes in two pediatric patients was performed using high resolution genetic analysis techniques, microarray comparative genomic hybridization (array CGH) and multiplex ligation-dependent probe amplification (MLPA) as well as FISH. The aim was to come to a more precise characterization of the genotype/phenotype relationship. Case 1 was a girl of 25 months, showing areas of hypopigmentation along the lines of Blaschko and no other developmental abnormality. She carried a ring chromosome 19 which we found not to have resulted in loss of subtelomeric sequences, ruling out the possibility that a small subtelomeric loss was causally related to this patient's phenotype. Case 2 was a 9-year-old girl with facial anomalies and mild growth and mental retardation carrying an unidentified addition on chromosome 2p. We found that the addition was duplicated 2q35-q37.3 and that the addition was not accompanied by loss of 2pter or any other chromosomal region. Together with literature data, we hypothesize that pediatric patients with 'pure' trisomy 2q including bands 2q35-q37.1 may have a moderate clinical phenotype as opposed to patients with duplications proximal to 2q33 or patients with duplications 2q3 with accompanying distal deletion. These two examples illustrate the additional value of new, high resolution genetic analysis techniques for a better characterization of the genotype/phenotype relationship in childhood chromosomal disorders.


Synthesis of spiropyrans via the Rh(III)-catalyzed annulation of 3-aryl-2H-benzo[b][1,4]oxazines with diazo ketoesters.
Rh(III)-Catalyzed 1 : 2 coupling of 3-aryl-2H-benzo[b][1,4]oxazines with α-diazo-β-ketoesters has been realized for the mild synthesis of spiropyrans. The reaction proceeded via twofold C-H activation followed by unusual [3+3] and [4+2] annulation with decent functional group tolerance. Moreover, a pyranoid-skeleton intermediate was isolated as a key intermediate as a result of monoalkylation and enol oxygen annulation, which offers direct mechanistic insight.


Secondary Metabolites with Nitric Oxide Inhibition from Marine-Derived Fungus Alternaria sp. 5102.
Two new benzofurans, alternabenzofurans A and B (1 and 2) and two new sesquiterpenoids, alternaterpenoids A and B (3 and 4), along with 18 known polyketides (5-22), were isolated from the marine-derived fungus Alternaria sp. 5102. Their structures were elucidated on the basis of extensive spectroscopic analyses (1D and 2D NMR, HR-ESIMS, and ECD) and X-ray crystallography, as well as the modified Mosher's method. Compounds 2, 3, 5, 7, 9-18, and 20-22 exhibited potent anti-inflammatory activity by inhibiting the production of NO in RAW264.7 cells activated by lipopolysaccharide with IC50 values in the range from 1.3 to 41.1 μM. Structure-activity relationships of the secondary metabolites were discussed.


Specific depressive symptoms predict remission to aripiprazole augmentation in late-life treatment resistant depression.
To identify which specific depressive symptoms predict remission to aripiprazole augmentation in late-life treatment resistant depression. This is a secondary analysis of data from a late-life treatment resistant depression trial examining the safety and efficacy of aripiprazole augmentation. Participants aged 60 and above were randomized to aripiprazole augmentation (N = 91) versus placebo (N = 90). The main outcome was depression remission. Clinical predictors included individual Montgomery-Asberg Depression Rating Scale (MADRS) item scores categorized as symptomatic (scores >2) or nonsymptomatic (scores ≤2). Three MADRS items predicted depression remission with aripiprazole augmentation: symptomatic scores on sleep disturbance and nonsymptomatic scores on apparent sadness and inability to feel. The 2-way and 3-way interaction terms of these MADRS items were not significant predictors of remission; therefore, the models' ability to predict remission was not improved by combining the significant MADRS items. The identification of specific depressive symptoms, which can be clinically assessed, can be used to inform treatment decisions. Older adults with treatment resistant depression that present with sleep disturbances, lack of apparent sadness, or lack of inability to feel should be considered for aripiprazole augmentation.


Synthesis of brain DNA during acquisition of an active avoidance task.
The possible involvement of cerebral DNA synthesis in the learning process was examined in rats injected intracerebrally with 3H thymidine. During the period of incorporation (4.5 hr) one rat was trained to an active avoidance task while a second animal was kept in the same experimental room. In comparison with control rats paired to learning animals, the concentration of PCA-soluble radioactivity and of radioactive DNA of the cerebral cortex increased in all animal groups, i.e., control rats paired to non-learning animals, learning rats and non-learning rats. No change occurred in liver. In the cerebral cortex the slope of the regression line obtained by plotting the concentration of radioactive DNA versus the concentration of PCA-soluble radioactivity was lower in learning rats than in the group of pooled control animals. A comparable effect was noted in the hippocampus. In non-learning animals a similar decrease was present in the cerebral cortex and in cerebellum. In addition, it was found that in learning animals the percent incorporation was inversely related to the total number of avoidances only in the cerebral cortex. In non-learning rats a similar inverse relationship was present in the cerebral cortex and in cerebellum. In the former region the regression line of learning rats was shifted upwards in comparison with the regression line of non-learning animals. These results are interpreted to indicate that the incorporation of 3H-thymidine into cerebral DNA is directly related to the level of stress and is increased by learning.


Immunization of bovines with an aspartic proteinase precursor isolated from Boophilus microplus eggs.
The capacity of the Boophilus Yolk pro-Cathepsin (BYC) to induce a protective immune response in cattle against Boophilus microplus infestation was tested by vaccination experiments and by inoculation of monoclonal antibody (MAb) against BYC into fully engorged tick females. In immunization experiments the measurement of various biological parameters demonstrated a partial protection against B. microplus. A continuous decrease in the levels of specific antibodies was observed over 11 months when six bovines were maintained in field conditions. The inoculation of the MAb into tick females produced a dose-dependent decrease in oviposition and survival of the ectoparasite compared to the control.


Attitudes toward Alzheimer's disease and dementia caregiving and health outcomes: Racial and ethnic differences.
This study aimed to explore racial/ethnic differences in the attitudes toward Alzheimer's Disease (AD) and dementia caregiving among midlife women who were family caregivers of persons living with AD (MWPLAD) in the U.S. and examine the associations of the attitudes to their health outcomes. This was a cross-sectional online survey study among 172 MWPLAD. The instruments included: the Attitude toward AD and Related Dementias Scale, the Questions on Attitudes toward AD Caregiving, the Social Readjustment Rating Scale, the EQ-5D-5L and the Midlife Women's Symptom Index. Multiple linear regression analyses were conducted. There were significant racial/ethnic differences in caregivers' attitudes toward dementia caregiving, health-related quality of life, and total severity scores of symptoms (p < .01). Controlling for covariates including race/ethnicity, caregivers' positive attitudes toward dementia caregiving were significantly associated with their health outcomes (p ≤ .05). Interventions for MWPLAD need to consider racial/ethnical differences in their attitudes toward dementia caregiving.


Contemporary management of stage I and II seminoma.
Seminoma represents about 60 % of all testicular germ cell tumors. At presentation about 80 % of patients have stage I and about 15 % have stage II disease. The last three decades have seen a substantial change in the philosophy of management with the success of surveillance as a strategy to minimize unnecessary treatment, recognition of the late effects of radiation therapy, and the success of cisplatin-based chemotherapy as curative treatment either in the first-line or salvage setting. Overall, in stage I disease where 80-85 % are cured with orchiectomy alone, efforts now are directed at reducing the burden of the disease and its diagnosis on patients with increasing utilization of surveillance and decreased employment of adjuvant therapy. For stage II disease, balancing the relative toxicities of radiation and chemotherapy while avoiding the use of multimodality therapy due to the additive long-term toxicity has become the priority.


Mg(++)-induced endothelial cell migration: substratum selectivity and receptor-involvement.
The activation of endothelial cells during angiogenesis requires cell spreading and migration. These processes are influenced by extracellular signals such as chemoattractants from the local microenvironment. We have shown previously that transmembrane Ca++ influx is necessary for motility and cell spreading, thus we hypothesized that the extracellular divalent cations Mg++ and Ca++ may regulate human umbilical vein endothelial cell (HUVEC) spreading and act as chemoattractants. Studies demonstrated that extracellular Mg++ induced a statistically better spread phenotype when cells were plated on multiple extracellular matrix substrata; Ca++ promoted cell spreading only on vitronectin. Mg++ but not Ca++ acted as a potent chemoattractant when HUVEC migrated on gelatin- and type IV collagen- but not on vitronectin-coated filters. A checkerboard analysis of migration showed that Mg++ induces both chemokinetic and chemotactic migration peaking at 0.1 and 10 mM, respectively. An equivalent effect of oligomycin was seen on motility to Mg++ or to vascular endothelial growth factor (VEGF) in extracellular Mg(++)-free conditions, ruling out an exclusive role for Mg++ as a migration energy producer. The Mg(++)-stimulated chemotaxis was inhibited > 60% by pertussis toxin, d-erythrosphingosine, and tyrphostin B48, but unaffected by cholera toxin exposure. These data suggest that Mg(++)-induced chemotaxis may be promoted through a Gi protein-coupled receptor pathway with a requirement for protein kinase C activity and protein tyrosine phosphorylation. Thus, Mg++ may be a newly recognized receptor-mediated chemoattractant for endothelial cells.