Achieving permanency for LGBTQ youth.
This article brings together two significant efforts in the child welfare field: achieving permanence for youth in out-of-home care and meeting the needs of lesbian, gay, bisexual, transgender and questioning (LGBTQ) youth. During the past several years, a national movement has taken place to assure all children and youth have a permanent family connection before leaving the child welfare system; however, LGBTQ youth are not routinely included in the permanency discussions. At the same time, efforts in addressing the needs of LGBTQ youth have increased, but permanency is rarely mentioned as a need. This article offers models of permanence and practices to facilitate permanence with LGBTQ youth and their families. It also offers a youth-driven, individualized process, using youth development principles to achieve relational, physical, and legal permanence. Reunification efforts are discussed, including services, supports, and education required for youth to return to their family of origin. For those who cannot return home, other family resources are explored. The article also discusses cultural issues as they affect permanence for LGBTQ youth, and, finally, addresses the need for ongoing support services to sustain and support permanency.


Mathematical modeling of dormant cell formation in growing biofilm.
Understanding the dynamics of dormant cells in microbial biofilms, in which the bacteria are embedded in extracellular matrix, is important for developing successful antibiotic therapies against pathogenic bacteria. Although some of the molecular mechanisms leading to bacterial persistence have been speculated in planktonic bacterial cell, how dormant cells emerge in the biofilms of pathogenic bacteria such as Pseudomonas aeruginosa remains unclear. The present study proposes four hypotheses of dormant cell formation; stochastic process, nutrient-dependent, oxygen-dependent, and time-dependent processes. These hypotheses were implemented into a three-dimensional individual-based model of biofilm formation. Numerical simulations of the different mechanisms yielded qualitatively different spatiotemporal distributions of dormant cells in the growing biofilm. Based on these simulation results, we discuss what kinds of experimental studies are effective for discriminating dormant cell formation mechanisms in biofilms.


Using telehealth to deliver Qi Gong and Tai Chi programs: A mixed-methods systematic review on feasibility, acceptability and participant engagement factors.
Due to the COVID-19 pandemic, the use of digitally delivered exercise classes to promote physical activity has become widespread amongst various populations as an alternative to in-person activities. To examine the feasibility, acceptability, and participant engagement variables to delivering Qi Gong and Tai Chi programs through telehealth interventions. Ten databases (Seven English databases; three Chinese databases) were searched between October and November 2021. Studies published in English or Chinese, or having translations in English or Chinese, were included. Titles and abstracts of identified articles were screened, relevant studies were then retrieved for full-text screening. Study selection, assessment of methodological quality, data extraction, data transformation, and data synthesis were completed following a convergent integrated approach to mixed method systematic reviews. Seven articles were included in review. Digital literacy of both participants and providers was found to be a significant hurdle towards digital program implementation. There were no notable issues pertaining to access to an internet connection, participant safety, program costs, or connectivity. A major theme for sustaining program engagement was found to be individual perceived relevance for intervention involvement. Online social involvement was noted to be both a facilitator for participant acceptability and engagement. Overall, participants expressed satisfaction with the use of telehealth, while providers expressed acceptability concerns regarding quality of care. It is recommended that planned measures be taken prior to program commencement to decrease digital literacy requirements while also including a participatory approach to encourage uptake. During the program, provision of technical support alongside appropriate social-environmental engagement facilitators would promote sustained adherence.


Central respiratory effects versus neuromuscular actions of nerve agents.
The relative contributions of peripheral neuromuscular and central nervous system components in the respiratory failure following acute exposure to organophosphorous anticholinesterase (AChE) agents remain unclear. We examined the effects of the nerve agents, soman, sarin, tabun, and VX on diaphragm contraction, diaphragm electromyogram (EMG), phrenic nerve activity, medullary respiratory-related unit activity, and airflow in the cat. The agents were infused at the rate of 1 LD50 per 15 minutes until respiratory arrest, at which time the phrenic nerve was stimulated supramaximally to test diaphragmic contraction. We found that one of the first signs of respiratory distress is disruption of the normal firing pattern of the medullary respiratory-related neurons. This is followed by changes in phrenic nerve activity, diaphragm EMG, diaphragm contraction and airflow. At the time of respiratory arrest, the medullary respiratory-related units and the phrenic nerve have stopped firing. Immediately following cessation of spontaneous respiration, the diaphragm was tested by stimulating the phrenic nerve with 2 msec pulses of 500 msec duration at 10 Hz and at 100 Hz. Stimulation at 10 Hz consistently produced a frequency-following contraction, while stimulation at 100 Hz produced a tetanic contraction. We conclude that loss of central respiratory drive is the predominant cause of nerve agent-induced respiratory failure, as the diaphragm muscle still contracts tetanically when challenged with a 100 Hz train for 500 msec at the time of respiratory arrest.


Myricitrin Modulates NADPH Oxidase-Dependent ROS Production to Inhibit Endotoxin-Mediated Inflammation by Blocking the JAK/STAT1 and NOX2/p47phox Pathways.
Myricitrin, a naturally occurring polyphenol hydroxy flavonoid, has been reported to possess anti-inflammatory properties. However, the precise molecular mechanism of myricitrin's effects on LPS-induced inflammation is unclear. In the present study, myricitrin significantly alleviated acute lung injury in mice. Myricitrin also markedly suppressed the production of NO, TNF-α, IL-6, and MCP-1 in RAW264.7 macrophage cells. The inhibition of NO was concomitant with a decrease in the protein and mRNA levels of iNOS. The phosphorylation of JAKs and STAT-1 was abrogated by myricitrin. Furthermore, myricitrin inhibited the nuclear transfer and DNA binding activity of STAT1. The JAK-specific inhibitor ruxolitinib simulated the anti-inflammatory effect of myricitrin. However, myricitrin had no impact on the MAPK signalling pathway. Myricitrin attenuated the generation of intracellular ROS by inhibiting the assembly of components of the gp91phox and p47phox. Suppression of ROS generation using NAC or apocynin or by silencing gp91phox and p47phox all demonstrated that decreasing the level of ROS inhibited the LPS-induced inflammatory response. Collectively, these results confirmed that myricitrin exhibited anti-inflammatory activity by blocking the activation of JAKs and the downstream transcription factor STAT1, which may result from the downregulation of NOX2-dependent ROS production mediated by myricitrin.


Complex ovarian cysts in postmenopausal women are not associated with ovarian cancer risk factors. Preliminary data from the plco cancer screening trial.
PURPOSE: We assessed whether ovarian abnormalities detected on ultrasound in postmenopausal women are precursors to ovarian cancer.METHODS: We compared the transvaginal ultrasound findings from the initial examination of twenty thousand postmenopausal women enrolled to date in an ongoing randomized trial of cancer screening to data on the established risk factors for ovarian cancer obtained from self-administered questionnaires. We distinguished cysts with the suspicious characteristics of a septum, solid component, irregular or thick wall ("complex cysts") from simple sonolucent cysts with none of those features.RESULTS: High parity, protective for cancer, was negatively associated with complex cysts (Odds Ratio ["OR"] for five or more births versus no births = 0.72, 95% CI = 0.53-0.97), but long-term oral contraceptive use was not (OR = 0.96, 95% CI = 0.76-1.20). A family history of ovarian cancer or multiple breast cancers, a strong risk factor for cancer, was not associated with complex cysts (OR = 0.99, 95% CI = 0.68-1.44). Other abnormalities found on ultrasound (including simple cysts, bilateral cysts, or all abnormalities combined) also did not share the established risk factors for ovarian malignancy. We formed no combination of features of abnormalities (septum, echogenicity, size, or papillary projection) with the cancer risk factor profile.CONCLUSIONS: Although a very small proportion of the clinically silent ovarian abnormalities found on ultrasound are found to be ovarian cancers, the remaining complex cysts and other clinically suspicious abnormalities do not appear to be the immediate precursors of ovarian cancer.


Online Medical Education and Examinations during COVID-19: Perspectives of a Teaching Associate.
The novel coronavirus disease 2019 (COVID-19) pandemic has not only challenged global health systems but also social, economic, and educational systems. In this short communication, our focus is on its impact on medical education in Pakistan. We discuss the structure of undergraduate medical education in Pakistan; and how it has evolved in the wake of COVID-19. We describe our role as teaching associates (TAs) at the Aga Khan University (AKU); and how it has enabled us to be a part of the transition to online medical education, with a specific focus on online examinations in medical schools. Key Words: Medical education, Online examinations, COVID-19, Pandemic.


Epigenetic mutations in CDKN2A in western Swedish families with hereditary malignant melanoma.
This study aimed to identify the molecular genetic variations associated with an increased risk of hereditary malignant melanoma (HMM) in the western Swedish population. In 68 families with increased hereditary susceptibility to malignant melanoma, we previously reported a low frequency of alterations in the CDKN2A gene, which is regarded as the major melanoma predisposition gene. Among these alterations, we identified a novel mutation in 3 families (Asp108Tyr). In the present study, we focused on the possible role of heritable epimutations as a cause of the silencing of the CDKN2A gene. We used two different technical approaches to detect changes in CpG methylation in the promoter region of the CDKN2A gene; methylation-specific PCR (MSP) analysis of bisulfite-converted DNA and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). From families who tested negative for germ-line CDKN2A mutations, 64 unrelated patients with hereditary melanoma were included in the study. We showed a consistent lack of hypermethylation in the promoter region of CDKN2A in patients with HMM in our western Swedish population. A putative germ-line methylation of the CDKN2A, if any, is therefore likely to be a rare event in hereditary melanoma. This study demonstrates that there are probably additional and as yet unknown genetic factors present in western Swedish HMM families.


An /spl omega/-automata approach to the representation of bilevel images.
We use /spl omega/-automata (i.e., automata over infinite words) as a device for representing bilevel images. A major advantage of our approach, as opposed to using the conventional finite automata, lies in that /spl omega/-automata are capable of representing image objects of zero size, such as lines and points. To demonstrate the feasibility of our approach, we also show how a number of image processing operations, including shift, flip, rotation, complement, boundary, difference, union, intersection, and size, can be effectively carried out in the framework of /spl omega/-automata. In particular, the size of an image represented by an /spl omega/-automaton is measured based on the theory of Markov chains. In comparison with other automata-based image representation schemes reported in the literature, our approach is capable of supporting a richer set of operations, which can be performed on the automata directly and easily.


AMP-activated protein kinase in metabolic control and insulin signaling.
The AMP-activated protein kinase (AMPK) system acts as a sensor of cellular energy status that is conserved in all eukaryotic cells. It is activated by increases in the cellular AMP:ATP ratio caused by metabolic stresses that either interfere with ATP production (eg, deprivation for glucose or oxygen) or that accelerate ATP consumption (eg, muscle contraction). Activation in response to increases in AMP involves phosphorylation by an upstream kinase, the tumor suppressor LKB1. In certain cells (eg, neurones, endothelial cells, and lymphocytes), AMPK can also be activated by a Ca(2+)-dependent and AMP-independent process involving phosphorylation by an alternate upstream kinase, CaMKKbeta. Once activated, AMPK switches on catabolic pathways that generate ATP, while switching off ATP-consuming processes such as biosynthesis and cell growth and proliferation. The AMPK complex contains 3 subunits, with the alpha subunit being catalytic, the beta subunit containing a glycogen-sensing domain, and the gamma subunits containing 2 regulatory sites that bind the activating and inhibitory nucleotides AMP and ATP. Although it may have evolved to respond to metabolic stress at the cellular level, hormones and cytokines such as insulin, leptin, and adiponectin can interact with the system, and it now appears to play a key role in maintaining energy balance at the whole body level. The AMPK system may be partly responsible for the health benefits of exercise and is the target for the antidiabetic drug metformin. It is a key player in the development of new treatments for obesity, type 2 diabetes, and the metabolic syndrome.


Human factor H (FH) impairs protective meningococcal anti-FHbp antibody responses and the antibodies enhance FH binding.
The meningococcal 4CMenB vaccine (Bexsero; Novartis) contains four antigens that can elicit serum bactericidal activity, one of which is factor H (FH)-binding protein (FHbp). FHbp specifically binds human complement FH. When humans are immunized, FHbp is expected to form a complex with FH, which could affect immunogenicity and safety. Wild-type mice (whose FH does not bind to FHbp) and human FH transgenic mice were immunized with three doses of 4CMenB, and their responses were compared. There were no significant differences between the serum bactericidal responses of transgenic and wild-type mice to strains with all of the antigens mismatched for 4CMenB except PorA or NadA. In contrast, against a strain mismatched for all of the antigens except FHbp, the transgenic mice had 15-fold weaker serum bactericidal antibody responses (P = 0.0006). Binding of FH downregulates complement. One explanation for the lower anti-FHbp serum bactericidal activity in the transgenic mice is that their postimmunization serum samples enhanced the binding of FH to FHbp, whereas the serum samples from the wild-type mice inhibited FH binding. Control antiserum from transgenic mice immunized with a low-FH-binding mutant FHbp (R41S) vaccine inhibited FH binding. Two 4CMenB-vaccinated transgenic mice developed serum IgM autoantibodies to human FH. Thus, human FH impairs protective serum anti-FHbp antibody responses, in part by skewing the antibody repertoire to FHbp epitopes outside the FH binding site. FHbp vaccines that bind FH may elicit FH autoantibodies. Mutant FHbp antigens with low FH binding could improve protection and, potentially, vaccine safety in humans. Two serogroup B meningococcal vaccines contain a novel antigen called factor H (FH)-binding protein (FHbp). FHbp specifically binds human FH, a plasma protein that downregulates complement. One vaccine (4CMenB; Novartis) is licensed in Europe, Canada, and Australia. When humans are immunized, FHbp can complex with FH. We compared the immunogenicity of 4CMenB vaccine in wild-type mice, whose own FH does not bind to FHbp, and human FH transgenic mice. Transgenic mice had respective antibody responses similar to those of wild-type mice to 4CMenB antigens that do not bind FH. However, the protective antibody responses of the transgenic mice to FHbp were impaired, largely because the antibodies did not inhibit but rather enhanced the binding of FH to FHbp. Two transgenic mice developed serum IgM autoantibodies to FH. Mutant FHbp antigens with low FH binding likely will elicit greater protection in humans than FHbp vaccines that bind FH and have a lower risk of FH autoantibodies.


Temporal masking reveals properties of sound-evoked inhibition in duration-tuned neurons of the inferior colliculus.
The inferior colliculus (IC) is the first place in the central auditory pathway where duration-selective neurons are found. Previous neuropharmacological and electrophysiological studies have shown that they are created there and have led to a conceptual model in which excitatory and inhibitory inputs are offset in time so that the cell fires only when sound duration is such that onset- and offset-evoked excitation coincide; the response is suppressed by inhibition at other durations. We tested predictions from the model using paired tone stimulation and extracellular recording in the IC of the big brown bat, Eptesicus fuscus. Responses to a best duration (BD) tone were used as a probe to examine the strength and time course of inhibition activated by a nonexcitatory (NE) tone of the same frequency but differing in duration. As the relative time between the BD and NE tones was varied, the activity evoked by the BD tone was affected in ways comparable with backward, simultaneous, and forward masking. Responses to the BD tone were completely suppressed at short interstimulus intervals when the BD tone preceded the NE tone. Suppression was also seen when the stimuli temporally overlapped and summed and at intervals when the BD tone followed the NE tone. The results show that duration-selective neurons receive an onset-evoked, inhibitory input that precedes their excitatory input. The period of leading inhibition was correlated with BD and first spike latency. The results suggest how inhibition in the CNS could explain temporal masking phenomena, including backward masking.


Asymptomatic cerebral bleeds in patients with aplastic anemia.
Several studies suggest that cerebral microbleeds (CMB) seen on gradient echo magnetic resonance imaging (GE-MRI) of brain increase the future risk of intracranial hemorrhage (ICH). We investigated 26 newly diagnosed patients of aplastic anemia (AA) with GE-MRI of brain who were otherwise neurologically asymptomatic. These patients were then further followed up for a period of 6 months for development of overt ICH. The median age of patients was 20.5 years (range 12-40 years). The median values of complete blood counts at the time of diagnosis were hemoglobin 5.7 gm/dl (range 2.5-9.2 gm/dl), white cell count 2,320/μl (800-7,000/μl), and platelet count 11,500/μl (7000-45,000/μl). Three patients were detected to have CMB while two patients had asymptomatic cerebral macrobleeds (>1 cm). During the follow-up period of 6 months, two patients developed spontaneous ICH. None of the two patients had CMB at diagnosis. In conclusion, asymptomatic CMB were found in 11.5 % of patients with AA. The overall prevalence of asymptomatic ICH (CMB & macrobleeds) was 19.2 %. Further studies with larger number of patients are required to clearly delineate the association.


Late rectal and bladder toxicity following radiation therapy for prostate cancer: Predictive factors and treatment results.
This study aimed at investigating factors associated to late rectal and bladder toxicity following radiation therapy and the effectiveness of Hyperbaric Oxygen Therapy (HBOT) when toxicity is grade ≥2. Radiation is frequently used for prostate cancer, but a 5-20% incidence of late radiation proctitis and cystitis exists. Some clinical and dosimetric factors have been defined without a full agreement. For patients diagnosed of late chronic proctitis and/or cystitis grade ≥2 treatment is not well defined. Hyperbaric Oxygen Therapy (HBOT) has been used, but its effectiveness is not well known. 257 patients were treated with radiation therapy for prostate cancer. Clinical, pharmacological and dosimetric parameters were collected. Patients having a grade ≥2 toxicity were treated with HBOT. Results of the intervention were measured by monitoring toxicity by Common Toxicity Criteria v3 (CTCv3). Late rectal toxicity was related to the volume irradiated, i.e. V50 > 53.64 (p = 0.013); V60 > 38.59% (p = 0.005); V65 > 31.09% (p = 0.002) and V70 > 22.81% (p = 0.012). We could not correlate the volume for bladder. A total of 24 (9.3%) patients experienced a grade ≥2. Only the use of dicumarinic treatment was significant for late rectal toxicity (p = 0.014). A total of 14 patients needed HBOT. Final percentage of patients with a persistent toxicity grade ≥2 was 4.5%. Rectal volume irradiated and dicumarinic treatment were associated to late rectal/bladder toxicity. When toxicity grade ≥2 is diagnosed, HBOT significantly ameliorate symptoms.


The effect of gemfibrozil, niacin and cholestyramine combination therapy on metabolic syndrome in the Armed Forces Regression Study.
Metabolic syndrome is a powerful predictor of cardiovascular events independent of overt diabetes. Dietary restriction and weight loss modify metabolic syndrome components. This study addresses whether combination pharmacologic therapy focused on dyslipidemia provides additional benefit. This study examines the effect of 1 year of gemfibrozil, niacin and cholestyramine therapy on a baseline of aggressive dietary and lifestyle intervention in 143 clinically stable, nondiabetic patients with coronary disease, randomized into a double-blind, placebo-controlled trial. Cohort characteristics included age 63 ± 7 years, 92% men, 43% with previous myocardial infarction, systolic blood pressure 139 ± 17 mm Hg, triglycerides 168 ± 81 mg/dL and high-density lipoprotein cholesterol 34 ± 6 mg/dL. The mean number of metabolic syndrome components decreased from 2.2 ± 0.9 to 1.5 ± 1.1, P < 0.001, and metabolic syndrome prevalence decreased from 38% to 18% (P < 0.001) for the entire cohort. In the lifestyle intervention and placebo group, the mean number of metabolic syndrome components decreased from 2.2 ± 0.9 to 1.9 ± 1.1 (P = 0.01), and prevalence of metabolic syndrome decreased from 44% to 30% (P = 0.15). A far more marked change was observed with lifestyle intervention and pharmacologic therapy: abnormal metabolic components decreased from 2.2 ± 0.9 to 1.0 ± 1.0 (P < 0.001), and prevalence of metabolic syndrome decreased from 32% to 6% (P < 0.001). The combination of gemfibrozil, niacin and cholestyramine has profound, beneficial effects on the components of metabolic syndrome. These benefits are additive to those seen with aggressive diet and lifestyle modification.


[Gallbladder extirpation in The Netherlands; frequency, surgical mortality and postoperative complications (1987-1989)].
In view of the fast-growing popularity of laparoscopic cholecystectomy, a retrospective analysis was made of 'traditional' cholecystectomy in the Netherlands in the period 1987-1989 (data provided by the Health Care Information Centre Foundation), as compared with the period 1979-1981 (data provided by the Medical Registration Foundation). As regards frequency, the number of cholecystectomies had decreased by 25.5% compared with the period 1979-1981. The number of cholecystectomies with exploration of the choledochus had decreased by 43.8%. The surgical mortality in the period 1987-1989 amounted to 1.4%. Postoperative complications, including wound infections, were relatively infrequent, occurring in 4.3% and 1.5%, respectively, of the patients. Acute cholecystitis, age greater than 70 years and choledochus exploration proved to be risk factors with substantially higher surgical mortality and postoperative morbidity.


Gene interactions affecting muscle organization in Caenorhabditis elegans.
Revertants of unc-15(e73)I, a paralyzed mutant with an altered muscle paramyosin, include six dominant and two recessive intragenic unc-15 revertants, two new alleles of the previously identified suppressor gene, sup-3 V, and a new suppressor designated sup-19(m210)V. The recessive intragenic unc-15 revertants exhibit novel alterations in paramyosin paracrystal structure and distribution, and these alterations are modified by interaction with unc-82(e1220)IV, another mutation that affects paramyosin. A strain containing both unc-15 and a mutation in sup-3 V that restores movement was mutagenized, and paralyzed mutants resembling unc-15 were isolated. Twenty mutations that interfere with suppression were divided into three classes (nonmuscle, sus-1, and mutations within sup-3) based on phenotype, genetic map position and dominance. The nonmuscle mutations include dumpy and uncoordinated types that have no obvious direct effect on muscle organization. Two recessive mutations define a new gene, sus-1 III. These mutations modify the unc-15(e73) phenotype to produce a severely paralyzed, dystrophic double mutant that is not suppressed by sup-3. Five semidominant, intragenic sup-3 antisuppressor mutations, one of which occurred spontaneously, restore the wild-type sup-3 phenotype of nonsuppression. However, reversion of these mutants generated no new suppressor alleles of sup-3, suggesting that the sup-3 antisuppressor alleles are not wild type but may be null alleles.


Preoperative normalization of cortisol levels in Cushing's disease after medical treatment: consequences for somatostatin and dopamine receptor subtype expression and in vitro response to somatostatin analogs and dopamine agonists.
Corticotroph pituitary adenomas often highly express the dopamine 2 receptor (D₂R) and somatostatin receptor subtype 5 (sst₅). The sst₂ expression is relatively low, likely resulting from downregulating effects of high cortisol levels. This may explain why the sst₂-preferring somatostatin analog octreotide, compared with the multi-receptor-targeting somatostatin analog pasireotide, is generally ineffective in Cushing's disease. Our objective was to compare sst and D₂R expression levels between adenomas from patients with elevated and normalized preoperative urinary free cortisol excretion. Corticotroph adenoma tissue was examined from patients from group 1 (n = 22; elevated preoperative urinary free cortisol) and group 2 (n = 11; mean duration of preoperative normocortisolism 10 weeks). Somatotroph adenoma tissue from 10 acromegalic patients was examined to compare receptor expression profiles. We evaluated receptor mRNA and protein expression levels and effects of octreotide, pasireotide, and cabergoline on ACTH secretion by cultured human corticotroph adenoma cells. The sst₂ mRNA expression in group 2 was 10-fold higher than in group 1 (P < .01), even comparable to that in somatotroph adenomas. There were no statistically significant differences in sst₅ and D₂R mRNA expression or in sst₂, sst₅, and D₂R protein expression between both groups of corticotroph adenomas. In responders, octreotide (n = 2 out of 4; -30.5% ± 10.4%) was less potent than pasireotide (n = 5 out of 6; -47.0% ± 4.2%) and cabergoline (n = 3 out of 4; -41.9% ± 3.1%) with respect to inhibition of ACTH secretion by adenomas from group 2. After achieving normocortisolism induced by medical therapy, cortisol-mediated sst₂ downregulation on corticotroph adenomas appears to be a reversible process at the mRNA but not at the protein level. Octreotide remains less potent than pasireotide and cabergoline with respect to in vitro inhibition of ACTH secretion. Whether sustained normocortisolism induced by medical therapy induces re-expression of functional sst₂ protein in corticotroph adenomas and whether this increases the ACTH-lowering potency of octreotide remains to be established.


Infrared emission by fine water aerosols and fogs.
Water aerosols, even when so finely divided as to be invisible, are capable of very strong absorption and emission in the infrared. This effect is pronounced in the 8-13-micro atmospheric window, owing to the 10(4) increase in the absorptivity of liquid water there over that for water vapor, and it contributes to the well known continuum in this spectral region. Water aerosol is found wherever suitable condensation nuclei exist and the relative humidity is above about 60%. Aerosol droplets increase in size and number with increasing relative humidity, affecting atmospheric radiance measurements accordingly. Trace quantities of aerosol can easily account for emission levels exceeding those of water vapor at 8-13 micro and are clearly indicated in cases where observed radiance levels cannot be accounted for by classical vapor band wing absorption theories. The aerosol emission mechanism is not associated with the formation or growth of the water droplets per se, but simply operates when droplets exist in the airborne state. Fog measurements are discussed and curves presented showing attenuation ratios between wavelengths in the visible and at 8-13 micro. Steam emission measurements leading to the formulation of an aerosol emission model are described briefly.


Risk accuracy of type 2 diabetes in middle aged adults: Associations with sociodemographic, clinical, psychological and behavioural factors.
To identify the proportion of individuals with an accurate perception of their risk of type 2 diabetes (T2D) prior to, immediately after and eight weeks after receiving a personalised risk estimate. Additionally, we aimed to explore what factors are associated with underestimation and overestimation immediately post-intervention. Cohort study based on the data collected in the Diabetes Risk Communication Trial. We included 379 participants (mean age 48.9 (SD 7.4) years; 55.1% women) who received a genotypic or phenotypic risk estimate for T2D. While only 1.3% of participants perceived their risk accurately at baseline, this increased to 24.7% immediately after receiving a risk estimate and then dropped to 7.3% at eight weeks. Those who overestimated their risk at baseline continued to overestimate it, whereas those who underestimated their risk at baseline improved their risk accuracy. We did not identify any other characteristics associated with underestimation or overestimation immediately after receiving a risk estimate. Understanding a received risk estimate is challenging for most participants with many continuing to have inaccurate risk perception after receiving the estimate. Individuals who overestimate or underestimate their T2D risk before receiving risk information might require different approaches for altering their risk perception.


Retention strategies and predictors of attrition in an urban pediatric asthma study.
The Urban Environment and Childhood Asthma (URECA) study is a multicenter prospective birth cohort study designed to examine factors related to the development of childhood asthma and allergies in an inner-city population. The retention of these participants has been challenging due to high mobility, inconsistent phone service, custody issues, and stressful life situations. In this article, we describe the specific retention challenges we encountered during the first 2 years of follow-up in URECA and the strategies we utilized to address them. We also examine how selected maternal characteristics and other factors are related to retention and missed study visits. Strategies implemented to engage participants included: collecting updated and alternative contact information, after-hours phone calls to participants, culturally competent staff, flexible study event scheduling, clinic visit transportation, quarterly newsletters, retention events, drop-in home visits, and cell phone reimbursements. An internally developed web-based data management system enabled close monitoring by site teams and the coordinating center. The rate of deactivations was calculated using survival analysis. Characteristics of active and deactivated participants were compared using the chi-squared test with a Cochran-Mantel - Haenszel adjustment for study site. The proportion of missed visits of the total expected in the first 2 years was calculated and compared by family characteristics using an ANOVA model or a trend test controlling for study site. All analyses were performed using SAS version 9.1 (Cary, NC). The 2-year retention rate was 89%. Participation in the first study event predicted subsequent engagement in study activities. Mothers who did not complete the first visit were more likely to miss future events (46.1% vs. 8.9%, p<0.0001) and to be deactivated (38.5% vs. 4.5%, p<0.0001). Mothers under 18 years of age were more likely to leave the study compared to older mothers (22.7% vs. 10.1%, p = 0.02). Also, mothers who were married missed fewer events than those not married (8.8% vs. 15.6%, p = 0.01). In addition, deactivations were more common when the child had entered daycare by 3 months of age (10.9% vs. 3.6%, p = 0.05). The URECA population is predominantly minority, thus our findings might not be generalizable to other populations. Furthermore, we may not be able to observe the effects that might exist in a more diverse population. For example, 86% of the mothers are unmarried, making it difficult to reliably examine the effect of marital status. In research, successfully engaging and retaining participants is essential for achieving the study objectives. Identifying factors related to missed visits and deactivations are the initial step in recognizing the potential at-risk participants and can enable the design of targeted strategies to retain participants.


Mining the low molecular weight proteome of blood.
Serum and plasma are composed of highly complex protein/peptide mixtures resulting from the systemic monitoring of every biological process in a living organism. Some of these sentinel changes are extremely short-lived while others produce more stable by-products. In addition, since biological events occur simultaneously and with overlapping physiological demands, separating the desired ones from "background" changes is an exceptional challenge. In this review, we outline a definition of the "low molecular weight proteome" as a valuable subcomponent of the blood proteome. We make a case that this derivative proteome is as information rich and equally complex as the parent proteome. We discuss some of the technical challenges in the analysis of the low molecular weight proteome with an emphasis on MS-based analytical approaches. With specific example of several reported methodologies we attempt to frame the current state-of-the-art in study design as a guide to future efforts.


A novel myeloid-restricted zebrafish CCAAT/enhancer-binding protein with a potent transcriptional activation domain.
The CCAAT/enhancer-binding protein (C/EBP) family consists of transcription factors essential for hematopoiesis. The defining feature of the C/EBPs is a highly conserved carboxy-terminal bZIP domain that is necessary and sufficient for dimerization and DNA binding, whereas their amino-terminal domains are unique. This study reports a novel c/ebp gene (c/ebp1) from zebrafish that encodes a protein homologous to mammalian C/EBPs within the bZIP domain, but with an amino terminus lacking homology to any C/EBP or to any known sequence. In zebrafish embryos, c/ebp1 expression was initially observed in cells within the yolk sac circulation valley at approximately the 16-to 18-somite stage, and at 24 hours postfertilization (hpf), also in circulating cells. Most c/ebp1(+) cells also expressed a known early macrophage marker, leukocyte-specific plastin (l-plastin). Expression of both markers was lost in cloche, a mutant affecting hematopoiesis at the level of the hemangioblast. Expression of both markers was retained in m683 and spadetail, mutants affecting erythropoiesis, but not myelopoiesis. Further, c/ebp1 expression was lost in a mutant with defective myelopoiesis, but intact erythropoiesis. These data suggest that c/ebp1 is expressed exclusively in myeloid cells. In electrophoretic mobility shift assays, c/ebp1 was able to bind a C/EBP consensus DNA site. Further, a chimeric protein containing the amino-terminal domain of c/ebp1 fused to the DNA-binding domain of GAL4 induced a GAL4 reporter 4000-fold in NIH3T3 cells. These results suggest that c/ebp1 is a novel member of the C/EBP family that may function as a potent transcriptional activator in myeloid cells.


Predicting crystal growth via a unified kinetic three-dimensional partition model.
Understanding and predicting crystal growth is fundamental to the control of functionality in modern materials. Despite investigations for more than one hundred years, it is only recently that the molecular intricacies of these processes have been revealed by scanning probe microscopy. To organize and understand this large amount of new information, new rules for crystal growth need to be developed and tested. However, because of the complexity and variety of different crystal systems, attempts to understand crystal growth in detail have so far relied on developing models that are usually applicable to only one system. Such models cannot be used to achieve the wide scope of understanding that is required to create a unified model across crystal types and crystal structures. Here we describe a general approach to understanding and, in theory, predicting the growth of a wide range of crystal types, including the incorporation of defect structures, by simultaneous molecular-scale simulation of crystal habit and surface topology using a unified kinetic three-dimensional partition model. This entails dividing the structure into 'natural tiles' or Voronoi polyhedra that are metastable and, consequently, temporally persistent. As such, these units are then suitable for re-construction of the crystal via a Monte Carlo algorithm. We demonstrate our approach by predicting the crystal growth of a diverse set of crystal types, including zeolites, metal-organic frameworks, calcite, urea and l-cystine.


Study of crotoxin on the induction of paralysis in extraocular muscle in animal model.
Crotoxin is the major toxin of the venom of the South American rattlesnake Crotalus durissus terrificus, capable of causing a blockade of the neurotransmitters at the neuromuscular junction. The objective of this study was to appraise the action and effectiveness of the crotoxin induced paralysis of the extraocular muscle and to compare its effects with the botulinum toxin type A (BT-A). The crotoxin, with LD50 of 1.5 µg, was injected into the superior rectus muscle in ten New Zealand rabbits. The concentration variance was 0.015 up to 150 µg. Two rabbits received 2 units of botulinum toxin type A for comparative analysis. The evaluation of the paralysis was performed using serial electromyography. After the functional recovery of the muscles, which occurred after two months, six rabbits were sacrificed for anatomopathology study. The animals did not show any evidence of systemic toxicity. Transitory ptosis was observed in almost every animal and remained up to fourteen days. These toxins caused immediate blockade of the electrical potentials. The recovery was gradual in the average of one month with regeneration signs evident on the electromyography. The paralysis effect of the crotoxin on the muscle was proportional to its concentration. The changes with 1.5 µg crotoxin were similar to those produced by the botulinum toxin type A. The histopathology findings were localized to the site of the injection. No signs of muscle fiber's necrosis were seen in any sample. The alterations induced by crotoxin were also proportional to the concentration and similar to botulinum toxin type A in concentration of 1.5 µg. Crotoxin was able to induce transitory paralysis of the superior rectus muscle. This effect was characterized by reduction of action potentials and non-specific signs of fibrillation. Crotoxin, in concentration of 1.5 µg was able to induce similar effects as botulinum toxin type A.


Preparation and properties of mitochondria derived from synaptosomes.
A method has been developed whereby a fraction of rat brain mitochondria (synaptic mitochondria) was isolated from synaptosomes. This brain mitochondrial fraction was compared with the fraction of "free" brain mitochondria (non-synaptic) isolated by the method of Clark & Nicklas (1970). (J. Biol. Chem. 245, 4724-4731). Both mitochondrial fractions are shown to be relatively pure, metabolically active and well coupled. 2. The oxidation of a number of substrates by synaptic and non-synaptic mitochondria was studied and compared. Of the substrates studied, pyruvate plus malate was oxidized most rapidly by both mitochondrial populations. However, the non-synaptic mitochondria oxidized glutamate plus malate almost twice as rapidly as the synaptic mitochondria. 3. The activities of certain tricarboxylic acid-cycle and related enzymes in synaptic and non-synaptic mitochondria were determined. Citrate synthase (EC 126.96.36.199), isocitrate dehydrogenase (EC 188.8.131.52) and malate dehydrogenase (EC 22.214.171.124) activities were similar in both fractions, but pyruvate dehydrogenase (EC 18.104.22.168) activity in non-synaptic mitochondria was higher than in synaptic mitochondria and glutamate dehydrogenase (EC 188.8.131.52) activity in non-synaptic mitochondria was lower than that in synaptic mitochondria. 4. Comparison of synaptic and non-synaptic mitochondria by rate-zonal separation confirmed the distinct identity of the two mitochondrial populations. The non-synaptic mitochondria had higher buoyant density and evidence was obtained to suggest that the synaptic mitochondria might be heterogeneous. 5. The results are also discussed in the light of the suggested connection between the heterogeneity of brain mitochondria and metabolic compartmentation.


How far can systematic reviews inform policy development for "wicked" rural health service problems?
Policy makers and researchers increasingly look to systematic reviews as a means of connecting research and evidence more effectively with policy. Based on Australian research into rural and remote primary health care services, we note some concerns regarding the suitability of systematic review methods when applied to such settings. It suggests that rural and other health services are highly complex and researching them is akin to dealing with "wicked" problems. It proposes that the notion of "wicked" problems may inform our understanding of the issues and our choice of appropriate methods to inform health service policy. Key issues including the complexity of health services, methodological limitations of traditional reviews, the nature of materials under review, and the importance of the service context are highlighted. These indicate the need for broader approaches to capturing relevant evidence. Sustained, collaborative synthesis in which complexity, ambiguity and context is acknowledged is proposed as a way of addressing the wicked nature of these issues.


Grandmother's Life Satisfaction and Influencing Factors by Grandparenting.
The study was to compare the factors of life satisfaction between grandmothers parenting and not parenting their grandchildren. A descriptive design with a convenience sampling was used for this study. From communities in S and U city, 85 parenting grandmothers (PG) and 103 non-parenting grandmothers (NPG) were recruited. The PG were those grandmothers who cared for preschooler grandchildren for their daughter or daughter-in-law who was employed. The demographics of the two groups were similar, however the value of grandparenting was significantly higher in the PG than the NPG (t=4.56, p<.001). In the PG, strong and significant correlations were found among the value of grandparenting, health status, quality of relations with adult children, and life satisfaction. However, demographics were more related to health status and life satisfaction in the NPG. The value of grandparenting, health status, and quality of grandmother-adult children relations were found to be significant factors of life satisfaction (F=20.75, p<.001) explaining 42% of the variances. In the NPG, only health status was a significant factor (F=50.66, p<.001) explaining 33% of the variances. This study shows that grandmothers' perceptions of grandparenting and family relationships need to be incorporated into the lifestyle in order to support parenting grandmothers' life satisfaction while grandmothers' health is the common concern of elderly women's life satisfaction.


An overview of cytokines and heat shock response in polytraumatized patients.
Early after injury, local tissue damage induces a local and systemic inflammatory response that activates the immune system and leads to the development of systemic inflammatory response syndrome (SIRS). This post-traumatic response often results in uncontrolled release of inflammatory mediators and over-activation of the immune system, which occasionally results in multiple organ dysfunction syndrome (MODS). In parallel, a state of immunosuppression develops. This counter-regulating suppression of different cellular and humoral immune functions has been termed "compensatory anti-inflammatory response syndrome (CARS)." Both SIRS and CARS occur simultaneously even in the initial phase after injury. Pro- and anti-inflammatory cytokines have been suggested to play a major role in development of SIRS, although the degree of involvement of the different cytokines is quite disparate. While TNF-α and IL-1β are quite irrelevant for predicting organ dysfunction, IL-6 is the parameter that best predicts mortality. The hyperinflammatory state seems to be the cause of post-traumatic immunosuppression and heat shock proteins (HSPs), which have been proposed as one of the endogenous stimuli for the deterioration of the immune system acting as danger-associated molecular patterns (DAMPs). Extracellular HSPA1A released from injured tissues increase up to ten times immediately after trauma and even more in patients with MODS. It has powerful immune properties that could contribute to post-traumatic immunosuppression through several mechanisms that have been previously described, so HSPs could represent trauma-associated immunomodulatory mediators. For this reason, HSPA1A has been suggested to be a helpful early prognostic biomarker of trauma after severe injury: serial quantification of serum HSPA1A and anti-Hsp70 concentrations in the first hours after trauma is proposed to be used as a predictive biomarker of MODS and immunosuppression development in polytraumatized patients.


Chronic stress impairs spatial memory and motivation for reward without disrupting motor ability and motivation to explore.
This study uses an operant, behavioral model to assess the daily changes in the decay rate of short-term memory, motivation, and motor ability in rats exposed to chronic restraint. Restraint decreased reward-related motivation by 50% without altering memory decay rate or motor ability. Moreover, chronic restraint impaired hippocampal-dependent spatial memory on the Y maze (4-hr delay) and produced CA3 dendritic retraction without altering hippocampal-independent maze navigation (1-min delay) or locomotion. Thus, mechanisms underlying motivation for food reward differ from those underlying Y maze exploration, and neurobiological substrates of spatial memory, such as the hippocampus, differ from those that underlie short-term memory. Chronic restraint produces functional, neuromorphological, and physiological alterations that parallel symptoms of depression in humans.


Grass inflorescence architecture and evolution: the origin of novel signaling centers.
Contents 367 I. 367 II. 368 III. 370 IV. 371 371 References 371 SUMMARY: A central goal of evo-devo is to understand how morphological diversity arises from existing developmental mechanisms, requiring a clear, predictive explanatory framework of the underlying developmental mechanisms. Despite an ever-increasing literature on genes regulating grass inflorescence development, an effective model of inflorescence patterning is lacking. I argue that the existing framework for grass inflorescence development, which invokes homeotic shifts in multiple distinct meristem identities, obscures a recurring theme emerging from developmental genetic studies in grass models, that is that inflorescence branching is regulated by novel localized signaling centers. Understanding the origin and function of these novel signaling centers will be key to future evo-devo work on the grass inflorescence.


Distinct timescales of population coding across cortex.
The cortex represents information across widely varying timescales. For instance, sensory cortex encodes stimuli that fluctuate over few tens of milliseconds, whereas in association cortex behavioural choices can require the maintenance of information over seconds. However, it remains poorly understood whether diverse timescales result mostly from features intrinsic to individual neurons or from neuronal population activity. This question remains unanswered, because the timescales of coding in populations of neurons have not been studied extensively, and population codes have not been compared systematically across cortical regions. Here we show that population codes can be essential to achieve long coding timescales. Furthermore, we find that the properties of population codes differ between sensory and association cortices. We compared coding for sensory stimuli and behavioural choices in auditory cortex and posterior parietal cortex as mice performed a sound localization task. Auditory stimulus information was stronger in auditory cortex than in posterior parietal cortex, and both regions contained choice information. Although auditory cortex and posterior parietal cortex coded information by tiling in time neurons that were transiently informative for approximately 200 milliseconds, the areas had major differences in functional coupling between neurons, measured as activity correlations that could not be explained by task events. Coupling among posterior parietal cortex neurons was strong and extended over long time lags, whereas coupling among auditory cortex neurons was weak and short-lived. Stronger coupling in posterior parietal cortex led to a population code with long timescales and a representation of choice that remained consistent for approximately 1 second. In contrast, auditory cortex had a code with rapid fluctuations in stimulus and choice information over hundreds of milliseconds. Our results reveal that population codes differ across cortex and that coupling is a variable property of cortical populations that affects the timescale of information coding and the accuracy of behaviour.


Becoming 'whole' again: a qualitative study of women's views of recovering from anorexia nervosa.
This study explored how women made sense of their recovery from Anorexia Nervosa (AN). Semi-structured telephone interviews were carried out with fifteen women who had received a diagnosis of AN and defined themselves as either recovered or in recovery. Data were analysed using interpretative phenomenological analysis (IPA). The women described their experiences in terms of three broad areas; being anorexic; the process of change; and being recovered. Transcending these themes was a series of dichotomies involving splits between their mind and body, AN behaviour and cognitions and their rational and irrational side. Further, they indicated that recovery reflects the time when these many different components of their selves are no longer divided and that this was often facilitated through therapy and close relationships which enabled them to find non bodily means to express their distress. Therapy should therefore aim to facilitate a sense of becoming 'whole' again.


Teflon cylindrical phantom for delivery quality assurance of stereotactic body radiotherapy (SBRT).
At our institution the standard delivery quality assurance (DQA) procedure for tomotherapy plans is accomplished with a water equivalent phantom, EDR2 film, and ion chamber point-dose measurements. Most plans deliver at most 5 Gy to the dose plane; however, recently a stereotactic body radiotherapy (SBRT) protocol has produced plans delivering upwards of 12 Gy to the film plane. EDR2 film saturates at a dose of ~ 7 Gy, requiring a modification of our DQA procedure for SBRT plans. To reduce the dose to the film plane and accommodate a possible move to SBRT using Varian RapidArc, a Teflon phantom has been constructed and tested. Our Teflon phantom is cylindrical in shape and of a similar design to the standard phantom. The phantom was MVCT scanned on the TomoTherapy system with images imported into the TomoTherapy and Varian Eclipse planning systems. Phantom images were smoothed to reduce artifacts for treatment planning purposes. Verification SBRT plans were delivered with film and point-dose benchmarked against the standard procedure. Verification tolerance criteria were 3% dose difference for chamber measurements and a gamma pass rate > 90% for film (criteria: 3 mm DTA, 3% dose difference, 10% threshold). The phantom sufficiently reduced dose to the film plane for DQA of SBRT plans. Both planning systems calculated accurate point doses in phantom, with the largest differences being 2.4% and 4.4% for TomoTherapy and Rapid Arc plans. Measured dose distributions correlated well with planning system calculations (γ < 1 for > 95%). These results were comparable to the standard phantom. The Teflon phantom appears to be a potential option for SBRT DQA. Preliminary data show that the planning systems are capable of calculating point doses in the Teflon, and the dose to the film plane is reduced sufficiently to allow for a direct measured DQA without the need for dose rescaling.


Disrupting the Balance of Protein Quality Control Protein UBQLN2 Accelerates Tau Proteinopathy.
Tau protein accumulation drives toxicity in several neurodegenerative disorders. To better understand the pathways regulating tau homeostasis in disease, we investigated the role of ubiquilins (UBQLNs)-a class of proteins linked to ubiquitin-mediated protein quality control (PQC) and various neurodegenerative diseases-in regulating tau. Cell-based assays identified UBQLN2 as the primary brain-expressed UBQLN to regulate tau. UBQLN2 efficiently lowered wild-type tau levels regardless of aggregation, suggesting that UBQLN2 interacts with and regulates tau protein under normal conditions or early in disease. Moreover, UBQLN2 itself proved to be prone to accumulation as insoluble protein in male and female tau transgenic mice and the human tauopathy progressive supranuclear palsy. Genetic manipulation of UBQLN2 in a tauopathy mouse model demonstrated that a physiological UBQLN2 balance is required for tau homeostasis. UBQLN2 overexpression exacerbated phosphorylated tau pathology and toxicity in mice expressing P301S mutant tau, whereas P301S mice lacking UBQLN2 showed significantly reduced phosphorylated tau. Further studies support the view that an imbalance of UBQLN2 perturbs ubiquitin-dependent PQC and autophagy. We conclude that changes in UBQLN2 levels, whether because of pathogenic mutations or secondary to disease states, such as tauopathy, contribute to proteostatic imbalances that exacerbate neurodegeneration.SIGNIFICANCE STATEMENT We defined a role for the protein quality control protein Ubiquilin-2 (UBQLN2), in age-related neurodegenerative tauopathies. This group of disorders is characterized by the accumulation of tau protein aggregates, which differ when UBQLN2 levels are altered. Given the lack of effective disease-modifying therapies for tauopathies and the function of UBQLN2 in handling various disease-linked proteins, we explored the role of UBQLN2 in regulating tau. We found that UBQLN2 reduced tau levels in cell models but behaved differently in mouse brain, where it accelerated mutant tau pathology and tau-mediated toxicity. A better understanding of the diverse functions of regulatory proteins like UBQLN2 can elucidate some of the causative factors in neurodegenerative disease and outline new routes to therapeutic intervention.


Explaining the Association between Driver's Age and the Risk of Causing a Road Crash through Mediation Analysis.
It has been widely reported that younger and older drivers have an excess risk of causing a road crash. Two casual hypotheses may coexist: the riskier driving behaviors and age-related mechanisms in extreme age groups (direct path) and the different environmental and vehicle circumstances (indirect path). Our aim was to quantify, through a mediation analysis, the percentage contribution of both paths. A case-control study was designed from the Spanish Register of Road Crashes with victims from 2014 to 2017. Assuming a quasi-induced exposure approach, controls were non-responsible drivers involved in clean collisions between two or more vehicles (n = 52,131). Responsible drivers for these collisions plus drivers involved in single crashes constituted the case group (n = 82,071). A logit model in which the outcome was the log (odds) of causing a road crash and the exposure was age groups was adjusted for driver, vehicle and environmental factors. The highest crash risk was observed in extreme age groups, compared to the 35-44 year old age group: the youngest (18-24 years old, odds ratio = 2.14, 95% confidence interval: 2.06-2.24) and the oldest drivers (>74 years old, odds ratio = 3.30, 95% confidence interval: 3.04-2.58). The mediation analysis identified the direct path as the main explanatory mechanism for these increases: 89% in the youngest and 93% in the oldest drivers. These data support the hypothesis that the excess crash risk observed for younger and older drivers is mainly related to their higher frequency of risky driving behaviors and age-related loss of capabilities. Preventive strategies in extreme-aged drivers should focus on decreasing these behaviors.


[Trial of the clinical use of mithramycin in treating testicular cancer].
The data on efficacy of mitramycin, an antitumor antibiotic in treatment of 32 patients with cancer of the testicle are presented. The objectively pronounced effect was observed in 37.5 per cent of the cases, mitramycin being effective in patients with tumors resistant to bleomycin, vinblastin and cis-dichlordiaminoplatinum. Nausea and vomiting were the most frequent side effects of mitramycin use. The hemorrhagic syndrome was recorded in 2 patients. The regimen of the mitramycin intravenous administration in a dose of 25--30 microgram/kg once in 2 days was well tolerated by the patients and may be recommended for the treatment of testicle cancer.


[A study on the relationship among estrogen receptor, progesterone receptor and glucose-6-phosphate dehydrogenase activity in primary breast cancer].
The relationships among estrogen receptor (ER), progesterone receptor (PgR) and glucose-6-phosphate dehydrogenase (G6PD) activity demonstrated by histochemical technique were studied in 85 cases of primary breast cancer. The ER positive rate was 71.8% and the PgR positive rate was 54.1%. A close correlation was obtained between the PgR and ER positivity or the semiquantitative grades. The G6PD activity in ER or PgR positive group was higher than that in the negative group. Moreover, the elevated G6PD activity was also correlated with the increased semiquantitative grades of ER or PgR. Our findings support the views that both PgR and G6PD are proteins induced by estrogen and may represent markers of functional ER in breast cancer. This suggests that simultaneous assay of ER, PgR and/or G6PD activity may be more reliable to predict the hormone dependence of the tumor.


Spontaneous unscarred uterine rupture at 13 weeks of gestation after in vitro fertilization-embryo transfer: A case report and literature review.
Uterine rupture (UR) during pregnancy is a serious obstetric complication. Here we report a case of spontaneous rupture in an unscarred uterus at 13 weeks of gestation after in vitro fertilization embryo transfer, which is not common in past references. Our focus is to understand the relationship between systemic lupus erythematosus (SLE) and UR. A 33-year-old infertile woman with a history of SLE became pregnant after in vitro fertilization embryo transfer. She presented with sudden mental fatigue and dyspnea, accompanied by sweating, dizziness and lower abdominal pain at 13 weeks of gestation. Blood analysis revealed anemia. Ultrasonography and plain computed tomography scan revealed intrauterine early pregnancy with effusion in pelvic and abdominal cavity. Laparotomy confirmed the diagnosis of UR. The patient underwent emergency laparotomy. Upon surgery, multiple myometrium was weak with only serosal layer visible, and there was a 2.5 cm irregular breach with exposed placenta and villous tissue in the posterior wall of the uterus. After removing intrauterine fetus and repairing the breach, there was still persistent intraperitoneal hemorrhage. The patient underwent subtotal hysterectomy finally. Postoperative recovery was uneventful. The patient was discharged on the 8th day after operation. Combined efforts of specialists from ultrasound, imaging and gynecologist led to the successful diagnosis and management of this patient. We should be cautious about the occurrence of unscarred uterus rupture during pregnancy of the women with the disease of SLE and long-term glucocorticoid treatment. In IVF, we had better transfer one embryo for these patients with the history of SLE. Obstetricians should strengthen labor tests to detect early signs of UR of the patients with SLE and long term glucocorticoid treatment. Once UR is suspected, prompt surgical treatment is needed as soon as possible.


Group I metabotropic glutamate antagonist reduces acute neuronal degeneration and behavioral deficits after traumatic brain injury in rats.
Recent studies indicate that acute activation of Group I mGluRs following traumatic brain injury (TBI) contributes to the ensuing pathophysiology. The present study examined the effects of post-TBI administration of the selective mGluR1 antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA) on acute neuronal degeneration in the hippocampus and long-term sensorimotor and learning/memory outcome. In Experiment 1, 26 rats received 0.4, 2.0, or 10.0 nmol AIDA or artificial CSF vehicle infusion into the hippocampus starting 5 min postinjury. At 24 h after TBI characteristic pyramidal cell degeneration was observed in Fluoro-Jade-stained coronal sections of the CA2/3 sectors of the dorsal hippocampus. The mean (+/-SEM) number of Fluoro-Jade-positive neurons in the 10 nmol AIDA group (184 +/- 32) was significantly less (P < 0.05) than the vehicle group (310 +/- 47). In Experiment 2, 20 rats were trained on sensorimotor and memory tasks prior to parasagittal fluid percussion TBI. Rats were administered 10 nmol AIDA or vehicle as in Experiment 1. Rats were assessed on beam walking and radial arm maze (RAM) performance weekly for 6 weeks after TBI. Acquisition of a Morris water maze (MWM) task was assessed on days 11-15 after TBI. The AIDA-treated group had significantly reduced deficits in beam walk, MWM, and RAM performance compared to the vehicle-treated group. These data indicate that injury-induced acute activation of mGluR1 receptors contributes to both the cellular pathology and the behavioral morbidity associated with TBI.


The R27080 glycoprotein is abundantly secreted from human cytomegalovirus-infected fibroblasts.
A 45 kDa glycoprotein was purified from the culture media of human cytomegalovirus (HCMV)-infected fibroblasts. N-terminal sequencing revealed that the protein, R27080, is the translation product of the R27080 open reading frame of HCMV. R27080 is highly glycosylated and contains no cysteine or methionine residues. Proteolytic cleavage of R27080 by a furin-like enzyme was analysed in transfected COS-7 cells. R27080 is the first identified viral protein secreted from HCMV-infected cells.


[Molecular identification and characteristics of hRPC11, the smallest specific subunit of human RNA polymerase III].
Full-length copies of cDNA of the hRPC11 gene encoding the smallest specific subunit of nuclear RNA polymerase III were identified among human transcripts with the use of the RT-PCR technique. The cloning of the first orthologue of the subunit RPC11 from a multicellular organism and the comparison of subunit hRPC11 of Homo sapiens (108 aa; M(r), 12.3 kDa; pI 8.05) deduced from the cDNA primary structure with the homologous components of RNA polymerase III from Saccharomyces cerevisiae and Schizosaccharomyces pombe revealed the most important functional domains: a Zn-binding motif of the classic type (CxxCx16-17CxxC) at the N-terminal region, and two extended regions of homology (KEVDDVLGG and RSADEPM) in the central and C-terminal parts of the molecule, respectively. The C-terminus of the RPC11 subunits is highly homologous to the unique zinc ribbon of the elongation factor TFIIS, which suggests a role for this subunit in the elongation or termination of RNA synthesis.


Association of cerebral perfusion pressure with headache in women with pre-eclampsia.
To study estimated cerebral perfusion pressure and its relation to headache and scotomata in women with pre-eclampsia. Prospective, observational study. University teaching hospitals. Seventy-nine pre-eclamptic women with (n = 42) and without (n = 37) headache. Patients with scotomata were also studied separately. Transcranial Doppler ultrasound was used to estimate the resistance index, pulsatility index, and estimated cerebral perfusion pressure in the middle cerebral artery. eCPP data were plotted on the same axes as the mean (and 5th and 95th% prediction limits) eCPP data from 63 normal pregnant women followed longitudinally through pregnancy. Data outside of the 95% prediction limits were regarded as abnormal. Data from the pre-eclamptic women were also expressed in terms of the number of standard deviations from the mean value established for normal pregnancy (multiples of the standard deviation: MOS). All studies were prior to labour, under similar conditions, and before volume expansion or treatment. Analysis of data was performed using Student's t test, Mann-Whitney U test, ANOVA, and Fisher's exact test with two-tailed P < 0.05, and receiver operating characteristic curve analysis with a one-tailed P < 0.05. Resistance index, pulsatility index, and eCPP. Pre-eclamptic women with headache were much more likely to have abnormal eCPP (34/42; 88%) than those without headache (18/37; 49%), P = 0.004, OR 4.5 (95% CI 1.5 to 13.9). There were no differences in terms of MOS in the resistance index or pulsatility index between the two groups, but estimated perfusion pressure, expressed as multiples of the standard deviation in the group with headache, was significantly higher than in the women without. Headache was noted in both over-perfusion and under-perfusion states. Only women with headache had scotomata, and their presence was not related to the severity of the headache or any difference in resistance indices or eCPP. Headache in women with pre-eclampsia is strongly associated with the presence of abnormal cerebral perfusion pressure. This information may be of use in clinical management.


Protective effects of MiR-146b in cerebral infarction via targeting SIRT1/FOXO1 signaling pathway.
To observe the therapeutic effect of micro ribonucleic acid (miR)-146b on brain tissue injury in rats with cerebral infarction (CI) by regulating the Sirtuin 1 (SIRT1)/forkhead box protein O1 (FOXO1) signaling pathway, a rat model of CI was established. Lentiviral cells were used to transfect and silence or overexpress miR-146b. The rats were divided into the miR-146b inhibitor group (Inhibitors), miR-146b mimic group (Mimics) and normal group (Control). Then quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the transfection rate of miR-146b in rat brain tissues in each group. The improved method was adopted to score the nerves of rats, and the infarction volume of rats in each group was determined. Subsequently, the levels of superoxide dismutase (SOD) and reactive oxygen species (ROS) in the brain tissues in each group were measured via enzyme-linked immunosorbent assay (ELISA), the apoptosis of nerve cells in the brain tissues was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and glial fibrillary acidic protein (GFAP), S100β gene and SIRT1/FOXO1 pathway-related genes and proteins in the brain tissues were determined through qRT-PCR and Western blotting. MiR-146b exhibited a high expression in Mimics and an extremely low expression in Inhibitors. Rats in Mimics were normal in movement, and their neurological scores were close to those in Control. Rats in Inhibitors could walk normally, and their neurological scores were notably higher than those in other groups (P<0.05). In addition, Inhibitors had a remarkably larger CI volume (P<0.05), a remarkably increased ROS level and a significantly reduced SOD level compared with those in other groups. Moreover, TUNEL staining results manifested that apoptotic cells, especially glial cells, were notably increased in Inhibitors compared with those in Mimics. Besides, the messenger RNA (mRNA) expression levels of S100β and GFAP in Inhibitors were higher than those in other groups (P<0.05). SIRT1 and FOXO1 genes were increased in Mimics, which were close to those in Control. According to Western blotting results, the protein expression levels of SIRT1 and FOXO1 in Mimics were notably higher than those in Inhibitors. MiR-146b can play a protective role in CI rats by activating the SIRT1/FOXO1 signaling pathway, lowering the oxidative stress level and reducing brain tissue apoptosis.


Safe and effective plasma exchange to remove antibodies prior to xenogeneic heart transplantation in small primates.
The ability of an on-line, rapid plasma exchange (PE) system to remove circulating antibodies in preparation for xenogeneic heart transplantation was studied. Plasma exchanges were performed 27 times on 13 rhesus monkeys weighing from 6.5 to 12.0 kg, using systemic heparinization, without untoward effects. Blood flow rates of 22-72 ml/min resulted in plasma collection rates of 7-22.5 ml/min. Serum immunoglobulin levels were decreased by more than 90%, and specific antiendothelial xenoreactive IgM was completely removed after two plasma exchanges. Transferrin levels were decreased 85-95%, and complement levels fell by greater than 80%. Platelets were partially conserved, with removal rates of 18-60%. All factors returned to normal ranges within 48 hours and no bleeding complications were encountered. When antiendothelial antibodies were removed in this manner, survival of a pig heart transplanted into a rhesus monkey was extended to 12 hours, from a baseline of 2 hours, without treatment.


Rationale for Polyclonal Intravenous Immunoglobulin Adjunctive Therapy in COVID-19 Patients: Report of a Structured Multidisciplinary Consensus.
Adjunctive therapy with polyclonal intravenous immunoglobins (IVIg) is currently used for preventing or managing infections and sepsis, especially in immunocompromised patients. The pathobiology of COVID-19 and the mechanisms of action of Ig led to the consideration of this adjunctive therapy, including in patients with respiratory failure due to the SARS-CoV-2 infection. This manuscript reports the rationale, the available data and the results of a structured consensus on intravenous Ig therapy in patients with severe COVID-19. A panel of multidisciplinary experts defined the clinical phenotypes of COVID-19 patients with severe respiratory failure and, after literature review, voted for the agreement on the rationale and the potential role of IVIg therapy for each phenotype. Due to the scarce evidence available, a modified RAND/UCLA appropriateness method was used. Three different phenotypes of COVID-19 patients with severe respiratory failure were identified: patients with an abrupt and dysregulated hyperinflammatory response (early phase), patients with suspected immune paralysis (late phase) and patients with sepsis due to a hospital-acquired superinfection (sepsis by bacterial superinfection). The rationale for intravenous Ig therapy in the early phase was considered uncertain whereas the panelists considered its use in the late phase and patients with sepsis/septic shock by bacterial superinfection appropriate. As with other immunotherapies, IVIg adjunctive therapy may have a potential role in the management of COVID-19 patients. The ongoing trials will clarify the appropriate target population and the true effectiveness.


Crestal sinus lift using an implant with an internal L-shaped channel: 1-year after loading results from a prospective cohort study.
To evaluate the clinical and radiographic outcomes of a one-stage crestal sinus elevation procedure using a self-tapping endosseous implant system (iRaise, Maxillent, Herzliya, Israel) developed for sinus augmentation, 1 year after loading. Patients needing restoration in the posterior maxilla with a residual alveolar crest of 3 to 8 mm in height and 5 mm in width distal to the canine as measured on CBCT scan were treated using the iRaise sinus lift system. Outcome measures were: implant and prosthetic failures, any complications, increased bone height (iBH), marginal bone loss (MBL), implant stability quotient (ISQ), radiographic tissue remodelling patterns using the sinus grafting remodelling index (SGRI), volumetric measurements of sinus graft, patient self-reported post-surgical swelling, consumption of pain medication and histological analysis. A total of 30 consecutive participants with a mean age of 54.2 ± 9.4 years underwent a transcrestal elevation of the sinus membrane, insertion of bone graft, and implant placement. A total of 50 implants were placed (30 iRaise system implants and 20 adjunctive iSure implants, Maxillent). The mean follow-up was 15.8 ± 2.1 months after implant loading. One patient dropped out at the 1-year after loading follow-up examination. No implants and no prostheses failed during the entire follow-up. One patient experienced a small membrane tear. Before implant insertion, the mean residual alveolar ridge height was 4.64 ± 0.86 mm (range: 3.4-6.4 mm; 95% CI: 4.39-5.01 mm). One year after loading, the bone height was 16.86 ± 3.13 mm (95% CI 15.83-18.07 mm). At the 1-year after loading follow-up, the mean MBL was 0.19 ± 1.05 mm (95% CI 0.02-0.78 mm). The mean ISQ at implant placement was 65.2 ± 5.4 (95% CI 63.6-67.4) and increased during the healing period reaching the mean value of 73.6 ± 3.7 (95% CI 73.1-75.9; range 62-79). The difference was statistically significant (8.4 ± 5.3; 95% CI 5.9-39.7; P = 0.0000). One year after loading, SGRI score was evaluated in 23 implants. Overall, the mean SGRI value was 2.29 ± 2.41 mm (95% CI 1.22-2.98 mm). Bone volume at implant placement was 2.41 ± 0.25 CC (95% CI 2.22-2.48 CC). During the 6-month, submerged healing period, a slight bone contraction of 11.3% were observed. (2.13 ± 0.24 CC;95% CI 2.02-2.26; difference = 0.27 ± 0.25 CC; 95% CI 0.10-0.36; P = 0.0011). At the first year post-loading period, the bone graft remained stable (2.11 ± 0.22 CC; 95% CI 2.02-2.24). The difference was not statistically significant (0.02 ± 0.07 CC; 95% CI 0.01-0.04; P = 0.2166). From the patient's point of view, the mean pain value was 0.52 ± 0.74 (range 0-3); mean swelling value was 0.27 ± 0.52 (range 0-2); and the mean consumption of analgesic was 0.87 ± 4.94 tablets (range 0-4) 3 days after surgery. Morphological and histomorphometric analyses showed that all the samples had a normal structure without inflammatory infiltrate, six months after healing. The following fractions (%) were found: bone (immature bone + mature bone): 44.07 ± 4.91; residual biomaterial: 23.98 ± 2.64; medullary spaces: 31.95 ± 3.16. Sinus floor augmentation can be successfully accomplished with a transcrestal approach using a dedicated implant system. A physiologic contraction of 11.3% of the original volume of the bone graft was experienced during the first 6 months of healing; afterwards, no additional graft volume reduction was observed. Long-term clinical studies are needed to confirm these preliminary results.


A systematic review and meta-analysis of epidemiology of depression in people living with HIV in east Africa.
Depression is the most prevalent psychiatric disorder among people living with HIV (PLWHIV) and is associated with poor quality of life, additional comorbidities, disability, unemployment, poorer therapeutic outcomes and risky behaviors. The present systematic review and meta-analysis aims to systematically summarize empirical evidence and to formulate recommendations for future research. We searched PubMed, EMBASE, SCOPUS, and relevant literature for possible studies to include. A qualitative and quantitative analysis was undertaken for this systematic review. Subgroup and sensitivity analysis were performed. Cochran's Q- and the I2 test were used to assess heterogeneity. The presence of publication bias was evaluated by using Egger's test and visual inspection of the symmetry in funnel plots. Of 283 titles initially identified, 81 abstracts were eligible for review. Of these, 46 articles qualified for full text review and 19 were retained. In our meta-analysis the pooled prevalence of depression in PLWHIV was 38% (95% CI 29.30-47.54). The pooled prevalence estimates of depression was 49.79% in Ethiopia and 30.88% in Uganda. In addition, the prevalence of depression was 12.40% and 46% as measured by diagnostic and screening instrument respectively. Our qualitative synthesis showed that factors such as having opportunistic infection, perceived stigma, negative life event, WHO clinical staging of disease, hospitalization in the past one month, stressful life events, food insecurity, self-efficacy, missed frequency of clinic visit, frequency of follow-up, older age, low income, urban residence and being government employee were strongly and significantly associated with depression in PLWHIV in east Africa. The pooled prevalence estimates of prevalence of depression in PLWHIV was 38%. The prevalence estimates of depression in PLWHIV in Ethiopia was significantly higher than Uganda. In addition the prevalence of depression was significantly higher in studies conducted by screening than diagnostic instrument. Routine screening and integrated management of depression into the existing HIV care services is warranted. Validation and use of standard instrument to assess depression in PLWHIV is needed. Moreover, longitudinal and community based studies focusing on incidence and determinates of depression in PLWHIV are recommended.


Local adaptation and population differentiation at the interleukin 13 and interleukin 4 loci.
A 25.6 kb region at chromosome 5q31, covering the entire human interleukin 13 (IL-13) and interleukin 4 (IL-4) genes, has been reported to be associated with bronchial asthma. We have examined nucleotide variations at this locus in African, European American, and Japanese populations, using 120 diallelic variants. A block of strong linkage disequilibrium (LD) (mid R:D'mid R:>0.7) spans a 10 kb region containing IL-4 in European American and Japanese populations, and is present but less clear in African samples. Two major haplotypes at IL-4 account for >80% of haplotypes in European Americans and Japanese. These haplotypes are common and quite diverged from each other and the ancestral haplotype, resulting in highly significant deviations from neutrality. F(ST) statistics show that European American and Japanese populations are unusually distinct at the IL-4 locus. The most common haplotype in the European American population is much less common in the Japanese population, and vice versa. This implies that natural selection has acted on IL-4 haplotypes differently in different populations. This selected variation at IL-4 may account for some genetic variance underlying susceptibility to asthma and other allergic diseases. The strong LD observed in the IL-4 region may allow more efficient disease-association studies using this locus.


Differential effect of environmental conditions on the growth and regulation of the fumonisin biosynthetic gene FUM1 in the maize pathogens and fumonisin producers Fusarium verticillioides and Fusarium proliferatum.
The effects of ecophysiological factors, temperature and solute potential, on both the growth and the regulation of the fumonisin biosynthetic FUM1 gene were studied and compared in one isolate each of the two closely related fumonisin-producing and maize pathogens Fusarium verticillioides and Fusarium proliferatum. The effect of solute potential and temperature was examined on in vitro mycelia growth and on the expression of the FUM1 gene, quantified by species-specific real-time reverse transcriptase-PCR assays. Although both isolates showed similar two-dimensional profiles of growth, for F. verticillioides, optimal growth conditions were maintained at higher temperatures and lower solute potential values. FUM1 gene expression was markedly induced at 20 degrees C in both isolates, under suboptimal conditions for growth; however, their expression patterns differed in relation to solute potential. Whereas FUM1 expression was induced in response to increasing water stress in the isolate of F. verticillioides, the F. proliferatum one showed a stable expression pattern regardless of water potential conditions. These results suggest a differential regulation of fumonisin biosynthesis in these isolates of the two species that might be related to their different host range, and play an ecological role. Additionally, environmental conditions leading to water stress (drought) might result in increased risk of fumonisin contamination of maize caused by F. verticillioides.


Wound closure in flexion versus extension following total knee arthroplasty: a systematic review.
Optimising knee range of motion following total knee arthroplasty (TKA) is important for patient satisfaction, functional outcome and early rehabilitation to promote accelerated discharge. Historically, wound closure following TKA has been performed in extension. It has been suggested that knee position during wound closure may influence range of motion and clinical outcomes following TKA. The purpose of this study was to determine whether TKA wounds should be closed in flexion or extension. An electronic search of MEDLINE, EMBASE, CINAHL and AMED databases was made in addition to a review of unpublished material. All included papers were critically appraised using a modified PEDro (Physiotherapy Evidence Database) critical appraisal tool. Three papers were eligible, assessing 237 TKAs. On analysis, patients with TKA wounds closed in flexion had greater flexion range of motion and required less domiciliary physiotherapy compared to those with wounds closed in full extension. The specific degree of knee flexion used when closing total knee replacement wounds may be an important variable to clinical outcome. However, the present evidence-base is limited in both size and methodological quality.


The recent expansion of Fox Sparrow (Passerella iliaca iliaca) breeding range into the northeastern United States.
The breeding range of the Eastern Fox Sparrow (Passerella iliaca iliaca) is generally recognized as comprising the boreal forest of Canada. However, recent observations suggest that the species is present during the summer months throughout much of the northeastern US, unexpected for a species characterized as a passage migrant in the region. To clarify, I conducted a literature review to document the historical status of the species in the northeastern US and then analyzed observations submitted to eBird to describe its recent and current status in the region. Historical accounts consistently identify Fox Sparrow as a passage migrant through the region during early spring and late fall. Beginning in the early 1980s, observers began noting regular extralimital records of Fox Sparrow in northern Maine. A single nest was discovered in the state in 1983, and another in northern New Hampshire in 1997. Despite the paucity of breeding records, observations submitted to eBird suggest that the southern limit of the breeding range of Fox Sparrow has expanded rapidly to the south and west in recent years. The proportion of complete checklists submitted to eBird that contained at least one observation of Fox Sparrow grew at an annual rate of 18% from 2003-2016 and was independent of observer effort. Fox Sparrow now occurs regularly on mountaintops and in young stands of spruce (Picea spp.) and balsam fir (Abies balsamea) during the breeding season throughout northern and western Maine and northern New Hampshire, with occasional records from the Green Mountains of Vermont and the Adirondack Mountains of New York. The cause of this rapid expansion of its breeding range is unknown, but may be related to an increase in the amount of young conifer forest in the northeastern US created by commercial timber harvest.


A four PDZ domain-containing splice variant form of GRIP1 is localized in GABAergic and glutamatergic synapses in the brain.
We have isolated, from a rat brain cDNA library, a clone corresponding to a 2779-bp cDNA encoding a novel splice form of the glutamate receptor interacting protein-1 (GRIP1). We call this 696-amino acid splice form GRIP1c 4-7 to differentiate it from longer splice forms of GRIP1a/b containing seven PDZ domains. The four PDZ domains of GRIP1c 4-7 are identical to PDZ domains 4-7 of GRIP1a/b. GRIP1c 4-7 also contains 35 amino acids at the N terminus and 12 amino acids at the C terminus that are different from GRIP1a/b. In transfected HEK293 cells, a majority of GRIP1c 4-7 was associated with the plasma membrane. GRIP1c 4-7 interacted with GluR2/3 subunits of the alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor. In low density hippocampal cultures, GRIP1c 4-7 clusters colocalized with GABAergic (where GABA is gamma-aminobutyric acid) and glutamatergic synapses, although a higher percentage of GRIP1c 4-7 clusters colocalized with gamma-aminobutyric acid, type A, receptor (GABA(A)R) clusters than with alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor clusters. Transfection of hippocampal neurons with hemagglutinin-tagged GRIP1c 4-7 showed that it could target to the postsynaptic complex of GABAergic synapses colocalizing with GABA(A)R clusters. GRIP1c 4-7-specific antibodies, which did not recognize previously described splice forms of GRIP1, recognized a 75-kDa protein that is enriched in a postsynaptic density fraction isolated from rat brain. EM immunocytochemistry experiments showed that in intact brain GRIP1c 4-7 concentrates at postsynaptic complexes of both type I glutamatergic and type II GABAergic synapses although it is also presynaptically localized. These results indicate that GRIP1c 4-7 plays a role not only in glutamatergic synapses but also in GABAergic synapses.


Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch.
Topical capsaicin formulations are used for pain management. Safety and modest efficacy of low-concentration capsaicin formulations, which require repeated daily self-administration, are supported by meta-analyses of numerous studies. A high-concentration capsaicin 8% patch (Qutenza™) was recently approved in the EU and USA. A single 60-min application in patients with neuropathic pain produced effective pain relief for up to 12 weeks. Advantages of the high-concentration capsaicin patch include longer duration of effect, patient compliance, and low risk for systemic effects or drug-drug interactions. The mechanism of action of topical capsaicin has been ascribed to depletion of substance P. However, experimental and clinical studies show that depletion of substance P from nociceptors is only a correlate of capsaicin treatment and has little, if any, causative role in pain relief. Rather, topical capsaicin acts in the skin to attenuate cutaneous hypersensitivity and reduce pain by a process best described as 'defunctionalization' of nociceptor fibres. Defunctionalization is due to a number of effects that include temporary loss of membrane potential, inability to transport neurotrophic factors leading to altered phenotype, and reversible retraction of epidermal and dermal nerve fibre terminals. Peripheral neuropathic hypersensitivity is mediated by diverse mechanisms, including altered expression of the capsaicin receptor TRPV1 or other key ion channels in affected or intact adjacent peripheral nociceptive nerve fibres, aberrant re-innervation, and collateral sprouting, all of which are defunctionalized by topical capsaicin. Evidence suggests that the utility of topical capsaicin may extend beyond painful peripheral neuropathies.


Reference and point-of-care testing for G6PD deficiency: Blood disorder interference, contrived specimens, and fingerstick equivalence and precision.
Certain clinical indications and treatments such as the use of rasburicase in cancer therapy and 8-aminoquinolines for Plasmodium vivax malaria treatment would benefit from a point-of-care test for glucose-6-phosphate dehydrogenase (G6PD) deficiency. Three studies were conducted to evaluate the performance of one such test: the STANDARD™ G6PD Test (SD BIOSENSOR, South Korea). First, biological interference on the test performance was evaluated in specimens with common blood disorders, including high white blood cell (WBC) counts. Second, the test precision on fingerstick specimens was evaluated against five individuals of each, deficient, intermediate, and normal G6PD activity status. Third, clinical performance of the test was evaluated at three point-of-care settings in the United States. The test performed equivalently to the reference assay in specimens with common blood disorders. High WBC count blood samples resulted in overestimation of G6PD activity in both the reference assay and the STANDARD G6PD Test. The STANDARD G6PD Test showed good precision on multiple fingerstick specimens from the same individual. The same G6PD threshold values (U/g Hb) were applied for a semiquantitative interpretation for fingerstick- and venous-derived results. The sensitivity/specificity values (95% confidence intervals) for the test for G6PD deficiency were 100 (92.3-100.0)/97 (95.2-98.2) and 100 (95.7-100.0)/97.4 (95.7-98.5) for venous and capillary specimens, respectively. The same values for females with intermediate (> 30% to ≤ 70%) G6PD activity were 94.1 (71.3-99.9)/88.2 (83.9-91.7) and 82.4 (56.6-96.2)/87.6(83.3-91.2) for venous and capillary specimens, respectively. The STANDARD G6PD Test enables point-of-care testing for G6PD deficiency.


Population pharmacokinetics and bayesian estimator of cyclosporine in pediatric renal transplant patients.
Cyclosporine A (CsA) is an immunosuppressive drug widely used in pediatric renal graft recipients. Its large interindividual pharmacokinetic variability and narrow therapeutic index render therapeutic drug monitoring necessary. However, information about CsA pharmacokinetics is scarce and no population pharmacokinetic (popPK) studies in these populations have been reported so far. to the objectives of this study were 1) to develop a PKpop model and identify the individual factors influencing the variability of CsA pharmacokinetics in pediatric kidney recipients; and 2) to build a Bayesian estimator allowing the estimation of the main PK parameters and exposure indices to CsA on the basis of a limited sampling strategy (LSS). The popPK analysis was performed using the NONMEM program. A total of 256 PK profiles of CsA collected in 98 pediatric renal transplant patients (mean age 9.7 +/- 4.5 years old) within the first year posttransplantation were studied. A 2-compartment model with first-order elimination, and Erlang distribution to describe the absorption phase, fitted the data adequately. For Bayesian estimation, the best LSS was determined based on its performance in estimating area under the concentration-time curve (AUC0-12h) and validated in an independent group of 20 patients. The popPK analysis identified body weight and posttransplant delay as individual factors influencing the apparent central volume of distribution and the apparent clearance, respectively. Bayesian estimation allowed accurate prediction of AUC0-12h using predose, C1h, and C3h blood samples with a mean bias between observed and estimated AUC of 0.5% +/- 11% and good precision (root mean square error = 10.9%). This article reports the first popPK study of CsA in pediatric renal transplant patients. It confirms the reliability and feasibility of CsA AUC estimation in this population. The body weight and the posttransplantation delay were identified to influence PK interindividual variability of CsA and were included in the Bayesian estimator developed, which could be helpful in further clinical trials.


Evaluation of disinfectants in the domestic environment under 'in use' conditions.
An 'in use' test was developed to investigate effectiveness of disinfectant application and of detergent of hot water cleaning at kitchen, bathroom and toilet sites in the domestic environment. Detergent and hot water cleaning produced no observable reduction in microbial contamination. Single and daily application tests demonstrated that hypochlorite and phenolic disinfectants can be used to produce substantial reductions in bacterial contamination in the home. Results indicate that maximum protection afforded by disinfection is relatively brief; 3-6 h after disinfection, contamination levels were only marginally less than those observed at pretreatment. Some suggestions are made for improvements in home hygiene.


SLE: idiopathic or drug-induced?
Procainamide has become the most frequent cause of the drug-induced lupus syndrome. Like other drugs that produce this syndrome, procainamide induces disease that closely resembles idiopathic SLE but differs from it in race and sex distribution, in rare involvement of the kidneys and central nervous system, and in the absence of antibody to native DNA. Although complete remission of the signs and symptoms of the disease occurs in most patients following discontinuation of the drug, some patients continue to be symptomatic and require treatment with corticosteroids. With prolonged procainamide therapy, antinuclear antibody develops in at least 50% of patients, and the lupus syndrome develops in approximately 20%. At present, it does not appear that a cumulative or daily dose of procainamide can be exclusively implicated in the appearance of antinuclear antibody or symptoms. Acetylation status may be one of the determining factors in the development of the SLE syndrome.


Blood transfusion safety in Africa: a literature review of infectious disease and organizational challenges.
Blood safety remains an important public health concern in Africa where lack of availability or provision of unsafe blood adversely impacts morbidity and mortality in the region. In recognition of this shortfall, the World Health Organization (WHO) established a goal of regional blood safety by 2012 through improved "organization and management, blood donor recruitment and collection, testing of donor blood as well as appropriate clinical use of blood" (Tagny et al: Transfusion. 2008;48:1256-1261; Tapko et al: Status of Blood Safety in the WHO African Region: Report of the 2006 Survey http://www.afro.who.int/en/divisions-a-programmes/dsd/health-technologies-a-laboratories.html. Brazzaville, Republic of Congo: WHO Regional Office for Africa; 2006). Although there has been substantial progress toward meeting these objectives, there are continued obstacles to both development and sustainability. In a setting where transfusion oversight is still being improved, transfusion-transmitted infections are of real concern. The high prevalence of some transfusion-transmissible agents such as hepatitis B virus and HIV in the general population means that some infected blood units escape detection by even well-performed laboratory testing, resulting in potential downstream transmission to patients. The spectrum of transfusion-transmitted infection include conventional as well as exotic pathogens, many of which are endemic to the region, thereby imparting ongoing challenges to recruitment and testing strategies.