Estradiol assays--The path ahead.
Estradiol quantitation is useful in the clinical assessment of diseases like hypogonadism, hirsutism, polycystic ovary syndrome (PCOS), amenorrhea, ovarian tumors and for monitoring response in women receiving aromatase inhibitor therapy. Physiologically relevant serum estradiol concentration in women can span across four orders of magnitude. For example, in women undergoing ovulation induction serum estradiol concentration can range between 250-2000 pg/mL whereas aromatase inhibitor therapy can decrease serum estradiol concentration to <5 pg/mL. While high-through-put automated un-extracted (direct) immunoassays accommodate the growing clinical need for estradiol quantitation, are amenable to implementation by most hospital clinical laboratories, they display a significant loss of specificity and accuracy at low concentrations. Most clinical scenarios (example: estradiol monitoring in fertility treatments) place a modest demand on accuracy and precision of the assay in use but accurate quantitation of estradiol in certain clinical scenarios (pediatric and male patients and for monitoring aromatase inhibitor therapy) can be challenging using currently available immunoassays since the direct immunoassays are prone to issues with sub-optimal accuracy and specificity due to cross reactivity with estradiol conjugates and metabolites. In this review we discuss the bases for the evolution of estradiol assays from extracted (indirect) radio-immunoassays to direct immunoassays to liquid-chromatography tandem mass spectrometry (LC-MS/MS) based assays, discuss technical factors relevant for development and optimization of a LC-MS/MS assay for estradiol and present the details and performance characteristics of an ultra-sensitive LC-MS/MS estradiol assay with a limit of quantitation of 0.2 pg/mL.


A Set of Eight Key Questions Helps to Classify Common Vestibular Disorders-Results From the DizzyReg Patient Registry.
Precise history taking is the key to develop a first assumption on the diagnosis of vestibular disorders. Particularly in the primary care setting, algorithms are needed, which are based on a small number of questions and variables only to guide appropriate diagnostic decisions. The aim of this study is to identify a set of such key variables that can be used for preliminary classification of the most common vestibular disorders. A four-step approach was implemented to achieve this aim: (1) we conducted an online expert survey to collect variables that are meaningful for medical history taking, (2) we used qualitative content analysis to structure these variables, (3) we identified matching variables of the patient registry of the German Center for Vertigo and Balance Disorders, and (4) we used classification trees to build a classification model based on these identified variables and to analyze if and how these variables contribute to the classification of common vestibular disorders. We included a total of 1,066 patients with seven common vestibular disorders (mean age of 51.1 years, SD = 15.3, 56% female). Functional dizziness was the most frequent diagnosis (32.5%), followed by vestibular migraine (20.2%) and Menière's disease (13.3%). Using classification trees, we identified eight key variables which can differentiate the seven vestibular disorders with an accuracy of almost 50%. The key questions comprised attack duration, rotational vertigo, hearing problems, turning in bed as a trigger, doing sport or heavy household chores as a trigger, age, having problems with walking in the dark, and vomiting. The presented algorithm showed a high-face validity and can be helpful for taking initial medical history in patients with vertigo and dizziness. Further research is required to evaluate if the identified algorithm can be applied in the primary care setting and to evaluate its external validity.


Feline aminopeptidase N serves as a receptor for feline, canine, porcine, and human coronaviruses in serogroup I.
Two members of coronavirus serogroup I, human respiratory coronavirus HCV-229E and porcine transmissible gastroenteritis virus (TGEV), use aminopeptidase N (APN) as their cellular receptors. These viruses show marked species specificity in receptor utilization, as HCV-229E can utilize human but not porcine APN, while TGEV can utilize porcine but not human APN. To determine whether feline APN could serve as a receptor for two feline coronaviruses in serogroup I, feline infectious peritonitis virus (FIPV) and feline enteric coronavirus (FeCV), we cloned the cDNA encoding feline APN (fAPN) by PCR from cDNA isolated from a feline cell line and stably expressed it in FIPV- and FeCV-resistant mouse and hamster cells. The predicted amino acid sequence of fAPN shows 78 and 77% identity with human and porcine APN, respectively. When inoculated with either of two biologically different strains of FIPV or with FeCV, fAPN-transfected mouse and hamster cells became infected and viral antigens developed in the cytoplasm. Infectious FIPV was released from hamster cells stably transfected with fAPN. The fAPN-transfected mouse and hamster cells were challenged with other coronaviruses in serogroup I including canine coronavirus, porcine coronavirus TGEV, and human coronavirus HCV-229E. In addition to serving as a receptor for the feline coronaviruses, fAPN also served as a functional receptor for each of these serogroup I coronaviruses as shown by development of viral antigens in the cytoplasm of infected mouse or hamster cells stably transfected with fAPN. In contrast, fAPN did not serve as a functional receptor for mouse hepatitis virus (MHV-A59), which is in serogroup II and utilizes mouse biliary glycoprotein receptors unrelated to APN. Thus, fAPN serves as a receptor for a much broader range of group I coronaviruses than human and porcine APNs. The human, porcine, and canine coronaviruses in serogroup I that are able to use fAPN as a receptor have previously been shown to infect cats without causing disease. Therefore, host factors in addition to receptor specificity apparently affect the virulence and transmissibility of nonfeline serogroup I coronaviruses in the cat.


Antitumor activity of immunotoxins with T-cell receptor-like specificity against human melanoma xenografts.
In this study, we have explored the use of Fab-toxin proteins (immunotoxin) to target antigen-specific MHC-peptide complexes of in vitro and in vivo cancer cells. A human phage display library was used to screen for T-cell receptor (TCR)-like antibodies that are highly specific for the peptide melanoma-associated antigen MART-1(26-35) presented by HLA-A201. We also used previously selected TCR-like antibodies specific for the peptide melanoma-associated antigen gp100(280-288) presented by HLA-A201. The recombinant immunotoxin constructs were generated by fusing the targeting Fab fragment to a truncated form of Pseudomonas exotoxin, PE38KDEL. These immunotoxins bound with high affinity to the EBV-transformed JY cell line pulsed with the aforementioned peptides and internalized within 30 min. A significant inhibition of protein synthesis, which resulted in cell death, was detected at 24 h. MART-1-specific and gp100-specific immunotoxins bound and killed HLA-A201 melanoma MART-1(+) and gp100(+) cell lines that were presented at natural levels but do not bind to HLA-A201(-) or to HLA-A201(+) MART-1(-) and gp100(-) cell lines. In severe combined immunodeficient mice, MART-1 and gp100 immunotoxins significantly and discriminately inhibited human melanoma growth. These results show that MHC class I/peptide complexes can serve as a specific target for passive immunotherapy of cancer.


Single-Phase Formation of Rh2 O3 Nanoparticles on h-BN Support for Highly Controlled Methane Partial Oxidation to Syngas.
Single-phase formation of active metal oxides on supports has been vigorously pursued in many catalytic applications to suppress undesired reactions and to determine direct structure-property relationships. However, this is difficult to achieve in nanoscale range because the effect of non-uniform metal-support interfaces becomes dominant in the overall catalyst growth, leading to the nucleation of various metastable oxides. Herein, we develop a supported single-phase corundum-Rh2 O3 (I) nanocatalyst by utilizing controlled interaction between metal oxide and h-BN support. Atomic-resolution electron microscopy and first-principle calculation reveal that single-phase formation occurs via uniform and preferential attachment of Rh2 O3 (I) (110) seed planes on well-defined h-BN surface after decomposition of rhodium precursor. By utilizing the Rh/h-BN catalyst in methane partial oxidation, syngas is successfully produced solely following the direct route with keeping a H2 /CO ratio of 2, which makes it ideal for most downstream chemical processes.


Selection of reference genes for quantitative real-time PCR expression studies of microdissected reproductive tissues in apomictic and sexual Boechera.
Apomixis, a natural form of asexual seed production in plants, is considered to have great biotechnological potential for agriculture. It has been hypothesised that de-regulation of the sexual developmental pathway could trigger apomictic reproduction. The genus Boechera represents an interesting model system for understanding apomixis, having both sexual and apomictic genotypes at the diploid level. Quantitative qRT-PCR is the most extensively used method for validating genome-wide gene expression analyses, but in order to obtain reliable results, suitable reference genes are necessary. In this work we have evaluated six potential reference genes isolated from a 454 (FLX) derived cDNA library of Boechera. RNA from live microdissected ovules and anthers at different developmental stages, as well as vegetative tissues of apomictic and sexual Boechera, were used to validate the candidates. Based on homologies with Arabidopsis, six genes were selected from a 454 cDNA library of Boechera: RPS18 (Ribosomal sub protein 18), Efalpha1 (Elongation factor 1 alpha), ACT 2 (Actin2), UBQ (polyubiquitin), PEX4 (Peroxisomal ubiquitin conjugating enzyme) and At1g09770.1 (Arabidopsis thaliana cell division cycle 5). Total RNA was extracted from 17 different tissues, qRT-PCRs were performed, and raw Ct values were analyzed for primer efficiencies and gene ratios. The geNorm and normFinder applications were used for selecting the most stable genes among all tissues and specific tissue groups (ovule, anthers and vegetative tissues) in both apomictic and sexual plants separately. Our results show that BoechRPS18, BoechEfα1, BoechACT2 and BoechUBQ were the most stable genes. Based on geNorm, the combinations of BoechRPS18 and BoechEfα1 or BoechUBQ and BoechEfα1 were the most stable in the apomictic plant, while BoechRPS18 and BoechACT2 or BoechUBQ and BoechACT2 performed best in the sexual plant. When subgroups of tissue samples were analyzed, different optimal combinations were identified in sexual ovules (BoechUBQ and BoechEfα1), in anthers from both reproductive systems (BoechACT2 and BoechEfα1), in apomictic vegetative tissues (BoechEfα1 and BoechACT2) and sexual vegetative tissues (BoechRPS18 and BoechEfα1). NormFinder ranked BoechACT2 as the most stable in the apomictic plant, while BoechRPS18 was the best in the sexual plant. The subgroups analysis identified the best gene for both apomictic and sexual ovules (BoechRPS18), for anthers from both reproductive system (BoechEfα1) and for apomictic and vegetative tissues (BoechACT2 and BoechRPS18 respectively) From a total of six tested genes, BoechRPS18, BoechEfα1, BoechACT2 and BoechUBQ showed the best stability values. We furthermore provide detailed information for the accurate normalization of specific tissue gene expression analyses of apomictic and sexual Boechera.


Legal and policy aspects of home care coverage.
Home health care is a compassionate, cost-effective, and practical alternative for some individuals who require long-term or constant care. However, the coverage of home health care costs is far from comprehensive under the Medicare, Medicaid, and private pay systems. A uniform and comprehensive coverage system is necessary.


Colchicine for secondary prevention of cardiovascular disease.
Preliminary evidence demonstrating that adding 0.5 mg of colchicine per day to statin and antiplatelet therapy reduced the risk of acute coronary events in patients with stable coronary artery disease has raised the hope that it may prove effective for the long-term secondary prevention of cardiovascular disease. The ability of colchicine to suppress blood levels of inflammatory mediators and prevent cholesterol-crystal-induced neutrophil-mediated inflammation implicated in the progression and instability of atherosclerosis adds plausibility to this clinical observation. Early intestinal intolerance in some patients is well recognized, but clinical experience gained over more than half a century with the continuous use of colchicine for the prevention of neutrophil-mediated inflammation in patients with familial Mediterranean fever and gout indicates that low-dose long-term therapy is safe. Nonetheless, before colchicine can be recommended for the secondary prevention of cardiovascular disease, further studies are required to confirm its safety and efficacy in a broad range of patients with coronary disease, and to determine whether doses of colchicine less than 0.5 mg/day might be effective and even better tolerated. Trials exploring the role of colchicine in the treatment of patients with acute coronary syndromes would also be of special interest but may require the use of doses higher than those used for long-term secondary prevention.


Ellagic Acid Alleviates Rheumatoid Arthritis in Rats through Inhibiting MTA1/HDAC1-Mediated Nur77 Deacetylation.
Ellagic acid (EA) was reported to play protective roles in rheumatoid arthritis (RA). It was found that the level of metastasis-associated gene 1 (MTA1)/histone deacetylase 1 (HDAC1) protein complex was downregulated by polyphenols in several human disorders. Notably, inhibition of MTA1 or HDAC1 has anti-inflammatory effects on RA. Therefore, our study is aimed at investigating whether EA prevents RA progression through regulating the MTA1/HDAC1 complex. Herein, the human fibroblast-like synoviocyte (FLS) cell line MH7A was treated with TNF-α to induce an inflammation model in vitro and then incubated with different concentrations of EA. Western blot analysis showed that EA reduced MTA1 expression in a dose-dependent manner in MH7A cells. Then, TNF-α-treated MH7A cells were incubated with EA alone or together with MTA1 overexpression plasmid (pcDNA-MTA1), and we found that EA inhibited proliferation, inflammation cytokine levels, and oxidative stress marker protein levels and promoted apoptosis in MH7A cells, while MTA1 overexpression abolished these effects. Moreover, coimmunoprecipitation assay verified the interaction between MTA1 and HDAC1. EA downregulated the MTA1/HDAC1 complex in MH7A cells. MTA1 knockdown inhibited proliferation, inflammation, and oxidative stress and promoted apoptosis in MH7A cells, while HDAC1 overexpression reversed these effects. Moreover, chromatin immunoprecipitation assay indicated that EA inhibited HDAC1-mediated Nur77 deacetylation. Rescue experiments demonstrated that Nur77 knockdown reversed the effects of EA on MH7A cell biological behaviors. Additionally, EA treatment attenuated arthritis index, paw swelling, synovial hyperplasia, and inflammation in collagen-induced arthritis (CIA) rats. In conclusion, EA inhibited proliferation, inflammation, and oxidative stress and promoted apoptosis in MH7A cells and alleviated the severity of RA in CIA rats though downregulating MTA1/HDAC1 complex and promoting HDAC1 deacetylation-mediated Nur77 expression.


[Memantine for treatment of behavioural disturbances and psychotic symptoms in moderate to moderately severe Alzheimer dementia: a naturalistic study in outpatient services in Austria].
We conducted an open, 16-week study on the efficacy of memantine on behavioral disturbances and psychotic symptoms in moderate to moderately severe Alzheimer s disease in daily routine. Fifty-three patients of 20 outpatient centers in Austria were recruited. The Neuropsychiatric Inventory (NPI) was defined as main outcome measure. After 16 weeks the total NPI score improved by 4,6 points (p<0.01). The caregiver distress score was also significantly reduced. The most pronounced improvements were seen in the NPI components depression (-24,6%), aberrant motor behavior (-16,9%), agitation/agression, fear, apathy, disinhibition and disturbances in appetite and eating behavior (-11,3%, each). Our naturalistic study is in line with the results of controlled trials in moderate and severe Alzheimer dementia stages. Controlled clinical trials which have behavioral disturbances and psychotic symptoms as primary endpoint are needed to define the true potential of memantine in mild dementia stages.


[Reactivation of ocular toxoplasmosis after laser in situ keratomileusis].
Laser in situ keratomileusis (LASIK) is a safe and efficient refractive surgical procedure that provides excellent results in most cases. Several complications have been reported, most of them related to the posterior segment of the eye. Although they are quite rare, a growing number of vitreoretinal pathologic conditions after LASIK have been reported. To date no article has reported an inflammatory or infectious disease of the posterior segment after a LASIK procedure. We report a case of reactivation of toxoplasmic chorioretinitis that occurred 5 days after a LASIK procedure. Clinical outcome was spontaneously favorable after 1 month, with no loss of vision. Although a causal effect between LASIK and toxoplasmic chorioretinitis reactivation cannot be proven with a single case report, we stress the importance of dilated fundus examination in LASIK preoperative assessment: our case suggests that in the presence of preoperative toxoplasmic chorioretinitis scars, increased retinal monitoring is required.


Chapter 1: Sinonasal anatomy and function.
An understanding of paranasal sinus anatomy based on important fixed landmarks rather than variable anatomy is critical to ensure safe and complete surgery. The concept of the paranasal surgical box defines the anatomic limits of dissection. The boundaries of the surgical box include the middle turbinate medially, orbital wall laterally, and skull base superiorly. The "vertical component" of the surgical box defines the boundaries of the frontal recess and includes the middle turbinate and intersinus septum medially, medial orbital wall and orbital roof laterally, nasofrontal beak anteriorly, and skull base and posterior table of frontal sinus posteriorly. The paranasal sinuses are divided into anterior, posterior, and sphenoidal functional cavities based on their distinct drainage pathways into the nose. The ultimate goal of surgery is to create a functional sinus cavity. Application of the paranasal surgical box and its vertical component enables the surgeon to view the limits of dissection with a single position of the endoscope. This will ensure complete dissection of the functional sinonasal compartments and effectively avoid leaving behind disconnected cells from the surgical cavity, mucocele formation, mucous recirculation, overcome obstructive phenomenon and enable maximal delivery of topical therapy in the post-operative setting. This article reviews the structure and function of the nasal cartilages and turbinates. It also describes the concept of the paranasal surgical box, key anatomical landmarks and limits of dissection. Normal anatomy and common variants of normal anatomy are discussed.


Direct imaging of nanoscale dissolution of dicalcium phosphate dihydrate by an organic ligand: concentration matters.
Unraveling the kinetics and mechanisms of sparingly soluble calcium orthophosphate (Ca-P) dissolution in the presence of organic acids at microscopic levels is important for an improved understanding in determining the effectiveness of organic acids present in most rhizosphere environments. Herein, we use in situ atomic force microscopy (AFM) coupled with a fluid reaction cell to image dissolution on the (010) face of brushite, CaHPO4 · 2H2O, in citrate-bearing solutions over a broad concentration range. We directly measure the dependence of molecular step retreat rate on citrate concentration at various pH values and ionic strengths, relevant to soil solution conditions. We find that low concentrations of citrate (10-100 μM) induced a reduction in step retreat rates along both the [100]Cc and [101]Cc directions. However, at higher concentrations (exceeding 0.1 mM), this inhibitory effect was reversed with step retreat speeds increasing rapidly. These results demonstrate that the concentration-dependent modulation of nanoscale Ca-P phase dissolution by citrate may be applied to analyze the controversial role of organic acids in enhancing Ca-P mineral dissolution in a more complex rhizosphere environment. These in situ observations may contribute to resolving the previously unrecognized interactions of root exudates (low molecular weight organic acids) and sparingly soluble Ca-P minerals.


Sex Differences in Cancer Genomes: Much Learned, More Unknown.
Cancer is a leading cause of death worldwide. Sex influences cancer in a bewildering variety of ways. In some cancer types, it affects prevalence; in others, genomic profiles, response to treatment, or mortality. In some, sex seems to have little or no influence. How and when sex influences cancer initiation and progression remain a critical gap in our understanding of cancer, with direct relevance to precision medicine. Here, we note several factors that complicate our understanding of sex differences: representativeness of large cohorts, confounding with features such as ancestry, age, obesity, and variability in clinical presentation. We summarize the key resources available to study molecular sex differences and suggest some likely directions for improving our understanding of how patient sex influences cancer behavior.


Influence of substrate structure on substrate binding to the renal organic cation/H+ exchanger.
The carrier-mediated exchange of H+ for organic cations ("OC/H+ exchange") is the active step in OC secretion in renal proximal tubules. Although hydrophobicity is known to be an important criterion for binding of substrates to this transporter, the degree to which steric parameters of substrate structure influence binding to the exchanger is unclear. We examined this issue by measuring the inhibition of OC/H+ exchange produced by a group of quaternary ammonium compounds which share a common structural motif: an N1-pyridinium residue. Activity of the OC/H+ exchanger was determined by measuring transport of [14C]tetraethylammonium (TEA) in brush-border membrane vesicles (BBMV) from rabbit renal cortex. Transport was measured in the presence of a pH gradient (pHin 6.0; pHout 7.5) to maximize TEA/H+ exchange. Apparent inhibitory constants (Ki values) for each test agent were measured. The test agents included 4-phenylpyridiniums and 3-phenylpyridiniums, quinoliniums and acridiniums. The planar structure of these compounds permits a direct test of whether the presence of planar hydrophobic mass in different orientations relative to the pyridinium motif exerts a systematic effect on substrate binding to the OC/H+ exchanger. The hydrophobicity of each group of compounds was systematically varied by addition of different substituents at the quaternary nitrogen. Whereas decreases in Ki proved to be proportional to hydrophobicity, the position of the phenyl-ring substituent(s) had no effect on substrate interaction with the exchanger. The results led to the development of a preliminary quantitative structure-activity relationship (QSAR) correlating substrate hydrophobicity and substrate binding to the OC/H+ exchanger. This QSAR was used to predict the binding of 1-methyl-4-phenylpyridinium (MPP+), (+) and (-)nicotine, (+) and (-)ephedrine, quinine and quinidine to the OC/H+ exchanger. Molecular graphics representation of the 3D structures of the test agents was used to develop a working model of a hydrophobic, planar receptor surface on the OC/H+ exchanger against which substrates are suggested to interact during binding. Development of the QSAR and receptor surface model open the way to quantitative tests of the specific physical and structural determinants of substrate selectivity by the renal OC/H+ exchanger.


Nutrition-Sensitive Agriculture: A Systematic Review of Impact Pathways to Nutrition Outcomes.
The role of agriculture in reducing undernutrition is widely recognized, yet there is also consensus on the need to make the sector nutrition-sensitive. Evidence on the impact pathways from nutrition-sensitive agriculture (NSA) interventions, agricultural interventions with specific nutrition objectives, and actions detailing each temporal stage to reach nutrition outcomes is limited, however. We thus synthesized study results regarding impact of NSA interventions on nutrition outcomes relating to undernutrition, and constructed an impact pathway by mapping the evidence on each temporal stage from interventions to nutrition outcomes. We used Preferred Reporting Items for Systematic Reviews and Meta-Analyses to conduct and report our systematic review of studies on NSA interventions implemented in low- and lower-middle-income countries. Forty-three studies that met the inclusion criteria were extracted and synthesized across impact and pathways analyses. We carried out a thematic analysis of the effect of NSA interventions using evidence-based indicators and constructed the pathways by adopting a published framework on agriculture to nutrition pathways. Our findings reveal that NSA interventions can significantly improve dietary practices, and have the potential to enhance care practices and reduce occurrence of diseases, indicating their effectiveness in simultaneously addressing multiple determinants of undernutrition. However, NSA interventions have a lesser impact on nutritional status. NSA interventions lead to nutrition outcomes through 5 key pathways: food production, nutrition-related knowledge, agricultural income, women's empowerment, and strengthening of local institutions. We emphasize the need to carefully design, implement, and evaluate interventions with consideration for factors affecting impact pathways. Future research should focus on the effect of interventions combining multisector components, and pathways through non-food-production-related income, women's empowerment, strengthening of local institutions, food prices at intervention level, and expenditure on health care.


Transition-Metal-Catalyzed 1,2-Diaminations of Olefins: Synthetic Methodologies and Mechanistic Studies.
1,2-Diamines are synthetically important motifs in organo-catalysis, natural products, and drug research. Continuous utilization of transition-metal based catalyst in direct 1,2-diamination of olefines, in contrast to metal-free transformations, with numerous impressive advances made in recent years (2015-2023). This review summarized contemporary research on the transition-metal catalyzed/mediated [e. g., Cu(II), Pd(II), Fe(II), Rh(III), Ir(III), and Co(II)] 1,2-diamination (asymmetric and non-asymmetric) especially emphasizing the recent synthetic methodologies and mechanistic understandings. Moreover, up-to-date discussion on (i) paramount role of oxidant and catalyst (ii) key achievements (iii) generality and uniqueness, (iv) synthetic limitations or future challenges, and (v) future opportunities are summarized related to this potential area.


Clinical heterogeneity of acquired hemophilia A: a description of 4 cases.
Acquired hemophilia A is a rare but severe auto-immune bleeding disorder characterized by the presence of autoantibodies directed against clotting factor VIII. Acquired hemophilia A may be idiopathic or associated with several conditions, such as postpartum, autoimmune diseases, malignancies or drugs. The treatment modalities of bleeding episodes and eradication of the factor VIII auto-antibody depend on the titer of anti-factor VIII:C and may include desmopressin (DDAVP), prednisolone, prednisolone-cyclophosphamide, high dose intravenous gammaglobulin, FVIII-VWF concentrate and/or recombinant FVIIa (rFVIIa). In this study we report four cases of autoimmune factor VIII inhibitors (2 associated with autoimmune disorders, 2 idiopathic) demonstrating the heterogeneity of this disease from pathogenic, clinical, therapeutic and prognostic points of view.


Management of acute-onset and life-threatening respiratory distress of unusual aetiology.
A 30-year-old female experienced severe acute respiratory distress in her apartment assumed to be due to an allergic asthma. Upon arrival of the emergency physician at the scene the patient was unconscious and cyanotic. Auscultation yielded no respiratory sounds despite visible efforts of the patient. Mask ventilation was virtually impossible. Endotracheal intubation was performed but complicated by a distinct resistance. Ventilation remained difficult, despite antiobstructive medication and deep general anaesthesia. Fiberoptic bronchoscopy in the hospital finally showed a bulk of granulomatous tissue located just above the tracheal bifurcation. Here, the authors report a rare case of acute-onset respiratory distress due to Wegener's granulomatosis.


Validation of Six Commercial Antibodies for the Detection of Heterologous and Endogenous TRPM8 Ion Channel Expression.
TRPM8 is a non-selective cation channel expressed in primary sensory neurons and other tissues, including the prostate and urothelium. Its participation in different physiological and pathological processes such as thermoregulation, pain, itch, inflammation and cancer has been widely described, making it a promising target for therapeutic approaches. The detection and quantification of TRPM8 seems crucial for advancing the knowledge of the mechanisms underlying its role in these pathophysiological conditions. Antibody-based techniques are commonly used for protein detection and quantification, although their performance with many ion channels, including TRPM8, is suboptimal. Thus, the search for reliable antibodies is of utmost importance. In this study, we characterized the performance of six TRPM8 commercial antibodies in three immunodetection techniques: Western blot, immunocytochemistry and immunohistochemistry. Different outcomes were obtained for the tested antibodies; two of them proved to be successful in detecting TRPM8 in the three approaches while, in the conditions tested, the other four were acceptable only for specific techniques. Considering our results, we offer some insight into the usefulness of these antibodies for the detection of TRPM8 depending on the methodology of choice.


Antibody-drug conjugates: the chemistry behind empowering antibodies to fight cancer.
For more than a century, the concept of a "magic bullet" to deliver cytotoxic therapy to the site of disease has been envisioned but only recently have technological advances enabled antibody-drug conjugates to fulfill that dream. The recent approvals of brentuximab vedotin and ado-trastuzumab emtansine and emerging data for many molecules in clinical trials highlight the potential for antibody-drug conjugates to offer new therapeutic options for patients. This chapter reviews the evolution, state of the art, and potential future improvements that are enabling rapid development of this important class of cancer therapeutics.


Research on rural residence and access to drug abuse services: where are we and where do we go?
Illicit drug use is common in rural areas, but very little research has investigated rural populations' access to drug abuse services. To describe the current state of the scientific literature on access to drug abuse services in rural areas and suggest directions for future research. We performed a literature review of published articles on rural drug abuse services and summarized the findings according to potential, realized, accommodating, and acceptable access. Relevant articles on rural access to medical, alcohol, and mental health care were selected to supplement the scarce literature specific to drug abuse. A limited body of work indicates that rural populations have lower availability and utilize needed drug abuse services less frequently than their urban counterparts. Even less is known about the accommodation and acceptability of drug abuse programs serving rural populations. Research that investigates the existence and determinants of problems with access to drug abuse services is greatly needed to enable policy makers, drug treatment managers, and practitioners to better meet the needs of their rural clientele. As this field of inquiry advances, methodologies for constructing drug abuse service areas and measuring consumers' evaluations must be developed.


Regulation of spermiogenesis, spermiation and blood-testis barrier dynamics: novel insights from studies on Eps8 and Arp3.
Spermiogenesis in the mammalian testis is the most critical post-meiotic developmental event occurring during spermatogenesis in which haploid spermatids undergo extensive cellular, molecular and morphological changes to form spermatozoa. Spermatozoa are then released from the seminiferous epithelium at spermiation. At the same time, the BTB (blood-testis barrier) undergoes restructuring to facilitate the transit of preleptotene spermatocytes from the basal to the apical compartment. Thus meiotic divisions take place behind the BTB in the apical compartment to form spermatids. These germ cells enter spermiogenesis to transform into elongating spermatids and then into spermatozoa to replace those that were released in the previous cycle. However, the mole-cular regulators that control spermiogenesis, in particular the dynamic changes that occur at the Sertoli cell-spermatid interface and at the BTB, are not entirely known. This is largely due to the lack of suitable animal models which can be used to study these events. During the course of our investigation to develop adjudin [1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide] as a potential male contraceptive, this drug was shown to 'accelerate' spermiation by inducing the release of premature spermatids from the epithelium. Using this model, we have identified several molecules that are crucial in regulating the actin filament network and the unique adhesion protein complex at the Sertoli cell-spermatid interface known as the apical ES (ectoplasmic specialization). In the present review, we critically evaluate these and other findings in the literature as they relate to the restricted temporal and spatial expression of two actin regulatory proteins, namely Eps8 (epidermal growth factor receptor pathway substrate 8) and Arp3 (actin-related protein 3), which regulate these events.


Dyscalculia and dyslexia after right hemisphere injury in infancy.
To use the findings from neuropsychological evaluation and functional magnetic resonance imaging (fMRI) to assess interhemispheric reorganization of function after early unilateral brain injury. The study focused on one case of early brain injury that resulted in both dyscalculia and dyslexia. Brain injury was studied using both structural and fMRI. Intellectual function was evaluated using the Wechsler Intelligence Scale for Children, Third Edition, while visuospatial skills were assessed using the Block Design subtest of the Wechsler Intelligence Scale for Children, Third Edition, and Judgment of Line Orientation subtest. The Selective Reminding Test and the Recurring Figures Test were used to evaluate memory and orientation; language and speech skills were evaluated using the Boston Naming Test, Controlled Oral Word Association, Gates-MacGinitie Reading Test, and color naming. Various methods were used to study arithmetic skills, including the Wide Range Achievement Test-Revised and the Peabody Individual Achievement Test. The control group for fMRI consisted of nine normal subjects. Neuropsychological laboratory in primary care hospital. A 17-year-old boy who had sustained a closed head injury associated with a partially depressed, right parietal skull fracture, and right temporal hemorrhage in a motor vehicle crash at age 7 months (November 9, 1977). Subsequent social behavior was normal, but the patient had difficulty throughout school in mathematics and spelling and was characterized as having a "short attention span." None. Standardized tests of arithmetic and reading supplemented by an assessment of calculation and quantitative skills. While performing calculations, fMRI disclosed predominantly left hemisphere activation involving the frontal and posterior parietal regions, whereas this task produced bilateral activation of the supramarginal gyrus in seven of nine normal subjects. Neuropsychological findings confirmed the presence of dyscalculia and dyslexia despite normal intellectual functioning. Visuospatial skills ranged from the low normal to average level. The fMRI findings were consistent with early interhemispheric transfer of visuospatial skills normally committed to the right parietal area to the left parietal region. The patient's dyscalculia and reading ability raise a question of acquired left parietal dysfunction as a consequence of the competition between verbal and visuospatial functions for left hemisphere representation. Interhemispheric reorganization of function may be bidirectional rather than a feature unique to the left hemisphere substrate for language.


Quantitative trait linkage analysis by generalized estimating equations: unification of variance components and Haseman-Elston regression.
Two of the major approaches for linkage analysis with quantitative traits in humans include variance components and Haseman-Elston regression. Previously, these were viewed as quite separate methods. We describe a general model, fit by use of generalized estimating equations (GEE), for which the variance components and Haseman-Elston methods (including many of the extensions to the original Haseman-Elston method) are special cases, corresponding to different choices for a working covariance matrix. We also show that the regression-based test of Sham et al. ([2002] Am. J. Hum. Genet. 71:238-253) is equivalent to a robust score statistic derived from our GEE approach. These results have several important implications. First, this work provides new insight regarding the connection between these methods. Second, asymptotic approximations for power and sample size allow clear comparisons regarding the relative efficiency of the different methods. Third, our general framework suggests important extensions to the Haseman-Elston approach which make more complete use of the data in extended pedigrees and allow a natural incorporation of environmental and other covariates.


Comparative trials on hybrid walking systems for people with paraplegia: an analysis of study methodology.
A new orthosis (SEPRIX) which combines user friendliness with low energy cost of walking has been developed and will be subject to a clinical comparison with conventional hip-knee-ankle-foot orthoses. In designing such comparative trials it was considered it may be worthwhile to use previous clinical studies as practical examples. A literature search was conducted in order to select all comparative trials which have studied two walking systems (hip-knee-ankle-foot orthoses) for patients with a complete thoracic lesion. Study population, intervention, study design, outcome measurement and statistical analyses were examined. Statistical power was calculated where possible. Of 12 selected studies, 7 were simple A-B comparisons, 2 A-B comparisons with a replication, 2 cross-over trials and 1 nonrandomised parallel group design, the last of which was considered internally invalid due to severe confounding by indication. All A-B comparisons were considered internally invalid as well, since they have not taken into account that a comparison of two orthoses requires a control for aspecific effects (like test effects) which may cause a difference. Statistical power could only be examined in 4 studies and the highest statistical power achieved in one study was 47%. It is concluded that statistical power was too low to be able to detect differences. Even analysis through interval estimation showed that the estimation of the difference was too imprecise to be useful. Since the majority of the surveyed papers have reported small studies (of only 4-6 patients), it is assumed that lack of statistical power is a more general problem. Three possibilities are discussed in order to enhance statistical power in comparative trials, i.e. multicentre studies, statistical pooling of results and improving the efficiency of study design by means of interrupted time series designs.


FIELD EVALUATION OF FYFANON EW AGAINST AEDES AEGYPTI: A LOW ODOR ULTRA-LOW VOLUME FORMULATION OF MALATHION.
A low odor formulation of ultra-low volume (ULV) malathion (Fyfanon EW®) mosquito adulticide was evaluated in the field for its efficacy using caged female Aedes aegypti. Cages were placed in three rows, 30 m apart at 30, 60, and 90 m from the spray line. The product was applied at the manufacturer's suggested operational rate of 0.28 liter/min (9.5 fl oz/min) and at the maximum label rate of 0.37 liter/min (12.6 fl oz/min) with a Guardian 190ES truck mounted ULV sprayer. At 1 h post-treatment for the manufacturer's suggested operational rate, adult mortality ranged from 85% at 30 m to 46% at 90 m (overall average 65.5%). At 24 h post-treatment, mortality was significantly greater at each distance with complete control of caged mosquitoes at 30 m and >95% at 90 m. Overall, 24-h average mortality at this rate was 96.8%. At the maximum label rate, mosquito mortality at 1 h was considerably greater at all distances and ranged from about 89% to 75% with an overall average of 84.3%. At 24 h post-treatment, complete mortality was recorded at all transect distances at this higher rate. In conclusion, our results showed that at 24 h, Fyfanon EW® was considered very effective when applied by ULV truck mounted ground equipment for area-wide control of mosquitoes.


Genome-wide DNA methylation alteration in prenatally stressed Brahman heifer calves with the advancement of age.
Possible phenotypic impairments associated with maternal stress during gestation in beef cattle may be explained by epigenetic effects. This study examined the impact of prenatal transportation stress on DNA methylation of lymphocytes of Brahman cows over the first 5 years of life. Methylation analysis through reduced representation bisulphite sequencing was conducted on DNA from lymphocytes from 28 paired samples from 6 prenatally stressed (PNS) and 8 control (Control) females obtained initially when they were 28 days of age and 5 years of age. There were 14,386 CpG (C = cytosine; p = phosphate; G = guanine) sites differentially methylated (P < 0.01) in 5-yr-old Control cows compared to their lymphocyte DNA at 28 days of age, this number was slightly decreased in 5-yr-old PNS with 13,378 CpG sites. Only 2,749 age-related differentially methylated CpG sites were seen within PNS females. There were 2,637 CpG sites differentially methylated (P < 0.01) in PNS cows relative to Controls at 5 years of age. There were differentially methylated genes in 5-yr-old cows that contributed similarly to altered gene pathways in both treatment groups. Canonical pathways altered in PNS compared to Control cows at 5 years of age were mostly related to development and growth, nervous system development and function, and immune response. Prenatal stress appeared to alter the epigenome in Brahman cows compared to Control at 5 years of age, which implies a persistent intervention in DNA methylation in lymphocytes, and may confer long-lasting effects on gene expression, and consequently relevant phenotypic changes.


Parental perspectives on adolescent hearing loss risk and prevention.
Data indicate that 1 in 6 adolescents has high-frequency hearing loss, which is typically noise related and preventable. Parental participation improves the success of adolescent behavioral interventions, yet little is known about parental perspectives regarding adolescent noise-induced hearing loss. To perform a survey to determine parental knowledge of adolescent hearing loss and willingness to promote hearing conservation to discern information that is critical to design adolescent hearing loss prevention programs. A cross-sectional, Internet-based survey of a nationally representative online sample of parents of 13- to 17-year-olds. A survey conducted with the C.S. Mott Children's Hospital National Poll on Children's Health, a recurring online survey. Parental knowledge of adolescent hearing loss and willingness to promote hearing conservation. Of 716 eligible respondents, 96.3% of parents reported that their adolescent was slightly or not at all at risk of hearing problems from excessive noise, and 69.0% had not spoken with their adolescent about noise exposure, mainly because of the perceived low risk. Nonetheless, to protect their adolescents' hearing, more than 65.0% of parents are either willing or very willing to consider limiting time listening to music, limiting access to excessively noisy situations, or insisting on the use of hearing protection (earplugs or earmuffs). Higher parental education increased the odds of promoting hearing-protective strategies. Parents were less likely to insist on hearing protection for older adolescents. Parents who understood that both volume and time of exposure affect hearing damage were more likely to have discussed hearing loss with their adolescent (odds ratio [OR], 1.98; 95% CI, 1.29-3.03). The odds of discussing hearing loss were also increased for those who were willing or very willing to limit time listening to music (OR, 1.88; 95% CI, 1.19-2.26) and to insist on hearing protection (OR, 1.92; 95% CI, 1.15-3.18) compared with parents who were very unwilling, unwilling, or neutral. Despite the rising prevalence of acquired adolescent hearing loss, few parents believe their adolescent is at risk. Those with higher education are more willing to promote hearing conservation, especially with younger adolescents. To create effective hearing conservation programs, parents need better education on this subject as well as effective and acceptable strategies to prevent adolescent noise exposure.


Diagnostic tests for influenza infection.
The 2009 H1N1 pandemic focused attention on the speed and accuracy of influenza diagnostic methods. This review provides an update on current tests and new developments. Widely used rapid antigen tests and immunofluorescence tests were generally less sensitive for 2009 H1N1 influenza than for seasonal influenza. In addition, marked variability was reported for the same tests in different settings and patient groups. The advantages of molecular testing gained wide recognition, namely high sensitivity, speed compared with culture, ability to assess viral load and to identify subtype. Although adoption of influenza molecular testing can be expected to accelerate, immunoassays and rapid cultures performed on site retain advantages for many facilities. Falsely negative results were seen with all methods, especially for samples collected very early or late. Influenza diagnostic test performance can be adversely affected by viral genetic and antigenic changes and should be re-assessed annually. Variability in sensitivity and specificity of the same test in different settings highlights the need for each laboratory to ensure optimal procedures and work with clinicians to improve sample quality. Manufacturers have been motivated to improve immunoassays and develop simpler and faster multiplex molecular tests, hopefully in advance of the next pandemic.


The sequential determination of nitrite, N-nitroso compounds and nitrate and its application.
The selective determination of nitrite, N-nitroso compounds as a group and nitrate can be accomplished directly on most food or other matrices by quantifying the nitric oxide released following the additions in sequence of acetic acid, hydrogen bromide and titanous chloride under an atmosphere of nitrogen. Most of the many other compounds potentially formed from nitrite in a biological system are either decomposed to nitric oxide in the refluxing solvent system alone or else do not yield nitric oxide at any stage throughout the determinations of nitrite and N-nitroso compounds. Only nitrolic acids and S-nitrothiols, like nitrosamines and nitrosamides, require the use of hydrogen bromide for breakdown to nitric oxide. The application of the present procedure to the determination of nitrite and N-nitroso compounds (as a group) in a series of animal diets has shown the presence of levels of nitrite below the limit of detection of more conventional methods, even in those diets not deliberately treated with nitrite. Evidence was also obtained for the presence of non-volatile, non-extractable N-nitroso compounds in diets both treated and untreated with high levels of nitrite. Confirmation was provided in the case of one diet not treated with nitrite, in that it was found to convert morpholine into its N-nitroso derivative, which was detected by gas chromatography with a Thermal Energy Analyzer detector.


Is the Utilization of Helicobacter pylori Stool Antigen Tests Appropriate in an Urban Canadian Population?
Helicobacter pylori stool antigen test (HpSAT) appropriateness was investigated by assessing its testing and positivity rates in Calgary, Canada. The laboratory information system was accessed for all patients who received an HpSAT in 2018. Testing volume, test results, age, and sex of patients were collected. Sociodemographic risk factors and geospatial analysis were performed by matching laboratory data to the 2016 census data. Testing appropriateness was defined as a concordance between testing and positivity rates for each sociodemographic variable. In 2018, 25,518 H pylori stool antigen tests were performed in Calgary, with an overall positivity rate of 14.7%. Geospatial mapping demonstrated significant distribution variations of testing and positivity rates of HpSAT in the city. Certain sociodemographic groups studied (eg, recent immigrants) appeared to be appropriately tested (testing rate relative risk [RR] = 2.26, positivity rate RR = 4.32; P < .0001), while other groups (eg, male) may have been undertested (testing rate RR = 0.85, positivity rate RR = 1.14; P < .0001). Determining concordance of testing and positivity rate of a laboratory test can be used for assessing testing appropriateness for other diseases in other jurisdictions. This study demonstrated some at-risk patients may be missed for H pylori testing.


Regulation of MUC5 and MUC1 gene expression: correlation with airway mucous differentiation.
The purpose of this paper was to obtain probes to study the structure and function of mucins in rat models of airway cell differentiation and disease. We report the isolation and characterization of the rat cDNA homologue of the human airway secretory mucin, MUC5. Furthermore, we demonstrate the coordinate regulation of the expression of MUC5 and MUC1 (a membrane-bound mucin) and mucous differentiation. The rat MUC5 was cloned by the RT-PCR using motifs conserved in the secretory mucins, MUC2 and MUC5. The rat cDNA revealed a high degree of sequence similarity to human MUC5 (73% at the amino acid level). Alignments with three other secretory mucins (human MUC5, human MUC2, rat MUC2), indicated a conservation of the cysteines and of the octapeptide motifs, but a lack of conservation of a short tandem repeat sequence that is found only in the human MUC5. Northern analysis of MUC1 and MUC5 indicated a specific tissue-restricted pattern of expression. Surprisingly, rat MUC5 exhibited a monodisperse signal, a characteristic that is unusual for most secretory mucins, including the human MUC5. Expression of MUC1 and MUC5 correlated with mucous differentiation. Both genes were expressed at undetectable or very low levels in undifferentiated cultures, but both mucins became strongly expressed during mucous differentiation. Furthermore, neither mucin gene was expressed in retinoid-deficient cultures that undergo squamous instead of mucous differentiation. These studies demonstrate that expression of MUC1 and MUC5 is coordinately regulated with airway mucous cell differentiation. These cDNAs should provide useful tools to study mucin synthesis during differentiation and disease.


The global transcriptomic signature in sinonasal tissues reveals roles for tissue type and chronic rhinosinusitis disease phenotype.
RNA sequencing (RNA-Seq) allows the characterization of a global transcriptomic signature in a least-biased fashion, but few studies have applied this method to investigate the pathophysiology of CRS. We collected mucosal tissue samples from 6 CRS without nasal polyps (CRSsNP), 6 CRS with nasal polyps (CRSwNP), and 6 control patients. Additional matched polyp samples were collected from the 6 CRSwNP patients. RNA was extracted and sequenced on the Illumina HiSeq-2500. Differential gene expression and pathway analyses were performed. CRSsNP showed evidence of upregulated interferon-mediated immunity, MHC-class-I mediated antigen presentation, CXCR3 binding, neutrophil chemotaxis and degranulation, and potential downregulation of genes related to cilia movement and production. CRSwNP polyp tissue showed upregulation of B-cell mediated immune responses, but reduced expression of genes related to epithelial morphogenesis and haemostasis. Polyps also showed a generalized reduction of positive gene regulation. The sinonasal transcriptomic signature was largely determined by tissue type (polyp versus mucosa) and disease phenotype, with minimal signal originating from the individual patient. RNA-Seq is a useful tool to explore the complex pathophysiology of CRS. Our findings stress the importance of tissue selection in molecular research utilizing sinonasal tissue, and demonstrate the limitation of the sNP/wNP paradigm (and the importance of endotyping). On the other hand, classical CRSsNP/wNP disease phenotypes played some role in determining the global transcriptomic signature, and should not be hastily discarded. The value of RNA-Seq-described transcriptomic signatures in exploring endotypes is yet to be explored in future studies.


Noncontrast CT in deep cerebral venous thrombosis and sinus thrombosis: comparison of its diagnostic value for both entities.
With its highly variable clinical presentation, the diagnosis of cerebral venous sinus thrombosis (SVT), and especially of deep venous thrombosis (DVT), as rare but important causes of stroke is challenging. Because noncontrast cranial CT (NCCT) is still the imaging technique of choice in most emergency departments, we aimed to investigate its value in the diagnosis of SVT and DVT. Screening our patient data base, we identified 8 patients with DVT and 25 patients with SVT. We also included a control group of 36 patients who had presented with clinical signs of DVT or SVT but in whom thrombosis was subsequently excluded. MR imaging, multidetector row CT angiography (MDCTA), and/or digital subtraction angiography (DSA) were used as the reference standard. Three independent readers assessed the NCCTs for the presence of direct and indirect signs of DVT or SVT. Direct signs included the presence of hyperattenuated sinuses (ie, cord sign) or veins (ie, attenuated vein sign), whereas parenchymal edema and hemorrhage were indirect signs. The sensitivity and specificity of the attenuated vein sign for the diagnosis of DVT were 100%, and 99.4%, respectively, whereas the sensitivity and specificity of the cord sign for SVT were 64.6% and 97.2%, respectively. The sensitivity and specificity values of NCCT were 93.7% and 98% for intracerebral edema and 94.8% and 98.7% for intracerebral hemorrhages, respectively. Although NCCT is insufficient to exclude a SVT, its value in the emergency diagnosis of DVT seems to be very high.


Extensive Perineural Invasion vs Nerve Caliber to Assess Cutaneous Squamous Cell Carcinoma Prognosis.
Perineural invasion (PNI) is an adverse risk feature in cutaneous squamous cell carcinoma (CSCC) that affects patient prognosis and disease management. However, research comparing different PNI patterns on patient outcomes is limited. To compare 4 assessments of PNI in CSCC, their associations with poor outcomes, and implications for their inclusion in the Brigham and Women's Hospital (BWH) staging system. This retrospective cohort study was performed at a single tertiary care institution and compared 4 PNI assessments: nerve caliber, number of involved nerves per section, PNI maximal depth, and PNI location with respect to tumor. Patients with primary, localized, invasive CSCC with PNI diagnosed between January 1, 2000, and December 31, 2017, were identified via an electronic in-house database. Available pathology slides were secondarily reviewed by study authors. Relevant patient and tumor characteristics and outcomes were abstracted from the medical record. Data analysis was performed between September 6 and October 20, 2022. Risks of recurrence, disease-specific death, and a composite end point (any poor outcome) were calculated via multivariable stepwise Fine and Gray competing-risks regression. Considered revisions to the BWH staging system were assessed via receiver operating characteristic curves and test characteristics. This study included 140 patients with CSCC, with a mean (SD) age of 75.1 (11.2) years. More than half of the patients were men (93 [66.4%]), and most identified as White (132 [94.3%]). Of the 4 PNI assessments studied, only involvement of multiple nerves was associated with poor outcomes. Perineural invasion of 5 or more distinct nerves (extensive PNI [ePNI]) was independently associated with local recurrence (subhazard ratio [SHR], 13.83 [95% CI, 3.50-54.62]; P < .001), disease-specific death (SHR, 6.20 [95% CI, 1.59-24.21]; P = .009), and any poor outcome (SHR, 10.21 [95% CI, 2.88-36.15]; P < .001). A revised BWH staging system with substitution of ePNI for large-caliber PNI resulted in improved area under the curve and test characteristics compared with current BWH staging criteria that use nerve caliber as the measure of PNI. The findings of this cohort study suggest that ePNI is the best prognostic measure of PNI. Because ePNI obviated the need for a micrometer and had superior prognostic capacity to nerve caliber in this cohort, ePNI should be considered for inclusion in CSCC tumor staging. Inclusion of ePNI as a high-risk factor in CSCC staging systems may optimize patient selection for primary treatment and adjuvant interventions.


Spontaneous disruption of mycotic aneurysm involving innominate artery.
We report a case of ruptured mycotic aneurysm involving innominate artery requiring an urgent surgical treatment. A 62-yr-old woman presented with fever and dyspnea. Previously, she was diagnosed with colon cancer and received right hemicolectomy and one cycle of adjuvant chemotherapy. On echocardiogram, pericardial effusion was noted and emergency pericardiocentesis was performed. CT scan revealed aortic aneurysm involving ascending aorta and innominate artery, and thrombi surrounding those structures. Patch repair of the defect in the ascending aorta and ringed Goretex graft to bypass the innominate and ascending aorta were performed. We believe that this is the first case of ruptured mycotic aneurysm involving innominate artery.


Community-level HIV intervention in 5 cities: final outcome data from the CDC AIDS Community Demonstration Projects.
This study evaluated a theory-based community-level intervention to promote progress toward consistent condom and bleach use among selected populations at increased risk for HIV infection in 5 US cities. Role-model stories were distributed, along with condoms and bleach, by community members who encouraged behavior change among injection drug users, their female sex partners, sex workers, non-gay-identified men who have sex with men, high-risk youth, and residents in areas with high sexually transmitted disease rates. Over a 3-year period, cross-sectional interviews (n = 15,205) were conducted in 10 intervention and comparison community pairs. Outcomes were measured on a stage-of-change scale. Observed condom carrying and intervention exposure were also measured. At the community level, movement toward consistent condom use with main (P < .05) and nonmain (P < .05) partners, as well as increased condom carrying (P < .0001), was greater in intervention than in comparison communities. At the individual level, respondents recently exposed to the intervention were more likely to carry condoms and to have higher stage-of-change scores for condom and bleach use. The intervention led to significant communitywide progress toward consistent HIV risk reduction.


Genetic and nongenetic factors contributing to differences in αS-casein phosphorylation isoforms and other major milk proteins.
Relative concentrations of αS-casein (αS-CN) phosphorylation isoforms vary considerably among milk of individual cows. We aimed to explore to what extent genetic and other factors contribute to the variation in relative concentrations of αS-CN phosphorylation isoforms and the phosphorylation degree of αS-CN defined as the proportion of isoforms with higher degrees of phosphorylation. We also investigated the associations of genetic variants of milk proteins and casein haplotypes with relative concentrations of αS-CN phosphorylation isoforms and with the phosphorylation degree of αS-CN in French Montbéliarde cattle from the cheese production area of Franche-Comté. Detailed milk protein composition was determined by liquid chromatography coupled with electrospray ionization mass spectrometry from 531 test-day morning milk samples. Parity, lactation stage, and genetic variation of cows contributed to the phenotypic variation in relative concentrations of individual αS-CN phosphorylation isoforms and in the phosphorylation degree of αS-CN. As lactation progressed, we observed a significant increase for relative concentrations of αS-CN isoforms with higher degrees of phosphorylation (αS1-CN-9P, αS2-CN-13P, and αS2-CN-14P) as well as for the phosphorylation degree of both αS1-CN and αS2-CN. Furthermore, the β-CN I variant was associated with a greater proportion of isoforms with lower degrees of phosphorylation (αS1-CN-8P, αS2-CN-10P, and αS2-CN-11P); the β-CN B variant was associated with a greater proportion of isoforms with higher degrees of phosphorylation (αS1-CN-9P, αS2-CN-12P to αS2-CN-14P). The heritability estimates were low to moderate for relative concentrations of αS2-CN phosphorylation isoforms (0.07 to 0.32), high for relative concentrations of αS1-CN-8P (0.84) and αS1-CN-9P (0.56), and moderate for phosphorylation degrees of αS1-CN (0.37) and αS2-CN (0.23). Future studies investigating relations between the phosphorylation degree of αS-CN and technological properties of milk will be beneficial for the dairy industry.


Identification of maverick, a novel member of the TGF-beta superfamily in Drosophila.
The transforming growth factor-beta (TGF-beta) superfamily of structurally related ligands regulates essential signaling pathways that control many aspects of cell behavior in organisms across the phylogenetic spectrum. Here we report the identification of maverick (mav), a gene that encodes a new member of the TGF-beta superfamily in Drosophila. Phylogenetic analysis and sequence comparison suggest that Mav cannot be easily assigned to any one sub-family, since it is equally related to BMP, activin and TGF-beta ligands. mav maps to the fourth chromosome and is expressed throughout development. In situ hybridization experiments reveal the presence of maternally derived mav transcript in precellular blastoderm embryos. Later in development, mav is expressed in a dynamic pattern in the developing gut, both in endodermal and visceral mesodermal cells. In adult females, high levels of mav mRNA are present in late stage egg chambers.


Epidermal cell differentiation in Arabidopsis determined by a Myb homolog, CPC.
The roots of plants normally carry small hairs arranged in a regular pattern. Transfer DNA-tagged lines of Arabidopsis thaliana included a mutant with few, randomly distributed root hairs. The mutated gene CAPRICE (CPC) encoded a protein with a Myb-like DNA binding domain typical of transcription factors involved in animal and plant development. Analysis in combination with other root hair mutations showed that CPC may work together with the TTG gene and upstream of the GL2 gene. Transgenic plants overexpressing CPC had more root hairs and fewer trichomes than normal. Thus, the CPC gene determines the fate of epidermal cell differentiation in Arabidopsis.


Barriers to mental health treatment for military wives.
An Internet-based survey sought information about barriers to mental health services for military wives. On the basis of qualitative work, an Internet-based program was created to identify military wives who may have major depressive disorder. Women (N=569, ages 18 to 56) were recruited from 45 states and eight foreign countries. Most participants (78%) reported mild to severe depression. Many (44%) reported unaddressed mental health needs. Barriers included inability to attend daytime appointments (38%), inability to find a counselor who understands the needs of military spouses (35%), inability to find a counselor the participant could trust (29%), concerns about confidentiality (26%), and lack of knowledge about where to get services (25%). The barriers reported differed markedly from those described by distressed women in the general population. Military wives are an underserved population. Knowledge of military culture is essential for civilian mental health providers working with military wives.


CMV quantitative PCR in the diagnosis of CMV disease in patients with HIV-infection - a retrospective autopsy based study.
Patients with advanced HIV infection at the time of diagnosis and patients not responding to antiretroviral therapy are at risk of cytomegalovirus (CMV) disease. Earlier studies of patients with HIV infection have demonstrated that the diagnosis is often first made post-mortem. In recent years new molecular biological tests have become available for diagnosis of CMV disease. Although clinical evaluation of tests for diagnosis of CMV disease in HIV-infected individuals is suboptimal without autopsy, no results from such studies have been published. The aim of this study was to explore the diagnostic utility of CMV quantitative polymerase chain reaction (PCR) in plasma from HIV and CMV seropositive patients who died during the period 1991-2002 and in whom autopsy was performed. Autopsy was performed in all cases, as part of routine evaluation of HIV-infected cases followed at Ullevaal University Hospital. Of 125 patients included, 53 had CMV disease, 37 of whom were first diagnosed at autopsy. CMV disease was diagnosed either by ophthalmoscopic findings typical of CMV retinitis, biopsy or autopsy. One or two plasma samples taken prior to the first diagnosis of CMV disease (alive or at autopsy) or death without CMV disease were analysed by CMV quantitative PCR. Sensitivity, specificity, positive and negative predictive values were calculated for different CMV viral load cut-offs and according to detection of viraemia in one versus two samples. Twenty-seven of 53 patients with CMV disease (51%) and 10 of 72 patients without CMV disease (14%) had detectable viraemia in at least one sample. Sensitivity and negative predictive value (NPV) of the test, maximised with a cut-off at the test's limit of detection of CMV viraemia (400 copies/mL), were 47% and 70%, respectively. With cut-off at 10 000 copies/mL, specificity and positive predictive value (PPV) were 100%. With a requirement for CMV viraemia in two samples, specificity and PPV were 100% in patients with CMV viraemia above the limit of detection. Our results indicate that quantitative CMV PCR is best used to rule in, rather than to rule out CMV disease in HIV-infected individuals at high risk.


Non-Hodgkin's lymphomas in 137 patients aged 70 years or older: a retrospective European Organization for Research and Treatment of Cancer Lymphoma Group Study.
The results of a European Organization for Research and Treatment of Cancer (EORTC) retrospective study on non-Hodgkin's lymphoma (NHL) in elderly patients (greater than or equal to 70 years of age) seen in Europe in 1984 are reported. A precodified form was sent to 55 European institutes in order to evaluate the incidence of NHL in the elderly with regard to natural history, treatment-related toxicity, response, and survival. Thirteen institutes participated in the study. One hundred thirty-seven cases of NHL were observed in the elderly during 1984, making up 28% of the total number of NHL seen in those institutes. The median age was 77 years; 21% of the patients had favorable (low-grade) and 73% unfavorable (intermediate- and high-grade) histology, according to the Working Formulation. Stage at presentation was localized (I and II) in 60% and advanced in 37% of the patients. Most of the physicians used standard therapy regimens at reduced doses, from the beginning of the treatment. Sixty patients (44%) underwent a "conservative" treatment (one or two antineoplastic drugs or local field radiotherapy) and 77 (56%) an "aggressive" treatment (polychemotherapy regimens or extended field radiotherapy). Response was similar between the two treatment groups, but severe and lethal toxicity was significantly higher among patients treated with aggressive therapy. Prospective randomized studies are clearly needed to define the optimal treatment in elderly patients with advanced unfavorable NHL.


Nutritive perfusion at donor site after microvascular fibula transfer.
There are many reports on the versatility of the fibular flap, but only a few studies have reported on the morbidity, and none on the nutritive perfusion, of the donor site. This study describes for the first time the quantitative investigation of nutritive perfusion at the donor site after osteomyo-cutaneous fibula transfer. Tissue nutrition of the lower leg was measured in 25 patients by micro-lightguide spectrophotometry and laser Doppler flowmetry. In a standardized examination, hemoglobin oxygenation and blood flow of the donor leg and the contralateral leg (intraindividual control) were measured at the nutritive region of the peroneal artery (I), posterior tibial artery (II), and anterior tibial artery (III). In the operated leg, blood flow was significantly reduced in region I with the sacrificed peroneal artery, and significantly increased in region II and III, probably for compensation (P = 0.03). Decreased hemoglobin oxygenation and blood flow of the peroneal region at the donor site were without significance in comparison to the control leg (P = 0.55 and P = 0.35, respectively). Decreased nutritive perfusion at the donor site was below the threshold of clinical manifestation, and supports the low donor site morbidity following fibular grafting.


Accuracy of surgical guides made from conventional and a combination of digital scanning and rapid prototyping techniques.
Surgical guides aid in accurately placing dental implants to achieve a predictable restorative outcome. Which surgical guide fabrication technique results in the most accurately fitting surgical guide is unknown. The purpose of this investigation was to determine the internal fit of dental implant surgical guides on dentate and edentulous ridges by using implant surgical guides fabricated from conventional and computer-aided design/computer-aided manufacturing (CAD/CAM) techniques. Eighty surgical guides were fabricated from conventional and CAD/CAM techniques; half were designed from Kennedy Class 2 (K2) casts, and half were designed from Kennedy Class 3 (K3) casts. Conventional surgical guides were fabricated from acrylic resin. The CAD/CAM surgical guides were scanned by using cone beam computed tomography (CBCT) or an optical scan (OS). The guides were printed with stereolithography (SL) or 3-dimensional digital printing (3DP). All surgical guides were cemented to their respective design casts, sectioned, and measured at standardized locations. A 2-way ANOVA and the post hoc Fisher least square difference t test was performed (α=.05). The 2-way ANOVA indicated that the difference between surgical guide groups and Kennedy class was statistically significant (P<.05) and the interaction between groups and Kennedy class was statistically significant (P<.05). The OS/3DP CAD/CAM guide was the best-fitting cast for the K2 cast group, and the conventional guide was the best-fitting guide for the K3 group. Conventionally fabricated and OS surgical guides have greater accuracy of fit than CBCT scanned surgical guides.


Haemodynamic and neurohormonal responsiveness to different stress tests in mitral valve prolapse.
In this study the blood pressure, heart rate, plasma noradrenaline and plasma adrenaline responses to various forms of sympatho-neural stress were evaluated in patients with mitral valve prolapse (MVP). Sympathetic reactivity in different subgroups of MVP were related to the degree of ventricular arrhythmia. Thirty-eight patients with mitral valve prolapse and 17 healthy controls were studied. All underwent 24-h ECG recording, 2-D echocardiography, head-up tilt to 60 degrees, pressor tests (sustained handgrip, mental arithmetic, cold pressor) and psychological assessment. The blood pressure, noradrenaline and adrenaline response to stress in patients without premature ventricular contraction were similar to those of the controls. In patients with unifocal premature ventricular contraction (PVC) less than 300/h, responses were similar to normal but were associated with higher plasma noradrenaline levels in the basal state and a diminished response to isometric stress. In patients with more than 300/h unifocal premature ventricular contraction, pairs of premature ventricular contraction, or runs of ventricular tachycardia there were lower blood pressure values in the basal state with reduced blood pressure, heart rate and plasma noradrenaline and adrenaline responses to head-up tilt and sustained handgrip, but marked increases in blood pressure, heart rate and plasma noradrenaline levels during the cold pressor test. Our data suggest different degrees of autonomic involvement in mitral valve prolapse which may be related to the various degrees of arrhythmia which seem to contribute to their symptoms.


Functional diversity and specificity of neostriatal interneurons.
The firing of neostriatal spiny neurons in response to an excitatory input is modulated and sculpted by a variety of factors. Neostriatal interneurons are phenotypically diverse and have properties that enable them to specifically, but differentially, influence the activity of spiny neurons. Each of the three types of GABAergic interneurons produces a strong inhibitory postsynaptic potential in spiny neurons, the function of which is probably to influence the precise timing of action potential firing in either individual or ensembles of spiny neurons. By contrast, the role of cholinergic interneurons is to modulate the sub- and supra-threshold responses of spiny neurons to cortical and/or thalamic excitation, particularly in reward-related activities. Both classes of interneurons are important sites of action of neuromodulators in neostriatum, and act in different but complementary ways to modify the activity of the spiny projection neurons.


Comparison of Renal Anastomosing Hemangiomas in End-Stage and Non-End-Stage Kidneys: A Meta-Analysis With a Report of 2 Cases.
Renal anastomosing hemangioma (RAH) is a very rare distinct entity composed of anastomosing sinusoidal (spleen-like) capillary-sized vessels lined by flat or hobnail endothelial cells. Most of the published cases of RAH occurred in the setting of end-stage renal disease (ESRD). We present 2 cases of RAH in ESRD along with a literature review. We compared clinicopathologic features of RAHs in end-stage and non-end-stage kidneys. A meta-analysis was conducted with PubMed and a manual search through references of relevant publications. Individual patient data gathered from the literature were used in the analysis. Our systematic review revealed 49 RAHs, including our 2 cases. Thirty-two (65.3%) cases were in ESRD, only 17 (34.7%) were in patients with non-ESRD. RAHs in ESRD were in younger patients, smaller in size, multifocal, and seen more with renal epithelial neoplasms when compared with RAHs in non-ESRD ( P < .05). Extramedullary hematopoiesis was seen mostly in RAHs in ESRD kidneys (85% vs 41.7%) ( P = .018). Follow-up data were available for 25 cases with a mean follow-up of 24.58 ± 38.54 months. Recurrence, metastasis, or death have never been described related to RAH in any patients. In conclusion, RAHs are rare and mostly arise in kidneys with end-stage damage. RAHs in ESRD and non-ESRD differ in terms of clinicopathologic features.


The biochemical characterization of aggrecan from normal and tibial-dyschondroplastic chicken growth-plate cartilage.
Tibial dyschondroplasia (TD) is a disorder of endochondral ossification characterized by the presence of an avascular, non-mineralized cartilage lesion extending from the growth plate into the metaphysis. Cells within the TD growth plate fail to differentiate to full hypertrophy, and instead appear to maintain a 'pre-hypertrophic' or 'transitional' status. Studies of the expression and distribution of cartilage matrix macromolecules in the TD growth plate have shown a marked decrease in the levels of aggrecan in the TD matrix. In the present study we compared the biochemical characteristics of the aggrecan molecules extracted from normal epiphyseal and TD cartilage. We have shown three major differences between normal and TD cartilage aggrecan. These are: (1) increase in molecular mass; (2) increase in the number of keratan sulphate chains; and (3) difference in the pattern of sulphation in TD aggrecan. Such changes in biochemical characteristics of the aggrecan monomers in TD cartilage may be associated with the lack of mineralization of the diseased cartilage. The present study provides a basis for further investigations into the importance of proteoglycans in normal and pathological bone development.


Novel aminoacylases from Streptomyces griseus DSM 40236 and their recombinant production in Streptomyces lividans.
Amino acid-based surfactants are valuable compounds for cosmetic formulations. The chemical synthesis of acyl amino acids is conventionally performed by the Schotten-Baumann reaction using fatty acyl chlorides, but aminoacylases have also been investigated for use in biocatalytic synthesis with free fatty acids. Aminoacylases and their properties are diverse; they belong to different peptidase families and show differences in substrate specificity and biocatalytic potential. Bacterial aminoacylases capable of synthesis have been isolated from Burkholderia, Mycolicibacterium, and Streptomyces. Although several proteases and peptidases from S. griseus have been described, no aminoacylases from this species have been identified yet. In this study, we investigated two novel enzymes produced by S. griseus DSM 40236T . We identified and cloned the respective genes and recombinantly expressed an α-aminoacylase (EC18.104.22.168), designated SgAA, and an ε-lysine acylase (EC18.104.22.168), designated SgELA, in S. lividans TK23. The purified aminoacylase SgAA was biochemically characterized, focusing on its hydrolytic activity to determine temperature- and pH optima and stabilities. The aminoacylase could hydrolyze various acetyl amino acids at the Nα -position with a broad specificity regarding the sidechain. Substrates with longer acyl chains, like lauroyl amino acids, were hydrolyzed to a lesser extent. Purified aminoacylase SgELA specific for the hydrolysis of Nε -acetyl-l-lysine was unstable and lost its enzymatic activity upon storage for a longer period but could initially be characterized. The pH optimum of SgELA was pH 8.0. While synthesis of acyl amino acids was not observed with SgELA, SgAA catalyzed the synthesis of lauroyl-methionine.


Yoga for People With Chronic Pain in a Community-Based Setting: A Feasibility and Pilot RCT.
The purpose of this feasibility pilot study was to assess benefits of 8 weeks of yoga in people with chronic pain. Participants completed baseline assessments and were randomized to yoga or usual care. Yoga was offered twice a week for 8 weeks. We assessed feasibility and the Brief Pain Inventory (BPI) was the primary outcome, assessing pain-severity and pain interference on daily activities. Eighty-three people were recruited; 67 people completed the study and were included in the analyses. Average age of participants was 50.78 ± 10.43 years and most participants had pain >10 years. The intervention appeared feasible and there were significant improvements (P < .05) in multiple measures for the yoga group, including a decrease in BPI interference scores from 7.15 ± 1.70 to 6.14 ± 2.21 (P = .007). There was a significant difference in body responsiveness and pain management scores between groups at 8 weeks. It appears that yoga was feasible and positively influenced multiple outcome measures for people with chronic pain.


[Acute myeloid leukemia originating from the same leukemia clone after the complete remission of acute lymphoid leukemia].
A 22-year-old female was diagnosed as having acute lymphoid leukemia (ALL) in February 1995, from the findings of peroxidase negative, CD10+, CD19+, TdT+ and rearrangement of IgH and TCR beta. AdVP (doxorubicin, vincristine and prednisolone) therapy achieved a complete remission (CR). Bone marrow transplantation had to be abandoned because of the lack of an HLA-identical donor. Intensification therapy was thus carried out repeatedly. In June 1998, myeloblast with Auer rods, peroxidase positive, CD13+, CD33+ and HLA-DR+, appeared. The patient was diagnosed as having lineage switch acute myeloid leukemia (AML) from ALL. Though A-DMP (cytosine arabinoside, daunorubicin, 6-mercaptopurine) therapy was resistant, AdVP therapy led to a CR. The patient died of cardiotoxicity from anthracyclines in February 1999. From the results of the Ramasamy method using the clonal rearrangements of the Ig heavy chain gene locus, the origin of the pathological cells of ALL and AML was indicated to be the same leukemia clone.


Health-Promoting Phenolic Compound Accumulation, Antioxidant Response, Endogenous Salicylic Acid Generation, and Biosynthesis Gene Expression in Germinated Pigeon Pea Seeds Treated with UV-B Radiation.
Germinated pigeon pea seeds (GPPSs) are good dietary supplements with satisfactory nutritional and medicinal values. In this study, UV-B treatment was used to promote the accumulation of health-promoting phenolic compounds (10 flavonoids and 1 stilbene) in GPPS. The total yield of 11 phenolic compounds (235 839.76 ± 17 118.24 ng/g DW) significantly improved (2.53-fold increase) in GPPSs exposed to UV-B radiation (3 W/m2) for 8 h, whereas free amino acid and reducing sugar contents exhibited a decreasing tendency during UV-B exposure. Meanwhile, the positive response in the antioxidant activities of enzymes and nonenzymatic extracts was noticed in UV-B-treated GPPSs. Moreover, UV-B radiation could cause tissue damages in hypocotyls and cotyledons of the GPPSs and enhance the generation of endogenous salicylic acid, thus activating the expression of biosynthesis genes (especially CHS and STS1). Overall, the simple UV-B supplementation strategy makes GPPSs more attractive as functional foods/nutraceuticals in diet for promoting human health.


Cost-effectiveness in surgery: concepts of cost-utility analysis explained.
Economic evaluations are increasingly becoming part of the surgical evidence base. With health and research guidelines emphasizing both clinical and economic benefits, surgeons will need to consider the impact of economic evaluations in the future. It seems reasonable that surgical costs in the public healthcare sector should be justified by the benefits that clinical interventions offer. Thus, it is vital to understand the methodological differences, reported outcomes and limitations of economic evaluations pertinent to surgical practice as well. As terminology and concepts can be unfamiliar to surgeons, understanding results from these studies can seem difficult. This article aims to inform surgical readers of the processes involved in performing economic evaluations to determine and compare the cost-effectiveness of treatments. The various types of economic evaluations, their uses, design characteristics, model parameters, interpretation of outputs, uncertainty analyses and notable limitations are considered. Through a hypothetical clinical example that compares costs and effects of surgical versus medical treatment for cancer, key concepts in economic evaluations are considered.


Mindfulness and clinical correlates in methamphetamine use disorder.
Mindfulness-based interventions are increasingly used for the treatment of substance use disorders, including methamphetamine use disorder (MUD). Literature indicates that trait mindfulness may play a key role in the effectiveness of these treatments on therapeutic outcome, yet no prior studies have tested for differences in trait mindfulness between individuals with MUD and healthy control participants. Such differences are important for treatment implementation. The goals of this study were to evaluate trait mindfulness and to determine its clinical correlates in individuals with MUD. A group of participants with MUD at varying lengths of abstinence from methamphetamine (< 1h to 90 days; mean 5.4 ± 12.5 days; N=95, 53 female, 42 male) and a healthy control group (N=65, 30 female, 35 male) completed the Mindfulness Attention Awareness Scale (MAAS). Group differences and relationships between trait mindfulness and several measures of drug use and psychiatric symptoms were evaluated. In participants with MUD, trait mindfulness was 10% lower than in healthy controls (p < 0.001), but it was not significantly correlated with measures of drug use or craving. Across both groups, trait mindfulness was negatively correlated with state anxiety, depression, emotional dysregulation, impulsivity, and a history of childhood trauma, while it was positively correlated with self-compassion (ps < 0.001). The deficit in trait mindfulness in MUD presents a capacity that can be targeted for improved treatment outcome with mindfulness-based therapies. Trait mindfulness is inversely related to mood dysregulation.


Helical vortex formation in three-dimensional electrochemical systems with ion-selective membranes.
The rate of electric-field-driven transport across ion-selective membranes can exceed the limit predicted by Nernst (the limiting current), and encouraging this "overlimiting" phenomenon can improve efficiency in many electrochemical systems. Overlimiting behavior is the result of electroconvectively induced vortex formation near membrane surfaces, a conclusion supported so far by two-dimensional (2D) theory and numerical simulation, as well as experiments. In this paper we show that the third dimension plays a critical role in overlimiting behavior. In particular, the vortex pattern in shear flow through wider channels is helical rather than planar, a surprising result first observed in three-dimensional (3D) simulation and then verified experimentally. We present a complete experimental and numerical characterization of a device exhibiting this recently discovered 3D electrokinetic instability, and show that the number of parallel helical vortices is a jump-discontinuous function of width, as is the overlimiting current and overlimiting conductance. In addition, we show that overlimiting occurs at lower fields in wider channels, because the associated helical vortices are more readily triggered than the planar vortices associated with narrow channels (effective 2D systems). These unexpected width dependencies arise in realistic electrochemical desalination systems, and have important ramifications for design optimization.


Associations of Age at Diagnosis and Duration of Diabetes With Morbidity and Mortality Among Older Adults.
Older adults vary widely in age at diagnosis and duration of type 2 diabetes, but treatment often ignores this heterogeneity. To investigate the associations of diabetes vs no diabetes, age at diagnosis, and diabetes duration with negative health outcomes in people 50 years and older. This cohort study included participants in the 1995 through 2018 waves of the Health and Retirement Study (HRS), a population-based, biennial longitudinal health interview survey of older adults in the US. The study sample included adults 50 years or older (n = 36 060) without diabetes at entry. Data were analyzed from June 1, 2021, to July 31, 2022. The presence of diabetes, specifically the age at diabetes diagnosis, was the main exposure of the study. Age at diagnosis was defined as the age when the respondent first reported diabetes. Adults who developed diabetes were classified into 3 age-at-diagnosis groups: 50 to 59 years, 60 to 69 years, and 70 years and older. For each diabetes age-at-diagnosis group, a propensity score-matched control group of respondents who never developed diabetes was constructed. The association of diabetes with the incidence of key outcomes-including heart disease, stroke, disability, cognitive impairment, and all-cause mortality-was estimated and the association of diabetes vs no diabetes among the age-at-diagnosis case and matched control groups was compared. A total of 7739 HRS respondents developed diabetes and were included in the analysis (4267 women [55.1%]; mean [SD] age at diagnosis, 67.4 [9.9] years). The age-at-diagnosis groups included 1866 respondents at 50 to 59 years, 2834 at 60 to 69 years, and 3039 at 70 years or older; 28 321 HRS respondents never developed diabetes. Age at diagnosis of 50 to 59 years was significantly associated with incident heart disease (hazard ratio [HR], 1.66 [95% CI, 1.40-1.96]), stroke (HR, 1.64 [95% CI, 1.30-2.07]), disability (HR, 2.08 [95% CI, 1.59-2.72]), cognitive impairment (HR, 1.30 [95% CI, 1.05-1.61]), and mortality (HR, 1.49 [95% CI, 1.29-1.71]) compared with matched controls, even when accounting for diabetes duration. These associations significantly decreased with advancing age at diagnosis. Respondents with diabetes diagnosed at 70 years or older only showed a significant association with the outcome of elevated mortality (HR, 1.08 [95% CI, 1.01-1.17]). The findings of this cohort study suggest that age at diabetes diagnosis was differentially associated with outcomes and that younger age groups were at elevated risk of heart disease, stroke, disability, cognitive impairment, and all-cause mortality. These findings reinforce the clinical heterogeneity of diabetes and highlight the importance of improving diabetes management in adults with earlier diagnosis.


The role of lymphstasis in atherogenesis.
The cardiac lymphatics are responsible for the transport of all the lipoproteins and cholesterol from the extravascular myocardial tissue, although little is known about the filtration and lymphatic clearance of the coronary artery wall. It is postulated that a critical factor in the genesis of arteriosclerosis is lymphstasis, which adequately explains the positive correlation with the known risk factors for coronary artery disease and the negative correlation with high-density lipoproteins. Further research is necessary in this little-known area to better understand the etiology of atherosclerosis.


The first mesozoic ants.
Two worker ants preserved in amber of Upper Cretaceous age have been found in New Jersey. They are the first undisputed remains of social insects of Mesozoic age, extending the existence of social life in insects back to approximately 100 million years. They are also the earliest known fossils that can be assigned with certainty to aculeate Hymenoptera. The species, Sphecomyrma freyi, is considered to represent a new subfamily (Sphecomyrminae), more primitive than any previously known ant group. It forms a near-perfect link between certain nonsocial tiphiid wasps and the most primitive myrmecioid ants.


Chronic use of benzodiazepines and psychomotor and cognitive test performance.
The performance of 43 long-term users (average = 5 years) of benzodiazepine (BZ) medications was examined on a battery of behavioral tasks, cognitive tests, and subjective mood rating scales. The performance of the chronic BZ users did not differ significantly from age- and sex-matched anxious subjects, except that critical flicker fusion (CFF) thresholds were lower and subjective ratings of tranquilization were higher in the BZ users. Twenty-two subjects were reexamined in order to determine the acute effects of BZ medications in long-term users. The acute administration of BZ medications significantly increased CFF thresholds, improved digit-symbol substitution test performance, impaired the delayed recall of verbal material, increased subjective ratings of tranquilization, and reduced physical sedation. Motor performance tests were not impaired and subjective feelings of sedation were not increased after the acute administration of BZs by chronic users. During withdrawal from long-term BZ use (17 subjects), CFF thresholds were elevated, subjective ratings of physical sedation and anxiety were increased, but performance on other psychomotor and cognitive tests was not altered. The results suggest that tolerance develops selectively to different behavioral and subjective effects of BZ medications with their continued use. Tolerance failed to develop to the antianxiety effects, the reduction of CFF threshold, and to the impairment of short-term memory caused by BZs. However, chronic users of BZ medications failed to demonstrate psychomotor-impairing or sedating effects to BZ medications. The results have implications for evaluating the safety of the long-term use of BZ medications.


High speed holographic digital recorder.
Concepts, feasibility experiments, and key component developments are described for a holographic digital record/reproduce system with the potential for 1.0 Gbit/sec rates and higher. Record rates of 500 Mbits/sec have been demonstrated with a ten-channel acoustooptic modulator array and a mode-locked, cavity-dumped argon-ion laser. Acoustooptic device technology has been advanced notably during the development of mode lockers, cavity dumpers, beam deflectors, and multichannel modulator arrays. The development of high speed multichannel photodetector arrays for the readout subsystem requires special attention. The feasibility of 1.0 Gbits/sec record rates has been demonstrated.


Integrating patterns of thermal tolerance and phenotypic plasticity with population genetics to improve understanding of vulnerability to warming in a widespread copepod.
Differences in population vulnerability to warming are defined by spatial patterns in thermal adaptation. These patterns may be driven by natural selection over spatial environmental gradients, but can also be shaped by gene flow, especially in marine taxa with high dispersal potential. Understanding and predicting organismal responses to warming requires disentangling the opposing effects of selection and gene flow. We begin by documenting genetic divergence of thermal tolerance and developmental phenotypic plasticity. Ten populations of the widespread copepod Acartia tonsa were collected from sites across a large thermal gradient, ranging from the Florida Keys to Northern New Brunswick, Canada (spanning over 20° latitude). Thermal performance curves (TPCs) from common garden experiments revealed local adaptation at the sampling range extremes, with thermal tolerance increasing at low latitudes and decreasing at high latitudes. The opposite pattern was observed in phenotypic plasticity, which was strongest at high latitudes. No relationship was observed between phenotypic plasticity and environmental variables. Instead, the results are consistent with the hypothesis of a trade-off between thermal tolerance and the strength of phenotypic plasticity. Over a large portion of the sampled range, however, we observed a remarkable lack of differentiation of TPCs. To examine whether this lack of divergence is the result of selection for a generalist performance curve or constraint by gene flow, we analyzed cytochrome oxidase I mtDNA sequences, which revealed four distinct genetic clades, abundant genetic diversity, and widely distributed haplotypes. Strong divergence in thermal performance within genetic clades, however, suggests that the pace of thermal adaptation can be relatively rapid. The combined insight from the laboratory physiological experiments and genetic data indicate that gene flow constrains differentiation of TPCs. This balance between gene flow and selection has implications for patterns of vulnerability to warming. Taking both genetic differentiation and phenotypic plasticity into account, our results suggest that local adaptation does not increase vulnerability to warming, and that low-latitude populations in general may be more vulnerable to predicted temperature change over the next century.


Analytically oriented psychotherapy in schizotypal and borderline patients: at the border of treatability.
Analytically oriented psychotherapy (AOP) has been considered the treatment of choice for borderline patients and a useful technique in the treatment of schizotypal patients. There are many exceptions, however, in addition to a number of borderline and schizotypal patients who are just barely amenable to this modality: they are at the border of treatability by AOP. Limitations relating to time, cost, and the availability of therapists trained in this discipline render it important to delineate the factors which conduce either to the success or failure of AOP. From the author's clinical impressions about borderline and schizotypal patients at the border of treatability by AOP, a number of such factors emerge. On the positive side: likeableness, autoplastic defenses, high motivation, psychological-mindedness, genuine concern, good moral sense, self-discipline, and low impulsivity. Negative factors include, beside the opposites to the aforementioned, vengefulness and parental abusiveness or exploitation. A scale for measuring the balance between these positive and negative factors is proposed. Its use may, it is hoped, improve forecast, during initial consultation, as to which borderline and schizotypal patients will respond favorably to AOP.