A clinically applicable molecular-based classification for endometrial cancers.
Classification of endometrial carcinomas (ECs) by morphologic features is inconsistent, and yields limited prognostic and predictive information. A new system for classification based on the molecular categories identified in The Cancer Genome Atlas is proposed. Genomic data from the Cancer Genome Atlas (TCGA) support classification of endometrial carcinomas into four prognostically significant subgroups; we used the TCGA data set to develop surrogate assays that could replicate the TCGA classification, but without the need for the labor-intensive and cost-prohibitive genomic methodology. Combinations of the most relevant assays were carried forward and tested on a new independent cohort of 152 endometrial carcinoma cases, and molecular vs clinical risk group stratification was compared. Replication of TCGA survival curves was achieved with statistical significance using multiple different molecular classification models (16 total tested). Internal validation supported carrying forward a classifier based on the following components: mismatch repair protein immunohistochemistry, POLE mutational analysis and p53 immunohistochemistry as a surrogate for 'copy-number' status. The proposed molecular classifier was associated with clinical outcomes, as was stage, grade, lymph-vascular space invasion, nodal involvement and adjuvant treatment. In multivariable analysis both molecular classification and clinical risk groups were associated with outcomes, but differed greatly in composition of cases within each category, with half of POLE and mismatch repair loss subgroups residing within the clinically defined 'high-risk' group. Combining the molecular classifier with clinicopathologic features or risk groups provided the highest C-index for discrimination of outcome survival curves. Molecular classification of ECs can be achieved using clinically applicable methods on formalin-fixed paraffin-embedded samples, and provides independent prognostic information beyond established risk factors. This pragmatic molecular classification tool has potential to be used routinely in guiding treatment for individuals with endometrial carcinoma and in stratifying cases in future clinical trials.


Semiconductor surface emitting lasers for photon pairs generation.
We study the feasibility of generating photon pairs in a resonant Vertical-Cavity Surface-Emitting Laser (VCSEL) as a result of a third-order non-linear, four wave mixing interaction. We focus on degenerate four wave mixing in the spontaneous regime where two pump photons are annihilated to create a pair of signal and idler photons. Using the methods of quantum optics, we calculate the two-photon production rate, the spectrum of the generated photons, and the signal-idler cross-correlations. We highlight how the dispersion of the medium in the VCSEL cavity (a regular GaAs configuration) significantly diminishes the two-photon production rate. Based on our results, we enumerate the characteristics of a VCSEL that would be suitable for photon pair generation.


Adrenal enlargement and failure of suppression of circulating cortisol by dexamethasone in patients with malignancy.
The aim of this study was to further elucidate the activity of the hypothalamo-pituitary-adrenal (HPA) axis in patients with malignancy and to correlate this with the size of the adrenal glands. Fourteen patients with a variety of malignancies were studied prior to receiving cytotoxic chemotherapy. During routine staging computerized tomographic (CT) scans, the size of the body, medial and lateral limbs of the adrenal glands were measured and compared with those of a normal group of patients studied previously. Measurements of 09:00 h serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels were made before and after the administration of dexamethasone (0.5 mg 6-hourly for 48 h) in addition to the peak cortisol response to i.v corticotropin releasing hormone (CRH). Overall, patients with malignancy had significantly larger adrenal glands than patients without malignancy; those with non-haematological malignancies had larger glands than patients with haematological malignancies. Following dexamethasone to suppress circulating cortisol levels, nine patients (64%) demonstrated abnormal resistance with cortisol levels > 50 nmol l(-1): mean value 294 nmol l(-1) (range 67-1147). Those patients who failed to suppress after dexamethasone had significantly larger adrenal glands than those that did suppress and tended to have non-haematological malignancies. ACTH levels were undetectable or low in three patients in whom it was measured and who did not suppress with dexamethasone. Following CRH, the cortisol levels were highest (823 and 853 nmol l(-1)) in two of these patients. Malignancy is associated with diffuse enlargement of the adrenal glands and resistance to dexamethasone-induced suppression of the HPA axis, which is not due to ectopic ACTH secretion. This disturbance of the normal control of the HPA axis is unexplained and its functional significance remains uncertain.


siRNA-directed clusterin silencing promotes cisplatin antitumor activity in human non-small cell lung cancer xenografts in immunodeficient mice.
In a previous analysis using a lung cancer cell lines model, we have found that therapies directed against sCLU and its downstream signaling targets pAkt and pERK1/2 may have the potential to enhance the efficacy of cisplatin (DDP)-based chemotherapy in vitro. Here, we investigated the therapies directed against sCLU on the DDP-based chemotherapy in vivo, and explored the mechanism. Using lung cancer cell lines, A549 cells and DDP-resistant A549 cells (A549DDP), we determined the effect of sCLU silencing using short interfering double-stranded RNA (siRNA) on chemosensitivity in immunocompromised mice bearing A549DDP tumors. We then determined the effect of sCLU overexpression via stable sCLU transfection on chemosensitivity in immunocompromised mice bearing A549 tumors. The effect of sCLU silencing or overexpression on pAkt and pERK1/2 expression and chemosensitivity in vivo was detected by western blot assay. The results showed sCLU silencing increased the chemosensitivity of A549DDP cells to DDP in vivo via downregulation of pAkt and pERK1/2 expression. And sCLU overexpression decreased the chemosensitivity of A549 cells to DDP in vivo via upregulation of pAkt and pERK1/2 expression. DDP-induced sCLU activation, which involved induction of pAkt and pERK1/2 activation that confer DDP resistance in immunocompromised mice. Alteration of this balance allows sensitisation to the antitumor activity of cisplatin chemotherapy.


A selective role for dopamine D₄ receptors in modulating reward expectancy in a rodent slot machine task.
Cognitive distortions regarding gambling outcomes confer vulnerability to pathological gambling. Using a rat slot machine task (rSMT), we previously demonstrated that the nonspecific D₂ agonist quinpirole enhances erroneous expectations of reward on near-miss trials, suggesting a pivotal role for the D₂ receptor family in mediating the near-miss effect. Identifying which receptor subtype is involved could facilitate treatment development for compulsive slot machine play. Thirty-two male Long Evans rats learned the rSMT. Three flashing lights could be set to on or off. A win was signaled if all three lights were set to on, whereas any other light pattern indicated a loss. Rats then chose between responding on the collect lever, which delivered 10 sugar pellets on win trials but a 10-second time penalty on loss trials, or to start a new trial instead. Performance was assessed following systemic administration of selective D₂, D₃, and D₄ receptor ligands. The selective D₂ antagonist L-741,626, the D₃ antagonist SB-277011-A, and the D₃ agonist PD128,907 had no effect. In contrast, the selective D₄ agonist PD168077 partially mimicked quinpirole's effects, increasing erroneous collect responses on nonwin trials, whereas the D₄ antagonist L-745,870 improved the error rate. L-745,870 was also the only antagonist that could attenuate the deleterious effects of quinpirole. The dopamine D₄ receptor is critically involved in signaling reward expectancy in the rSMT. The ability of L-745,870 to reduce the classification of losses as wins suggests that D₄ antagonists could be effective in treating problematic slot machine play.


Identifying, Understanding, and Addressing Disparities in Glaucoma Care in the United States.
Glaucoma is the leading cause of irreversible blindness worldwide, currently affecting around 80 million people. Glaucoma prevalence is rapidly rising in the United States due to an aging population. Despite recent advances in the diagnosis and treatment of glaucoma, significant disparities persist in disease detection, management, and outcomes among the diverse patient populations of the United States. Research on disparities is critical to identifying, understanding, and addressing societal and healthcare inequalities. Disparities research is especially important and impactful in the context of irreversible diseases such as glaucoma, where earlier detection and intervention are the primary approach to improving patient outcomes. In this article, we first review recent studies identifying disparities in glaucoma care that affect patient populations based on race, age, and gender. We then review studies elucidating and furthering our understanding of modifiable factors that contribute to these inequities, including socioeconomic status (particularly age and education), insurance product, and geographic region. Finally, we present work proposing potential strategies addressing disparities in glaucoma care, including teleophthalmology and artificial intelligence. We also discuss the presence of non-modifiable factors that contribute to differences in glaucoma burden and can confound the detection of glaucoma disparities. By recognizing underlying causes and proposing potential solutions, healthcare providers, policymakers, and other stakeholders can work collaboratively to reduce the burden of glaucoma and improve visual health and clinical outcomes in vulnerable patient populations.


[Spinal cord ischemia in the postoperative period of aortic surgery].
Paraplegia is a fearful and not uncommon complication of aortic clamping in surgical procedures involving thoracic and abdominal aorta. We report a case of transient spinal cord ischemia during the early postoperative period of aortobifemoral bypass in a 69-year-old male with arteriosclerosis obliterans, hypertension, type II diabetes mellitus and COLD. The anesthetic procedure was combined (peridural + intubation and mechanical ventilation + isofluorane). Two hypotensive episodes of about 80 mmHg developed, one after induction and another in the Reanimation area. The first one had a short duration, whereas the second one required the administration of colloids, crystalloids and blood. The infrarenal aortic clamping time was 35 minutes. In the early postoperative period the patient had clinical features consistent with spinal ischemia, which progressively recovered. To prevent spinal ischemia during surgery a shorter duration than 30 minutes of aortic clamping, a higher distal perfusion pressures higher than 60 mmHg during clamping, and the attempt to exclude the least possible number of intercostal and/or lumbar vessels are recommended. Drugs (corticosteroids, naloxone) and hypothermia can be useful.


Safety of subcutaneous and sublingual immunotherapy with allergoids in children: a real-life pharmacovigilance study.
Aims: Allergen-specific immunotherapy uses a sublingual (sublingual immunotherapy [SLIT]) or subcutaneous (subcutaneous immunotherapy [SCIT]) route. This pharmacovigilance study aimed to determine the number and type of adverse drug reactions (ADRs) for SLIT and SCIT using carbamylated monomeric allergoids (CMAs) in children. Materials & methods: This pharmacovigilance study analyzed real-world post-marketing reports collected from a safety database of Lais sublingual tablets and injective Lais-in, containing CMAs for over 10 years. Results & conclusion: From January 2009 to September 2022, 26,107 doses of Lais-in were administered in children; only two nonserious related ADRs (incidence: 0.000077%) were reported. Regarding SLIT, the results showed only 12 spontaneous nonserious ADR reports (incidence: 0.000004%). These data showed the excellent safety profile of both SLIT and SCIT CMAs.


Ultra-durable rotary micromotors assembled from nanoentities by electric fields.
Recently, we reported an innovative type of micromotors consisting of nanowires as rotors and patterned Au/Ni/Cr nanodisks as bearings. The dimensions of micromotors were less than 1 μm, and could continuously rotate for 15 hours over 240 000 cycles. To understand the limitation of their lifetime, we systematically investigated the rotation dynamics by analytical modeling and determined the time-dependent torques and forces involved in the rotation. From the forces and torques, the extent of wear of micromotors was successfully derived, which agreed well with the experimental characterization. The results also proved that the frictional force linearly increases with the loading in such rotary nanodevices operating in suspension, consistent with the prediction of the non-adhesive multi-asperity friction theory. With these understandings, we enhanced the design of micromotors and achieved an operation lifetime of 80 hours and over 1.1 million total rotation cycles. This research, shedding new light on the frictional mechanism of recently reported nanowire micromotors with demonstration of the most durable rotary nanomechanical devices of similar dimensions to the best of our knowledge, can be inspiring for innovative design of future nanomechanical devices with ultra-long lifetime for practical applications.


The miR-205-5p/BRCA1/RAD17 Axis Promotes Genomic Instability in Head and Neck Squamous Cell Carcinomas.
Defective DNA damage response (DDR) is frequently associated with tumorigenesis. Abrogation of DDR leads to genomic instability, which is one of the most common characteristics of human cancers. TP53 mutations with gain-of-function activity are associated with tumors under high replicative stress, high genomic instability, and reduced patient survival. The BRCA1 and RAD17 genes encode two pivotal DNA repair proteins required for proper cell-cycle regulation and maintenance of genomic stability. We initially evaluated whether miR-205-5p, a microRNA (miRNA) highly expressed in head and neck squamous cell carcinoma (HNSCC), targeted BRCA1 and RAD17 expression. We found that, in vitro and in vivo, BRCA1 and RAD17 are targets of miR-205-5p in HNSCC, leading to inefficient DNA repair and increased chromosomal instability. Conversely, miR-205-5p downregulation increased BRCA1 and RAD17 messenger RNA (mRNA) levels, leading to a reduction in in vivo tumor growth. Interestingly, miR-205-5p expression was significantly anti-correlated with BRCA1 and RAD17 targets. Furthermore, we documented that miR-205-5p expression was higher in tumoral and peritumoral HNSCC tissues than non-tumoral tissues in patients exhibiting reduced local recurrence-free survival. Collectively, these findings unveil miR-205-5p's notable role in determining genomic instability in HNSCC through its selective targeting of BRCA1 and RAD17 gene expression. High miR-205-5p levels in the peritumoral tissues might be relevant for the early detection of minimal residual disease and pre-cancer molecular alterations involved in tumor development.


Endothelial heparanase secretion after acute hypoinsulinemia is regulated by glucose and fatty acid.
Following diabetes, the heart increases its lipoprotein lipase (LPL) at the coronary lumen by transferring LPL from the cardiomyocyte to the endothelial lumen. We examined how hyperglycemia controls secretion of heparanase, the enzyme that cleaves myocyte heparan sulphate proteoglycan to initiate this movement. Diazoxide (DZ) was used to decrease serum insulin and generate hyperglycemia. A modified Langendorff technique was used to separate coronary from interstitial effluent, which were assayed for heparanase and LPL. Within 30 min of DZ, interstitial heparanase increased, an effect that closely mirrored an augmentation in interstitial LPL. Endothelial cells were incubated with palmitic acid (PA) or glucose, and heparanase secretion was determined. PA increased intracellular heparanase, with no effect on secretion of this enzyme. Unlike PA, glucose dose-dependently lowered endothelial intracellular heparanase, which was strongly associated with increased heparanase activity in the incubation medium. Preincubation with cytochalasin D or nocodazole prevented the high glucose-induced depletion of intracellular heparanase. Our data suggest that following hyperglycemia, translocation of LPL from the cardiomyocyte cell surface to the apical side of endothelial cells is dependent on the ability of the fatty acid to increase endothelial intracellular heparanase followed by rapid secretion of this enzyme by glucose, which requires an intact microtubule and actin cytoskeleton.


Extravasation injuries: a review.
Extravasation injuries are common emergencies in clinical practice. If they are not recognized and treated promptly, they can lead to deleterious functional and cosmetic outcomes. There is a vast range of agents involved in these injuries and marked paucity of evidence to support their specific management. Following an extensive literature review, we outline management principles for clinicians involved in the care of patients with extravasation injuries. Key parameters in deciding appropriate management plans include the volume/toxicity of the agent, the necrosis interval of the injury, patient-related factors, as well as the facilities and expertise available in the setting of individual cases of extravasation.


Floral traits influence the opportunity for selection among male gametophytes: independent and combined effects of style length and petal area.
Strong correlations between traits can obscure their independent effects on components of reproduction. Style length (SL) and petal area (PA) vary within species, for example, but their independent effects on the opportunity for selection among pollen genotypes are poorly understood. Previous work in Clarkia detected a positive effect of SL on pollen receipt, potentially intensifying selection. However, this apparent effect of SL may be influenced by a correlated trait, such as PA. Here, we examine the independent effects of these two traits on pollen receipt and performance. We collected petals and styles from wild populations of two insect-pollinated Clarkia taxa and estimated the independent and combined effects of SL and PA on pollen receipt and performance. In both taxa, SL and PA are positively correlated. In C. unguiculata, both traits positively and independently affect pollen receipt, but in C. xantiana ssp. xantiana, the two traits act only in combination to affect pollen receipt. In both taxa, pollen receipt positively affects the numbers of pollen tubes entering and penetrating the style, as well as pollen tube attrition. The effects of SL and PA on pollen receipt and performance are taxon specific. In C. unguiculata, both traits may be independent targets of selection due to their effects on pollen receipt. In C. xantiana ssp. xantiana, by contrast, the combined (but not independent) effects of SL and PA influence pollen receipt. Ecological differences between these taxa require exploration to understand the mechanisms by which these traits affect pollinator behavior.


Kidney targeting and puncturing during percutaneous nephrolithotomy: recent advances and future perspectives.
Precise needle puncture of the kidney is a challenging and essential step for successful percutaneous nephrolithotomy (PCNL). Many devices and surgical techniques have been developed to easily achieve suitable renal access. This article presents a critical review to address the methodologies and techniques for conducting kidney targeting and the puncture step during PCNL. Based on this study, research paths are also provided for PCNL procedure improvement. Most relevant works concerning PCNL puncture were identified by a search of Medline/PubMed, ISI Web of Science, and Scopus databases from 2007 to December 2012. Two authors independently reviewed the studies. A total of 911 abstracts and 346 full-text articles were assessed and discussed; 52 were included in this review as a summary of the main contributions to kidney targeting and puncturing. Multiple paths and technologic advances have been proposed in the field of urology and minimally invasive surgery to improve PCNL puncture. The most relevant contributions, however, have been provided by the application of medical imaging guidance, new surgical tools, motion tracking systems, robotics, and image processing and computer graphics. Despite the multiple research paths for PCNL puncture guidance, no widely acceptable solution has yet been reached, and it remains an active and challenging research field. Future developments should focus on real-time methods, robust and accurate algorithms, and radiation free imaging techniques.


Utilizing Healthcare Developments, Demographic Data with Statistical Techniques to Estimate the Diarrhoea Prevalence in India.
Diarrhoea is one of the leading causes of morbidity and mortality in developing countries in Africa and South Asia such as India. Prevalence of diarrheal diseases in those countries is higher than developed western world and largely has been associated with socio-economic and sanitary conditions. However, present available data has not been sufficiently evaluated to study the role of other factors like healthcare development, population density, sex and regional influence on diarrheal prevalence pattern. Study was performed to understand the relationship of diarrheal prevalence with specific measures namely; healthcare services development, demographics, population density, socio-economic conditions, sex, and regional prevalence patterns in India. Data from Annual national health reports and other epidemiological studies were included and statistically analyzed. Our results demonstrate significant correlation of the disease prevalence pattern with certain measures like healthcare centers, population growth rate, sex and region-specific morbidity. Available information on sanitation like water supply and toilet availability and socioeconomic conditions like poverty and literacy measures could only be associated as trends of significance. This study can be valuable for improvisation of appropriate strategies focused on important measures like healthcare resources, population growth and regional significances to evaluate prevalence patterns and management of the diarrhoea locally and globally.


Intra and Inter-Observer Reliability and Repeatability of Metatarsus Adductus Angle in Recreational Football Players: A Concordance Study.
Metatarsus adductus (MA) is a congenital foot deformity often unrecognized at birth. There is adduction of the metatarsals, supination of the subtalar joint, and plantarflexion of the first ray. The aims of this study were to assess the intra and inter-reader reliability of the radiographic MA measurement angles used in the literature. Methods: All consecutive recreational football players who practice activity more than 5 h/week over 21 years of age with MA by roentgenographic evaluation on weight-bearing dorsoplantar images were included in a cross-sectional study. Controls were matched to cases according to age and gender. We assess all radiographic measurements to evaluate metatarsus adductus with the different measurements frequently used in the literature: Sgarlato, modified Sgarlato, Rearfoot, Root, Engel, modified Engel, Kite, Kilmartin, modified Kilmartin, Simons, and Laaveg & Ponseti. Results: The variables measured in 80 weight-bearing dorsoplantar foot radiographs show excellent reliability ranging p > 0.900 in Sgarlato and modified Sgarlato with low SEM, CV, and MCD. Rearfoot, Root, Engel, modified Engel, Kite, Kilmartin, Simons, Laaveg & Ponseti, and modified Kilmartin's angles showed intra or inter reliability with ICC lower than <0.900, systematic differences between intersession or inter observers, or high MCD value. Conclusion: It is more suitable to measure the MA angle with the Sgarlato and modified Sgarlato techniques to show higher reliability and repeatability for intra and inter-observer.


Paranasal sinus pathologies in patients presenting with headache as the primary symptom.
Headache is a frequent symptom of lesions in the paranasal sinuses. Although some inflammatory symptoms are suggestive of pathologies of the paranasal sinuses, occasional headache is sometimes the major presenting symptom. In a retrospective study, we examined the chart histories of 36 patients presenting for treatment at our hospital from 1 January 1992 to 30 June 2001 who were diagnosed as having pathologies of the paranasal sinuses with the primary symptom being headache. All patients had been evaluated with complete otolaryngological and neurological examinations, diagnostic nasal endoscopy, and sinus computed tomographic (CT) scans. Sinus surgery was arranged after failure in performing appropriate medical treatment. Among the 36 patients, 33 showed significant improvement after sinus operation (92%). A paranasal sinus aetiology of headache is an important factor in the differential diagnosis of chronic headache. Those patients who are clinically suspected of having headaches arising from paranasal sinus pathology should receive comprehensive otorhinolaryngological examination and evaluation. Nasal endoscopy and sinus CT scans are good diagnostic tools. Surgical management may be beneficial in those for whom medical treatment fails to resolve the problem.


Liposome-mediated transfer of simian virus 40 DNA and minichromosome into mammalian cells.
We have investigated the use of liposomes as carriers for the transfer of simian virus 40 (SV40) DNA into mammalian cells. The amount of DNA entrapped in liposomes was dependent on the input DNA concentration and lipid composition. DNA remained intact after liposome encapsulation and was resistant to deoxyribonuclease digestion. Combined transfer to and expression of liposome-entrapped SV40 DNA in monkey kidney cells was assayed by infectious plaque formation. Negatively-charged liposomes containing phosphatidylserine were more effective in DNA transfer and expression than neutral liposomes. The inclusion of carrier salmon sperm DNA inhibited liposome-entrapped SV40 DNA infectivity. Infectivity of liposome-entrapped DNA was directly related to both liposome DNA concentration and number of vesicles added. Liposome-entrapped SV40 minichromosome was 20-fold more infective than free minichromosome, but only 20% more infective than liposome-entrapped SV40 DNA. Thus, the presence of hyperacetylated histones on the DNA failed to enhance liposome-mediated DNA transfer appreciably. Incubation of cells with various modulators of endocytosis implicated the endocytotic pathway in the mechanism of liposome-mediated DNA transfer. These studies show that liposomes are suitable carriers for the introduction of viral DNA and chromatin into mammalian cells.


De novo assembly, gene annotation and marker development using Illumina paired-end transcriptome sequences in celery (Apium graveolens L.).
Celery is an increasing popular vegetable species, but limited transcriptome and genomic data hinder the research to it. In addition, a lack of celery molecular markers limits the process of molecular genetic breeding. High-throughput transcriptome sequencing is an efficient method to generate a large transcriptome sequence dataset for gene discovery, molecular marker development and marker-assisted selection breeding. Celery transcriptomes from four tissues were sequenced using Illumina paired-end sequencing technology. De novo assembling was performed to generate a collection of 42,280 unigenes (average length of 502.6 bp) that represent the first transcriptome of the species. 78.43% and 48.93% of the unigenes had significant similarity with proteins in the National Center for Biotechnology Information (NCBI) non-redundant protein database (Nr) and Swiss-Prot database respectively, and 10,473 (24.77%) unigenes were assigned to Clusters of Orthologous Groups (COG). 21,126 (49.97%) unigenes harboring Interpro domains were annotated, in which 15,409 (36.45%) were assigned to Gene Ontology(GO) categories. Additionally, 7,478 unigenes were mapped onto 228 pathways using the Kyoto Encyclopedia of Genes and Genomes Pathway database (KEGG). Large numbers of simple sequence repeats (SSRs) were indentified, and then the rate of successful amplication and polymorphism were investigated among 31 celery accessions. This study demonstrates the feasibility of generating a large scale of sequence information by Illumina paired-end sequencing and efficient assembling. Our results provide a valuable resource for celery research. The developed molecular markers are the foundation of further genetic linkage analysis and gene localization, and they will be essential to accelerate the process of breeding.


A DNA prime-Mycobacterium bovis BCG boost vaccination strategy for cattle induces protection against bovine tuberculosis.
The variable efficacy of bacillus Calmette-Guérin (Mycobacterium bovis BCG) in protecting humans and cattle against tuberculosis has prompted a search for a more effective vaccination regimen. A prime-boost strategy was investigated in cattle naturally sensitized to environmental mycobacteria by using a combination of three DNA vaccines coding for Hsp 65, Hsp 70, and Apa for priming, followed by a boost with BCG prior to experimental challenge with virulent M. bovis. Controls were vaccinated with DNA or BCG alone or were not vaccinated. The immune responses were monitored throughout the study, and protection was assessed based on reductions in the numbers of lesions and viable mycobacteria in lymph node samples. Vaccination with BCG alone or with a DNA prime-BCG boost regimen induced high levels of antigen-specific gamma interferon (IFN-gamma) in whole-blood cultures. In the prime-boost group there were fewer animals with severe lung lesions, fewer lymph nodes with lesions per animal, a smaller proportion of animals with lesions, lower mean lung and lymph node lesion scores, and less M. bovis isolated from retropharyngeal and thoracic lymph nodes compared to the results obtained for the nonvaccinated animals. The prime-boost regimen induced significant enhancement of protection in six parameters, compared with significant enhancement of protection in only two parameters for BCG alone. In addition, following challenge, in vitro IFN-gamma responses against ESAT-6 and CFP-10, as well as bovine tuberculin-induced skin test and in vitro IFN-gamma responses, were identified as immunological markers that predicted protection. The use of the prime-boost strategy suggested that a combination of vaccines may be better than a single vaccine for protection against tuberculosis.


Cellular expression and functional characterization of four hyperpolarization-activated pacemaker channels in cardiac and neuronal tissues.
Hyperpolarization-activated cation currents (I(h)) have been identified in cardiac pacemaker cells and a variety of central and peripheral neurons. Four members of a gene family encoding hyperpolarization-activated, cyclic nucleotide-gated cation channels (HCN1--4) have been cloned recently. Native I(h) currents recorded from different cell types exhibit distinct activation kinetics. To determine if this diversity of I(h) currents may be caused by differential expression of HCN channel isoforms, we investigated the cellular distribution of the transcripts of HCN1--4 in the murine sinoatrial node, retina and dorsal root ganglion (DRG) by in situ hybridization. In the sinoatrial node, the most prominently expressed HCN channel is HCN4, whereas HCN2 and HCN1 are detected there at moderate and low levels, respectively. Retinal photoreceptors express high levels of HCN1, whereas HCN2, 3 and 4 were not found in these cells. In DRG neurons, the dominant HCN transcript is HCN1, followed by HCN2. We next determined the functional properties of recombinant HCN1--4 channels expressed in HEK293 cells. All four channel types gave rise to I(h) currents but displayed marked differences in their activation kinetics. Our results suggest that the heterogeneity of native I(h) currents is generated, at least in part, by the tissue-specific expression of HCN channel genes.


Identification of new potential candidates to inhibit EGF via machine learning algorithm.
One of the cost-effective alternative methods to find new inhibitors has been the repositioning approach of existing drugs. The advantage of computational drug repositioning method is saving time and cost to remove the pre-clinical step and accelerate the drug discovery process. Hence, an ensemble computational-experimental approach, consisting of three different steps, a machine learning model, simulation of drug-target interaction and experimental characterization, was developed. The machine learning type used here was different tree classification method, which is one of the best randomize machine learning model to identify potential inhibitors from weak inhibitors. This model was trained more than one-hundred times, and forty top trained models were extracted for the drug repositioning step. The machine learning step aimed to discover the approved drugs with the highest possible success rate in the experimental step. Therefore, among all the identified molecules with more than 0.9 probability in more than 70% of the models, nine compounds, were selected. Besides, out of the nine chosen drugs, seven compounds have been confirmed to inhibit EGF in the published articles since 2019. Hence, two identified compounds, in addition to gefitinib, as a positive control, five weak-inhibitors and one neutral, were considered via molecular docking study. Finally, eight proposed drugs, including gefitinib, were investigated using MTT assay and In-Cell ELISA to characterize the drugs effect on A431 cell growth and EGF-signaling. From our experiments, we could conclude that salicylic acid and piperazine could play an EGF-inhibitor role like gefitinib.


A dose of realism for healthy urban policy: lessons from area-based initiatives in the UK.
Many urban policies aim to improve areas and address socioeconomic deprivation. The resulting investment is often delivered through area-based programmes which incorporate initiatives to improve the physical, social and economic environment. Hypotheses that these investments can contribute to wider public health strategies are based on epidemiological data and used to support the concept of healthy urban policy. However, there is little evidence on their ability to generate positive impacts on socioeconomic or health outcomes. The lack of validating evidence on actual impacts raises two important questions: (1) Is area-based investment an effective strategy to tackle socioeconomic deprivation? (2) What is the prospect for new and improved evaluations to provide stronger evidence? Both the programmes of area investment and their accompanying evaluations have been criticised for being overly ambitious in what can be achieved by the investment and what can be measured by an evaluation. Area-based approaches to tackling deprivation have their advantages but a mix of area and individual-level targeting is likely to be needed. While there is scope to improve the utility of evaluation data there are also inevitable constraints on assessing and attributing impacts from urban investment. The inherent limitations to an area-based approach and the ongoing constraints on impact evaluation will inevitably temper expectations of what healthy urban policy can achieve. However, lack of evidence is not grounds to abandon the concept of healthy urban policy; adoption of more realistic expectations together with improved evaluation data may help to increase its credibility.


Atmospheric ammonia, volatile fatty acids, and other odorants near beef feedlots.
Intensive livestock operations can release odorous gases from stored or land-applied manure. We measured concentrations of dust and 14 odor-causing gases at increasing distances from four feedlots near Lethbridge, southern Alberta, Canada. Concentration was determined from the amount of total dust or gas accumulated in the sampIers, and the volume of air sampled. Adjacent the feedlots, the maximum concentration of many volatile fatty acids exceeded reported odor detection thresholds; the maximum ammonia concentration was close to the threshold. Ammonia and butyric acid approached or exceeded their individual odor thresholds as far as 200 m downwind of the feedlots. Highest concentrations were measured adjacent to land where manure was being applied. None of the odorant concentrations exceeded their irritation threshold. There was a positive relationship between ammonia concentration and odor intensity as well as dry deposition. Much of the emitted ammonia was deposited to soil immediately downwind, enough to supply all the nitrogen needed for crop growth. Odorant concentrations declined sharply with distance, though measurable odor occasionally persisted to 1 km from the feedlot, beyond the minimum separation guidelines (Alberta) for a single residential dwelling. The weekly averaged total suspended particulates (> 5 microm) were below the Alberta guideline criterion except for one period. Differences among feedlots in odorant plume concentrations were partly related to the stocking density of feedlots, which presumably affects manure moisture and amount of volatiles within the pens.


Modeling, molecular dynamics, and docking assessment of transcription factor rho: a potential drug target in Brucella melitensis 16M.
The zoonotic disease brucellosis, a chronic condition in humans affecting renal and cardiac systems and causing osteoarthritis, is caused by Brucella, a genus of Gram-negative, facultative, intracellular pathogens. The mode of transmission and the virulence of the pathogens are still enigmatic. Transcription regulatory elements, such as rho proteins, play an important role in the termination of transcription and/or the selection of genes in Brucella. Adverse effects of the transcription inhibitors play a key role in the non-successive transcription challenges faced by the pathogens. In the investigation presented here, we computationally predicted the transcription termination factor rho (TtFRho) inhibitors against Brucella melitensis 16M via a structure-based method. In view the unknown nature of its crystal structure, we constructed a robust three-dimensional homology model of TtFRho's structure by comparative modeling with the crystal structure of the Escherichia coli TtFRho (Protein Data Bank ID: 1PVO) as a template in MODELLER (v 9.10). The modeled structure was optimized by applying a molecular dynamics simulation for 2 ns with the CHARMM (Chemistry at HARvard Macromolecular Mechanics) 27 force field in NAMD (NAnoscale Molecular Dynamics program; v 2.9) and then evaluated by calculating the stereochemical quality of the protein. The flexible docking for the interaction phenomenon of the template consists of ligand-related inhibitor molecules from the ZINC (ZINC Is Not Commercial) database using a structure-based virtual screening strategy against minimized TtFRho. Docking simulations revealed two inhibitors compounds - ZINC24934545 and ZINC72319544 - that showed high binding affinity among 2,829 drug analogs that bind with key active-site residues; these residues are considered for protein-ligand binding and unbinding pathways via steered molecular dynamics simulations. Arg215 in the model plays an important role in the stability of the protein-ligand complex via a hydrogen bonding interaction by aromatic-π contacts, and the ADMET (absorption, distribution, metabolism, and excretion) analysis of best leads indicate nontoxic in nature with good potential for drug development.


Direct determination of equilibrium potentials for hydrogen oxidation/production by open circuit potential measurements in acetonitrile.
Open circuit potentials were measured for acetonitrile solutions of a variety of acids and their conjugate bases under 1 atm H2. Acids examined were triethylammonium, dimethylformamidium, 2,6-dichloroanilinium, 4-cyanoanilinium, 4-bromoanilinium, and 4-anisidinium salts. These potentials, along with the pKa values of the acids, establish the value of the standard hydrogen electrode (SHE) potential in acetonitrile as -0.028(4) V vs the ferrocenium/ferrocene couple. Dimethylformamidium forms homoconjugates and other aggregates with dimethylformamide; open circuit potentials (OCPs) were used to quantify the extent of these reactions. Overpotentials for electrocatalytic hydrogen production and oxidation were determined from open circuit potentials and voltammograms of acidic or basic catalyst solutions under H2. For these solutions, agreement between OCP values and potentials calculated using the Nernst equation is within 12 mV. Use of the measured equilibrium potential allows direct comparison of catalytic systems in different media; it requires neither pKa values, homoconjugation constants, nor the SHE potential.


Qualitative regional differences in adipose tissue growth and cellularity in male Wistar rats fed ad libitum.
Adipose tissue grows primarily by a combination of increases in fat cell volume (hypertrophy) and in fat cell number (hyperplasia), but the regional growth pattern of white adipose tissue depots in animal species and in the human is still unclear. In this study we characterized fully the age-related changes in adipose tissue growth, composition, and cellularity of four fat depots of male Wistar rats that varied in age from 7 wk to 15 mo and in body weight from 178 to 808 g. Body weight and the weight of each of the four adipose depots studied (epididymal, mesenteric, subcutaneous inguinal, and retroperitoneal) increased progressively with age and ad libitum feeding. Comparison of the cellularity of the four adipose depots, however, showed remarkable and significant differences in the pattern of growth within the same animals. The cumulative growth of the two intraabdominal fat depots (mesenteric and epididymal) was due mostly to hypertrophy (increases in cell volume of 83 and 64%, respectively), whereas the growth of the other two depots (retroperitoneal and inguinal) was due predominantly to hyperplasia (increases in cell number of 58- and 65%, respectively). These findings uncover major and unexpected regional differences in the modulation of adipose tissue growth within aging animals fed ad libitum and suggest local, region-specific regulatory controls of this growth.


Mechanisms of tumor cell invasion and angiogenesis in the central nervous system.
Despite extensive progress in characterizing the genetic events involved in the development of gliomas, the cellular origin and the defined molecular mechanisms that lead to their occurrence are still unclear. It is known that tumours are of monoclonal origin. This is contrasted by the fact that gliomas frequently express features of different glial cell lineages. With the identification of pluripotent neural stem cells and the growth factors that control neural cell development, we are now making early inroads towards understanding glial cell migration as well as the neural cell plasticity within the adult central nervous system (CNS). Gliomas share several fetal antigens with immature brain cells. It is therefore tempting to speculate that the migration of neural precursor cells actually represents the normal counterpart of glioma cell migration. The migratory behavior of gliomas may be due to a predetermined interplay between normal brain tissue and the migrating cells, where the brain represents a permissive tissue for guiding cells with certain phenotypic traits to migrate along specific anatomical structures. Malignant progression is also accompanied by extensive angiogenesis which is especially prominent in glioblastoma multiforme (GBM). For cell proliferation to take place, several cell signaling cues mediated by specific growth factors are shared between the glioma cells and the endothelial cells while others are unique for endothelial cells. Therefore the endothelial cell compartment represents a promising target for novel therapeutic strategies including gene therapy and cell-based therapies.


Voltage-Gated Ca2+ Channels in Dopaminergic Substantia Nigra Neurons: Therapeutic Targets for Neuroprotection in Parkinson's Disease?
The loss of dopamine (DA)-producing neurons in the substantia nigra pars compacta (SN) underlies the core motor symptoms of the progressive movement disorder Parkinson's disease (PD). To date, no treatment to prevent or slow SN DA neurodegeneration exists; thus, the identification of the underlying factors contributing to the high vulnerability of these neurons represents the basis for the development of novel therapies. Disrupted Ca2+ homeostasis and mitochondrial dysfunction seem to be key players in the pathophysiology of PD. The autonomous pacemaker activity of SN DA neurons, in combination with low cytosolic Ca2+ buffering, leads to large somatodendritic fluctuations of intracellular Ca2+ levels that are linked to elevated mitochondrial oxidant stress. L-type voltage-gated Ca2+ channels (LTCCs) contribute to these Ca2+ oscillations in dendrites, and LTCC inhibition was beneficial in cellular and in vivo animal models of PD. However, in a recently completed phase 3 clinical trial, the dihydropyridine (DHP) LTCC inhibitor isradipine failed to slow disease progression in early PD patients, questioning the feasibility of DHPs for PD therapy. Novel evidence also suggests that R- and T-type Ca2+ channels (RTCCs and TTCCs, respectively) represent potential PD drug targets. This short review aims to (re)evaluate the therapeutic potential of LTCC, RTCC, and TTCC inhibition in light of novel preclinical and clinical data and the feasibility of available Ca2+ channel blockers to modify PD disease progression. I also summarize their cell-specific roles for SN DA neuron function and describe how their gating properties allow activity (and thus their contribution to stressful Ca2+ oscillations) during pacemaking.


Education Intervention on Chronotherapy for Final-Year Pharmacy Students.
Chronotherapy involves altering the timing of medication administration in coordination with the body's circadian rhythms to improve the overall control of disease and to minimise treatment side effects. Training on chronotherapy requires students to map different topics learnt in earlier years of their professional degree and apply these concepts clinically. This requires strategic educational design. Therefore, the aim of the study was to develop, implement and evaluate an educational intervention focusing on the application of chronotherapy for final-year undergraduate pharmacy students. An educational intervention utilizing multiple learning strategies for enhancing chronotherapy related awareness was designed and implemented in the final year undergraduate pharmacy cohort at the University of Sydney Australia (2013). A custom-designed questionnaire measuring awareness about (13 items scored 0 or 1), and attitudes (12 items scored on a Likert scale of 1-5) towards chronotherapy was administered pre and post intervention to evaluate its impact. The pre-intervention mean total awareness and attitude scores were 6.5 ± 2.0 (score range 0-13) and 47.4 ± 6.9 (score range 12-60) respectively. The mean total post-intervention scores were significantly higher for total awareness (10.1 ± 1.9) and attitude (54.0 ± 6.0). Carefully designed educational interventions utilising pedagogic principles for pharmacy students can improve awareness of and enhance positive attitudes toward pharmacists' roles in optimizing drug therapy using chronotherapy.


A translational rheostat for RFLAT-1 regulates RANTES expression in T lymphocytes.
Activation of T lymphocytes by specific antigen triggers a 3- to 7-day maturation process. Terminal differentiation begins late after T cell activation and involves expression of effector genes, including the chemokine RANTES and its major transcriptional regulator, RANTES factor of late-activated T lymphocytes-1 (RFLAT-1). In this article we demonstrate that RFLAT-1 expression is translationally regulated through its 5'-UTR and in a cell type-specific manner. Overexpression of the translation initiation factor eIF4E increases RFLAT-1 protein, while inhibition of Mnk1, which phosphorylates eIF4E, reduces RFLAT-1 production, indicating cap-dependent translational regulation. These events are regulated by ERK-1/2 and p38 MAP kinases and allow T cells to rapidly adjust RANTES expression in response to changes in the cellular environment, such as stress and/or growth factors. These findings provide a molecular mechanism for a rheostat effect of increasing or decreasing RANTES expression at sites of inflammation. Memory T cells, already poised to make RANTES, are finely regulated by translational control of the major transcription factor regulating RANTES expression. This is the first example of such a mechanism regulating a chemokine, but it seems likely that this will prove to be a general way for cells to rapidly respond to stress, cytokines, and other proinflammatory factors in their local environment.


Racial Disparities in Incidence and Outcomes Among Patients With COVID-19.
Initial public health data show that Black race may be a risk factor for worse outcomes of coronavirus disease 2019 (COVID-19). To characterize the association of race with incidence and outcomes of COVID-19, while controlling for age, sex, socioeconomic status, and comorbidities. This cross-sectional study included 2595 consecutive adults tested for COVID-19 from March 12 to March 31, 2020, at Froedtert Health and Medical College of Wisconsin (Milwaukee), the largest academic system in Wisconsin, with 879 inpatient beds (of which 128 are intensive care unit beds). Race (Black vs White, Native Hawaiian or Pacific Islander, Native American or Alaska Native, Asian, or unknown). Main outcomes included COVID-19 positivity, hospitalization, intensive care unit admission, mechanical ventilation, and death. Additional independent variables measured and tested included socioeconomic status, sex, and comorbidities. Reverse transcription polymerase chain reaction assay was used to test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A total of 2595 patients were included. The mean (SD) age was 53.8 (17.5) years, 978 (37.7%) were men, and 785 (30.2%) were African American patients. Of the 369 patients (14.2%) who tested positive for COVID-19, 170 (46.1%) were men, 148 (40.1%) were aged 60 years or older, and 218 (59.1%) were African American individuals. Positive tests were associated with Black race (odds ratio [OR], 5.37; 95% CI, 3.94-7.29; P = .001), male sex (OR, 1.55; 95% CI, 1.21-2.00; P = .001), and age 60 years or older (OR, 2.04; 95% CI, 1.53-2.73; P = .001). Zip code of residence explained 79% of the overall variance in COVID-19 positivity in the cohort (ρ = 0.79; 95% CI, 0.58-0.91). Adjusting for zip code of residence, Black race (OR, 1.85; 95% CI, 1.00-3.65; P = .04) and poverty (OR, 3.84; 95% CI, 1.20-12.30; P = .02) were associated with hospitalization. Poverty (OR, 3.58; 95% CI, 1.08-11.80; P = .04) but not Black race (OR, 1.52; 95% CI, 0.75-3.07; P = .24) was associated with intensive care unit admission. Overall, 20 (17.2%) deaths associated with COVID-19 were reported. Shortness of breath at presentation (OR, 10.67; 95% CI, 1.52-25.54; P = .02), higher body mass index (OR per unit of body mass index, 1.19; 95% CI, 1.05-1.35; P = .006), and age 60 years or older (OR, 22.79; 95% CI, 3.38-53.81; P = .001) were associated with an increased likelihood of death. In this cross-sectional study of adults tested for COVID-19 in a large midwestern academic health system, COVID-19 positivity was associated with Black race. Among patients with COVID-19, both race and poverty were associated with higher risk of hospitalization, but only poverty was associated with higher risk of intensive care unit admission. These findings can be helpful in targeting mitigation strategies for racial disparities in the incidence and outcomes of COVID-19.


What does the dissociation between the results of video head impulse versus caloric testing reveal about the vestibular dysfunction in Ménière's disease?
It is suggested that the different results of rotational (video head impulse - vHIT) and caloric tests in patients with Ménière's disease (MD) may be a consequence of the physical enlargement of the membranous duct in the hydropic labyrinths in MD, causing a reduced response to caloric stimulation. There have been reports that the results of two tests of semicircular canal function, the caloric response and the responses to vHIT do not agree. This retrospective study at a tertiary referral hospital examined this disagreement. This study reviewed the data of 22 patients who met the AAO-HNS criteria for MD and who had both caloric and vHIT testing. There was a clear dissociation: patients with MD had a small or absent response to caloric stimulation of their affected ear, whilst their response to vHIT was in the normal range. The accepted Gentine model of the mechanism of caloric stimulation could account for this dissociation: the increased diameter of the semicircular duct in hydropic labyrinths resulting in endolymph circulation within the duct itself and so a smaller thermally induced pressure across the cupula. The increased duct diameter will have little effect on responses to rotation.


Endoscopic Endonasal-Assisted Resection of Orbital Schwannoma.
Orbital schwannomas are rare and despite a variety of external surgical approaches previously utilized, removal of tumors located in the deep orbital apex remains challenging. The endoscopic endonasal approach has been used increasingly for various apical tumours, but few describe this technique for orbital schwannomas. The authors describe 2 cases of orbital schwannoma removed via an endoscopic endonasal assisted approach. The first patient was a 31-year-old Cantonese female who was found to have an 11 × 8 × 8 mm right orbital apical schwannoma which was removed using an endoscopic endonasal sphenoethmoidal approach. The second patient was a 78-year-old white male who had a 28 × 17 × 18 mm orbital schwannoma removed via a transcaruncular and endoscopic endonasal-assisted approach. These findings suggest that the use of an endonasal approach may facilitate the safe removal of selected medially located orbital schwannomas whose posterior margins involve the orbital apex.


The activity pattern of the lumbo-pelvic muscles during prone hip extension in athletes with and without hamstring strain injury.
Altered muscular activation pattern has been associated with musculoskeletal disorders. Some previous studies have demonstrated muscle weakness or tightness in athletes who have sustained hamstring (HAM) injuries. However, no study has clinically investigated the muscular activity pattern in subjects with HAM strain injuries. To investigate the activity pattern of the ipsilateral erector spinae (IES), contralateral erector spinae (CES), gluteus maximus (GM), and medial and lateral HAM muscles during the prone hip extension (PHE) test in athletes with and without history of HAM strain injury. Cross-sectional non-experimental study design. A convenience sample of 20 soccer athletes participated in the study. Subjects were categorized into two groups: those with history of HAM strain injury (n=10, mean age = 22.6 ± 3.74) and without history of HAM strain (n =10, mean age = 22.45 ± 3.77). Three repetitions of the PHE were performed by each subject, and the electromyographic (EMG) outputs of the IES, CES, GM, and HAM muscles were recorded, processed and normalized to maximum voluntary electrical activity (MVE). Independent t-tests were used for comparing activation means of each muscle between athletes with and without history of HAM strain injury. There were significant differences in EMG activity of the GM (p= 0.04) and medial HAM (p = 0.01) between two groups. No significant difference was found in EMG signals of the IES (p= 0.26), CES (= 0.33) and lateral HAM (p= 0.58) between the two groups. Greater although non-significant normalized EMG outputes of IES, CES and lateral HAM were seen in athletes with history of HAM strain compared to those without HAM strain. The findings of this study demonstrated greater normalized EMG activity of GM and medial HAM tested in athletes with history of HAM strain compared to those without HAM strain (altered activation pattern). 3a.


The journal club. Teaching critical evaluation of clinical literature in an evidence-based environment.
To develop a curriculum in epidemiology, biostatistics and experimental design that uses a journal club format for resident instruction and to assess participants' response to this format. A curriculum over 12 months included 24 concepts descriptive of topics considered critical in the assessment and evaluation of literature descriptive of clinical practice and patient care. There was one two-hour session per month for 12 months. Two sets of articles were distributed for each session. The first set consisted of literature on the topics of epidemiology, biostatistics and experimental design. These concepts increased in complexity throughout the academic year, starting from simple concepts, such as P values, and progressing to more-involved and complicated concepts, such as meta-analysis. The second set of articles consisted of literature on clinical topics. It was intended to illustrate and emphasize the concepts of experimental design and statistical analysis presented in the first set of articles. These clinical articles were both contemporary and historical and were from a variety of medical disciplines, including internal medicine, obstetrics and gynecology, orthopedics, infectious disease, anesthesiology, pediatrics and psychiatry. A questionnaire was distributed to the students at the conclusion of the curriculum. This format was well received by both residents and staff. Eighty-five percent of the residents expressed interest in continuing the format without a major change. Fifteen percent requested restricting the clinical literature to obstetrics and gynecology. This format proved an excellent method of training residents in evaluating clinical literature and providing familiarity with concepts in epidemiology, biostatistics and experimental design.


Forests and Their Canopies: Achievements and Horizons in Canopy Science.
Forest canopies are dynamic interfaces between organisms and atmosphere, providing buffered microclimates and complex microhabitats. Canopies form vertically stratified ecosystems interconnected with other strata. Some forest biodiversity patterns and food webs have been documented and measurements of ecophysiology and biogeochemical cycling have allowed analyses of large-scale transfer of CO2, water, and trace gases between forests and the atmosphere. However, many knowledge gaps remain. With global research networks and databases, and new technologies and infrastructure, we envisage rapid advances in our understanding of the mechanisms that drive the spatial and temporal dynamics of forests and their canopies. Such understanding is vital for the successful management and conservation of global forests and the ecosystem services they provide to the world.


When colocation is not enough: a case study of General Practitioner Super Clinics in Australia.
Developed nations are implementing initiatives to transform the delivery of primary care. New models have been built around multidisciplinary teams, information technology and systematic approaches for chronic disease management (CDM). In Australia, the General Practice Super Clinic (GPSC) model was introduced in 2010. A case study approach was used to illustrate the development of inter-disciplinary CDM over 12 months in two new, outer urban GPSCs. A social scientist visited each practice for two 3-4-day periods. Data, including practice documents, observations and in-depth interviews (n=31) with patients, clinicians and staff, were analysed using the concept of organisational routines. Findings revealed slow, incremental evolution of inter-disciplinary care in both sites. Clinic managers found the facilitation of inter-disciplinary routines for CDM difficult in light of competing priorities within program objectives and the demands of clinic construction. Constraints inherent within the GPSC program, a lack of meaningful support for transformation of the model of care and the lack of effective incentives for collaborative care in fee-for-service billing arrangements, meant that program objectives for integrated multidisciplinary care were largely unattainable. Findings suggest that the GPSC initiative should be considered a program for infrastructure support rather than one of primary care transformation.


Implementation of advanced radiotherapy technology to improve clinical outcomes in rural NSW.
Availability of advanced radiotherapy technology to treat cancer is limited in regional Australia. At Central West Cancer Care Centre, the utilisation rate of intensity-modulated radiotherapy and volumetric modulated arc therapy was significantly lower compared to other NSW public health services. Stereotactic ablative body radiotherapy treatment was not available at Central West Cancer Care Centre. To increase the intensity-modulated radiotherapy/volumetric modulated arc therapy utilisation rate and to make stereotactic ablative body radiotherapy treatment available through quality improvement projects with multi-disciplinary collaboration. Central West Cancer Care Centre is part of Western NSW Local health District. Central West Cancer Care Centre has two linear accelerators for delivering intensity-modulated radiotherapy, volumetric modulated arc therapy and stereotactic ablative body radiotherapy treatments, and a computed tomography simulator with 4D computed tomography capability. Intensity-modulated radiotherapy/volumetric modulated arc therapy utilisation rate increases to > 65% Stereotactic ablative body radiotherapy available to Central West Cancer Care Centre patients STRATEGY FOR CHANGE: A multi-disciplinary active of team radiation oncologists, medical physics specialists and radiation therapists developed an implementation plan for each treatment technique. There was a significant increase in use of advanced techniques. The impact on patients included the following: Fewer side effects and improved control of disease as the advanced techniques directed the dose to the tumour and reduced the radiation dose to organ at risk. Treatment completed sooner than conventional radiotherapy, as the required dose required fewer trips to the hospital. Rural and remote patients were not required to travel to a metropolitan centre to have stereotactic ablative body radiotherapy treatment. Strong commitment from a trained team and a collaborative approach is important for the implementation of advanced technology in regional centres.


SVDSS: structural variation discovery in hard-to-call genomic regions using sample-specific strings from accurate long reads.
Structural variants (SVs) account for a large amount of sequence variability across genomes and play an important role in human genomics and precision medicine. Despite intense efforts over the years, the discovery of SVs in individuals remains challenging due to the diploid and highly repetitive structure of the human genome, and by the presence of SVs that vastly exceed sequencing read lengths. However, the recent introduction of low-error long-read sequencing technologies such as PacBio HiFi may finally enable these barriers to be overcome. Here we present SV discovery with sample-specific strings (SVDSS)-a method for discovery of SVs from long-read sequencing technologies (for example, PacBio HiFi) that combines and effectively leverages mapping-free, mapping-based and assembly-based methodologies for overall superior SV discovery performance. Our experiments on several human samples show that SVDSS outperforms state-of-the-art mapping-based methods for discovery of insertion and deletion SVs in PacBio HiFi reads and achieves notable improvements in calling SVs in repetitive regions of the genome.


A Review of Opioid-Sparing Modalities in Perioperative Pain Management: Methods to Decrease Opioid Use Postoperatively.
There is an epidemic of opioid use, abuse, and misuse in the United States, which results in significant morbidity and mortality. It may be difficult to reduce perioperative opioid use given known acute surgical trauma and resultant pain; however, the discrete and often limited nature of postoperative pain also may make management easier in part by utilizing nonopioid modalities, such as regional anesthesia/analgesia, and multimodal analgesia, which may decrease the need for powerful opioids. This article reviews the relevant literature describing the use of adjunct medications, regional anesthesia and analgesic techniques, and regional block additives in the context of providing adequate pain control while lessening opioid use.


Preparation Method and In Vitro Characterization of Nanoparticles Sensitive to Tumor Microenvironment.
Immunotherapy is considered a powerful clinical strategy aiming to boost the immune system to fight cancer. In this context, nanomaterials (NMs) are uniquely suited to improve the development and the broad implementation of cancer immunotherapies by overcoming several challenges. In fact, NMs can be rationally designed to navigate complex physical barriers, respond to tumor microenvironments, and enhance/modulate immune system activation. Here, we present a method to prepare stimuli-responsive biocompatible nanoparticles (NPs) able to target the tumor microenvironment. Moreover, we describe protocols to characterize the physical-chemical properties of NPs as well as to evaluate their biocompatibility and therapeutic potential in vitro on three-dimensional (3D) tumor spheroids.


Evaluation of superficial musculoaponeurotic system flap and fat graft outcomes for benign and malignant parotid disease.
(1) To evaluate the effectiveness of the superficial musculoaponeurotic system (SMAS) flap and free fat graft in reconstructing the parotidectomy defect. (2) To evaluate the long-term viability of the free fat graft following parotidectomy for benign and malignant disease, including in the postradiation setting. Prospective study of consecutive patients. Academic tertiary care medical center. Subjects and Methods Thirty-one consecutive patients underwent parotidectomy with SMAS flap and free fat graft reconstruction from 2006 to 2012. Data were compiled through a manual chart review. Twenty-three of the 31 total patients had benign disease, including pleomorphic adenoma, oncocytoma, and Warthin tumor. The 8 remaining patients (9 parotidectomies) underwent surgery for malignant disease, followed by postoperative radiation. The average age was 56 years (range, 16-84 years). The mean follow-up was 22.5 months. Satisfactory volumetric symmetry was achieved in all procedures for benign and malignant disease. Magnetic resonance imaging confirmed long-term fat graft viability in the postradiation setting. There was 1 case of Frey syndrome and no cases of unexpected, permanent facial nerve weakness among the patients. The combined technique of SMAS flap and free fat graft is effective for immediate reconstruction of the parotidectomy defect with minimal morbidity and low complication rates. This study demonstrates long-term viability of the free fat graft even in the setting of postoperative radiation.


Racial ethnic differences in rates and determinants of deceased donor kidney transplantation.
Contemporary studies have not comprehensively compared waiting times and determinants of deceased donor kidney transplantation across all major racial ethnic groups in the Unites States. Here, we compared relative rates and determinants of waitlisting and deceased donor kidney transplantation among 503,090 nonelderly adults of different racial ethnic groups who initiated hemodialysis between1995 and 2006 with follow-up through 2008. Annual rates of deceased donor transplantation from the time of dialysis initiation were lowest in American Indians/Alaska Natives (2.4%) and blacks (2.8%), intermediate in Pacific Islanders (3.1%) and Hispanics (3.2%), and highest in whites (5.9%) and Asians (6.4%). Lower rates of deceased donor transplantation among most racial ethnic minority groups appeared primarily to reflect differences in time from waitlisting to transplantation, but this was not the result of higher rates of waitlist inactivity or removal from the waitlist. The fraction of the reduced transplant rates attributable to measured factors (e.g., demographic, clinical, socioeconomic, linguistic, and geographic factors) varied from 14% in blacks to 43% in American Indians/Alaska Natives compared with whites. In conclusion, adjusted rates of deceased donor kidney transplantation remain significantly lower among racial ethnic minorities compared with whites; generally, differences in time to waitlisting were not as pronounced as differences in time between waitlisting and transplantation. Determinants of delays in time to transplantation differed substantially by racial ethnic group. Area-based efforts targeted to address racial- and ethnic-specific delays in transplantation may help to reduce overall disparities in deceased donor kidney transplantation in the United States.


Severe acute pancreatitis: a possible role of intramyocardial cytokine production.
Several mechanisms are involved in the development of the local and systemic response in acute pancreatitis. Cardiovascular system may be affected throughout the clinical course of acute pancreatitis. The aim was to evaluate local myocardial cytokine production, as well as, functional and histological myocardial alterations in severe acute pancreatitis. The animals were divided into three groups: Group 1: control; Group 2: sham; Group 3: severe acute pancreatitis. Echocardiographic assessment of cardiac function, serum levels of amylase and cytokines (TNF-α, IL-6 and IL-10), and mRNA expression of TNF-α, IL-6 and TGF-β were measured. Myocardial tissue alterations were analysed by histological examination. The serum TNF-α and IL-10 levels were significant higher in AP 2h group. The mRNA IL-6 levels from group AP 2h were statistically higher. The mRNA TNF-α level from sham group and AP 2h were statistically lower. Significant changes in the left ventricular diameter were found in AP 2h and AP 12h groups. There were statistical changes for vacuolar degeneration, picnosis and loss of nucleus, and lymphocytes. We found cardiac and histological changes compatible with the inflammatory process triggered by SAP with the promotion of local myocardial cytokine production.


The latent herpes simplex virus type 1 genome copy number in individual neurons is virus strain specific and correlates with reactivation.
The viral genetic elements that determine the in vivo reactivation efficiencies of fully replication competent wild-type herpes simplex virus (HSV) strains have not been identified. Among the common laboratory strains, KOS reactivates in vivo at a lower efficiency than either strain 17syn+ or strain McKrae. An important first step in understanding the molecular basis for this observation is to distinguish between viral genetic factors that regulate the establishment of latency from those that directly regulate reactivation. Reported here are experiments performed to determine whether the reduced reactivation of KOS was associated with a reduced ability to establish or maintain latent infections. For comparative purposes, latent infections were quantified by (i) quantitative PCR on DNA extracted from whole ganglia, (ii) the number of latency-associated transcript (LAT) promoter-positive neurons, using KOS and 17syn+ LAT promoter-beta-galactosidase reporter mutants, and (iii) contextual analysis of DNA. Mice latently infected with 17syn+-based strains contained more HSV type 1 (HSV-1) DNA in their ganglia than those infected with KOS strains, but this difference was not statistically significant. The number of latently infected neurons also did not differ significantly between ganglia latently infected with either the low- or high-reactivator strains. In addition to the number of latent sites, the number of viral genome copies within the individual latently infected neurons has recently been demonstrated to be variable. Interestingly, neurons latently infected with KOS contained significantly fewer viral genome copies than those infected with either 17syn+ or McKrae. Thus, the HSV-1 genome copy number profile is viral strain specific and positively correlates with the ability to reactivate in vivo. This is the first demonstration that the number of HSV genome copies within individual latently infected neurons is regulated by viral genetic factors. These findings suggest that the latent genome copy number may be an important parameter for subsequent induced reactivation in vivo.


[Ileoanal reservoir: new concepts and current results].
More than 1,800 ileoanal pouches have been performed at the Mayo Clinic since 1981 and results have been satisfactory in more than 90% of the patients. However, we continue to search for alternatives to improve postoperative results and avoid the complications that currently occur in a minority of patients. During the last two years new concepts and surgical techniques for the construction of the ileoanal reservoir have been described. Herein we present those innovations and compare them to our current institutional practice.


Immunohistochemical and immunoblotting detection of cytokeratin in smooth muscle tumors.
Forty-six smooth muscle tumors, including 35 of gastrointestinal origin, were studied immunohistochemically for the localization of cytokeratin using a variety of monoclonal antibodies. In formalin-fixed, paraffin-embedded material, six of 40 leiomyomas, two of five leiomyosarcomas and one leiomyoblastoma were immunoreactive for cytokeratin in a few tumor cells. A proportion of non-neoplastic smooth muscle cells also exhibited a positive reaction. In fresh frozen sections of one gastric leiomyosarcoma, a high percentage of tumor cells were reactive with nine of the eleven anti-cytokeratin monoclonal antibodies examined. Cytokeratin-positive cytoplasmic filaments were further demonstrated by immunoelectron microscopy. By immunoblot analysis, an extract of this immunohistochemically cytokeratin-positive leiomyosarcoma showed a distinct band at the same position as an extract of pancreas, whereas no bands were seen in an extract of a cytokeratin-negative esophageal leiomyosarcoma. These immunohistochemical and immunoblotting findings indicate that a certain subset of smooth muscle neoplasms express genuine cytokeratin filaments.


Climate change, human impacts, and the resilience of coral reefs.
The diversity, frequency, and scale of human impacts on coral reefs are increasing to the extent that reefs are threatened globally. Projected increases in carbon dioxide and temperature over the next 50 years exceed the conditions under which coral reefs have flourished over the past half-million years. However, reefs will change rather than disappear entirely, with some species already showing far greater tolerance to climate change and coral bleaching than others. International integration of management strategies that support reef resilience need to be vigorously implemented, and complemented by strong policy decisions to reduce the rate of global warming.


A qualitative study of organisational resilience in care homes in Scotland.
Providing care for the dependent older person is complex and there have been persistent concerns about care quality as well as a growing recognition of the need for systems approaches to improvement. The I-SCOPE (Improving Systems of Care for the Older person) project employed Resilient Healthcare (RHC) theory and the CARE (Concepts for Applying Resilience) Model to study how care organisations adapt to complexity in everyday work, with the aim of exploring how to support resilient performance. The project was an in-depth qualitative study across multiple sites over 24 months. There were: 68 hours of non-participant observation, shadowing care staff at work and starting broad before narrowing to observe care domains of interest; n = 33 recorded one-to-one interviews (32 care staff and one senior inspector); three focus groups (n = 19; two with inspectors and one multi-disciplinary group); and five round table discussions on emergent results at a final project workshop (n = 31). All interviews and discussion groups were recorded and transcribed verbatim. Resident and family interviews (n = 8) were facilitated through use of emotional touchpoints. Analysis using QSR NVivo 12.0 focused on a) capturing everyday work in terms of the interplay between demand and capacity, adaptations and intended and unintended outcomes and b) a higher-level thematic description (care planning and use of information; coordination of everyday care activity; providing person-centred care) which gives an overview of resilient performance and how it might be enhanced. This gives important new insight for improvement. Conclusions are that resilience can be supported through more efficient use of information, supporting flexible adaptation, coordination across care domains, design of the physical environment, and family involvement based on realistic conversations about quality of life.


Imaging modalities in hand osteoarthritis--and perspectives of conventional radiography, magnetic resonance imaging, and ultrasonography.
Hand osteoarthritis (OA) is very frequent in middle-aged and older women and men in the general population. Currently, owing to high feasibility and low costs, conventional radiography (CR) is the method of choice for evaluation of hand OA. CR provides a two-dimensional picture of bony changes, such as osteophytes, erosions, cysts, and sclerosis, and joint space narrowing as an indirect measure of cartilage loss. There are several standardized scoring methods for evaluation of radiographic hand OA. The scales have shown similar reliability, validity, and sensitivity to change, and no conclusion about the preferred instrument has been drawn. Patients with hand OA may experience pain, stiffness, and physical disability, but the associations between radiographic findings and clinical symptoms are weak to moderate and vary across studies. OA is, indeed, recognized to involve the whole joint, and modern imaging techniques such as ultrasound (US) and magnetic resonance imaging (MRI) could be valuable tools for better evaluation of hand OA. Standardized scoring methods have been proposed for both modalities. Several studies have examined the validity of US features in hand OA, whereas knowledge of the validity of MRI is more limited. However, both synovitis (detected by either US or MRI) and MRI-defined bone marrow lesions have been associated with pain, indicating that treatment of inflammation is important for pain management in hand OA. Both US and MRI have shown better sensitivity than CR in detection of erosions, and this may indicate that erosive hand OA may be more common than previously thought.


Efficient generation of neural stem cell-like cells from adult human bone marrow stromal cells.
Clonogenic neural stem cells (NSCs) are self-renewing cells that maintain the capacity to differentiate into brain-specific cell types, and may also replace or repair diseased brain tissue. NSCs can be directly isolated from fetal or adult nervous tissue, or derived from embryonic stem cells. Here, we describe the efficient conversion of human adult bone marrow stromal cells (hMSC) into a neural stem cell-like population (hmNSC, for human marrow-derived NSC-like cells). These cells grow in neurosphere-like structures, express high levels of early neuroectodermal markers, such as the proneural genes NeuroD1, Neurog2, MSl1 as well as otx1 and nestin, but lose the characteristics of mesodermal stromal cells. In the presence of selected growth factors, hmNSCs can be differentiated into the three main neural phenotypes: astroglia, oligodendroglia and neurons. Clonal analysis demonstrates that individual hmNSCs are multipotent and retain the capacity to generate both glia and neurons. Our cell culture system provides a powerful tool for investigating the molecular mechanisms of neural differentiation in adult human NSCs. hmNSCs may therefore ultimately help to treat acute and chronic neurodegenerative diseases.


Health in Chile's Recent Constitutional Process: A Qualitative Thematic Analysis of Civil Proposals.
(1) Background: In response to the recent political crisis in Chile, the "Agreement for Social Peace and the New Constitution'' was approved. We aimed to analyze the health-related civil proposals uploaded to the official website for popular participation in the new constitution in Chile. (2) Methods: We carried out a qualitative thematic analysis of 126 health-related valid proposals. Moreover, we analyzed their link to the Health Goals 2030, established by the Ministry of Health of Chile and to the Sustainable Development Goals (SDGs). (3) Results: Sixteen main categories were reached. In all, they were organized into four main areas: (i) the right to health and the establishment of a universal health system; (ii) effective access to selected healthcare services; (iii) improving health outcomes for all and for the relevant subgroups; and (iv) the social determinants of health, health in all the policies, and community health. We found that these four areas were strongly linked to the Health Goals 2030 for Chile and to the SDGs. (4) Conclusions: Despite the fact that the new constitutional proposal was rejected in September 2022, the civil health-related proposals and the areas of health and healthcare were of interest to the citizens as the request showed a strong demand from the population for participation in matters of health, healthcare, and public health.


The G72/G30 gene complex and cognitive abnormalities in schizophrenia.
A recently discovered gene complex, G72/G30 (hereafter G72, but now termed DAOA), was found to be associated with schizophrenia and with bipolar disorder, possibly because of an indirect effect on NMDA neurotransmission. In principle, if G72 increases risk for psychosis by this mechanism, it might impact with greater penetrance those cortically based cognitive and neurophysiological functions associated with NMDA signaling. We performed two independent family-based association studies (one sample contained more than 200 families and the other more than 65) of multiple SNPs in the G72 region and of multiple SNPs in the gene for D-amino acid oxidase (DAAO), which may be modulated by G72. We examined the relationship between select cognitive measures in attention, working memory, and episodic memory and a restricted set of G72 SNPs in over 600 normal controls, schizophrenic patients, and their nonpsychotic siblings using mixed model ANOVAs. We also determined genotype effects on neurophysiology measures in normal controls using the fMRI BOLD response obtained during activation procedures involving either episodic memory or working memory. There were no significant single G72 SNP associations and clinical diagnosis in either sample, though one approached significance (p=0.06). Diagnosis by genotype interaction effects for G72 SNP 10 were significant for cognitive variables assessing working memory and attention (p=0.05), and at the trend level for episodic memory, such that in the schizophrenia group an exaggerated allele load effect in the predicted directions was observed. In the fMRI paradigms, a strong effect of G72 SNP 10 genotype was observed on BOLD activation in the hippocampus during the episodic memory paradigm. Tests of association with DAAO were consistently nonsignificant. We present evidence that SNP variations in the G72 gene region increase risk of cognitive impairment in schizophrenia. SNP variations were not strongly associated with clinical diagnosis in family-based analyses.


On-the-Job Productivity Losses Among Employees With Health Problems: The Role of Work Accommodations.
Debates about the productivity impact of work accommodations typically focus on employment and labor force participation outcomes. This study considers whether accommodations mediate on-the-job productivity losses among employees who report health problems. The study uses ordered logistic regression to predict employees' self-reported productivity losses as a function of health problems and experiences with needed work accommodations. On average, the odds that an employee who did not get a needed accommodation reported higher levels of lost productivity are 5.11 times the odds for an employee who got a needed accommodation. Although health problems make it difficult for many employees to perform well on the job, accommodations could reduce productivity losses in some cases. Nonetheless, more research on the impact of specific kinds of accommodations for different chronic conditions is warranted.


Activation energy study of electron transport in high performance short wavelengths quantum cascade lasers.
We present a method to study current paths through quantum cascade lasers (QCLs). The temperature dependence of the current is measured at a fixed voltage. At low temperatures we find activation energies that correspond to the energy difference between the injector ground state and the upper laser level. At higher temperatures additional paths with larger activation energies are found. Application of this method to high performance QCLs based on strained InGaAs/InAlAs quantum wells and barriers with different band-offsets allows us to identify individual parasitic current paths through the devices. The results give insight into the transport properties of quantum cascade lasers thus providing a useful tool for device optimization.


Noninvasive screening tests for metastatic melanoma: rationale and results.
When melanoma metastasizes to distant organs, the most common sites of involvement are lung, liver, bone and brain. In addition to conventional x-ray and radioisotopic studies, ultrasonography and computed tomography are being utilized in increasing frequency. The yield and reliability of these noninvasive tests among patients with various stages of melanoma are presented. Other than chest x-rays, the routine use of such tests to screen patients with early melanoma for occult lesions of the liver, bone and brain is not indicated. Even among patients with advanced melanomas, such tests should be used for staging purpose only in patients with symptoms or specific indications.


Derm-ographics: The Australian Dermatologist and Social Media.
Social media significantly affects how patients understand their health and choose their healthcare providers, yet Australian dermatologists have a limited online presence compared to their global peers.


Fluid tagging for CT colonography: effectiveness of a 2-hour iodinated oral preparation after incomplete optical colonoscopy.
To evaluate the distal extent and attenuation of bowel opacification achieved after administration of a single low volume dose of oral contrast 2 hours before computed tomographic colonography (CTC) after incomplete optical colonoscopy. This retrospective study included 144 patients undergoing CTC after incomplete colonoscopy from April 2006 to July 2008 at 2 separate medical centers. Each patient received 20 to 30 mL of diatrizoate meglumine and diatrizoate sodium solution 2 hours before being scanned. The distalmost extent of opacification was: stomach/small bowel, n = 13; cecum, n = 2; ascending colon, n = 7; transverse colon, n = 19; descending colon, n = 14; sigmoid colon, n = 24; rectum, n = 65. The mean attenuation of each opacified segment was: cecum, 449 Hounsfield units (HU); ascending colon, 474 HU; transverse colon, 468 HU; descending colon, 421 HU; sigmoid colon, 391 HU; and rectum, 382 HU. In 103 (71.5%) patients, oral contrast reached the distal colon (descending colon, sigmoid colon, or rectum). The oral contrast did not reach the colon in only 13 (9.0%) patients. Oral administration of a small volume hyperosmolar oral contrast agent 2 hours before CTC results in satisfactory colonic opacification in the majority of patients. Adding same-day fluid tagging in incomplete colonoscopy patients presenting for completion CTC should result in adequate fluid opacification for most of the colon, especially proximal segments not visualized at the time of incomplete colonoscopy.


Nanoscale organization of thiol and arylsulfonic acid on silica leads to a highly active and selective bifunctional, heterogeneous catalyst.
Ordered mesoporous silicas functionalized with alkylsulfonic acid and thiol group pairs have been shown to catalyze the synthesis of bisphenols from the condensation of phenol and various ketones, with activity and selectivity highly dependent on the distance between the acid and thiol. Here, a new route to thiol/sulfonic acid paired catalysts is reported. A bis-silane precursor molecule containing both a disulfide and a sulfonate ester bond is grafted onto the surface of ordered mesoporous silica, SBA-15, followed by simultaneous disulfide reduction and sulfonate ester hydrolysis. The resulting catalyst, containing organized pairs of arylsulfonic acid and thiol groups, is significantly more active than the alkylsulfonic acid/thiol paired catalyst in the synthesis of bisphenol A and Z, and this increase in activity does not lead to a loss of regioselectivity. The paired catalyst has activity similar to that of a randomly bifunctionalized arylsulfonic acid/thiol catalyst in the bisphenol A reaction but exhibits greater activity and selectivity than the randomly bifunctionalized catalyst in the bisphenol Z reaction.


Language disorder and retrospectively reported sexual abuse of girls: severity and disclosure.
Despite emerging evidence for an association between communication disorders and maltreatment, little research has examined sexual abuse characteristics or disclosure experiences among individuals with language disorder (LD). Given that communication difficulties may constitute a barrier to disclosure, the disclosure experiences among individuals with and without communication difficulties may also differ. Five-year-old children identified with a language and/or speech disorder from a nonclinical community sample and a control group were followed to adulthood in a prospective longitudinal study. At age 31, participants completed a behaviorally specific questionnaire on experiences of sexual abuse and questionnaires on disclosure experiences and social reactions to disclosure. Due to low endorsement of sexual victimization among male participants and low sample size, results are reported for women only and exclude nine participants with speech disorder without LD. Participation rates were 28 of 40 in the LD cohort and 45 of 51 controls. Sexual victimization severity was defined using an index combining five indicators (duration, invasiveness, relationship to perpetrator, coercive tactics used, and number of perpetrators). Subthreshold sexual victimization was defined as a single, noncontact incident with a perpetrator unknown to the child; experiences with greater severity were classified as child sexual abuse. Among women who reported sexual victimization by age 18, invasiveness and overall severity were greater in the LD cohort than in the control cohort. Women in the LD cohort (43%) were more likely than controls (16%) to report child sexual abuse, excluding subthreshold experiences. There were no differences between cohorts in probability of disclosure, latency to disclosure, or social reactions. Women with a history of child LD in a nonclinical sample reported substantial child sexual abuse experiences. Implications for understanding associations between LD and mental health and for prevention and early intervention are discussed.


Studies on the polyphenol metabolism of tissue cultures derived from the tea pant (Camellia sinensis L.).
1. The growth characteristics on various media of solid and liquid suspension cultures derived from the stem of the tea plant are described; chlorophyll and anthocyanin synthesis occurred in the light. 2. Only the simplest catechins and leucoanthocyanins were present in callus tissue, although oligomeric and polymeric leucoanthocyanin fractions were also represented. Light caused an increase in all monomeric components analysed, but inhibited polymerization of the leucoanthocyanins. 3. The polyphenol oxidase activity of cultures was comparable with that of the apical regions of the intact plant, and was inversely correlated with growth rate. 4. Growth was stimulated by hormonal variation, and inhibited by high concentrations of sucrose and by high light-intensity; polyphenol concentrations were generally inversely correlated with growth rate. 5. From the inability of callus tissue and of cultured root apices to synthesize complex catechins, it is inferred that complex catechin formation in intact plants is associated with the process of cell vacuolation.


A reappraisal of loop diuretic choice in heart failure patients.
The health and economic burden of heart failure is significant and continues to grow each year. Loop diuretics are an integral part of symptom management in heart failure. Furosemide is used disproportionately compared with other loop diuretics, and there is currently no guidance for physicians regarding which agent to choose. However, there exist pharmacologic differences as well as other mechanistic differences that appear to favor torsemide use over furosemide. Compared with furosemide, torsemide improves surrogate markers of heart failure severity such as left ventricular function, plasma brain natriuretic peptide levels, and New York Heart Association functional class and may also reduce hospitalizations, readmissions, and mortality. Data suggest that these benefits could be mediated through torsemide's ability to positively affect the renin-angiotensin-aldosterone system. Specifically, torsemide has been shown to inhibit aldosterone secretion, synthesis, and receptor binding in vitro, as well as decrease transcardiac extraction of aldosterone, myocardial collagen production, and cardiac fibrosis in patients with heart failure. We identified pertinent literature using keyword MEDLINE searches and cross-referencing prior bibliographies. We summarize the available data suggesting potential benefits with torsemide over furosemide, and call attention to the need for a reappraisal of diuretic use in heart failure patients and also for a well-powered, randomized control trial assessing torsemide versus furosemide use.


Chemically directed assembly of photoactive metal oxide nanoparticle heterojunctions via the copper-catalyzed azide-alkyne cycloaddition "click" reaction.
Metal oxides play a key role in many emerging applications in renewable energy, such as dye-sensitized solar cells and photocatalysts. Because the separation of charge can often be facilitated at junctions between different materials, there is great interest in the formation of heterojunctions between metal oxides. Here, we demonstrate use of the copper-catalyzed azide-alkyne cycloaddition reaction, widely referred to as "click" chemistry, to chemically assemble photoactive heterojunctions between metal oxide nanoparticles, using WO(3) and TiO(2) as a model system. X-ray photoelectron spectroscopy and Fourier-transform infrared spectroscopy verify the nature and selectivity of the chemical linkages, while scanning electron microscopy reveals that the TiO(2) nanoparticles form a high-density, conformal coating on the larger WO(3) nanoparticles. Time-resolved surface photoresponse measurements show that the resulting dyadic structures support photoactivated charge transfer, while measurements of the photocatalytic degradation of methylene blue show that chemical grafting of TiO(2) nanoparticles to WO(3) increases the photocatalytic activity compared with the bare WO(3) film.


Antiplatelet therapy in thrombotic thrombocytopenic purpura.
The presence of platelet-fibrin microthrombotic occlusions in the arterioles and capillaries of involved tissues of patients with TTP has suggested a role for platelet aggregation in this disorder. Inhibitors of platelet aggregation have been reported to produce resolution of thrombocytopenia and clinical improvement in many instances. Failure of such agents to produce a clinical effect has been attributed to inadequate dose-duration, severity and extent of end organ/vascular involvement, long-term or secondary effects of the etiologic principal leading to patient deterioration and/or demise. On the other hand, the parallel use of several treatment modalities that themselves may produce clinical effect confounds the interpretation that anti-platelet agents alone may have been responsible for clinical improvement. Nonetheless, complete remission has been reported in a number of TTP patients when the combination ASA/dipyridamole was used alone or together with plasmapheresis, splenectomy, and/or other antiplatelet agents. The evidence for a beneficial clinical effect would seem strongest for the use of this combination early in the course of the disease. More limited and less conclusive has been the experience with sulfinpyrazone, with ticlopidine, and with intravenous PGI2 infusions in TTP. Reports of clear-cut benefit with each of these agents have been rare. Finally, serial dextran infusions have apparently produced amelioration of the clinical syndrome in certain individuals. Assessment of benefit of dextran infusions from retrospective series has been limited by antecedent use of splenectomy. The use of red cell and plasma infusions during splenectomy has been argued to provide some benefit. However, it is likely that dextran can produce definite responses in certain patients. Unfortunately, therapeutic efficacy has been judged from such anecdotal reports and retrospective series. No prospective controlled trials of any of these approaches are available.