COVID-19 vaccines should be evaluated from the societal perspective.
The COVID-19 pandemic demonstrates the importance of valuing vaccines from a broad societal perspective (SP), as opposed to a narrower health-payer perspective (HPP). COVID-19's catastrophic global impacts extend not only to its health-related effects, but also to the profound macroeconomic losses caused by lockdowns required for disease control, leading to the worst global economic crisis in a century. COVID-19 vaccination (CV) has been the central policy tool for resolving this economic crisis, and it has been hypothesized that this macroeconomic benefit alone justifies the cost of CV many times over.Yet HPP-based vaccine valuations are wholly insensitive to this enormous benefit, not allowing it to influence the allocation of given health budgets nor the determination of the magnitudes of such budgets, thereby risking inadequate societal spending on CV. HPP allocates given health budgets to maximize only health, giving no weight to macroeconomic outcomes, causing allocative inefficiency by not allowing welfare-improving trade-offs of health for wealth. HPP assumes health budgets are optimal, not scrutinizing whether their scale adequately reflects the macroeconomic benefits of health spending, thereby risking productive inefficiency by foregoing health spending increases such as on CV that could raise both population-level health and wealth. These allocative and productive inefficiencies in turn distort for-profit R&D incentives, risking dynamic inefficiency. And since the socio-economic and health burdens of COVID-19 are disproportionately borne by the worse off, HPP's failure to promote optimal levels of societal investment in CV may disproportionately burden the worse off as well, exacerbating inequality. Vaccine valuations from the societal perspective allow the allocation and determination of health budgets to reflect macroeconomic and distributional values, thereby promoting allocative, productive, and dynamic efficiency, as well as equity. These considerations of efficiency and equity support evaluating CV, and to ensure a level playing field, all vaccines, from a societal perspective.


Epidemiology of neonatal jaundice at the University Hospital of the West Indies.
To describe the epidemiology of neonatal jaundice at the University Hospital of the West Indies (UHWI). A retrospective review of all neonates at the UHWI with clinically significant jaundice between January 1, 2006 and June 30, 2007 was performed. Demographic, clinical and laboratory data were collected. Descriptive analyses were performed. The incidence of clinically significant neonatal jaundice at the UHWI was 4.6% for the study period. There were 103 male (61%) and 67 (39%) female infants. The aetiology ofjaundice in the infant was attributed to ABO incompatibility in 59 (35%), infection in 30 (18%), prematurity in 19 (11%), G6PD deficiency in 8 (5%), Rhesus incompatibility in 6 (3.5%) and no cause was identified in 16 (9%) infants. There was a low incidence (26%) ofscreening for G6PD deficiency although it was the most common aetiology for infants presenting from home. Nine (5%) neonates required exchange blood transfusion. Infants admitted from home had a significantly higher mean total bilirubin value at presentation, a significantly higher mean peak bilirubin level andpresented significantly later than those who were admitted from the postnatal ward (p < 0.001). One patient was discharged with a diagnosis of bilirubin encephalopathy but defaulted from follow-up. Two neonates died but from causes unrelated to neonatal jaundice. Sixty-two patients (37%) were followed-up post discharge; 50% had hearing tests done, all tests were normal. Sixty-one (98%) infants had normal development at the time of the study; one patient had impaired motor development but this infant also had a myelomeningocoele. To further reduce morbidity associated with neonatal jaundice at the UHWI, there should be increased screening for G6PD deficiency; current systems in place for follow-up and monitoring of infants discharged from hospital prior to 72 hours must also be expanded and strengthened.


Olfactory ensheathing glia enhances reentry of axons into the brain from peripheral nerve grafts bridging the substantia nigra with the striatum.
Reconstruction of lost axonal pathways in the central nervous system (CNS) is possible with the use of peripheral nerve grafts (PNG). However, these permit the entry of axons, while their reentry back into the CNS is compromised. Olfactory ensheathing glia (OEG) may permit this reentry of axons if cografted with PNG. We compared the number of tyrosine-hydroxylase positive (TH+) fibers reinnervating PNGs and crossing the graft-striatum interface in PNG placed between the substantia nigra and the striatum in rats receiving both PNG and OEGs and animals receiving PNG only. More TH fibers were seen inside the grafts when OEG was cografted. Although the number of fibers decreases along the graft's length, this effect is less severe when OEG is present. TH+ fibers are seen crossing the PNG-striatum interface in the OEG group. This is correlated with a higher synaptic density at the striatum near the graft when OEG is co-grafted. While these results must be replicated in animal models of Parkinsonism, their implications may apply both to the treatment of Parkinson's disease and to other pathologies, such as spinal cord lesions, where regeneration of long axonal pathways is necessary.


Decreased c-Myc mRNA Stability via the MicroRNA 141-3p/AUF1 Axis Is Crucial for p63α Inhibition of Cyclin D1 Gene Transcription and Bladder Cancer Cell Tumorigenicity.
Bladder cancer (BC) ranks as the sixth most common cancer in the United States and is the leading cause of death in patients with urinary malignancies. p63 is a member of the p53 family and is believed to function as a tumor suppressor in human BCs. Our most recent studies revealed a previously unknown function of the RING of XIAP in promoting microRNA 4295 (miR-4295) transcription, thereby reducing p63α protein translation and enhancing normal urothelial transformation, whereas p63α upregulates hsp70 transcription, subsequently activating the HSP70/Wasf3/Wave3/matrix metalloproteinase 9 (MMP-9) axis and promoting BC cell invasion via initiating the transcription factor E2F1. In this study, we found that p63α inhibited cyclin D1 protein expression, subsequently decreasing the ability of BC cell anchorage-independent growth in vitro and tumorigenicity in vivo Mechanistic studies demonstrated that p63α expression is able to downregulate cyclin D1 gene transcription through attenuation of c-Myc mRNA stability. We further show that the reduction of miR-141-3p expression by p63α directly releases its inhibition of 3' untranslated region (UTR) activity of AU-rich element RNA-binding factor 1 (AUF1) mRNA, thereby increasing AUF1 protein translation and further resulting in degradation of c-Myc mRNA, which, in turn, reduces cyclin D1 gene transcription and BC cell anchorage-independent growth. Collectively, our results demonstrate that p63α is a negative regulator of BC cell tumorigenic growth, a distinctly different function than its promotion of BC invasion, thus providing further new insight into the "two faces" of p63α in regulation of BC cell tumorigenic growth and progression/invasion.


The Role of the Oral Microbiota in the Etiopathogenesis of Oral Squamous Cell Carcinoma.
Dysbiosis in the oral environment may play a role in the etiopathogenesis of oral squamous cell carcinoma (OSCC). This review aims to summarize the current knowledge about the association of oral microbiota with OSCC and to describe possible etiopathogenetic mechanisms involved in processes of OSCC development and progression. Association studies included in this review were designed as case-control/case studies, analyzing the bacteriome, mycobiome, and virome from saliva, oral rinses, oral mucosal swabs, or oral mucosal tissue samples (deep and superficial) and comparing the results in healthy individuals to those with OSCC and/or with premalignant lesions. Changes in relative abundances of specific bacteria (e.g., Porphyromonas gingivalis, Fusobacterium nucleatum, Streptococcus sp.) and fungi (especially Candida sp.) were associated with OSCC. Viruses can also play a role; while the results of studies investigating the role of human papillomavirus in OSCC development are controversial, Epstein-Barr virus was positively correlated with OSCC. The oral microbiota has been linked to tumorigenesis through a variety of mechanisms, including the stimulation of cell proliferation, tumor invasiveness, angiogenesis, inhibition of cell apoptosis, induction of chronic inflammation, or production of oncometabolites. We also advocate for the necessity of performing a complex analysis of the microbiome in further studies and of standardizing the sampling procedures by establishing guidelines to support future meta-analyses.


Molecular Epidemiological Surveillance of CTX-M-15-producing Klebsiella pneumoniae from the patients of a teaching hospital in Sindh, Pakistan.
Background The presence of Extended-spectrum β-lactamase positive bacteria in hospital setting is an aggravating influential factor for hospitalized patients, and its consequences may be hazardous. Therefore, there is a need for rapid detection methods for newly emerging drug-resistant bacteria. This study was aimed at the molecular characterization of Extended-spectrum β-lactamase -positive Klebsiella pneumoniae isolates recovered from the patients of a teaching hospital in Sindh, Pakistan. Methods A total of 513 K. pneumoniae isolates were obtained from various clinical samples during June 2019 to May 2020. The collected isolates were investigated for antimicrobial susceptibility (antibiogram), and PCR and DNA sequencing were performed to analyse the ESBL genes. Results Among the 513 isolates, as many as 359 (69.9%) were Extended-spectrum β-lactamase producers and 87.5% were multi-drug resistant, while none had resistance to imipenem. PCR scored 3% blaTEM, 3% blaSHV, and 60% blaCTX-M-15 genes for the tested isolates. Conclusion The study showed that CTX-M-15 was the major prevalent Extended-spectrum β-lactamase type among the isolates. Additionally, all the isolates were susceptible to carbapenems. Screening and detection of Extended-spectrum β-lactamase tests are necessary among all isolates from the enterobacteriaceae family in routine microbiology laboratory to prevent associated nosocomial infections. A larger study is essential to understand molecular epidemiology of Extended-spectrum β-lactamase producing organisms to minimize morbidities due to these multidrug resistant organisms.


[Patterns of alcohol use and related issues: analysis of nurses' knowledge].
Descriptive study that aimed to identify and compare the nurses' knowledge addressed to patterns of alcohol use and related issues. The study included 185 nurses of which 84 had attended a training course on the subject. Data were collected through a questionnaire of knowledge showing that while the trained group obtained the highest average on correct answers, there was a lack of knowledge in both groups, especially with regard to the identification of complications from alcohol use. Important definitions to nursing practice in the area of addictions are presented, suggesting that future training may consider the various dimensions involved in caring for people with problems related to alcohol.


Exploring the immune interactions between Oncomelania hupensis and Schistosoma japonicum, with a cross-comparison of immunological research progress in other intermediate host snails.
Schistosomiasis, the second largest parasitic disease in the world after malaria, poses a significant threat to human health and causes public health issues. The disease primarily affects populations in economically underdeveloped tropical regions, earning it the title of "neglected tropical disease". Schistosomiasis is difficult to eradicate globally if medication alone is used. One of the essential elements of thorough schistosomiasis prevention and control is the management and disruption of the life cycle of intermediate host snails. The key approach to controlling the transmission of schistosomiasis is to control the intermediate hosts of the schistosome to disrupt its life cycle. We believe that approaching it from the perspective of the intermediate host's immunity could be an environmentally friendly and potentially effective method. Currently, globally significant intermediate host snails for schistosomes include Oncomelania hupensis, Biomphalaria glabrata, and Bulinus truncatus. The immune interaction research between B. glabrata and Schistosoma mansoni has a history of several decades, and the complete genome sequencing of both B. glabrata and B. truncatus has been accomplished. We have summarized the immune-related factors and research progress primarily studied in B. glabrata and B. truncatus and compared them with several humoral immune factors that O. hupensis research focuses on: macrophage migration inhibitory factor (MIF), Toll-like receptors (TLRs), and thioredoxin (Trx). We believe that continued exploration of the immune interactions between O. hupensis and Schistosoma japonicum is valuable. This comparative analysis can provide some direction and clues for further in-depth research. Comparative immunological studies between them not only expand our understanding of the immune defense responses of snails that act as intermediaries for schistosomes but also facilitate the development of more comprehensive and integrated strategies for schistosomiasis prevention and control. Furthermore, it offers an excellent opportunity to study the immune system of gastropods and their co-evolution with pathogenic organisms.


Healing of surgically created defects in the equine superficial digital flexor tendon: effects of pulsing electromagnetic field therapy on collagen-type transformation and tissue morphologic reorganization.
The effect of pulsing electromagnetic field (PEMF) therapy on the healing of surgically created defects in equine superficial digital flexor tendons was evaluated. Defects were created in both front superficial digital flexor tendons of 20 horses. The defect in 1 limb was exposed to a PEMF for 2 hours daily. The other limb served as a control. Histologic and immunofluorescent evaluations were done in horse killed at postsurgical weeks 2, 4, 8, 12, and 24. Therapy with the PEMF significantly (P less than 0.05) delayed the maturation of the tissue formed within the defect at postsurgical weeks 8 and 12, as determined by histologic examination. The collagen-type transformation was also delayed by the PEMF therapy, but to a degree that was not significant.


Telemedicine in vascular surgery: clinical experience in a single centre.
Over a three-year period we performed 630 carotid endarterectomy procedures in 588 patients. From these we selected 90 patients (group A) who fulfilled the criteria for discharge one day after surgery. These patients were given an electronic blood pressure meter, a video phone for use at home and an antihypertensive drug (amlodipine). Using web-based video conferencing, we monitored the patients every 4 hours for the first two days. The other 498 patients (group B) were discharged on the second postoperative day. There were no significant differences between the groups in demographic characteristics, risk factors, carotid lesions, operative time, postoperative complications or blood loss. No cervical hematomas developed in group A. No patients needed to be readmitted because of major complications relating to the carotid endarterectomy. During the video-communication, 28 patients (31%) with a hypertensive crisis were treated by administration of amlodipine. At discharge, a questionnaire showed that there was a feeling of insecurity in both groups: 87% in group A vs. 79% in group B (P > 0.05). In group A, insecurity decreased after the first video connection and disappeared after the 8th day postoperatively. Telemedicine appears feasible and useful in carotid endarterectomy and may have other applications in vascular surgery care.


[CLINICAL EFFICACY OF SUBLINGUAL IMMUNOTHERAPY WITH CEDAR POLLEN IN A YEAR OF MASSIVE CEDAR POLLEN DISPERSAL AND ITS EFFECT ON JAPANESE CYPRESS POLLINOSIS].
We investigated the effect of sublingual immunotherapy (SLIT) on Japanese cedar and cypress pollinosis in a mass scattering year of cedar pollen (total counts: 12353 grains/cm2, approximately four times the average). SLIT patients of 84 in the first year, 107 in the second year and 67 in the third year treated with Cedarcure® were included. During the 2023 cedar and cypress pollen dispersal season, nasal and eye symptoms and general symptoms were examined using a visual analog scale (VAS). The VAS during the cedar season significantly decreased to improve with the number of years of SLIT, but the VAS during the cypress period slightly increased. A questionnaire survey before SLIT revealed that only 0.9% to 3.6% of patients had strong cypress symptoms. However, sneezing (p<0.01), rhinorrhea, itchy eyes and total symptoms (p<0.05) in the third year of SLIT were significantly stronger during the cypress period than during the cedar period. The VAS of total symptoms during the Japanese cedar pollen season were not affected by the pollen count, and the cure rate was affected by SLIT in the third year. The clinical efficacy of cedar SLIT on cedar pollinosis was high even in a mass scattering year, and the effect increased with the number of years of treatment. On the other hand, it was shown that the clinical efficacy on cypress pollinosis was insufficient.


Adult-onset obesity induced by early life overnutrition could be reversed by moderate caloric restriction.
Overnutrition during the suckling period (small litter, SL) results in the development of adult-onset obesity. Our aim was to investigate whether two levels of caloric restriction (CR) in the early postweaning period can reverse obese phenotype in SL rats. The normal litter (NL) had 12 pups/dam and SL had 3 male pups/dam from the postnatal day 3 until day 21. After weaning, rats consumed lab chow as indicated: 1) NL and SL groups were on ad libitum regimen up to day 140, 2) another SL group was pair-fed (SL/PF) to NL(∼14% reduction), 3) SL/PF/AL group was pair-fed up to day 94 and then switched to ad libitum feeding, 4) SL/CR group received 24% reduction (moderate CR) in food intake compared with SL, and 5) SL/CR/AL group was on 24% CR up to day 94 and then switched to ad libitum feeding. Pair-feeding reduced body weight gains and serum insulin and leptin levels compared with SL rats, but these parameters were restored to SL levels in the SL/PF/AL rats after switching to ad libitum feeding. Interestingly, the moderate CR normalized these parameters in SL/CR and SL/CR/AL rats compared with NL. The expression of neuropeptide Y, proopiomelanocortin, and leptin receptor returned to control levels in hypothalami from SL/CR and SL/CR/AL rats. These results indicate that appropriate manipulation of energy intake during the early postweaning period could lead to longer-lasting effects on the regulation of body weight homeostasis via reversal of the early preweaning programming effects on the hypothalamic appetite regulation mechanism.


[Future perspectives in the therapy of asthma in children].
Asthma therapy recognizes three fundamental key points: primary prevention, secondary prevention, including the control of inflammatory mechanisms and related symptoms, and tertiary prevention, consisting in the treatment of the early phases leading to airway remodelling. As for primary prevention in infants at ''high risk'' exclusive breastfeeding for at least 3-6 months and the prevention of allergen exposure, respiratory infections and tobacco smoking are recommended. Recent findings suggest a possible protective role of diet (i.e. the intake of vegetables and vitamins and the pre-probiotics). About secondary prevention, the efficacy of drugs suggested by international guidelines (GINA or ARIA) such as antihistamines, leukotriene modifiers and inhaled corticosteroids, it is well known; such drugs can be variably used in different associations, in accordance with the clinical features of the single patient. Among the new therapeutic perspectives, a special attention should be paid to anti-IgE monoclonal antibodies and other humanized monoclonal antibodies targeting and neutralizing inflammatory cytokines; chimeric allergens blocking mast cell receptors; recombinant interleukins with ''anti-inflammatory'' or ''anti-allergic'' properties; in vitro expansion of T lymphocytes with regulatory functions (Treg), and their possible therapeutic approach. Moreover, new experimental observations have identified the role of molecules derived from engineering technologies able to control allergic inflammation. As for prevention and treatment of allergic symptoms, specific immunotherapy has a relevant role, moreover in the paediatric area: it finds progressively greater consensus in terms of both efficacy and safety and is finally recognized in the latest GINA and ARIA guidelines. Tertiary prevention, which concerns the so called ''airway remodeling'', includes new therapeutic approaches such as montelukast, which can control fibroblasts proliferation and their transformation in myofibroblasts, and phosphodiesterase inhibitors. Finally, the use of peptide and non-peptide antagonists of Bradykinin B2 receptors seems to be of great interest.


Cardiac involvement in Churg-Strauss syndrome.
Churg-Strauss syndrome (CSS) is a rare form of systemic vasculitis. Previous studies showing cardiac involvement in CSS patients were limited in the number of patients and were often based solely on clinical manifestations. The aim of the present study was to determine in detail the incidence of cardiac involvement in a large population of ambulatory CSS patients. Thirty-two consecutive patients with CSS in remission (mean +/- SD duration of disease between diagnosis and enrollment 6.1 +/- 5.8 years, mean +/- SD age 61 +/- 10 years) who were previously unaware of cardiac involvement were compared with 32 randomly selected age- and sex-matched control subjects, using clinical evaluation, electrocardiography (EKG), echocardiography, and cardiac magnetic resonance imaging (MRI). Detailed cardiac evaluation revealed a 62% prevalence of cardiac involvement in CSS patients compared with 3% in controls (P < 0.001), with clinical symptoms in 26% and 3%, respectively (P = 0.009), EKG abnormalities in 66% and 3%, respectively (P < 0.001), and echocardiographic defects in 50% and 3%, respectively (P < 0.001). Cardiac MRI detected cardiac manifestations in 62% of CSS patients. In the presence of cardiac MRI abnormalities, echocardiography could detect cardiac involvement with a sensitivity of 83% and a specificity of 80%. The absence of symptoms or EKG abnormalities did not exclude cardiac involvement, because abnormalities could still be detected in 38% of these patients at the time of echocardiography or cardiac MRI. These results demonstrate a high incidence of cardiac involvement in CSS patients. Systematic cardiac evaluation including detailed imaging is required to properly identify CSS patients with cardiac involvement.


High-resolution magnetic resonance histology of the embryonic and neonatal mouse: a 4D atlas and morphologic database.
Engineered mice play an ever-increasing role in defining connections between genotype and phenotypic expression. The potential of magnetic resonance microscopy (MRM) for morphologic phenotyping in the mouse has previously been demonstrated; however, applications have been limited by long scan times, availability of the technology, and a foundation of normative data. This article describes an integrated environment for high-resolution study of normal, transgenic, and mutant mouse models at embryonic and neonatal stages. Three-dimensional images are shown at an isotropic resolution of 19.5 microm (voxel volumes of 8 pL), acquired in 3 h at embryonic days 10.5-19.5 (10 stages) and postnatal days 0-32 (6 stages). A web-accessible atlas encompassing this data was developed, and for critical stages of embryonic development (prenatal days 14.5-18.5), >200 anatomical structures have been identified and labeled. Also, matching optical histology and analysis tools are provided to compare multiple specimens at multiple developmental stages. The utility of the approach is demonstrated in characterizing cardiac septal defects in conditional mutant embryos lacking the Smoothened receptor gene. Finally, a collaborative paradigm is presented that allows sharing of data across the scientific community. This work makes magnetic resonance microscopy of the mouse embryo and neonate broadly available with carefully annotated normative data and an extensive environment for collaborations.


Blasticidin A as an inhibitor of aflatoxin production by Aspergillus parasiticus.
Blasticidin A, an antibiotic, showed strong inhibitory activity toward aflatoxin production by Aspergillus parasiticus. Its structure was characterized by NMR and chemical degradation experiments as 1, which is a tetramic acid derivative with a highly oxygenated long alkyl chain similar to aflastatin A (2). Absolute configurations of the eight chiral centers at C-4, 6, 31, 32, 33, 34, 35 and 37 of 1 were chemically determined. Blasticidin A almost completely inhibited aflatoxin production at 0.5 microM.


Direct observation of atomic step edges on the rutile TiO2(110)-(1 × 1) surface using atomic force microscopy.
Clarifying the atomic configuration of step edges on a rutile TiO2 surface is crucial for understanding its fundamental reactivity, and the direct observation of atomic step edges is still a challenge. AFM is a powerful tool for investigating surface structures with true atomic resolution, and it provides the opportunity to resolve the real structure of step edges with improved techniques. In this work, we successfully imaged the atomic configuration of 001 and 1-11 step edges on the surface of rutile TiO2(110)-(1 × 1), and we present the direct observation of oxygen vacancies along the 1-11 step edges, indicating that one 1-11 step edge site corresponds to one oxygen vacancy using AFM. We also made use of the simultaneous AFM/STM measurements to explore the electronic structure of step edges, which enhanced the evidence of oxygen vacancies existing along the 1-11 step edges and further demonstrated that the 001 step edge was terminated by an O row. The effect of the reduced 1-11 step edges was explored by probing the O2 adsorption and the nucleation behavior of gold clusters. It was found that oxygen vacancies along the 1-11 step edges could contribute to O2 dissociative adsorption and there was no obvious difference compared with the oxygen vacancies on the flat terrace. The reduced step edge and terrace likewise acted as nucleation and growth sites for gold atoms/nanoparticles, in line with previous reports. The present study provides a complete characterization of the atomic configuration of the step edges on the TiO2(110) surface and plays an important role in investigating the surface chemistry of metal oxides.


[Interaction of electrophilic alkylating agents with nucleophilic sites of mitochondria].
The electrophilic alkylating agents having different numbers of electrophilic groups with nucleophilic sites of mitochondria were studied. Bifunctional compounds were found to modify the structure of mitochondria so that some of the sulfhydryl groups become inaccessible for titrating ions of Ag+. Monofunctional agents caused no changes in the number of determinable sulfhydryl groups and prevented the effect of bifunctional compounds. The linkage formed between the electrophilic residue and the nucleophilic site is stable in the absence of electron transport. During the transport of electrons in the respiratory chain the linkage becomes labile and the electrophilic residue chips off. A scheme of interaction of electrophilic alkylating agents with nucleophilic sites of mitochondria is proposed.


Clinical and neuropathological findings of acute carbon monoxide toxicity in chihuahuas following smoke inhalation.
Three adult Chihuahuas were presented for evaluation after smoke inhalation during a house fire. All three dogs received supportive care and supplemental oxygen. After initial improvement, the dogs developed seizures. Despite anticonvulsant therapy and supportive care, the dogs died. The brains of two dogs were examined. Lesions were identified that were compatible with acute carbon monoxide (CO) toxicity. Lesions were confined to the caudate nucleus, the globus pallidus, and the substantia nigra bilaterally, as well as the cerebellum, cerebral cortex, and dorsal thalamus. This case report describes the clinicopathological sequelae in acute CO toxicity.


Abrupt discontinuation of psychotropic drugs during pregnancy: fear of teratogenic risk and impact of counselling.
To assess the consequences to mother and baby of abruptly discontinuing antidepressant or benzodiazepine medication during pregnancy and to assess the impact of our counselling. All women who consulted the Motherisk Program between November 1996 and December 1997 and who stopped taking antidepressant or benzodiazepine medication when pregnancy was confirmed agreed to participate in the study. Subjects were interviewed, received counselling, and completed a questionnaire 1 month after their initial call and after the birth of their baby. Of 36 women who completed the study, 34 discontinued their medication abruptly for fear of harming the fetus, 28 on the advice of their physician; 26 (70.3%) women reported physical and psychological adverse effects, 11 reported psychological effects only, and 11 reported suicidal ideation (4 were admitted to hospital). After counselling, 22 of 36 (61.1%) women resumed taking their medication, and 4 found that they no longer required it. One woman had a therapeutic abortion and 2 experienced spontaneous abortions; there were therefore 35 healthy babies (including 2 sets of twins) born to 33 women; 14 of 21 mothers breast-fed their babies while taking their psychotropic medication, with no adverse effects reported. When assessing the risks and benefits of taking psychotropic medication during pregnancy, women and their physicians should be aware that the abrupt discontinuation of psychotropic drugs can lead to serious adverse effects. Counselling is effective in reassuring women to adhere to therapy.


Selected Orthodontic Principles for Management of Cranio-Maxillofacial Deformities.
An understanding of fundamental orthodontic principles involving diagnosis, treatment planning, and clinical strategies is essential for achieving successful outcomes in the treatment of craniofacial patients, particularly cleft lip/palate. This article focuses on: customizing a mandibular dental arch form using the WALA ridge; accurately diagnosing the maxillary skeletal transverse dimension (cusp to cusp/fossa to fossa); coordinating the upper dental arch with the lower; using a smiling profile and glabella vertical to assess anteroposterior jaw position; and leveling the mandibular curve of Spee while considering the lower one-third of the face. These concepts influence treatment outcomes to the extent they are used.


Methylene blue counteracts H2S toxicity-induced cardiac depression by restoring L-type Ca channel activity.
We have previously reported that methylene blue (MB) can counteract hydrogen sulfide (H2S) intoxication-induced circulatory failure. Because of the multifarious effects of high concentrations of H2S on cardiac function, as well as the numerous properties of MB, the nature of this interaction, if any, remains uncertain. The aim of this study was to clarify 1) the effects of MB on H2S-induced cardiac toxicity and 2) whether L-type Ca(2+) channels, one of the targets of H2S, could transduce some of the counteracting effects of MB. In sedated rats, H2S infused at a rate that would be lethal within 5 min (24 μM·kg(-1)·min(-1)), produced a rapid fall in left ventricle ejection fraction, determined by echocardiography, leading to a pulseless electrical activity. Blood concentrations of gaseous H2S reached 7.09 ± 3.53 μM when cardiac contractility started to decrease. Two to three injections of MB (4 mg/kg) transiently restored cardiac contractility, blood pressure, and V̇o2, allowing the animals to stay alive until the end of H2S infusion. MB also delayed PEA by several minutes following H2S-induced coma and shock in unsedated rats. Applying a solution containing lethal levels of H2S (100 μM) on isolated mouse cardiomyocytes significantly reduced cell contractility, intracellular calcium concentration ([Ca(2+)]i) transient amplitudes, and L-type Ca(2+) currents (ICa) within 3 min of exposure. MB (20 mg/l) restored the cardiomyocyte function, ([Ca(2+)]i) transient, and ICa The present results offer a new approach for counteracting H2S toxicity and potentially other conditions associated with acute inhibition of L-type Ca(2+) channels.


Characterization of an interspersed repetitive DNA element in the genome of Trypanosoma cruzi.
We report the molecular characterization of a middle repetitive DNA sequence, named C6, isolated from the Trypanosoma cruzi genome. C6 appears to be a composite repeated element since 3 subregions may be defined within it on the basis of sequence similarities with other T. cruzi genomic sequences. Sequences homologous to C6 are interspersed in the genome and can be mapped out on most chromosomal bands of different T. cruzi. strains. The copy number of the C6 element is about 1000 per haploid genome. Given the species specificity and different genomic distribution of C6 homologous sequences among the T. cruzi strains the C6 element could be a useful probe for diagnosis and typing of parasites. C6 is a polymorphic marker with potential as a tool for physical mapping of the T. cruzi genome.


A novel role for HEB downstream or parallel to the pre-TCR signaling pathway during alpha beta thymopoiesis.
TCR gene rearrangement and expression are central to the development of clonal T lymphocytes. The pre-TCR complex provides the first signal instructing differentiation and proliferation events during the transition from CD4-CD8-TCR- double negative (DN) stage to CD4+CD8+ double positive (DP) stage. How the pre-TCR signal leads to downstream gene expression is not known. HeLa E-box binding protein (HEB), a basic helix-loop-helix transcription factor, is abundantly detected in thymocytes and is thought to regulate E-box sites present in many T cell-specific gene enhancers, including TCR-alpha, TCR-beta, and CD4. Targeted disruption of HEB results in a 5- to 10-fold reduction in thymic cellularity that can be accounted for by a developmental block at the DN to DP stage transition. Specifically, a dramatic increase in the CD4low/-CD8+CD5lowHSA+TCRlow/- immature single positive population and a concomitant decrease in the subsequent DP population are observed. Adoptive transfer test shows that this defect is cell-autonomous and restricted to the alpha beta T cell lineage. Introduction of an alpha beta TCR transgene into the HEBko/ko background is not sufficient to rescue the developmental delay. In vivo CD3 cross-linking analysis of thymocytes indicates that TCR signaling pathway in the HEBko/ko mice appears intact. These findings suggest an essential function of HEB in early T cell development, downstream or parallel to the pre-TCR signaling pathway.


CCAAT/enhancer binding protein alpha regulates p21 protein and hepatocyte proliferation in newborn mice.
CCAAT/enhancer binding protein alpha (C/EBP alpha) is expressed at high levels in quiescent hepatocytes and in differentiated adipocytes. In cultured cells, C/EBP alpha inhibits cell proliferation in part via stabilization of the p21 protein. The role of C/EBP alpha in regulating hepatocyte proliferation in vivo is presented herein. In C/EBP alpha knockout newborn mice, p21 protein levels are reduced in the liver, and the fraction of hepatocytes synthesizing DNA is increased. Greater than 30% of the hepatocytes in C/EBP alpha knockout animals continue to proliferate at day 17 of postnatal life when cell division in wild-type littermates is low (3%). p21 protein levels are relatively high in wild-type neonates but undetectable in C/EBP alpha knockout mice. The reduction of p21 protein in the highly proliferating livers that lack C/EBP alpha suggests that p21 is responsible for C/EBP alpha-mediated control of liver proliferation in newborn mice. During rat liver regeneration, the amounts of both C/EBP alpha and p21 proteins are decreased before DNA synthesis (6 to 12 h) and then return to presurgery levels at 48 h. Although C/EBP alpha controls p21 protein levels, p21 mRNA is not influenced by C/EBP alpha in liver. Using coimmunoprecipitation and a mammalian two-hybrid assay system, we have shown the interaction of C/EBP alpha and p21 proteins. Study of p21 stability in liver nuclear extracts showed that C/EBP alpha blocks proteolytic degradation of p21. Our data demonstrate that C/EBP alpha regulates hepatocyte proliferation in newborn mice and that in liver, the level of p21 protein is under posttranscriptional control, consistent with the hypothesis that protein-protein interaction with C/EBP alpha determines p21 levels.


Influence of exposure and toxicokinetics on measures of aquatic toxicity for organic contaminants: a case study review.
This theoretical and case study review of dynamic exposures of aquatic organisms to organic contaminants examines variables important for interpreting exposure and therefore toxicity. The timing and magnitude of the absorbed dose change when the dynamics of exposure change. Thus, the dose metric for interpreting toxic responses observed during such exposure conditions is generally limited to the specific experiment and cannot be extrapolated to either other experiments with different exposure dynamics or to field exposures where exposure dynamics usually are different. This is particularly true for mixture exposures, for which the concentration and composition and, therefore, the timing and magnitude of exposure to individual components of different potency and potentially different mechanisms of action can vary. Aquatic toxicology needs studies that develop temporal thresholds for absorbed toxicant doses to allow for better extrapolation between conditions of dynamic exposure. Improved experimental designs are required that include high-quality temporal measures of both the exposure and the absorbed dose to allow better interpretation of data. For the short term, initial water concentration can be considered a conservative measure of exposure, although the extent to which this is true cannot be estimated specifically unless the dynamics of exposure as well as the toxicokinetics of the chemicals in the exposure scenario for the organism of interest are known. A better, but still limited, metric for interpreting the exposure and, therefore, toxicity is the peak absorbed dose, although this neglects toxicodynamics, requires appropriate temporal measures of accumulated dose to determine the peak concentration, and requires temporal thresholds for critical body residue for each component of the mixture.


Thirty-Year Trends in the Incidence of Atrial Fibrillation: The ARIC Study.
Background Long-term data to study recent trends in the incidence of atrial fibrillation (AF), overall and among sex and race groups, are scarce. We evaluated the 30-year trends in the incidence of AF in the ARIC (Atherosclerosis Risk in Communities) study cohort and explored race and sex differences in these trends. Methods and Results We included 15 343 men and women aged 45 to 64 years in 1987 to 1989 without AF from 4 US communities in the ARIC cohort. Incident AF was identified based on study ECGs, hospital discharge codes, and death certificates through 2017. We calculated age and period-specific incidence rates (IRs) of AF. We used Poisson regression to calculate IR ratios of AF over time adjusting for age, sex, and race. A total of 3241 AF cases were identified during a mean (SD) follow-up of 22 years (8.4 years) (599 in Black participants, 2642 in White participants, 1582 in women, and 1659 in men). Overall, the IR of AF in the ARIC cohort was 9.6 per 1000 person-years (6.9 in Black participants, 10.5 in White participants, 8.1 in women, and 11.6 in men). Age-specific IR by time period did not show significant changes over time. In a model adjusted for sex, race, and age group, the rate of AF did not change significantly from 1987 to 1991 compared with 2012 to 2017 (IR ratio, 1.10 [95% CI, 0.88-1.36] comparing 2012-2017 with 1987-1991). Similarly, no evidence of changes over time in AF rates were identified in men and women or White and Black participants separately. Conclusions Even though IRs of AF increase as age increases, our analysis provided evidence suggesting that the overall IRs of AF have not changed over time in a multicenter cohort of Black and White individuals in the United States from 1987 to 2017.


Mapping the value for money of precision medicine: a systematic literature review and meta-analysis.
This study aimed to quantify heterogeneity in the value for money of precision medicine (PM) by application types across contexts and conditions and to quantify sources of heterogeneity to areas of particular promises or concerns as the field of PM moves forward. A systemic search was performed in Embase, Medline, EconLit, and CRD databases for studies published between 2011 and 2021 on cost-effectiveness analysis (CEA) of PM interventions. Based on a willingness-to-pay threshold of one-time GDP per capita of each study country, the net monetary benefit (NMB) of PM was pooled using random-effects meta-analyses. Sources of heterogeneity and study biases were examined using random-effects meta-regressions, jackknife sensitivity analysis, and the biases in economic studies checklist. Among the 275 unique CEAs of PM, publicly sponsored studies found neither genetic testing nor gene therapy cost-effective in general, which was contradictory to studies funded by commercial entities and early stage evaluations. Evidence of PM being cost-effective was concentrated in a genetic test for screening, diagnosis, or as companion diagnostics (pooled NMBs, $48,152, $8,869, $5,693, p < 0.001), in the form of multigene panel testing (pooled NMBs = $31,026, p < 0.001), which only applied to a few disease areas such as cancer and high-income countries. Incremental effectiveness was an essential value driver for varied genetic tests but not gene therapy. Precision medicine's value for money across application types and contexts was difficult to conclude from published studies, which might be subject to systematic bias. The conducting and reporting of CEA of PM should be locally based and standardized for meaningful comparisons.


Management of patients with decompensated hepatitis B virus associated [corrected] cirrhosis.
1. Hepatitis B virus replication is associated with a severe outcome in patients with decompensated cirrhosis. 2. Viral suppression induced by antivirals results in a clinical improvement that allows liver transplantation to be delayed or avoided. 3. Early treatment intervention is mandatory in patients with decompensated cirrhosis because of the delay in the restoration of liver functions. 4. Lamivudine is no longer the drug of choice because the initial enthusiasm has been tempered by the high rate of resistance development. 5. Early add-on therapy with adefovir allows us to rescue lamivudine resistance, but its use may be limited by nephrotoxicity. 6. Studies are ongoing with the newer generation of antivirals (telbivudine, tenofovir, entecavir, and emtricitabine) in monotherapy or in combination to determine the best strategy for achieving rapid and prolonged suppression of viral replication. These improved strategies should enhance treatment success enough to obtain clinical stabilization, to delay or prevent the need for transplantation, and to reduce the risk of hepatitis B virus recurrence on the graft.AASLD.


Do ants need to be old and experienced to teach?
Learning is widespread in invertebrates. However, whether social insects improve their recruitment skills with experience is only beginning to be investigated. Tandem running is a one-to-one form of recruitment used by certain species of ant. It is a remarkable communication system that meets widely accepted criteria for teaching in non-human animals. Here, we determined experimentally to what extent participation in, and efficient execution of, tandem running depends on either the age or the experience of worker ants. To investigate these issues, we constructed colonies of the ant Temnothorax albipennis with different compositions of inexperienced and experienced workers from different age cohorts and then examined which ants participated in tandem runs when they emigrated. Our results show that the ability to participate actively in recruitment by tandem running is present in all worker age groups but the propensity to participate varies with experience rather than age per se. Experienced individuals were more likely to engage in tandem runs, either as leaders or as followers, than young inexperienced individuals, and older experienced ants were more likely to lead tandems than older inexperienced ants. Young inexperienced ants led faster, more rapidly dispersing and less accurately orientated tandem runs than the older experienced ants. Our study suggests that experience (rather than age per se) coupled to stimulus threshold responses might interact to promote a division of labour so that a suitable number of workers actively participate in tandem runs.


A combination of multiple autoantibodies is associated with the risk of Alzheimer's disease and cognitive impairment.
Autoantibodies are self-antigen reactive antibodies that play diverse roles in the normal immune system, tissue homeostasis, and autoimmune and neurodegenerative diseases. Anti-neuronal autoantibodies have been detected in neurodegenerative disease serum, with unclear significance. To identify diagnostic biomarkers of Alzheimer's disease (AD), we analyzed serum autoantibody profiles of the HuProt proteome microarray using the discovery set of cognitively normal control (NC, n = 5) and AD (n = 5) subjects. Approximately 1.5-fold higher numbers of autoantibodies were detected in the AD group (98.0 ± 39.9/person) than the NC group (66.0 ± 39.6/person). Of the autoantigen candidates detected in the HuProt microarray, five autoantigens were finally selected for the ELISA-based validation experiment using the validation set including age- and gender-matched normal (NC, n = 44), mild cognitive impairment (MCI, n = 44) and AD (n = 44) subjects. The serum levels of four autoantibodies including anti-ATCAY, HIST1H3F, NME7 and PAIP2 IgG were significantly different among NC, MCI and/or AD groups. Specifically, the anti-ATCAY autoantibody level was significantly higher in the AD (p = 0.003) and MCI (p = 0.015) groups compared to the NC group. The anti-ATCAY autoantibody level was also significantly correlated with neuropsychological scores of MMSE (rs = - 0.229, p = 0.012), K-MoCA (rs = - 0.270, p = 0.003), and CDR scores (rs = 0.218, p = 0.016). In addition, a single or combined occurrence frequency of anti-ATCAY and anti-PAIP2 autoantibodies was significantly associated with the risk of MCI and AD. This study indicates that anti-ATCAY and anti-PAIP2 autoantibodies could be a potential diagnostic biomarker of AD.


A quantitative exploration of the subjective burden experienced by nurses when caring for patients with delirium.
The aim of this study is to examine the subjective burden experienced by nurses when they provide care for patients with acute delirium. Nurses' responses to dealing with the increased functional and copious demands associated with caring for a patient with delirium are not well explored. The study was descriptive and retrospective, adopting quantitative research methodologies. The Strain of Care for Delirium Index (SCDI) was used to collect data in 2007 from a random sample of the national nurses' register (n=800), in the Republic of Ireland. The subjective burden that nurses experience when caring for patients with delirium was high (M=2.97). The hyperactive/hyperalert subscale was deemed the most challenging to deal with (M=3.41). In relation to individual behaviours, the patients who averaged highest in terms of burden are those who are uncooperative and difficult to manage (M=3.58). This study represents the first reported measurement and examination of the subjective burden nurses experience when caring for patients with delirium, following initial development and testing of a sensitive tool (International Journal of Nursing Studies41, 775). Findings outlined the subtypes and behaviours that increase the burden of caring for patients with delirium. This is an issue that needs to be addressed and further research is needed to explore the impact of nurse reactions further and to identify supportive/preventative methods for nurses. A specific examination into the factors that cause high levels of strain needs is required. This study highlights and confirms that nursing patients with delirium is challenging for nurses. It raises awareness of the practice and policy implications of nurses' potential negative reactions to these patients. It highlights the need for additional training and education to ensure that nurses understand this condition to provide for prevention, early detection and prompt intervention.


Exploration of Stable Strontium Phosphide-Based Electrides: Theoretical Structure Prediction and Experimental Validation.
Inspired by the successful synthesis of alkaline-earth-metals-based electrides [Ca24Al28O64]4+(e-)4 (C12A7:e-) and [Ca2N]+:e- and high-throughput database screening results, we explore the potential for new electrides to emerge in the Sr-P system through a research approach combining ab initio evolutionary structure searches and experimental validation. Through employing an extensive evolutionary structure search and first-principles calculations, we first predict the new structures of a series of strontium phosphides: Sr5P3, Sr8P5, Sr3P2 and Sr4P3. Of these structures, we identify Sr5P3 and Sr8P5 as being potential electrides with quasi-one-dimensional (1D) and zero-dimensional (0D) character, respectively. Following these theoretical results, we present the successful synthesis of the new compound Sr5P3 and the experimental confirmation of its structure. Although density functional calculations with the generalized gradient approximation predict Sr5P3 to be a metal, electrical conductivity measurement reveal semiconducting properties characterized by a distinct band gap, which indicates that the newly synthesized Sr5P3 is an ideal one-dimensional electride with the half-filled band by unpaired electrons. In addition to presenting the novel electride Sr5P3, we discuss the implications of its semiconducting nature for 1D electrides in general and propose a mechanism for the formation of electrides with an orbital level diagram based on first-principles calculations.


Step length is associated with comprehensive frailty status in community-dwelling older people.
To examine spatial-temporal gait parameters associated with comprehensive frailty status in community-dwelling, independent older people. This cross-sectional study included 225 older people (≥65 years) living independently in the community. The Kihon Checklist was used to assess comprehensive frailty status, and participants were classified as robust, pre-frailty, or frailty. A sheet-type plantar pressure sensor was used to evaluate the following gait parameters, which were extracted at the usual and fast pace: gait speed, cadence, stride time, step length-to-height ratio (step length/height), step width, stance duration, double-support time, and variability of each gait parameter. Ordinal logistic regression analysis adjusted for confounding factors was performed to determine the association between gait parameters and frailty status. In addition, the ability to discriminate frailty status was evaluated by receiver operating characteristic (ROC) curve analysis for gait parameters that were significantly associated with frailty status. Frailty status was pre-frailty in 79 (35.1%) and frailty in 30 (13.3%) participants. Ordinal logistic regression analysis showed a significant association of step length/height (%) at both usual and fast pace with frailty status, even after adjustment for confounding factors (usual pace: odds ratio [OR] = 0.93 [95% confidence interval, CI: 0.86-0.99]; fast pace: OR = 0.93 [95% CI: 0.87-0.99]). ROC curve analysis identified step length/height at fast pace in women as the best discriminator between frailty and non-frailty (area under the curve 0.69, cut-off value 43.4%, sensitivity 50%, specificity 82%). Step length appears to be a useful gait parameter for discriminating frailty status in community-dwelling, independent older people. Geriatr Gerontol Int 2023; ••: ••-••.


[Alcohol experience, alcohol knowledge, and alcohol expectancy in early adolescents].
This study was to explore the prevalence of alcohol experiences and to identify the expectancy on the effects of alcohol and alcohol knowledge in early adolescents. The cross-sectional survey of 1854 students from seven middle schools in one district of Seoul was conducted by convenience sampling. Alcohol experience and early onset of alcohol use were measured by the Youth Risk Behavior Survey. Alcohol expectancy was measured by an Alcohol Effects Questionnaire. Over sixty five percent of adolescents reported that they had previous drinking experiences. The participants with no alcohol drinking experience had a lower level of alcohol knowledge than those with experience(t=2.73, p=.007). In expectancy on effects of alcohol, girls had a more positive alcohol expectation than boys(t=-2.54, p=.011). Alcohol knowledge negatively correlated with alcohol expectancy(r=-.40 p=.000). In regression of alcohol expectancy, gender and alcohol knowledge were significant predictors explaining 17%. The results support that alcohol expectancy is an important link with early drinking experiences and alcohol knowledge, focusing on the importance of gender differences. Therefore, an alcohol prevention program in early adolescence is needed and should be focused on multidimensionality of the alcohol expectancy with developmental and psychosocial factors for early adolescents.


A nationwide prospective registry of bortezomib-based therapy in light chain (AL) amyloidosis.
Until recently, no drug was labeled for AL amyloidosis. In 2011, the Italian Medicines Agency started a program to grant access to upfront bortezomib to patients with AL amyloidosis. All subjects were enrolled in a prospective online registry. Response was evaluated after two cycles to assess the possibility of continuing treatment. A total of 764 patients were included until 2019, and 615 were evaluable. Sixteen percent of patents had advanced (stage-IIIb) heart involvement, and 27% had severe or end-stage renal failure. Bortezomib delivery was possible in stage-IIIb patients at a reduced dose. Bortezomib discontinuation was associated with increasing age, advanced heart involvement and bi-weekly administration. Fifty-nine percent of subjects attained a hematologic response and 14% a cardiac response. Bortezomib-based therapy tends to be discontinued early in elderly patients and in advanced disease. Nevertheless, early response to therapy is possible in this challenging population.


Possible role of nutrients in neoplasia.
The relationship between cancer and diet is supported by epidemiological evidence suggesting that diet is a factor in the development of cancer of various organs including the esophagus, stomach, liver, and large bowel. The role of depressed immunocompetency, especially during critical periods of growth and development, is stressed as a possible important consequence of nutritional insults leading to carcinoma. Study of the relationships among nutritional factors, host-defense mechanisms, and carcinogens to carcinogenesis is significant since, theoretically, manipulation of diet could suppress or prevent chemically induced cancers. The distinction should be emphasized, however, between "nutrients," those elements of one's intake that are essential because the body is unable to synthesize them de novo, and "diet," which refers to everything that is ingested. It is the components of diet, chemicals in particular, that are most convincingly implicated as carcinogens, while it is doubtful that nutrient deficiencies or excesses have a direct causal relationship with the onset or development of cancer. Rather, nutrition probably exerts its carcinogenic effects indirectly; nutrients possibly enhance chemical carcinogenesis multifactorially by mechanisms linked to their ability to: (a) act as carriers of carcinogens or their precursors; (b) alter intestinal flora so that carcinogenic reactions are facilitated; (c) enhance levels and reactivity of cocarcinogens; (d) influence absorptive properties or morphology of tissues so that carcinogenic activity is enhanced; and/or (e) modify host-defense mechanisms that normally protect the organism.


Linkage and linkage disequilibrium in chromosome band 1p36 in American Chaldeans with inflammatory bowel disease.
The idiopathic inflammatory bowel diseases (IBDs), consisting of Crohn's disease and ulcerative colitis, are complex genetic disorders involving chronic inflammation of the intestines. Multiple genetic loci have been implicated through genome-wide searches, but refinement of localization sufficient to undertake positional cloning efforts has been problematic. This difficulty can be obviated through identification of ancestrally shared regions in genetic isolates, such as the Chaldean population, a Roman Catholic group from Iraq. We analyzed four multiply affected American Chaldean families with inflammatory bowel disease not known to be related. We observed evidence for linkage and linkage disequilibrium in precisely the same region of chromosome band 1p36 reported previously in an outbred population. Maximal evidence for linkage was observed near D1S1597 by multipoint analysis (MLOD = 3.01, P = 6.1 x 10(-5)). A shared haplotype (D1S507 to D1S1628) was observed over 27 cM between two families. There was homozygous sharing of a 5 cM portion of that haplotype in one family and over a <1 cM region in the second family. Homozygous sharing of this haplotype near D1S2697 and D1S3669 was observed in one individual in a third multiply affected family, with heterozygous sharing in a fourth family. Linkage in outbred families as well as in this genetic isolate indicates that a pathophysiologically crucial IBD susceptibility gene is located in 1p36. These findings provide a unique opportunity to refine the localization and identify a major susceptibility gene for a complex genetic disorder.


Insulin Receptor Substrate p53 Ameliorates High-Glucose-Induced Activation of NF-κB and Impaired Mobility of HUVECs.
Diabetes-related macrovascular and microvascular complications lead to poor prognosis. Insulin receptor substrate p53 (IRSp53) is known to act as a substrate for the insulin receptor tyrosine kinase, but its role in endothelial dysfunction remains unclear. Human umbilical vein endothelial cells (HUVECs) treated with D-glucose at different concentrations and a streptozocin-induced rat diabetes mellitus (DM) model were used to investigate the effects of hyperglycemia on the expression levels of IRSp53 and galectin-3 (gal-3) and the inflammatory state and mobility of HUVECs. Thereafter, IRSp53-overexpressing HUVECs and IRSp53-knockdown HUVECs were established using IRSp53-overexpressing lentivirus or IRSp53-siRNA to explore the role of IRSp53 in the HUVEC inflammatory state and HUVEC mobility. D-glucose at high concentration (HG) and hyperglycemia were found to induce downregulation of IRSp53 and upregulation of gal-3 in vitro and in vivo. Treatment with HG resulted in activation of NF-κB in HUVECs and impaired HUVEC mobility. Insulin restored HG-induced changes in the expression levels of IRSp53 and gal-3 in HUVECs and protected the cells from NF-κB activation and impaired mobility. Overexpression of IRSp53 inhibited the activation of NF-κB in HUVECs and strengthened HUVEC migration. Knockdown of IRSp53 facilitated the activation of NF-κB in HUVECs and decreased HUVEC migration. However, neither overexpression nor knockdown of IRSp53 altered the effects of insulin on HG-induced detrimental changes in HUVECs. HG and hyperglycemia resulted in downregulation of IRSp53 in vitro and in vivo. IRSp53 is concluded to inhibit the activation of NF-κB in HUVECs and to strengthen HUVEC migration.


Optimal Quantification of Contact Inhibition in Cell Populations.
Contact inhibition refers to a reduction in the rate of cell migration and/or cell proliferation in regions of high cell density. Under normal conditions, contact inhibition is associated with the proper functioning tissues, whereas abnormal regulation of contact inhibition is associated with pathological conditions, such as tumor spreading. Unfortunately, standard mathematical modeling practices mask the importance of parameters that control contact inhibition through scaling arguments. Furthermore, standard experimental protocols are insufficient to quantify the effects of contact inhibition because they focus on data describing early time, low-density dynamics only. Here we use the logistic growth equation as a caricature model of contact inhibition to make recommendations as to how to best mitigate these issues. Taking a Bayesian approach, we quantify the trade off between different features of experimental design and estimates of parameter uncertainty so that we can reformulate a standard cell proliferation assay to provide estimates of both the low-density intrinsic growth rate, λ, and the carrying capacity density, K, which is a measure of contact inhibition.


Dysplastic squamous cells are frequently present in urine cytology specimens of patients with high-grade urothelial carcinoma.
In urothelial carcinoma (UCA), squamous differentiation (SqD) occurs mainly in high-grade UCA with invasion. Therefore, we sought to determine the frequency of dysplastic squamous cells (DSC) in urine specimens obtained from patients with high-grade UCA asking if DSC could serve as a surrogate marker for high-grade UCA. We searched for cases with a histologic diagnosis of high-grade UCA and available concurrent cytology, yielding 93 surgical specimens (including 71 biopsies, 12 cystectomies, 5 nephrectomies, 4 ureterectomies, and 1 urethrectomy) from 68 patients with 98 urine cytology samples. Both cytology and histologic specimens were evaluated for the presence of any SqD on histology and the presence of DSC on cytology besides urothelial cells. Forty-three of 68 patients (63%) had a cytologic diagnosis of 'positive/suspicious'. Twenty-one patients (30%) had surgical specimens that showed SqD. Seventeen patients had urine cytology specimens showing DSC (25%). Thirteen of these 17 patients showed DSC with concurrent malignant urothelial cells, while 4 patients displayed only isolated DSC. SqD is common in patients with high-grade UCA. DSC were detected in a subset of specimens from patients with high-grade UCA. In some instances, isolated DSC on cytology may represent the only evidence of an unsampled high-grade malignancy.


An optical telemetry device to identify which dolphin produces a sound.
A small telemetry device, called a "vocalight," was designed for attachment to a dolphin's head using a suction cup. The vocalight lights up a variable number of light-emitting diodes depending upon the loudness of sounds received at a hydrophone within the suction cup. If vocalights matched for sensitivity are put on each dolphin within a captive group, observers can identify which dolphin produces a vocalization. Use of vocalights indicates that source levels of whistles from captive bottlenosed dolphins, Tursiops truncatus, range from approximately 125 to over 140 dB re: 1 microPa at 1 m.


Associations of baseline obstructive sleep apnea and sleep macroarchitecture with cognitive function after 8 years in middle-aged and older men from a community-based cohort study.
Previous prospective studies examining associations of obstructive sleep apnea and sleep macroarchitecture with future cognitive function recruited older participants, many demonstrating baseline cognitive impairment. This study examined obstructive sleep apnea and sleep macroarchitecture predictors of visual attention, processing speed, and executive function after 8 years among younger community-dwelling men. Florey Adelaide Male Ageing Study participants (n = 477) underwent home-based polysomnography, with 157 completing Trail-Making Tests A and B and the Mini-Mental State Examination. Associations of obstructive sleep apnea (apnea-hypopnea index, oxygen desaturation index, and hypoxic burden index) and sleep macroarchitecture (sleep stage percentages and total sleep time) parameters with future cognitive function were examined using regression models adjusted for baseline demographic, biomedical, and behavioural factors, and cognitive task performance. The mean (standard deviation) age of the men at baseline was 58.9 (8.9) years, with severe obstructive sleep apnea (apnea-hypopnea index ≥30 events/h) in 9.6%. The median (interquartile range) follow-up was 8.3 (7.9-8.6) years. A minority of men (14.6%) were cognitively impaired at baseline (Mini-Mental State Examination score <28/30). A higher percentage of light sleep was associated with better Trail-Making Test A performance (B = -0.04, 95% confidence interval [CI] -0.06, -0.01; p = 0.003), whereas higher mean oxygen saturation was associated with worse performance (B = 0.11, 95% CI 0.02, 0.19; p = 0.012). While obstructive sleep apnea and sleep macroarchitecture might predict cognitive decline, future studies should consider arousal events and non-routine hypoxaemia measures, which may show associations with cognitive decline.


Diffusion in avian lungs.
Arterial PO2 in resting, normoxic avian lungs in not at the level of predicted for an ideal crosscurrent lung. In contrast to healthy alveolar lungs, such a reduction in efficiency of O2 exchange from optimal levels cannot be totally explained by ventilation/perfusion inequality, and the discrepancy is most likely related to diffusion resistances. The diffusing capacity of avian lungs (DLO2) will depend on: 1) stratification in the air capillaries, 2) blood-gas barrier morphology, 3) O2-Hb kinetics ( theta ), and 4) diffusive/perfusive conductance (D/ beta bQ) matching. Stratification in air capillaries, the membrane diffusing capacity, and time available in pulmonary capillaries for arterialization do not appear to be limiting at rest. D/ beta bQ inequality is expected in normoxic avian lungs but predictive models show that this should not limit O2 uptake. However, these resistances may interact in crosscurrent lungs or there may be other unknown diffusion limitations (e.g., theta ) to reduce PaO2 in birds. Recent morphologic evidence suggests DLO2 may increase in birds during exercise and V/Q and D/ beta bQ inequality would be expected to have less of an effect during hypoxia. Together, these factors may reconcile the relatively low PaO2 in resting birds at sea level and their ability to exercise at high altitudes.


Evaluation of recovery time of tear film function and ocular surface after discontinuing oral isotretinoin treatment for acne vulgaris : Correlation between oral isotretinoin and tear film function.
This study aimed to evaluate the recovery time of tear film function and ocular surface after discontinuing systemic isotretinoin treatment. This was a prospective, cross-sectional study. 34 eyes of 17 patients treated with low- dose oral isotretinoin (< 0.5 mg/kg/day) were enrolled. The modified OSDI score, tear break-up time, Schirmer test, and corneal staining were performed in all patients at baseline, during the course of treatment and after withdrawing treatment every two weeks until the result returned to baseline. Tear breakup time appeared to be the most sensitive and changed significantly at 2 weeks after starting treatment (p < 0.001) and returned to baseline at 4 weeks after withdrawal from treatment (p < 0.001). The Schirmer test results significantly decreased at 6 weeks and returned to baseline at 4 weeks after withdrawal from treatment (p < 0.001). OSDI scores were significantly changed at 6 weeks after treatment (81.8%) and returned to baseline at 2 weeks (54.5%) after withdrawal from treatment. No significant change was found in the MGD. Corneal staining was significantly positive 90.9% 6 weeks after starting treatment and returned to baseline 6 weeks after withdrawal from treatment (p < 0.001). Dry eye disease can return to baseline levels after treatment withdrawal. At least 6 weeks later, they could wear contact lenses again, and it was useful to prepare all patients requiring further ocular surgery.


Essential role of GTP in epinephrine stimulation of human fat cell adenylate cyclase.
The activity of epinephrine-sensitive adenylate cyclase of human fat cell ghosts is markedly enhanced by the GTP analog 5'-guanylyl-imidodiphosphate (GMP-P(NH)P), but a similar effect of GTP itself has not been heretofore demonstrable. In the present work, comparison of adenylate cyclase activity in the presence of epinephrine alone versus epinephrine plus GTP showed that at 37 degrees C GTP doubled activity (10-min incubation); at 30 degrees C less than half this effect was apparent. However, time course studies at both 30 and 37 degrees C showed that comparisons at a single point in time based on ratios of hormone-stimulated activity to basal or basal plus GTP were misleading, since basal activities were not linear with time and were inhibited by GTP. The inhibitory effect of GTP on basal activity was seen at both temperatures but at 37 degrees C decreased with time so that by 10 min the inhibition was no longer apparent. The time course data showed clearly that epinephrine alone did not stimulate adenylate cyclase activity; rather, the hormone merely prevented fall-off of initial rate of unstimulated (basal) enzyme activity. Only when GTP was added together with epinephrine was an unequivocal stimulation of enzyme activity observed. GTP effect was dose-dependent with half-maximal enhancement of epinephrine stimulation at 1.0 microM GTP. The GTP effect was not hormone-receptor mediated, since no shift was seen of the epinephrine dose-response curve toward higher sensitivity. GTP enhancement of epinephrine stimulation occurred over a wide range of ATP concentrations (0.01-3.0 mM) and affected the substrate Km only minimally. GTP-enhanced activity thus occurred through increased V max of the hormone-sensitive adenylate cyclase.


Silver-mediated methoxycarbonyltetrafluoroethylation of arenes.
In the presence of silver(I) fluoride, highly fluorinated olefins react readily under solvent-free conditions with arenes via CH-substitution. This transformation could be used to synthesize various methoxycarbonyltetrafluoroethylated aromatic triazenes and anisoles under high functional group tolerance. The method could be applied to the synthesis of a formal fluorinated bioisostere of the NSAID flurbiprofen. To the best of our knowledge, this is the first example which uses highly fluorinated olefins for the perfluoroalkylation of aromatic substrates.


The selection of marmoset monkeys (Callithrix jacchus) in pharmaceutical toxicology.
Prior to controlled clinical trials in human volunteers or patients it is required that novel pharmaceuticals are evaluated for pre-clinical safety in a rodent and a non-rodent ('second') species. In most cases the rodent species used has been the rat and the second species has been the dog or macaque (usually cynomolgus or rhesus) monkey. However, there is an increasing trend within the United Kingdom (UK) pharmaceutical industry to use the common marmoset (Callithrix jacchus) for pre-clinical toxicology programmes. This paper examines the practicality of using the common marmoset (henceforth referred to as 'the marmoset') in toxicological testing and reviews metabolic and pharmacodynamic similarities between this species and humans. It then discusses some of the advantages and disadvantages of the use of this species when compared with two other alternatives to the dog and macaque, namely the ferret and minipig. In particular, the marmoset has clear advantages over the macaque in terms of animal welfare and practicality. There is regulatory acceptance of this species for Investigational New Drug (IND), Clinical Trial Exemption (CTX), New Drug Application (NDA) and Marketing Authorization Application (MAA) registrations. Whilst the dog is likely to be maintained as the primary non-rodent species in toxicology, the marmoset has been, and will likely continue to be, adopted as an additional non-rodent species in pre-clinical toxicology programmes where appropriate.


How sustained is 24-hour diffusion-weighted imaging lesion reversal? Serial magnetic resonance imaging in a patient cohort thrombolyzed within 4.5 hours of stroke onset.
Here, we assessed how sustained is reversal of the acute diffusion lesion (RAD) observed 24 hours after intravenous thrombolysis, and the relationships between RAD fate and early neurological improvement. We analyzed 155 consecutive patients thrombolyzed intravenously 152 minutes (median) after stroke onset and who underwent 3 MR sessions: 1 before and 2 after treatment (median times from onset, 25.6 and 54.3 hours, respectively). Using voxel-based analysis of diffusion-weighted imaging (DWI)1, DWI2, and DWI3 lesions on coregistered image data sets, we assessed the outcome of RAD voxels (hyperintense on DWI1 but not on DWI2) as transient or sustained on DWI3, and their relationships with early neurological improvement, defined as ΔNational Institutes of Health Stroke Scale ≥8 or National Institutes of Health Stroke Scale ≤1 at 24 hours. Tmax and apparent diffusion coefficient values were compared between sustained and transient RAD voxels. The median (interquartile range) baseline National Institutes of Health Stroke Scale and DWI1 lesion volume were 11 (7-18) mL and 15.6 (6.0-50.9) mL, respectively. The median (interquartile range) RAD volume on DWI2 was 2.8 (1.1-6.6) mL, of which 70% was sustained on DWI3. Sixteen (10.3%) patients had sustained RAD ≥10 mL. As compared with transient RAD voxels, sustained RAD voxels had nonsignificantly higher baseline apparent diffusion coefficient values (median [interquartile range], 793 [717-887] versus 777 [705-869]×10(-6) mm(2)·s (-1), respectively; P=0.08) and significantly better perfusion (Tmax, mean±SD, 6.3±3.2 versus 7.8±4.0 s; P<0.001). At variance with transient RAD, the volume of sustained RAD was associated with early neurological improvement in multivariate analysis (odds ratio, 1.08; 95% confidence interval, [1.01-1.17], per 1-mL increase; P=0.03). After thrombolysis, over two-thirds of the DWI lesion reversal captured on 24-hour follow-up MR is sustained. Sustained DWI lesion reversal volume is a strong imaging correlate of early neurological improvement.


Phase II study of a high-dose ifosfamide-based chemotherapy regimen with growth factor rescue in recurrent aggressive NHL. High response rates and limited toxicity, but limited impact on long-term survival.
The purpose of the study was to evaluate in patients with recurrent intermediate-grade NHL, the tolerance to and efficacy of an intensive salvage regimen consisting of high doses of ifosfamide, etoposide and mitoxantrone with G-CSF support, followed by autologous stem cell transplantation and to identify prognostic factors for survival in patients with recurrent aggressive lymphoma. Patients with recurrent intermediate-grade NHL under the age of 60 years were eligible. Induction consisted of ifosfamide 10 g/m(2) and etoposide 900 mg/m(2) with G-CSF 5 microg/kg twice a day. Upon recovery, patients underwent stem cell apheresis. Patients achieving complete remission (CR) underwent autologous stem cell transplantation using BEAM conditioning. Those with partial remission (PR) received treatment with ifosfamide 10 g/m(2), mitoxantrone 20 mg/m(2) and G-CSF 5 microg/kg. Those with CR received BEAM, those with PR received cyclophosphamide 4.5 g/m(2), etoposide 1200 mg/m(2) and cisplatin 135 mg/m(2) with stem cell rescue followed by BEAM. Antibiotic prophylaxis was given with all treatment cycles. The results were compared with those obtained in a prior study that used MINE-ESHAP salvage. Forty-four patients with recurrent intermediate-grade NHL were enrolled between March 1994 and September 1996. Median age was 50 years (24-61). Eleven patients had transformed lymphoma and seven had a T cell phenotype. Response rate to the high-dose ifosfamide regimen was 77% +/- 12% after two cycles and the complete response rate was 41% +/- 14%. Myelosuppression was profound but short. Median nadir ANC was 0 and the median duration of ANC <0.5 x 10(9)/l was 6 days (range 3-12). No severe infections occurred; 55% of the patients required blood transfusion and 42% required platelet transfusions. Myelosuppression and transfusion requirements were similar after the first and second cycles. Thirty-five of the 44 patients proceeded to autologous stem cell transplantation and one transplant-related death occurred. With a median follow-up of 52 months, progression-free survival at 2 years is 38% +/- 14% and survival is 52% +/- 15%. Data from these 44 patients were pooled with data on 53 patients who had received salvage treatment with MINE-ESHAP, for a multivariate analysis of prognostic factors. In multivariate analysis, serum LDH was strongly associated with survival. The use of a more intensive salvage regimen, did not result in a significant increase in long-term outcome, despite a high response rate. In conclusion, duration of treatment, response rates, treatment-related mortality and survival compare favorably with previous salvage regimens, but recurrence remains a major problem. Long-term survival in recurrent large cell lymphoma is influenced more by disease characteristics than by the type of salvage regimen used.


Detection of response to tumor microenvironment-targeted cellular immunotherapy using nano-radiomics.
Immunotherapies, including cell-based therapies, targeting the tumor microenvironment (TME) result in variable and delayed responses. Thus, it has been difficult to gauge the efficacy of TME-directed therapies early after administration. We investigated a nano-radiomics approach (quantitative analysis of nanoparticle contrast-enhanced three-dimensional images) for detection of tumor response to cellular immunotherapy directed against myeloid-derived suppressor cells (MDSCs), a key component of TME. Animals bearing human MDSC-containing solid tumor xenografts received treatment with MDSC-targeting human natural killer (NK) cells and underwent nanoparticle contrast-enhanced computed tomography (CT) imaging. Whereas conventional CT-derived tumor metrics were unable to differentiate NK cell immunotherapy tumors from untreated tumors, nano-radiomics revealed texture-based features capable of differentiating treatment groups. Our study shows that TME-directed cellular immunotherapy causes subtle changes not effectively gauged by conventional imaging metrics but revealed by nano-radiomics. Our work provides a method for noninvasive assessment of TME-directed immunotherapy potentially applicable to numerous solid tumors.


Geographic variation in bacterial communities associated with the red turpentine beetle (Coleoptera: Curculionidae).
Bacterial communities are known to play important roles in insect life histories, yet their consistency or variation across populations is poorly understood. Bacteria associated with the bark beetle Dendroctonus valens LeConte from eight populations, ranging from Wisconsin to Oregon, were evaluated and compared. We used the culture-independent technique of denaturing gradient gel electrophoresis to visualize bacterial diversity, or individual operational taxonomic units (OTUs), from individual beetles. One-way analysis of similarities was used to test for differences of bacterial communities between sites. Analysis of community profiles showed that individual beetles on average contained 10 OTUs, with frequency of association from 2 to 100% of beetles. OTU sequences most closely matched beta- and gamma-proteobacteria, and one each matched Bacilli and Actinobacteria. Several OTUs were particularly abundant, most notably an Actinobacterium from 100% and two Proteobacteria from 60% of beetles sampled. Some OTUs were similar to previously described bacteria with known biochemical capabilities and ecological functions, suggesting that some bacterial associates of D. valens may contribute to its ability to exploit a resource low in nutrients and high in defensive compounds. There were significant differences of bacterial communities between sites. The strength of these differences was positively correlated with distance between sites, although additional unexplained factors also contribute to the variation.


Optimization of Pt-C Deposits by Cryo-FIBID: Substantial Growth Rate Increase and Quasi-Metallic Behaviour.
The Focused Ion Beam Induced Deposition (FIBID) under cryogenic conditions (Cryo-FIBID) technique is based on obtaining a condensed layer of precursor molecules by cooling the substrate below the condensation temperature of the gaseous precursor material. This condensed layer is irradiated with ions according to a desired pattern and, subsequently, the substrate is heated above the precursor condensation temperature, revealing the deposits with the shape of the exposed pattern. In this contribution, the fast growth of Pt-C deposits by Cryo-FIBID is demonstrated. Here, we optimize various parameters of the process in order to obtain deposits with the lowest-possible electrical resistivity. Optimized ~30 nm-thick Pt-C deposits are obtained using ion irradiation area dose of 120 μC/cm2 at 30 kV. This finding represents a substantial increment in the growth rate when it is compared with deposits of the same thickness fabricated by standard FIBID at room temperature (40 times enhancement). The value of the electrical resistivity in optimized deposits (~4 × 104 µΩ cm) is suitable to perform electrical contacts to certain materials. As a proof of concept of the potential applications of this technology, a 100 µm × 100 µm pattern is carried out in only 43 s of ion exposure (area dose of 23 μC/cm2), to be compared with 2.5 h if grown by standard FIBID at room temperature. The ion trajectories and the deposit composition have been simulated using a binary-collision-approximation Monte Carlo code, providing a solid basis for the understanding of the experimental results.


The role of speciation in positive Lowenstein-Jensen culture isolates from a high tuberculosis burden country.
To determine the need for routine speciation of positive Lowenstein-Jensen mycobacterial cultures in HIV-infected patients suspected of having pulmonary tuberculosis at Mulago Hospital in Kampala, Uganda. Sputum and bronchoalveolar lavage Lowenstein-Jensen mycobacterial culture isolates from consecutive, HIV-infected patients admitted to Mulago Hospital with 2 weeks or more of cough were subjected to IS6110 PCR and rpoB genetic analysis to determine the presence of Mycobacterium tuberculosis complex (MTBC) and non-tuberculous mycobacteria (NTM). Eighty (100%) mycobacterial cultures from 65 patients were confirmed to be members of MTBC. Subsequent analysis of the cultures from 54 patients by PCR and sequence analyses to identify co-infection with NTM confirmed the presence of MTBC as well as the presence of Micrococcus luteus (n = 4), Janibacter spp. (n = 1) and six cultures had organisms that could not be identified. Presumptive diagnosis of tuberculosis on the basis of a positive Lowenstein-Jensen culture is sufficient in HIV-infected Ugandans suspected of having tuberculosis. Routine molecular confirmation of positive Lowenstein-Jensen cultures is unnecessary in this low resource setting.


Control of circadian rhythms and photoperiodic flowering by the Arabidopsis GIGANTEA gene.
Photoperiodic responses in plants include flowering that is day-length-dependent. Mutations in the Arabidopsis thaliana GIGANTEA (GI) gene cause photoperiod-insensitive flowering and alteration of circadian rhythms. The GI gene encodes a protein containing six putative transmembrane domains. Circadian expression patterns of the GI gene and the clock-associated genes, LHY and CCA1, are altered in gi mutants, showing that GI is required for maintaining circadian amplitude and appropriate period length of these genes. The gi-1 mutation also affects light signaling to the clock, which suggests that GI participates in a feedback loop of the plant circadian system.


Clinical practice guidelines for therapeutic drug monitoring of teicoplanin: a consensus review by the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring.
Owing to its low risk of adverse effects, teicoplanin has been extensively used in patients with infections caused by MRSA. To promote the better management of patients receiving teicoplanin, we have updated the guidelines for therapeutic drug monitoring (TDM). The guidelines were developed by a committee following the methodology handbook published by the Japanese Medical Information Distribution Service. Nine clinical questions were selected. The committee conducted a systematic review and meta-analysis to establish evidence-based recommendations for the target trough concentration (Cmin). An initial electronic database search returned 515 articles, and 97 articles qualified for a full review. Four and five studies were included for the efficacy evaluation of cut-off Cmin values of 15 and 20 mg/L, respectively. Compared with Cmin < 15 mg/L, a target Cmin value of 15-30 mg/L resulted in increased clinical efficacy in patients with non-complicated MRSA infections (OR = 2.68; 95% CI = 1.14-6.32) without an increase in adverse effects. Although there was insufficient evidence, target Cmin values of 20-40 mg/L were suggested in patients with complicated or serious MRSA infections. A 3 day loading regimen followed by maintenance treatment according to renal function was recommended to achieve the target trough concentrations. Because of the prolonged half-life of teicoplanin, measurement of the Cmin value on Day 4 before reaching steady state was recommended. The new guideline recommendations indicate the target Cmin value for TDM and the dosage regimen to achieve this concentration and suggest practices for specific subpopulations.


Ethical beliefs related to HIV and AIDS among nursing students in South Africa and the United States: a cross-sectional analysis.
The ethical issues associated with HIV and AIDS are challenging and complex because of beliefs about HIV and AIDS, stigma surrounding the epidemic, lack of knowledge, and fear. Both South Africa and the United States have a nursing code of ethics which endorses a nurse's responsibility to maintain a patient's right to confidentiality, involvement in decision-making, autonomy, and informed consent. However, nursing students may inappropriately handle ethical challenges in practice related to HIV and AIDS. The objective of this study was to determine the ethical beliefs held by nursing students regarding testing, confidentiality, serostatus disclosure, and the environment of care related to HIV and AIDS in South Africa and the United States. This study utilized a descriptive, correlational design with a cross-sectional time dimension. Data were collected during March-April 2007 in South Africa and the United States. 136 nursing students in South Africa and 198 nursing students in the United States participated in the study. The participants included nursing students in enrolled and professional bridging programs in South Africa and from traditional and accelerated baccalaureate entry programs in the United States. In both countries, the participants were mostly female and heterosexual. In South Africa, participants were mostly black (93.3%) while in the United States the participants were mostly white (76.6%). Over 95% of eligible nursing students participated in the study in both countries. After evaluating the findings in the context of ethical standards, 0% of the 198 nursing students in the US had beliefs that were fully supportive of the nursing standards of ethical practice regarding caring for HIV-positive persons, while only 11.5% of the South African participants were fully supportive. Despite their identified lack of training in HIV and AIDS nursing, nursing students in South Africa were much more willing to protect patient confidentiality than nursing students in the United States. Nursing students' beliefs and attitudes related to HIV and AIDS are not congruent with the ethical principles guiding nursing. To facilitate support for the ethical principles of nursing in the context of HIV and AIDS, nursing students need guided experiences to assess personal attitudes and beliefs about HIV and AIDS and direct care opportunities to destigmatize the epidemic in order to meet the ethical standards of nursing practice.


Reduction of Inflammation and Colon Injury by a Spearmint Phenolic Extract in Experimental Bowel Disease in Mice.
Background: Inflammatory Bowel Diseases (IBD) encompasses both Crohn's Disease and Ulcerative Colitis, known to be connected to an enlarged risk for developing colorectal cancer (CRC). Spearmint (Mentha spicata L.) is a Mediterranean plant used as an aromatic agent, and studies have mainly focused on the essential oil suggesting an anti-inflammatory activity. This work aimed to perform a preliminary screening of the in vivo anti-inflammatory effects of a spearmint phenolic extract in an acute inflammation model, in a chronic inflammation model of colitis, and also study the effects in vitro on a colon cancer model. Methods: Spearmint extract was administered to rats of a paw oedema model (induced by carrageenan) and to mice from a TNBS-induced colitis model in parallel with studies using HT-29 CRC cells. Results: Administration of the extract led to reduced paw inflammation, reduction of colon injury and inflammation, with attenuation of histological markers, and reduction of iNOS expression. It repressed the in vitro movement of HT-29 cells in a wound healing assay. Conclusions: These findings suggest that spearmint extract exhibits acute and chronic anti-inflammatory activity and is able to inhibit migration of cancer cells, suggesting a potential role in the supplementary therapy of IBD patients.


Rapid serotyping of human rotavirus strains by solid-phase immune electron microscopy.
Nine cell culture-adapted, as well as 30 clinical, human rotavirus (HRV) strains from fecal extracts of children with primary HRV infection were typed by rapid solid-phase immune electron microscopy with protein A and absorbed DS-1 (HRV serotype 2), Wa (serotype 1), and VA70 (assumed serotype 3) rabbit immune sera. As a reference typing test for cell culture-adapted strains, the neutralization assay was used, whereas for noncultivatable strains typing was done for comparison, indirectly, based upon the differential neutralization reactivity of convalescent-phase serum samples from patients with primary HRV infection versus the three reference HRV serotypes. Typing results by solid-phase immune electron microscopy for all strains examined were in complete agreement with those obtained by the neutralization assay, both on cell culture-adapted strains with the three reference rabbit antisera and on three reference HRV strains with human convalescent-phase serum samples. Since adaptation to growth in cell cultures of clinical HRV strains from stool specimens is a time-consuming procedure and is often unsuccessful, solid-phase immune electron microscopy is preferred over the neutralization assay, giving results in about 16 h and also allowing typing of HRV strains from stool specimens low in virus particles. In addition, HRV strains reacting differently from the three reference serotypes may be easily selected by solid-phase immune electron microscopy for further characterization, as was the case for one strain in this study.


Carbamazepine prevents imipramine-induced behavioural sensitization to the dopamine D(2)-like receptor agonist quinpirole.
Chronic treatment with antidepressants potentiates the behavioural sensitivity to the administration of dopamine receptor agonists. Such supersensitivity might be involved in the mechanism of action of antidepressant drugs, but it has also been suggested to play a role in the mechanisms underlying antidepressant treatment-related mania (i.e. antidepressant-induced mood switch and rapid cycling). Consistently to this hypothesis, we have recently shown that lithium salts, which are poorly effective in antidepressant-related mania, fail to prevent the development of imipramine-induced supersensitivity to the locomotor effect of the dopamine D(2)-like receptor agonist quinpirole. In the present paper, we report the ability of carbamazepine, an anticonvulsant with antimanic and mood stabiliser properties, to prevent the development of supersensitivity to the locomotor response to quinpirole induced by chronic treatment with imipramine. The present results, together with the results of our previous study, might contribute to explain the different responsiveness to lithium and carbamazepine observed in some manic patients, and are consistent with the clinical data suggesting that carbamazepine might be more effective than lithium in antidepressant-related mania.


Identification of First-in-Class Inhibitors of Kallikrein-Related Peptidase 6 That Promote Oligodendrocyte Differentiation.
Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) that causes severe motor, sensory, and cognitive impairments. Kallikrein-related peptidase (KLK)6 is the most abundant serine protease secreted in the CNS, mainly by oligodendrocytes, the myelin-producing cells of the CNS, and KLK6 is assumed to be a robust biomarker of MS, since it is highly increased in the cerebrospinal fluid (CSF) of MS patients. Here, we report the design and biological evaluation of KLK6's low-molecular-weight inhibitors, para-aminobenzyl derivatives. Interestingly, selected hit compounds were selective of the KLK6 proteolytic network encompassing KLK1 and plasmin that also participate in the development of MS physiopathology. Moreover, hits were found noncytotoxic on primary cultures of murine neurons and oligodendrocyte precursor cells (OPCs). Among them, two compounds (32 and 42) were shown to promote the differentiation of OPCs into mature oligodendrocytes in vitro constituting thus emerging leads for the development of regenerative therapies.


One center in Brussels has consistently had the lowest HbA1c values in the 4 studies (1994-2009) by the Hvidoere International Study Group on Childhood Diabetes: What are the "recipes"?
The principal aims of therapeutic management of the child, adolescent and adult with type 1 diabetes are to allow good quality of life and to avoid long-term complications (retinopathy, neuropathy, nephropathy, cardiovascular disease, etc.) by maintaining blood glucose concentrations close to normal level. Glycated hemoglobin levels (HbA1c) provide a good criterion of overall glycemic control. The Hvidoere Study Group (HSG) on Childhood Diabetes, founded in 1994, is an international group representing about twenty highly experienced pediatric centers from Europe, North America, Japan and Australia. Four international comparisons of metabolic control (1995, 1998, 2005, 2009) have been performed. The one center that has consistently had the lowest HbA1c values (approximate 7.3% or 56.3 mmol/mol) is my center in Brussels. This is more often obtained with a twice-daily free-mixed regimen with additional supplemental fast insulins ad hoc. The so-called "Dorchy's recipes" are summarized. The conclusion is that the number of daily insulin injections, 2 or ≥ 4, or the use of pumps, by itself does not necessarily give better results. Intensified therapy should not depend upon the number of insulin doses per day, by syringe, pen or pump but rather should be redefined as to intent-to-treat ascertainment (i.e., goals). When there are no mutually agreed upon goals for BG and/or HbA1c, when there is insufficient education and psychosocial support by the medical team or at home, there is likely to be poor outcomes, as shown by the HSG. One of our recipes is not to systematically replace rapid-acting human insulins by fast-acting analogues. Because the multicenter studies of the HSG, performed in developed countries without financial restriction, show that treatment of childhood diabetes is inadequate in general and that levels of HbA1c are very different, diabetes treatment teams should individually explore the reasons for failure, without any prejudice or bias. Any dogmatism must be avoided. Treatment cost vs results must also be taken into account.