Controlled evaluation of a community based injury prevention program in Australia.
To evaluate the effects of a community based, all age, all injury prevention program, the Safe Living Program, on injury risk and injury rates. A quasiexperimental population based evaluation using an intervention and comparison community design. The intervention community (Shire of Bulla, n = 37,257) is an outer metropolitan area of Melbourne, Australia. The demographically matched comparison community (Shire of Melton, n=33,592) is located nearby. The Safe Living Program in the Shire of Bulla targeted injury reduction in all settings with a focus on high risk groups. Strategies included program publicity, education and training, injury hazard reduction, and environmental change. Baseline and follow up measures of program reach, risk factors, and injury rates in both communities were used to evaluate program process, impact, and outcome. Increase in program awareness was moderate and similar to other community based programs. The program achieved injury hazard reduction on the road, in schools, and, to a more limited extent, in the home. Other changes in injury risk factors could not necessarily be attributed to the program as similar changes were observed in the comparison community. No significant changes were found in rates of injury deaths, hospitalisations, or emergency department presentations in the Shire of Bulla after six years. Self reported household injuries, mostly minor, were reduced in the intervention community, but had been higher at program launch than in the comparison community. The Safe Living Program was unable to replicate the significant reductions in injuries reported in other community based interventions. Replication of apparently successful community based injury prevention programs in different settings and populations requires evidence based interventions, sustained and effective program penetration, reliable data systems to measure change, at least one control community, and sufficient budget and time for effects to be observable.


Explorations into neolignan biosynthesis: concise total syntheses of helicterin B, helisorin, and helisterculin A from a common intermediate.
Helicterins A and B (1 and 2), helisorin (3), and helisterculin A (4) are structurally unique natural products with the ability to combat the avian myeloblastosis virus. Biogenetically, their architectures are considered to be products of seemingly straightforward Diels-Alder, radical-based, or acid-induced dimerizations of common, simpler precursors. Yet, the pursuit of such blueprints in the laboratory has failed thus far in enabling their successful synthesis. Herein, we describe the first total syntheses of three of these natural products. Key features include the use of a building block distinct from Nature's likely starting material, highly complex retro Diels-Alder/Diels-Alder reaction cascades, an unconventional protecting group to achieve the proper balance of chemical reactivity on sensitive scaffolds, and several carefully developed reaction conditions that effectively balance competing reaction pathways.


[Identification of Group A streptococci from throats of school children in Northern Taiwan].
A total of 2,750 strains of beta-hemolytic streptococci was isolated from 10, 510 throat swabs collected from school children in the Taipei area. Most of them were classified as group A (61%) and group G (34%), and about 5% belonged to other groups or unclassified strains. 1, 772 strains of beta-hemolytic streptococci isolated from healthy school children, and 69 strains from sick school children were grouped by the Lancefield precipitin test, fluorescent antibody technique and/or bacitracin paper disk method. A satisfactory correlation (over 90%) was obtained by the latter 2 methods, when compared with the results of the Lancefield technique. The occurrance of false negative or false positive was only 1 or 5%, respectively.


Low literacy is associated with increased risk of hospitalization and death among individuals with heart failure.
Low literacy increases the risk for many adverse health outcomes, but the relationship between literacy and adverse outcomes in heart failure (HF) has not been well studied. We studied a cohort of ambulatory patients with symptomatic HF (NYHA Class II-IV within the past 6 months) who were enrolled in a randomized controlled trial of self-care training recruited from internal medicine and cardiology clinics at four academic medical centers in the US. The primary outcome was combined all-cause hospitalization or death, with a secondary outcome of hospitalization for HF. Outcomes were assessed through blinded interviews and subsequent chart reviews, with adjudication of cause by a panel of masked assessors. Literacy was measured using the short Test of Functional Health Literacy in Adults. We used negative binomial regression to examine whether the incidence of the primary and secondary outcomes differed according to literacy. Of the 595 study participants, 37 % had low literacy. Mean age was 61, 31 % were NYHA class III/IV at baseline, 16 % were Latino, and 38 % were African-American. Those with low literacy were older, had a higher NYHA class, and were more likely to be Latino (all p < 0.001). Adjusting for site only, participants with low literacy had an incidence rate ratio (IRR) of 1.39 (95 % CI: 0.99, 1.94) for all-cause hospitalization or death and 1.36 (1.11, 1.66) for HF-related hospitalization. After adjusting for demographic, clinical, and self-management factors, the IRRs were 1.31 (1.06, 1.63) for all-cause hospitalization and death and 1.46 (1.20, 1.78) for HF-related hospitalization. Low literacy increased the risk of hospitalization for ambulatory patients with heart failure. Interventions designed to mitigate literacy-related disparities in outcomes are warranted.


Intraperitoneal transmitters in suckling white-footed mice, Peromyscus leucopus.
Intraperitoneal transmitter implantation in suckling white-footed mice, Peromyscus leucopus, was studied. Postnatal morphological development varied. Age ranged from 9 to 16 days, and body weight ranged from 4.4 to 7.3 g. Interference by mothers prevented successful implantation on sucklings which retained their neonatal appearance. Growth was measured in 6 sucklings for 21 days. Observed growth rates based on daily weight gain per 24 h were 0.29 and 0.32 g for implanted and control mice, respectively. Transmitter implantation resulted in a significant short-term weight loss (mean = 0.56 g) which was recouped prior to weaning. There was no evidence of impaired coordination or locomotor disability. This study concluded that intraperitoneal implantation is possible in suckling P. leucopus if surgery is delayed until venter pelage has developed sufficiently and eyes have been open at least 2 days. A few implications of using this technique to radio track small mammals are suggested.


Imaging of Genetic Thoracic Aortopathy.
Aortopathy is a term most commonly used to describe a group of genetic diseases that predispose patients to an elevated risk of aortic events including aneurysm and acute aortic syndrome. Types of genetic aortopathy are classified as either heritable or congenital, with heritable thoracic aortic disease (HTAD) further subclassified into syndromic HTAD or nonsyndromic HTAD, the former of which is associated with specific phenotypic features. Radiologists may be the first physicians to encounter features of genetic aortopathy, either incidentally or at the time of an acute aortic event. Identifying patients with genetic aortopathy is of substantial importance to clinicians who manage thoracic aortic disease, because aortic diameter thresholds for surgical intervention are often lower than those for nongenetic aortopathy related to aging and hypertension. In addition, when reparative surgery is performed, the approach and extent of the repair may differ in patients with genetic aortopathy. The radiologist should also be familiar with competing diagnoses that can result in acute aortic events, mainly acquired inflammatory and noninflammatory thoracic aortic disease, because these conditions may be associated with increased risks of similar pathologic endpoints. Because many imaging and phenotypic features of various types of genetic aortopathy overlap, diagnosis and determination of appropriate follow-up recommendations can be challenging. A multidisciplinary approach with the use of imaging is often required and, once the diagnosis is made, imaging has additional importance because of the need for lifelong follow-up. ©RSNA, 2022.


Shall Organized Medicine be Unified, or Separate?
At present, physicians in California who choose to join organized medicine do so through their county medical societies, and membership in the California Medical Association and the American Medical Association is then automatic. At the March meeting of the CMA House of Delegates, question was raised whether membership in CMA, and the AMA, or both should remain automatic.The House requested an ad hoc committee to cause a "poll and its attendant statements to be developed by May 21 for copy distribution to component medical societies and printing in the CMA membership news media-with mailing of the official questionnaires to the society members on September 1, 1971." Members will be asked to express their opinions by ballot in September.The Speaker of the House appointed an ad hoc committee of the House to conduct this informed opinion poll of the membership. The committee has met to set ground rules, prepare accurate pro and con statements and write the poll questions-in accord with the directions of the House action.The Informed Membership Opinion Poll Committee, with the advice of Decision Making Information, Inc., an independent consultant, prepared statements regarding unified and separate membership in CMA and AMA from comments which were solicited from every county medical society. A statement by legal counsel for the California Medical Association on the structural relationship of AMA, CMA and component societies, and the statements on unified or separate membership prepared by the committee appear on the following two pages.


Lung endothelial cell apoptosis during ischemic acute kidney injury.
Kidney ischemia-reperfusion injury (IRI) activates cellular and soluble mediators that drive lung inflammatory cascades, tumor necrosis factor receptor 1 (TNFR1)-mediated programmed cell death, and microvascular barrier dysfunction, leading to acute lung injury. We hypothesized that lung microvascular endothelial cells (ECs), with their integral role in maintaining the lung-semipermeable barrier, were key cellular targets of TNFR1-mediated apoptosis during ischemic AKI. Male C57/BL6 mice and Sprague-Dawley rats underwent 60 min of bilateral renal pedicle occlusion (IRI) or sham laparotomy (sham) and were killed at 4 or 24 h. Colocalization with TUNEL, DAPI, and CD34 was performed to identify EC-specific apoptosis. Mouse ECs (CD45/CD31) isolated with novel tissue digestion techniques and magnetic microbead sorting underwent quantitative real-time polymerase chain reaction SuperArray analysis with 84 apoptosis-related genes. In parallel, rat lung microvascular ECs grown to confluence were treated with serum from rats obtained following sham or kidney IRI. Rat lung microvascular ECs treated +/- etanercept, a TNF-α/TNFR1 signaling inhibitor, underwent custom real-time polymerase chain reaction analysis for proapoptotic and TNF superfamily transcriptional events, and apoptosis was identified with caspase 3 and poly(ADP-ribose) polymerase activity assays. In vivo, TUNEL-positive cells colocalized with CD34 in whole-lung tissue and isolated lung ECs demonstrated a proapoptotic transcriptome during ischemic AKI. In vitro, ischemic AKI incited proapoptotic (FasL, Dapk1, Bcl10) and TNF superfamily (TNFR1, TNFR2, TNF-α) gene activation and increased caspase 3 and poly(ADP-ribose) polymerase activity at 24 h versus sham. Compared with vehicle, treatment of rat lung microvascular ECs with etanercept inhibited proinflammatory gene activation (E-selectin, intercellular adhesion molecule 1, interleukin 6, RhoB) and apoptosis during ischemic AKI. Ischemic AKI drives distinct proinflammatory and proapoptotic changes in the pulmonary EC transcriptome with TNFR1-dependent caspase activation and programmed cell death. Further investigation of potential EC mechanisms of kidney-lung crosstalk during AKI may identify potential therapeutic targets for this deadly disease.


Remyelinated lesions in multiple sclerosis: magnetic resonance image appearance.
Various types of pathologic mechanisms in multiple sclerosis (MS) can alter magnetic resonance imaging (MRI) signals, and the appearance of remyelinated lesions on MRI is largely unknown. To describe the MRI appearance of remyelinated lesions in MS. Comparison of postmortem MRI findings with histopathologic findings. Brain donations from a general community. Patients Magnetic resonance images from 36 rapid autopsies yielded 161 areas that could be matched with histologic characteristics, including 149 focal T2-weighted abnormalities, with a range of signal intensities on T1-weighted images. In a subset of 49 lesions, magnetization transfer ratio could be determined. An observer blinded to the MRI findings assessed the presence of remyelination using light microscopic criteria; in 25 areas, in situ hybridization was used to assess the presence of oligodendrocytes expressing proteolipid protein messenger RNA. Remyelinated areas were found in 67 lesions (42%): partial remyelination was present in 30 lesions (19%), whereas 37 lesions (23%) were fully remyelinated. Remyelinated lesions contained enhanced numbers of oligodendrocytes containing proteolipid protein messenger RNA. All areas with remyelination shown histopathologically were hyperintense on T2-weighted images. Strong hypointensity on T1-weighted images was significantly associated (chi2 = 29.8, P<.001) with demyelinated and partially remyelinated lesions compared with fully remyelinated lesions. The magnetization transfer ratio of remyelinated lesions (mean [SD], 27.6% [41%]) differed (F = 46.3, P<.001) from both normal-appearing white matter (35.2% [32%]) and demyelinated lesions (22.3% [48%]). Remyelinated lesions return an abnormal signal on T2-weighted images. Both T1-weighted images and magnetization transfer ratio may have (limited) additional value in separating lesions with and without remyelination.


Discordant CD34+ cell results in peripheral blood and hematopoietic progenitor cell-apheresis product: implications for clinical decisions and impact on patient treatment.
A 50-year-old male with T-cell lymphoma presented for autologous peripheral blood stem cell transplantation. After granulocyte-colony-stimulating factor (G-CSF) mobilization, his peripheral blood CD34+ cell count was 166 × 10(6) /L on the day before collection, which predicted a high yield of CD34+ cells in the apheresis product. The first two collections had yields much lower than expected, triggering an investigation and changes to the apheresis collection methods since mobilization appeared adequate from the peripheral CD34+ values. Changes to the apheresis collection variables and instrumentation did not improve the yields in the next three collections. The laboratory investigation demonstrated that there was an interfering substance in the patient's plasma that was causing falsely high peripheral blood CD34+ cell values and that the low CD34+ cell yields in the collections were consistent with the actual peripheral blood CD34+ cell value. Based on this finding and after discussion with the clinical service, the patient then received plerixafor to increase the number of circulating CD34+ cells before Collections 6 and 7. The patient went on to achieve the target CD34+ cell dose and subsequently underwent a successful autologous transplant with full hematopoietic engraftment. This case demonstrates the importance of timely and critical review of laboratory results in the context of the specific patient. This case exemplifies how diligent review of laboratory results and open communication among the various teams can positively affect patient outcomes.


Development, characterization, and hematopoietic differentiation of Griscelli syndrome type 2 induced pluripotent stem cells.
Griscelli syndrome type 2 (GS-2) is a rare, autosomal recessive immune deficiency syndrome caused by a mutation in the RAB27A gene, which results in the absence of a protein involved in vesicle trafficking and consequent loss of function of in particular cytotoxic T and NK cells. Induced pluripotent stem cells (iPSC) express genes associated with pluripotency, have the capacity for infinite expansion, and can differentiate into cells from all three germ layers. They can be induced using integrative or non-integrative systems for transfer of the Oct4, Sox2, Klf4, and cMyc (OSKM) transcription factors. To better understand the pathophysiology of GS-2 and to test novel treatment options, there is a need for an in vitro model of GS-2. Here, we generated iPSCs from 3 different GS-2 patients using lentiviral vectors. The iPSCs were characterized using flow cytometry and RT-PCR and tested for the expression of pluripotency markers. In vivo differentiation to cells from all three germlines was tested using a teratoma assay. In vitro differentiation of GS-2 iPSCs into hematopoietic stem and progenitor cells was done using Op9 feeder layers and specified media. All GS-2 iPSC clones displayed a normal karyotype (46XX or 46XY) and were shown to express the same RAB27A gene mutation that was present in the original somatic donor cells. GS-2 iPSCs expressed SSEA1, SSEA4, TRA-1-60, TRA-1-81, and OCT4 proteins, and SOX2, NANOG, and OCT4 expression were confirmed by RT-PCR. Differentiation capacity into cells from all three germ layers was confirmed using the teratoma assay. GS-2 iPSCs showed the capacity to differentiate into cells of the hematopoietic lineage. Using the lentiviral transfer of OSKM, we were able to generate different iPSC clones from 3 GS-2 patients. These cells can be used in future studies for the development of novel treatment options and to study the pathophysiology of GS-2 disease.


Lack of objective response of myelodysplastic syndromes and acute myeloid leukemia to decitabine after failure of azacitidine.
The hypomethylating agents azacitidine and decitabine are standard therapy for myelodysplastic syndromes (MDS), and are often used to treat patients with acute myeloid leukemia (AML) unlikely to benefit from cytotoxic chemotherapy. Switching hypomethylating agents after treatment failure is common, but this approach is not well studied. We retrospectively reviewed data on 25 patients with MDS, MDS/myeloproliferative neoplasm (MDS/MPN) or AML who were treated with decitabine after primary or secondary azacitidine failure at the University of Maryland Greenebaum Cancer Center. Five patients with MDS or MDS/MPN achieved stable disease with decitabine, but no patient achieved complete or partial remission or hematologic improvement. Most patients discontinued therapy due to disease progression or death after a median of 2 cycles and median survival was 5.9 months after decitabine initiation. Based on our data, decitabine therapy after azacitidine failure is of little benefit beyond disease stabilization in some patients.


Comparison of Patients With Emmetropia and Presbyopia and Different Accommodation Who Undergo Unilateral or Bilateral Implantation of a Trifocal IOL.
To compare visual outcomes and satisfaction in patients with emmetropia, presbyopia, and greater or lesser residual accommodation who undergo unilateral or bilateral implantation of a trifocal diffractive intraocular lens (IOL). A multicenter, multisurgeon study was performed to evaluate outcomes in patients with emmetropia and presbyopia who underwent refractive lens exchange followed by implantation of a FineVision trifocal IOL (PhysIOL). The inclusion criteria were as follows: emmetropia, sphere -0.25 to +0.50 diopters (D), cylinder less than 0.75 D, and manifest refractive spherical equivalent (MRSE) of -0.25 to +0.25 D. All patients also had to have an uncorrected distance visual acuity (UDVA) of Snellen 0.9 or better in each eye. The sample was divided into different clusters based on two variables: eyes operated on (monocular or binocular) and age either younger than 55 years or 55 years or older. Thus, four possible groups were created. Visual and refractive performance, patient satisfaction, and spectacle independence were assessed. A total of 690 eyes from 431 patients were evaluated. There was no difference in postoperative uncorrected (UDVA) and corrected (CDVA) distance visual acuity between the groups. Binocular uncorrected near vision (UNVA) was better in patients who underwent surgery on both eyes regardless of age (median [interquartile range]: 0.00 [0.00; 0.10] vs 0.10 [0.00; 0.10] logMAR; P < .001). Binocular uncorrected intermediate vision (UIVA) was better in patients who underwent surgery on both eyes aged younger than 55 years than in those who underwent surgery in one eye aged 55 years or older (median [interquartile range]: 0.18 [0.10; 0.18] vs 0.30 [0.18; 0.30] logMAR; P < .001). The efficacy and safety indexes were 0.98 ± 0.09 and 1.01 ± 0.06, respectively. A total of 93.3% of eyes were within the 0.50 D range in postoperative MRSE. Visual dysphotopsia was worse in patients with both eyes operated on, although the differences were not statistically significant. The study shows that after refractive lens exchange, patients with emmetropia and presbyopia who received a trifocal IOL in one or both eyes achieved good UNVA, UIVA, and UDVA. Regarding near binocular visual acuity, results were better for patients who underwent surgery on both eyes than for those who underwent surgery on one eye. Regarding binocular intermediate visual acuity, patients aged younger than 55 years with both lenses replaced had better results than those 55 years or older with only one lens replaced. However, no significant differences were observed in UDVA or patient satisfaction. [J Refract Surg. 2023;39(12):817-824.].


Systemic Administration with Bacteria-Inspired Nanosystems for Targeted Oncolytic Therapy and Antitumor Immunomodulation.
Malignant tumors represent a formidable global health challenge, compelling the pursuit of innovative treatment modalities. Oncolytic therapy has emerged as a promising frontier in antitumor strategies. However, both natural agents (such as oncolytic bacteria or viruses) and synthetic oncolytic peptides confront formidable obstacles in clinical trials, which include the delicate equilibrium between safety and efficacy, the imperative for systemic administration with targeted therapy, and the need to counteract oncolysis-induced immunosuppression. To overcome these dilemmas, we have developed biomimetic nanoengineering to create oncolytic bacteria-inspired nanosystems (OBNs), spanning from hierarchical structural biomimicry to advanced bioactive biomimicry. Our OBNs harbor inherent oncolytic potential, including functionalized oligosaccharides mimicking bacterial cell walls for optimal blood circulation and tumor targeting, tumor acidity-switchable decoration for tumor-specific oncolysis, stereospecific tryptophan-rich peptides for robust oncolytic activity, encapsulated tumor immunomodulators for enhanced immunotherapy, and innate multimodal imaging potential for biological tracing. This work elucidates the efficacy and mechanisms of OBNs, encompassing primary tumor suppression, metastasis prevention, and recurrence inhibition. Systemic administration of d-chiral OBNs has demonstrated superior oncolytic efficacy, surpassing intratumoral injections of clinical-grade oncolytic peptides. This work heralds an era in biomimetic engineering on oncolytic agents, promising the revolutionization of contemporary oncolytic therapy paradigms for clinical translation.


Characterization of somatostatin receptor subtype 2 expression in stably transfected A-427 human cancer cells.
Although radiolabeled somatostatin analogs have become highly prevalent in the diagnosis and treatment of somatostatin receptor subtype (sst)-positive tumors, there are relatively few options with respect to sst-positive tumor cell lines and animal models. It would be highly beneficial, particularly for therapeutic purposes, to have several clones of one human sst2-positive cell line that express a range of sst2 concentrations for evaluating the dose response and intracellular processing of radiolabeled somatostatin analogs. The human non-small cell lung cancer line A-427 was stably transfected with a hemagglutinin-tagged human sst2. Expression of the receptor was evaluated in vitro using flow cytometry, saturation binding analysis, internalization assays, and quantitative polymerase chain reaction. The receptor expression was also validated in an in vivo mouse model in biodistribution and micro-positron emission tomography (microPET) studies using the somatostatin analog octreotide (OC), which was linked to the (64)Cu chelator 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), or (64)Cu-TETA-OC. Stable clones were isolated, and four clones (2, 4, 5, and 7) were chosen for further examination. In vitro assays showed that clone 4 had no expression of sst2, whereas the others had various levels in the order of 7 > 2 > 5. Biodistribution studies with (64)Cu-TETA-OC showed the same rank order, with tumor uptake of the clones ranging from 0.8 to 6.5% injected dose/g. These studies showed that there was a strong correlation among the in vitro assays and between the in vitro assays and the biodistribution. MicroPET confirmed significant uptake of (64)Cu-TETA-OC in clone 7 and background uptake in clone 4. These studies show that clones of a human cell line can be produced expressing various levels of sst2 that should be useful for the future evaluation of radiolabeled somatostatin analogs.


Weekday variation in triglyceride concentrations in 1.8 million blood samples.
Triglyceride (TG) concentration is used as a marker of cardiometabolic risk. However, diurnal and possibly weekday variation exists in TG concentrations. The objective of this work was to investigate weekday variation in TG concentrations among 1.8 million blood samples drawn between 2008 and 2015 from patients in the Capital region of Denmark. Plasma TG was extracted from a central clinical laboratory information system. Weekday variation was investigated by means of linear mixed models. In addition to the profound diurnal variation, the TG concentration was 4.5% lower on Fridays compared with Mondays (P < 0.0001). The variation persisted after multiple adjustments for confounders and was consistent across all sensitivity analyses. Out-patients and in-patients, respectively, had 5.0% and 1.9% lower TG concentrations on Fridays compared with Mondays (both P < 0.0001). The highest weekday variations in TG concentrations were recorded for out-patients between the ages of 9 and 26 years, with up to 20% higher values on Mondays compared with Fridays (all P < 0.05). In conclusion, TG concentrations were highest after the weekend and gradually declined during the week. We suggest that unhealthy food intake and reduced physical activity during the weekend increase TG concentrations which track into the week. This weekday variation may carry implications for public health and future research practice.


Primary and reoperative parathyroid operations in hyperparathyroidism of multiple endocrine neoplasia type 1.
Operation and reoperation for hyperparathyroidism in multiple endocrine neoplasia type 1 (MEN 1) is controversial regarding surgical strategy, preoperative localization, and biochemical indexes of recurrence. Fifty patients with MEN 1 with hyperparathyroidism were followed up 2 to 27 years after subtotal (SPX; n = 35) or total parathyroidectomy with forearm autografiing (TPX; n = 15), including 24 who underwent 28 reoperations because of persistent or recurrent hyperparathyroidism. Persistent or recurrent hyperparathyroidism was seen in 66% and 20% of patients after SPX involving extirpation of at least 3 glands and TPX, respectively, and 100% after single-gland excision as a primary procedure. After reoperation, hypercalcemia was reversed in 33% of patients by SPX and 61% by intended TPX procedures. All patients received vitamin D substitution after TPX, but restricted thyroid function allowed withdrawal in all but 10 patients (36%). Intact serum parathyroid hormone levels in nongrafted and grafted arms rose with time, but only exceptional ratios localized graft recurrence. Localization of recurrent hyperparathyroidism was achieved with 11C-labeled methionine positron emission tomography. MEN 1 hyperparathyroidism has a high risk of recurrence, and operation may include primarily SPX of at least 3 glands or TPX, although the latter includes a higher risk of long-term hypoparathyroidism. Reoperation should involve TPX with recognition of the enhanced recurrence rate in individuals with postoperative hyperparathyroidism.


Epidemiologic burden of hospitalisation for congestive heart failure among adults aged ≥19 years in the Philippines.
The study determined the prevalence of hospitalisation due to congestive heart failure (CHF) among adult patients aged 19 years and above in the Philippines and its 17 regions in 2014. It also determined the demographic profile of these patients, aetiology and type of CHF, comorbidities, duration of hospitalisation and the overall in-hospital mortality rate. Data collection was done using the hospitalisation claims database of the Philippine Health Insurance Corporation (PhilHealth). All patient claims for CHF, that is, patients who were admitted from 1 January to 31 December 2014, were included. Descriptive statistics were utilised to obtain the results. The prevalence rate was 1.6% or 1648 cases of CHF for every 100 000 patient claims for medical conditions in 2014. The mean age was 52.6±15.1 years. There was no sex predilection. Only 22.67% of the hospitalisation claims for CHF listed possible specific aetiologies, the most common of which was hypertensive heart disease (86.7%). There were more cases of systolic compared to diastolic heart failure. The mean length of hospital stay was 5.9 days (+8.2) days (median 4 days), with an overall in-hospital mortality rate of 8.2%. There were 16 cases of heart failure for every 1000 Filipino patients admitted due to a medical condition in 2014. Hypertension was possibly the most common aetiologic factor. Compared to western and Asia-Pacific countries, the local mortality rate was relatively higher.


An approach for quantitative mapping of synaptic periactive zone architecture and organization.
Following exocytosis at active zones, synaptic vesicle membranes and membrane-bound proteins must be recycled. The endocytic machinery that drives this recycling accumulates in the periactive zone (PAZ), a region of the synapse adjacent to active zones, but the organization of this machinery within the PAZ, and how PAZ composition relates to active zone release properties, remains unknown. The PAZ is also enriched for cell adhesion proteins, but their function at these sites is poorly understood. Here, using Airyscan and stimulated emission depletion imaging of Drosophila synapses, we develop a quantitative framework describing the organization and ultrastructure of the PAZ. Different endocytic proteins localize to distinct regions of the PAZ, suggesting that subdomains are specialized for distinct biochemical activities, stages of membrane remodeling, or synaptic functions. We find that the accumulation and distribution of endocytic but not adhesion PAZ proteins correlate with the abundance of the scaffolding protein Bruchpilot at active zones-a structural correlate of release probability. These data suggest that endocytic and exocytic activities are spatially correlated. Taken together, our results identify novel relationships between the exocytic and endocytic apparatus at the synapse and provide a new conceptual framework to quantify synaptic architecture.


Assessing the effect of vibrotactile feedback during continuous multidirectional platform motion: a frequency domain approach.
This study uses frequency domain techniques to demonstrate the effect of vibrotactile feedback during continuous multidirectional perturbations of a support platform. Eight subjects with bilateral or unilateral vestibular loss were subjected to two-axis pseudo random surface platform motion while donning a multi-axis feedback balance aid that mapped body tilt estimates onto their trunks via a 3-row by 16-column array of tactile vibrators (tactors). Four tactor display configurations with spatial resolutions ranging between 22.5 degrees and 90 degrees , in addition to the tactors off configuration, were evaluated. Power spectral density (PSD) functions of body sway in the anterior-posterior (A/P) and medial-lateral (M/L) directions were computed at frequencies ranging from 0.0178 Hz to 3.56 Hz. Transfer functions between the platform motion and body sway were also computed. Vibrotactile feedback produced significant decreases in A/P and M/L spectral power, decreased transfer function gains up to a frequency of 1.8 Hz and 0.6 Hz in the A/P and M/L directions, respectively, and increased phase leads above 0.3 Hz. The lack of a consistent difference among tactor configurations argue in favor of the simplest 4-column configuration during multidirectional continuous surface perturbations.


Pre-Pregnancy Body Mass Index Is Associated with Dietary Inflammatory Index and C-Reactive Protein Concentrations during Pregnancy.
There have been a limited number of studies examining the association between pre-pregnancy body mass index (BMI) and dietary inflammation during pregnancy. Our aim is to examine the association between pre-pregnancy BMI and the Dietary Inflammatory Index (DII)™ and C-reactive protein (CRP) concentrations during pregnancy. The study included 631 pregnant American women from the National Health and Nutrition Examination Survey (NHANES) cross-sectional examinations from 2003 to 2012. Pre-pregnancy BMI was calculated based on self-reported pre-pregnancy weight and measured height. The cut-offs of <18.5 (underweight), 18.5-24.9 (normal), 25.0-29.9 (overweight), and ≥30 kg/m² (obese) were used to categorize the weight status of pregnant women prior to pregnancy. The DII, a literature-based dietary index to assess the inflammatory properties of diet, was estimated based on a one-day 24-h recall. Multivariable linear and logistic regressions were performed to estimate beta coefficients and the adjusted odds ratios (AORs) and 95% confidence intervals (95% CIs) on the association of pre-pregnancy BMI categories with the DII and CRP concentrations during pregnancy. After controlling for variables including: race/ethnicity, family poverty income ratio, education, marital status, month in pregnancy, and smoking status during pregnancy; women who were obese before pregnancy (n = 136) had increased odds for being in the highest tertile of the DII and CRP concentrations compared to women with normal weight (AORs 2.40, 95% CIs 1.01-5.71; AORs 24.84, 95% CIs 6.19-99.67, respectively). These findings suggest that women with pre-pregnancy obesity had greater odds of reporting higher DII and having elevated CRP. In conclusion, high pre-pregnancy BMI was associated with increased odds of pro-inflammatory diet and elevated CRP levels during pregnancy in the USA.


Long-term follow-up and prognostic factors in Ewing's sarcoma. A multivariate analysis of 116 patients from a single institution.
The records of 116 patients from a single center (1970-1993) with newly diagnosed Ewing's sarcoma or primitive neuroectodermal tumor were reviewed retrospectively. The aim of this study was to ascertain the impact of pretreatment variables on disease-free survival. Median age was 14 years (range 1-34). Twenty patients presented with metastatic disease. Treatment consisted of systemic multiagent chemotherapy plus local irradiation (39%), wide resection (22%), or both (35%). Median potential follow-up was 10.7 years (range 2-26). Three patients developed second malignancies (1 breast carcinoma, 2 acute myeloid leukemias). Median time to relapse was 24 months (range 3-143). The actuarial disease-free survival was 37.4% at 5 years, 33.3% at 10 years and 27.8% at 15 years. Neoadjuvant chemotherapy and a therapy-induced tumor necrosis > or = 90% were associated with a better outcome. Patients undergoing surgical resection had a superior disease-free survival than those treated without surgery (45 vs. 18% at 10 years, p = 0.0009). Multiple regression analysis showed that raised serum lactate dehydrogenase levels (p < 0.001), hypoalbuminemia (p = 0.001) and distant metastases at diagnosis (p = 0.03) were independent adverse prognostic factors. In conclusion, one third of patients with Ewing's sarcoma become long-term survivors with combined modality treatment. Late relapses and second neoplasms are of concern. Prognostic factors should be considered in the selection of therapy, and the value of serum albumin warrants confirmatory studies.


Intrathecal cyclosporin prolongs survival of late-stage ALS mice.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by upper and lower motor neuron death with ascending paralysis leading to death. In a transgenic mouse model of ALS (SOD1-G93A) weakness appears at 3 months of age, and because of progressive paralysis leads to death by 5 months. Cyclosporin A (CsA) is well known, for its extracerebral effect, as an immunosuppressant in organ transplantation. When able to access the brain, CsA is an effective neuroprotective agent mainly due to its protection of mitochondria through inhibition of the mitochondrial permeability transition. CsA does not cross the intact blood-brain barrier and was in the present study delivered to the brain through an infusion into the lateral cerebral ventricle. Injections started at the onset of late disease when weakness of the hindlimbs was apparent. CsA treatment prolonged the survival of ALS transgenic mice as compared to vehicle-treated controls. This finding implicates mitochondrial function in ALS and may have significance for human disease.


Association of XRCC1 polymorphisms and risk of differentiated thyroid carcinoma: a case-control analysis.
Numerous single-nucleotide polymorphisms (SNPs) of the DNA repair gene XRCC1 have been described. These SNPs have been increasingly studied in the epidemiology of various cancer types. In this study we evaluated the risk association between six common SNPs of the XRCC1 gene and differentiated thyroid carcinoma (DTC). We conducted a case-control study of 251 subjects with DTC, 145 subjects with benign thyroid disease, and 503 cancer-free controls. Polymerase chain reaction-restriction fragment length polymorphism assays were performed for genotyping. Multivariate logistic regression analysis was performed for risk estimation. Expectation-maximization algorithm and bayesian methods were used to estimate haplotype frequencies. Multivariate analysis demonstrated an increased risk of DTC for the Arg194Trp heterozygous polymorphic (CT) genotype (odds ratio [OR]: 1.4, 95% confidence interval [CI]: 0.9-2.1). Multivariate analysis demonstrated a decreased risk of DTC for the Arg399Gln homozygous polymorphic (AA) genotype (OR: 0.5, 95% CI: 0.3-0.8) and the polymorphic (A) allele (OR: 0.7, 95% CI: 0.5-1.0). Compared to the most commonly observed haplotype (CGTCGA), multiple haplotypes were associated with a significantly increased risk of DTC, with the CGTTGG haplotype demonstrating the strongest association (OR: 5.0, 95% CI: 1.9-13.2). The XRCC1 194Trp variant allele may be associated with increased risk of DTC, while the XRCC1 399Gln variant allele may be associated with decreased risk of DTC. The utility of XRCC1 haplotypes in predicting DTC risk deserves further investigation with direct haplotype measurement.


Infantile hypertrophic pyloric stenosis in patients with esophageal atresia.
Patients born with esophageal atresia (EA) have a higher incidence of infantile hypertrophic pyloric stenosis (IHPS), suggestive of a relationship. A shared etiology makes sense from a developmental perspective as both affected structures are foregut derived. A genetic component has been described for both conditions as single entities and EA and IHPS are variable components in several monogenetic syndromes. We hypothesized that defects disturbing foregut morphogenesis are responsible for this combination of malformations. We investigated the genetic variation of 15 patients with both EA and IHPS with unaffected parents using exome sequencing and SNP array-based genotyping, and compared the results to mouse transcriptome data of the developing foregut. We did not identify putatively deleterious de novo mutations or recessive variants. However, we detected rare inherited variants in EA or IHPS disease genes or in genes important in foregut morphogenesis, expressed at the proper developmental time-points. Two pathways were significantly enriched (p < 1 × 10-5 ): proliferation and differentiation of smooth muscle cells and self-renewal of satellite cells. None of our findings could fully explain the combination of abnormalities on its own, which makes complex inheritance the most plausible genetic explanation, most likely in combination with mechanical and/or environmental factors. As we did not find one defining monogenetic cause for the EA/IHPS phenotype, the impact of the corrective surgery could should be further investigated.


Inhibition of protein breakdown by epidermal growth factor in IMR90 human fibroblasts and other mammalian cell lines.
1. Epidermal growth factor (EGF) inhibits intracellular protein breakdown in IMR90 human fibroblasts and other cell lines having EGF receptors. 2. Inhibition is achieved within 1 h of exposure to the growth factor and is reversed equally rapidly upon removal of EGF. 3. EGF inhibits protein breakdown and stimulates protein and DNA labelling with similar dependency on concentration. Half-maximal effects for all processes with IMR90 and AG2804 cell lines occur at 0.2 nM- and 0.05 nM-EGF respectively. 4. EGF and insulin effects on protein breakdown are additive only when the factors are included at suboptimal concentrations. 5. The apparent Kd for EGF binding in several cell lines is approximately 10-fold higher than the concentration needed for half-maximal inhibition of protein breakdown. 6. Down-regulation of EGF receptors in IMR90 cells produced a 60% decrease in the binding of 125I-labelled EGF. This was accompanied by a displacement of the concentration curve for EGF inhibition of protein breakdown by approximately two orders of magnitude, suggesting that protein breakdown can no longer respond to the down-regulated receptor-growth-factor complex. 7. Phorbol esters decrease the inhibitory effect of EGF, but not of insulin, on protein breakdown in IMR90 cells.


Mitral annular calcification progression and the risk of atrial fibrillation: results from MESA.
To determine if progression of mitral annular calcium (MAC) detected by cardiac computed tomography (CT) predicts incident atrial fibrillation (AF). This analysis included 5683 participants (mean age 64 ± 10 years; 52% women; 40% whites; 27% blacks; 21% Hispanics; 12% Chinese-Americans) from the Multi-Ethnic Study of Atherosclerosis. MAC was measured by cardiac CT at baseline and at a follow-up CT scan over a mean time of 2.4 ± 0.84 years. AF was ascertained by review of hospital discharge records and from Medicare claims data through 31 December 2012. Cox regression was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between MAC progression and AF. Over a median follow-up of 8.6 years, a total of 533 (9.4%) incident AF cases were detected. In a model adjusted for age, sex, race/ethnicity, education, income, baseline MAC, systolic blood pressure, body mass index, diabetes, smoking, total cholesterol, high-density lipoprotein cholesterol, antihypertensive medications, lipid-lowering therapies, and aspirin, any MAC progression (>0/year) was associated with an increased risk for AF (HR = 1.50, 95% CI = 1.20-1.87). Multiplicative interactions were not significant between MAC progression and AF by age (<65 year vs. older), sex, or race/ethnicity (whites vs. non-whites). Important prognostic information regarding AF risk is obtained with follow-up MAC measurement, as the risk for participants with any MAC progression was substantively greater than participants without progression. MAC progression may detect underlying left atrial abnormalities that predispose to AF.


FastSkin® Concept: A Novel Treatment for Complex Acute and Chronic Wound Management.
Successful treatments for acute and chronic skin wounds remain challenging. The goal of this proof-of-concept study was to assess the technical feasibility and safety of a novel wound treatment solution, FastSkin®, in a pig model. FastSkin® was prepared from skin micrografts patterned in blood using acoustic waves. Upon coagulation, the graft was transferred on a silicone sheet and placed on wounds. Six full-thickness wounds were created at the back of two pigs and treated with either FastSkin®, split-thickness skin graft (positive control), a gauze coverage (negative control, NC1), or blood patterned without micrografts (negative control, NC2). Silicone sheets were removed after 7, 14, and 21 days. Wound healing was monitored for six weeks and evaluated macroscopically for re-epithelialization and morphometrically for residual wound area and wound contraction. Tissue regeneration was assessed with histology after six weeks. Re-epithelialization was faster in wounds covered with FastSkin® treatments compared to NC2 and in NC2 compared to NC1. Importantly, an enhanced collagen organization was observed in FastSkin® in contrast to NC treatments. In summary, two clinically approved skin wound treatments, namely micrografting and blood clot graft, were successfully merged with sound-induced patterning of micrografts to produce an autologous, simple, and biologically active wound treatment concept.


From complication to litigation: The importance of non-technical skills in the management of complications.
Complications do occur in daily clinical life and can sometimes lead to litigation, which adversely affect the entire health care system, leading to a loss of confidence in medical providers, an increase in defensive medical practice and high professional indemnity insurance costs. Some complications are inevitable but can be minimised by completing a structured training programme. The likelihood of litigation can be reduced when adequate and clear information is given to the patient preoperatively. Non-technical skills are essential in complication management and crucial if confronted with litigation. Checklists and documentation of medication and surgical steps should be routine in all surgeries. Awareness of the complexity of the planned operation, theatre set-up and equipment are important in preventing complications. Mental preparation of surgeons is of the utmost importance in order to be able to confront any problem. When complications occur, remaining calm, calling for assistance, effective team leadership and harmony in the team are important in managing the situation. Good and effective communication with the patient and relatives, offering explanations, apologies and timely intervention without delays reduce the risk of litigation and strengthen any defence in court.


Flow chart to benchmark.
Benchmarking is the process used to search for best-in-class, compare results, discover the enablers of superior process performance, and take action to achieve quantum process improvement. It sounds simple, but all too often benchmarking efforts fail. The first obstacle often is failing to understand how work is currently being performed. Through linear flow charts, connection charts, and cross-functional flow charts, teams identify each step in a process, see how the people in the process interact, follow the work flow, and label the type of a step. When this is accompanied by supporting documentation, this method provides teams a way to visually see the work flow and know where there are glitches and where things are going well. Through flow charting, benchmarking teams can understand what they are doing so they know what to look for in a benchmarking partner and how to identify the enablers of a superior performance. Without flow charting, teams will not get the maximum benefit from benchmarking.


The relationship between recent alcohol use and sexual behaviors: gender differences among sexually transmitted disease clinic patients.
Binge drinking is associated with risky sexual behaviors and sexually transmitted diseases (STDs). Few studies have investigated this by gender or in an STD clinic. This cross-sectional study examined the association between binge drinking and risky sexual behaviors/STDs among patients attending an urban STD clinic. A total of 671 STD clinic patients were tested for STDs, and queried about recent alcohol/drug use and risky sexual behaviors using audio computer-assisted-self-interview. The association between binge drinking and sexual behaviors/STDs was analyzed using logistic regression adjusting for age, employment, and drug use. Binge drinking was reported by 30% of women and 42% of men. Gender differences were found in rates of receptive anal sex which increased linearly with increased alcohol use among women but did not differ among men. Within gender analyses showed that women binge drinkers engaged in anal sex at more than twice the rate of women who drank alcohol without binges (33.3% vs. 15.9%; p < 0.05) and 3 times the rate of women who abstained from alcohol (11.1%; p < 0.05). Having multiple sex partners was more than twice as common among women binge drinkers than women abstainers (40.5% vs. 16.8%; p < 0.05). Gonorrhea was nearly 5 times higher among women binge drinkers compared to women abstainers (10.6% vs. 2.2%; p < 0.05). The association between binge drinking and sexual behaviors/gonorrhea remained after controlling for drug use. Among men, rates of risky sexual behaviors/STDs were high, but did not differ by alcohol use. Rates of binge drinking among STD clinic patients were high. Among women, binge drinking was uniquely associated with risky sexual behaviors and an STD diagnosis. Our findings support the need to routinely screen for binge drinking as part of clinical care in STD clinics. Women binge drinkers, in particular, may benefit from interventions that jointly address binge drinking and risky sexual behaviors. Developing gender-specific interventions could improve overall health outcomes in this population.


Genome linkage screen for prostate cancer susceptibility loci: results from the Mayo Clinic Familial Prostate Cancer Study.
Prostate cancer is one of the most common cancers among men and has long been recognized to occur in familial clusters. Brothers and sons of affected men have a twofold to threefold increased risk of developing prostate cancer. However, identification of genetic susceptibility loci for prostate cancer has been extremely difficult. Several putative loci identified by genetic linkage have been reported to exist on chromosomes 1 (HPC1, PCAP, and CAPB), X (HPCX), 17 (HPC2), and 20 (HPC20), with genes RNASEL (HPC1) and ELAC2 (HPC2) tentatively defined. In this study, we report our genome linkage scan in 160 prostate cancer families, using the ABI Prism Linkage Mapping Set Version 2 with 402 microsatellite markers. The most significant linkage was found for chromosome 20, with a recessive model heterogeneity LOD score (HLOD) of 4.77, and a model-free LOD score (LOD - ZLR) of 3.46 for the entire group of pedigrees. Linkage for chromosome 20 was most prominent among families with a late age of diagnosis (average age at diagnosis >/= 66 years; maximum LOD - ZLR = 2.82), with <5 affected family members (LOD - ZLR = 3.02), with presence of hereditary prostate cancer (LOD - ZLR = 2.81), or with no male-to-male transmission of disease (LOD - ZLR = 3.84). No other chromosome showed significant evidence for linkage. However, chromosomes 6 and X showed suggestive results, with maximum LOD - ZLR values of 1.38 and 1.36, respectively. Subset analyses suggest additional chromosomal regions worth further follow-up.


[Effect of the composition of liver perfusion media on functional properties of isolated hepatocytes and effectiveness of the isolation method].
Yield, viability and respiratory activity of hepatocytes isolated from rat after liver perfusion by media with various composition have been studied. Collagenase, EDTA or citrate were used as disaggregative agents, as well as sucrose or NaCl as a main osmotic component. The yield of intact cells after perfusion by different media decreased in the following order, collagenase -NaCl-->EDTA-sucrose-->citrate-sucrose-->EDTA-NaCl. The rate of endogenous respiration in hepatocytes isolated by non-enzymatic methods with EDTA did not depend on the nature of main osmotic component and was by 40% lower than in the cells isolated by the enzymatic method, however uncoupler-stimulated respiration changed significantly less. Replacement of EDTA by citrate increased the rate of endogenous respiration and particularly the uncoupler-stimulated respiration. The results show that the nature of disaggregative agent and main osmotic component has the influence on efficiency of cell isolation method as well as metabolic state of isolated hepatocytes. Sucrose leads to the cell shrinkage and have additional to Ca(2+)-chelator desaggregative effect, citrate plays two functions both as Ca(2+)-chelator and as mitochondrial substrate.


The physics of organic superconductors.
The upper temperature for superconductivity in organic conductors has increased from 1 kelvin in 1980, when the phenomenon was discovered in the quasi-one-dimensional cation radical salt tetramethyltetraselenafulvalene phosphorus heptafluoride to 12 kelvin in a new series of organic salts that show nearly two-dimensional electronic properties. These superconductors are attracting interest because of the wide range of new phenomena that they exhibit, including the competition between various ground states, the influence of a magnetic field on a quasi-one-dimensional conductor, the quantization of the Hall effect in a three-dimensional material, the giant magnetoresistance effects related to the two-dimensional nature of the Fermi surface of some materials, and the coherent voltage oscillation of a spin-modulated ground state. Furthermore, there is reason to believe that organic conductors with high superconducting transition temperatures could be produced in the near future. The recent finding of superconductivity in "fullerene" doped with alkali metals supports this optimism.


Reduced 10-year risk of developing cardiovascular disease after participating in a lifestyle programme in primary care.
Background: Despite well-known preventive effects for future cardiovascular disease (CVD) risk through lifestyle changes, scientific evaluations of lifestyle programmes in primary care are scarce. Moreover, structured lifestyle counselling is still not integrated in everyday clinical practice. We aimed to evaluate change in cardiovascular risk factors and Framingham 10-year risk score of developing CVD in men and women at high cardiovascular risk after participation in a structured lifestyle programme over 1 year. A single-group study was carried out with a 1-year follow-up including before and after measurements.Methods: The lifestyle programme comprised five appointments to a district nurse over 1 year, focussing on lifestyle habits based on motivational interviewing. Fasting blood samples and anthropometric measurements were obtained at baseline and 1-year follow-up. The 10-year risk of CVD was calculated according to Framingham general CVD risk score.Results: A total of 404 patients were included in the study. There was a positive change over 1 year in the total study population for all risk factors evaluated. This included improvements in weight, waist circumference, blood pressure, blood lipids, and fasting glucose. The 10-year risk of developing CVD decreased for the total population from 24.8% to 21.4% at 1 year, equivalent to a 14% decrease.Conclusions: A structured lifestyle programme in primary care contributes to significant improvements of cardiovascular risk factors and the reduction of 10-year risk for CVD for both men and women at high cardiovascular risk.


Evolution of Cooperation in the Presence of Higher-Order Interactions: From Networks to Hypergraphs.
Many real systems are strongly characterized by collective cooperative phenomena whose existence and properties still need a satisfactory explanation. Coherently with their collective nature, they call for new and more accurate descriptions going beyond pairwise models, such as graphs, in which all the interactions are considered as involving only two individuals at a time. Hypergraphs respond to this need, providing a mathematical representation of a system allowing from pairs to larger groups. In this work, through the use of different hypergraphs, we study how group interactions influence the evolution of cooperation in a structured population, by analyzing the evolutionary dynamics of the public goods game. Here we show that, likewise to network reciprocity, group interactions also promote cooperation. More importantly, by means of an invasion analysis in which the conditions for a strategy to survive are studied, we show how, in heterogeneously-structured populations, reciprocity among players is expected to grow with the increasing of the order of the interactions. This is due to the heterogeneity of connections and, particularly, to the presence of individuals standing out as hubs in the population. Our analysis represents a first step towards the study of evolutionary dynamics through higher-order interactions, and gives insights into why cooperation in heterogeneous higher-order structures is enhanced. Lastly, it also gives clues about the co-existence of cooperative and non-cooperative behaviors related to the structural properties of the interaction patterns.


Temperature effect on the bandgaps of surface and bulk acoustic waves in two-dimensional phononic crystals.
In this paper, we analyzed the temperature effect on two-dimensional phononic crystals. Bandgap variations of both of the bulk modes and surface modes due to changing of temperature in an air/quartz band structure from 0 to 50 degrees C were calculated and discussed. The results show that the elastic bandgaps can be enlarged or reduced by adjusting the temperature of the band structure. The temperature effects potentially can be used for fine-tuning of the phononic bandgap frequency.


Agonist-induced isomerization of the alpha 1-adrenergic receptor: kinetic analysis using broken-cell and solubilized preparations.
The affinity of agonists but not antagonists at hepatic membrane alpha 1-adrenergic receptors is temperature dependent; a 100-fold higher affinity is observed at 4 degrees C than at 37 degrees C. The relationship between these two agonist affinity states was investigated by using a strategy that allows the kinetics of this transition to be examined under equilibrium conditions. When competition assays are performed at 37 degrees C for varying intervals and the reaction mixture is then rapidly cooled by freezing, allowed to thaw, and further equilibrated at 4 degrees C, a rapid and progressive decrease (t1/2 of 1-2 min) in agonist affinity occurs, the extent of which is directly related to the incubation time at 37 degrees C. This decrease in agonist affinity is sustained as long as agonist is present but can be reversed by its subsequent removal. In contrast, no change in affinity is seen in identical experiments when antagonists are employed as the competing ligand. High-affinity binding of agonists is also demonstrated in short-term nonequilibrium experiments, indicating that the low-temperature incubations do not induce, but rather stabilize, a receptor conformation of high affinity for agonists. These findings suggest that the predominantly low-affinity binding of agonists to alpha 1-adrenergic receptors demonstrated in equilibrium studies at physiological temperatures may be the result of a ligand-driven decrease in affinity. Since the transition in receptor affinity for agonists occurs not only in broken-cell preparations but also after detergent solubilization of the membrane receptor, it most likely is due to an agonist-induced change in the conformation of the receptor protein per se.(ABSTRACT TRUNCATED AT 250 WORDS)


Some effects of diazepam on pregnancy in the Balb/C mouse.
Female Balb/C mice aged 60 to 72 days were mated with males aged 60 to 150 days and conception was diagnosed when a vaginal plug was noted. Females were randomized into five groups, Group A animals were fed a mixture of diazepam-propylene glycol which contained 0.02 mg. of diazepam in 0.1 ml. solution per day from day 1 to 9 of the gestation. Group B animals were fed the same mixture on days 5 to 12 of the gestation. Groups C and D animals were fed 0.1 ml. of propylene glycol on gestational days 1 to 9 and 5 to 12, respectively. Group E animals served as pure controls and were fed no drug or vehicle. All animals were killed on pregnancy day 15; All pups were counted, weighed, and studied grossly for anomalies. All uteri were scored for absorption sites. Nonpregnant uteri were studied histologically and scored for day of estrogen cycle. Animals fed diazepam on days 5 to 12 of gestation (Group B) had a significantly fewer number of pregnancies than did the other groups (p smaller than 0.001). In addition, pups delivered of diazepam-fed mice were heavier than control animals. No significant differences were noted, however, with respect to litter size, number of resorption sites, or presence of gross anomalies. In view of these data it would seem prudent to continue to avoid the use of diazepam during pregnancy.


Long-term results of continuous subcutaneous recombinant PTH (1-34) infusion in children with refractory hypoparathyroidism.
Hypoparathyroidism in children is most often due to mutations in genes involved in parathyroid development and calcium homeostasis signaling. Some rare cases result from autoimmune attack on the parathyroid glands as a part of the type 1 polyglandular failure syndrome (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy). The majority of cases of pediatric hypoparathyroidism are well controlled under conventional treatment with calcium and vitamin D analogs. However, this treatment may be difficult to manage, especially in two situations: 1) in the context of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy and 2) activating mutations in the calcium-sensing receptor. We successfully treated three patients with hypoparathyroidism with continuous subcutaneous administration of rhPTH(1-34) (recombinant human PTH(1-34)), two of which were refractory to conventional therapy.


V-Shaped Tröger Oligothiophenes Boost Triplet Formation by CT Mediation and Symmetry Breaking.
A new family of molecules obtained by coupling Tröger's base unit with dicyanovinylene-terminated oligothiophenes of different lengths has been synthesized and characterized by steady-state stationary and transient time-resolved spectroscopies. Quantum chemical calculations allow us to interpret and recognize the properties of the stationary excited states as well as the time-dependent mechanisms of singlet-to-triplet coupling. The presence of the diazocine unit in Tröger's base derivatives is key to efficiently producing singlet-to-triplet intersystem crossing mediated by the role of the nitrogen atoms and of the almost orthogonal disposition of the two thiophene arms. Spin-orbit coupling-mediated interstate intersystem crossing (ISC) is activated by a symmetry-breaking process in the first singlet excited state with partial charge transfer character. This mechanism is a characteristic of these molecular triads since the independent dicyanovinylene-oligothiophene branches do not display appreciable ISC. These results show how Tröger's base coupling of organic chromophores can be used to improve the ISC efficiency and tune their photophysics.


Urinary Exosomal microRNA-451-5p Is a Potential Early Biomarker of Diabetic Nephropathy in Rats.
Non-invasive renal signatures can help in serial monitoring of diabetic patients. We tested whether urinary exosomal (UE) microRNA (miR) analysis could non-invasively predict renal pathology in diabetic rats during the course of diabetes. Diabetes mellitus (DM) was induced in male Wistar rats by a single intraperitoneal injection of streptozotocin (STZ, 50 mg/kg body weight). Non-diabetic control (CTRL) rats were injected with vehicle. Insulin (INS) treatment (5U/d, s.c.) was provided to 50% of the DM rats. Urine samples were collected at weeks 3, 6, and 9 following injections and UE prepared. An increase in miR-451-5p and miR-16, observed by pilot small RNA sequencing of UE RNA, was confirmed by quantitative real-time polymerase chain reaction (qPCR) and selected for further study. Subsets of rats were euthanized after 3, 6, and 9 weeks of diabetes for renal pathology analysis, including determination of the tubulointerstitial fibrotic index (TFI) and glomerulosclerotic index (GI) scores. qPCR showed a substantial rise in miR-451-5p in UE from DM rats during the course of diabetes, with a significant rise (median fold change >1000) between 3 and 6 weeks. Moreover, UE miR-451-5p at 6 weeks predicted urine albumin at 9 weeks (r = 0.76). A delayed but significant rise was also observed for miR-16. In contrast, mean urine albumin only increased 21% between 3 and 6 weeks (non-significant rise), and renal TFI and GI were unchanged till 9 weeks. Renal expression of miR-451-5p and miR-16 (at 10 weeks) did not correlate with urine levels, and moreover, was negatively associated with indices of renal pathology (r≥-0.70, p = 0.005 for TFI and r≥-0.6, p≤0.02 for GI). Overall, a relative elevation in renal miR-451-5p and miR-16 in diabetes appeared protective against diabetes-induced kidney fibrosis; while UE miR-451-5p may hold prognostic value as an early and sensitive non-invasive indicator of renal disease.


Effect of drought acclimation on antioxidant system and polyphenolic content of Foxtail Millet (Setaria italica L.).
The impact of climate change-induced drought stress on global food security and environmental sustainability is a serious concern. While previous research has highlighted the potential benefits of drought hardening in improving plants' ability to withstand drought, the exact underlying physiological mechanisms in millet plants (Setaria italica L.) have not been explored. This study aimed to investigate the impact of drought hardening on antioxidant defense and polyphenol accumulation in different millet genotypes ('PI 689680' and 'PI 662292') subjected to different treatments: control (unstressed), drought acclimation (two stress episodes with recovery), and non-acclimation (single stress episode with no recovery). The results showed that drought stress led to higher levels of polyphenols and oxidative damage, as indicated by increased phenolic, flavonoid, and anthocyanin levels. Non-acclimated (NA) plants experienced more severe oxidative damage and inhibition of enzymes associated with the ascorbate glutathione cycle compared to drought-acclimated plants. NA plants also exhibited a significant reduction in photosynthesis and tissue water content. The expression of genes related to antioxidants and polyphenol synthesis was more pronounced in non-acclimated plants. The study demonstrated that drought hardening not only prepared plants for subsequent drought stress but also mitigated damage caused by oxidative stress in plant physiology. Drought-acclimated (DA) plants displayed improved drought tolerance, as evidenced by better growth, photosynthesis, antioxidant defense, polyphenol accumulation, and gene expression related to antioxidants and polyphenol synthesis. In conclusion, the research advocates for the use of drought hardening as an effective strategy to alleviate the negative impacts of drought-induced metabolic disturbances in millet. The online version contains supplementary material available at 10.1007/s12298-023-01366-w.


Pharmacodynamic characterization of the efficacy signals due to selective BRAF inhibition with PLX4032 in malignant melanoma.
About 65% to 70% of melanomas harbor a mutation in v-raf murine sarcoma viral oncogene homolog B1 (BRAF) that causes the steady-state activation of extracellular signal-regulated kinase (ERK). We sought to investigate the efficacy of PLX4032 (BRAF inhibitor) to identify patterns/predictors of response/resistance and to study the effects of BRAF in melanoma. Well-characterized melanoma cell lines, including several with acquired drug resistance, were exposed to PLX4032. Growth inhibition, phosphosignaling, cell cycle, apoptosis, and gene expression analyses were performed before and after exposure to drug. Using a growth-adjusted inhibitory concentration of 50% cutoff of 1 microM, 13 of 35 cell lines were sensitive to PLX4032, 16 resistant, and 6 intermediate (37%, 46%, and 17% respectively). PLX4032 caused growth inhibition, G(0)/G(1) arrest, and restored apoptosis in the sensitive cell lines. A BRAF mutation predicted for but did not guarantee a response, whereas a neuroblastoma RAS viral oncogene homolog mutation or wild-type BRAF conferred resistance. Cells with concurrent BRAF mutations and melanocortin 1 receptor germ line variants and/or a more differentiated melanocyte genotype had a preferential response. Acquired PLX4032 resistance reestablishes ERK signaling, promotes a nonmelanocytic genotype, and is associated with an increase in the gene expression of certain metallothioneins and mediators of angiogenesis. PLX4032 has robust activity in BRAF mutated melanoma. The preclinical use of this molecule identifies criteria for its proper clinical application, describes patterns of and reasons for response/resistance, and affords insight into the role of a BRAF mutation in melanoma.


Changes in Basic Movement Ability and Activities of Daily Living After Hip Fractures: Correlation Between Basic Movement Scale and Motor-Functional Independence Measure Scores.
The aim of this study was to examine the correlation between basic movement ability and activities of daily living (ADL) in elderly patients after hip fracture surgery and predict ADL outcomes from changes in basic movement ability. Fifty-four patients receiving rehabilitation after hip fracture surgery were collected prospectively. Ambulatory ability was evaluated using a Basic Movement Scale (BMS), and ADL was evaluated using the motor subscale of the Functional Independence Measure (motor-FIM). From the results of evaluating BMS and motor-FIM weekly, the important postoperative period to regain ADL was investigated. There was a close correlation between BMS and motor-FIM scores at each evaluation point (r = 0.971, P < 0.001) and a significant correlation between weekly BMS and motor-FIM gains (r = 0.741, P < 0.001). Cluster analysis of BMS scores from postoperative week (POW) 2 to 12 showed three patterns of change, with BMS scores at POW 2 reflecting the outcome. The very strong correlation between BMS and motor-FIM scores suggests that BMS is a favorable indicator of changes in ADL. Because basic movement ability at POW 2 also reflected the prognosis, constructive interventions should be implemented early to help patients ambulate and regain other basic movements by no later than POW 2.


Electronic-Brain Medical Erudite: its past, present, and future.
Electronic-Brain Medical Erudite (EBME) is a large medical consultation system. Its core is the Enormous Knowledge Base of Disease Diagnosis Criteria (EKBDDC), which contains diagnostic criteria of 1,001 diagnostic entities and describes nearly 4,000 items of diagnostic indicators. EBME was implemented initially on a low-cost popular microcomputer, written in BASIC. This system can aid in the prompting of typical diseases and the teaching of diagnosis. We have performed a preliminary evaluation of EBME. Its performance on a series of trials with a total of 815 cases appeared qualitatively similar to that of the hospital clinicians. The diagnostic accordance rates were 89.7, 89.4, and 85% respectively. Recently, it is being transferred to a 386 microcomputer with a relational database, FoxBASE PLUS. This system will be improved, expanded, and connected with international medical information systems.


Prevalence of genotypic resistance to nucleoside analogues and protease inhibitors in antiretroviral-naive HIV patients in Campania, Italy.
The aim of our study was to determine the prevalence of genotypic resistance to nucleoside analogues and protease inhibitors before and after 1997, the year of introduction of Highly Active Antiretroviral Therapy (HAART) in Campania (Italy). Forty-eight plasma HIV-RNA positive patients who had not been previously treated for HIV infection (naïve) were enrolled in two Divisions of Infectious Diseases. The main demographic characteristics were collected for each subject and the primary mutant genotypes were sought only in HIV-RNA positive patients with viral loads higher than 10,000 copies/ml. The diagnosis of HIV infection dated back to before 1996 for 21 out of 48 patients and to after 2000 for the other 27. INNO-Line Probe Assay (LiPA) HIV-RT and INNO-LiPA HIV protease (Innogenetics, Italy) were used to detect mutations conferring resistance to zidovudine, didanosine, zalcitabine, lamivudine, stavudine, saquinavir, indinavir, rotonavir, nelfinavir and amprenavir. No mutations associated with primary resistance to nucleoside analogues and protease inhibitors were detected in the 21 patients who had acquired HIV infection before 1996, whereas one or more mutations were seen in three of the 27 (11.1%) patients with HIV infection diagnosed after 2000. This study confirms that LiPA is a suitable tool for epidemiological surveys of HIV genotypic primary resistance. Drug-resistant HIV-1 genotypes, resistant both to nucleoside analogues and protease inhibitors, were detected only in subjects who had acquired HIV infection after 2000, most of whom had zidovudine-resistant mutants. These data suggest that the introduction of HAART has brought about the circulation of drug-resistant HIV genotypes.


Early nonresponse determined by the clinical global impressions scale predicts poorer outcomes in youth with schizophrenia spectrum disorders naturalistically treated with second-generation antipsychotics.
The use of early response/nonresponse (ER/ENR) to antipsychotics as a predictor for ultimate response/nonresponse (UR/UNR) may help decrease inefficacious treatment continuation. However, data have been limited to adults, and ER/ENR has only been determined using time-consuming psychopathology rating scales. In the current study, we assessed if early improvement on the Clinical Global Impressions-Improvement (CGI-I) scale predicted UR/UNR in psychiatrically ill youth started on antipsychotic treatment. Seventy-nine youth aged 6-19 years, with schizophrenia spectrum disorders, treated naturalistically with aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone and evaluated monthly, were divided into ER/ENR groups at week 4, using at least "minimally improved" on the CGI-I scale. Prediction using week 4 ER/ENR status for UR (CGI-I=at least "much improved"), effectiveness and adverse effect outcomes at 8-12 weeks were assessed. At 4 weeks, 45.6% of subjects were ER and 54.4% were ENR without differences regarding baseline demographic, illness, and treatment variables, except for higher age (p=0.034) and maximum risperidone dose (p=0.0043) in ENR. ER/ENR status at 4 weeks predicted UR/UNR at week 12 significantly (p<0.0001): Sensitivity=68.9%, specificity=85.3%, positive predictive value=86.1%, negative predictive value=67.4%. At weeks 4, 8, and 12, ER patients improved significantly more on the CGI-I, CGI-Severity, and Children's Global Assessment of Functioning scales, and more ER patients reached UR compared with ENR patients (83.3% vs. 34.9%, all p<0.0001). ENR patients had more extrapyramidal side effects (EPS) at weeks 4, 8, and 12 (p=0.0019-0.0079). UR was independently associated with ER (odds ratio [OR]=18.09; 95% confidence interval [CI]=4.71-91.68, p<0.0001) and psychosis not otherwise specified (NOS) (OR=4.82 [CI: 1.31-21.41], p=0.017) (r(2)=0.273, p<0.0001). Older age and EPS were associated with ENR; ENR and schizophrenia were associated with UNR in naturalistically treated youth with schizophrenia spectrum disorders. Early CGI-I-based treatment decisions require further consideration and study.


Genetically predicted serum testosterone and risk of gynecological disorders: a Mendelian randomization study.
Testosterone plays a key role in women, but the associations of serum testosterone level with gynecological disorders risk are inconclusive in observational studies. We leveraged public genome-wide association studies to analyze the effects of four testosterone related exposure factors on nine gynecological diseases. Causal estimates were calculated by inverse variance-weighted (IVW), MR-Egger and weighted median methods. The heterogeneity test was performed on the obtained data through Cochrane's Q value, and the horizontal pleiotropy test was performed on the data through MR-Egger intercept and MR-PRESSO methods. "mRnd" online analysis tool was used to evaluate the statistical power of MR estimates. The results showed that total testosterone and bioavailable testosterone were protective factors for ovarian cancer (odds ratio (OR) = 0.885, P = 0.012; OR = 0.871, P = 0.005) and endometriosis (OR = 0.805, P = 0.020; OR = 0.842, P = 0.028) but were risk factors for endometrial cancer (OR = 1.549, P < 0.001; OR = 1.499, P < 0.001) and polycystic ovary syndrome (PCOS) (OR = 1.606, P = 0.019; OR = 1.637, P = 0.017). dehydroepiandrosterone sulfate (DHEAS) is a protective factor against endometriosis (OR = 0.840, P = 0.016) and premature ovarian failure (POF) (OR = 0.461, P = 0.046) and a risk factor for endometrial cancer (OR= 1.788, P < 0.001) and PCOS (OR= 1.970, P = 0.014). sex hormone-binding globulin (SHBG) is a protective factor against endometrial cancer (OR = 0.823, P < 0.001) and PCOS (OR = 0.715, P = 0.031). Our analysis suggested causal associations between serum testosterone level and ovarian cancer, endometrial cancer, endometriosis, PCOS, POF.


Modified silica nanoparticle coatings: Dual antifouling effects of self-assembled quaternary ammonium and zwitterionic silanes.
This work examines the antifouling effect of quaternary ammonium silane (QAS) grafted from coatings of silica nanoparticles (SiNPs), independently and in combination with a zwitterionic sulfobetaine (SB) silane. The binding of QAS to the SiNP coatings was monitored using quartz crystal microgravimetry with dissipation monitoring (QCM-D) under varied pH and solution concentrations. Adsorption of bovine serum albumin protein was reduced on QAS modified SiNP coatings prepared under alkaline conditions due to the proposed generation of a pseudozwitterionic interface, where the underlying SiNP surface presents an anionic charge at high pH. Significant reductions in protein binding were achieved at low functionalization concentrations and short modification times. Additionally, SiNP coatings modified with a combination of QAS and SB chemistries were investigated. Surface modifications were performed sequentially, varying silane concentration and order of addition, and monitored using QCM-D. Dual-functionalized surfaces presented enhanced resistance to protein adsorption compared to QAS or SB modified surfaces alone, even at low functionalization concentrations. The antiadhesive and antibacterial properties of functionalized surfaces were investigated by challenging the surfaces against the bacterium Escherichia coli. All dual-functionalized coatings showed equal or reduced bacterial adhesion compared to QAS and SB functionalizations alone, while coatings functionalized with high concentrations of combined chemistries reduced the adhesion of bacteria by up to 95% compared to control SiNP surfaces.


Pain management in adult dental patients: the art and science of successful regimens.
Pain is a protective mechanism for the body; it occurs whenever any tissues are being damaged, and it causes the individual to react to remove the pain stimulus. Most ailments of the body cause pain, and the ability to diagnose different diseases depends to a considerable extent on the physician's knowledge of the various qualities of pain. In dentistry, pain may be expected, i.e., caused by dental procedures, and its management should commence preoperatively. This article is a review of pharmacologic pain management in adult dental patients. It discusses the pharmacology and therapeutic utilization of opioid and nonopioid analgesics and the selection of single and combined analgesic regimens.


A visual method of determining marginal placement of crowns: Part II. Marginal placement of posterior crowns.
In the second part of a two-part study on the necessity for subgingival crown placement, photographs of 527 Saudi citizens (285 men and 242 women) with natural and exaggerated smiles were made. The photographs revealed that a substantial percentage of the participants did not exhibit the gingival tissue of their posterior maxillary teeth (41.7% to 70.2%) and mandibular teeth (92.8% to 98.5%) during a natural smile. A comparison of the posterior tooth visibility of male and female subjects revealed statistically significant differences in the following situations: the gingival section of maxillary first molars, the occlusal section of the mandibular first molars, and the occlusal section of the second premolars during a natural smile, and the occlusal section of the mandibular first and second premolars during an exaggerated smile. Therefore, an analysis of each individual's smile should be included among the factors considered when placement of coronal margins is determined.


Photoassisted electrolysis of water by irradiation of a titanium dioxide electrode.
Ultraviolet irradiation (351, 364 nm) of the n-type semiconductor TiO(2) as the single crystal electrode of an aqueous electrochemical cell evolves O(2) at the TiO(2) electrode and H(2) at the Pt electrode. The gases are typically evolved in a two: one (H(2):O(2)) volume ratio. The photoassisted reaction seems to require applied voltages, but values as low as 0.25 V do allow the photoassisted electrolysis to proceed. Prolonged irradiation in either acid or base evolves the gaseous products in amounts which clearly demonstrate that the reaction is catalytic with respect to the TiO(2). The wavelength response of the TiO(2) and the correlation of product yield and current are reported. The results support the claim that TiO(2) is a true photoassistance agent for the electrolysis of water. Minimum optical storage efficiencies of the order of 1% can be achieved by the production of H(2).


Interest in lifestyle advice at lung cancer screening: Determinants and preferences.
Lung cancer screening could be a 'teachable moment' for behaviour change. Little is known about how advice about smoking cessation, or other behavioural cancer risk factors, would be received in this setting. Using a population-based survey of 459 English adults (current smokers and recent quitters aged 50-75) we assessed willingness to receive lifestyle advice (about smoking, diet, weight, physical activity, alcohol consumption) at lung screening. Additional items assessed whether advice should be provided following abnormal screening results, the potential impact of advice on screening uptake, and preferred timing of advice. Overall, 64% (n = 292) of participants were willing to receive lifestyle advice at lung screening. A greater proportion of participants were willing to receive advice in a scenario where results required further investigation (83%; p < 0.01). However, 14% indicated the provision of lifestyle advice would make them less willing to attend lung screening. Non-White ethnicity and greater cancer risk factor awareness were associated with willingness to receive advice (p < 0.05). Half of smokers (51%) were willing to receive cessation advice. There was also interest in advice about diet (47%), weight (43%), physical activity (32%), and alcohol consumption (17%) among people not meeting current recommendations for these behaviours. There was a preference for advice to be delivered at the screening appointment (38%, n = 108) over other time-points. Lung screening may offer an opportunity to provide advice about behavioural cancer risk factors. Future work should consider how to deliver effective interventions in this setting to support behaviour change, without affecting screening uptake.


Clostridium Difficile: Reducing Infections Using an Evidence-Based Practice Initiative.
Nosocomial Clostridium difficile (C. difficile) infections are adverse incidents that affect immunocompromised hospitalized patients. High-touch surface areas within the patient's environment are frequently overlooked and are a source of microscopic bacterial transmission. This article examines whether the use of a standardized protocol for cleaning high-touch surface areas would reduce the incidence of hospital-acquired C. difficile infection. The initiative targeted five high-touch surfaces, and nurses were educated about these findings. Baseline data on the C. difficile infection rate was collected from four specialty medical-surgical oncology units. A pilot period of the Five by Five initiative evaluated C. difficile infection rates after staff cleaning of these high-touch surfaces. This initiative accounted for a statistically significant reduction in C. difficile infections. The use of a standardized cleaning initiative was effective in reducing C. difficile infections. Nursing staff perceived that the education was easy to remember and supported efficient implementation.


Imagery May Arise from Associations Formed through Sensory Experience: A Network of Spiking Neurons Controlling a Robot Learns Visual Sequences in Order to Perform a Mental Rotation Task.
Mental imagery occurs "when a representation of the type created during the initial phases of perception is present but the stimulus is not actually being perceived." How does the capability to perform mental imagery arise? Extending the idea that imagery arises from learned associations, we propose that mental rotation, a specific form of imagery, could arise through the mechanism of sequence learning-that is, by learning to regenerate the sequence of mental images perceived while passively observing a rotating object. To demonstrate the feasibility of this proposal, we constructed a simulated nervous system and embedded it within a behaving humanoid robot. By observing a rotating object, the system learns the sequence of neural activity patterns generated by the visual system in response to the object. After learning, it can internally regenerate a similar sequence of neural activations upon briefly viewing the static object. This system learns to perform a mental rotation task in which the subject must determine whether two objects are identical despite differences in orientation. As with human subjects, the time taken to respond is proportional to the angular difference between the two stimuli. Moreover, as reported in humans, the system fills in intermediate angles during the task, and this putative mental rotation activates the same pathways that are activated when the system views physical rotation. This work supports the proposal that mental rotation arises through sequence learning and the idea that mental imagery aids perception through learned associations, and suggests testable predictions for biological experiments.


[Medical treatment of unruptured ectopic pregnancy].
Ectopic pregnancy is the implantation of fertilized ovum on any tissue other than the endometrial lining of the uterus. To evaluate the effectiveness and safeness of methotrexate in the treatment of unruptured ectopic pregnancy. From January 2000 to October 2002 five patients were diagnosed with unruptured ectopic pregnancy in Hospital Juarez de Mexico. The inclusion criteria were: hemodynamic stability, gestational sac of < 40 mm, serum beta-hCG concentration < 15,000 mIU/L and future fertility desire. Systemic methotrexate was administered as an intramuscular injection of 50 mg. Evaluation was based on transvaginal ultrasonography, beta-hCG levels and hysterosalpingography. Five patients with unruptured ectopic pregnancy were treated with methotrexate. Successful rate, after one or two injections, was 100% (5 patients). The size of ectopic pregnancy as estimated by ultrasonographic was 33.33 mm. Negligible plasma beta-hCG values were reached 45.6 +/- 19.85 days after the time of treatment. Ultrasonographic scanning demonstrated progressive disorganization and the gestational sac disappeared at 134 days after treatment. There were no adverse effects from the chemotherapy. In 3 of 4 women who underwent hysterosalpingography following treatment, patency of the affected tube was observed. Three women experienced an intrauterine pregnancy spontaneously in the methotrexate group. Systemic methotrexate treatment is safety and effective in the treatment of unruptured ectopic pregnancy, for woman with future desire of fertility and if it has unruptured, conservative treatment using methotrexate is an excellent choice.


Multiple endpoints to evaluate pristine and remediated titanium dioxide nanoparticles genotoxicity in lung epithelial A549 cells.
Titanium dioxide nanoparticles (TiO2 NP) are broadly used in a wide range of applications. Several studies have reported that TiO2 NP possess cytotoxic and genotoxic properties that could induce adverse health effects in humans. The FP7 Sanowork project was aimed to minimize occupational hazard and exposure to engineered nanomaterials (ENM), including TiO2 NP, through the surface modification in order to avoid possible adverse toxic effects for humans. In this study we investigated cytotoxicity, genotoxicity and epigenetic properties of TiO2 NP uncoated and coated with silica or citrate, as well as of the benchmark material P25. We used a panel of in vitro assays in the human lung epithelial cell line A549, in order to better understand if the remediation strategy adopted was able to counteract possible toxic effects of uncoated TiO2 NP. Our results showed that the uncoated TiO2 NP were both cytotoxic and genotoxic, and the remediation strategy adopted did not reduce the adverse effects of uncoated TiO2 NP. In particular, the presence of citrate was able to increase their cytotoxicity and genotoxicity, exerting also epigenotoxic effects, as evaluated by the marked reduction of LINE-1 methylation levels.


Leishmaniasis: current treatment and prospects for new drugs and vaccines.
Leishmaniasis is a disease that ranges in severity from skin lesions to serious disfigurement and fatal systemic infection. WHO estimates that the disease results in 2 million new cases a year, threatens 350 million people in 88 countries and that there are 12 million people currently infected worldwide. Current treatment is based on chemotherapy, which relies on a handful of drugs with serious limitations such as high cost, toxicity, difficult route of administration and lack of efficacy in endemic areas. Pentavalent antimonials have been the mainstay of antileishmanial therapy for over 70 years with second line drugs, Amphotericin B and Pentamidine, used in case of antimonial failure. Since the introduction of miltefosine at the beginning of this century, no new antileishmanial compounds have been approved for human treatment. Leishmaniasis is considered one of a few parasitic diseases likely to be controllable by vaccination. However, to date no such vaccine is available despite substantial efforts by many laboratories. The development of a safe, effective and affordable antileishmanial vaccine is a critical global public-health priority. This review outlines the current status of vaccine development and looks at the currently available chemotherapy as well as examples of drugs in development and different approaches to antileishmanial drug discovery and identification of novel antiparasitic compounds.


Molecular demographic history of the annual sunflowers Helianthus annuus and H. petiolaris--large effective population sizes and rates of long-term gene flow.
Hybridization between distinct species may lead to introgression of genes across species boundaries, and this pattern can potentially persist for extended periods as long as selection at some loci or genomic regions prevents thorough mixing of gene pools. However, very few reliable estimates of long-term levels of effective migration are available between hybridizing species throughout their history. Accurate estimates of divergence dates and levels of gene flow require data from multiple unlinked loci as well as an analytical framework that can distinguish between lineage sorting and gene flow and incorporate the effects of demographic changes within each species. Here we use sequence data from 18 anonymous nuclear loci in two broadly sympatric sunflower species, Helianthus annuus and H. petiolaris, analyzed within an "isolation with migration" framework to make genome-wide estimates of the ages of these two species, long-term rates of gene flow between them, and effective population sizes and historical patterns of population growth. Our results indicate that H. annuus and H. petiolaris are approximately one million years old and have exchanged genes at a surprisingly high rate (long-term N(ef)m estimates of approximately 0.5 in each direction), with somewhat higher rates of introgression from H. annuus into H. petiolaris than vice versa. In addition, each species has undergone dramatic population expansion since divergence, and both species have among the highest levels of genetic diversity reported for flowering plants. Our results provide the most comprehensive estimate to date of long-term patterns of gene flow and historical demography in a nonmodel plant system, and they indicate that species integrity can be maintained even in the face of extensive gene flow over a prolonged period.


Pharmacogenetics of common SNP affecting drug metabolizing enzymes: comparison of allele frequencies between European and Malaysian/Singaporean.
Compared to Europe, data on genetic variation in genes transcribing drug metabolizing enzymes among Asian is limited due to ethnic diversity. Here we compare frequencies for clinically relevant single nucleotide polymorphism (SNP) commonly observed in drug metabolizing enzymes between European and Malaysian/Singaporean. Minor allele frequencies (MAF) for the indicated SNPs for European, South Asian and East Asian populations were obtained from the NCBI website (https://www.ncbi.nlm.nih.gov/snp). The SNP prevalence among Malaysian/Singaporean was characterized from gene association studies. Generally, some SNPs in CYP2D6 and CYP2C19 do not show good agreement between the two populations as to the MAF value obtained. CYP2D6*4 tends to be more common among European, whereas CYP2D6*10 is more common in Malays and Chinese among Singaporean. Regardless of different phenotype, MAF of CYP2D6*4 for Indians is similar to that seen by the European. Singaporeans show smaller MAF for CYP2C19*17 but higher CYP2C19*2 frequencies as opposed to European ones. Following growing attention to the contribution of CYP3A4/5, N-acetyltransferases (NAT2), thiopurine methyltransferase (TPMT) and uridine diphosphate glucuronosyltransferases (UGT)2B7 in predicting drug response across Europe, there are limited pharmacogenetics (PGx) studies examining the gene-drug interaction among Malaysian/Singaporean. To better understand the heterogeneity of the drug response, PGx studies for the abovementioned enzymes between ethnics in Malaysian/Singaporean should be identified.


Assessing PD-L1 Expression in Head and Neck Squamous Cell Carcinoma: Trials and Tribulations.
Immune checkpoint inhibitors have improved the outcome of patients diagnosed with inoperable recurrent or metastatic head and neck squamous cell carcinoma. However, as only a subset of head and neck cancer patients benefit from this treatment, biomarkers predicting treatment response help guide physicians in their clinical decision-making. PD-L1 expression assessed by immunohistochemistry is the single most clinically relevant biomarker predicting response to PD-1-blocking antibodies. Here, we discuss in which clinical context assessment of PD-L1 expression is instrumental for the choice of therapy, how pathologists score it, and how it affects the approval of anti-PD-1 antibodies. Furthermore, we discuss the heterogeneity of PD-L1 expression and review technical aspects of determining this prominent biomarker-knowledge that might influence clinical decision-making.


Synthesis of piperlongumine analogues and discovery of nuclear factor erythroid 2-related factor 2 (Nrf2) activators as potential neuroprotective agents.
The cellular antioxidant system plays key roles in blocking or retarding the pathogenesis of adult neurodegenerative disorders as elevated oxidative stress has been implicated in the pathophysiology of such diseases. Molecules with the ability in enhancing the antioxidant defense thus are promising candidates as neuroprotective agents. We reported herein the synthesis of piperlongumine analogues and evaluation of their cytoprotection against hydrogen peroxide- and 6-hydroxydopamine-induced neuronal cell oxidative damage in the neuron-like PC12 cells. The structure-activity relationship was delineated after the cytotoxicity and protection screening. Two compounds (4 and 5) displayed low cytotoxicity and confer potent protection of PC12 cells from the oxidative injury via upregulation of a panel of cellular antioxidant molecules. Genetically silencing the transcription factor Nrf2, a master regulator of the cellular stress responses, suppresses the cytoprotection, indicating the critical involvement of Nrf2 for the cellular action of compounds 4 and 5 in PC12 cells.