Classification of depressive disorders in the DSM-V: proposal for a two-dimension system.
The number of categories and specifiers for mood disorders has increased with each successive edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM). Many of these categories and specifiers can be viewed as an effort to map the various permutations of severity and chronicity that characterize the depressive disorders. However, this has resulted in a system that (a) is unnecessarily complex and unwieldy, (b) has created problems with artificial distinctions between categories and artifactual comorbidity, and (c) at the same time obscures what may be more fundamental distinctions. A potentially useful and more parsimonious approach to capturing much of the heterogeneity of depressive disorders is to classify the depressive disorders along 2 dimensions, 1 reflecting severity and the other, chronicity. Considerations in the development of these dimensions are discussed, and a set of examples is presented. Although further research and discussion are needed to determine the optimal form of these dimensions, the next edition of the DSM should consider replacing many of the existing categories and specifiers for depressive disorders with the simpler approach of classifying depressive disorders using the 2 dimensions of severity and chronicity.


Regulation of NMDA-stimulated [14C]GABA and [3H]acetylcholine release by striatal glutamate and dopamine receptors.
Striatal function is heavily influenced by glutamatergic and dopaminergic afferent input. To ultimately better understand how the N-methyl-D-aspartate (NMDA) antagonist, phencyclidine (PCP), alters striatal function, we sought to determine how NMDA receptor function is influenced by activation of other glutamatergic receptors and by dopaminergic receptors. To this end, we used NMDA-stimulated efflux of [14C]GABA and [3H]acetylcholine (ACh) from striatal slices to assess the influence of these receptors on NMDA function. NMDA-stimulated [14C]GABA release was more sensitive to NMDA and glycine antagonists than was [3H]ACh release, suggesting that different NMDA receptors regulate the release of these neurotransmitters. Furthermore, NMDA-stimulated [3H]ACh release was inhibited by a D2 receptor mechanism whereas NMDA-stimulated [14C]GABA release was enhanced by D1 receptor activation. NMDA and (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrobromide (AMPA) interact additively to evoke [3H]ACh release, and synergistically to evoke [14C]GABA release. An additive effect of NMDA and kainate (KA) was found on [14C]GABA release, but NMDA and KA acted in a less than additive manner in evoking [3H]ACh release. KA-stimulated [3H]ACh release was largely blocked by NMDA antagonists, suggesting mediation through activation of NMDA receptors, probably secondary to KA-induced glutamate release. A selective group II metabotropic receptor agonist inhibited NMDA-stimulated [14C]GABA and [3H]ACh release. On the other hand, NMDA-stimulated [14C]GABA release was potentiated by activation of group I metabotropic receptors. Thus, in addition to the differential modulation by D1- and D2-like receptors, the release of striatal neurotransmitters by NMDA receptor activation depends on the extent to which the other glutamate receptors, both ionotropic and metabotropic, are activated.


Acute Pain Management in Hospitalized Adult Patients with Opioid Dependence: A Narrative Review and Guide for Clinicians.
Pain management is a core competency of hospital medicine, and effective acute pain management should be a goal for all hospital medicine providers. The prevalence of opioid use in the United States, both therapeutic and non-medical in origin, has dramatically increased over the past decade. Although nonopioid medications and nondrug treatments are essential components of managing all acute pain, opioids continue to be the mainstay of treatment for severe acute pain in both opioid-naïve and opioid-dependent patients. In this review, we provide an evidence-based approach to appropriate and safe use of opioid analgesics in treating acute pain in hospitalized patients who are opioid-dependent. Journal of Hospital Medicine 2017;12:375-379.


Chemoreceptor Diversity in Apoid Wasps and Its Reduction during the Evolution of the Pollen-Collecting Lifestyle of Bees (Hymenoptera: Apoidea).
Chemoreceptors help insects to interact with their environment, to detect and assess food sources and oviposition sites, and to aid in intra- and interspecific communication. In Hymenoptera, species of eusocial lineages possess large chemoreceptor gene repertoires compared with solitary species, possibly because of their additional need to recognize nest-mates and caste. However, a critical piece of information missing so far has been the size of chemoreceptor gene repertoires of solitary apoid wasps. Apoid wasps are a paraphyletic group of almost exclusively solitary Hymenoptera phylogenetically positioned between ant and bee, both of which include eusocial species. We report the chemosensory-related gene repertoire sizes of three apoid wasps: Ampulex compressa, Cerceris arenaria, and Psenulus fuscipennis. We annotated genes encoding odorant (ORs), gustatory, and ionotropic receptors and chemosensory soluble proteins and odorant-binding proteins in transcriptomes of chemosensory tissues of the above three species and in early draft genomes of two species, A. compressa and C. arenaria. Our analyses revealed that apoid wasps possess larger OR repertoires than any bee lineage, that the last common ancestor of Apoidea possessed a considerably larger OR repertoire (∼160) than previously estimated (73), and that the expansion of OR genes in eusocial bees was less extensive than previously assumed. Intriguingly, the evolution of pollen-collecting behavior in the stem lineage of bees was associated with a notable loss of OR gene diversity. Thus, our results support the view that herbivorous Hymenoptera tend to possess smaller OR repertoires than carnivorous, parasitoid, or kleptoparasitic species.


Complex calculations: ethical issues in involving at-risk healthy individuals in dementia research.
In dementia research evidence is mounting that therapeutic strategies that target moderate and even mild Alzheimer's disease may be missing the 'therapeutic window'. Given that the neuropathology that leads to Alzheimer's disease probably begins somewhere between 10 and 15 years before symptoms manifest, many believe that the optimal therapeutic strategy would target persons in the earliest phases of disease development or even earlier. This would include, for example, persons with prodromal Alzheimer's and even persons who are deemed at risk. Given the nature of research involving the central nervous system, it is conceivable that some therapeutic investigations may involve an increase over minimal risk. This paper examines how, in dementia research, at-risk persons, although healthy, bring multiple and intersecting vulnerabilities to the prospect of research participation even though they are clinically healthy. Current guidelines for research ethics may not provide adequately for the nuances of 'healthy individuals' and their possible vulnerabilities. In the context of neurodegenerative disease, the fact of being 'at risk' alters the vulnerability profile in significant ways. While healthy persons who are at risk of developing dementia may not appear to warrant placement in the research category of vulnerable participants (alongside prisoners, pregnant women and children) careful regard for the vulnerabilities that arise as a result of the intersecting circumstances of being healthy and at risk of an incurable disease are worthy of increased attention and consideration, particularly as the research effort for the increasingly prevalent disease of Alzheimer's moves forward.


Longitudinal Neuropsychological Outcome in Taiwanese Alzheimer's Disease Patients Treated with Medication.
The longitudinal change of neuropsychological tests (NPTs) in treated Alzheimer's disease (AD) is essential to understand the interplay of a therapeutic response from medication and a disease decline due to degenerative processes. The aim of our study is to investigate the annual cognitive progression as measured by commonly used NPTs in treated AD patients and to assess the potential predictors of disease progression. Participants (N=455) diagnosed with AD and treated with cholinesterase inhibitors (ChEIs) or memantine at memory clinics in three hospitals in southern Taiwan from January 2009 to December 2014 were enrolled in this prospectively registered study. The mean follow-up duration was 3.2 ± 0.9 years. The patients' severity of AD ranged from very mild (clinical dementia rating (CDR) scales = 0.5) to moderate (CDR = 2.0). At baseline and for each year, participants were assessed by various NPTs commonly used in clinical practice, including the Mini-Mental State Examination (MMSE), Cognitive Abilities Screening Instrument (CASI), CDR and CDR-sum of boxes (CDR-SB). All enrolled participants were assessed for at least two years during follow-up. We used mixed-effect models to examine annual progression in the whole group and to compare the cognitive progression between the subgroups with very mild AD and mild to moderate AD. Potential predictors of disease progression, including age, gender, the type of ChEI, and Apolipoprotein E (APOE) genotype, were also analyzed. Among the study population, the rate of change in MMSE scores were -1.15 points per year, CASI scores were -4.27 points per year, and CDR-SB scores were 0.81 points per year. The slope of annual changes of NPTs differed significantly between the CDR 0.5 group and the CDR 1 to 2 group. The most significant predictors of the faster progression were increasing age and higher CDR stage at entry; however, different types of ChEI therapy (donepezil vs. rivastigmine users), and APOE genotype were not associated with the rate of disease progression. This longitudinal data shows the mean annual change of the MMSE, CASI, CDR, and CDR-SB in treated AD patients. The data may provide clinicians with information regarding to the cognitive decline rate in every year while their AD patients receive approved pharmacological therapy in real-world practice. Increasing age and severity of dementia when receiving therapy are the main factors that associated with faster deterioration.


The effect of age and sodium depletion on cardiovascular response to orthostasis.
To test the hypothesis that normal age-related limitations in cardiovascular homeostasis may become clinically significant under stress, the cardiovascular response to postural change was assessed in six young and six old healthy subjects before and after modest diuretic-induced sodium depletion. Before diuresis, systolic blood pressure was maintained (from 110 +/- 4 to 113 +/- 6 mm Hg) while heart rate increased 22% (from 67 +/- 2 to 82 +/- 5 beats/min) at 3 minutes after 60-degree upright tilt in young subjects. After a significant diuretic-induced weight reduction and natriuresis, the young again maintained systolic blood pressure (from 110 +/- 4 to 110 +/- 6 mm Hg) and increased heart rate 49% (from 68 +/- 2 to 101 +/- 5 beats/min; p less than 0.05, compared with prediuresis values) in response to the same postural stimulus. During the prediuresis tilt, the older subjects showed no change in systolic blood pressure (from 132 +/- 4 to 134 +/- 6 mm Hg) and a 9% increase in heart rate (from 68 +/- 3 to 74 +/- 2 beats/min). After a similar significant weight reduction and sodium loss, the older subjects showed a significant reduction in systolic blood pressure (from 132 +/- 6 to 108 +/- 6 mm Hg; p less than 0.05) and a 17% increase in heart rate (from 69 +/- 4 to 81 +/- 3 beats/min; p less than 0.05) during tilt compared with values in young subjects. Three of six elderly subjects noted postural symptoms. These results suggest that, although the healthy old may appear well compensated under optimal conditions, decreased cardiovascular reserve renders them susceptible to postural change following mild sodium depletion.


From song dialects to speciation in white-crowned sparrows.
The behavioural signals used in mate selection are a key component in the evolution of premating isolating barriers and, subsequently, the formation of new species. The importance of mating signals has a long tradition of study in songbirds, where many species differ in their song characteristics. In oscine songbirds, individual birds usually learn their songs from a tutor. Mistakes during learning can help generate geographic dialects, akin to those within human language groups. In songbirds, dialect differences can often be substantial and there is an intuitive connection between the evolution of song amongst populations at a small scale, and the more substantive song differences between bird species and presumably used in species recognition. However, studies investigating the concordance between putative genetic and behavioural boundaries have generated mixed results. In many cases, this is possibly a function of the poor resolving power of the genetic markers employed. In this issue of Molecular Ecology, Lipshutz et al. () combine genomic markers with a robust behavioural assay to address the importance of song variation amongst white-crowned sparrow (Zonotrichia leucophrys) subspecies.


Evaluation of toxicity of commercial ophthalmic fluoroquinolone antibiotics as assessed on immortalized corneal and conjunctival epithelial cells.
To evaluate the toxicity of a variety of the fluoroquinolone antibiotics on the ocular surface by using tissue culture models of corneal epithelial cells and conjunctival epithelial cells. Immortalized conjunctival (CCC) and human corneal (HCE) epithelial cells were grown and when confluent the cells allowed to air dry for 1 hour. Medium was then replaced with 100 microL of one of the following: 1) Vigamox [moxifloxacin (0.5%: MX)]; (2) Zymar [gatifloxacin (0.3%: GA)]; 3) Quixin [levofloxacin (0.5%: LE)]; 4) Ocuflox [ofloxacin (0.3%: OF)]; 5) Ciloxan [ciprofloxacin (0.3%: CP)]; 6) medium (viable control); 7) "normal"/physiologic saline; 8) formalin (dead control). After one hour, 150 microL of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazonium bromide was added and incubated for 4 hours. After decanting, precipitate was dissolved in 150 microL of isopropanol. Absorbance was determined at 572 nm. The lowest amount of cell death was associated with the viable control. All ophthalmic preparations showed both corneal and conjunctival cell toxicity. Aside from the viable control, normal saline showed the next lowest amount of toxicity. Of the topical ocular antibiotics tested, MX showed the least amount of toxicity. All of the other antibiotics tested were statistically indistinguishable from each other. All of the topical ocular antibiotics tested showed evidence of both corneal and conjunctival toxicity (MX < OF < or = LE < or = CP < or = GA), although only MX was statistically significant. Whether this finding reflects on in vivo wound healing remains to be determined. This model provides a rapid and cost-effective method to screen for surface toxicity of topical agents.


Blending conjugated polymers without phase separation for fluorescent colour tuning of polymeric materials through FRET.
The fluorescence properties of conjugated polymer blends were investigated using a combination of excitation energy donor and acceptor conjugated polymers encapsulated by identical cyclic sidechains. Wearing this 'uniform', the polymers did not phase-separate in the blends. As such, these polymers provide an effective ensemble for designing fluorescent polymeric materials.


Validation of genomics-based prognostic tests in malignant pleural mesothelioma.
Malignant pleural mesothelioma (MPM) is a highly lethal neoplasm with limited pretreatment prognostication strategies. In this report, we examine the accuracy of a previously proposed prognostic test in an independent cohort of MPM patients. This test uses simple ratios of gene expression levels to provide a novel prognostication scheme. Gene expression data using high-density oligonucleotide microarrays (approximately 22,000 genes) were obtained for a new cohort of human MPM tumors from patients undergoing similar treatments (n = 39). The relative expression levels for specific genes were also determined using real-time quantitative reverse transcription-PCR. We also used a subset of these tumors associated with widely divergent patient survival (n = 23) as a training set to identify new treatment-specific candidate prognostic molecular markers and gene ratio-based prognostic tests. The predictive nature of these newly discovered markers and gene ratio-based prognostic tests were then examined in an independent group of tumors (n = 52) using microarray data and quantitative reverse transcription-PCR. Previously described MPM prognostic genes and gene ratio-based prognostic tests predicted clinical outcome in 39 independent MPM tumor specimens in a statistically significant manner. Newly discovered treatment-specific prognostic genes and gene ratio-based prognostic tests were highly accurate and statistically significant when examined in an independent group of 52 tumors from patients undergoing similar treatment. The data support the use of gene ratios in translating gene expression data into easily reproducible, statistically validated clinical tests for the prediction of outcome in MPM.


Hemoglobin A1c-Using Epidemiology to Guide Medical Practice: Kelly West Award Lecture 2020.
The discovery that HbA1c was a valid and reliable measure of average glucose exposure was one of the most important advances in diabetes care. HbA1c was rapidly adopted for monitoring glucose control and is now recommended for the diagnosis of diabetes. HbA1c has several advantages over glucose. Glucose assessment requires fasting, has poor preanalytic stability, and is not standardized; concentrations are acutely altered by a number of factors; and measurement can vary depending on sample type (e.g., plasma or whole blood) and source (e.g., capillary, venous, interstitial). HbA1c does not require fasting, reflects chronic exposure to glucose over the past 2-3 months, and has low within-person variability, and assays are well standardized. One reason HbA1c is widely accepted as a prognostic and diagnostic biomarker is that epidemiologic studies have demonstrated robust links between HbA1c and complications, with stronger associations than those observed for usual measures of glucose. Clinical trials have also demonstrated that lowering HbA1c slows or prevents the development of microvascular disease. As with all laboratory tests, there are some clinical situations in which HbA1c is unreliable (e.g., certain hemoglobin variants, alterations in red blood cell turnover). Recent studies demonstrate that fructosamine and glycated albumin may be substituted as measures of hyperglycemia in these settings. Other approaches to monitoring glucose have recently been introduced, including continuous glucose monitoring, although this technology relies on interstitial glucose and epidemiologic evidence supporting its routine use has not yet been established for most clinical settings. In summary, a large body of epidemiologic evidence has convincingly established HbA1c as a cornerstone of modern diabetes care.


CDH23 mutation and phenotype heterogeneity: a profile of 107 diverse families with Usher syndrome and nonsyndromic deafness.
Usher syndrome type I is characterized by congenital hearing loss, retinitis pigmentosa (RP), and variable vestibular areflexia. Usher syndrome type ID, one of seven Usher syndrome type I genetic localizations, have been mapped to a chromosomal interval that overlaps with a nonsyndromic-deafness localization, DFNB12. Mutations in CDH23, a gene that encodes a putative cell-adhesion protein with multiple cadherin-like domains, are responsible for both Usher syndrome and DFNB12 nonsyndromic deafness. Specific CDH23 mutational defects have been identified that differentiate these two phenotypes. Only missense mutations of CDH23 have been observed in families with nonsyndromic deafness, whereas nonsense, frameshift, splice-site, and missense mutations have been identified in families with Usher syndrome. In the present study, a panel of 69 probands with Usher syndrome and 38 probands with recessive nonsyndromic deafness were screened for the presence of mutations in the entire coding region of CDH23, by heteroduplex, single-strand conformation polymorphism, and direct sequence analyses. A total of 36 different CDH23 mutations were detected in 45 families; 33 of these mutations were novel, including 18 missense, 3 nonsense, 5 splicing defects, 5 microdeletions, and 2 insertions. A total of seven mutations were common to more than one family. Numerous exonic and intronic polymorphisms also were detected. Results of ophthalmologic examinations of the patients with nonsyndromic deafness have found asymptomatic RP-like manifestations, indicating that missense mutations may have a subtle effect in the retina. Furthermore, patients with mutations in CDH23 display a wide range of hearing loss and RP phenotypes, differing in severity, age at onset, type, and the presence or absence of vestibular areflexia.


Investigating the efficacy of medical management for canine structural epilepsy.
Structural epilepsy in dogs is often treated medically with a combination of antiseizure drugs (ASDs) and other concurrent therapies for the primary condition. Unlike idiopathic epilepsy, there have been few studies on the efficacy of medical management in structural epilepsy. This study investigated factors affecting treatment outcomes in dogs medically managed for structural epilepsy. Cases of 71 dogs diagnosed with structural epilepsy were identified from a referral hospital database and data were analysed retrospectively. Efficacy of treatment was assessed by survival time, seizure-free period after diagnosis and overall seizure control. Results showed that the most significant prognostic indicator was the occurrence of status epilepticus (SE) before diagnosis, with these dogs having reduced survival times, shorter seizure-free periods after diagnosis and overall worse seizure control. Cluster seizure history showed similar, although not statistically significant, trends in treatment efficacy. Treatment outcomes were not significantly impacted by ASD therapy used or by specific diagnosis, with the exception of meningoencephalitis of unknown aetiology cases surviving longer. Overall, medical management of canine structural epilepsy achieves the best treatment outcomes when the patient has no history of SE. This study may provide a basis for future investigations into the treatment of canine structural epilepsies.


Long-term preclinical evaluation of the intracorporeal use of advanced local hemostatics in a damage-control swine model of grade IV liver injury.
The purpose of this study was to evaluate the long-term efficacy and safety of kaolin- and chitosan-based hemostatic agents for hemorrhage control in a 14-day survival, damage-control swine model of Grade IV liver injury. A total of 48 anesthetized pigs (40 kg) underwent a 35% total blood volume bleed, cooling to 34°C and a standardized liver injury. The animals were randomized to standard gauze control (SG, n = 12), QuikClot Combat Gauze (QCCG, n = 12), Celox (CX, n = 12), or Celox Gauze (CXG, n = 12) packing. At 15 minutes, shed blood was calculated, followed by damage-control closure. At 48 hours, pack removal and definitive closure was performed. At 14-day sacrifice, the liver, kidney, heart, lung, and small bowel standard intra-abdominal organs were sampled for histopathological examination. Uncontrolled blood loss at 2 minutes demonstrated internal consistency of the injury. Blood loss at 15 minutes was significantly lower in the CX and QCCG arms (SG, 11.1 ± 1.1 mL/kg; QCCG, 5.3 ± 1.2 mL/kg; CX, 5.7 ± 1.2 mL/kg; and CXG, 10.1 ± 1.3 mL/kg; p = 0.002). Forty-eight-hour survival was 50.0% for SG, 58.3% for QCCG, 83.3% for CX, and 41.7% for CXG (p = 0.161). Fourteen-day survival was 41.7% (5) for SG, 50.0% (6) for QCCG, 58.3% (7) for CX, and 41.7% (5) for CXG (p = 0.821). Four CX and two QCCG deaths were caused by bowel obstruction; one SG death was caused by sepsis; the remainder was caused by blood loss.Histopathology in one CX animal demonstrated eosinophilic material within a coronary vessel consistent with granule embolization. Celox and QuikClot Combat Gauze were effective hemostatic adjuncts to standard intracavitary damage-control packing. The hemostasis was durable, facilitating pack removal, and definitive closure at reoperation. There was however an increase in the development of intra-abdominal adhesions resulting in small bowel obstruction. The potential for distant embolization of granular agents warrants further investigation.


Allopregnanolone: The missing link to explain the effects of stress on tic exacerbation?
The neurosteroid allopregnanolone (3α-hydroxy-5α-pregnan-20-one; AP) elicits pleiotropic effects in the central nervous system, ranging from neuroprotective and anti-inflammatory functions to the regulation of mood and emotional responses. Several lines of research show that the brain rapidly produces AP in response to acute stress to reduce the allostatic load and enhance coping. These effects not only are likely mediated by GABAA receptor activation but also result from the contributions of other mechanisms, such as the stimulation of membrane progesterone receptors. In keeping with this evidence, AP has been shown to exert rapid, potent antidepressant properties and has been recently approved for the therapy of moderate-to-severe postpartum depression. In addition to depression, emerging evidence points to the potential of AP as a therapy for other neuropsychiatric disorders, including anxiety, seizures, post-traumatic stress disorder and cognitive problems. Although this evidence has spurred interest in further therapeutic applications of AP, some investigations suggest that this neurosteroid may also be associated with adverse events in specific disorders. For example, our group has recently documented that AP increases tic-like manifestations in several animal models of tic disorders; furthermore, our results indicate that inhibiting AP synthesis and signalling reduces the exacerbation of tic severity associated with acute stress. Although the specific mechanisms of these effects remain partially elusive, our findings point to the possibility that the GABAergic activation by AP may also lead to disinhibitory effects, which could interfere with the ability of patients to suppress their tics. Future studies will be necessary to verify whether these mechanisms may apply to other externalising manifestations, such as impulse-control problems and manic symptoms.


An Indicator to Prioritize the Mechanical Ventilators Replacement in a Secondary Care Hospital in Mexico.
This paper presents a practical application of health technology assessment for 21 mechanical ventilators, located at a secondary care Hospital in the State of Mexico, Mexico. A global indicator is obtained, by using a mathematical tool, which involves 14 variables grouped into three partial indicators: technical, clinical and economic. The final aim of this approach is to provide evidence for decision-making, in order to prioritize the replacement of medical equipment, taking into consideration its performance features, the needs of demand for care, and the economic implications for the Hospital.Clinical Relevance-Invasive Mechanical Ventilation (IMV), is a clinical procedure which implies a total or partial replacement of lung function. Given the life support implications, it is important to assure security and reliability in medical equipment intended for this therapy. Therefore, in order to keep updated the IMV devices, in addition to requiring preventive maintenance programs, medical technology replacement programs are necessary.


Histological studies of surgically resected hepatocellular carcinoma following combined radiotherapy and hyperthermia.
Four cases of hepatocellular carcinoma (HCC) were surgically resected following combined radiotherapy (RT) and hyperthermia (HT). Complete necrosis of the tumor without viable tumor cell was found in one case and extensive tumor necrosis was observed in the other three cases; the percentage of necrosis in the specimens were 40%, 70%, and 80%, respectively. Histologic assessment showed mainly coagulative necrosis in the tumor with focal liquefactive necrosis. Cystic dilatation of sinusoids was observed in both tumor and nontumorous normal liver tissue. Other changes in normal liver tissue were unremarkable except for infiltration of inflammatory cells, fatty change, and proliferation of the bile ducts which can usually be seen beyond the area where any space occupying lesions are present. It is concluded that combined radiotherapy and hyperthermia can significantly induce coagulative necrosis of hepatocellular carcinoma with nonsignificant minimal histologic changes in adjacent nontumorous liver tissue.


General practice on a new housing estate. 1956.
An analysis has been carried out of the records kept for the year 1953 by six doctors practising on a new housing estate near London. The population of the estate is described in terms of age, sex, and social class. 76 per cent. of the registered patients consulted a doctor at some time during the year, the consultation rate per person being 4.1 based on the average registered population; females had more consultations than males; 80 per cent. of all consultations were made by people under the age of 45. One-sixth of the patients accounted for about half of the consultations, and 30 per cent. of the consultations were made by the 7 per cent. of registered patients who consulted twelve or more times in the year. The consultation rates showed a slight, but statistically significant, social gradient, with more consultations among patients in the lower social classes. The illness rate was 26 per person, and was higher among males in infancy and old age, and among females between the ages of 5 and 64. A method of estimating the duration of sickness in terms of the period under medical care was employed. This showed that 70 per cent. of all illnesses were dealt with in single consultations, and that only 3 per cent. of illnesses were under care for more than 90 days. Over half of the practice population were under care for less than 5 days, and only 8 per cent. for more than 90 days. The proportion of patients having more than 30 days sickness generally increased with age, but there was a slight fall among the women aged 65 and over. Certificates were issued at the rate of about one for every five consultations, two-thirds of these being necessitated by the requirements of the National Insurance regulations. Prescriptions were issued at the rate of about one per consultation, the prescription rate being 41 per person. Only 5 per cent. of the practice population consulted the doctor but did not obtain a prescription. About 30 per cent. of the patients who consulted a doctor were referred outside the practices, 80 per cent. of all referrals being to hospitals, either as inpatients or as out-patients. The person-hospital referral rate was 20 per 100, and there were 31 referrals for every 100 registered patients. Males over 65 had the highest rates for consultations, illnesses, prescriptions, and referrals. The reason for this is discussed. The value of record-keeping by general practitioners is stressed, together with the need for a generally accepted method of expressing rates in studies of this kind.


Design and implementation of a hospital-based usability laboratory: insights from a Department of Veterans Affairs laboratory for health information technology.
Although the potential benefits of more usable health information technologies (HIT) are substantial-reduced HIT support costs, increased work efficiency, and improved patient safety--human factors methods to improve usability are rarely employed. The US Department of Veterans Affairs (VA) has emerged as an early leader in establishing usability laboratories to inform the design of HIT, including its electronic health record. Experience with a usability laboratory at a VA Medical Center provides insights on how to design, implement, and leverage usability laboratories in the health care setting. The VA Health Services Research and Development Service Human-Computer Interaction & Simulation Laboratory emerged as one of the first VA usability laboratories and was intended to provide research-based findings about HIT designs. This laboratory supports rapid prototyping, formal usability testing, and analysis tools to assess existing technologies, alternative designs, and potential future technologies. RESULTS OF IMPLEMENTATION: Although the laboratory has maintained a research focus, it has become increasingly integrated with VA operations, both within the medical center and on a national VA level. With this resource, data-driven recommendations have been provided for the design of HIT applications before and after implementation. The demand for usability testing of HIT is increasing, and information on how to develop usability laboratories for the health care setting is often needed. This article may assist other health care organizations that want to invest in usability resources to improve HIT. The establishment and utilization of usability laboratories in the health care setting may improve HIT designs and promote safe, high-quality care for patients.


Combined GM-CSF treatment and M-CSF inhibition of tumor-associated macrophages induces dendritic cell-like signaling in vitro.
Macrophages demonstrate plasticity, and tumor-associated macrophages (TAM) can function as immunosuppressive cells in the tumor microenvironment. Therefore, in this study, we aimed to reprogram TAM in vitro with cytokine signal alteration. Granulocyte macrophage colony stimulating factor (GM-CSF) treatment alone did not lead to changes in the expression of M1 (including IL-1β, TNFα and CXCL-10) or M2 (including CD36, CD206 and CCL17) molecules by TAM in vitro, although they adopted a round morphology and were less adhesive to the culture dish. When macrophage colony stimulating factor (M-CSF) signals were suppressed by siRNA against the M-CSF receptor (M-CSFR) in conjunction with GM-CSF treatment, the signal transduction pathway of TAM was altered, and the expression of STAT1, STAT5 and STAT6, which are usually expressed by dendritic cells, was increased. However, the same treatment did not alter the TAM expression pattern of M1/M2 marker molecules. With respect to the NF-κB pathway, GM-CSF and M-CSFR siRNA combination treatment significantly induced the expression of p65, which is usually not expressed by TAM, while p50 and p105 expression by TAM was not affected by the treatment. These findings indicate that our model could not redirect TAM to a monocyte-derived dendritic cell-like phenotype based on the analysis of M1/M2 marker expression, but it was able to modify cell signaling pathways toward a dendritic cell-like pattern. Therefore, the present data suggest that TAM demonstrate plasticity toward dendritic cell-like signal transduction patterns, and that the alteration of the tumor microenvironment has the potential to reverse the immunosuppressive properties of TAM.


Pharmacokinetics of hexamethylmelamine administered via the Ip route in an oil emulsion vehicle.
Saline and Intralipid were compared as vehicles for the ip administration of hexamethylmelamine (HMM) in mice. The drug proved stable over at least 7 weeks in solution and 2 years in crystal form. Fiftyfold higher concentrations of HMM could be achieved in Intralipid than in saline. The peritoneal pharmacokinetics were first-order and linear over the concentration range of HMM in Intralipid from 50 to 2000 micrograms/ml. The mean peritoneal half-life of HMM in Intralipid was 12.5-fold greater than the mean half-life of HMM in saline at the same concentration. Peritoneal concentration X time drug exposure, as measured by the area under the curve in single-dose elimination experiments, was 1200-fold greater for HMM at 2000 micrograms/ml in Intralipid than at 50 micrograms/ml, near saturation, in saline. The steady-state peritoneal to plasma concentration ratios were 96-104 for HMM in Intralipid at concentrations of 300-2000 micrograms/ml, and the peritoneal concentration that could be maintained by the constant ip infusion of HMM at 2000 micrograms/ml in Intralipid was at least 1600-fold greater than that maintainable with HMM in saline. The mean peritoneal clearance calculated by two independent methods and at three different concentrations of HMM in Intralipid was 0.112 +/- 0.016 ml/minute. HMM in Intralipid is a stable formulation that can be used to increase peritoneal exposure to HMM and may potentially be used iv as well.


Disseminated mucormycosis presenting with lower extremity weakness.
Mucormycosis is an uncommon, but important opportunistic fungal infection. The most commonly reported areas of infection are pulmonary, rhinocerebral and cutaneous. It has only rarely been reported to cause peripheral neurological symptoms. This report presents the case of a patient who presented with ascending paralysis due to pulmonary mucormycosis. The presentation is believed to be due to a lesion which abutted the vertebral column and caused infarction of the spinal cord.


[Role of xanthine oxidase and xanthine dehydrogenase systems in thymocyte apoptosis, induced by papaverine].
It has been established that papaverine as well as other xenobiotics (dexamethasone and nitrosodimethylamine) [figure: see text] provoked the thymocyte death like apoptosis. The increase of the quantity of double-strand, single-strand DNA breaks and low molecular weight fragments of DNA preceded cell death. In papaverine-induced process of thymocyte apoptosis the total activity of xanthine oxidase in thymocytes strongly elevated long before their death, the conversion of xanthine dehydrogenase (D-form) to xanthinoxidase (O-form) and accumulation of O-form in the cultural medium took place. Direct stimulating effect of papaverine on O-form of enzyme in thymocyte lysate was revealed. The used digitonin thymocytes were divided into cytoplasmic and structural component fractions. It was shown that about 80% of total xanthinoxidase activity was concentrated in cytoplasma while only 20% of its activity was found in structural components. More higher ratio of xanthinoxidase/xanthindehydrogenase (XO/XDH) was observed and papaverine-induced changes of these enzyme forms activities were expressed more brightly in the structural components, than in the thymocyte cytoplasma. During the process of developing thymocytes apoptosis caused by papaverine the reaction of lipid peroxidation was intensified. XO-hypoxanthin system displaying prooxidant influence on cells increased the cytotoxic effect of papaverine but the presence of allopurinol or catalase and superoxidedismutase decreased it. Besides, cytotoxic action on thymocytes of allopurinol itself as well as hypoxanthin itself was revealed.


Horizontal-plane arm movements with direction reversals performed by normal individuals and individuals with down syndrome.
We examined the systematic variation in shoulder and elbow torque, as well as movement kinematics, for horizontal-plane arm movements with direction reversals performed by normal individuals and individuals with Down syndrome. Eight neurologically normal individuals and eight individuals with Down syndrome performed horizontal, planar reversal movements to four different target locations. The four locations of the targets were chosen such that there is a systematic increase in elbow interaction torque for each of the four different target locations. This systematic increase in interaction torque has previously been shown to lead to progressively larger movement reversal errors, and trajectories that do not show a sharp reversal of direction, for movements to and from the target in patients who have proprioceptive abnormalities. We computed joint torques at the elbow and shoulder and found a high correlation between elbow and shoulder torque for the neurologically normal subjects. The ratio of joint torques varied systematically with target location. These findings extend previously reported findings of a linear synergy between shoulder and elbow joints for a variety of point-to-point movements. There was also a correlation between elbow and shoulder torque in individuals with Down syndrome, but the magnitude of the correlation was less. The ratio of joint torques changed systematically with target direction in individuals with Down syndrome but was slightly different from the ratio observed for neurologically normal individuals. The difference in the ratio was caused by the generation of proportionately more elbow torque than shoulder torque. The fingertip path of individuals with Down syndrome showed a sharp reversal in moving toward and then away from the target. In this respect, they were similar to neurologically normal individuals but dissimilar to individuals with proprioceptive deficits. Finally, we observed that individuals with Down syndrome spend proportionately more time in the vicinity of the target than normal individuals. Collectively these results show that there is a systematic relationship between joint torques at the elbow and shoulder. This relationship is present for reversal movements and is also present in individuals with Down syndrome.


Validation of the FACIT-fatigue subscale, selected items from FACT-thrombocytopenia, and the SF-36v2 in patients with chronic immune thrombocytopenia.
To assess the validity and reliability of the fatigue subscale of the Functional Assessment of Chronic Illness Therapy (FACIT-F), a 6-item subset from the thrombocytopenia subscale of the Functional Assessment of Cancer Therapy (FACT-Th6) and the Short Form-36 Version 2 (SF-36v2) in 2 clinical trials of the thrombopoietin receptor agonist eltrombopag in chronic immune thrombocytopenia (ITP) patients. In the 6-month, RAndomized placebo-controlled ITP Study with Eltrombopag (RAISE; n = 197), the FACIT-F, FACT-Th6, and SF-36v2 were administered at baseline, day 43, weeks 14 and 26, or early withdrawal. In the ongoing open-label extension study, Eltrombopag EXTENDed Dosing Study (EXTEND; n = 154), measures were administered at baseline, at the beginning of each stage, and at permanent discontinuation of study medication. FACIT-F, FACT-Th6, and SF-36v2 demonstrated acceptable internal consistency reliability (i.e., all Cronbach's alphas >0.70) and test-retest reliability (all intraclass correlation coefficients >0.70). Construct validity was supported by moderate (0.35 < r < 0.50) to strong (r > 0.50) inter-measure correlations for baseline and change scores. A small to medium magnitude of effect was captured by the FACIT-F and FACT-Th6 among patients who experienced sustained platelet responses. Results provide support for the validity, reliability, and responsiveness of the FACIT-F, FACT-Th6, and SF-36v2 in chronic ITP patients.


A novel approach to treating a post-sternotomy internal mammary artery pseudoaneurysm.
Pseudoaneurysms of the internal mammary artery are a rare complication of median sternotomy. They may clinically present as a pulsatile mass or with signs of rupture and haemodynamic instability. In stable patients, percutaneous thrombin injection of the pseudoaneurysm is a safe and minimally invasive procedure to treat the pseudoaneurysm and avoid further surgery. We present a case of a pseudoaneurysm of a branch of the right internal mammary artery post-median sternotomy with no signs or symptoms of haemodynamic instability. The pseudoaneurysm was successfully treated with ultrasound-guided percutaneous thrombin injection.


Attention-deficit hyperactivity disorder and the gene for the dopamine D5 receptor.
A recent study has suggested a possible association of a polymorphism near the dopamine D5 receptor gene (DRD5) and attention-deficit hyperactivity disorder. The polymorphism studied was a (CA)n repeat located in the cosmid containing the D5 receptor gene2 and the allele that was reported to be associated with attention-deficit hyperactivity disorder (ADHD) was the 148-bp allele. In this study we sought to replicate this finding by testing for biased transmission of the alleles at this same polymorphism in a sample of 92 families with an ADHD proband. We did not observe significant evidence for biased transmission of the 148-bp allele, however we did observe biased transmission of two other alleles, the 136-bp allele and the 146-bp allele. For these two alleles the bias was for these two alleles not to be transmitted to the ADHD children. The number of informative transmissions for these two alleles was small, therefore it would be premature to make any conclusions from our study concerning the role of DRD5 in ADHD.


Selection of candidates for cardiac resynchronization therapy: late gadolinium enhanced cardiac magnetic resonance as a new and promising predictor of intraventricular dyssynchrony.
Cardiac resynchronization therapy (CRT) is an important therapeutic option for patients with intraventricular conduction delay and has been shown to reduce mortality and morbidity in selected heart failure patients. Several echocardiographic methods have been proposed to define intraventricular delay and to select candidates for CRT, such as color coded tissue Doppler echocardiography and speckle tracking. Since, up to 30% of these carefully selected patients do not receive benefit; predictors of response to CRT still remain a topic of ongoing investigations. Recently, myocardial fibrosis defined by late gadolinium enhancement on cardiac magnetic resonance (CMR) imaging has been introduced as promising predictor of both intraventricular dyssynchrony and response to CRT. The focus of the present review is the major echocardiographic modalities to select CRT candidates, the potential role of cardiac fibrosis detected by CMR in this respect, and the possible relation of it with the presence of intraventricular dyssynchrony.


Epidermoid cyst occurring within an intrapancreatic accessory spleen. A case report and review of the literature.
Epidermoid cysts occurring within intrapancreatic accessory spleens are exceptionally rare entities, with only 21 previously reported cases. Their clinical presentation prior to pathologic assessment can raise concern for possible malignancy; however, they behave in a benign fashion. A 62-year-old male presented with complaints of abdominal pain. Imaging revealed left-sided retroperitoneal mass and surgical exploration was recommended. Surgery revealed a cystic cavity containing necrotic debris originating from the tail of the pancreas. Microscopy was consistent with an epidermoid cyst arising within an intrapancreatic accessory spleen with positive immunoperoxidase staining for CEA. Epidermoid cysts occurring within intrapancreatic accessory spleens can mimic a malignant process both clinically and radiographically. Surgery with pathologic assessment is the only reliable means of diagnosis. While they are a very rare entity, it is an important component of a complete differential diagnosis for a patient presenting with a pancreatic tail mass.


Polymer mechanochemistry: from destructive to productive.
When one brings "polymeric materials" and "mechanical action" into the same conversation, the topic of this discussion might naturally focus on everyday circumstances such as failure of fibers, fatigue of composites, abrasion of coatings, etc. This intuitive viewpoint reflects the historic consensus in both academia and industry that mechanically induced chemical changes are destructive, leading to polymer degradation that limits materials lifetime on both macroscopic and molecular levels. In the 1930s, Staudinger observed mechanical degradation of polymers, and Melville later discovered that polymer chain scission caused the degradation. Inspired by these historical observations, we sought to redirect the destructive mechanical energy to a productive form that enables mechanoresponsive functions. In this Account, we provide a personal perspective on the origin, barriers, developments, and key advancements of polymer mechanochemistry. We revisit the seminal events that offered molecular-level insights into the mechanochemical behavior of polymers and influenced our thinking. We also highlight the milestones achieved by our group along with the contributions from key comrades at the frontier of this field. We present a workflow for the design, evaluation, and development of new "mechanophores", a term that has come to mean a molecular unit that chemically responds in a selective manner to a mechanical perturbation. We discuss the significance of computation in identifying pairs of points on the mechanophore that promote stretch-induced activation. Attaching polymer chains to the mechanophore at the most sensitive pair and locating the mechanophore near the center of a linear polymer are thought to maximize the efficiency of mechanical-to-chemical energy transduction. We also emphasize the importance of control experiments to validate mechanochemical transformations, both in solution and in the solid state, to differentiate "mechanical" from "thermal" activation. This Account offers our first-hand perspective of the change-in-thinking in polymer mechanochemistry from "destructive" to "productive" and looks at future advances that will stimulate this growing field.


Understanding the impact of RapidArc therapy delivery errors for prostate cancer.
The purpose of this study is to simulate random and systematic RapidArc delivery errors for external beam prostate radiotherapy plans in order to determine the dose sensitivity for each error type. Ten prostate plans were created with a single 360° arc. The DICOM files for these treatment plans were then imported into an in-house computer program that introduced delivery errors. Random and systematic gantry position (0.25°, 0.5°, 1°), monitor unit (MU) (1.25%, 2.5%, 5%), and multileaf collimator (MLC) position (0.5, 1, 2 mm) errors were introduced. The MLC errors were either random or one of three types of systematic errors, where the MLC banks moved in the same (MLC gaps remain unchanged) or opposing directions (increasing or decreasing the MLC gaps). The generalized equivalent uniform dose (gEUD) was calculated for the original plan and all treatment plans with errors introduced. The dose sensitivity for the cohort was calculated using linear regression for the gantry position, MU, and MLC position errors. Because there was a large amount of variability for systematic MLC position errors, the dose sensitivity of each plan was calculated and correlated with plan MU, mean MLC gap, and the percentage of MLC leaf gaps less than 1 and 2 cm for each individual plan. We found that random and systematic gantry position errors were relatively insignificant (< 0.1% gEUD change) for gantry errors up to 1°. Random MU errors were also insignificant, and systematic MU increases caused a systematic increase in gEUD. For MLC position errors, random MLC errors were relatively insignificant up to 2 mm as had been determined in previous IMRT studies. Systematic MLC shift errors caused a decrease of approximately -1% in the gEUD per mm. For systematic MLC gap open errors, the dose sensitivity was 8.2%/mm and for MLC gap close errors the dose sensitivity was -7.2%/mm. There was a large variability for MLC gap open/close errors for the ten RapidArc plans which correlated strongly with MU, mean gap width, and percentage of MLC gaps less than 1 or 2cm. This study evaluates the magnitude of various simulated RapidArc delivery errors by calculating gEUED on various prostate plans.


Repair and survival of the innominate artery late after transection.
Survival of major thoracic arteries transected by blunt trauma usually depends on immediate surgical repair. However, the authors report a case in which a 54-year-old man had survived an untreated complete transection of the innominate artery 20 years before. He presented with subclavian steal syndrome and transient ischemic attacks. There was wide separation between the proximal and distal stumps of the artery with no apparent continuity of tissue between them. A 10-mm Gore-Tex graft was successfully used as a bypass from the ascending aorta to the distal carotid bifurcation. Survival of the innominate artery transection without treatment and late onset of symptoms has not previously been described.


Predicting the success of IVF: external validation of the van Loendersloot's model.
Is the predictive model for IVF success proposed by van Loendersloot et al. valid in a different geographical and cultural context? The model discriminates well but was less accurate than in the original context where it was developed. Several independent groups have developed models that combine different variables with the aim of estimating the chance of pregnancy with IVF but only four of them have been externally validated. One of these four, the van Loendersloot's model, deserves particular attention and further investigation for at least three reasons; (i) the reported area under the receiver operating characteristics curve (c-statistics) in the temporal validation setting was the highest reported to date (0.68), (ii) the perspective of the model is clinically wise since it includes variables obtained from previous failed cycles, if any, so it can be applied to any women entering an IVF cycle, (iii) the model lacks external validation in a geographically different center. Retrospective cohort study of women undergoing oocyte retrieval for IVF between January 2013 and December 2013 at the infertility unit of the Fondazione Ca' Granda, Ospedale Maggiore Policlinico of Milan, Italy. Only the first oocyte retrieval cycle performed during the study period was included in the study. Women with previous IVF cycles were excluded if the last one before the study cycle was in another center. The main outcome was the cumulative live birth rate per oocytes retrieval. Seven hundred seventy-two women were selected. Variables included in the van Loendersloot's model and the relative weights (beta) were used. The variable resulting from this combination (Y) was transformed into a probability. The discriminatory capacity was assessed using the c-statistics. Calibration was made using a logistic regression that included Y as the unique variable and live birth as the outcome. Data are presented using both the original and the calibrated models. Performance was evaluated correlating the mean predicted chances of live births in the five quintiles and the observed rates. Two-hundred-eleven live births (27%) were obtained. The c-statistic was 0.64 (95% CI: 0.61-0.67, P < 0.001). The slope of the linear predictor (calibration slope) expressed as an Odds Ratio was 1.81 (95% CI: 1.46-2.24, P < 0.001), corresponding to a beta of 0.630. The calibration intercept was +0.349 (P = 0.13). While a clear discrepancy exists using the original model, data appear properly distributed with the calibrated model. The Pearson coefficient of the correlation between the mean predicted chances of live births in the five quintiles and the observed rates was 0.99 (P = 0.002). Data were collected retrospectively, thus exposing them to potential inaccuracies. The selection criteria for access to IVF adopted in our center might be too stringent, leading to the exclusion of women with a poor, yet acceptable chance of live birth. Therefore, the validity of the model in women with a very low chance of live birth could not be tested. The van Loendersloot's model can be used in other contexts but it is important that it has local calibration. It may help in counseling couples about their chance of success but it cannot be used to exclude treatments. Further research is needed to improve the discriminatory performance of IVF predictive models. None. Not applicable.


Successful management of delayed-onset adenosine deaminase deficiency with novel mutation.
A 4-year-old boy presented with acute-onset autoimmune cytopenia with severe, persistent lymphopenia, autoimmune thyroiditis, elevated IgE and glucose 6-phosphate dehydrogenase enzyme deficiency. In immunologic evaluation, lower T, B and natural killer cells and higher levels of adenosine deaminase (ADA) metabolites were observed. The compound heterozygous novel ADA gene mutations causing ADA deficiency were detected. Successful immunologic and metabolic cure was achieved with enzyme replacement therapy, followed by reduced intensity conditioning hematopoietic stem cell transplantation from a matched unrelated donor. An interesting aspect of this patient is the detection of novel compound heterozygous mutations without consanguinity and a secondary outcome is the recovery of glucose 6-phosphate dehydrogenase deficiency after hematopoietic stem cell transplantation.


[Distribution of sodium and potassium in avian skeletal muscles].
Studies have been made on the peculiarities of distribution of Na+ and K+ in functionally different skeletal muscles of 6 species of birds. Comparison of tissue concentration ratio K+/Na+ as well as of distribution coefficients of these ions in tissue and the external medium revealed that selectivity of muscles to K+ and Na+ is related to functional specialization of the contractile mechanism. Dynamic contractile parameters in avian muscles were studied. It was shown that distribution coefficient of K+ and Na+ in muscles is quantitatively related to the velocity of development of isometric contraction. The described dependence between the ionic selectivity of muscle and their morpho-functional characteristics corresponds to the general pattern of this dependence established for skeletal muscles of other Vertebrates.


Variant GPI structure in relation to membrane-associated functions of a murine folate receptor.
Two variant sublines of murine L1210 leukemia cells (L1210A and L1210JF) overexpress the cell surface folate receptor (FR). The membrane bound FR in L1210A cells exhibited significantly (up to 17-fold) greater relative affinities for (6S)-N5-methyltetrahydrofolate, (6S)-N5-formyltetrahydrofolate and methotrexate compared to the FR in L1210JF cells. Furthermore, receptor-mediated transport of [3H]-(6S)-N5-methyltetrahydrofolate was much more efficient in L1210A cells compared to L1210JF cells. When solubilized with Triton X-100, the ligand binding characteristics of FR from both sublines resembled those of the receptor associated with L1210 JF cell membranes. N-terminal amino acid sequence analysis as well as RT-PCR analysis of the entire coding region revealed a single species of FR in both cells, identical to murine FR-alpha. The FR in L1210JF cells was sensitive to phosphatidylinositol specific phospholipase C (PI-PLC) indicating the presence of a glycosyl-phosphatidylinositol (GPI) membrane anchor while the FR in L1210A cells was resistant to PI-PLC; however, the FR in L1210A cells was released from plasma membranes by nitrous acid, as expected for GPI and its PI-PLC resistant structural variants. Treatment of L1210A cell membranes with mild base rendered the protein PI-PLC sensitive as expected for GPI anchors acylated in the inositol ring and also decreased the affinities of the membrane associated FR for reduced folates. When the cDNA for murine FR-alpha was expressed in parental L1210 cells the protein was PI-PLC resistant but was sensitive to PI-PLC when the cDNA was expressed in human 293 fibroblasts. In L1210JF, L1210A, and parental L1210 cells, several cell surface proteins, including FR, incorporated [3H]ethanolamine, a component of the GPI membrane anchor; however, the labeled proteins were released by PI-PLC only in L1210JF cells. The above results preclude any peculiarity of the FR polypeptide in either L1210 subline as the basis for the observed differences in PI-PLC sensitivity and membrane-associated functions of FR. Partial deglycosylation of membrane associated FR from either cell with N-glycanase did not influence its ligand binding characteristics. The results of this study lead to the hypothesis that variant GPI structures may modulate the function of a protein by influencing its conformation/topography in the membrane. Such effects may be identified by their disappearance/reduction upon detergent solubilization or mild base treatment of the membrane.


Imaging systems and applications: introduction to the feature.
Imaging systems have numerous applications in industrial, military, consumer, and medical settings. Assembling a complete imaging system requires the integration of optics, sensing, image processing, and display rendering. This issue features original research ranging from design of stimuli for human perception, optics applications, and image enhancement to novel imaging modalities in both color and infrared spectral imaging, gigapixel imaging as well as a systems perspective to imaging.


Exploring the Possible Impact of Unbalanced Open-Label Drop-In of Glucose-Lowering Medications on EXSCEL Outcomes.
EXSCEL (Exenatide Study of Cardiovascular Event Lowering) assessed the impact of once-weekly exenatide 2 mg versus placebo in patients with type 2 diabetes mellitus, while aiming for glycemic equipoise. Consequently, greater drop-in of open-label glucose-lowering medications occurred in the placebo group. Accordingly, we explored the potential effects of their unbalanced use on major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction or nonfatal stroke, and all-cause mortality (ACM), given that some of these agents are cardioprotective. Cox hazard models were performed by randomized treatment for drug classes where >5% open-label drop-in glucose-lowering medication occurred, and for glucagon-like peptide-1 receptor agonists (GLP-1 RAs; 3.0%) using three methodologies: drop-in visit right censoring, inverse probability for treatment weighting (IPTW), and applying drug class risk reductions. Baseline glucose-lowering medications for the 14 752 EXSCEL participants (73.1% with previous cardiovascular disease) did not differ between treatment groups. During median 3.2 years follow-up, open-label drop-in occurred in 33.4% of participants, more frequently with placebo than exenatide (38.1% versus 28.8%), with metformin (6.1% versus 4.9%), sulfonylurea (8.7% versus 6.9%), dipeptidyl peptidase-4 inhibitors (10.6% versus 7.5%), SGLT-2i (10.3% versus 8.1%), GLP-1 RA (3.4% versus 2.4%), and insulin (13.8% versus 9.4%). The MACE effect size was not altered meaningfully by right censoring, but the favorable HR for exenatide became nominally significant in the sulfonylurea and any glucose-lowering medication groups, while the ACM HR and p-values were essentially unchanged. IPTW decreased the MACE HR from 0.91 (P=0.061) to 0.85 (P=0.008) and the ACM HR from 0.86 (P=0.016) to 0.81 (P=0.012). Application of literature-derived risk reductions showed no meaningful changes in MACE or ACM HRs or P values, although simulations of substantially greater use of drop-in cardioprotective glucose-lowering agents demonstrated blunting of signal detection. EXSCEL-observed HRs for MACE and ACM remained robust after right censoring or application of literature-derived risk reductions, but the exenatide versus placebo MACE effect size and statistical significance were increased by IPTW. Effects of open-label drop-in cardioprotective medications need to be considered carefully when designing, conducting, and analyzing cardiovascular outcome trials of glucose-lowering agents under the premise of glycemic equipoise. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01144338.


CXCL12-mediated monocyte transmigration into brain perivascular space leads to neuroinflammation and memory deficit in neuropathic pain.
Emerging clinical and experimental evidence demonstrates that neuroinflammation plays an important role in cognitive impairment associated with neuropathic pain. However, how peripheral nerve challenge induces remote inflammation in the brain remains largely unknown. Methods: The circulating leukocytes and plasma C-X-C motif chemokine 12 (CXCL12) and brain perivascular macrophages (PVMs) were analyzed by flow cytometry, Western blotting, ELISA, and immunostaining in spared nerve injury (SNI) mice. The memory function was evaluated with a novel object recognition test (NORT) in mice and with Montreal Cognitive Assessment (MoCA) in chronic pain patients. Results: The classical monocytes and CXCL12 in the blood, PVMs in the perivascular space, and gliosis in the brain, particularly in the hippocampus, were persistently increased following SNI in mice. Using the transgenic CCR2RFP/+ and CX3CR1GFP/+ mice, we discovered that at least some of the PVMs were recruited from circulating monocytes. The SNI-induced increase in hippocampal PVMs, gliosis, and memory decline were substantially prevented by either depleting circulating monocytes via intravenous injection of clodronate liposomes or blockade of CXCL12-CXCR4 signaling. On the contrary, intravenous injection of CXCL12 at a pathological concentration in naïve mice mimicked SNI effects. Significantly, we found that circulating monocytes and plasma CXCL12 were elevated in chronic pain patients, and both of them were closely correlated with memory decline. Conclusion: CXCL12-mediated monocyte recruitment into the perivascular space is critical for neuroinflammation and the resultant cognitive impairment in neuropathic pain.


The cyclophilin CYP20-2 modulates the conformation of BRASSINAZOLE-RESISTANT1, which binds the promoter of FLOWERING LOCUS D to regulate flowering in Arabidopsis.
Brassinosteroids (BRs) regulate many physiological processes during plant development, including flowering. However, little is known about the components of BR signaling that mediate flowering. Here, we report that BRASSINAZOLE-RESISTANT1 (BZR1), the conformation of which is altered by a cyclophilin (CYP20-2), binds cis-elements in the FLOWERING LOCUS D (FLD) promoter to regulate flowering. Both bzr1-1D and fld-4 showed delayed flowering. Electrophoretic mobility shift assay and chromatin immunoprecipitation revealed that BZR1 bound to a putative BR response cis-element and suppressed the expression of FLD. Overexpression of FLD partially rescued the late flowering of pBZR1:mBZR1(Pro234-Leu)-CFP (mx3). Yeast two-hybrid and pull-down assays demonstrated that BZR1 interacts with CYP20-2. Arabidopsis thaliana CYP20-2 had greater peptidyl-prolyl cis-trans isomerase activity than did wheat (Triticum aestivum) CYP20-2. Fourier transform infrared spectroscopy revealed conformation changes in BZR1, dependent on interaction with CYP20-2. Due to differences in activity and substrate preference between CYP20-2 proteins from wheat and Arabidopsis, At-CYP20-2-overexpressing lines showed earlier flowering, whereas Ta CYP20-2 lines flowered later. Immunoblot and chromatin immunoprecipitation assays showed that histone H3 trimethyl Lys4 and H3 acetylation levels were negatively correlated with the transcription of FLD (a putative histone demethylase) in various lines. Therefore, a conformational change of BZR1 mediated by CYP20-2 causes altered flowering through modulation of FLD expression.


[Early diagnosis of phenylketonuria. Physiopathology of the neuronal damage and therapeutic options].
Phenylketonuria, also known as PKU, is the most frequent congenital inborn error of metabolism. The severe form or classic PKU untreated causes intellectual disability, although with the early detection programs in the neonatal period, diagnosis and treatment prevent the appearance of the symptoms. Despite early diagnosis and treatment we have observed some neurotoxicity in treated PKU patients. We analyzed the factors involved apart from the toxicity due to the high cerebral concentrations of phenylalanine (Phe), the defects of synthesis of neurotransmitters, the alteration of cerebral myelination, the effect of the elevation of Phe in the processes of transport and distribution of neutral amino acids with an abnormal synthesis of brain proteins, plasma and cerebral tyrosine deficiency, the neurotoxicity of Phe metabolites, the defect of cholesterol biosynthesis or the increase of oxidative stress. White matter alterations in early treated PKU patients have an important role in neurological manifestations. The treatment of PKU is for life and is based on the reduction of foods containing Phe combined with the administration of a special formula or tetrahydrobiopterin (BH4) treatment. New therapeutic options will be analyzed.


Comparative phylogenetic analysis of the evolution of semelparity and life history in salmonid fishes.
The selective pressures involved in the evolution of semelparity and its associated life-history traits are largely unknown. We used species-level analyses, independent contrasts, and reconstruction of ancestral states to study the evolution of body length, fecundity, egg weight, gonadosomatic index, and parity (semelparity vs. degree of iteroparity) in females of 12 species of salmonid fishes. According to both species-level analysis and independent contrasts analysis, body length was positively correlated with fecundity, egg weight, and gonadosomatic index, and semelparous species exhibited a significantly steeper slope for the regression of egg weight on body length than did iteroparous species. Percent repeat breeding (degree of iteroparity) was negatively correlated with gonadosomatic index using independent contrasts analysis. Semelparous species had significantly larger eggs by species-level analysis, and the egg weight contrast for the branch on which semelparity was inferred to have originated was significantly larger than the other egg weight contrasts, corresponding to a remarkable increase in egg weight. Reconstruction of ancestral states showed that egg weight and body length apparently increased with the origin of semelparity, but fecundity and gonadosomatic index remained more or less constant or decreased. Thus, the strong evolutionary linkages between body size, fecundity, and gonadosomatic index were broken during the transition from iteroparity to semelparity. These findings suggest that long-distance migrations, which increase adult mortality between breeding episodes, may have been necessary for the origin of semelparity in Pacific salmon, but that increased egg weight, leading to increased juvenile survivorship, was crucial in driving the transition. Our analyses support the life-history hypotheses that a lower degree of repeat breeding is linked to higher reproductive investment per breeding episode, and that semelparity evolves under a combination of relatively high juvenile survivorship and relatively low adult survivorship.


[Dynamics of morphometric parameters of skeletal bone in inhabitants of Saint-Petersburg].
2102 roentgenograms of the left manus bones from both sexes subjects with normal health status aged up to 18 were studied to detect peculiarities of skeleton maturity of St. Petersburg inhabitants. TW-2 modified Tanner-Whitehouse method was used. It was demonstrated that children living in St. Petersburg are characterized with the excess of skeletal age over chronological one almost in all age groups, which is maximum typically during first years and minimum by the end of puberty. The process of bone maturity is not successive. Highest growth rate of skeletal maturity were found in prepubescent and puberty. Sex differences established are also noted. Girls were above boys in skeletal age at 7, 8, 9 and 10 years.


Association of visit-to-visit variability of hemoglobin A1c and medication adherence.
Medication nonadherence is widespread, but there are few efficient means of detecting medication nonadherence at the point of care. Visit-to-visit variability in clinical biomarkers has shown inconsistent efficiency to predict medication adherence. To examine the performance of visit-to-visit variability (VVV) of hemoglobin A1c to predict nonadherence to antidiabetic medications. In this cross-sectional study using a clinical and administrative database, adult members of a managed care plan at a safety-net medical center from 2008 to 2012 were included if they had ≥ 3 noninsulin antidiabetic prescription fills within the same class and ≥ 3 A1c measurements between the first and last prescription fills. The independent variable was VVV of A1c (within-subject standard deviation of A1c), and the dependent variable was medication adherence (defined by medication possession ratio) determined from pharmacy claims. Unadjusted and adjusted multivariate logistic regression models were created to examine the relationship between VVV of A1c and medication nonadherence. Receiver-operating characteristic (ROC) curves assessed the performance of the adjusted model at discriminating adherence from nonadherence. Among 632 eligible subjects, mean A1c was 7.7% ± 1.3%, and 83% of the sample was nonadherent to antidiabetic medications. Increasing quintiles of VVV of A1c and medication nonadherence were both associated with increased within-subject mean A1c and younger subject age. The logistic regression model (adjusted for age, sex, race/ethnicity, within-subject mean A1c, number of A1c measurements, number of days between the first and last antidiabetic medication prescription fills, and rate of primary care visits during the study period) showed a nonsignificant association of VVV of A1c and medication nonadherence (OR = 1.19, 95% CI = 0.42-3.38 for the highest quintile of VVV). Adding VVV of A1c to a model including age, sex, and race only modestly improved the C-statistic of the ROC curve from 0.6786 to 0.7064. VVV of A1c is not a robust predictor of antidiabetic medication nonadherence. Further innovation is needed to develop novel methods of detecting nonadherence.


Transparent Polycrystalline Magnesium Aluminate Spinel Fabricated by Spark Plasma Sintering.
Polycrystalline magnesium aluminate (MgAl2 O4 ) spinel (PMAS) exhibits a unique combination of physical, chemical, mechanical, and optical properties, which makes it useful for a wide range of applications, including UV lenses for lithography, electroinsulation, and structural windows for both VIS and IR region radiation and armor applications. Conventional two-stage processing of PMAS involves prolonged pressureless sintering followed by hot isostatic pressing. The costly processing of high-quality transparent PMAS ceramic is the main reason for the limited usage of this material in industry. Spark plasma sintering (SPS) is a relatively novel one-stage, rapid, and cost-effective sintering technique, which holds great potential for producing high-quality optical materials. Here, recent advances in the fabrication of transparent PMAS by the SPS approach, the influence of sintering parameters on microstructure evolution during densification, and their effects on the optical and mechanical properties of the material are reviewed.


Chronic effects of exposure to a pharmaceutical mixture and municipal wastewater in zebrafish.
Pharmaceuticals and personal care products (PPCPs) are discharged in municipal wastewater. Effects in aquatic organisms exposed to individual pharmaceuticals in the laboratory have raised concerns regarding the environmental impacts of PPCPs, yet environmental exposures are always to complex mixtures. In this study, adult zebrafish (Danio rerio) showed significantly decreased embryo production after a 6 week exposure to a pharmaceutical mixture (MIX; 0.5 and 10μgL(-1)) of acetaminophen, carbamazepine, gemfibrozil and venlafaxine and to diluted wastewater effluent (WWE; 5% and 25%). Atretic oocytes and altered ovarian histology were significantly increased in female zebrafish exposed to both concentrations of MIX or WWE, which indicates a direct effect on oocyte development that may account for reduced embryo production. Apoptosis within the thecal and granulosa cell layers was identified in female zebrafish with atresia. Exposures to MIX or WWE at both concentrations severely altered kidney proximal tubule morphology, but no histological impacts on other organs were observed. Exposure of embryos to MIX or WWE at the high concentration significantly increased the incidence of developmental abnormalities. Embryo mortality was elevated with exposure to the high concentration of MIX. These studies indicate that chronic exposure of fish to pharmaceutical mixtures and wastewater impacts reproduction and induces histopathological changes, similar to what we have previously seen with single compound exposures. These data suggest that fish populations exposed to pharmaceuticals discharged in wastewater are at risk of negative impacts to reproductive capacity and health.


Complex shape deformations of homogeneous poly(N-isopropylacrylamide)/graphene oxide hydrogels programmed by local NIR irradiation.
Stimuli-responsive hydrogels, with programmable shape deformations upon external stimuli, have promising applications in diverse fields. Complex shape deformation through precise remote control of the direction, position and degree of deformation is critical for practical applications. Herein, we describe a novel and facile method that enables remote and instant programming of the deformation direction, position and degree of homogeneous poly(N-isopropylacrylamide)/graphene oxide (PNIPAM/GO) nanocomposite hydrogels through local near infrared (NIR) laser irradiation. Under NIR irradiation, GO nanosheets absorb NIR light, which transforms into heat and induces the phase transition of PNIPAM. Due to the slow heat transfer of the hydrogels, the irradiated part of the PNIPAM/GO hydrogels shrinks more than the un-irradiated part, leading to the folding or bending of the gels toward the irradiated part. The deformation degree of the hydrogels can be adjusted by changing the composition (e.g., GO concentration) or the thickness of the hydrogels and the irradiation parameters, including power density of NIR laser and irradiation time. Impressively, by simply programming the local irradiation on different parts of hydrogel strips, sheets and gel samples with other shapes, the hydrogel samples can undergo complex shape deformations from 1D to 2D and 2D to 3D, and imitate the postures of a human and the closing of the leaves of mimosa.


Challenges and Solutions for the Implementation of Shared Decision-making in Breast Reconstruction.
Patient-centered care is a hallmark of quality in healthcare. It is defined as care that is respectful of, and responsive to, individual patient preferences, needs, and values, while ensuring patients are informed and engaged in the treatment decision-making process. We reviewed the literature and drew upon our own experiences to study the implementation of tools intended to facilitate shared decision-making in breast reconstruction. For women with breast cancer, decision-making about breast reconstruction is often a challenging and perplexing process. The variety of choices available regarding timing and type of reconstruction and the unique individual patient and clinical treatment variables to consider can further complicate decisions. Accordingly, strategies to facilitate the decision-making process and enable patients and clinicians to make high-quality decisions about breast reconstruction are an essential component of comprehensive breast cancer care. Shared decision making is one proposed model to support informed and preference-sensitive decision-making in line with the principles of patient-centered care. Despite an emerging level of interest in shared decision making, there remains a lack of clarity regarding what the process involves and how to effectively implement it into clinical practice. Thus, widespread adoption of shared decision making remains lacking in clinical practice for women considering postmastectomy breast reconstruction. To address these gaps, this article reviews the principles of shared decision making, explores ways shared decision making can be utilized for patients who are candidates for breast reconstruction, and provides a practical overview to facilitate implementation of shared decision making into clinical practice.


Soybean isoflavone ameliorates β-amyloid 1-42-induced learning and memory deficit in rats by protecting synaptic structure and function.
This research aims to investigate whether soybean isoflavone (SIF) could alleviate the learning and memory deficit induced by β-amyloid peptides 1-42 (Aβ 1-42) by protecting the synapses of rats. Adult male Wistar rats were randomly allocated to the following groups: (1) control group; (2) Aβ 1-42 group; (3) SIF group; (4) SIF + Aβ 1-42 group (SIF pretreatment group) according to body weight. The 80 mg/kg/day of SIF was administered orally by gavage to the rats in SIF and SIF+Aβ 1-42 groups. Aβ 1-42 was injected into the lateral cerebral ventricle of rats in Aβ 1-42 and SIF+Aβ 1-42 groups. The ability of learning and memory, ultramicrostructure of hippocampal synapses, and expression of synaptic related proteins were investigated. The Morris water maze results showed the escape latency and total distance were decreased in the rats of SIF pretreatment group compared to the rats in Aβ1-42 group. Furthermore, SIF pretreatment could alleviate the synaptic structural damage and antagonize the down-regulation expressions of below proteins induced by Aβ1-42: (1) mRNA and protein of the synaptophysin and postsynaptic density protein 95 (PSD-95); (2) protein of calmodulin (CaM), Ca(2+) /calmodulin-dependent protein kinase II (CaMK II), and cAMP response element binding protein (CREB); (3) phosphorylation levels of CaMK II and CREB (pCAMK II, pCREB). These results suggested that SIF pretreatment could ameliorate the impairment of learning and memory ability in rats induced by Aβ 1-42, and its mechanism might be associated with the protection of synaptic plasticity by improving the synaptic structure and regulating the synaptic related proteins.


HSAS-MD Analyzer: A Hybrid Security Analysis System Using Model-Checking Technique and Deep Learning for Malware Detection in IoT Apps.
Established Internet of Things (IoT) platforms suffer from their inability to determine whether an IoT app is secure or not. A security analysis system (SAS) is a protective shield against any attack that breaks down data privacy and security. Its main task focuses on detecting malware and verifying app behavior. There are many SASs implemented in various IoT applications. Most of them build on utilizing static or dynamic analysis separately. However, the hybrid analysis is the best for obtaining accurate results. The SAS provides an effective outcome according to many criteria related to the analysis process, such as analysis type, characteristics, sensitivity, and analysis techniques. This paper proposes a new hybrid (static and dynamic) SAS based on the model-checking technique and deep learning, called an HSAS-MD analyzer, which focuses on the holistic analysis perspective of IoT apps. It aims to analyze the data of IoT apps by (1) converting the source code of the target applications to the format of a model checker that can deal with it; (2) detecting any abnormal behavior in the IoT application; (3) extracting the main static features from it to be tested and classified using a deep-learning CNN algorithm; (4) verifying app behavior by using the model-checking technique. HSAS-MD gives the best results in detecting malware from malicious smart Things applications compared to other SASs. The experimental results of HSAS-MD show that it provides 95%, 94%, 91%, and 93% for accuracy, precision, recall, and F-measure, respectively. It also gives the best results compared with other analyzers from various criteria.


[NIH stroke scale and its adaptation to Spanish].
In recent years, the NIH stroke scale (National Institute of Health Stroke Scale, NIHSS) has become the most popular used scale to assess the initial and final neurological status of stroke patients who receive experimental drugs. One of the problems with this scale in our country is the language question, making mandatory to adapt it into Spanish. To obtain a Spanish version of the NIHSS and verify that it has the same advantages and utilities as the original version. A Spanish translation of the original version of NIHSS was obtained. The final Spanish version for the different items and the instructions to carry out each one of the items were decided by consensus by the neurovascular unit team. The word list and sentences and the drawings of objects and that used to assess visual extinction were obtained from the Boston aphasia test (adapted previously to our language). Once adapted to the Spanish version, the NIHSS, scores obtained during the acute stroke phase were correlated with the cerebral infarct volumes and with the location of the arterial occlusion. As predictable, there is a good correlation between the neurological situation of the patient (NIHSS) and the presence of middle cerebral artery occlusion assessed by Transcranial Doppler. Doppler situation at baseline, 12, 24 and 48 hours was significantly related (p = 0.001) with the NIHSS at any time. There is a good correlation between the NIHSS score and cerebral infarct volumes measured by computed tomography (n = 72; r = 0.794; p < 0.0001) and by magnetic resonance diffusion- 192 weighted image (n = 38; r = 0.674; p < 0.001). This adaptation of the NIH stroke scale to Spanish will allow wider availability and routine use in the stroke units.


Hip Muscle Strengthening for Knee Osteoarthritis: A Systematic Review of Literature.
Osteoarthritis (OA) of the knee joint results in chronic pain and functional decline among older adults. Hip muscle weakness has been observed in persons with knee OA and is claimed to increase the medial compartment loading on the knee joint. Although individual studies are available, no review has yet integrated the literature on the benefits of hip muscle strengthening for persons with knee OA. This review aims to systematically summarize the current evidence on the effectiveness of hip muscle strengthening on knee pain, lower extremity function, and biomechanical measures of the knee in persons with knee OA. An extensive electronic literature search was conducted in the databases PubMed, Scopus, Cumulative Index to Nursing and Allied Health (CINAHL), Cochrane Central Register of Controlled Trials (CENTRAL), and Physiotherapy Evidence Database (PEDro) to identify the published trials in the English language from January 1990 to August 2017. Randomized controlled trials that studied the effectiveness of hip muscle strengthening in persons with knee OA on knee pain, physical function, and biomechanical measures of the knee were considered for inclusion. The key word combinations were knee osteoarthritis, degenerative arthritis, arthralgia, muscle strengthening, and resistance training using the Boolean operators AND, OR. Two reviewers independently performed the study selection, and a third reviewer intervened when the consensus was not attained. Quality assessment of the included studies was carried out using the PEDro scale. The search produced 774 results, from which 81 full-text articles were studied. Five randomized controlled trials of good methodological quality, including 331 participants, were included in the review. The effectiveness of hip muscle strengthening was assessed in isolation, combination, and comparison with other lower extremity exercise. Overall, the studies reported clear benefits of hip muscle strengthening on knee pain, physical function, and hip muscle strength. However, hip muscle strengthening was ineffective in improving the biomechanical measures such as dynamic alignment and knee adduction (also known as valgus) moment. The current review identified strong, high-quality evidence to recommend hip muscle strengthening in the conservative management of persons with knee OA. Further research is needed to establish the underlying mechanisms for the clinical benefits.


Thermally Conductive MXene.
MXene materials, which consist of nitrides, carbides, or carbonitrides of transition metals, possess a distinctive multilayered structure resulting from the specific etching of the "A" layer from MAX phase precursors. This unique structure allows for tunable properties through intercalation and surface modification. Beyond their structural novelty, MXenes exhibit exceptional thermal conductivity, mechanical resilience, and versatile surface functionalization capabilities, rendering them highly versatile for a wide range of applications. They are particularly renowned for their multifaceted utility and are emerging as outstanding candidates in applications requiring robust thermal conductivity. MXenes, when integrated into textile, fiber, and film forms, have gained increasing relevance in fields where efficient heat management is essential. This work provides a comprehensive exploration of MXene materials, delving into their inherent structure and thermal properties. This Perspective places particular emphasis on their crucial role in efficient heat dissipation, which is vital for the development of wearable heaters and related technologies. Engineered compounds such as MXenes have become indispensable for personal and industrial heating applications, and the advancement of wearable electronic devices necessitates heaters with specific properties, including transparency, mechanical reliability, and adaptability. Recent advancements in emergent thermally conductive MXene compounds are discussed in this study, shedding light on their potential contributions across various domains, including wearable heaters and biosensors for healthcare and environmental monitoring. Furthermore, the versatile nature of MXene materials extends to their application in interfacial solar steam generation, representing a breakthrough approach for solar water desalination. This multifaceted utility underscores the vast potential of MXenes in addressing various pressing challenges.


Amyloidogenic and associated proteins in systemic amyloidosis proteome of adipose tissue.
In systemic amyloidoses, widespread deposition of protein as amyloid causes severe organ dysfunction. It is necessary to discriminate among the different forms of amyloid to design an appropriate therapeutic strategy. We developed a proteomics methodology utilizing two-dimensional polyacrylamide gel electrophoresis followed by matrix-assisted laser desorption/ionization mass spectrometry and peptide mass fingerprinting to directly characterize amyloid deposits in abdominal subcutaneous fat obtained by fine needle aspiration from patients diagnosed as having amyloidoses typed as immunoglobulin light chain or transthyretin. Striking differences in the two-dimensional gel proteomes of adipose tissue were observed between controls and patients and between the two types of patients with distinct, additional spots present in the patient specimens that could be assigned as the amyloidogenic proteins in full-length and truncated forms. In patients heterozygotic for transthyretin mutations, wild-type peptides and peptides containing amyloidogenic transthyretin variants were isolated in roughly equal amounts from the same protein spots, indicative of incorporation of both species into the deposits. Furthermore novel spots unrelated to the amyloidogenic proteins appeared in patient samples; some of these were identified as isoforms of serum amyloid P and apolipoprotein E, proteins that have been described previously to be associated with amyloid deposits. Finally changes in the normal expression pattern of resident adipose proteins, such as down-regulation of alphaB-crystallin, peroxiredoxin 6, and aldo-keto reductase I, were observed in apparent association with the presence of amyloid, although their levels did not strictly correlate with the grade of amyloid deposition. This proteomics approach not only provides a way to detect and unambiguously type the deposits in abdominal subcutaneous fat aspirates from patients with amyloidoses but it may also have the capability to generate new insights into the mechanism of the diseases by identifying novel proteins or protein post-translational modifications associated with amyloid infiltration.


The effects of partial extraction of TnC upon the tension-pCa relationship in rabbit skinned skeletal muscle fibers.
The activation of contraction in vertebrate skeletal muscle involves the binding of Ca2+ to low-affinity binding sites on the troponin C (TnC) subunit of the regulatory protein troponin. The present study is an investigation of possible cooperative interactions between adjacent functional groups, composed of seven actin monomers, one tropomyosin, and one troponin, along the same thin filament. Single skinned fibers were obtained from rabbit psoas muscles and were then placed in an experimental chamber containing relaxing solution maintained at 15 degrees C. Isometric tension was measured in solutions containing maximally and submaximally activating levels of free Ca2+ (a) in control fiber segments, (b) in the same segments after partial extraction of TnC, and finally (c) after recombination of TnC into the segments. The extraction was done at 11-13 degrees C in 20 mM Tris, 5 mM EDTA, pH 7.85 or 8.3, a procedure derived from that of Cox et al. (1981. Biochem. J. 195:205). Extraction of TnC was quantitated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the control and experimental samples. Partial extraction of TnC resulted in reductions in tension during maximal Ca activation and in a shift of the relative tension-pCa (i.e., -log[Ca2+]) relationship to lower pCa's. The readdition of TnC to the extracted fiber segments resulted in a recovery of tension to near-control levels and in the return of the tension-pCa relation to its original position. On the basis of these findings, we conclude that the sensitivity to Ca2+ of a functional group within the thin filament may vary depending upon the state of activation of immediately adjacent groups.


Complementary and alternative medicine in children with diffuse intrinsic pontine glioma-A SIOPE DIPG Network and Registry study.
Diffuse intrinsic pontine glioma (DIPG) is a rare and aggressive childhood brainstem malignancy with a 2-year survival rate of <10%. This international survey study aims to evaluate the use of complementary and alternative medicine (CAM) in this patient population. Parents and physicians of patients with DIPG were asked to participate in a retrospective online survey regarding CAM use during time of illness. Between January and May 2020, 120 parents and 75 physicians contributed to the online survey. Most physicians estimated that <50% of their patients used CAM, whereas 69% of the parents reported using CAM to treat their child during time of illness. Cannabis was the most frequently used form of CAM, followed by vitamins and minerals, melatonin, curcumin, and boswellic acid. CAM was mainly used with the intention of direct antitumor effect. Other motivations were to treat side effects of chemotherapy or to increase comfort of the child. Children diagnosed from 2016 onwards were more likely to use CAM (χ2 = 6.08, p = .014). No significant difference was found between CAM users and nonusers based on ethnicity (χ2 = 4.18, p = .382) or country of residence (χ2 = 9.37, p = .154). Almost 50% of the physicians do not frequently ask their patients about possible CAM use. This survey demonstrates that worldwide, a considerable number of patients with DIPG use CAM. Physicians should be more aware of potential CAM use and actively discuss the topic. In addition, more research is needed to gain knowledge about possible anticancer effects of CAM and (positive/negative) interactions with conventional therapies.


Inadequate Status and Low Awareness of Folate in Switzerland-A Call to Strengthen Public Health Measures to Ensure Sufficient Intakes.
Folate plays an essential role in the prevention of neural tube defects, yet little is known about the folate status of women of reproductive age or to what degree the general population is aware of the importance of folate in early-life development. We aimed to determine folate status in women of reproductive age and pregnant women in Switzerland, and to assess folate awareness in the Swiss population. In a convenience sample of 171 women of reproductive age and 177 pregnant women throughout Switzerland, we measured red blood cell (RBC) folate concentration. In a second convenience sample (n = 784, men and women) we assessed folate knowledge with an online survey. RBC folate concentration (median interquartile range) was 442 (366, 564) nmol/L in women of reproductive age and 873 (677, 1177) nmol/L in pregnant women. Folate deficiency (RBC folate <340 nmol/L) was found in 19.9% of women of reproductive age and 2.8% of pregnant women, while 91.8% of women of reproductive age and 52.0% of pregnant women showed folate concentrations indicating an elevated risk of neural tube defects (RBC folate <906 nmol/L). The online survey showed that a high proportion (≥88%) of participants were aware of folate's role in neural tube defect (NTD) prevention and fetal development, yet knowledge about dietary sources and national recommendations of folate supplementation when planning pregnancy were limited. The high prevalence of folate inadequacy in Swiss women suggests an elevated risk of neural tube defects and calls for urgent measures to increase folate intakes.


Protective Effect of Baicalin on Chlorpyrifos-Induced Liver Injury and Its Mechanism.
Chlorpyrifos (CPF) plays a vital role in the control of various pests in agriculture and household life, even though some studies have indicated that CPF residues pose a significant risk to human health. Baicalin (BA) is a flavonoid drug with an obvious effect on the prevention and treatment of liver diseases. In this study, the protective effect of BA in vitro and in vivo was investigated by establishing a CPF-induced AML12 cell damage model and a CPF-induced Kunming female mouse liver injury model. The AML12 cell damage model indicated that BA had a good positive regulatory effect on various inflammatory factors, redox indexes, and abnormal apoptosis factors induced by CPF. The liver injury model of female mice in Kunming showed that BA significantly improved the liver function indexes, inflammatory response, and fibrosis of mice. In addition, BA alleviated CPF-induced AML12 cell damage and Kunming female mouse liver injury by enhancing autophagy and regulating apoptosis pathways through Western blotting. Collectively, these data suggest that the potential mechanism of BA is a multi-target and multi-channel treatment for chlorpyrifos-induced liver injury.