Ghrelin, hypothalamus-pituitary-adrenal (HPA) axis and Cushing's syndrome.
Ghrelin, a peptide predominantly produced by the stomach, has been discovered as a natural ligand of the GH Secretagogue receptor type 1a (GHS-R1a), known as specific for synthetic GHS. Ghrelin has recently attracted considerable interest as a new orexigenic factor. However, ghrelin exerts pleiotropic actions that are explained by the widespread distribution of ghrelin and GHS-R expression. Besides strong stimulation of GH secretion, the neuroendocrine ghrelin actions also include significant stimulation of both lactotroph and corticotroph secretion; all these actions depend on acylation of ghrelin in serine-3 that allows binding and activation of the GHS-R1a. However, GHS-R subtypes are likely to exist; they also bind unacylated ghrelin that is, in fact, the most abundant circulating form and exerts some biological actions. Ghrelin secretion is mainly regulated by metabolic signals, namely inhibited by feeding, glucose and insulin while stimulated by energy restriction. The role of glucocorticoids on ghrelin synthesis and secretion is still unclear although morning ghrelin levels have been found reduced in some patients with Cushing's syndrome; this, however, would simply reflect its negative association to body mass. Ghrelin, like synthetic GHS, stimulates ACTH and cortisol secretion in normal subjects and this effect is generally sensitive to the negative glucocorticoid feedback. It is remarkable that, despite hypercortisolism, ghrelin as well as synthetic GHS display marked increase in their stimulatory effect on ACTH and cortisol secretion in patients with Cushing's disease. This is even more intriguing considering that the GH response to ghrelin and GHS is markedly reduced by glucocorticoid excess. It has been demonstrated that the ACTH-releasing effect of ghrelin and GHS is purely mediated at the central level in physiological conditions; its enhancement in the presence of ACTH-secreting tumours is, instead, likely to reflect direct action on GHS receptors present on the neoplastic tissues. In fact, peculiar ACTH hyperresponsiveness to ghrelin and GHS has been observed also in ectopic ACTH-secreting tumours.


A look-up-table digital predistortion technique for high-voltage power amplifiers in ultrasonic applications.
In this paper, we present a digital predistortion technique to improve the linearity and power efficiency of a high-voltage class-AB power amplifier (PA) for ultrasound transmitters. The system is composed of a digital-to-analog converter (DAC), an analog-to-digital converter (ADC), and a field-programmable gate array (FPGA) in which the digital predistortion (DPD) algorithm is implemented. The DPD algorithm updates the error, which is the difference between the ideal signal and the attenuated distorted output signal, in the look-up table (LUT) memory during each cycle of a sinusoidal signal using the least-mean-square (LMS) algorithm. On the next signal cycle, the error data are used to equalize the signal with negative harmonic components to cancel the amplifier's nonlinear response. The algorithm also includes a linear interpolation method applied to the windowed sinusoidal signals for the B-mode and Doppler modes. The measurement test bench uses an arbitrary function generator as the DAC to generate the input signal, an oscilloscope as the ADC to capture the output waveform, and software to implement the DPD algorithm. The measurement results show that the proposed system is able to reduce the second-order harmonic distortion (HD2) by 20 dB and the third-order harmonic distortion (HD3) by 14.5 dB, while at the same time improving the power efficiency by 18%.


Discovery of Selective Toxoplasma gondii Dihydrofolate Reductase Inhibitors for the Treatment of Toxoplasmosis.
A safer treatment for toxoplasmosis would be achieved by improving the selectivity and potency of dihydrofolate reductase (DHFR) inhibitors, such as pyrimethamine (1), for Toxoplasma gondii DHFR ( TgDHFR) relative to human DHFR ( hDHFR). We previously reported on the identification of meta-biphenyl analog 2, designed by in silico modeling of key differences in the binding pocket between TgDHFR and hDHFR. Compound 2 improves TgDHFR selectivity 6.6-fold and potency 16-fold relative to 1. Here, we report on the optimization and structure-activity relationships of this arylpiperazine series leading to the discovery of 5-(4-(3-(2-methoxypyrimidin-5-yl)phenyl)piperazin-1-yl)pyrimidine-2,4-diamine 3. Compound 3 has a TgDHFR IC50 of 1.57 ± 0.11 nM and a hDHFR to TgDHFR selectivity ratio of 196, making it 89-fold more potent and 16-fold more selective than 1. Compound 3 was highly effective in control of acute infection by highly virulent strains of T. gondii in the murine model, and it possesses the best combination of selectivity, potency, and prerequisite drug-like properties to advance into IND-enabling, preclinical development.


Vascular ring anomalies in cats: 20 cases (2000-2018).
To report the clinical characteristics, types of vascular ring anomalies (VRA), operative findings, complications, and survival after surgical treatment of cats with VRA. Retrospective, multi-institutional case series. Client- or shelter-owned cats presenting to academic, referral veterinary institutions. Medical records of cats with VRA that underwent surgical treatment were reviewed. Signalment, relevant medical history, clinical signs, diagnostic imaging, surgical findings, complications, and survival were recorded. Twenty cats with VRA were included. Vascular ring anomalies were most commonly (75% [15/20]) diagnosed in cats less than 1 year old, with no breed or sex predilection. Regurgitation was the most common clinical sign, present in 18 of 20 (90%) cats. A persistent right aortic arch was diagnosed in 17 of 20 (85%) cats, with concurrent aberrant left subclavian artery in four of the cats. Surgical treatment was associated with survival to discharge in 18 of 20 (90%) cats. Persistent clinical signs were reported in nine of 13 (69%) cats, and radiographic evidence of megaesophagus persisted in four of 13 (31%) cats, with a median follow-up of 275 days after discharge. Persistent right aortic arch was the most commonly diagnosed VRA in cats in this series, although multiple anomalies were observed. Surgical treatment of VRA in cats was associated with a high survival to discharge, although persistence of clinical signs and megaesophagus was noted in 69% and 31% of the cats, respectively. Surgical treatment of VRA in cats is associated with a high survival rate; however, persistence of clinical signs is an expected outcome.


Social support buffers the effect of self-esteem on quality of life of early-stage cervical cancer survivors in Taiwan.
The purpose of this study was to examine the effects of self-esteem and social support on quality of life (QoL) in stage I and II cervical cancer survivors. The sample consisted of 110 participants who had been diagnosed with stage I-II cervical cancer and had completed their treatment 5 years or more before data collection. Each participant completed four structured questionnaires: a demographic-disease survey, the Rosenberg Self-Esteem Scale, Medical Outcomes Study Social Support Survey, and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30. Data were analyzed using descriptive statistics, independent sample t-test, one-way ANOVA, and hierarchical multiple linear regression analyses. The participants' mean age was 60.74 ± 10.69 years. Better QoL was significantly associated with younger age, higher self-esteem, and stronger social support; in addition, social support buffered the effect of self-esteem on global QoL. Together, five variables (age, time since treatment, self-esteem, social support, and the interaction term of self-esteem and social support) explained 36% of the variance in global QoL, with self-esteem being the strongest predictor. The results of this study advance current knowledge of QoL in cervical cancer survivors by demonstrating that survivors with low self-esteem and social support tend to have lower QoL than those with low self-esteem but high social support. Health professionals should help survivors seek support and provide appropriate strategies to expand their social networks and enhance their self-esteem to improve their global QoL after cervical cancer.


Levels of human erythrocyte membrane-bound and cytosolic glycohydrolases are associated with oxidative stress in erectile dysfunction patients.
Oxidative stress (OS) and production of NO, by endothelium nitric oxide synthetase (eNOS), are involved in the pathophysiology of erectile dysfunction (ED). Moreover, OS induces modifications of the physicochemical properties of erythrocyte (RBC) plasma membranes and of the enzyme content of the same membranes. Due to their role in signalling early membrane alterations in OS-related pathologies, several plasma membrane and cytosolic glycohydrolases of human RBC have been proposed as new markers of cellular OS. In RBC, NOS can be activated and deactivated by phosphorylation/glycosylation. In this regulatory mechanism O-β-N-AcetylGlucosaminidase is a key enzyme. Cellular levels of O-GlcNAcylated proteins are related to OS; consequently dysfunctional eNOS O-GlcNAcylation seems to have a crucial role in ED. To elucidate the possible association between RBC glycohydrolases and OS, plasma hydroperoxides and antioxidant total defenses (Lag-time), cytosolic O-β-N-AcetylGlucosaminidase, cytosolic and membrane Hexosaminidase, membrane β-D-Glucuronidase, and α-D-Glucosidase have been studied in 39 ED patients and 30 controls. In ED subjects hydroperoxides and plasma membrane glycohydrolases activities are significantly increased whereas Lag-time values and cytosolic glycohydrolases activities are significantly decreased. These data confirm the strong OS status in ED patients, the role of the studied glycohydrolases as early OS biomarker and suggest their possible use as specific marker of ED patients, particularly in those undergoing nutritional/pharmacological antioxidant therapy.


Transformation of nanoparticles into compacts: A study on PLGA and celecoxib nanoparticles.
Oral delivery of nanoparticles possesses many advantages for delivery of active pharmaceutical ingredients (APIs) to the gastrointestinal tract. However, the poor physical stability of nanoparticles in liquid state is often a challenge. Removing water from the nanosuspensions and transforming the nanoparticles into solid particulate matter in the form of, e.g., tablets could be a potential approach to increase the stability of nanoparticles. The aim of this study was to transform nanoparticles into compacts and to investigate the redispersion of nanoparticles from compacts as well as the dissolution behavior of these compacts. DL-lactide-co-glycolide copolymer (PLGA) nanoparticles and celecoxib (CLX) nanoparticles were used as two model nanoparticle systems and fabricated into nano-embedded microparticles (NEMs) and subsequently compressed into compacts. The compacts were evaluated with respect to the redispersibility of the nanoparticles, as well as the dissolution characteristics of CLX. The results showed that the NEMs could be readily compressed into compacts with sufficient mechanical strength. The size of the redispersed PLGA nanoparticles from the compacts using 2-hydroxypropyl-β-cyclodextrin (HPβCD) as stabilizer was comparable to the original nanoparticles. In contrast, the redispersibility of CLX nanoparticles from the compacts was not as effective as for the PLGA nanoparticles evidenced by a significant increase in the size and polydispersity index (PDI) of the redispersed nanoparticles. Nonetheless, an obvious enhancement in dissolution rate of CLX was observed from the compacts with CLX nanoparticles. It is concluded that transforming polymeric nanoparticles into compacts via NEMs provides stabilization and allows redispersion into original nanoparticles. Despite the reduced redispersibility, compacts loaded with nanoparticles exhibited improved dissolution rate compared with the crystalline drug. Loading of nanoparticles into compacts is a promising approach to overcome the poor stability of nanoparticle within oral drug delivery of nanoparticles.


Vision-based safe autonomous UAV docking with panoramic sensors.
The remarkable growth of unmanned aerial vehicles (UAVs) has also sparked concerns about safety measures during their missions. To advance towards safer autonomous aerial robots, this work presents a vision-based solution to ensuring safe autonomous UAV landings with minimal infrastructure. During docking maneuvers, UAVs pose a hazard to people in the vicinity. In this paper, we propose the use of a single omnidirectional panoramic camera pointing upwards from a landing pad to detect and estimate the position of people around the landing area. The images are processed in real-time in an embedded computer, which communicates with the onboard computer of approaching UAVs to transition between landing, hovering or emergency landing states. While landing, the ground camera also aids in finding an optimal position, which can be required in case of low-battery or when hovering is no longer possible. We use a YOLOv7-based object detection model and a XGBooxt model for localizing nearby people, and the open-source ROS and PX4 frameworks for communication, interfacing, and control of the UAV. We present both simulation and real-world indoor experimental results to show the efficiency of our methods.


Practitioner ethics and managed care.
Mental health services provided through a managed care company cause some serious ethical concerns for providers and potentially for licensing boards. Confidentiality, record keeping, abandonment of patients, and informed consent are a few of the major issues confronting providers and the patients with whom they work. The importance of these issues for providers and the need for managed care companies and their employees to pay more attention to these ethical problems are covered in this article.


Executive Summary of the NHLBI Workshop Report: Leveraging Current Scientific Advancements to Understand Sarcoidosis Variability and Improve Outcomes.
Sarcoidosis is a systemic granulomatous disease that primarily affects the lung; it is associated with significant disparities, more commonly impacting those in the prime of their lives (age 20-50 yr, with a second peak after age 60 yr), black individuals, and women. However, the burden of disease, the ability to diagnose and prognose organ involvement and course, as well as specific treatment options, management options, and disease pathogenesis remain poorly understood. As a result, the National Heart, Lung, and Blood Institute undertook a sarcoidosis workshop, "Leveraging Current Scientific Advancements to Understand Sarcoidosis Variability and Improve Outcomes," to help address these issues by defining the scientific and clinical priorities to improve sarcoidosis care. The overarching recommendations from this workshop are outlined in the following summary and detailed in the accompanying articles. The recommendations included establishing collaborations and networks to conduct research based on consensus definitions of disease phenotypes and standards of care, and to provide clinical outreach to areas with a burden of disease to improve care. These collaborative networks would also serve as the hub to conduct clinical trials of devastating phenotypes (e.g., cardiac, neurologic, and fibrotic disease) not only for treatment but to enhance our understanding of the burden of disease. In addition, the networks would be used to leverage state-of-the-art "omics" and systems biology research, as well as other studies to advance understanding of disease pathogenesis, and development of biomarkers and therapeutic targets, with a goal to translate this information to improve care of individuals with sarcoidosis.


Infratrochlear neuralgia: A prospective series of seven patients treated with infratrochlear nerve blocks.
Background Infratrochlear neuralgia is a recently described painful cranial neuropathy that causes pain in the internal angle of the orbit and the medial upper eyelid, the upper bridge of the nose and/or the lacrimal caruncle. We aim to present seven new cases of infratrochlear neuralgia treated with anaesthetic nerve blocks. Methods Over an 18-month period, we prospectively identified seven cases of infratrochlear neuralgia among the patients attending the Headache Unit in a tertiary hospital. Anaesthetic blocks were performed by injecting 0.5 cc of bupivacaine 0.5% at the emergence of the nerve above the internal canthus. Results All patients were women, and the mean age was 49.1 years (standard deviation, 17.9). The pain appeared at the internal angle of the orbit and/or the medial upper eyelid in six cases, and the whole territory of the infratrochlear nerve in one case. Six patients had continuous pain and one had episodes lasting 8-24 hours. All patients showed sensory disturbances within the painful area and tenderness upon palpation of the infratrochlear nerve. Nerve blocks resulted in complete and long-lasting relief in four patients and short-lasting relief in the other three patients. Conclusions Infratrochlear neuralgia should be considered among the neuralgic causes of orbital and periorbital pain. Anaesthetic blocks may assist clinicians in the diagnosis and may also be an effective therapy.


The quantitative insulin sensitivity check index is not able to detect early metabolic alterations in young patients with polycystic ovarian syndrome.
To verify whether QUICKY is a suitable method for the identification of metabolic deterioration in normal weight patients affected by polycystic ovarian syndrome (PCOS). Prospective clinical study. Seventy-nine PCOS normal weight adolescent subjects, 50 eumenorrheic, normal weight, non-hirsute controls matched for age and BMI. Quantitative insulin sensitivity check index (QUICKY) and integrated secretory area under the curve of insulin values (I-AUC) during oral glucose tolerance test were calculated. Seventy-nine PCOS and 50 controls were studied. Normal insulin sensitivity was defined as upper control 95th percentile by QUICKY values <0.31, I-AUC at 180 min < 16,645. When applying the calculated I-AUC cut-off, 41 PCOS were classified as normoinsulinemic and 38 as hyperinsulinemic, whereas using the calculated QUICKY cut-off, only 19 PCOS could be classified as insulin resistant (IR). Fifteen out of the 60 non-IR PCOS presented hyperinsulinemia; fasting glucose and insulin levels and QUICKY were not sufficient to identify these subjects. Thus, QUICKY displayed a low sensitivity (44%) and specificity (91%) in the diagnosis of the metabolic disorder disclosed by I-AUC. CONCLUSIONS.: In young normal weight patients with PCOS the prevalence of early alterations of insulin metabolism are not detectable by QUICKY studies.


Team-based care of the thoracic surgical patient.
Although team-based care has been shown in many sectors to improve outcomes, very little work has been done with the thoracic surgical patient. This review article focuses on this and, extrapolating from other closely related surgical fields, teamwork in thoracic surgery will be reviewed for outcome efficacy and substance. The optimal team has been shown to display behaviors that allow them to model future needs, predict disaster, be adaptable to change, and promote team cohesiveness all with a positive effect on perioperative outcome. The suboptimal team will have transactional leadership, poor communication, ineffective conflict resolution, and hold rigid beliefs about other team members. To improve outcome, the thoracic surgical team, centered on the anesthesiologist and surgeon, will display the 'Big 5' attributes of highly effective teams. There are attributes of poor teams, which the dyad should avoid in order to increase the team's function and thus outcome.


The surgical treatment of non-metastatic melanoma in a Clinical National Melanoma Registry Study Group (CNMR): a retrospective cohort quality improvement study to reduce the morbidity rates.
Reproducible, high-quality surgery is a key point in the management of cancer patients. Quality indicators for surgical treatment of melanoma has been presented with benchmarks but data on morbidity are still limited. This study presents the quality indicators on morbidity after surgical treatment for non-metastatic skin melanoma in an Italian registry. Data were extracted from the Central National Melanoma Registry (CNMR) promoted by the Italian Melanoma Intergroup (IMI). All surgical procedures (WE, SNLB or LFND) for non-metastatic skin melanoma between January 2011 and February 2017 were evaluated for inclusion in the study. Only centers with adequate completeness of information (> 80%) were included in the study. Short-term complications (wound infection, dehiscence, skin graft failure and seroma) were investigated. Wound infection rate was 1.1% (0.4 to 2.7%) in WE, 1.3% (0.7 to 2.5%) in SLNB and 4.1% (2.1 to 8.0%) in LFND. Wound dehiscence rate was 2.0% (0.8 to 5.1%) in WE, 0.9% (0.2 to 3.0%) in SLNB and 2.8% (0.9 to 8.6%) in LFND. Seroma rate was 4.2% (1.5 to 11.1%) in SLNB and 15.1% (4.6 to 39.9%) in LFND. Unreliable information was found on skin graft failure. Our findings contribute to available literature in setting up the recommended standards for melanoma centers, thus improving the quality of surgery offered to patients. A consensus on the core issues around surgical morbidity is needed to provide practical guidance on morbidity prevention and management.


COX-2 Regulates the insulin-like growth factor I-induced potentiation of Zn(2+)-toxicity in primary cortical culture.
The pretreatment of cultured cortical neurons with neurotrophic factors markedly potentiates the cytotoxicity induced by low concentrations of Zn(2+) or excitotoxins. In the current study, we investigated the mechanism underlying the insulin-like growth factor-I (IGF-I)-induced Zn(2+) toxicity potentiation. The pretreatment of primary cortical cultures for more than 12 h with 100 ng/ml of IGF-I increased the cytotoxicity induced by 80 microM Zn(2+) by more than 2-fold. The IGF-I-enhanced cell death was blocked by the COX-2-specific inhibitors N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS-398; 10-100 microM) and 1-[(4-methylsulfonyl)phenyl]-3-trifluoro-methyl-5-[(4-fluoro)phenyl]pyrazole (SC58125; 10 microM) and by the antioxidant trolox (30 microM). In addition, it was observed that COX-2 expression was increased 12 to 24 h after IGF-I treatment. Preincubation of cortical cultures with IGF-I increased arachidonic acid (AA)-induced cytotoxicity, and AA increased Zn(2+) toxicity, which suggested the involvement of COX activity in these cellular responses. Moreover, enhanced COX-2 activity led to a decrease in the cell's reducing power, as indicated by a gradual depletion of intracellular GSH. Cortical neurons pretreated with IGF-I and then Zn(2+) showed consistently enhanced reactive oxygen species production, which was repressed by NS-398 and SC58125. Cortical neurons treated with Zn(2+) and then AA displayed the increased ROS production, which was also suppressed by NS-398 and SC58125. These results suggest that COX-2 is an endogenous factor responsible for the IGF-I-induced potentiation of Zn(2+) toxicity and that enhanced COX-2 activity leads to a decrease in the cell's reducing power and an increase in ROS accumulation in primary cortical cultures.


Aggressive Video Games Are Not a Risk Factor for Mental Health Problems in Youth: A Longitudinal Study.
Recent preregistered studies and analyses have suggested that links between aggressive video games (AVGs) and aggression-related outcomes may have been exaggerated in previous literature. However, concerns about AVGs remain. Although the impact of aggressive games on aggressive behaviors has been the subject of approximately a dozen preregistered studies, the potential impact of aggressive games on the player's mental health symptoms has not been the subject of similar preregistered analyses. In the current study, a sample of more than 3000 youth from Singapore were examined by using preregistered analyses to determine whether early exposure to aggressive games was predictive of anxiety, depression, somatic symptoms, or attention deficit hyperactivity disorder 2 years later. Analyses suggested that exposure to AVGs is not a risk factor for later mental health symptoms.


Cytomegalovirus-induced salivary gland pathology: resistance to kinase inhibitors of the upregulated host cell EGFR/ERK pathway is associated with CMV-dependent stromal overexpression of IL-6 and fibronectin.
Recently we identified a relationship between human cytomegalovirus (hCMV) and human salivary gland (SG) mucoepidermoid carcinoma (MEC) in over 90% of cases; tumorigenesis in these cases uniformly correlated with active hCMV protein expression and an upregulation of the EGFR → ERK pathway. Our previously characterized, novel mouse organ culture model of mouse CMV (mCMV)-induced tumorigenesis displays a number of histologic and molecular characteristics similar to human MEC. Newborn mouse submandibular glands (SMGs) were incubated with 1 × 105 PFU/ml of lacZ-tagged mCMV RM427+ on day 0 for 24 hours and then cultured in virus-free media for a total of 6 or 12 days with or without EGFR/ERK inhibitors and/or aciclovir. SMGs were collected for histology, immunolocalization (pERK, FN, IL-6), viral distribution, or Western blot analysis (pERK). Here we report: (1) mouse SMG tumors soon exhibit an acquired resistance to EGFR/ERK pathway kinase inhibitors, alone or in combination; (2) long term tumor regression can only be sustained by concurrent inhibitor and antiviral treatment; (3) CMV-dependent, kinase inhibitor resistance is associated with overexpression of fibronectin and IL-6 proteins in abnormal stromal cells. Acquired resistance to kinase inhibitors is dependent upon CMV dysregulation of alternative pathways with downstream effectors common with the targeted pathway, a phenomenon with important therapeutic implications for human MEC of salivary glands.


Protein tyrosine phosphatase-PEST and β8 integrin regulate spatiotemporal patterns of RhoGDI1 activation in migrating cells.
Directional cell motility is essential for normal development and physiology, although how motile cells spatiotemporally activate signaling events remains largely unknown. Here, we have characterized an adhesion and signaling unit comprised of protein tyrosine phosphatase (PTP)-PEST and the extracellular matrix (ECM) adhesion receptor β8 integrin that plays essential roles in directional cell motility. β8 integrin and PTP-PEST form protein complexes at the leading edge of migrating cells and balance patterns of Rac1 and Cdc42 signaling by controlling the subcellular localization and phosphorylation status of Rho GDP dissociation inhibitor 1 (RhoGDI1). Translocation of Src-phosphorylated RhoGDI1 to the cell's leading edge promotes local activation of Rac1 and Cdc42, whereas dephosphorylation of RhoGDI1 by integrin-bound PTP-PEST promotes RhoGDI1 release from the membrane and sequestration of inactive Rac1/Cdc42 in the cytoplasm. Collectively, these data reveal a finely tuned regulatory mechanism for controlling signaling events at the leading edge of directionally migrating cells.


Chronic facial pain following injection of sodium tetradecyl sulphate into an intraparotid haemolymphangioma.
We report a rare case of chronic facial pain following sclerotherapy for intraparotid haemolymphangioma, thereby highlighting an important clinical consideration when advising this treatment option as an alternative to surgery in the head and neck. Case report, with a review of relevant literature. Sclerotherapy of lymphangiomata is well reported in the literature. Unusually, our young patient with an intraparotid haemolymphangioma experienced severe, chronic pain following intralesional injection of sodium tetradecyl sulphate, which required management by a specialist pain service. We discuss the technique of sclerotherapy for such lesions, and also discuss the potential side effects of two agents commonly used in our centre: OK 432 and sodium tetradecyl sulphate. Non-surgical treatments of lymphangiomata and venous vascular malformations are not without complication. Both patient and clinician should be aware of this, and of the other potential side effects of sclerotherapy, prior to its use in the head and neck.


Giving to the Good and the Needy: Parental Support of Grown Children.
Parents may provide many types of support to their grown children. Parents aged 40 to 60 (N = 633) reported the support they exchange with each child over age 18 (n = 1,384). Mothers and fathers differentiated among children within families, but provided emotional, financial, and practical help on average every few weeks to each child. Offspring received most assistance when they: (a) had greater needs (due to problems or younger age) or (b) were perceived as more successful. Parents received more from high achieving offspring. Findings support contingency theory; parents give more material and financial support to children in need. Motivation to enhance the self or to assure support later in life may explain support to high achieving offspring.


Two-dimensional transition metal carbides as supports for tuning the chemistry of catalytic nanoparticles.
Supported nanoparticles are broadly employed in industrial catalytic processes, where the active sites can be tuned by metal-support interactions (MSIs). Although it is well accepted that supports can modify the chemistry of metal nanoparticles, systematic utilization of MSIs for achieving desired catalytic performance is still challenging. The developments of supports with appropriate chemical properties and identification of the resulting active sites are the main barriers. Here, we develop two-dimensional transition metal carbides (MXenes) supported platinum as efficient catalysts for light alkane dehydrogenations. Ordered Pt3Ti and surface Pt3Nb intermetallic compound nanoparticles are formed via reactive metal-support interactions on Pt/Ti3C2Tx and Pt/Nb2CTx catalysts, respectively. MXene supports modulate the nature of the active sites, making them highly selective toward C-H activation. Such exploitation of the MSIs makes MXenes promising platforms with versatile chemical reactivity and tunability for facile design of supported intermetallic nanoparticles over a wide range of compositions and structures.


Primary talon cusp.
Talon cusps are seen most frequently on maxillary incisors. Only recently have reports of talon cusps on primary teeth appeared. This was a case involving a primary maxillary lateral incisor.


Fast reconstruction of compact context-specific metabolic network models.
Systemic approaches to the study of a biological cell or tissue rely increasingly on the use of context-specific metabolic network models. The reconstruction of such a model from high-throughput data can routinely involve large numbers of tests under different conditions and extensive parameter tuning, which calls for fast algorithms. We present fastcore, a generic algorithm for reconstructing context-specific metabolic network models from global genome-wide metabolic network models such as Recon X. fastcore takes as input a core set of reactions that are known to be active in the context of interest (e.g., cell or tissue), and it searches for a flux consistent subnetwork of the global network that contains all reactions from the core set and a minimal set of additional reactions. Our key observation is that a minimal consistent reconstruction can be defined via a set of sparse modes of the global network, and fastcore iteratively computes such a set via a series of linear programs. Experiments on liver data demonstrate speedups of several orders of magnitude, and significantly more compact reconstructions, over a rival method. Given its simplicity and its excellent performance, fastcore can form the backbone of many future metabolic network reconstruction algorithms.


Colpocephaly in two siblings: further evidence of a genetic transmission.
Colpocephaly is an abnormal congenital enlargement of the occipital horns of the lateral ventricles, which has typically been associated with learning disability, seizures, and motor and visual abnormalities. This study describes familial colpocephaly in two siblings with different fathers in a Dominican family. There were no other neurological problems in their relatives. Child 1 is a 7-year-old girl, who has had partial epileptic seizures since 4 years of age. She attends a mainstream school. She has coloboma and chorioretinic atrophy in her right eye and a right microphthalmia. MRI revealed colpocephaly and hypogenesis of the corpus callosum. Her brother, aged 2 years 8 months showed a mild delay in speech acquisition. He has had three febrile convulsions and two non-febrile tonic-clonic seizures since 6 months of age. Neurological and ophthalmological examinations were normal. MRI documented colpocephaly with right occipital horn prevalence. There are only two literature reports of genetically transmitted colpocephaly hypothesised in two identical twins and in two brothers. In the children in this study, a genetic basis for colpocephaly is confirmed. We hypothesised a maternal transmission with X-linked or autosomal dominance with an incomplete penetrance model of inheritance.


Lower extremity function following partial calcanectomy in high-risk limb salvage patients.
Partial calcanectomy (PC) is an established limb salvage procedure for treatment of deep heel ulceration with concomitant calcaneal osteomyelitis. The purpose of this study is to determine if a relationship exists between the amount of calcaneus removed during PC and the resulting lower extremity function and limb salvage outcomes. Consecutive PC patients were retrospectively divided into two cohorts defined by the amount of calcaneus resected before wound closure: patients in cohort 1 retained = 50% of calcaneus, while patients in cohort 2 underwent resection of >50% of the calcaneus. The Lower Extremity Function Scale (LEFS) was used to assess postoperative lower extremity function. The average amount of calcaneus resected was 13% ± 9.2 (1-39%) and 74% ± 19.5 (51-100) in cohorts 1 and 2, respectively (P < 0.0001). Below knee amputation was performed in 7 (28%) and 5 (29%) of subjects in cohorts 1 and 2, respectively (P = 1.0). The average LEFS score was 33.9 ± 15.0 for subjects in cohort 1 and 36.2 ± 19.9 for the subjects cohort 2 (P = 0.8257) which correlates to "moderate to quite a bit of difficulty." Our study suggests that regardless of the amount of calcaneus resected, PC provides a viable treatment option for high-risk patients with calcaneal osteomyelitis.


Master plan lays foundation for facility investments.
Because construction and renovation projects can involve substantial risk, a healthcare organization should closely assess the economic implications before work begins. A facility master plan--a phased program of facility investment--can forecast the economic value of various options. It also helps ensure that projects comply with a hospital's long-term objectives.


Quality of life and job satisfaction of nurses.
The purpose of this study was to determine whether there is a relation between job satisfactionand quality of life (QOL) of nurses. The study was based on a sample of 501 nurses. Job satisfaction was measured by means of the Short Form Minnesota Questionnaire and QOL by means of WHOQOL-BRIEE The results demostrated a positive correlation between job satisfaction and QOL. It was also found that job satisfaction and QOL scores of nurses showed a significant difference according to their age, economic level, marital status, duration of working life, and position at work.


Efficient Pre-mRNA Cleavage Prevents Replication-Stress-Associated Genome Instability.
Cellular mechanisms that safeguard genome integrity are often subverted in cancer. To identify cancer-related genome caretakers, we employed a convergent multi-screening strategy coupled to quantitative image-based cytometry and ranked candidate genes according to multivariate readouts reflecting viability, proliferative capacity, replisome integrity, and DNA damage signaling. This unveiled regulators of replication stress resilience, including components of the pre-mRNA cleavage and polyadenylation complex. We show that deregulation of pre-mRNA cleavage impairs replication fork speed and leads to excessive origin activity, rendering cells highly dependent on ATR function. While excessive formation of RNA:DNA hybrids under these conditions was tightly associated with replication-stress-induced DNA damage, inhibition of transcription rescued fork speed, origin activation, and alleviated replication catastrophe. Uncoupling of pre-mRNA cleavage from co-transcriptional processing and export also protected cells from replication-stress-associated DNA damage, suggesting that pre-mRNA cleavage provides a mechanism to efficiently release nascent transcripts and thereby prevent gene gating-associated genomic instability.


Air pollution sources and childhood asthma attacks in Catano, Puerto Rico.
Asthma prevalence in the Cataño Air Basin of Puerto Rico is 27% for children aged 13-14 years and 45% for children aged 5-6 years. There is concern that these rates are related to air pollution. The authors conducted a nested case-control study to evaluate whether proximity to air pollution point sources was associated with increased risk of asthma attacks. For 1997-2001, 1,382 asthma-related medical visits (International Classification of Diseases, Ninth Revision, codes 493 and 493.9) in children under 17 were identified through health insurance claims. Controls were children with no asthma attacks who were randomly selected from enrollees in two health insurance companies by incidence density sampling (1:5) and matched to cases on gender, age, insurance company, and event date. The distance from a point source to the subject's residence area represented a surrogate exposure measurement. Odds ratios for a 1-km decrease in distance were obtained by conditional logistic regression. Risk of asthma attack was associated with residing near a grain mill (odds ratio (OR) = 1.35), petroleum refinery (OR = 1.44), asphalt plant (OR = 1.23), or power plant (OR = 1.28) (all p's < 0.05). Residence near major air emissions sources (>100 tons/year) increased asthma attack risk by 108% (p < 0.05). These results showed that proximity to some air pollution sources is associated with increased risks of asthma attacks.


2019 Novel coronavirus: where we are and what we know.
There is a current worldwide outbreak of a new type of coronavirus (2019-nCoV), which originated from Wuhan in China and has now spread to 17 other countries. Governments are under increased pressure to stop the outbreak spiraling into a global health emergency. At this stage, preparedness, transparency, and sharing of information are crucial to risk assessments and beginning outbreak control activities. This information should include reports from outbreak sites and from laboratories supporting the investigation. This paper aggregates and consolidates the virology, epidemiology, clinical management strategies from both English and Chinese literature, official news channels, and other official government documents. In addition, by fitting the number of infections with a single-term exponential model, we report that the infection is spreading at an exponential rate, with a doubling period of 1.8 days.


[18F]fluoro-L-dopa for the in vivo study of intracerebral dopamine.
6-[18F]Fluoro-L-dopa was designed to trace the dopamine metabolism in the brain with positron tomography. 6-[18F]Fluoro-L-dopa resembles natural L-dopa biochemically, it crosses the blood-brain barrier with the similar kinetics, it is decarboxylated by dopa decarboxylase and is stored intraneuronally in vesicles. In addition the rate of O-methylation of 6-[18F]fluoro-L-dopa by catechol-O-methyl transferase is only 1/4 of that of natural L-dopa. The low rate of O-methylation, especially in the periphery, is particularly beneficial for PT investigations of the brain. The radiotracer has been synthesized using a variety of electrophilic fluorinating agents.


[Drug modulation of thromboxane A2/prostacyclin balance and lipid peroxidation in patients with coronary artery disease].
Sixty patients with coronary artery disease (CAD) were investigated in a randomized, placebo-controlled study. Therapeutic dose of diltiazem markedly inhibited the production of whole blood thromboxane A2(TXA2), but had no effect on the production of prostacyclin(PGI2). Both aspirin 20mg/d and diltiazem plus aspirin had marked inhibitive effects on both TXA2 and PGI2. The order of potency of the three regimens in decreasing TXA2/PGI2 ratio was diltiazem plus aspirin greater than diltiazem greater than aspirin. Diltiazem, aspirin and combination of both all decreased significantly serum lipid peroxides level, but had no effect on serum superoxide dismutase concentration. The results indicate that both therapeutic dose of diltiazem and low-dose of aspirin may modulate TXA2/PGI2 balance and inhibit lipid peroxidation in CAD and that the combination of both drugs may result in best therapeutic effect.


Use of a green fluorescent strain for analysis of Xylella fastidiosa colonization of Vitis vinifera.
Xylella fastidiosa causes Pierce's disease of grapevine as well as several other major agricultural diseases but is a benign endophyte in most host plants. X. fastidiosa colonizes the xylem vessels of host plants and is transmitted by xylem sap-feeding insect vectors. To understand better the pattern of host colonization and its relationship to disease, we engineered X. fastidiosa to express a green fluorescent protein (Gfp) constitutively and performed confocal laser-scanning microscopic analysis of colonization in a susceptible host, Vitis vinifera. In symptomatic leaves, the fraction of vessels colonized by X. fastidiosa was fivefold higher than in nearby asymptomatic leaves. The fraction of vessels completely blocked by X. fastidiosa colonies increased 40-fold in symptomatic leaves and was the feature of colonization most dramatically linked to symptoms. Therefore, the extent of vessel blockage by bacterial colonization is highly likely to be a crucial variable in symptom expression. Intriguingly, a high proportion (>80%) of colonized vessels were not blocked in infected leaves and instead had small colonies or solitary cells, suggesting that vessel blockage is not a colonization strategy employed by the pathogen but, rather, a by-product of endophytic colonization. We present evidence for X. fastidiosa movement through bordered pits to neighboring vessels and propose that vessel-to-vessel movement is a key colonization strategy whose failure results in vessel plugging and disease.


Effect of Faculty Development Activities on Dental Hygiene Faculty Perceptions of and Teaching About Motivational Interviewing: A Pilot Study.
The aims of this pilot study were to assess dental hygiene faculty members' perceptions of the importance of motivational interviewing (MI) and their confidence in teaching students about MI and to determine the effect of MI training sessions on those perceptions. Participants were a convenience sample of all 16 dental hygiene faculty members who teach in the clinic at the University of Michigan School of Dentistry. Participants' perceptions were assessed prior to a workshop in MI (pretest), immediately after the workshop (posttest 1), and eight months after the workshop, at the end of the academic year (posttest 2). During the same period, some of the workshop participants took part in team grading sessions of audio recordings of student-patient MI interactions. The results showed that the majority of the faculty members perceived it was important to personally embrace the overall spirit of MI during patient care, and they were confident supporting students as well. Their ratings for embracing the spirit of MI increased from pretest to posttest 1, but slightly decreased at posttest 2. This trend was also seen in their assessment of the importance of and their confidence in teaching the eight MI strategies over time. Among the workshop participants, 56% were part of team grading; they reported the most helpful professional development activities overall were team grading (58%) and the workshop (25%). These results suggest the importance of making use of a variety of faculty development activities and of introducing appropriate follow-up to training sessions over time to ensure long-lasting effects. Future research using carefully designed, multi-institution, longitudinal studies is needed to determine the most effective ways to prepare dental hygiene faculty members to educate their students about MI.


Adhesion mechanisms of the contact interface of TiO2 nanoparticles in films and aggregates.
Fundamental knowledge about the mechanisms of adhesion between oxide particles with diameters of few nanometers is impeded by the difficulties associated with direct measurements of contact forces at such a small size scale. Here we develop a strategy based on AFM force spectroscopy combined with all-atom molecular dynamics simulations to quantify and explain the nature of the contact forces between 10 nm small TiO(2) nanoparticles. The method is based on the statistical analysis of the force peaks measured in repeated approaching/retracting loops of an AFM cantilever into a film of nanoparticle agglomerates and relies on the in-situ imaging of the film stretching behavior in an AFM/TEM setup. Sliding and rolling events first lead to local rearrangements in the film structure when subjected to tensile load, prior to its final rupture caused by the reversible detaching of individual nanoparticles. The associated contact force of about 2.5 nN is in quantitative agreement with the results of molecular dynamics simulations of the particle-particle detachment. We reveal that the contact forces are dominated by the structure of water layers adsorbed on the particles' surfaces at ambient conditions. This leads to nonmonotonous force-displacement curves that can be explained only in part by classical capillary effects and highlights the importance of considering explicitly the molecular nature of the adsorbates.


A New and Automated Method for Improving Georeferencing in Nighttime Thermal ECOSTRESS Imagery.
Georeferencing accuracy plays a crucial role in providing high-quality ready-to-use remote sensing data. The georeferencing of nighttime thermal satellite imagery conducted by matching to a basemap is challenging due to the complexity of thermal radiation patterns in the diurnal cycle and the coarse resolution of thermal sensors in comparison to sensors used for imaging in the visual spectral range (which is typically used for creating basemaps). The presented paper introduces a novel approach for the improvement of the georeferencing of nighttime thermal ECOSTRESS imagery: an up-to-date reference is created for each to-be-georeferenced image, derived from land cover classification products. In the proposed method, edges of water bodies are used as matching objects, since water bodies exhibit a relatively high contrast with adjacent areas in nighttime thermal infrared imagery. The method was tested on imagery of the East African Rift and validated using manually set ground control check points. The results show that the proposed method improves the existing georeferencing of the tested ECOSTRESS images by 12.0 pixels on average. The strongest source of uncertainty for the proposed method is the accuracy of cloud masks because cloud edges can be mistaken for water body edges and included in fitting transformation parameters. The georeferencing improvement method is based on the physical properties of radiation for land masses and water bodies, which makes it potentially globally applicable, and is feasible to use with nighttime thermal infrared data from different sensors.


Web 2.0 and pharmacy education.
New types of social Internet applications (often referred to as Web 2.0) are becoming increasingly popular within higher education environments. Although developed primarily for entertainment and social communication within the general population, applications such as blogs, social video sites, and virtual worlds are being adopted by higher education institutions. These newer applications differ from standard Web sites in that they involve the users in creating and distributing information, hence effectively changing how the Web is used for knowledge generation and dispersion. Although Web 2.0 applications offer exciting new ways to teach, they should not be the core of instructional planning, but rather selected only after learning objectives and instructional strategies have been identified. This paper provides an overview of prominent Web 2.0 applications, explains how they are being used within education environments, and elaborates on some of the potential opportunities and challenges that these applications present.


A comparison of methods to test mediation and other intervening variable effects.
A Monte Carlo study compared 14 methods to test the statistical significance of the intervening variable effect. An intervening variable (mediator) transmits the effect of an independent variable to a dependent variable. The commonly used R. M. Baron and D. A. Kenny (1986) approach has low statistical power. Two methods based on the distribution of the product and 2 difference-in-coefficients methods have the most accurate Type I error rates and greatest statistical power except in 1 important case in which Type I error rates are too high. The best balance of Type I error and statistical power across all cases is the test of the joint significance of the two effects comprising the intervening variable effect.


Probing interaction of a trilysine peptide with DNA underlying formation of guanine-lysine cross-links: insights from molecular dynamics.
DNA-protein cross-links constitute bulky DNA lesions that interfere with the cellular machinery. Amongst these stable covalently tethered adducts, the efficient nucleophilic addition of the free amino group of lysines onto the guanine radical cation has been evidenced. In vitro addition of a trilysine peptide onto a guanine radical cation generated in a TGT oligonucleotide is so efficient that competitive addition of a water molecule, giving rise to 8-oxo-7,8-dihydroguanine, is not observed. This suggests a spatial proximity between guanine and lysine for the stabilization of the prereactive complex. We report all-atom microsecond scale molecular dynamics simulations that probe the structure and interactions of the trilysine peptide (KKK) with two oligonucleotides. Our simulations reveal a strong, electrostatically driven yet dynamic interaction, spanning several association modes. Furthermore, the presence of neighbouring cytosines has been identified as a factor favoring KKK binding. Relying on ab initio molecular dynamics on a model system constituted of guanine and methylammonium, we also corroborate a mechanistic pathway involving fast deprotonation of the guanine radical cation followed by hydrogen transfer from ammonium leaving as a result a nitrogen reactive species that can subsequently cross-link with guanine. Our study sheds new light on a ubiquitous mechanism for DNA-protein cross-links also stressing out possible sequence dependences.


[The occlusal and functional rehabilitation of a lower canine in complete osseous inclusion].
The aim of this paper is to show an occlusal and functional rehabilitation of a lower canine tooth in total osseous inclusion by means of surgical and orthodontic therapy. This rehabilitation is very important for mastication and for the correct function of the temporomandibular joint.


Loss of the calcium channel β4 subunit impairs parallel fibre volley and Purkinje cell firing in cerebellum of adult ataxic mice.
The auxiliary voltage-gated calcium channel subunit β4 supports targeting of calcium channels to the cell membrane, modulates ionic currents and promotes synaptic release in the central nervous system. β4 is abundant in cerebellum and its loss causes ataxia. However, the type of calcium channels and cerebellar functions affected by the loss of β4 are currently unknown. We therefore studied the structure and function of Purkinje cells in acute cerebellar slices of the β4 (-/-) ataxic (lethargic) mouse, finding that loss of β4 affected Purkinje cell input, morphology and pacemaker activity. In adult lethargic cerebellum evoked postsynaptic currents from parallel fibres were depressed, while paired-pulse facilitation and spontaneous synaptic currents were unaffected. Because climbing fibre input was spared, the parallel fibre/climbing fibre input ratio was reduced. The dendritic arbor of adult lethargic Purkinje cells displayed fewer and shorter dendrites, but a normal spine density. Accordingly, the width of the molecular and granular layers was reduced. These defects recapitulate the impaired cerebellar maturation observed upon Cav 2.1 ataxic mutations. However, unlike Cav 2.1 mutations, lethargic Purkinje cells also displayed a striking decrease in pacemaker firing frequency, without loss of firing regularity. All these deficiencies appear in late development, indicating the importance of β4 for the normal differentiation and function of mature Purkinje cells networks. The observed reduction of the parallel fibre input, the altered parallel fibre/climbing fibre ratio and the reduced Purkinje cell output can contribute to the severe motor impairment caused by the loss of the calcium channel β4 subunit in lethargic mice.


Urinary morbidity with a modified peripheral loading technique of transperineal (125)i prostate implantation.
Analysis of urinary morbidity within the first 12 months following a modified peripheral loading technique for permanent transperineal transrectal ultrasound (TRUS) guided (125)I prostate implantation and comparison of urinary morbidity with various clinical and implant parameters. Between October 1, 1996, and March 11, 1998, 87 patients with favorable, early stage prostate cancer were treated with permanent transperineal TRUS guided (125)I prostate implantation. A peripheral loading technique was utilized for source placement with 75-80% source distribution in the periphery and 20-25% source distribution centrally. A mean total activity of 38 mCi of (125)I was implanted (range, 19-66 mCi). The mean source activity was 0.43 mCi/source (range, 0.26-0.61 mCi/source) and the mean number of sources implanted was 88 (range, 56-134). The minimum prescribed dose to the prostate was 145 Gy. The median D(90), V(100), and V(150) were 152 Gy (range, 104-211 Gy), 92% (range, 71-99%), and 61% (range, 11-89%), respectively. The median follow-up time was 19 months (range, 12-29 months). Urinary morbidity was scored at 3 weeks and then at 3-month intervals for the first 2 years using a modified Radiation Therapy Oncology Group (RTOG) grading system (scale 0-5). Most patients developed at least minor urinary symptoms with frequency or nocturia being the most common. Overall, 79% (69/87) of patients experienced urinary morbidity with 21% (18/87) reporting no symptoms. The incidence of overall Grade 1 urinary morbidity was 37% (32/87); Grade 2 morbidity was 37% (32/87); and Grade 3 morbidity was 6% (5/87). There was no Grade 4 or 5 morbidity. The incidence of Grade 0 frequency/nocturia was 36% (31/87); Grade 1 was 33% (29/87); Grade 2 was 30% (26/87); and Grade 3 was 1% (1/87). Grade 0 dysuria was seen in 56% (49/87) of patients; 32% (28/87) had Grade 1; 10% (9/87) Grade 2; and 1% (1/87) Grade 3 dysuria. Most urinary symptoms started a few weeks after implantation and began to subside by 6 months. At 12 months, 22% (19/87) of patients had persistent urinary symptoms (78% Grade 0, 15% Grade 1, 3% Grade 2, and 3% Grade 3). The mean urethral point dose was 174 Gy (range, 99-315 Gy). The mean number of sources implanted correlated significantly with the likelihood of developing acute urinary morbidity (p = 0.03). The total activity implanted also correlated with the morbidity outcome dysuria (p = 0.01) with a threshold seen at 37 mCi. Urethral point dose, source activity, intraoperative TRUS prostate volume, D(90), V(100), V(150), patient age, pretreatment PSA, Gleason score, and T stage did not correlate with morbidity. Permanent transperineal TRUS guided (125)I prostate implantation using a modified peripheral loading technique is associated with mild urinary morbidity that resolves in 78% of patients by 12 months. Grade 3 urinary morbidity was encountered in only 6% (5/87) of patients. Urinary morbidity may be related to the total number of sources implanted and/or the total activity implanted. Overall urinary morbidity was not correlated with urethral point dose, source activity, intraoperative TRUS prostate volume, D(90), V(100), V(150), patient age, pretreatment PSA, Gleason score, and T stage. The low incidence of urinary morbidity may be a consequence of our modified peripheral loading technique and/or the selection of patients with good-to-excellent preimplant urological parameters. Longer follow-up is necessary to assess biochemical control rates and long-term morbidity.


Neurological manifestations in coronavirus disease 2019.
Coronavirus disease 2019 (COVID-19), an infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently hitting the world in the form of a pandemic. Given that some reports suggest that this infection can also occur with neurologic manifestations, this narrative review addresses the basic and clinical aspects concerning the nervous system involvement associated with this disease. More than one third of patients hospitalized for COVID-19 can present with both central and peripheral neurological manifestations. The former include dizziness and headache, while the latter include taste and smell disturbances. Other reported neurological manifestations are cerebrovascular disease and epileptic seizures. According to published reports, neurological disorders are not uncommon in COVID-19 and can sometimes represent the first manifestation of the disease; therefore, neurologists should consider this diagnostic possibility in their daily practice. Since maybe not all COVID-19 neurological manifestations are due to SARS-CoV-2 direct effects, it is important to monitor the rest of the clinical parameters such as, for example, oxygen saturation. Similarly, follow-up of patients is advisable, since whether neurological complications may develop lately is thus far unknown.


Lost in traffic? The K(+) channel of lily pollen, LilKT1, is detected at the endomembranes inside yeast cells, tobacco leaves, and lily pollen.
Fertilization in plants relies on fast growth of pollen tubes through the style tissue toward the ovules. This polarized growth depends on influx of ions and water to increase the tube's volume. K(+) inward rectifying channels were detected in many pollen species, with one identified in Arabidopsis. Here, an Arabidopsis AKT1-like channel (LilKT1) was identified from Lilium longiflorum pollen. Complementation of K(+) uptake deficient yeast mutants was only successful when the entire LilKT1 C-terminus was replaced by the AKT1 C-terminus. No signals were observed in the plasma membrane (PM) of pollen tubes after expression of fluorescence-tagged LilKT1 nor were any LilKT1-derived peptides detectable in the pollen PM by mass spectrometry analysis. In contrast, fluorescent LilKT1 partly co-localized with the lily PM H(+) ATPase LilHA2 in the PM of tobacco leaf cells, but exhibited a punctual fluorescence pattern and also sub-plasma membrane localization. Thus, incorporation of LilKT1 into the pollen PM seems tighter controlled than in other cells with still unknown trafficking signals in LilKT1's C-terminus, resulting in channel densities below detection limits. This highly controlled incorporation might have physiological reasons: an uncontrolled number of K(+) inward channels in the pollen PM will give an increased water influx due to the raising cytosolic K(+) concentration, and finally, causing the tube to burst.


The biology of xylem fluid-feeding insect vectors of Xylella fastidiosa and their relation to disease epidemiology.
Xylophagous leafhopppers are common and abundant insects of tropical and subtropical environments and play important ecological roles in these ecosystems. The feeding biology of these insects is unique in terms of their high feeding rates and a digestive physiology that allows them to assimilate amino acids, organic acids, and sugars at approximately 99% efficiency. For those species well studied, fluctuations in plant xylem chemistry and tension appear to determine the diurnal and seasonal use of their host plants. Relatively few species of xylem fluid-feeding leafhoppers are considered important pests in commercial agriculture, as they transmit the bacterial plant pathogen Xylella fastidiosa. X. fastidiosa induces diseases of grapevines, citrus, coffee, almond, alfalfa, stone fruits, landscape ornamentals, and native hardwoods for which there is no cure. Two Xylella diseases, citrus variegated chlorosis (CVC) and Pierce's disease (PD) of grapevines, have emerged as important issues within the past decade. In Brazil, CVC became important in the early 1990s and has now expanded throughout many citrus-growing areas of South America and threatens to spread to North America. The recent establishment of the exotic glassy-winged sharpshooter (Homalodisca coagulata) in California now threatens much of the United States' wine grape, table grape, and almond production. The spread of H. coagulata throughout southern California and the spread of CVC northward from Argentina through Brazil exemplifies the biological risks from exotic species. The occurrence and epidemiology of leafhopper-vectored Xylella diseases are discussed.


Prenatal Depression: Assessment and Outcomes among Medicaid Participants.
This study used bivariate and regression-adjusted analyses of participant-level survey and medical data to investigate prevalence of depression among pregnant Medicaid participants, correlates of depression, and the relationship between depression and pregnancy outcomes. The sample included Medicaid participants with a single gestation and valid depression data who were enrolled in Strong Start for Mothers and Newborns 2, a national preterm birth prevention program, from 2013 to 2017 (N = 37,287; 85% of total enrollment). Depression rates in Strong Start were high (27.5%). Depression was associated with being black; having other children, an unplanned pregnancy, or challenges accessing prenatal care; not having a co-resident spouse or partner; and experiencing intimate partner violence. After these and other risk factors were controlled for, depression remained associated with higher rates of preterm birth. Systematic screening and holistic approaches to prenatal care that address depression and associated risks could help reduce rates of preterm birth and other poor pregnancy outcomes.


Kinetic Modeling of pH-Dependent Oxidation of Dopamine by Iron and Its Relevance to Parkinson's Disease.
Parkinson's disease is the second most common neurodegenerative disease. While age is the most significant risk factor, the exact cause of this disease and the most effective approaches to mitigation remain unclear. It has long been proposed that dopamine may play a role in the pathology of Parkinson's disease in view of its ability to generate both protein-modifying quinones such as aminochrome and reactive oxygen species, especially in the presence of pathological iron accumulation in the primary site of neuron loss. Given the clinically measured acidosis of post-mortem Parkinson's disease brain tissue, the interaction between dopamine and iron was investigated over a pH range of 7.4 to 6.5 with emphasis on the accumulation of toxic quinones and generation of reactive oxygen species. Our results show that the presence of iron accelerates the formation of aminochrome with ferrous iron (Fe[II]) being more efficient in this regard than ferric iron (Fe[III]). Our results further suggest that a reduced aminochrome rearrangement rate coupled with an enhanced turnover rate of Fe[II] as a result of brain tissue acidosis could result in aminochrome accumulation within cells. Additionally, under these conditions, the enhanced redox cycling of iron in the presence of dopamine aggravates oxidative stress as a result of the production of damaging reactive species, including hydroxyl radicals.


[Beta-lactam antibiotic sensitivity of Gram-negative bacteria isolated from urology patients].
Sensitivity of 172 strains of gram-negative bacteria isolated from the urine of urological patients was tested to the beta-lactam antibiotics penicillin, oxacillin, carbenicillin, cefradin, cerhazolin, cephapirin, cefotaxim, and cefuroxim. The method of two-fold serial dilutions in a meat-peptone agar was used. In the therapeutic concentrations the above antibiotics except carbenicillin, cefotaxim and cefuroxim had no inhibitory effect on P. aeruginosa. With respect to E. coli the highest activity was observed with the use of carbenicillin and the new cephalosporins cephazolin, cephapirin, cefradin, cefotaxim and cefuroxim. A significant number of Proteus strains sensitive to the minimal concentrations of the cephalosporins and carbenicillin were detected. However, highly resistant strains were also isolated.


Persistent residues: interface with regulatory decisions.
The use of radiolabeled drugs and feed additives in experiments designed for preclearance approval of new animal drug applications (NADAs) demonstrates the presence of metabolites, including those which are covalently bound to macromolecules and which often persist in the edible tissues of target food animals. Isolation and characterization of these residues is often a difficult task. An outline of data development is explored in the context of toxicity assessment. Unless otherwise adjusted, the sponsor's method of residue analysis and drug withdrawal time reflect the influence of all related drug residues found in edible tissues. The use of bioavailability studies and their interaction with safety evaluation is discussed.


Post-operative atrial fibrillation: should we anticoagulate?
The prevalence of atrial fibrillation (AF) is estimated to be 12 million by the year 2030. A subset of those patients fall into the category of post-operative atrial fibrillation (POAF) and either develop POAF after cardiac procedures [coronary artery bypass graft (CABG) and valvular procedures] or non-cardiac procedures. With the rise in surgical procedures, POAF represents a significant economic burden. POAF usually converts to sinus rhythm on its own, prompting questions about whether there is a need to treat it and if there is a need for anticoagulation. This review discusses risk factors, pathophysiology, complications of POAF, and mechanisms of risk stratifying patients to determine when to anticoagulate.


Enhancement by dexamethasone of the therapeutic benefits of cisplatin via regulation of tumor angiogenesis and cell cycle kinetics in a murine tumor paradigm.
We have investigated in the current study, the possible modulatory effects of dexamethasone on cisplatin cytotoxicity in Ehrlich ascites carcinoma (EAC)-bearing female Swiss albino mice. Cisplatin (3.5mg/kg) was injected IP for 3 consecutive days in mice previously inoculated SC with EAC cells in the right flank. Dexamethasone (2.5mg/kg) was administered SC alone or 24h ahead of cisplatin challenge, and these regimens were given for 3 consecutive days. Dexamethasone enhanced the anti-tumor effects of cisplatin, clearly demonstrated by the increased mean tumor growth time (TGT) and tumor growth delay time (TGDT) values compared to cisplatin alone. The effects of dexamethasone on tumor angiogenesis and cell cycle distribution of EAC cells have been addressed as possible mechanisms, whereby the glucocorticoid could probably augment cisplatin cell-kill. Indeed, dexamethasone enhanced the angiostatic activity of cisplatin by 52.5%. The glucocorticoid also synchronized the EAC cells in the G2/M phase, secondary to its regulatory role on the transcriptional and translational activity in these cells, thus, exposing them to the dramatic cytotoxic potential of cisplatin. One could conclude that dexamethasone enhanced the anti-tumor effects of cisplatin via augmenting its angiostatic activity and modulating cell cycle kinetics. Also, dexamethasone did not alter cisplatin-induced nephrotoxicity, thus demonstrating an improved therapeutic potential.


Investigation of the relationship between trochlear morphology and medial patellar cartilage defect using magnetic resonance imaging.
The aim of this study was to evaluate trochlear morphology in patients with medial patellar cartilage defects via magnetic resonance imaging (MRI). Three hundred patients who were diagnosed with grade 2, 3 and 4 medial patellar cartilage defect using MRI according to the International Cartilage Repair Society Classification System and 100 control subjects were evaluated. Trochlear morphology was evaluated based on lateral trochlear inclination (LTI), medial trochlear inclination (MTI), sulcus angle( SA), femoral lateral and medial condyle symmetry, trochlear facet asymmetry, and trochlear width on the axial MR images. The mean SA was significantly higher in the medial patellar cartilage defect group compared to the control group (p<.05). The LTI and MTI of the cartilage defect group were significantly lower than those of the control group (p<.05). With the decreasing LTI and MTI, there was an increase in medial patellar cartilage loss. LTI (r=-0.46) and MTI (r=-0.53) were moderately correlated with SA. There was no significant differences in femoral lateral and medial condyle symmetry, trochlear facet asymmetry, and trochlear width between groups with and without medial patellar cartilge defect (p ˃ .05). A flattened medial trochlea is a risk factor for cartilage structural damage of the medial patellofemoral joint, and it plays a role in the development of a defect in the medial patellar cartilage. The medial patellar cartilage defect is associated with the flattened lateral trochlea.


Area 5 influences excitability within the primary motor cortex in humans.
In non-human primates, Brodmann's area 5 (BA 5) has direct connectivity with primary motor cortex (M1), is largely dedicated to the representation of the hand and may have evolved with the ability to perform skilled hand movement. Less is known about human BA 5 and its interaction with M1 neural circuits related to hand control. The present study examines the influence of BA 5 on excitatory and inhibitory neural circuitry within M1 bilaterally before and after continuous (cTBS), intermittent (iTBS), and sham theta-burst stimulation (sham TBS) over left hemisphere BA 5. Using single and paired-pulse TMS, measurements of motor evoked potentials (MEPs), short interval intracortical inhibition (SICI), and intracortical facilitation (ICF) were quantified for the representation of the first dorsal interosseous muscle. Results indicate that cTBS over BA 5 influences M1 excitability such that MEP amplitudes are increased bilaterally for up to one hour. ITBS over BA 5 results in an increase in MEP amplitude contralateral to stimulation with a delayed onset that persists up to one hour. SICI and ICF were unaltered following TBS over BA 5. Similarly, F-wave amplitude and latency were unaltered following cTBS over BA 5. The data suggest that BA 5 alters M1 output directed to the hand by influencing corticospinal neurons and not interneurons that mediate SICI or ICF circuitry. Targeting BA 5 via cTBS and iTBS is a novel mechanism to powerfully modulate activity within M1 and may provide an avenue for investigating hand control in healthy populations and modifying impaired hand function in clinical populations.


Uptake and metabolism of [3H]anandamide by rabbit platelets. Lack of transporter?
Anandamide is an endogenous ligand for cannabinoid receptor and its protein-mediated transport across cellular membranes has been demonstrated in cells derived from brain as well as in cells of the immune system. This lipid is inactivated via intracellular degradation by a fatty acid amidohydrolase (FAAH). In the present study, we report that rabbit platelets, in contrast to human platelets, do not possess a carrier-mediated mechanism for the transport of [3H]anandamide into the cell, i.e. cellular uptake was not temperature dependent and its accumulation was not saturable. This endocannabinoid appears to enter the cell by simple diffusion. Once taken up by rabbit platelets, [3H]anandamide was rapidly metabolized into compounds which were secreted into the medium. Small amounts of free arachidonic acid as well as phospholipids were amongst the metabolic products. FAAH inhibitors did not decrease anandamide uptake, whereas these compounds inhibited anandamide metabolism. In conclusion, anandamide is rapidly taken up by rabbit platelets and metabolized mainly into water-soluble metabolites. Interestingly, the present study also suggests the absence of a transporter for anandamide in these cells.


Personalization of multiple sclerosis treatments: using the chelation therapy approach.
Though Multiple Sclerosis (MS) sufferers are probably genetically predisposed, toxic metal poisoning (TMP) does seem an increasingly likely environmental trigger. The technique for measuring and clearing TMP was chelation therapy using ethylene-diamine-tetracetic acid (EDTA), which revealed aluminum accumulation in both cases. The first patient, initially benefiting from removing dental fillings that had leaked mercury, also showed gadolinium accumulation from scan contrast medium, and a genomic deficiency of glutathione transferase M1. Glutathione production was impaired and hence also liver detoxification functions. The personal protocol involved glutathione administration and deutrosulfazyme to enhance oxygenation and alleviate oxidative stress. As aluminum began to clear with EDTA infusion, the extracellular/intracellular water ratio was carefully monitored, and carbohydrates limited. In the second case, aluminum poisoning responded to EDTA chelation therapy with eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA), multivitamins, and glutathione administration, again followed by deutrosulfazyme, water ratio control, and dietary correction. The two personalized protocols presented here tend to confirm the hypothesis of TMP as an environmental or iatrogenic trigger for MS, especially when inadequate detoxification lies at the root. Cleansing by chelation therapy, properly understood, can be efficacious, especially bearing in mind the altered cellular water ratio.


Distinct sites in E-cadherin regulate different steps in Drosophila tracheal tube fusion.
We have investigated how E-cadherin controls the elaboration of adherens junction associated cytoskeletal structures crucial for assembling tubular networks. During Drosophila development, tracheal branches are joined at branch tips through lumens that traverse doughnut-shaped fusion cells. Fusion cells form E-cadherin contacts associated with a track that contains F-actin, microtubules, and Shot, a plakin that binds F-actin and microtubules. Live imaging reveals that fusion occurs as the fusion cell apical surfaces meet after invaginating along the track. Initial track assembly requires E-cadherin binding to beta-catenin. Surprisingly, E-cadherin also controls track maturation via a juxtamembrane site in the cytoplasmic domain. Fusion cells expressing an E-cadherin mutant in this site form incomplete tracks that contain F-actin and Shot, but lack microtubules. These results indicate that E-cadherin controls track initiation and maturation using distinct, evolutionarily conserved signals to F-actin and microtubules, and employs Shot to promote adherens junction-associated cytoskeletal assembly.


Miscoding potential of the N2-ethyl-2'-deoxyguanosine DNA adduct by the exonuclease-free Klenow fragment of Escherichia coli DNA polymerase I.
Acetaldehyde, a major metabolite of ethanol, reacts with dG residues in DNA, resulting in the formation of the N(2)-ethyl-2'-deoxyguanosine (N(2)-Et-dG) adduct. This adduct has been detected in lymphocyte DNA of alcohol abusers. To explore the miscoding property of the N(2)-Et-dG DNA adduct, phosphoramidite chemical synthesis was used to prepare site-specifically modified oligodeoxynucleotides containing a single N(2)-Et-dG. These N(2)-Et-dG-modified oligodeoxynucleotides were used as templates for primer extension reactions catalyzed by the 3' --> 5' exonuclease-free (exo(-)) Klenow fragment of Escherichia coli DNA polymerase I. The primer extension was retarded one base prior to the N(2)-Et-dG lesion and opposite the lesion; however, when the enzyme was incubated for a longer time or with increased amounts of this enzyme, full extension occurred. Quantitative analysis of the fully extended products showed the preferential incorporation of dGMP and dCMP opposite the N(2)-Et-dG lesion, accompanied by a small amounts of dAMP and dTMP incorporation and one- and two-base deletions. Steady-state kinetic studies were also performed to determine the frequency of nucleotide insertion opposite the N(2)-Et-dG lesion and chain extension from the 3' terminus from the dN.N(2)-Et-dG (N is C, A, G, or T) pairs. These results indicate that the N(2)-Et-dG DNA adduct may generate G --> C transversions in living cells. Such a mutational spectrum has not been detected with other methylated dG adducts, including 8-methyl-2'-deoxyguanosine, O(6)-methyl-2'-deoxyguanosine, and N(2)-methyl-2'-deoxyguanosine. In addition, N(2)-ethyl-2'-deoxyguanosine triphosphate (N(2)-Et-dGTP) was efficiently incorporated opposite a template dC during DNA synthesis catalyzed by the exo(-) Klenow fragment. The utilization of N(2)-Et-dGTP was also determined by steady-state kinetic studies. N(2)-Et-dG DNA adducts are also formed by the incorporation of N(2)-Et-dGTP into DNA and may cause mutations, leading to the development of alcohol- and acetaldehyde-induced human cancers.


(E)-Specific direct Julia-olefination of aryl alcohols without extra reducing agents promoted by bases.
An unprecedented base-promoted direct olefination of aryl alcohols with sulfones via a Julia-type reaction has been described. No extra reductants are needed for Julia reaction since alcohols work as double sources of aldehydes and the hydride. Generally high yields were given for both terminal and highly (E)-selective internal olefins.


[Thermotherapy in rheumatic diseases].
Heat and cold treatment are often used in the physical therapy of rheumatic diseases. Thermotherapy influences perfusion, muscular tone, pain, and inflamed arthritic joints. Cold applications are preferable in treating active arthritis. Heat treatment is advantageous in the management of less active arthritis and non-inflammatory rheumatic disorders. Current investigations demonstrate that thermotherapy influences the endocrine--an immune systems.


Respiratory muscle function in cystic fibrosis.
Maximal static expiratory and inspiratory mouth pressures (PEmax and PImax) and quadriceps femoris muscle strength were measured in 25 patients aged 16-28 years with cystic fibrosis (mean FEV1 46% predicted). Mean (SD) PEmax was 64% (18%) predicted (below 75% predicted in 16 of the 25 patients), and PImax was 64% (24%) predicted (below 75% predicted in 14 patients). Quadriceps muscle strength was 68% (20%) predicted (below 75% predicted in 17 patients). The relatively small reduction in respiratory muscle strength in these patients was unlikely to have contributed appreciably to their respiratory problems.


Identification and characterization of pptA: a gene involved in the phase-variable expression of phosphorylcholine on pili of Neisseria meningitidis.
Pili of pathogenic Neisseria are major virulence factors associated with adhesion, cytotoxicity, twitching motility, autoaggregation, and DNA transformation. Pili are modified posttranslationally by the addition of phosphorylcholine. However, no genes involved in either the biosynthesis or the transfer of phosphorylcholine in Neisseria meningitidis have been identified. In this study, we identified five candidate open reading frames (ORFs) potentially involved in the biosynthesis or transfer of phosphorylcholine to pilin in N. meningitidis. Insertional mutants were constructed for each ORF in N. meningitidis strain C311#3 to determine their effect on phosphorylcholine expression. The effect of the mutant ORFs on the modification by phosphorylcholine was analyzed by Western analysis with phosphorylcholine-specific monoclonal antibody TEPC-15. Analysis of the mutants showed that ORF NMB0415, now defined as pptA (pilin phosphorylcholine transferase A), is involved in the addition of phosphorylcholine to pilin in N. meningitidis. Additionally, the phase variation (high frequency on-off switching of expression) of phosphorylcholine on pilin is due to changes in a homopolymeric guanosine tract in pptA.


The efficacy of percutaneous cholecystostomy in critically ill patients.
Percutaneous cholecystostomy (PC) has been proposed as a method of biliary decompression in critically ill patients with acute cholecystitis. We evaluated the efficacy of PC in this setting. The charts of 33 critically ill patients (mean age 52, range 5-87) who underwent PC for suspected acute cholecystitis were retrospectively examined. Univariate analysis was performed to identify which patients might benefit from PC. PC was technically successful in all patients with no direct mortality or major complications. Failure to improve within 24 hours was associated with increased mortality (P = 0.02). A total of 22/33 patients improved, 17/33 survived, and 8/33 required surgery. PC delayed definitive operation in two patients. Cholelithiasis was associated with surgical intervention (P = 0.01) but not increased mortality. Favorable prognosticators for survival included gallbladder dilatation (P = 0.01), pericholecystic fluid (P = 0.01), and absence of a pulmonary artery catheter (P = 0.02). Predictors of improvement included gallbladder nonvisualization on hepatobiliary scan (P = 0.047), positive bile cultures (P = 0.017), and initial drainage of < / = 100 cc (P = 0.009). Age, laboratory data, the use of total parenteral nutrition, and intubation did not predict outcome. Nine positive bile cultures prompted antibiotic changes in five cases. Finally, PC was less expensive than open cholecystostomy ($1620 versus $3155). PC is a safe, cost-effective, minimally invasive procedure that has diagnostic and therapeutic value in critically ill patients with acute cholecystitis. The involvement of a general surgeon is important to ensure that those patients who do not improve within 24 hours receive early surgical intervention and provide long-term definitive care for those patients with cholelithiasis.


Aging and proinflammatory cytokines.
Aging is associated with increased inflammatory activity reflected by increased circulating levels of TNF-alpha, IL-6, cytokine antagonists and acute phase proteins in vivo. Epidemiologic studies suggest that chronic low-grade inflammation in aging promotes an atherogenic profile and is related to age-associated disorders (eg, Alzheimer disease, atherosclerosis, type 2 diabetes, etc.) and enhanced mortality risk. Accordingly, a dysregulated production of inflammatory cytokines has an important role in the process of aging. Studies of age-related differences in the production of proinflammatory cytokines in response to acute stimulations in vitro have yielded inconsistent results. However, in vivo infectious models show delayed termination of inflammatory activity and a prolonged fever response in elderly humans, suggesting that the acute phase response is altered in aging. However, a causal relation between the acute phase response and the increased mortality because of bacterial infections in older patients remains to be demonstrated.


Biochemistry and computer generated graph comparison of the structural and nonstructural proteins of spanish-1918 Influenza, pandemic-2009, and bird flu viruses.
The potential emergence of deadly pandemic influenza viruses is unpredictable and most have emerged with no forewarning. The distinct epidemiological and pathological patterns of the Spanish (H1N1), pandemic-2009 (H1N1), and avian influenza (H5N1), known as bird flu, viruses may allow us to develop a 'template' for possible emergence of devastating pandemic strains. Here, we provide a detailed molecular dissection of the structural and nonstructural proteins of this triad of viruses. GenBank data for three representative strains were analyzed to determine the polymorphic amino acids, genetic distances, and isoelectric points, hydrophobicity plot, and protein modeling of various proteins. We propose that the most devastating pandemic strains may have full-length PB1-F2 protein with unique residues, highly cleavable HA, and a basic NS1. Any newly emerging strain should be compared with these three strains, so that resources can be directed appropriately.


Annual research review: The (epi)genetics of neurodevelopmental disorders in the era of whole-genome sequencing--unveiling the dark matter.
Neurodevelopmental disorders (NDDs) are defined by a wide variety of behavioural phenotypes, psychopathology and clinically informed categorical classifications. Diagnostic entities include intellectual disability (ID), the autism spectrum (ASD) and attention-deficit/hyperactivity disorder (ADHD). The aetiopathogenesis of these conditions and disorders involves an interaction between both genetic and environmental risk factors on the developmental trajectory. Despite their remarkable genetic heterogeneity and complexity of pathophysiological mechanisms, NDDs display an overlap in their phenotypic features, a considerable degree of comorbidity as well as sharing of genetic and environmental risk factors. This review aims to provide an overview of the genetics and epigenetic of NDDs. Recent evidence suggests a critical role of defined and tightly regulated neurodevelopmental programs running out of control in NDDs, most notably neuronal proliferation and migration, synapse formation and remodelling, as well as neural network configuration resulting in compromised systems connectivity and function. Moreover, the machinery of epigenetic programming, interacting with genetic liability, impacts many of those processes and pathways, thus modifying vulnerability of, and resilience to, NDDs. Consequently, the categorically defined entities of ID, ADHD and ASD are increasingly viewed as disorders on a multidimensional continuum of molecular and cellular deficiencies in neurodevelopment. As such, this range of NDDs displays a broad phenotypic diversity, which may be explained by a combination and interplay of underlying loss- and potential gain-of-function traits. In this overview, we discuss a backbone continuum concept of NDDs by summarizing pertinent findings in genetics and epigenetics. We also provide an appraisal of the genetic overlap versus differences, with a focus on genome-wide screening approaches for (epi)genetic variation. Finally, we conclude with insights from evolutionary psychobiology suggesting positive selection for discrete NDD-associated traits.


Results of the 2016 International Skin Imaging Collaboration International Symposium on Biomedical Imaging challenge: Comparison of the accuracy of computer algorithms to dermatologists for the diagnosis of melanoma from dermoscopic images.
Computer vision may aid in melanoma detection. We sought to compare melanoma diagnostic accuracy of computer algorithms to dermatologists using dermoscopic images. We conducted a cross-sectional study using 100 randomly selected dermoscopic images (50 melanomas, 44 nevi, and 6 lentigines) from an international computer vision melanoma challenge dataset (n = 379), along with individual algorithm results from 25 teams. We used 5 methods (nonlearned and machine learning) to combine individual automated predictions into "fusion" algorithms. In a companion study, 8 dermatologists classified the lesions in the 100 images as either benign or malignant. The average sensitivity and specificity of dermatologists in classification was 82% and 59%. At 82% sensitivity, dermatologist specificity was similar to the top challenge algorithm (59% vs. 62%, P = .68) but lower than the best-performing fusion algorithm (59% vs. 76%, P = .02). Receiver operating characteristic area of the top fusion algorithm was greater than the mean receiver operating characteristic area of dermatologists (0.86 vs. 0.71, P = .001). The dataset lacked the full spectrum of skin lesions encountered in clinical practice, particularly banal lesions. Readers and algorithms were not provided clinical data (eg, age or lesion history/symptoms). Results obtained using our study design cannot be extrapolated to clinical practice. Deep learning computer vision systems classified melanoma dermoscopy images with accuracy that exceeded some but not all dermatologists.


Three distinct two-component systems are involved in resistance to the class I bacteriocins, Nukacin ISK-1 and nisin A, in Staphylococcus aureus.
Staphylococcus aureus uses two-component systems (TCSs) to adapt to stressful environmental conditions. To colonize a host, S. aureus must resist bacteriocins produced by commensal bacteria. In a comprehensive analysis using individual TCS inactivation mutants, the inactivation of two TCSs, graRS and braRS, significantly increased the susceptibility to the class I bacteriocins, nukacin ISK-1 and nisin A, and inactivation of vraSR slightly increased the susceptibility to nukacin ISK-1. In addition, two ABC transporters (BraAB and VraDE) regulated by BraRS and one transporter (VraFG) regulated by GraRS were associated with resistance to nukacin ISK-1 and nisin A. We investigated the role of these three TCSs of S. aureus in co-culture with S. warneri, which produces nukacin ISK-1, and Lactococcus lactis, which produces nisin A. When co-cultured with S. warneri or L. lactis, the braRS mutant showed a significant decrease in its population compared with the wild-type, whereas the graRS and vraSR mutants showed slight decreases. Expression of vraDE was elevated significantly in S. aureus co-cultured with nisin A/nukacin ISK-1-producing strains. These results suggest that three distinct TCSs are involved in the resistance to nisin A and nukacin ISK-1. Additionally, braRS and its related transporters played a central role in S. aureus survival in co-culture with the strains producing nisin A and nukacin ISK-1.


Biological control in the germination of seeds from two species native of the Cerrado region.
Microorganisms have been efficiently used for the biological control of phytopathogens through the production of antimicrobial substances. However, the objectives of this work were: to study the germination of Butia purpurascens Glassman and Butia archeri Glassman seeds in different substrates, to select and identify the endophytic and rhizospheric bacterial isolates of B. purpurascens and B. archeri, and to perform antibiosis tests based on the isolated microorganisms of these tree species. No difference was found between the cultivation substrates for the percentages of germination, hard seeds, and fungal contamination in the B. purpurascens seeds. The Bacillus subtilis isolated showed the best capacity for suppressing the growth of the two deteriorative fungi tested in B. purpurascens seeds. No difference was found for inhibition of the growth of Aspergillus niger fungus (deteriorative fungus of B. archeri seeds) between the microorganisms with Bacillus sp. and Brevibacillus brevis compared to the control. In the microbiolization of B. purpurascens and B. archeri seeds performed with microbiological solutions produced from the endophytic and rhizospheric strains of Bacillus sp., no differences were observed in the percentages of germination and contamination by fungi. For B. archeri seeds, there was contamination by fungi and bacteria after one day of cultivation, primarily in the regions with lesions caused by the extraction and scarification process.


Therapeutic relationships within child and adolescent mental health inpatient services: A qualitative exploration of the experiences of young people, family members and nursing staff.
Child and adolescent mental health services (CAMHS), especially inpatient units, have arguably never been more in demand and yet more in need of reform. Progress in psychotherapy and more broadly in mental health care is strongly predicted by the therapeutic relationship between professional and service user. This link is particularly pertinent in child and adolescent mental health inpatient services where relationships are especially complex and difficult to develop and maintain. This article describes a qualitative exploration of the lived experienced of 24 participants (8 young people, 8 family members/carers and 8 nursing staff) within inpatient CAMHS across four sites in the UK. We interviewed participants individually and analysed the transcripts using thematic analysis within a critical realist framework. We synthesised data across groups and present six themes, encapsulating the intricacies and impact of therapeutic relationships; their development and maintenance: Therapeutic relationships are the treatment, Cultivating connection, Knowledge is power, Being human, The dance, and It's tough for all of us in here. We hope these findings can be used to improve quality of care by providing a blueprint for policy, training, systemic structures and staff support.


The ABC-type multidrug resistance transporter LmrCD is responsible for an extrusion-based mechanism of bile acid resistance in Lactococcus lactis.
Upon prolonged exposure to cholate and other toxic compounds, Lactococcus lactis develops a multidrug resistance phenotype that has been attributed to an elevated expression of the heterodimeric ABC-type multidrug transporter LmrCD. To investigate the molecular basis of bile acid resistance in L. lactis and to evaluate the contribution of efflux-based mechanisms in this process, the drug-sensitive L. lactis NZ9000 DeltalmrCD strain was challenged with cholate. A resistant strain was obtained that, compared to the parental strain, showed (i) significantly improved resistance toward several bile acids but not to drugs, (ii) morphological changes, and (iii) an altered susceptibility to antimicrobial peptides. Transcriptome and transport analyses suggest that the acquired resistance is unrelated to elevated transport activity but, instead, results from a multitude of stress responses, changes to the cell envelope, and metabolic changes. In contrast, wild-type cells induce the expression of lmrCD upon exposure to cholate, whereupon the cholate is actively extruded from the cells. Together, these data suggest a central role for an efflux-based mechanism in bile acid resistance and implicate LmrCD as the main system responsible in L. lactis.


Cost effectiveness of interferon alpha2b combined with ribavirin for the treatment of chronic hepatitis C.
Treatment of chronic hepatitis C with Interferon (IFN) alpha2b monotherapy results in 10% to 15% sustained virological response (SVR). Combining IFN with ribavirin increases this response. In this analysis, using the Markov model, 6 treatment strategies for chronic hepatitis C (previously untreated) were compared on the basis of incremental cost per additional quality-adjusted life years ($/QALY). Our results showed that the no treatment strategy was associated with a cost of $38,747 and 13.10 QALYs. The strategy using IFN alone for 48 weeks was associated with a cost of $35,642 and 14.05 QALYs. The strategy using IFN monotherapy followed by combination therapy for nonresponders and relapsers was associated with a cost of $34, 561 and 15.53 QALYs. A similar strategy, but limiting combination to relapsers only, was associated with a cost of $34,758 and 14.40 QALYs. The strategy using IFN with ribavirin as the initial therapy for all patients was associated with a cost of $34,792 and 15.31 QALYs. Finally, the strategy using viral genotyping first and then adjusting the duration of combination therapy based on genotype was associated with a cost of $37,263 and 15.89 QALYs. The strategy using genotyping to guide duration of combination therapy was the most cost-effective approach with an incremental cost-effectiveness ratio of $7,500 per QALY. Sensitivity analyses confirmed the robustness of these results. We conclude that combination of IFN and ribavirin with duration of therapy based on the viral genotype, is a cost-effective approach in treating patients with chronic hepatitis C.


Soft micro-balloon paddy for brain retraction in the protection of neuronal tissue.
Brain protection is extremely important during arachnoidal dissection and brain separation with a metallic retractor to create a surgical corridor. We have designed a new type of paddy containing air-filled micro-balloons and cotton for use between the metallic retractor and the brain surface for maximal protection of the neuronal tissues from the pressure of the retractor. In neurosurgical operations, cotton paddies are commonly and generally used during the retraction of brain tissue. We hypothesized that air-filled micro-balloon paddies covered with cotton could be helpful in the gentle separation of brain tissue with metallic retractors for minimizing cerebral damage, and for separating sulcal and cisternal walls during brain operations. These paddies are 2 cm in width and 4 cm in length. Multiple air-filled silicon micro-balloons are located in a sheet with 1-2 mm separation from each other. These silicon micro-balloonoid sheets are covered with a cotton sheath. The thickness of this type of paddy is 2-3 mm from the anterior surface to the posterior surface. We used paddies in 86 brain operations where brain retraction was necessary to create a surgical corridor. There was no complication or unwanted events related with the use of these paddies. air-filled silicon micro-balloon paddies are useful materials for the gentle separation of brain tissue with a metallic retractor in order to minimize cerebral damage, and for the separation of sulcal and cisternal walls during the surgical intervention.