Quantification of human immunodeficiency virus type 1-infected mononuclear cells in peripheral blood of seropositive subjects by newly developed flow cytometry analysis of the product of an in situ PCR assay.
The presence of human immunodeficiency virus type 1 (HIV-1) proviral DNA in peripheral blood mononuclear cells (PBMC) of three groups (group 1, more than 500 CD4+ T cells per microliter; group 2, between 200 and 499 CD4+ T cells per microliter; group 3, fewer than 200 CD4+ T cells per microliter) of HIV-1-infected patients, in different stages of the disease, was determined by using a newly developed flow cytometry analysis of the product of in situ PCR assay and compared with other markers of viral replication (HIV-1 p24 antigenemia and viral isolation). Results showed varied percentages of HIV-1-infected PBMC, ranging from 0.6 to 20%. Patients with more than 500 CD4+ T cells per microliter showed the lowest percentage of HIV-1-infected PBMC (2.1 +/- 1.7), compared with patients with CD4+ T-cell counts of between 200 and 499 per microliter (6.5% +/- 4.1%; P < 0.001) and patients with fewer than 200 CD4+ T cells per microliter (4.9% +/- 4.7%; P < 0.05). The difference in the percentage of HIV-1-infected PBMC between group 2 and group 3 patients may in part reflect the loss of CD4+ T lymphocytes in more advanced stages of the disease. However, the results clearly indicate a striking coincidence between the fall of the CD4+ T-cell count below 400/microliter and the sharp increase in PBMC virus loading and p24 antigenemia. Since the procedure is relatively easy to perform, it could be used to monitor the evolution of HIV-1 infection and may prove a useful adjunct in tailoring therapeutic strategies.


Uncoating of human rhinovirus serotype 2 from late endosomes.
The internalization pathway and mechanism of uncoating of human rhinovirus serotype 2 (HRV2), a minor-group human rhinovirus, were investigated. Kinetic analysis revealed a late endosomal compartment as the site of capsid modification from D to C antigenicity. The conformational change as well as the infection was prevented by the specific V-ATPase inhibitor bafilomycin A1. A requirement for ATP was also demonstrated with purified endosomes in vitro. Capsid modifications occurred at a pH of 5.5 regardless of whether the virus was entrapped in isolated endosomes or free in solution. These findings suggest that the receptor is not directly involved in the structural modification of HRV2. Viral particles found in purified endosomes of infected cells were mostly devoid of RNA. This supports the hypothesis that uncoating of HRV2 occurs in intact endosomes rather than by a mechanism involving endosomal disruption with subsequent release of the RNA into the cytoplasm.


Frequently repeated glucose measurements overestimate the incidence of inpatient hypoglycemia and severe hyperglycemia.
The aim was to determine if frequently repeated glucose measurements mandated by an inpatient protocol led to falsely elevated reported rates of both hypo- and hyperglycemia. In our academic medical center, a mandatory standardized subcutaneous insulin order form and protocol was implemented in May 2006. We analyzed point-of-care blood glucose (BG) measurements collected on all medical/surgical wards during the month of August in both 2005 and 2006 by all BGs measured, by patient admission, and by monitored patient-day. We then repeated all analyses using an algorithm that excluded BG values if another BG was measured less than 5 minutes later or 5-60 minutes earlier. In 2005 versus 2006, there were 7034 versus 8016 glucoses measured in 397 versus 389 patients over 1704 versus 1710 patient days, respectively. Analyses based on patient-day balanced differences in BG measurement frequency and patient length of stay. In both years, failure to exclude repeat values overestimated both the proportion of patient days with hypoglycemia (3.5% versus 1.8% in 2005, p = .003; 2.6% versus 1.3% in 2006, p = .007) and severe hyperglycemia (9.3% versus 7.4% in 2005, p = .09; 7.7% versus 5.9% in 2006, p = .08). Mean, median, and proportion of patient-day means within our target range (80-150 mg/dl) were not significantly different. Glucometric reports should exclude repeated BG measurements from a single clinical episode of hypo- or hyperglycemia in order to accurately reflect inpatient glycemic control.


Mechanistically compatible mixtures of bacterial antagonists improve biological control of fire blight of pear.
Mixtures of biological control agents can be superior to individual agents in suppressing plant disease, providing enhanced efficacy and reliability from field to field relative to single biocontrol strains. Nonetheless, the efficacy of combinations of Pseudomonas fluorescens A506, a commercial biological control agent for fire blight of pear, and Pantoea vagans strain C9-1 or Pantoea agglomerans strain Eh252 rarely exceeds that of individual strains. A506 suppresses growth of the pathogen on floral colonization and infection sites through preemptive exclusion. C9-1 and Eh252 produce peptide antibiotics that contribute to disease control. In culture, A506 produces an extracellular protease that degrades the peptide antibiotics of C9-1 and Eh252. We hypothesized that strain A506 diminishes the biological control activity of C9-1 and Eh252, thereby reducing the efficacy of biocontrol mixtures. This hypothesis was tested in five replicated field trials comparing biological control of fire blight using strain A506 and A506 aprX::Tn5, an extracellular protease-deficient mutant, as individuals and combined with C9-1 or Eh252. On average, mixtures containing A506 aprX::Tn5 were superior to those containing the wild-type strain, confirming that the extracellular protease of A506 diminished the biological control activity of C9-1 and Eh252 in situ. Mixtures of A506 aprX::Tn5 and C9-1 or Eh252 were superior to oxytetracycline or single biocontrol strains in suppressing fire blight of pear. These experiments demonstrate that certain biological control agents are mechanistically incompatible, in that one strain interferes with the mechanism by which a second strain suppresses plant disease. Mixtures composed of mechanistically compatible strains of biological control agents can suppress disease more effectively than individual biological control agents.


The METABOLIC Study: multidimensional assessment of health and functional status in older patients with type 2 diabetes taking oral antidiabetic treatment.
The objective of the METABOLIC Study was to evaluate overall health status, with particular focus on assessment of functional status of older patients taking oral antidiabetic drug (OAD) treatment. The study included 1342 type 2 diabetes patients aged ≥ 65 years treated with OADs, with or without insulin, who had been referred to outpatients clinics across Italy. Information on diabetes (duration, medications taken during the last 3 months, hypoglycaemic events and diabetic complications) was collected by questionnaire, and the patients' overall health status was assessed using a multidimensional prognostic index. The sample recruited (mean age: 73.3 ± 5.5 years) had a mean duration of diabetes of 11.3 ± 8.2 years. Half were taking sulphonylureas alone or together with other medications, 9.7% were taking insulin in combination with other OADs, almost 30% were using biguanides and 6.2% were taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Also, 12% of patients reported hypoglycaemic events, 90% of whom were taking insulin or sulphonylureas. In addition, 81% of the participants were completely independent in their activities of daily living, while 19% were mildly, moderately or severely disabled. Age, female gender, hypoglycaemic events, neuropathy and low diastolic blood pressure were the main variables associated with disability. Disability is common in older diabetic patients and some associated factors, such as hypoglycaemia and low diastolic blood pressure, have been identified. Also identified was malnutrition as a specific factor associated with hypoglycaemic events independent of the use of insulin and sulphonylureas.


Changes in plasma lipid and antioxidant activity in rats as a result of naringin and red grapefruit supplementation.
The aim of this investigation was to compare the influence of naringin versus red grapefruit juice on plasma lipid levels and plasma antioxidant activity in rats fed cholesterol-containing and cholesterol-free diets. The antioxidant activity of a correlated quantity of red grapefruit juice was higher than that of naringin. Forty-two male Wistar rats were randomly divided into six groups of 7 named control, naringin, grapefruit, Chol, Chol/naringin, and Chol/grapefruit. The rats of the control group were fed basal diet (BD) and 1-2 mL of distilled water. To the BD of the other five groups were added 0.46-0.92 mg of naringin dissolved in 1-2 mL of distilled water (naringin), 1-2 mL of red grapefruit juice (grapefruit), 1% of nonoxidized cholesterol (NOC) and 1-2 mL of distilled water (Chol), 1% of NOC and 0.46-0.92 mg of naringin in 1-2 mL of water (Chol/naringin), and 1% of NOC and 1-2 mL of red grapefruit juice (Chol/grapefruit). After 30 days of different feeding, it was found that diets supplemented with red grapefruit juice and to a lesser degree with naringin improved the plasma lipid levels mainly in rats fed cholesterol and increased the plasma antioxidant activity. In conclusion, naringin is a powerful plasma lipid lowering and plasma antioxidant activity increasing flavonone. However, fresh red grapefruit is preferable than naringin: it more effectively influences plasma lipid levels and plasma antioxidant activity and, therefore, could be used as a valuable supplement for disease-preventing diets.


Spatial and temporal variation of compositional, functional, and phylogenetic diversity in ectoparasite infracommunities harboured by small mammals.
We studied patterns of compositional, functional, and phylogenetic α- and β-diversity in flea and gamasid mite infracommunities of small Siberian mammals, taking into account host-associated (species) and environmental (biome or sampling period) factors. We asked: (a) How do these factors and their interactions affect infracommunity diversity? (b) Does infracommunity composition, in terms of species, traits, and phylogenetic lineages, deviate from random? (c) Are species, traits, and phylogenetic lineages in infracommunities clustered or overdispersed?, and (d) Do patterns of diversity differ between the three diversity facets and/or the two ectoparasite taxa? We found that the α-diversity of infracommunities was strongly affected by host species, biome, and sampling period. The highest proportion of infracommunity diversity in both taxa was associated with the interaction between either host species and biome or host species and sampling period. Infracommunities of both taxa within, as well as between, host species, biomes, and sampling periods were characterized by the clustering of species, traits and lineages. The patterns of the effects of host species, biome, and sampling period on infracommunity diversity were congruent among the three diversity facets in both fleas and mites. We conclude that the assembly patterns in ectoparasite infracommunities mirror those characteristics of component and compound communities.


Assessment of association between muscular diagnosis in temporomandibular disorders with mandibular kinematics.
Objective: To study the association between mandibular kinematics and muscular diagnoses in temporomandibular disorders (TMD). Method: Retrospective, descriptive clinical study based on an analysis of 370 clinical records of muscle diagnoses in TMD. Statistical analysis was performed with the SPSS program. Results: Five different muscle diagnoses were considered. Myospasm and centrally mediated myalgia were discarded from the statistical analysis because of their low incidences. The diagnoses included in the analysis were protective co-contraction, myofascial pain, and myalgia. Decreased mandibular kinematics in the frontal and horizontal planes were related to myofascial pain. Mandibular kinematics with deflection in opening values decreased in the frontal plane, but intermediate or increased values in the horizontal plane were related to the protective co-contraction. Muscle pain with normal or increased mandibular kinematics was associated with a diagnosis of myalgia. Conclusion: Values of mandibular kinematics are correlated with the muscular diagnoses in TMD and are useful for diagnosis.


Sex-related differences in the normal cardiac response to upright exercise.
In previous studies from this laboratory, we found that approximately 30% of women with chest pain and normal coronary arteries demonstrated either a decrease in or a failure to increase radionuclide ejection fraction during exercise. To examine the hypothesis that this apparent abnormality in left ventricular function represents a physiologic difference between men and women, we prospectively studied central and peripheral cardiovascular responses to exercise in 31 age-matched healthy volunteers (16 women and 15 men). A combination of quantitative radionuclide angiography and expired-gas analysis was used to measure ejection fraction and relative changes in end-diastolic counts, stroke counts, count output, and arteriovenous oxygen difference during symptom-limited upright bicycle exercise. Normal male and female volunteers demonstrated comparable baseline left ventricular function and similar aerobic capacity, as determined by weight-adjusted peak oxygen consumption (22.1 +/- 5.1 and 22.6 +/- 4.3 ml/kg/min, respectively). However, their cardiac responses to exercise were significantly different. Ejection fraction increased from 0.62 +/- 0.09 at rest to 0.77 +/- 0.07 during exercise in men (p less than .001), but was unchanged from 0.63 +/- 0.09 at rest to 0.64 +/- 0.10 during exercise in women. The ejection fraction increased by 5 points or more in 14 of 15 men, but in only seven of the 16 women. End-diastolic counts increased by 30% in women (p less than .001), but was unchanged in men. Because decreases in ejection fraction were matched by increases in end-diastolic counts, relative increases in stroke counts and count output were the same for men and women. These data demonstrate a basic difference between men and women with respect to the mechanism by which they achieve a normal response of stroke volume to exercise; these differences must be taken into account when measurements of cardiac function during exercise stress are used for diagnostic purposes.


Design and engineering of artificial biosynthetic pathways-where do we stand and where do we go?
The production of commodity and specialty chemicals relies heavily on fossil fuels. The negative impact of this dependency on our environment and climate has spurred a rising demand for more sustainable methods to obtain such chemicals from renewable resources. Herein, biotransformations of these renewable resources facilitated by enzymes or (micro)organisms have gained significant attention, since they can occur under mild conditions and reduce waste. These biotransformations typically leverage natural metabolic processes, which limits the scope and production capacity of such processes. In this mini-review, we provide an overview of advancements made in the past 5 years to expand the repertoire of biotransformations in engineered microorganisms. This ranges from redesign of existing pathways driven by retrobiosynthesis and computational design to directed evolution of enzymes and de novo pathway design to unlock novel routes for the synthesis of desired chemicals. We highlight notable examples of pathway designs for the production of commodity and specialty chemicals, showcasing the potential of these approaches. Lastly, we provide an outlook on future pathway design approaches.


Safer Prescribing for Hospitalized Older Adults with an Electronic Health Records-Based Prescribing Context.
Hospitalized older adults are at risk of receiving potentially inappropriate medication (PIM) doses, driven in part by age-independent dose defaults used by electronic health records (EHRs), leading providers to prescribe for older adults as they do for younger adults. We studied whether an automated EHR-based medication support tool would reduce PIM dosing for hospitalized older adults. Pre-post study design. Tertiary care, level 1 trauma, academic medical center in Oregon. Hospitalized adults 75 years and older in the inpatient, nonemergency setting prescribed medications with geriatric-specific dose considerations. An EHR-based, automated set of evidence-based, age-specific dose and frequency defaults called the Geriatric Prescribing Context (GPC). The process measure is percentage of orders consistent with geriatric dose recommendations, and outcome measures are average dose (AD) in milligrams and total daily dose (TDD) in milligrams in the 12 months before and after implementation. Use of recommended geriatric doses with the context improved for all 10 of the most commonly ordered medications. In the year after implementation, there was a trend toward decreasing TDD and AD across all drug classes. The GPC is a simple, elegant, and effective means to align prescribing practices with safety standards for older adults, improving prescribing safety for all. It works within the current prescriber workflow without triggering alert fatigue and requires minimal resources for development and maintenance.


Recruiting RCTs comparing CAS, CEA and best medical treatment for asymptomatic carotid stenosis.
The present paper summarizes the similarities and differences between recent and ongoing randomized controlled trials on optimal treatment of patients with severe but asymptomatic carotid stenosis. Protocol details will be discussed as well as needs for outcome and especially differentiation between patients with a low versus high risk for future events.


Heterologous expression of BI Ca2+ channels in dysgenic skeletal muscle.
We have examined the ability of BI (class A) Ca2+ channels, cloned from rabbit brain, to mediate excitation-contraction (E-C) coupling in skeletal muscle. Expression plasmids carrying cDNA encoding BI channels were microinjected into the nuclei of dysgenic mouse myotubes grown in primary culture. Ionic currents and intramembrane charge movements produced by the BI channels were recorded using the whole-cell patch-clamp technique. Injected myotubes expressed high densities of ionic BI Ca2+ channel current (average 31 pA/pF) but did not display spontaneous contractions, and only very rarely displayed evoked contractions. The expressed ionic current was pharmacologically distinguished from the endogenous L-type current of dysgenic skeletal muscle (Idys) by its insensitivity to the dihydropyridine antagonist (+)-PN 200-110. Peak BI Ca2+ currents activated with a time constant (tau a) of approximately 2 ms and inactivated with a time constant (tau h) of approximately 260 ms (20-23 degrees C). The time constant of inactivation (tau h) was not increased by substituting Ba2+ for Ca2+ as charge carrier, demonstrating that BI channels expressed in dysgenic myotubes do not undergo Ca(2+)-dependent inactivation. The average maximal Ca2+ conductance (Gmax) produced by the BI channels was quite large (approximately 534 S/F). In contrast, the average maximal charge movement (Qmax) produced in the same myotubes (approximately 2.7 nC/microF) was quite small, being barely larger than Qmax in control dysgenic myotubes (approximately 2.3 nC/microF). Thus, the ratio Gmax/Qmax for the BI channels was considerably higher than previously found for cardiac or skeletal muscle L-type Ca2+ channels expressed in the same system, indicating that neuronal BI Ca2+ channels exhibit a much higher open probability than these L-type Ca2+ channels.


Comparative Assessment of Anti-HLA Antibodies Using Two Commercially Available Luminex-Based Assays.
Allospecific anti-HLA antibodies (Abs) are associated with rejection of solid organ grafts. The 2 main kits to detect anti-HLA Ab in patient serum are commercialized by Immucor and One Lambda/ThermoFisher. We sought to compare the performance of both platforms. Background-adjusted mean fluorescence intensity (MFI) values were used from both platforms to compare sera collected from 125 pretransplant and posttransplant heart and lung transplant recipients. Most HLA class I (94.5%) and HLA class II (89%) Abs with moderate to high MFI titer (≥4000) were detected by both assays. A modest correlation was observed between MFI values obtained from the 2 assays for both class I (r = 0.3, r2 = 0.09, P < 0.0001) and class II Ab (r = 0.707, r2 = 0.5, P < 0.0001). Both assays detected anti-class I and II Ab that the other did not; however, no specific HLA allele was detected preferentially by either of the 2 assays. For a limited number of discrepant sera, dilution resulted in comparable reactivity profiles between the 2 platforms. Immucor and One Lambda/ThermoFisher assays have a similar, albeit nonidentical, ability to detect anti-HLA Ab. Although the correlation between the assays was present, significant variances exist, some of which can be explained by a dilution-sensitive "prozone" effect.


Sex steroids regulate liver fat content and body fat distribution in both men and women: a study in transgender persons.
Liver fat content and visceral fat volume are associated with insulin resistance and cardiovascular disease and are higher in men than in women. To determine the effect of estradiol and testosterone treatment on liver fat and visceral fat in trans gender persons. Open-label intervention study (SHAMVA) with a one year follow-up. Gender clinic in a hospital. 8 trans women and 18 trans men, receiving hormone treatment. Trans women received an antiandrogen and after 6 weeks estradiol was added. Trans men were randomized to receive triptorelin, testosterone and anastrozole for 12 weeks, or triptorelin and testosterone for 12 weeks, followed by only testosterone until week 52. Liver fat content, visceral and abdominal subcutaneous fat volume, measured by magnetic resonance spectrometry (MRS) or imaging (MRI) at baseline, 6, 8, 18, 58 weeks in transwomen or at baseline, 6, 12 weeks in trans men with anastrozole and at 52 weeks in trans men without anastrozole. In trans women, liver fat content decreased by 1.55% (-2.99 to -0.12) after 58 weeks, compared to week 6. Visceral fat did not change. In trans men with anastrozole, the liver fat content and visceral fat volume did not change. In trans men without anastrozole, after 52 weeks, liver fat content increased by 0.83% (0.14 to 1.52) and visceral fat volume increased by 34% (16 to 51). Sex hormones regulate liver fat content and visceral fat in men and women.


Defect statistics in the two-dimensional complex Ginzburg-Landau model.
The statistical correlations between defects in the two-dimensional complex Ginzburg-Landau model are studied in the defect-coarsening regime. In particular the defect-velocity probability distribution is determined and has the same high velocity tail found for the purely dissipative time-dependent Ginzburg-Landau (TDGL) model. The spiral arms of the defects lead to a very different behavior for the order parameter correlation function in the scaling regime compared to the results for the TDGL model.


Carrion's Disease: the Sound of Silence.
Carrion's disease (CD) is a neglected biphasic vector-borne illness related to Bartonella bacilliformis. It is found in the Andean valleys and is transmitted mainly by members of the Lutzomyia genus but also by blood transfusions and from mother to child. The acute phase, Oroya fever, presents severe anemia and fever. The lethality is high in the absence of adequate treatment, despite the organism being susceptible to most antibiotics. Partial immunity is developed after infection by B. bacilliformis, resulting in high numbers of asymptomatic carriers. Following infection there is the chronic phase, Peruvian warts, involving abnormal proliferation of the endothelial cells. Despite potentially being eradicable, CD has been expanded due to human migration and geographical expansion of the vector. Moreover, in vitro studies have demonstrated the risk of the development of antimicrobial resistance. These findings, together with the description of new Bartonella species producing CD-like infections, the presence of undescribed potential vectors in new areas, the lack of adequate diagnostic tools and knowledge of the immunology and bacterial pathogenesis of CD, and poor international visibility, have led to the risk of increasing the potential expansion of resistant strains which will challenge current treatment schemes as well as the possible appearance of CD in areas where it is not endemic.


Efficacy of Gold Nanoparticles against Drug-Resistant Nosocomial Fungal Pathogens and Their Extracellular Enzymes: Resistance Profiling towards Established Antifungal Agents.
Drug resistance of filamentous fungi to the commonly used antifungal agents is a major concern in medicine. Therefore, an effective approach to treat several opportunistic fungal infections is the need of the hour. Mentha piperita is used in home remedies to treat different disorders. Isolates of fungi were taken from hospitals in Riyadh, Saudi Arabia, and identified using molecular tools. Amphotericin B, Voriconazole, and Micafungin were applied to screen the resistance of these isolates using both disc and broth microdilution techniques. An aqueous extract of Mentha piperita was utilized to synthesize AuNPs and the nanoparticles were characterized using UV-Vis, FTIR, TEM, EDAX, and XRD. The AuNPs were tested for antifungal activity against the nosocomial fungal pathogens and the activity of extracellular enzymes of such pathogens were analyzed after treatment with AuNPs. We conclude that AuNPs synthesized using Mentha piperita do not possess especially effective antifungal properties against multi-drug resistant Aspergillus species. Five out of eighteen isolates were inhibited by AuNPs. When inhibition was observed, significant alterations in the activity profile of extracellular enzymes of the nosocomial fungi were observed.


Fluorescent anion sensor derived from cholic acid: the use of flexible side chain.
[structure: see text] The fluorescent photoinduced electron transfer (PET) chemosensors 1-3 were synthesized from cholic acid. 1 and 2 containing amidothiourea groups as anion receptive sites demonstrated much higher affinity toward anions than 3 containing traditional thiourea H-bond donating group. Comparative studies on their binding affinity toward carboxylates, dihydrogen phosphate, and halides revealed that the amidothiourea moiety on the C17 side chain could work cooperatively with H-bond donating groups on C7 and C12 to bind spherical halogen anions. An unexpected specific fluorescence enhancement of 1 by coordinating bromide ion was observed.


Spectral phase measurement of a Fano resonance using tunable attosecond pulses.
Electron dynamics induced by resonant absorption of light is of fundamental importance in nature and has been the subject of countless studies in many scientific areas. Above the ionization threshold of atomic or molecular systems, the presence of discrete states leads to autoionization, which is an interference between two quantum paths: direct ionization and excitation of the discrete state coupled to the continuum. Traditionally studied with synchrotron radiation, the probability for autoionization exhibits a universal Fano intensity profile as a function of excitation energy. However, without additional phase information, the full temporal dynamics cannot be recovered. Here we use tunable attosecond pulses combined with weak infrared radiation in an interferometric setup to measure not only the intensity but also the phase variation of the photoionization amplitude across an autoionization resonance in argon. The phase variation can be used as a fingerprint of the interactions between the discrete state and the ionization continua, indicating a new route towards monitoring electron correlations in time.


Effect of N-1/c-8 ring fusion and C-7 ring structure on fluoroquinolone lethality.
Quinolones rapidly kill bacteria by two mechanisms, one that requires protein synthesis and one that does not. The latter, which is measured as lethal action in the presence of the protein synthesis inhibitor chloramphenicol, is enhanced by N-1 cyclopropyl and C-8 methoxy substituents, as seen with the highly lethal compound PD161144. In some compounds, such as levofloxacin, the N-1 and C-8 substituents are fused. To assess the effect of ring fusion on killing, structural derivatives of levofloxacin and PD161144 differing at C-7 were synthesized and examined with Escherichia coli. A fused-ring derivative of PD161144 exhibited a striking absence of lethal activity in the presence of chloramphenicol. In general, ring fusion had little effect on lethal activity when protein synthesis was allowed, but fusion reduced lethal activity in the absence of protein synthesis to extents that depended on the C-7 ring structure. Additional fused-ring fluoroquinolones, pazufloxacin, marbofloxacin, and rufloxacin, also exhibited reduced activity in the presence of chloramphenicol. Energy minimization modeling revealed that steric interactions of the trans-oriented N-1 cyclopropyl and C-8 methoxy moieties skew the quinolone core, rigidly orient these groups perpendicular to core rings, and restrict the rotational freedom of C-7 rings. These features were not observed with fused-ring derivatives. Remarkably, structural effects on quinolone lethality were not explained by the recently described X-ray crystal structures of fluoroquinolone-topoisomerase IV-DNA complexes, suggesting the existence of an additional drug-binding state.


Chytrid fungi shape bacterial communities on model particulate organic matter.
Microbial colonization and degradation of particulate organic matter (POM) are important processes that influence the structure and function of aquatic ecosystems. Although POM is readily used by aquatic fungi and bacteria, there is a limited understanding of POM-associated interactions between these taxa, particularly for early-diverging fungal lineages. Using a model ecological system with the chitin-degrading freshwater chytrid fungus Rhizoclosmatium globosum and chitin microbeads, we assessed the impacts of chytrid fungi on POM-associated bacteria. We show that the presence of chytrids on POM alters concomitant bacterial community diversity and structure, including differing responses between chytrid life stages. We propose that chytrids can act as ecosystem facilitators through saprotrophic feeding by producing 'public goods' from POM degradation that modify bacterial POM communities. This study suggests that chytrid fungi have complex ecological roles in aquatic POM degradation not previously considered, including the regulation of bacterial colonization, community succession and subsequent biogeochemical potential.


Gambling from Seven Perspectives.
In recent decades, it has been recognized that certain behaviors resemble addictions to alcohol and other psychoactive substances (PAS). Based on the results of research for such behaviors, many authors have found that it is justified to consider them addictions not related to PAS or "behavioral" addictions and that in the classifications of mental disorders should be in the same group with addictions related to PAS. Compulsive activities that may include gambling, Internet use, playing video games, sex, eating, and shopping based on epidemiological and neurobiological characteristics have similarities to PAS addictions. Recognition of clinical and neurobiological similarities between the described behaviors and behaviors related to PAS use resulted in the inclusion of gambling disorders in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), and online gaming disorders are classified as conditions for further research. In the 11th revision of the International Classification of Diseases, gambling and gaming disorders are involved in behavioral addictions. Authors presented problem of gambling through sevne perspectives.


The effect of luminance differences on color assimilation.
The color appearance of a surface depends on the color of its surroundings (inducers). When the perceived color shifts towards that of the surroundings, the effect is called "color assimilation" and when it shifts away from the surroundings it is called "color contrast." There is also evidence that the phenomenon depends on the spatial configuration of the inducer, e.g., uniform surrounds tend to induce color contrast and striped surrounds tend to induce color assimilation. However, previous work found that striped surrounds under certain conditions do not induce color assimilation but induce color contrast (or do not induce anything at all), suggesting that luminance differences and high spatial frequencies could be key factors in color assimilation. Here we present a new psychophysical study of color assimilation where we assessed the contribution of luminance differences (between the target and its surround) present in striped stimuli. Our results show that luminance differences are key factors in color assimilation for stimuli varying along the s axis of MacLeod-Boynton color space, but not for stimuli varying along the l axis. This asymmetry suggests that koniocellular neural mechanisms responsible for color assimilation only contribute when there is a luminance difference, supporting the idea that mutual-inhibition has a major role in color induction.


Anti-TNF containing regimens may be associated with increased risk of Clostridioides difficile infection in patients with underlying inflammatory bowel disease.
Patients with inflammatory bowel disease (IBD) are at greater risk for Clostridioides difficile infection (CDI). There remain controversial issues about the association of infliximab therapy in IBD patients and CDI. The present work aimed to investigate the potential association between infliximab therapy and the risk of CDI in a group of Iranian patients with IBD. A total of 140 IBD patients were enrolled, their fresh stool specimens were obtained and used for C. difficile detection. The presence of toxin-encoding genes of C. difficile isolates were examined by PCR. Demographic data, frequency of defecation, antibiotic usage, and IBD therapy were recorded. About half of the IBD patients had a history of antibiotic usage, mostly metronidazole (11.4 %) alone, and metronidazole + ciprofloxacin (16.4 %) as drug combination. C. difficile was isolated from 17.1 % (24/140) of the IBD patients, and more than 90 % of the isolates were found to be toxigenic having genotypes of tcdA+/tcdB+ (18/22, 81.8 %), tcdA+/tcdB- (3/22, 13.6 %) and tcdA-/tcdB+ (1/22, 4.5 %). Interestingly, we only found a significant relationship between the emergence of CDI and the use of infliximab in combinations with other drugs (P = 0.023). In conclusion, there was a considerable incidence of CDI in Iranian patients with IBD. Our study also demonstrated that anti-TNF containing regimens in combinations with other immunosuppressive medications potentially may influence susceptibility to CDI in a group of patients with underlying IBD. Furthermore, our findings recommend avoiding the prolonged use of infliximab along with other corticosteroids or immunomodulators. Further validation studies are needed to better understand the mechanisms that regulate TNF-mediated pathways in CDI pathogenesis among IBD patients.


Oscillations and cell development in Dictyostelium discoideum stimulated by folic acid pulses.
Folic acid is known to be a chemoattractant of pre-aggregation cells of Dictyostelium discoideum. When supplied in pulses, folic acid induces biochemical oscillations and stimulates the development of pre-aggregation to aggregation-competent amoebae. The continuous supply of folic acid has no stimulatory effect. Folic-acid-induced oscillations are accompanied by periodic changes in the cyclic AMP concentration. Pulses of folic acid applied with rhythms between 7 and 11 min efficiently induce oscillations. In contrast, a rhythm of 2 min neither induces oscillations nor suppresses them. Cells start to oscillate with a rhythm of about 8 min. This inherent rhythm is independent of the inducing rhythm. Oscillating cells are less sensitive to folic acid than pre-oscillating ones. They respond only to high concentrations of folic acid which also interact with the oscillating system.


Predictors of readiness for oral rapid HIV testing by Chilean health care providers.
This study identified the personal characteristics that affect Chilean health care providers' readiness to adopt HIV Oral Rapid Testing (ORT) in Chile as a new clinical evidence-based practice (EBP). Using a cross-sectional research design, the study sampled 150 nurses, midwives, and physicians employed at four clinics within the Pontifícia Universidad Católica de Chile Health Network in Santiago. Participants completed a self-administered survey asking about their demographic background, EBP attitudes and experience, personal beliefs related to HIV, the importance of HIV testing, and perceived self-comfort in performing a rapid HIV test. Of the participants, 90% believed that incorporating ORT would make a positive difference in their practice and said that they would be willing to adopt the technology for that reason. Nonetheless, the providers reported a mean "readiness to implement ORT" score of 15.1 out of a possible value of 20, suggesting only moderate self-perceived readiness to adopt the EBP. Education, beliefs about evidence-based practice, perceived comfort in performing ORT, and perceived importance of HIV testing explained 43.6% of the variance in readiness to adopt ORT. The findings of this first ORT pre-implementation study in Chile can help guide policy makers and HIV stakeholders to prepare for and increase primary health care providers' readiness to successfully adopt this evidence-based technology. Successful adoption of ORT could increase Chile's capacity to reach HIV-vulnerable Chileans for testing and referral to care if infected, thus helping the country to reduce further transmission of the virus and its medical complications.


The relationship between religious activities and blood pressure in older adults.
To examine the relationship between religious activities and blood pressure in community-dwelling older adults. Blood pressure and religious activities were assessed in a probability sample of 3,963 persons age sixty-five years or older participating in the Duke EPESE survey. Participants were asked if their doctor had ever informed them that they had high blood pressure and if they were currently taking medication for high blood pressure. After the interview, systolic and diastolic blood pressure were measured following a standardized protocol. Data were available for three waves of the survey (1986, 1989-90, and 1993-94). Analyses were stratified by age (65-74 vs. over 75) and by race (Whites vs. Blacks) and were controlled for age, race, gender, education, physical functioning, body mass index, and, in longitudinal analyses, blood pressure from the previous wave. Cross-sectional analyses revealed small (1-4 mm Hg) but consistent differences in measured systolic and diastolic blood pressures between frequent (once/wk) and infrequent (< once/wk) religious service attenders. Lower blood pressures were also observed among those who frequently prayed or studied the Bible (daily or more often). Blood pressure differences were particularly notable in Black and younger elderly, in whom religious activity at one wave predicted blood pressures three years later. Among participants who both attended religious services and prayed or studied the Bible frequently, the likelihood of having a diastolic blood pressure of 90 mm Hg or higher was 40 percent lower than found in participants who attended religious services infrequently and prayed or studied the Bible infrequently (OR 0.60, 95% CI, 0.48-0.75, p < .0001). Among participants told they had high blood pressure, religiously active persons were more likely to be taking their blood pressure medication; this could not, however, explain the differences in blood pressure observed. While most religious activity was associated with lower blood pressure, those who frequently watched religious TV or listened to religious radio actually had higher blood pressures. Religiously active older adults tend to have lower blood pressures than those who are less active. This applies to attendance at religious services and private religious activities, but not to religious media. Physiological mechanisms are discussed.


Acute and chronic effect of sprint interval training combined with postexercise blood-flow restriction in trained individuals.
This investigation assessed the efficacy of sprint interval training (SIT) combined with postexercise blood-flow restriction as a novel approach to enhance maximal aerobic physiology and performance. In study 1, a between-groups design was used to determine whether 4 weeks (2 days per week) of SIT (repeated 30 s maximal sprint cycling) combined with postexercise blood-flow restriction (BFR) enhanced maximal oxygen uptake (V̇(O2max)) and 15 km cycling time-trial performance (15 km TT) compared with SIT alone (CON) in trained individuals. The V̇(O2max) increased after BFR by 4.5% (P = 0.01) but was unchanged after CON. There was no difference in 15 km TT performance after CON or BFR. In study 2, using a repeated-measures design, participants performed an acute bout of either BFR or CON. Muscle biopsies were taken before and after exercise to examine the activation of signalling pathways regulating angiogenesis and mitochondrial biogenesis. Phosphorylation of p38MAPK(Thr180/Tyr182) increased by a similar extent after CON and BFR. There was no difference in the magnitude of increase in PGC-1α, VEGF and VEGFR-2 mRNA expression between protocols; however, HIF-1α mRNA expression increased (P = 0.04) at 3 h only after BFR. We have demonstrated the potency of combining BFR with SIT in increasing V̇(O2max) in trained individuals, but this did not translate to an enhanced exercise performance. Sprint interval training alone did not induce any observable adaptation. Although the mechanisms are not fully understood, we present preliminary evidence that BFR leads to enhanced HIF-1α-mediated cell signalling.


[Genetic analysis of the resistance of mouse somatic cells to colchicine].
The genetic nature of the resistance of mouse L cells to 0.06 microgram/ml of colchicine (the first step of selection) was studied. Fluctuation tests showed that the generation of drug-resistant variants in the wild type population was random and did not depend on the action of the selective agent. The rate of spontaneous occurrence of this variants was approximately 2 . 10(-5) per cell per generation. Colchicine resistance proved to be relatively unstable: it was 2--3-fold less in all clones propagated in non-selective conditions for 25--33 days. Two mutagens, ethylmethanesulphonate and N-nitroso-N-methylurea, failed to induce colchicine resistance in conditions when they enhanced the frequency of 8-azaguanine-resistant cells 10-fold.


Polybrominated diphenyl ether flame retardants in Chesapeake Bay region, U.S.A., peregrine falcon (Falco peregrinus) eggs: urban/rural trends.
A total of 23 peregrine falcon (Falco peregrinus) eggs were obtained between 1993 and 2002 from 13 nests, encompassing 11 locations in the Chesapeake Bay region, U.S.A. When multiple eggs were available from the same clutch, average clutch contaminant concentrations were calculated. An overall median total polybrominated diphenyl ether (PBDE) level of 201 ng/g wet weight was determined for the eggs/clutches examined. The maximum in an individual egg, from an urban highway bridge site, was 354 ng/g. This egg also exhibited the highest BDE 209 burden (48.2 ng/g). Compared to distributions reported in fish and piscivorous birds, falcon eggs were enriched in the more brominated congeners. The BDE congeners 153, 99, and 100 constituted 26.0, 24.8, and 13.1%, respectively, of total PBDEs. In most aquatic species, BDE 47 is the most abundant congener reported; however, it constituted only 4.4% of total PBDEs in the eggs of the present study. The median BDE 209 concentration was 6.3 ng/g. The sum of the octa- to nonabrominated congeners (BDEs 196, 197, 206, 207, and 208) contributed, on average, 14.0% of total PBDEs, exceeding the contribution of BDE 209 (5.9%). Concentrations of polychlorinated biphenyls (PCBs) and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (4,4'-DDE) also were determined in a subset of 16 eggs (collected in 2001-2002 from six nests) and were an order of magnitude greater than the corresponding PBDEs. Median BDE 209 concentrations were significantly correlated (p < 0.01, Spearman R = 0.690) with the human population density of the area surrounding the nest. Total PBDEs, total PCBs, and 4,4'-DDE levels were not correlated to human population density.


Decreased secretion due to a Ca2+ influx defect in frog peptic cells isolated with EGTA.
Cells prepared from frog esophageal peptic glands by dispersal in low-Ca2+ medium (peptic acini) or 1 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA)-containing medium ("EGTA cells") were compared. EGTA cells were characterized by decreased secretory responses to agonists [bombesin (BB), acetylcholine, and isoproterenol] and intracellular messenger activators (forskolin, 12-O-tetradecanoyl-phorbol-13-acetate), decreased relative intrinsic efficacies of muscarinic agonists, and somatostatin insensitivity. Decreased BB and muscarinic receptor responses were not associated with changes in receptor number or characteristics. The time course of BB- and acetylcholine-stimulated pepsinogen secretion indicated that the marked reduction was confined largely to the late secretory phase (2-30 min), dependent on extracellular Ca2+, rather than early phase (less than 2 min) secretion, which is related to release of intracellular Ca2+. The defect could be reversed by the Ca2+ ionophore A23187. BB-stimulated intracellular Ca2+ mobilization measured with fura-2/AM was similar in the two cell preparations, whereas BB-stimulated 45Ca2+ uptake was reduced threefold in EGTA cells, and this defect was also reversed by A23187. Somatostatin inhibited both BB-stimulated secretion and 45Ca uptake by peptic acini, but it had no significant effect on these parameters in EGTA cells. Cytochalasin B inhibited BB stimulation in peptic acini but not EGTA cells. These findings suggest that peptic cells isolated with EGTA exhibit decreased secretory responses that are due at least in part to impairment of a mechanism for uptake of extracellular Ca2+.


Object constancy in adolescents with borderline personality disorder pathology.
Persistent, interpersonal difficulties are a core feature of borderline personality disorder (BPD). Theories propose that these may result from an insufficient object constancy, for example, the insufficient capacity to maintain feelings of closeness (FC) toward a person when he or she is absent. Based on this assumption, this study examined whether FC toward the mother or the best friend were more dependent on previous contact in adolescents with BPD pathology compared with healthy controls. In addition, the influence of different contact modes was explored. N = 52 female adolescents aged 14 to 18 years (n = 24 with ≥ 5 BPD symptoms [full-threshold BPD], n = 10 with 1-4 BPD symptoms [subthreshold BPD], n = 18 healthy controls) completed up to 12 e-diaries a day on 2 consecutive weekends. Using multilevel mixed-effect regression analyses, we found that the more BPD symptoms a patient fulfilled, the more dependent were FC toward the best friend on actual contact. In contrast, BPD pathology did not influence the dependency of the FC toward the mother on actual contact. Finally, the mode of contact seems to matter: The more BPD symptoms a patient met, the more was the FC toward the best friend dependent on personal compared with written or no contact, whereas phone or written contact was no different from no contact. The present findings partially support the theory of an insufficient object constancy in BPD that seems to become apparent in adolescence mainly in relationships with peers. Replication of the findings, particularly with regard to the impact of mode of contact, in larger samples is required. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Metastatic carcinoid tumor to the orbit and brain.
Carcinoid tumors constitute an uncommon source of metastatic lesions to the brain. We report the case of a 63-year-old man who initially sought treatment for proptosis 15 years before coming to our attention with a metastatic intracerebral left parietal carcinoid. The pathological features of the exenterated orbital mass were interpreted as undifferentiated carcinoma, and a lesion of the left lower lobe of the lung that had been removed 6 years earlier had been reported as metastatic malignant melanoma. The long duration between the initial diagnosis and the onset of neurological symptoms brought into question the original diagnosis, which, in retrospect, was most consistent with metastatic carcinoid. Staining for cytokeratin, neuron-specific enolase, and synaptophysin in the absence of staining for S-100 and HMB-45 supported the revised pathological diagnosis. Metastatic intracerebral carcinoid from an unrecognized bronchogenic source is a rare event, particularly after an orbital metastasis, but should be suspected when the clinical course is inconsistent with the more common causes of metastatic disease.


Soluble interleukin-15 receptor alpha (IL-15R alpha)-sushi as a selective and potent agonist of IL-15 action through IL-15R beta/gamma. Hyperagonist IL-15 x IL-15R alpha fusion proteins.
Interleukin-15 (IL-15) is crucial for the generation of multiple lymphocyte subsets (natural killer (NK), NK-T cells, and memory CD8 T cells), and transpresentation of IL-15 by monocytes and dendritic cells has been suggested to be the dominant activating process of these lymphocytes. We have previously shown that a natural soluble form of IL-15R alpha chain corresponding to the entire extracellular domain of IL-15R alpha behaves as a high affinity IL-15 antagonist. In sharp contrast with this finding, we demonstrate in this report that a recombinant, soluble sushi domain of IL-15R alpha, which bears most of the binding affinity for IL-15, behaves as a potent IL-15 agonist by enhancing its binding and biological effects (proliferation and protection from apoptosis) through the IL-15R beta/gamma heterodimer, whereas it does not affect IL-15 binding and function of the tripartite IL-15R alpha/beta/gamma membrane receptor. Our results suggest that, if naturally produced, such soluble sushi domains might be involved in the IL-15 transpresentation mechanism. Fusion proteins (RLI and ILR), in which IL-15 and IL-15R alpha-sushi are attached by a flexible linker, are even more potent than the combination of IL-15 plus sIL-15R alpha-sushi. After binding to IL-15R beta/gamma, RLI is internalized and induces a biological response very similar to the IL-15 high affinity response. Such hyper-IL-15 fusion proteins appear to constitute potent adjuvants for the expansion of lymphocyte subsets.


Neurotransmitter control of secretion.
It is very well established that the principal control of salivary secretion is derived from autonomic innervation. Transmission of a neural signal to a salivary gland acinar cell occurs chemically via neurotransmitters, the first messengers of a secretory response. Neurotransmitters bind to specific cell surface receptor proteins, an event which activates precise transduction mechanisms which then transfer the neural signal to the inside of the cell. There are two major transduction mechanisms operative in salivary gland acinar cells. One involves the generation of cAMP, the other involves the breakdown of plasma membrane polyphosphoinositides. For both mechanisms, the appropriate stimulated receptor activates a second plasma membrane protein, termed an N (or G) protein. The N protein requires GTP to activate an enzyme (adenylate cyclase or phospholipase C), which then catalyzes the formation of a second messenger (cAMP and inositol trisphosphate/diacylglycerol, respectively). This action provides the intracellular signal for secretory events (protein, fluid, electrolyte secretion) to begin.


Contrasting perceptions of distress by research personnel and their spinal cord injured subjects.
Theoretical approaches to the understanding of psychological adjustment in spinal cord injury have recently experienced a re-examination which seriously questions the traditional "stage theory" of adjustment. Despite limited empirical validation at best, the stage theory has not only enjoyed an unchallenged popularity amongst rehabilitation professionals but often has been imposed upon new SCI patients as a necessary criterion for hospital discharge. Experienced professionals have also been shown to exaggerate the distress of their SCI patients and these misperceptions tend to progressively worsen with length of clinical experience. The present study replicated and extended this tendency amongst research personnel and their SCI subjects. Staff members tended to over-estimate depression, anxiety, and social discomfort while under-estimating the optimism of their SCI subjects. Recommendations are made for the use of a questionnaire to measure their distress. Also, suggestions are made regarding the potential clinical utility of assessing the contrasting perceptions of distress by SCI patients and significant people in their rehabilitation and social environments.


Process evaluation of the Tier 1 Program of the project P.A.T.H.S.
To understand the implementation quality of the Tier 1 Program of the Project P.A.T.H.S., two observers carried out process evaluation in six schools randomly selected from the participating schools in the form of systematic observations of 12 units. Results showed that the overall level of program adherence was generally high, ranging from 50% to 95%, with an average of 84.5%. High implementation quality of the program in the areas of student interest, student participation and involvement, classroom control, use of interactive delivery method, use of strategies to enhance student motivation, instructors' familiarity with the students, opportunity for reflection, degree of achievement of the objectives, quality of preparation, overall implementation quality, and success of implementation was also observed. The findings provide support for the implementation quality of the program.


Common neurologic emergencies for nonneurologists: When minutes count.
Neurologic emergencies arise frequently and, if not diagnosed and treated quickly, can have devastating results, with high rates of long-term disability and death. Prompt recognition is an important skill. This article provides detailed analyses of acute stroke, subarachnoid hemorrhage, status epilepticus, and other neurologic emergencies for physicians who are not neurologists.


Expression and DNA binding activity of the Ku heterodimer in bladder carcinoma.
The Ku protein is a tightly associated heterodimer, comprised of 70-kilodalton (kD) and 86-kD subunits, that forms the DNA-dependent protein kinase (DNA-PK) complex together with the 470-kD DNA-PKcs catalytic subunit, and is involved mainly in DNA double-strand breaks (DSBs) repair. The objective of the current study was to investigate the expression and DNA-binding activity of the Ku protein in fresh tissues from patients with bladder carcinoma and to compare it with that in nontumor tissues obtained from the same organ. Moreover, the DNA-binding activity of Ku was assessed after exposure of the tumor cells to 1 or 2 grays (Gy) of X-rays. Furthermore, the level of phosphorylated Ku was analyzed in both the nuclear and cytoplasmic compartment of normal tissue after exposure to 2 Gy of X-rays. The expression and DNA-binding activity of Ku protein were assessed in tumor samples from patients who all were diagnosed with transitional cell carcinoma (TCC) of the bladder using Western blot analysis and the electrophoretic mobility shift assay, respectively. Enhanced Ku activity and expression were found in tumor tissue compared with normal tissue for each patient. Moreover, variations in Ku activity were found in a dose-dependent manner after the tumor cells were exposed to 1 or 2 Gy of X-rays. A decrease in phosphorylated Ku in the cytoplasm and a parallel increase in the nucleus of normal tissue cells were observed after exposure to X-rays. The results of the current study suggest a possible role of Ku in regulating the DNA-PK activity of DSBs repair in bladder tumors.


Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via ubiquitination and degradation of WNK4.
Pseudohypoaldosteronism type II (PHAII) is a rare Mendelian syndrome featuring hypertension and hyperkalemia resulting from constitutive renal salt reabsorption and impaired K(+) secretion. Recently, mutations in Kelch-like 3 (KLHL3) and Cullin 3 (CUL3), components of an E3 ubiquitin ligase complex, were found to cause PHAII, suggesting that loss of this complex's ability to target specific substrates for ubiquitination leads to PHAII. By MS and coimmunoprecipitation, we show that KLHL3 normally binds to WNK1 and WNK4, members of WNK (with no lysine) kinase family that have previously been found mutated in PHAII. We show that this binding leads to ubiquitination, including polyubiquitination, of at least 15 specific sites in WNK4, resulting in reduced WNK4 levels. Dominant disease-causing mutations in KLHL3 and WNK4 both impair WNK4 binding, ubiquitination, and degradation. WNK4 normally induces clearance of the renal outer medullary K(+) channel (ROMK) from the cell surface. We show that WT but not mutant KLHL3 inhibits WNK4-induced reduction of ROMK level. We show that PHAII-causing mutations in WNK4 lead to a marked increase in WNK4 protein levels in the kidney in vivo. These findings demonstrate that CUL3-RING (really interesting new gene) ligases that contain KLHL3 target ubiquitination of WNK4 and thereby regulate WNK4 levels, which in turn regulate levels of ROMK. These findings reveal a specific role of CUL3 and KLHL3 in electrolyte homeostasis and provide a molecular explanation for the effects of disease-causing mutations in both KLHL3 and WNK4.


N-Methyl-D-aspartate and quisqualate/DL-alpha-amino-3-hydroxy-5- methylisoxazole-4-propionic acid receptors: differential regulation by phospholipase C treatment.
The effect of phospholipase C (PLC) treatment of rat brain membranes on the binding properties of excitatory amino acid receptors was investigated using both a phosphsphatidylcholine-hydrolyzing PLC from Clostridium perfringens and a phosphatidylinositol-specific PLC from Bacillus thuringiensis. PLC from C. perfringens produced an increased affinity of the quisqualate/DL-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor for its ligand, whereas kainate receptor binding was not affected. Both kinetic analysis and equilibrium saturation experiments indicated that PLC treatment produced a decrease in affinity for [3H]N-(1-[thienyl]cyclohexyl)-piperidine [( 3H]TCP), a ligand for the N-methyl-D-aspartate (NMDA) receptor-associated ionic channel, when the channel was fully activated by high concentrations of glutamate and glycine but increased its binding under conditions in which the channel was presumably closed. This latter component of the binding was not due to an interaction of [3H]TCP with non-glutamate receptor sites, such as sigma opioid and histamine H3 receptors. Binding of [3H]glutamate and [3H] glycine to the NMDA receptors was not modified by PLC treatment, but there was a large decrease in the binding of the NMDA antagonist [3H]3-[(+/-)-2-carboxypiperazine-4-yl)propyl-1-phosphonic acid. Stimulation by glycine of [3H]glutamate binding was also abolished following PLC treatment. In contrast to PLC from C. perfringens, phosphatidylinositol-specific PLC treatment did not detectably modify the binding properties of the quisqualate/AMPA receptor or the NMDA receptor channel. These data indicate that alterations in the lipid microenvironment of the glutamate receptors modulate both the conformation and the function of the receptors and suggest a possible role for phospholipases in the regulation of synaptic transmission at excitatory synapses.


Comparative study of composition and biological activities of SDE prepared essential oils from flowers and fruits of two Hypericum species from central Iran.
Essential oil (EO) compositions of flowers and fruits of Hypericum perforatum L. and Hypericum scabrum L. growing wild in Kashan, central Iran, were determined by simultaneous steam distillation-solvent extraction method and analysed using GC-MS technique. Analysis revealed 28 identified compounds for H. perforatum, with two main components being α-pinene (25.36%) and α-amorphene (12.12%). Thirty-five compounds were identified in H. scabrum L. representing 98.60% of the oil with α-pinene (70.21%) and p-mentha-1,5-dien-8-ol (2.89%) as main components. Some new compounds were found in significant quantities which were not found in other chemotypes. The antioxidant activities of the EOs evaluated for the first time in this study using β-carotene bleaching and DPPH assays seemed to be attributed directly to α-pinene contents in them. Antibacterial activities of both mentioned EOs were higher than that of their main constituent, α-pinene, against Staphylococcus aureus and Escherichia coli.


Development of an Electrical Impedance Tomography Coupled Surgical Stapler for Tissue Characterization.
This study explores the feasibility of coupling Electrical Impedance Tomography (EIT) to a standard-of-care laparoscopic surgical stapler, stapler+EIT, with the long-term goal of enabling intraoperative tissue differentiation for tumor margin detection. Two custom printed-circuit-board-based electrode arrays with 60 and 8 electrodes, respectively, matching the stapler geometry, served as the jaws of an electrode-integrated surrogate stapler+EIT device. The device was evaluated through a series of simulations and bench-top imaging experiments of agar-gel phantoms and bovine tissue samples to evaluate the technique and determine optimal imaging parameters. Electrodes localized to only one jaw (the 60-electrode side) of the stapler outperformed a dual-jaw distribution of electrodes. Using this one-sided electrode array, reconstructions achieved an Area-Under-the-Curve (AUC) ≥ 0.94 for inclusions with conductivity contrasts of ≥30% for any size considered on measured agar-gel tests, and an AUC of 0.80 for bovine tissue samples. A stapler+EIT algorithm has been tuned and evaluated on challenging phantom tests and demonstrated to produce accurate reconstructions. This work is an important step in the development of a surgical stapler+EIT technique for margin assessment.


Point and interval estimates of partial population attributable risks in cohort studies: examples and software.
The concept of the population attributable risk (PAR) percent has found widespread application in public health research. This quantity describes the proportion of a disease which could be prevented if a specific exposure were to be eliminated from a target population. We present methods for obtaining point and interval estimates of partial PARs, where the impact on disease burden for some presumably modifiable determinants is estimated in, and applied to, a cohort study. When the disease is multifactorial, the partial PAR must, in general, be used to quantify the proportion of disease which can be prevented if a specific exposure or group of exposures is eliminated from a target population, while the distribution of other modifiable and non-modifiable risk factors is unchanged. The methods are illustrated in a study of risk factors for bladder cancer incidence (Michaud DS et al., New England J Med 340 (1999) 1390). A user-friendly SAS macro implementing the methods described in this paper is available via the worldwide web.


Varicoceles--a ten year retrospective review.
A retrospective survey of men having ligation of varicoceles for infertility from 1969-79 was carried out. Out of 95 patients 71 were traced. The wives of 35 of the patients (48%) subsequently became pregnant while 36 (52%) did not. Almost 60 per cent of patients with a post-operative sperm count more than 40 million/ml achieved a pregnancy. Approximately half the successful pregnancies were achieved within 2 1/2 years but successful pregnancies continued until 5 1/2 years after operation.


Systematic review and meta-analysis of anakinra, sarilumab, siltuximab and tocilizumab for COVID-19.
There is accumulating evidence for an overly activated immune response in severe COVID-19, with several studies exploring the therapeutic role of immunomodulation. Through systematic review and meta-analysis, we assess the effectiveness of specific interleukin inhibitors for the treatment of COVID-19. Electronic databases were searched on 7 January 2021 to identify studies of immunomodulatory agents (anakinra, sarilumab, siltuximab and tocilizumab) for the treatment of COVID-19. The primary outcomes were severity on an Ordinal Scale measured at day 15 from intervention and days to hospital discharge. Key secondary endpoints included overall mortality. 71 studies totalling 22 058 patients were included, 6 were randomised trials. Most studies explored outcomes in patients who received tocilizumab (60/71). In prospective studies, tocilizumab was associated with improved unadjusted survival (risk ratio 0.83, 95% CI 0.72 to 0.96, I2=0.0%), but conclusive benefit was not demonstrated for other outcomes. In retrospective studies, tocilizumab was associated with less severe outcomes on an Ordinal Scale (generalised OR 1.34, 95% CI 1.10 to 1.64, I2=98%) and adjusted mortality risk (HR 0.52, 95% CI 0.41 to 0.66, I2=76.6%). The mean difference in duration of hospitalisation was 0.36 days (95% CI -0.07 to 0.80, I2=93.8%). There was substantial heterogeneity in retrospective studies, and estimates should be interpreted cautiously. Other immunomodulatory agents showed similar effects to tocilizumab, but insufficient data precluded meta-analysis by agent. Tocilizumab was associated with a lower relative risk of mortality in prospective studies, but effects were inconclusive for other outcomes. Current evidence for the efficacy of anakinra, siltuximab or sarilumab in COVID-19 is insufficient, with further studies urgently needed for conclusive findings. CRD42020176375.


Effects of acetylsalicylic acid (aspirin) and naproxen sodium (naproxen) on ovulation, prostaglandin, and progesterone production in the rabbit.
To determine the effects of acetylsalicylic acid (aspirin) and naproxen sodium (naproxen) on ovulation, ovarian prostaglandins (PG), and P production in the rabbit via in vivo and in vitro studies. Aspirin and naproxen were administered i.v. 6.5 and 7 hours, respectively, after hCG administration to New Zealand White adult female rabbits. Laparotomy was performed 24 hours after hCG administration. For in vitro experiments, control animals underwent laparotomy 6.5 (aspirin) and 7 hours (naproxen) after hCG administration. The treated animal received aspirin and naproxen; laparotomy was performed 1 hour later. One ovary was perfused for 6 hours with aspirin or naproxen whereas the contralateral ovary served as a control and was perfused with control medium (M199; GIBCO, Grand Island, New York). Perfusate samples were collected at 1-hour intervals for PG and P determination. A conventional laboratory setting. In vivo experiments used i.v. administration of 100 mg/kg aspirin and 10 and 50 mg/kg naproxen. In vitro perfusion was also carried out with 100 micrograms/mL aspirin and 10 and 50 micrograms/mL naproxen added to the perfusate. Ovulatory efficiency (no. of ovulations/no mature follicles) and ovarian vein PG and P concentration were determined. Ovulatory efficiency was 88% for control, 41% for in vivo aspirin-treated, and 40% (10 mg/kg) and 0% (50 mg/kg) for naproxen-treated rabbits. Aspirin and naproxen were associated with decreased ovulatory efficiency when administered in vitro to both in vivo control and in vivo treated ovaries (control-medium = 70%; control-aspirin = 14%; aspirin-medium = 34%; aspirin-aspirin = 0%; control-naproxen = 25%; naproxen-medium = 38%; naproxen = 0% with 10 microgram/mL, and control-naproxen = 13%; naproxen-medium = 0%; naproxen = 0% with 50 micrograms/mL). Prostaglandin F2 alpha was undetectable in the perfusate of those ovaries perfused of those ovaries perfused either with aspirin or naproxen. Ovarian venous concentration of P in the perfusate was similar in all groups. Aspirin and naproxen significantly reduced ovulatory efficiency and PG production both in vivo and in vitro in hCG-treated rabbits. A critical period of 6.5 and 7 hours after hCG administration was established.


An anatomical study of the length of the neural pedicle after the bifurcation of the thoracodorsal nerve: implications for innervated free partial latissimus dorsi flaps.
For innervated functional muscle transplant procedures, it is essential to have knowledge about the length of nerve pedicles available for nerve anastomosis. For the latissimus dorsi muscle, the thoracodorsal nerve divides into two funicles that separately innervate the medial and lateral portions of the muscle. This suggests the possibility of a multiple, segmentally innervated latissimus dorsi muscle transfer. The branching and length of the thoracodorsal nerve distal to the bifurcation have not been described. This surgical-anatomical study presents anatomical data on these practical/clinical issues. Eleven latissimus dorsi muscles were dissected in eight adult embalmed human specimens. The thoracodorsal neurovascular bundle was dissected from insertion to proximal of the bifurcation. Measurements were taken indirectly from standardized photographic images and analyzed with ImageJ and standard spreadsheet software. The mean age of the specimens was 66 years. The median pedicle length of the lateral part of the muscle was 3.8 cm (range, 2.41 to 5.93 cm). The median length of the medial branch was 3.49 cm (range, 1.7 to 5.12 cm). Proximal branching of the medial pedicle of the bifurcation was identified in approximately two-thirds of the specimens and had a median of 3.55 cm (range, 2.54 to 4.68 cm). The veins and arteries showed a similar pattern, with a median length slightly less than that of the thoracodorsal nerve. The separate neurovascular branches and its minimal pedicle length make the latissimus dorsi muscle very suitable for single functional free muscle transfer, using only the lateral part of the latissimus dorsi muscle, and double functional free muscle transfer using only one vascular pedicle.


The reliability and concurrent validity of measurements used to quantify lumbar spine mobility: an analysis of an iphone® application and gravity based inclinometry.
PURPOSEAIM: This purpose of this study was to investigate the reliability, minimal detectable change (MDC), and concurrent validity of active spinal mobility measurements using a gravity-based bubble inclinometer and iPhone® application. MATERIALSMETHODS: Two investigators each used a bubble inclinometer and an iPhone® with inclinometer application to measure total thoracolumbo-pelvic flexion, isolated lumbar flexion, total thoracolumbo-pelvic extension, and thoracolumbar lateral flexion in 30 asymptomatic participants using a blinded repeated measures design. The procedures used in this investigation for measuring spinal mobility yielded good intrarater and interrater reliability with Intraclass Correlation Coefficients (ICC) for bubble inclinometry ≥ 0.81 and the iPhone® ≥ 0.80. The MDC90 for the interrater analysis ranged from 4° to 9°. The concurrent validity between bubble inclinometry and the iPhone® application was good with ICC values of ≥ 0.86. The 95% level of agreement indicates that although these measuring instruments are equivalent individual differences of up to 18° may exist when using these devices interchangeably. The bubble inclinometer and iPhone® possess good intrarater and interrater reliability as well as concurrent validity when strict measurement procedures are adhered to. This study provides preliminary evidence to suggest that smart phone applications may offer clinical utility comparable to inclinometry for quantifying spinal mobility. Clinicians should be aware of the potential disagreement when using these devices interchangeably. 2b (Observational study of reliability).


Personality effects on romantic relationship quality through friendship quality: a ten-year longitudinal study in youths.
This study examined whether individuals with different personality types (i.e., overcontrollers, undercontrollers, resilients) had different friendship quality development throughout adolescence. It also investigated whether personality types were indirectly related to romantic relationship quality in young adulthood, via friendship quality development in adolescence. The study employed six waves of longitudinal questionnaire data from Dutch youths who had a romantic relationship when they were young adults. Two age cohorts were followed, from 12 to 21 years and from 16 to 25 years, respectively. Findings showed that resilients reported higher mean levels of friendship quality during adolescence (i.e., more support from, less negative interaction with and less dominance from their best friend) than both overcontrollers and undercontrollers. Through the mean levels of friendship quality throughout adolescence, resilients indirectly experienced higher romantic relationship quality during young adulthood than both overcontrollers and undercontrollers. Thus, results provide support for a developmental model in which adolescent friendship quality is a mechanism linking personality types with young adulthood romantic relationship quality.


Prolonged fever and pyuria: an uncommon manifestation of Q fever.
A patient with Q fever is described who had been ill for a year before the diagnosis was made on the basis of serological data. In addition it was possible to isolate Coxiella burnetii, the causative agent by culture from the urine. This is very exceptional and is to our knowledge only the second case in which this has been achieved. The patient made a full recovery after lengthy treatment with tetracycline. Q fever should be considered in patients with pyrexia of unknown origin, particularly in travellers.


Analysis of the metabolic properties of maintenance hemodialysis patients with glucose-added dialysis based on high performance liquid chromatography quadrupole time-of-flight mass spectrometry.
The purpose of this study was to compare the metabolic properties of maintenance hemodialysis patients treated with glucose-containing and glucose-free dialysate using metabonomics. Pre- and post-dialysis serum samples from group G (-) using glucose-free dialysate, and group G (+) using glucose-added dialysate (glucose levels were 5.5 mmol/L) were analyzed and tested with high performance liquid chromatography quadrupole time-of-flight mass spectrometry. Orthogonal signal correction-partial least squares discriminate analysis revealed a significant difference in the post-dialysis metabolic properties between samples from the G (-) and G (+) groups, and concentrations of leucine and dihydroxyprostaglandin F2α were higher in the G (+) group than in the G (-) group. However, markers of reactive lipid mobilization and amino acid release, such as bile acids, aspartate, and valine, were lower in the G (+) group than in the G (-) group. There were no significant differences in excitatory neurotransmitters aspartate and phosphorylated anandamide. Use of liquid chromatography-tandem mass spectrometry metabonomics indicated that using glucose-added dialysate was superior to glucose-free dialysate in the protection of the central nervous system of maintenance hemodialysis patients, but had potential risks in stimulating oxidative stress.


Surface-Enhanced IR-Absorption Microscopy of Staphylococcus aureus Bacteria on Bactericidal Nanostructured Si Surfaces.
Surface-enhanced IR absorption (SEIRA) microscopy was used to reveal main chemical and physical interactions between Staphylococcus aureus bacteria and different laser-nanostructured bactericidal Si surfaces via simultaneous chemical enhancement of the corresponding IR-absorption in the intact functional chemical groups. A cleaner, less passivated surface of Si nanoripples, laser-patterned in water, exhibits much stronger enhancement of SEIRA signals compared to the bare Si wafer, the surface coating of oxidized Si nanoparticles and oxidized/carbonized Si (nano) ripples, laser-patterned in air and water. Additional very strong bands emerge in the SEIRA spectra on the clean Si nanoripples, indicating the potential chemical modifications in the bacterial membrane and nucleic acids during the bactericidal effect.


The perimenopausal hot flash: epidemiology, physiology, and treatment.
The "hot flash" (HF), or vasomotor instability, is experienced by 75% of perimenopausal and menopausal women in the United States. The experience for some women is a minor annoyance but for others, the HF is an intensely unpleasant sensation that is disruptive to their lives. The HF is thought to be triggered by a number of external and internal stimuli such as anxiety, stress, ambient high temperatures, caffeine, and alcohol. The thinner woman tends to experience more severe and frequent HFs than the woman with more adipose tissue, probably because of the ability of adipose tissue to transform androstenedione to estrone and estradiol. Smoking history also tends to be associated with the experience of HFs at an earlier age. The etiology of HFs in the decreasing estrogen state is related to the downward resetting of the hypothalamic thermoregulating mechanism, probably by the action of norepinephrine, which is usually modulated by estrogen. The body attempts to dissipate unwanted body heat by vasodilation, thus causing the sensation of the HF. The most successful treatment modalities have been hormone replacement therapy with estrogen and progesterone. Alpha 2-adrenergic blockers have also shown some limited effectiveness. Many alternative therapies such as vitamin E, primrose oil, dong quai, and black cohash have anecdotal support but have not been thoroughly studied. Relaxation, exercise, avoidance of triggering factors, and control of external environment have all been utilized with some success by women.


Service delivery and coverage in primary healthcare in a community-health project in Ibadan, Nigeria.
Standard health-service delivery aimed toward improving maternal and child health status remains elusive in Nigeria because of inaccuracies in data documentation leading to a lack of relatively stable evidence. Through a community-health project, this study tested the accuracy of record keeping in primary healthcare services in nine clinics run in Ibadan, Nigeria. A validation exercise was performed through a sample of the 10 most recent names extracted from three registers maintained by each clinic. A review of the register covering a period of four years showed a steady increase in: fully-immunised children, registration for antenatal care during the first trimester of pregnancy, the number of women who attended antenatal care at least three times, the overall number of women who booked for antenatal care and women who delivered in Eniosa Community-Health Project facilities over the four-year period. It was possible to trace 86% of those selected from the antenatal care register, 88.9% of those from the birth register and 81.1%of those from the immunisation register. Four women who should have been included for antenatal care, seven who had delivered (but were not in the register) and 13 who reportedly received immunisation but were not listed were found during the validation exercise. This study concludes that the names appearing in the register are likely to represent valid events, but that the registers did not capture all such events in the community.


Storage of human whole blood, but not isolated monocytes, preserves the distribution of monocyte subsets.
Human monocytes include CD14++CD16- (classical), CD14++CD16+ (intermediate), and CD14+CD16++ (non-classical) subsets with divergent roles in immune regulation and inflammation. Since the functional characterization of monocyte subsets is most commonly performed using isolated monocytes, we investigated the influence of different monocyte isolation protocols on the relative abundance of monocyte subsets. Using flow cytometric subset characterization directly in whole blood as a reference, we found that monocyte isolation by enrichment of peripheral blood mononuclear cells and subsequent depletion of non-monocytes by magnetic labeling did not alter the distribution of monocyte subsets. Particularly, we failed to detect a loss of CD16+ subsets upon monocyte isolation, although one of the negative depletion protocols used contained an anti-CD16 antibody to label granulocytes. Overnight storage of isolated monocytes induced a significant repartition of monocyte subsets towards CD14++CD16+ intermediate monocytes, which was barely seen in stored whole blood. We identified intermediate monocytes as main binding partners of platelet-derived extracellular vesicles (EVs) and propose that residual platelets contained in isolated monocyte preparations release EVs that induce the expression of the IgG receptor FcγRIII (CD16) on monocytes.


Focal brain dysfunction in a 41-year old man with familial alternating hemiplegia.
The acute pathophysiologic changes during hemiplegic spells and the long-term outcome of alternating hemiplegia remain obscure. In a 41-year-old male with familial alternating hemiplegia we found an increase in right frontal cerebral blood flow 3 h into a 5-h left hemiplegic episode. A repeat high-resolution brain SPECT study performed 26 h after the resolution of the left hemiplegia revealed normalization of the frontal blood flow accompanied by hyperperfusion in the right parietal lobe. An interictal SPECT scan several weeks later showed no asymmetries. Head CT and MRI scans were negative. Neuropsychologic assessment and neurologic examination revealed evidence of a diffuse disorder which predominantly involved the right hemisphere. To our knowledge, there are no previous correlative studies of serial high-resolution brain SPECT with MRI, or of detailed neuropsychologic assessment, in adult patients with such an advanced course of alternating hemiplegia of childhood.


Validity and Reliability of the Malay Version of the Identification of Functional Ankle Instability (IdFAI-M) Questionnaire among Malaysian University Athletes.
This study was designed to produce a validated and reliable Malay version of the Identification of Functional Ankle Instability (IdFAI-M) questionnaire. The cross-cultural adaptation was conducted based on standard guidelines to produce the Malay version of the Identification of Functional Ankle Instability (IdFAI-M) questionnaire. The reliability and validity testing were then performed among one hundred and twenty-three physically active University of Malaya students. Among them, twenty-two students also participated in the second return of the questionnaire over a two-week interval, which was then evaluated for test-retest reliability testing. The content validity for item-level (I-CVI) and Kappa values for all items were more than 0.7, respectively and the all scales-level (S-CVI) values were 0.983 (consistency), 0.967 (representativeness), 1.00 (relevance) and 0.983 (clarity). The questionnaire also demonstrated excellent reliability with an intraclass correlation coefficient (ICC2.1) above 0.850 for all items. It was observed that outer loading of most items were more than the minimum acceptable value (0.7). Fornell-Larcker criterion demonstrate all values for each reflective construct was larger than the correlations with other constructs, indicating discriminant. The cross-loading values of each item has shown a weak correlation with all other constructs, except for the one to which it was theoretically associated. The Malay version of the IdFAI (IdFAI-M) is a reliable and valid instrument that can be readily utilised to subjectively assess ankle instability.


The charming physician (El médico encantador): neurological conditions in a short story by Silvina Ocampo.
The Argentinian author Silvina Ocampo (1903-1993) left us a vast body of works which are considered outstanding in many ways. In 1960, she published a short story, entitled "El médico encantador" (The Charming Physician), in the renowned literary magazine Sur. The central character of this piece is a family doctor named Albino Morgan, who had a secret truth: in any house he visited, all variety of disease also entered. He brought with him the viruses he disseminated. The narrator of this short story-one of his patients-describes four of Morgan's diseases. These imaginary neurological conditions allowed Ocampo to explore improbable situations in everyday life.


Systolic hypertension in the elderly: controlled or uncontrolled.
ISH is a distinct pathogenetic entity defined by SBP readings of greater than or equal to 160 and DBP less than 90 mmHg. The etiology, although not well understood, is in some manner related to a reduction in connective tissue elasticity of large blood vessels and an increase in aortic impedance or a decrease in aortic wall compliance. The pathophysiologic consequences include an increased resistance to systolic ejection of blood and a disproportionate increase in SBP. Although not directly related, there is an important increase in peripheral vascular resistance. The prevalence of ISH in several studies is about 7 percent in those over age 60 and increases with age to nearly 20 percent in those over age 80. There is higher prevalence in females and nonwhites. The guidelines for detection of ISH are similar to those for blood pressure evaluation in general. Precautions for detection and evaluation in the elderly include multiple blood pressure measurements in the fasting state and sitting and supine blood pressure measurements before and during therapy. Pseudohypertension, although rare, should be kept in mind. There is a clear risk associated with ISH for stroke, CVD, and premature death, which increases with age and rising levels of SBP. ISH can be controlled effectively with pharmacologic therapies. A reasonable goal is a 20 mmHg reduction in systolic pressure. Proof of reduced risk for stroke, CHD, and death in those with controlled ISH remains to be demonstrated. The SHEP pilot study has demonstrated feasibility of addressing this issue. The full-scale SHEP study addresses this issue and has completed recruitment of the desired sample size and is in follow-up phase. Scheduled completion is in 1991. While we wait for the SHEP full-scale trial results, the prudent approach is for nonpharmacologic therapy and use of pharmacologic agents in that group of patients who demonstrate a large cardiovascular risk burden or increasing symptoms specifically associated with hypertension. The decision to treat must be on an individual patient basis. Pharmacologic therapy is possible in most patients with few or no adverse effects. The "low and slow" approach to therapy is helpful in minimizing these adverse effects. Low-dose diuretics have been documented to be effective in blood pressure control. Chlorthalidone, 12.5 or 25 mg per day, is suggested. Other agents, such as beta-blockers, reserpine, ACE inhibitors, and calcium channel blockers, are best used as Step 2 agents.


Interleukin-2 receptor-inducing factor(s) in adult T cell leukemia.
The expression of the interleukin-2 receptor (IL-2-R) is regulated by transcriptional and post-transcriptional mechanisms. IL-2-R gene expression is induced by pharmacological agents including calcium ions, phorbol esters such as phorbol myristate acetate (PMA) and forskolin (FK), a direct activator of adenylate cyclase. HTLV-I(+) leukemic T cells and T cell lines from patients with adult T cell leukemia (ATL) continuously expressed IL-2-R without production of IL-2. However, there was no abnormality of the structural gene for IL-2-R in these cell lines as well as in fresh leukemic cells of ATL. We have detected that many HTLV-I(+) T4(+) T cell lines constitutively produce a non-IL-2 lymphokine named ATL-derived factor (ADF), which induced the expression of the high-affinity IL-2-R on a variety of cells including HTLV-I(+) T cells, myeloid leukemia cells and YT cells. IL-2-R-inducing agents such as ADF and FK were shown to induce elevation of the mRNA levels for IL-2-R through transcriptional enhancement of the IL-2-R gene. The possible involvement of IL-2-R-inducing cytokines in the physiological lymphocyte activation and the leukemogenesis in ATL and other T cell leukemias is discussed.


The SPICE III study protocol and analysis plan: a randomised trial of early goaldirected sedation compared with standard care in mechanically ventilated patients.
Sedation strategy in critically ill patients who are mechanically ventilated is influenced by patient-related factors, choice of sedative agent and the intensity or depth of sedation prescribed. The impact of sedation strategy on outcome, in particular when delivered early after initiation of mechanical ventilation, is uncertain. To present the protocol and analysis plan of a large randomised clinical trial investigating the effect of a sedation strategy, in critically ill patients who are mechanically ventilated, based on a protocol targeting light sedation using dexmedetomidine as the primary sedative, termed "early goal-directed sedation", compared with usual practice. This is a multinational randomised clinical trial in adult intensive care patients expected to require mechanical ventilation for longer than 24 hours. The main exclusion criteria include suspected or proven primary brain pathology or having already been intubated or sedated in an intensive care unit for longer than 12 hours. Randomisation occurs via a secured website with baseline stratification by site and suspected or proven sepsis. The primary outcome is 90-day all-cause mortality. Secondary outcomes include death, institutional dependency, cognitive function and health-related quality of life 180 days after randomisation, as well as deliriumfree, coma-free and ventilation-free days at 28 days after randomisation. A predefined subgroup analysis will also be conducted. Analyses will be on an intention-to-treat basis and in accordance with this pre-specified analysis plan. SPICE III is an ongoing large scale clinical trial. Once completed, it will inform sedation practice in critically ill patients who are ventilated.


A tail of two signals: the C terminus of the A(2A)-adenosine receptor recruits alternative signaling pathways.
G protein-coupled receptors are endowed with carboxyl termini that vary greatly in length and sequence. In most instances, the distal portion of the C terminus is dispensable for G protein coupling. This is also true for the A(2A)-adenosine receptor, where the last 100 amino acids are of very modest relevance to G(s) coupling. The C terminus was originally viewed mainly as the docking site for regulatory proteins of the beta-arrestin family. These beta-arrestins bind to residues that have been phosphorylated by specialized kinases (G protein-coupled receptor kinases) and thereby initiate receptor desensitization and endocytosis. More recently, it has become clear that many additional "accessory" proteins bind to C termini of G protein-coupled receptors. The article by Sun et al. in the current issue of Molecular Pharmacology identifies translin-associated protein-X as yet another interaction partner of the A(2A) receptor; translin-associated protein allows the A(2A) receptor to impinge on the signaling mechanisms by which p53 regulates neuronal differentiation, but the underlying signaling pathways are uncharted territory. With a list of five known interaction partners, the C terminus of the A(2A) receptor becomes a crowded place. Hence, there must be rules that regulate the interaction. This allows the C terminus to act as coincidence detector and as signal integrator. Despite our ignorance about the precise mechanisms, the article has exciting implications: the gene encoding for translin-associated protein-X maps to a locus implicated in some forms of schizophrenia; A(2A) receptor agonists are candidate drugs for the treatment of schizophrenic symptoms. It is of obvious interest to explore a possible link.


Nitric oxide synthase in gingival tissues of patients with chronic periodontitis and with and without diabetes.
The purpose of this study was to evaluate the expression of inducible nitric oxide synthase (iNOS) in the gingival tissues of periodontitis patients with and without type 2 diabetes to assess whether NO plays a role in the severity of periodontitis in patients with diabetes. Patients with diabetes and healthy patients were used as controls. A total of 80 patients were evaluated in four groups (with 20 subjects each): patients with chronic periodontitis and diabetes (12 males and eight females; mean age, 52.1 +/- 6.9 years), patients with chronic periodontitis who were otherwise healthy (12 males and eight females; mean age, 43.1 +/- 8.9 years), periodontally healthy patients with diabetes (12 males and eight females; mean age 50.9 +/- 6.3 years), and systemically and periodontally healthy control subjects (12 males and eight females; mean age 29.8 +/- 9.2 years). Periodontal parameters were recorded. Immunohistochemistry was used to detect inflammation and iNOS expression in gingival tissues. Although periodontal parameters were slightly higher in periodontitis compared to diabetic periodontitis, immunohistochemical parameters were higher in diabetic periodontitis compared to periodontitis. All periodontal parameters were higher in patients with periodontitis and with/without diabetes compared to controls and patients with diabetes. All immunohistochemical parameters were higher in patients with diabetes and periodontitis compared to patients with only diabetes or periodontitis, but there was no difference between the latter two groups. There was a correlation between the expression of iNOS and inflammatory cells in controls, patients with diabetes, and patients with periodontitis but not in patients with diabetes and periodontitis. Inflammation and iNOS expression were more prominent in the gingiva of the patients with both diabetes and periodontitis. However, iNOS expression did not seem to have an additional detrimental effect on the course of periodontitis in patients with diabetes compared to those with periodontitis alone.


Evaluation of antimicrobial textiles for atopic dermatitis.
Functional textiles have been proposed as safe adjunct treatment for atopic dermatitis (AD). Some data have been published regarding their antimicrobial properties and their clinical efficacy. This study examined the physical and functional properties of 11 commercially available functional textiles, including their antimicrobial activity in vitro, as a function of multiple laundering cycles. All materials were weighed and examined under scanning electron microscopy (SEM) before and after laundering for fibre morphology and silver coating. Bioburden of newly purchased textiles was assessed by measuring bacterial colony forming units (CFU). Deliverable antimicrobial efficacy was evaluated in vitro for each specimen, before and after 30, 70, 100, 150 and 200 laundering cycles. Textile weight showed high variability. Damaged silver coating of variable degree was observed under SEM in most materials after laundering. Products made of silk showed smoother and tighter fibre morphology compared to cotton. The bacterial load of unwashed material ranged from <1 CFU to 35 CFU per 50 × 50 mm specimen. Most silver-containing products lost their antimicrobial activity rapidly after laundering. Silk and cotton retrieved products had no deliverable antimicrobial effect even in their original state. Elastic, lightweight textiles with smooth fibres are comfortable for daily use. Functional textiles rapidly losing their deliverable antimicrobial activity in vitro are not advisable for AD patients. Recommendations for functional textiles should be based on a combination of in vitro analysis of products in their original state and after laundering, together with real-life data obtained from controlled clinical trials.


Stillbirth risk in a second pregnancy.
To estimate the risk of stillbirth in a second pregnancy when previous stillbirth, preterm, and small-for-gestational age (SGA) births occurred in the previous pregnancy. This was a population-based cohort study in New South Wales Australia from 2002 to 2006. Singleton births in a first pregnancy were linked to a second pregnancy using data from the New South Wales Midwives Data Collection and the New South Wales Perinatal Death Database. Deaths were classified according to the Perinatal Mortality Classifications of the Perinatal Society of Australia and New Zealand. Crude and adjusted hazard ratios were estimated using a proportional hazards model. Delivery of an SGA newborn in the first pregnancy was associated with increased risks of stillbirth in a second pregnancy (hazard ratio 1.73, 95% confidence interval [CI] 1.15-2.60) and risk was further increased with prematurity (hazard ratio 5.65, 95% CI 1.76-18.12). Stillbirth in a first pregnancy had a nonsignificant association with stillbirth in the second pregnancy (hazard ratio 2.03, 95% CI 0.60-6.90). For women aged 30-34 years, the absolute risk of stillbirth up to 40 completed weeks of gestation was 4.84 per 1,000 among women whose first pregnancy was a stillbirth and 7.19 per 1,000 among women whose first pregnancy was preterm and SGA. Delivering an SGA and preterm neonate in a first pregnancy is associated with greater risks for stillbirth in a second pregnancy than delivering a previous stillbirth. All factors merit improved surveillance in a subsequent pregnancy, and research should address underlying factors common to all three outcomes.