Timelines in the diagnostic evaluation of people with suspected amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND)--a 20-year review: can we do better?
This paper examines diagnostic timelines for people suspected of having ALS/MND over a 20-year period, evaluates the impact of a 'fast track' diagnostic process and discusses typical causes of diagnostic delay. Key diagnostic timelines (dates of first symptom, diagnosis and death) were reviewed for people diagnosed between 1989 and 2008. Patients evaluated through a fast-track diagnostic process and those investigated through traditional neurology clinics were compared. Typical causes of diagnostic delay were investigated. Results showed that diagnostic timelines have been surprisingly consistent over this 20-year period. Time from first symptom to diagnosis hovered around 12 months, with the diagnosis typically being made around the midpoint (50% of total disease duration elapsed) of the disease pathway. The introduction of a fast-track process has not to date affected overall performance but has shortened times from referral to diagnosis. Diagnostic delays appear to be associated with clinical complexity and delays in referral, both within primary and secondary care services. In conclusion, more widespread implementation of fast-track processes could potentially reduce diagnostic delays. Educational interventions among health care professionals both in primary and secondary care may also help shorten diagnostic pathways.


Predictors of Frontal Plane Knee Moments During Side-Step Cutting to 45 and 110 Degrees in Men and Women: Implications for Anterior Cruciate Ligament Injury.
To compare frontal plane knee moments, and kinematics and kinetics associated with knee valgus moments between cutting to 45 and 110 degrees, and to determine the predictive value of kinematics and ground reaction forces (GRFs) on knee valgus moments when cutting to these angles. Also, to determine whether sex differences exist in kinematics and kinetics when cutting to 45 and 110 degrees. Cross-sectional study. Laboratory setting. Forty-five (20 females) healthy young adult soccer athletes aged 16 to 23 years. Kinematic and kinetic variables were compared between randomly cued side-step cutting maneuvers to 45 and 110 degrees. Predictors of knee valgus moment were determined for each task. Kinematic variables: knee valgus angle, hip abduction, and internal rotation angles. Kinetic variables: vertical, posterior, and lateral GRFs, and knee valgus moment. Knee valgus moments were greater when cutting to 110 degrees compared with 45 degrees, and females exhibited greater moments than males. Vertical and lateral GRFs, hip internal rotation angle, and knee valgus angle explained 63% of the variance in knee valgus moment during cutting to 45 degrees. During cutting to 110 degrees, posterior GRF, hip internal rotation angle, and knee valgus angle explained 41% of the variance in knee valgus moment. Cutting tasks with larger redirection demands result in greater knee valgus moments. Similar factors, including shear GRFs, hip internal rotation, and knee valgus position contribute to knee valgus loading during cuts performed to smaller (45 degrees) and larger (110 degrees) angles. Reducing vertical and shear GRFs during cutting maneuvers may reduce knee valgus moments and thereby potentially reduce risk for anterior cruciate ligament injury.


Parathyroid hormone-related protein production in the lamprey Geotria australis: developmental and evolutionary perspectives.
This study explored the distribution of parathyroid hormone-related protein (PTHrP) and its mRNA in tissues of the lamprey Geotria australis, a representative of one of the two surviving groups of an early and jawless stage in vertebrate evolution. For this purpose, antibodies to N-terminal and mid-molecule human PTHrP were used to determine the locations of the antigen. Sites of mRNA production were demonstrated by in situ hybridisation with a digoxigenin-labelled riboprobe to exon VI of the human PTHrP gene. The results revealed that antigen and its mRNA were widely distributed among similar sites of tissue localisation to those described for mammalian and avian species. However, some novel sites of localisation, such as in the gill and notochord, were also found. Some differences in PTHrP localisation were noted among individuals at different intervals of the life cycle, indicating that the distributions of PTHrP, and possibly its roles, change with the stage of development in this species. The widespread tissue distribution in G. australis implies diverse physiological roles for this protein. The presence of PTHrP in the lamprey, a representative of a group of vertebrates, which apparently evolved over 540 million years ago, strongly suggests that it is a protein of ancient origin. In addition, the successful use of antibodies and probes based on the human sequence in the lamprey also provides evidence that the PTHrP molecule may have been conserved from lampreys through to humans.


Pediatric surgical intraoperative consultations.
Six problems that have surgical implications and that may be encountered unexpectedly during urologic procedures in infants and children are discussed. Evolving practice and increased knowledge about these conditions require that the consultant's opinion regarding their management be updated. Discussed are the indications for concomitant appendectomy in young patients and the pros and cons regarding removal of a Meckel's diverticulum encountered unexpectedly. The necessity for and techniques used to preserve the spleen in the face of operative injury, presence of a splenic cyst, or a wandering spleen are discussed. Finally, the implications of finding a rotational abnormality of the gut are reviewed.


Trends in survival of patients diagnosed with cancer of the digestive organs in the Nordic countries 1964-2003 followed up to the end of 2006.
Cancers of the digestive organs (including the oesophagus, stomach, small intestine, colon, rectum and anus, liver, gallbladder, and pancreas) constitute one-fifth of all cancer cases in the Nordic countries and is a group of diseases with diverse time trends and varying consequences for public health. In this study we examine trends in relative survival in relation to the corresponding incidence and mortality rates in the Nordic countries during the period 1964-2003. Data were retrieved from the NORDCAN database for the period 1964 to 2003, grouped into eight 5-year periods of diagnosis. The patients were followed up until the end of 2006. Analysis comprised trends in 5-year relative survival, excess mortality and age-specific relative survival. Survival following cancers of the colon and rectum has increased continuously over the observed period, yet Danish patients fall behind those in the other Nordic countries. The largest inter-country variation is seen for the rare cancers in the small intestine. There has been little increase in prognosis for patients diagnosed with cancers of the liver, gallbladder or pancreas; 5-year survival is generally below 15%. Survival also remains consistently low for patients with oesophageal cancer, while minor increases in survival are seen among stomach cancer patients in all countries except Denmark. The concomitant incidence and mortality rates of stomach cancer have steadily decreased in each Nordic country at least since 1964. While the site-specific variations in mortality and survival largely reflect the extent of changing and improving diagnostic and clinical practices, the incidence trends highlight the importance of risk factor modification. Alongside the ongoing clinical advances, effective primary prevention measures, including the control of alcohol and tobacco consumption as well as changing dietary pattern, will reduce the incidence and mortality burden of digestive cancers in the Nordic countries.


Cholesterol net transport, esterification, and transfer in human hyperlipidemic plasma.
Cholesterol esterification, cholesteryl ester transfer between lipoproteins, and cholesterol transport between lipoproteins and cultured cells have been measured in the plasma of 22 patients with primary hyperlipidemia and 10 normolipidemic subjects. In hyperbetalipoproteinemia, increase in plasma low density lipoprotein levels was associated with a reduction of cholesteryl ester transfer rates, and with a reversal of the normal direction of sterol transport between fibroblasts and their plasma culture medium. Instead of net transport from cells to medium there was a net uptake of sterol from plasma by the cells, despite a level of plasma lecithin/cholesterol acyltransferase activity that was within the normal range. In dysbetalipoproteinemia, esterification rates were increased above normal levels, but cholesteryl ester transfer was reduced and the direction of sterol transport between the cells and plasma medium was reversed, as in the hyperbetalipoproteinemic group. In hypertriglyceridemia, those subjects with cardiovascular disease showed a metabolic pattern similar to the hyperbetalipoproteinemic group. The subjects in this group without symptoms of cardiovascular disease showed a normal direction of sterol transport, normal or raised rates of cholesteryl ester transfer between lipoproteins, and an increased rate of sterol esterification in plasma that decreased towards normal levels as plasma triglyceride levels decreased. Despite their quite distinct metabolic patterns there was no consistent difference between the two hypertriglyceridemic groups in triglyceride or cholesterol levels, very low density lipoprotein composition, or electrophoretic or isoelectric focussing patterns. All hypertriglyceridemic subjects with documented cardiovascular disease showed reversed cell-plasma sterol transport and all subjects without such disease showed a normal direction of cell-plasma sterol transport. The results of this study indicate major and reproducible abnormalities in plasma cholesterol metabolism in several groups of subjects with genetically distinct hyperlipidemias, who are at risk for atherosclerotic vascular disease. The possible predictive value of sterol metabolic measurements in the analysis of cardiovascular disease is discussed.


The price of anarchy in mobility-driven contagion dynamics.
Public policy and individual incentives determine the patterns of human mobility through transportation networks. In the event of a health emergency, the pursuit of maximum social or individual utility may lead to conflicting objectives in the routing strategies of network users. Individuals tend to avoid exposure so as to minimize the risk of contagion, whereas policymakers aim at coordinated behaviour that maximizes the social welfare. Here, we study agent-driven contagion dynamics through transportation networks, coupled to the adoption of either selfish- or policy-driven rerouting strategies. In analogy with the concept of price of anarchy in transportation networks subject to congestion, we show that maximizing individual utility leads to a loss of welfare for the social group, measured here by the total population infected after an epidemic outbreak.


Time course profiling of the retinal transcriptome after optic nerve transection and optic nerve crush.
A time-course analysis of gene regulation in the adult rat retina after intraorbital nerve crush (IONC) and intraorbital nerve transection (IONT). RNA was extracted from adult rat retinas undergoing either IONT or IONC at increasing times post-lesion. Affymetrix RAE230.2 arrays were hybridized and analyzed. Statistically regulated genes were annotated and functionally clustered. Arrays were validated by means of quantative reverse transcription polymerase chain reaction (qRT-PCR) on ten regulated genes at two times post-lesion. Western blotting and immunohistofluorescence for four pro-apoptotic proteins were performed on naïve and injured retinas. Finally, custom signaling maps for IONT- and IONC-induced death response were generated (MetaCore, Genego Inc.). Here we show that over time, 3,219 sequences were regulated after IONT and 1,996 after IONC. Out of the total of regulated sequences, 1,078 were commonly regulated by both injuries. Interestingly, while IONT mainly triggers a gene upregulation-sustained over time, IONC causes a transitory downregulation. Functional clustering identified the regulation of high interest biologic processes, most importantly cell death wherein apoptosis was the most significant cluster. Ten death-related genes upregulated by both injuries were used for array validation by means of qRT-PCR. In addition, western blotting and immunohistofluorescence of total and active Caspase 3 (Casp3), tumor necrosis factor receptor type 1 associated death domain (TRADD), tumor necrosis factor receptor superfamily member 1a (TNFR1a), and c-fos were performed to confirm their protein regulation and expression pattern in naïve and injured retinas. These analyses demonstrated that for these genes, protein regulation followed transcriptional regulation and that these pro-apoptotic proteins were expressed by retinal ganglion cells (RGCs). MetaCore-based death-signaling maps show that several apoptotic cascades were regulated in the retina following optic nerve injury and highlight the similarities and differences between IONT and IONC in cell death profiling. This comprehensive time course retinal transcriptome study comparing IONT and IONC lesions provides a unique valuable tool to understand the molecular mechanisms underlying optic nerve injury and to design neuroprotective protocols.


Are Upfront Levels for Colon "Polyps" Necessary? A Pragmatic Review.
Colon biopsies are among the most frequently examined specimens by pathologists. Many pathology practices, ours included, review upfront levels on all gastrointestinal biopsies. In our experience, when a lesion is present on specimens labeled "colon polyp," it is readily identified on the first level. To test our hypothesis, we re-reviewed 500 cases in which a lesion was identified histologically and determined if the diagnosis could be made on the first level. Furthermore, we examined 50 additional cases of high-grade dysplasia/carcinoma to determine if the higher-grade component was also present on the first level. Cases were retrieved for lesions that could account for a colon polyp clinically, and the first level was examined to determine if lesional tissue was present on the first level. Fifty additional cases of higher-grade lesions were included to ensure higher-grade lesions were present on the first level. Overall, 497/500 (99.4%) of the non-high-grade lesions were present on the first level, whereas 3/500 (0.6%) required the additional level for diagnosis. All 50 high-grade lesions were present on the first level examined. Many pathology practices routinely order upfront levels on all gastrointestinal biopsies, often generating 2 or 3 slides. Additional slides increase costs, increase the likelihood of laboratory-generated errors, and can waste limited tissue on small biopsies for which ancillary studies may be necessary. Our study showed that a single level is sufficient in the overwhelming majority of cases in which a lesion is identified histologically.


Mexican Americans and frailty: findings from the Hispanic established populations epidemiologic studies of the elderly.
We examined the prevalence of frailty among Mexican American older adults and explored the correlates associated with becoming frail to determine their affect on disability and morbidity in this population. We studied the trajectory of frailty over 10 years in 2049 Mexican Americans participating in the Hispanic Established Populations Epidemiologic Studies of the Elderly. We constructed a frailty index based on weight loss, exhaustion, grip strength, walking speed, and physical activity and collected data on sociodemographic and health status, comorbidities, and functional measures of performance. The sample was 58% female, with a mean age of 74.43 years (SD = 6.04) at baseline. Fifty-five percent of participants at baseline and 75% of the surviving sample at follow-up (n = 777) were classified as prefrail or frail. Of persons identified as frail at baseline, 84% died by the end of follow-up. Baseline age, diabetes, arthritis, smoking status, body mass index, cognition, negative affect, and number of comorbid conditions were predictors of frailty at follow-up (R(2) = 0.29; P < .05). Further research into ways to reduce the number of Mexican American older adults who become frail and disabled and therefore lose their independence is needed. Future studies should continue to examine the trajectory of frailty as a dynamic process that includes psychosocial and cognitive components.


Shape Estimation from Shading, Defocus, and Correspondence Using Light-Field Angular Coherence.
Light-field cameras are quickly becoming commodity items, with consumer and industrial applications. They capture many nearby views simultaneously using a single image with a micro-lens array, thereby providing a wealth of cues for depth recovery: defocus, correspondence, and shading. In particular, apart from conventional image shading, one can refocus images after acquisition, and shift one's viewpoint within the sub-apertures of the main lens, effectively obtaining multiple views. We present a principled algorithm for dense depth estimation that combines defocus and correspondence metrics. We then extend our analysis to the additional cue of shading, using it to refine fine details in the shape. By exploiting an all-in-focus image, in which pixels are expected to exhibit angular coherence, we define an optimization framework that integrates photo consistency, depth consistency, and shading consistency. We show that combining all three sources of information: defocus, correspondence, and shading, outperforms state-of-the-art light-field depth estimation algorithms in multiple scenarios.


Living on a farm: impact on asthma induction and clinical course.
Exposure to a farming environment protects individuals from respiratory allergy. The timing and duration of exposure seem to play critical roles. The largest reduction in risk of developing respiratory allergies is seen among those who are exposed prenatally and continuously thereafter. Contact with farm animals, at least in childhood, likely confers protection; other factors have not been completely identified. Also, the consumption of milk directly from the farm during childhood has been shown to be beneficial with respect to childhood asthma and allergies. Increased levels of microbial substances may contribute to the protective effects. The mechanisms by which such environmental exposures confer protection from respiratory allergies are not well understood. A number of gene-by-environment interactions have been observed with polymorphisms in genes of innate immunity receptors and exposure to farming environments. Increased levels of microbial exposures recognized by innate immune responses may affect adaptive immune responses resulting in decreased levels of atopic sensitization and asthma.


Phase II trial of intravenous flourouracil and subcutaneous interferon alfa-2b for biliary tract cancer.
To assess the efficacy of systemic intravenous-fluorouracil (5-FU) and subcutaneous recombinant human interferon alfa-2b (rIFN alpha-2b) in patients with measurable cancer of the biliary tree. Thirty-five patients (25 with cholangiocarcinoma and 10 with gallbladder carcinoma) were registered onto this phase II protocol between 1992 and 1995. Patients received a continuous infusion of 750 mg/m2/d of 5-FU on days 1 through 5 through a centrally placed venous catheter and a subcutaneous injection of 5 MU/m2 of rIFN alpha-2b on days 1, 3, and 5. Treatment cycles were repeated every 14 days; one course of therapy included four treatment cycles. Disease status was assessed every 8 weeks. Dosages were lowered for grade III mucositis. Fourteen patients had prior treatment and, before initiating this therapy, 17 patients required decompression of the biliary tree. Eleven of 32 (34%) assessable patients had a partial response. The median time to disease progression was 9.5 months, and the median survival time 12 months. Grade III to IV toxic effects were granulocytopenia (14%), mucositis (20%), diarrhea (9%), and dermatitis (11%). Grade III to IV asthenia and fatigue were observed in 6% of patients. Drug tolerance was better among previously untreated patients. To achieve a complete response, additional chemotherapy or radiotherapy should be considered when liver resection or transplantation is not feasible. However, if these results can be reproduced by other investigators, the regimen should be studied for adjuvant treatment of gallbladder carcinoma incidentally identified in patients undergoing cholecystectomy.


[Use of contraceptives in Norway in 2005].
New administration forms for hormonal contraception and a higher patient's charge for sterilisation of women have changed the pattern of contraceptive use in Norway. In October 2005, more than 5,000 women listed in a Webpanel of more than 50,000 subscribers were invited to participate in survey on contraceptive use. The response rate was 41%. 1,575 women, aged 20- 44 years, who were sexually active the last three months before the interview, did not plan to become pregnant and defined themselves as fertile were eligible for analysis. Over 90% of the respondents had used at least one contraceptive method during the last three months. 9% did not use contraceptives, 6% used "safe periods/coitus interruptus", whereas 13% used condom. 38% had used hormonal contraception, 23% intrauterine devices (hormonal IUD included) and 8% of the women were sterilized. The new administration forms of hormonal contraception; like contraceptive plaster, vaginal ring and implants had few users. Among hormonal users oral contraceptives dominates in all age groups. There were twice as many hormonal IUD users as cooper IUD users in all age groups. The Webpanel of women aged 20-44 years is fairly representative of Norwegian women, when compared with census data from Statistics Norway. Compared with previous contraceptive surveys in Norway, there are more users of hormonal contraceptives, predominantly oral contraceptives. The user rate of IUDs is fairly stable; but more women use hormonal IUDs than copper IUDs and fewer women are sterilized.


The use of Histolyn CYL in an enzyme immunoassay to detect Histoplasma capsulatum antibodies.
Histolyn CYL, the yeast phase reagent, has been employed as the antigen in an enzyme immunoassay (ELISA) to detect antibody to Histoplasma capsulatum in sera from experimentally sensitized rabbits and from humans with histoplasmosis. Three different lots of Histolyn CYL were initially evaluated with respect to antibody detection in individual and pooled rabbit serum specimens. Optimal reactivity was obtained with 4.5 micrograms (total dry weight) per ml of lots 2 and 3 of the reagent. The optimally diluted pooled reagent detected antibody titers ranging from 1:16 to 1:8192 in 36 rabbit sera. In contrast, a marked decrease in sensitivity was evidenced when the same sera were assayed by complement fixation and immunodiffusion tests with commercially available reference reagents. Complement fixation titers ranged from 0 to 1:128 and immunodiffusion tests on undiluted sera were positive with only 5 specimens. Twenty-five sera from patients with acute, chronic and disseminated histoplasmosis were also assayed by the ELISA with the reagent described above. Titers ranged from less than 1:16 to 1:20,480 or greater. Complement fixation titers ranged from 0 to 1:1024 (mycelial antigen) and from 0 to 1:256 (whole yeast cell antigen). No antibody was detected in 7 specimens with mycelial antigen or in 3 specimens with the yeast cell antigen. Immunodiffusion tests on undiluted sera were positive with 9 of 11 specimens. Minimal cross reactivity was evidenced when Histolyn CYL was used in the ELISA to detect anti-Coccidioides immitis antibody in sera from infected animals and humans. These data encourage the continued development of this method for the serodiagnosis of human histoplasmal infection.


Skin, Hair and Nail Supplements: An Evidence-Based Approach
Dermatology supplements, often marketed as "skin, hair, and nail" supplements, are becoming increasingly popular. However, many consumers lack an understanding of the science of dietary supplements or the specifics of the supplement industry. While certain supplements at the right dose in the right population may prove beneficial, the evidence is sparse for many supplements. In addition, the use of some supplements has resulted in serious adverse effects. From a regulatory standpoint, the US FDA recognizes dietary supplements as foods. This distinction has multiple ramifications, including the fact that manufacturers do not need to prove efficacy, safety, or quality prior to sale. Therefore, physicians and consumers must evaluate each supplement ingredient and formulation individually. This article outlines an evidence-based approach to assess dermatology supplements. As a starting point, all supplements should be evaluated for PPIES: purity, potency, interactions, efficacy, and safety.


α-Tocopheryl Succinate-Based Polymeric Nanoparticles for the Treatment of Head and Neck Squamous Cell Carcinoma.
The aim of this work is to study, in an in vitro head and neck squamous cell carcinomas model the anti-angiogenic and anti-migratory properties of self-assembled polymeric nanoparticles (NPs) with demonstrated selective anticancer activity. The NPs are based on α-tocopheryl succinate (α-TOS) encapsulated in the hydrophobic core of the NPs. We analyzed the effect of the newly synthetized α-TOS-loaded NPs in proliferating endothelial cells and hypopharynx carcinoma squamous cells and measured markers of angiogenesis, apoptosis and reactive oxygen species (ROS). α-TOS-loaded NPs suppressed angiogenesis by inducing accumulation of ROS and inducing apoptosis of proliferating endothelial cells. These NPs also decrease the number and quality of capillary-like tubes in an in vitro three-dimensional (3D) experiment, decrease the production of the pro-angiogenic vascular endothelial growth factor and down-regulate the expression of its receptor. The anti-migratory efficacy of α-TOS is corroborated in hypopharynx carcinoma cells by decreasing the secretion of matrix metalloproteases 2 and 9 (MMP-2 and MMP-9) and inhibiting cell migration. These results confirm that α-TOS-based NPs not only present anticancer properties, but also antiangiogenic properties, therefore making them promising candidates for multi-active combinatorial anticancer therapy.


An implicit body representation underlying human position sense.
Knowing the body's location in external space is a fundamental perceptual task. Perceiving the location of body parts through proprioception requires that information about the angles of each joint (i.e., body posture) be combined with information about the size and shape of the body segments between joints. Although information about body posture is specified by on-line afferent signals, no sensory signals are directly informative about body size and shape. Thus, human position sense must refer to a stored body model of the body's metric properties, such as body part size and shape. The need for such a model has long been recognized; however, the properties of this model have never been systematically investigated. We developed a technique to isolate and measure this body model. Participants judged the location in external space of 10 landmarks on the hand. By analyzing the internal configuration of the locations of these points, we produced implicit maps of the mental representation of hand size and shape. We show that this part of the body model is massively distorted, in a reliable and characteristic fashion, featuring shortened fingers and broadened hands. Intriguingly, these distortions appear to retain several characteristics of primary somatosensory representations, such as the Penfield homunculus.


Two-Dimensional Nanosheets from Redox-Active Superatoms.
We describe a new approach to synthesize two-dimensional (2D) nanosheets from the bottom-up. We functionalize redox-active superatoms with groups that can direct their assembly into multidimensional solids. We synthesized Co6Se8[PEt2(4-C6H4COOH)]6 and found that it forms a crystalline assembly. The solid-state structure is a three-dimensional (3D) network in which the carboxylic acids form intercluster hydrogen bonds. We modify the self-assembly by replacing the reversible hydrogen bonds that hold the superatoms together with zinc carboxylate bonds via the solvothermal reaction of Co6Se8[PEt2(4-C6H4COOH)]6 with Zn(NO3)2. We obtain two types of crystalline materials using this approach: one is a 3D solid and the other consists of stacked layers of 2D sheets. The dimensionality is controlled by subtle changes in reaction conditions. These 2D sheets can be chemically exfoliated, and the exfoliated, ultrathin 2D layers are soluble. After they are deposited on a substrate, they can be imaged. We cast them onto an electrode surface and show that they retain the redox activity of the superatom building blocks due to the porosity in the sheets.


Targeting the p38 MAPK pathway inhibits irinotecan resistance in colon adenocarcinoma.
Despite recent advances in the treatment of colon cancer, tumor resistance is a frequent cause of chemotherapy failure. To better elucidate the molecular mechanisms involved in resistance to irinotecan (and its active metabolite SN38), we established SN38-resistant clones derived from HCT-116 and SW48 cell lines. These clones show various levels (6- to 60-fold) of resistance to SN-38 and display enhanced levels of activated MAPK p38 as compared with the corresponding parental cells. Because four different isoforms of p38 have been described, we then studied the effect of p38 overexpression or downregulation of each isoform on cell sensivity to SN38 and found that both α and β isoforms are involved in the development of resistance to SN38. In this line, we show that cell treatment with SB202190, which inhibits p38α and p38β, enhanced the cytotoxic activity of SN38. Moreover, p38 inhibition sensitized tumor cells derived from both SN38-sensitive and -resistant HCT116 cells to irinotecan treatment in xenograft models. Finally, we detected less phosphorylated p38 in primary colon cancer of patients sensitive to irinotecan-based treatment, compared with nonresponder patients. This indicates that enhanced level of phosphorylated p38 could predict the absence of clinical response to irinotecan. Altogether, our results show that the p38 MAPK pathway is involved in irinotecan sensitivity and suggest that phosphorylated p38 expression level could be used as a marker of clinical resistance to irinotecan. They further suggest that targeting the p38 pathway may be a potential strategy to overcome resistance to irinotecan-based chemotherapies in colorectal cancer.


Characterization of cellular protective effects of ATP13A2/PARK9 expression and alterations resulting from pathogenic mutants.
Mutations in ATP13A2, which encodes a lysosomal P-type ATPase of unknown function, cause an autosomal recessive parkinsonian syndrome. With mammalian cells, we show that ATP13A2 expression protects against manganese and nickel toxicity, in addition to proteasomal, mitochondrial, and oxidative stress. Consistent with a recessive mode of inheritance of gene defects, disease-causing mutations F182L and G504R are prone to misfolding and do not protect against manganese and nickel toxicity because they are unstable as a result of degradation via the endoplasmic reticulum-associated degradation (ERAD)-proteasome system. The protective effects of ATP13A2 expression are not due to inhibition of apoptotic pathways or a reduction in typical stress pathways, insofar as these pathways are still activated in challenged ATP13A2-expressing cells; however, these cells display a dramatic reduction in the accumulation of oxidized and damaged proteins. These data indicate that, contrary to a previous suggestion, ATP13A2 is unlikely to convey cellular resilience simply by acting as a lysosomal manganese transporter. Consistent with the recent identification of an ATP13A2 recessive mutation in Tibetan terriers that develop neurodegeneration with neuronal ceroid lipofucinoses, our data suggest that ATP13A2 may function to import a cofactor required for the function of a lysosome enzyme(s).


Bumblebees display characteristics of active vision during robust obstacle avoidance flight.
Insects are remarkable flyers and capable of navigating through highly cluttered environments. We tracked the head and thorax of bumblebees freely flying in a tunnel containing vertically oriented obstacles to uncover the sensorimotor strategies used for obstacle detection and collision avoidance. Bumblebees presented all the characteristics of active vision during flight by stabilizing their head relative to the external environment and maintained close alignment between their gaze and flightpath. Head stabilization increased motion contrast of nearby features against the background to enable obstacle detection. As bees approached obstacles, they appeared to modulate avoidance responses based on the relative retinal expansion velocity (RREV) of obstacles and their maximum evasion acceleration was linearly related to RREVmax. Finally, bees prevented collisions through rapid roll manoeuvres implemented by their thorax. Overall, the combination of visuo-motor strategies of bumblebees highlights elegant solutions developed by insects for visually guided flight through cluttered environments.


[Diagnosis and treatment of rotator cuff tears].
A rotator cuff tear is a highly prevalent disorder, occurring in 25% of people over 60 years of age. In two thirds of patients the tear is small and asymptomatic. Acute, symptomatic cuff tears may occur in active sportsmen and women aged 30-50. There is often a considerable delay in diagnosis in this group, due to a lack of recognition by either the patient or the doctor. Recently identified risk factors for the development of cuff tear are nicotine abuse, hypercholesterolaemia, contralateral cuff tear and genetic predisposition. Conservative treatment can be very successful and consists of physical therapy and effective analgesics. Repeated steroid injections are harmful to the tendinous tissue and should be avoided. The aim of surgery is anatomical reinsertion of the ruptured tendon using an open or arthroscopic procedure. The arthroscopic procedure enables the surgeon to perform a more extensive evaluation and treatment of the joint. The arthroscopic procedure is technically more demanding than the open procedure, but seems to have a shorter rehabilitation period.


Pharmacological constriction of the lower oesophageal sphincter: a simple method of arresting variceal haemorrhage.
The effect of pharmacological constriction of the lower oesophageal sphincter (LOS) on oesophageal varices was investigated in an experimental study followed by a controlled clinical trial. In the experimental study intravariceal pressure was measured just above the LOS in 11 patients before and after constricting the LOS by intravenous pentagastrin. Intravariceal pressure fell from a mean of 23 (range 12-36) mmHg to 4 (range 0-7) mmHg (p less than 0.001). This marked pressure drop indicated the considerable compression of varices that occurred within the LOS. A prospective controlled clinical trial examined whether LOS constriction (effected by the longer acting metoclopramide) would compress varices sufficiently to arrest active variceal bleeding originating from the lowest 2 cm oesophagus--the area encircled by the LOS. Of 11 patients who received metoclopramide, 10 stopped bleeding compared with four of the 11 who received placebo (p less than 0.01). Pharmacological constriction of the LOS appears to offer a new and effective approach for arresting active bleeding from oesophageal varices.


Collaboration of Kras and androgen receptor signaling stimulates EZH2 expression and tumor-propagating cells in prostate cancer.
Elevation of the chromatin repression factor enhancer of zeste homolog (EZH2) is associated with progression and poor prognosis in several human cancers including prostate cancer. However, the mechanisms driving EZH2 expression are not fully understood. In this study, we investigated the functional synergy in prostate cancers in mice resulting from activation of the androgen receptor, Kras, and Akt, which drives three of the most frequently activated oncogenic signaling pathways in prostate cancer. Although, any two of these three events were sufficient to promote the formation and progression of prostate cancer, only the synergy of androgen receptor and Kras signaling could elevate EZH2 expression and expand prostate cancer progenitor cells in vivo. Our findings have revealed a genetic mechanism resulting in enhanced EZH2 expression during the progression of aggressive prostate cancer, with important implications for understanding how to target advanced disease where cancer progenitor cells may be critical.


Lumbar spine and proximal femur bone mineral density, bone mineral content, and bone area: United States, 2005-2008.
This report presents bone measurement data from dual-energy X-ray absorptiometry scans of the lumbar spine and proximal femur for persons aged 8 years and over from the National Health and Nutrition Examination Survey (NHANES) 2005-2008. Means, standard deviations, and selected percentiles were calculated for the proximal femur and lumbar spine (total and subregions) by sex, race and ethnicity, and age. Smoothed mean total lumbar spine and femur neck bone mineral density (BMD) were plotted by age, sex, and race and ethnicity. Multiple regression was used to test for significant interactions and to calculate mean total lumbar spine and femur neck BMD after adjusting for age, sex, and race and ethnicity. Differences by sex, race and ethnicity, and age were summarized by calculating the percent difference in adjusted means. Among scanned individuals, 11% lacked total lumbar spine data due to invalid data for one or more lumbar vertebrae, and 4% had invalid data for the proximal femur. Non-Hispanic black persons had 6% higher total lumbar spine BMD and 9%-10% higher femur neck BMD than non-Hispanic white persons. Mean total lumbar spine BMD and femur neck BMD did not differ between Mexican-American and non-Hispanic white persons in those under age 20. For those aged 20 and over, Mexican-American persons had 4% lower total lumbar spine BMD but 1% higher femur neck BMD than non-Hispanic white persons. Mean total lumbar spine BMD was 8%-17% higher in females aged 8-15 compared with males of the same age. In the age group 16-49, mean total lumbar spine BMD was similar or slightly higher for females compared with males, but after age 50 it was 60%-15% lower for females compared with males. Mean femur neck BMD was 5%-13% lower for females than males in all age groups except 12-15.


Pharmacotherapy Use in Older Patients With Heart Failure and Reduced Ejection Fraction After a Skilled Nursing Facility Stay.
Little is known about guideline-directed pharmacotherapy use in patients with heart failure and reduced ejection fraction (HFrEF) discharged to skilled nursing facilities (SNFs). This study aimed to describe the use of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blocker (ARBs) and evidence-based β-blockers (EBBBs) among older patients with HFrEF within 90 days after the SNF admission and to identify factors associated with receipt of these medications. With the use of Minimum Data Set 3.0 cross-linked with Medicare data (2011-2012), we studied 35,792 Americans aged ≥65 years with HFrEF admitted to 10,333 SNFs. The median age was 82 years, 59% were women, 81% had at least moderate physical limitations, and 39% had moderate/severe cognitive impairment. Fifty-six percent received an ACEI/ARB and 53% an EBBB; one-fourth received neither. In a multivariable log-binomial model, advanced age, severe physical limitations, and greater number of comorbid conditions not associated with heart failure were inversely associated with ACEI/ARB and EBBB receipt. Use of standard pharmacotherapy among patients with HFrEF after an SNF stay is higher than previously reported. In the absence of evidence demonstrating the effectiveness of ACEIs/ARBs and EBBBs in this population, whether or not improvements in prescribing are warranted remains unknown.


Over 70° thoracic idiopathic scoliosis: Results with screws or hybrid constructs.
Adolescent idiopathic scoliosis is the most common type of scoliosis. High degrees curve can be treated with the anterior, posterior, or combined anterior-posterior approach. Contrarily to the anterior approach, the posterior one is widely used nowadays for its good correction outcomes and relatively low-complication rate. We evaluated retrospectively 27 patients, treated with posterior approach. Patients were divided into two groups, namely pedicle screws group (PSG) and hybrid group (pedicle screws + sublaminar bands). Radiographic measurements, including thoracic and lumbar Cobb° measurements of primary and secondary curves, coronal balance and sagittal balance, kyphosis and lordosis, curve flexibility, first and last vertebra included in the arthrodesis, and implant density were evaluated. Clinical patients' satisfaction was also evaluated with Scoliosis Research Society (SRS) 24 questionnaire. Considering both groups, on preoperative X-rays, the average primary scoliotic curve angle was 83.56° ± 10.96° (range 70°-112°), whereas the global flexibility was 64° ± 7.63 (range 46°-72°). The curves were classified following the Lenke classification: 17 Type 1, 2 Type 2, and 8 Type 3. The primary curve resulted to be well corrected in both groups. In T0, the groups were homogeneous, but in T1 and follow-up, PSG stated a better mean value. No other significative differences can be found between groups for all other items (P > 0.05). Clinical results of SRS 24 were excellent in both groups. The posterior approach proved to be an excellent technique for obtaining good clinical and radiographic results if the surgeon adopts the third-generation high-density implants. III.


Large adrenal pseudocyst presenting with epigastric distress and abdominal distention.
We report a patient with a large adrenal pseudocyst presenting with epigastric distress and abdominal distention. A 35-year-old man presented with a 1-year history of nonspecific epigastric distress and abdominal distention. Routine laboratory tests and endocrine function tests were within the normal ranges. Magnetic resonance imaging (MRI) revealed a large left adrenal cyst. Adrenal cyst showed low intensity on T1-weighted MRI images and high density on T2-weighted MRI images. The patient underwent surgery, and the cyst was completely removed. Histological examination showed that the cyst wall consisted of hyalinized fibrous tissue without an epithelial or endothelial lining, and a diagnosis of an adrenal pseudocyst was made. Symptoms resolved after pseudocyst removal. The report showed a patient with adrenal pseudocyst, a rare and uncommon condition that was diagnosed on MR images and confirmed by histology. The epigastric distress and the abdominal distention resolved after the pseudocyst was surgically removed.


The 14q32 microRNA-487b targets the antiapoptotic insulin receptor substrate 1 in hypertension-induced remodeling of the aorta.
To study the role of microRNAs in hypertension-induced vascular pathology before the onset of symptoms of severe cardiovascular disease. MicroRNAs play a crucial role in cardiovascular disease. However, microRNAs are often studied in full-blown cardiovascular disease models, not during development of cardiovascular pathology. Angiotensin II was infused into healthy adult rats, inducing chronic hypertension, and microRNA expression profiles were obtained. The most prominently regulated microRNA, miR-487b, was further investigated, using primary cultures of rat aortic and human umbilical cord arterial cells. MiR-487b is predicted to target insulin receptor substrate 1 (IRS1). IRS1 plays an important role in both insulin signaling and cell proliferation and survival. IRS1 mRNA and protein levels were downregulated in aortae of hypertensive rats. MiR-487b binds directly to both rat and human IRS1 3'UTR and inhibits reporter gene expression in vitro. In primary rat and human arterial adventitial fibroblasts, inhibition of miR-487b leads to upregulation of IRS1 expression. Upregulation of miR-487b had the opposite effect, confirming direct targeting of IRS1 by miR-487b.Immunohistochemistry of aortic cross sections and rt/qPCR analyses of the separate aortic wall layers showed that both IRS1 and miR-487b were present mainly in the adventitia and less or not at all in the intima and tunica media. IRS1 expression in adventitial fibroblasts was predominantly nuclear and nuclear IRS1 is known to have antiapoptotic effects. Indeed, inhibition of miR-487b protected adventitial fibroblasts, and also medial smooth muscle cells, against serum starvation-induced apoptosis and increased cell survival. Angiotensin II-induced hypertension leads to upregulation of miR-487b, which targets IRS1. Via downregulation of IRS1, miR-487b can contribute to cell death and loss of adventitial and medial integrity during hypertension-induced vascular pathology.


The Impact of a Ballet and Modern Dance Performance on Heart Rate Variability in Collegiate Dancers.
Heart rate (HR) variability (HRV) is a useful tool for assessing cardiac autonomic function and identifying potential readiness to perform in athletic populations, but has yet to be investigated in dance populations. As such, HRV may be able to provide valuable insight into the preparedness of dancers and the demands of performance in a collegiate dance population. 29 female dancers were monitored leading up to and following a dance performance. Analysis of HRV focused on the square root of the mean squared differences of the successive RR intervals (RMSSD). A one-way ANOVA, with Bonferroni post-hoc, paired with magnitude-based-inferences (MBI) with effect sizes (ES) were used to analyze changes during the Winter Dance Concert, while the Recovery-Stress Questionnaire for Athletes (REST-Q Sport) measured the frequency of stress of dancers. When compared to baseline (69.8 ± 1.7 bpm), mean (HR) was increased at both pre-show recordings (76.5 ± 2.1 bpm and 75.6 ± 1.8 bpm). In contrast, RMSSD was significantly diminished (p < 0.05) at both pre-show recordings (40.6 ± 28.4 ms and 40.5 ± 21.8 ms) as compared to baseline (70.3 ± 38.4 ms). Dancers reported increased (p < 0.05) self-efficacy before the second show and at 36 h post-concert. As expected, Dance Exposure (DE) increased significantly (p < 0.05), while Academic Exposure (AE) was similar, during the week leading up to the dance concert. The results suggest dancers responded to concert dance performances similarly to other athletic populations approaching intense competition by exhibiting decreased parasympathetic activity prior to the dance performances, which returned to baseline values 36 h after their performances. Given the increase in self-efficacy, these fluctuations may indicate a readiness to a performance comparable to athletes.


[Neutralization of odors in colostomized patients. (multicenter study)].
The purpose of this study is to run a comparative, multi-centric study as a way to research and test two odor neutralizing agents having distinct forms, capsules or liquids. The objective is to identify an odor neutralizing agent which brings a solution to an as yet unsatisfactorily resolved problem, by this means providing greater security and discretion to a patient having undergone a colostomy and increasing that patient's quality of life. This study concludes that the capsule neutralizing agent appears to be the most desired treatment form both in the opinion of those having undergone a colostomy as among the researchers due to its efficiency and ease of use.


Phototunable Absorption and Nonlinear Optical Properties of Thermally Stable Dihydroazulene-Vinylheptafulvene Photochrome Pair.
The UV-vis absorption characteristics and nonlinear optical properties of a series of substituted dihydroazulene (DHA)/vinylheptafulvene (VHF) photoswitches are investigated by applying quantum calculations. Introduction of substituents at the seven-membered ring resulted in significant changes in their absorption properties depending on the nature and position of the substituent. Electron-donating groups at positions 5, 6, 7, and 8 generally exhibited red shifts with respect to the parent compound. However, the steric effect at positions 8a and 4 is responsible for the loss of planarity and conjugation, which generally leads to blue shifts. In contrast, any electron-withdrawing group, particularly at positions 8a and 4, would cause a blue shift. The presence of bulky groups at position 8a results in a loss of planarity and, as a result, a decrease in electronic conjugation within the molecule, resulting in a blue shift in the maximum absorption. When it comes to halogens, the red shift is directly correlated to the nucleophilicity; the higher the nucleophilicity, the larger the red shift. Regarding hyperpolarizability, the charge separation induces higher hyperpolarizabilities for all substituted VHFs compared to the corresponding DHAs, resulting in a much higher NLO response. In addition, for all DHA and VHF, the highest values of hyperpolarizabilities are calculated for 6-substituted systems. Finally, the objective of this detailed theoretical investigation is to continue exploring the photophysical properties of DHA-VHF through structural modifications.


Casualty treatment after earthquake disasters: development of a regional simulation model.
This paper presents a new approach to the casualty treatment problem following a large-scale disaster, based on a mathematical model of how a regional health-care system responds to an earthquake event. The numbers and locations of casualties rescued alive, the scale of pre-hospital care, the post-earthquake hospital capacity, and the transport system are inputs to the model. The model simulates the movement of casualties from the stricken areas to hospitals. It predicts the number of casualties that die as well as other statistics about the health-care system response, such as waiting time before treatment. The model can be run with varying input assumptions to simulate alternative disaster response strategies. Preliminary runs demonstrate the potential of the model as a tool for planning and training.


Risk factors associated with Cryptosporidia, Eimeria, and diarrhea in smallholder dairy farms in Mukurwe-ini Sub-County, Nyeri County, Kenya.
This study was undertaken to determine the household, calf management, and calf factors associated with the occurrence of Eimeria, Cryptosporidia, and diarrhea in pre-weaned calves reared in smallholder dairy farms in Mukurwe-ini Sub-County of Nyeri County, Kenya. In addition, the study also evaluated factors associated with average daily weight gain in the same pre-weaned calves. A total of 112 newborn calves (63 males and 49 females) on 111 farms (1 set of twins) were followed for 2 months between June 2013 and August 2013. Two calves were lost to follow-up. A pre-tested questionnaire was used to collect data on household characteristics and calf management practices in the 111 selected farms. On the first visit to the farm (within 7 days of the birth of the calf), blood samples were collected from the jugular vein to assess the level of maternal immunity acquired by the calf, by determining the serum total protein and selenium concentration. At 4 and 6 weeks of age, fecal samples from the calves were collected to assess the presence of Cryptosporidia and Eimeria oocysts. Every 2 weeks for 2 months, the calves and their environments were examined, their 2-week consumption and health history were recorded, and weights were estimated with a weight tape. Each of the factors was evaluated in a univariable regression model and only those found to be significant (p≤0.20) were included in a multivariable model. Elimination of non-significant factors was done in the multivariable model through a backward elimination procedure so that only those variables which were confounders, and/or significant at (p≤0.05) remained in the final model. About 37% (41/110) of the calves experienced diarrhea at least once during the 2-month study period. The overall period prevalence of Eimeria and Cryptosporidia was 42.7% (47/110) and 13.6% (15/110), respectively. Low serum protein was associated with 1.8 and 2.4 times the odds of Eimeria and Cryptosporidia infections, respectively. Lack of supervision of calf birth and low serum total protein were both associated with 1.3 times the odds of diarrhea incidence. Dirty calf pens, feeding <5 L of milk/day, and infection with Eimeria were associated with 0.105, 0.087, and 0.059 kg, respectively, reduced average daily weight gain of the calves. In the Kenyan context, calf diarrhea risk could be reduced through better supervision of parturition and colostrum provision. Specifically, the risk of Eimeria and Cryptosporidia infections could be reduced by optimizing the passive transfer of immunity to the newborn calves. Average weight gains of calves could be improved by good colostrum provision, pen hygiene, and preventing Eimeria infections.


Combined low vitamin D and K status amplifies mortality risk: a prospective study.
To explore the association of both plasma vitamin D and K concentrations with all-cause mortality, cardiovascular mortality, and cardiovascular events in the general population. We studied 4742 participants of the Prevention of REnal and Vascular ENd-Stage Disease (PREVEND) Study. At baseline, vitamin D and K status was determined by measurement of 25-hydroxyvitamin D [25(OH)D] and dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP), respectively. Patients were categorized into: 25(OH)D < 50 or ≥ 50 nmol/L and dp-ucMGP < 361 or ≥ 361 pmol/L with 25(OH)D > 75 nmol/L and dp-ucMGP < 361 pmol/L as reference. Cause of death was coded according to International Classification of Diseases 9&10 codes from the 2001-2003 examination until date of death/event or censoring date (January 1st, 2017). Mean age was 52.6 ± 11.9 years and 2513 (53%) were female. During a median of 14.2 year follow-up, 620 participants died of which 142 were due to cardiovascular causes. Combined low vitamin D and K status was present in 970 participants (20%) and was associated with a greater risk of all-cause mortality compared to high vitamin D and high vitamin K status group (n = 1424) after adjusting for potential confounders: hazard ratio 1.46 (95% confidence intervals 1.12-1.90). We observed similar trends, albeit non-significant for cardiovascular mortality, and cardiovascular events: 1.42 (0.79-2.55), 1.28 (0.93-1.77), respectively. Combined low vitamin D and K status are associated with increased all-cause mortality risk and possibly with cardiovascular mortality and cardiovascular events compared with adequate vitamin D and K status. Future studies should investigate the effect of combined vitamin D and K supplementation on clinical outcomes.


Bladder Cancer: Diagnosis and Treatment.
Bladder cancer is the sixth most prevalent malignancy in the United States and causes more than 16,000 deaths annually. The most common clinical presentation is asymptomatic hematuria, which should prompt evaluation with cystoscopy, renal function testing, and upper urinary tract imaging in adults 35 years and older and in those with irritative voiding symptoms, risk factors for bladder cancer, or gross hematuria at any age. Transurethral resection of the bladder tumor allows for definitive diagnosis, staging, and primary treatment. Non-muscle-invasive disease is treated with transurethral resection, most often followed by intravesical bacille Calmette-Guérin or intravesical chemotherapy. Bladder cancer that invades the muscle layer is typically treated with radical cystectomy and neoadjuvant chemotherapy because of higher rates of progression and recurrence. No major organization recommends screening asymptomatic adults for bladder cancer, and the U.S. Preventive Services Task Force concluded that current evidence is insufficient to assess the balance of benefits and harms of screening.


Iron fortification of foods: overcoming technical and practical barriers.
Iron fortification of food is a methodology utilized worldwide to address iron deficiency. A critical problem in some food fortification programs is the lack of bioavailability of iron compounds. This article reviews presentations on iron fortification programs in the Americas and the technical and practical barriers faced by the programs. Effective programmatic strategies will incorporate systematic consideration of sound program management, ensure consumption of fortified foods, and promote advocacy and supportive legislation. However, these factors are often overlooked or are not addressed coherently. Key components to consider in implementation of iron fortification programs include: utilization of foods and condiments containing fortificants that are bioavailable; program development and its implementation coordinated with targeted communications; utilizing resources from public/private sector partnerships; and operational research on how to overcome practical barriers for successful implementation of fortification.


Indigenous ectosymbiotic bacteria associated with diverse hydrothermal vent invertebrates.
Symbioses involving bacteria and invertebrates contribute to the biological diversity and high productivity of both aquatic and terrestrial environments. Well-known examples from chemosynthetic deep-sea hydrothermal vent environments involve ectosymbiotic microbes associated with the external surfaces of marine invertebrates. Some of these ectosymbioses confer protection or defence from predators or the environment itself, some are nutritional in nature, and many still are of unknown function. Several recently discovered hydrothermal vent invertebrates, including two populations of yeti crab (Kiwa spp.), a limpet (Symmetromphalus aff. hageni), and the scaly-foot snail (as yet undescribed), support a consortium of diverse bacteria. Comparisons of these ectosymbioses to those previously described revealed similarities among the associated microorganisms, suggesting that certain microbes are indigenous to the surfaces of marine invertebrates. In particular, members of the Thiovulgaceae (epsilonproteobacteria) and Thiotrichaceae (gammaproteobacteria) appear to preferentially form ectosymbioses with vent crustaceans and gastropods. Interactions between specific Proteobacteria and the surfaces of many marine invertebrates likely have ecological and evolutionary significance at these chemically challenging habitats.


Health care utilization and workplace interventions for neck and upper limb problems among newspaper workers.
Data on the use of various therapeutic interventions among working populations at risk for musculoskeletal disorders are rare, despite the need for such information in assessing adherence to best practices. Using the results of a cross-sectional survey of newspaper workers who reported neck and upper limb pain or discomfort (n = 309), we describe the prevalence of a wide range of clinical and workplace interventions. Information/education, exercises, and physical treatments were the most common interventions, and work changes were less prevalent. Those with more frequent, longer-duration, and/or more severe symptoms more commonly reported visits to physiotherapists and health practitioners at work and use of physical treatments, medications, and devices. The multiplicity of interventions used pose evaluation challenges for occupational health practitioners and researchers.


Temporal preference in individuals reporting chronic pain: discounting of delayed pain-related and monetary outcomes.
Opioid therapy for pain is associated with an increased risk for substance use disorders. This study's purpose was to determine the association between opioid misuse propensity (Screener and Opioid Assessment for Patients in Pain-Revised) and delay discounting (DD), a behavioral process linked to substance use disorders, which quantifies the extent to which outcomes are devalued because of their delay. Participants reporting chronic pain (N = 249) answered pain and opioid use questions and then completed 4 DD tasks. Each of these tasks assessed either money or pain consequences, framed as either rewards or punishments. Each task involved hypothetical choices between immediate smaller vs delayed larger consequences. The extant Monetary Choice Questionnaire assessed DD of money rewards, and a modified version assessed discounting of money losses (immediate smaller loss vs larger delayed loss). Based on the Monetary Choice Questionnaire, the novel Pain Relief Choice Questionnaire assessed choices between an immediate short duration of pain relief vs a longer duration of pain relief. Similarly, the novel Additional Pain Choice Questionnaire assessed choices between an immediate short duration of additional pain vs a longer duration of additional pain. Discounting of both additional pain and money losses were significantly associated with high Screener and Opioid Assessment for Patients in Pain-Revised scores-indicating participants at greatest risk for opioid misuse discount future punishments rather than future rewards compared with those at low risk. Measures of DD may have promise in more accurately identifying individuals at highest risk for opioid misuse during chronic opioid therapy.


Oblique magnetic resonance imaging of the cardiovascular system.
This exhibit demonstrates that cardiac anatomy can be imaged by MRI in oblique planes that are equivalent to views obtained radiographically or at angiocardiography. These MR images may be obtained either by simple patient positioning or by electronic rotation of the imaging axis. The advantages of this technique include its simplicity and its ability to show detailed anatomy noninvasively. Major cardiac structures including chambers, walls, vessels and bronchi are optimally demonstrated in long axis or cross section. This permits estimation of chamber volume, wall thickness, vessel position and variations from normal. Smaller structures are also well visualized. These include the pericardium, papillary muscles, azygos vein and some cross sectional anatomy of the coronary arteries and veins. The valvular structures can be shown during diastole or systole. The ability of MRI to show these cardiac structures due to the intrinsic contrast differences in signal intensity between muscle, fat, flowing blood and lung suggest an important future for MR cardiac imaging in a broad group of congenital and acquired diseases of the heart, pericardium and great vessels.


Age-related changes in prosodic features of maternal speech to prelingually deaf infants with cochlear implants.
This study investigated prosodic and structural characteristics of infant-directed speech to hearing-impaired infants as they gain hearing experience with a cochlear implant over a 12-month period of time. Mothers were recorded during a play interaction with their HI infants (N = 27, mean age 18.4 months) at 3, 6, and 12 months post-implantation. Two separate control groups of mothers with age-matched normal-hearing infants (NH-AM) (N = 21, mean age 18.1 months) and hearing experience-matched normal-hearing infants (NH-EM) (N = 24, mean age 3.1 months) were recorded at three testing sessions. Mothers produced less exaggerated pitch characteristics, a larger number of syllables per utterance, and faster speaking rate when interacting with NH-AM as compared to HI infants. Mothers also produced more syllables and demonstrated a trend suggesting faster speaking rate in speech to NH-EM relative to HI infants. Age-related modifications included decreased pitch standard deviation and increased number of syllables in speech to NH-AM infants and increased number of syllables in speech to HI and NH-EM infants across the 12-month period. These results suggest that mothers are sensitive to the hearing status of their infants and modify characteristics of infant-direct speech over time.


NF-X2 that binds to the DRA X2-box is activator protein 1. Expression cloning of c-Jun.
Human class II MHC Ag are a family of cell surface glycoproteins. Their constitutive expression is limited to B lymphocytes and thymic epithelial cells. In many other cells their expression can be induced by IFN-gamma. Conserved upstream promoter sequences regulate this tissue-specific expression of class II genes. In the DRA promoter, one of these cis-acting regulatory motifs is the X2-box to which nuclear factor X2 (NF-X2) binds. Here, we present the isolation and characterization of the full-length cDNA clone encoding NF-X2. This cDNA clone was isolated by expression cDNA cloning, and encodes the human c-Jun protein, which together with c-Fos forms the heterodimeric activator protein-1 transcription complex. Whereas c-Fos/c-Jun heterodimers do not exist in B cells, they form and bind to the X2-box in class II nonexpressing cells. Thus, c-Fos/c-Jun heterodimers might contribute to the repression of DRA gene expression.


BMP4 supports self-renewal of embryonic stem cells by inhibiting mitogen-activated protein kinase pathways.
The fate of pluripotent stem cells is tightly controlled during early embryonic development. Both the derivation and the maintenance of embryonic stem cells (ES cells) in vitro depend on feeder cell-derived growth factors that are largely unidentified. To dissect the mechanisms governing pluripotency, we conducted a screen to identify factors that are produced by mouse embryonic fibroblast STO cells and are required to maintain the pluripotency of ES cells. One of the factors is bone morphogenetic protein 4 (BMP4). Unexpectedly, the major effect of BMP4 on the self-renewal of ES cells is accomplished by means of the inhibition of both extracellular receptor kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) pathways, and inhibitors of ERK and p38 MAPKs mimic the effect of BMP4 on ES cells. Importantly, inhibition of the p38 MAPK pathway by SB203580 overcomes the block in deriving ES cells from blastocysts lacking a functional Alk3, the BMP type IA receptor. These results uncover a paradigm for BMP signaling in the biology of pluripotent stem cells.


The skin microbiome: current perspectives and future challenges.
Complex communities of bacteria, fungi, and viruses thrive on our skin. The composition of these communities depends on skin characteristics, such as sebaceous gland concentration, moisture content, and temperature, as well as on host genetics and exogenous environmental factors. Recent metagenomic studies have uncovered a surprising diversity within these ecosystems and have fostered a new view of commensal organisms as playing a much larger role in immune modulation and epithelial health than previously expected. Understanding microbe-host interactions and discovering the factors that drive microbial colonization will help us understand the pathogenesis of skin diseases and develop new promicrobial and antimicrobial therapeutics.


Racial and Ethnic Disparities in Health Information Technology Use and Associated Trends among Individuals Living with Chronic Diseases.
Health information technology (HIT) can enhance optimal health care access and utilization among individuals living with chronic diseases. This study aimed to provide population-level information on racial/ethnic disparities in HIT use and associated trends among those living with chronic diseases. The study sample consisted of adult respondents (≥18 years) of the 2011-2018 National Health Interview Survey living with at least 1 chronic condition. Binomial regression was used to analyze the association between race/ethnicity, year, and 4 measures of HIT use for patient-provider interaction. Regression parameter estimates were used to predict the trends in probability of the outcome variables across race/ethnicity. About 73% of the study sample were non-Hispanic Whites, 15% were non-Hispanic Blacks, and 13% were Hispanics. Compared to non-Hispanic Whites, there were decreased adjusted odds of any HIT use among non-Hispanic Blacks (OR = 0.72; 95% CI = 0.67, 0.76) and Hispanics (OR = 0.78; 95% CI = 0.72, 0.84). The likelihood of any HIT use increased with increasing year (OR: 1.16; 95% CI = 1.15, 1.18). Trends in racial/ethnic disparities were wider for email communication with provider and online prescription refill compared to online scheduling of appointment. The COVID-19 pandemic has led to accelerated adoption or expansion of HIT for patient care. Limited HIT use among non-Hispanic Blacks and Hispanics could worsen the disproportionate chronic disease burden, suboptimal clinical outcomes, and preventable health care costs experienced by this subpopulation. In conclusion, there is a need for intentional and strategic population-level interventions to increase HIT adoption and use among non-Hispanic Blacks and Hispanics living with chronic diseases.


Nonpolymorphic regions of p190, a protein of the Plasmodium falciparum erythrocytic stage, contain both T and B cell epitopes.
Two conserved regions from the genetically polymorphic p190 molecule of the malaria parasite Plasmodium falciparum have previously been expressed in Escherichia coli as separate polypeptides (190.L and 190.M) or as a single fusion protein (190.N). In the present study we investigated whether human B and T lymphocytes recognize these conserved regions. The more amino-terminal region, 190.L (corresponding to residues 188-363 of the encoded protein sequence) reacted preferentially with sera from donors living in a malaria-endemic area. Also, EBV-transformed B cells, from a healthy donor living in a malaria-mesoendemic area, were fused with a human-mouse hybrid line (SPM4-0), yielding two hybridomas whose products recognized both 190.L and the fusion protein 190.N, but not the 190.M polypeptide. A large number of p190-specific T cell clones were obtained from PBMC of a noninfected donor, after in vitro stimulation with the recombinant fusion protein 190.N. The clones reacted with intact, parasite-derived p190, as well as either 190.L or 190.M. Four clones that recognized the more amino-terminal fragment also responded to infected E. According to these results the more amino-terminal conserved sequences of p190 have the requisites to be immunogenic in humans.


Thyrotropin-releasing hormone-induced subcellular redistribution and down-regulation of G11alpha: analysis of agonist regulation of coexpressed G11alpha species variants.
Human embryonic kidney 293 cells that had been transfected to express the long isoform of the rat thyrotropin-releasing hormone (TRH) receptor (clone E2) were further transfected with a cDNA encoding the murine version of G11alpha. A clone was isolated (clone E2M11) that stably expressed murine as well as the endogenous human G11alpha. Subcellular fractionation demonstrated identical cellular distribution of the two species variants of this G protein. Sustained exposure of clone E2M11 cells to TRH resulted in substantial cellular redistribution and reduction in total cellular levels of G11alpha immunoreactivity. Fractions of both the exogenously introduced murine and endogenously expressed human isoforms of G11alpha were transferred from plasma membranes to low density membranes (detected as a shift from middle to low density regions on sucrose density gradients) and cytosol fractions. The plasma membrane redistribution to low density membrane was accompanied by a parallel redistribution of G protein beta subunits; however, there was no increase in beta subunits in the cytosol. The total cellular amount of G11alpha subunits was decreased to 21% and 59% for human and murine isoforms, respectively, and beta subunits were decreased to 68% after sustained treatment with TRH compared with controls (100%). Such data are consistent with the notion that the agonist-occupied long isoform of the rat TRH receptor may be able to partially differentiate between the endogenous (human) and exogenous (murine) G11alpha. This was not a reflection that the murine G protein was expressed but incorrectly folded as both species variants of G11alpha were solubilized equally from E2M11 membranes by sodium cholate. Using this system, we demonstrate both agonist-induced subcellular redistribution and down-regulation of G11alpha and beta subunit proteins in response to activation of a phospholipase C coupled receptor.


Prophylactic and therapeutic efficacy of Australian-registered insecticide formulations against Old World screwworm (Chrysomya bezziana) infestation.
To determine the prophylactic and therapeutic efficacy of Australian-registered insecticide formulations against Old World screwworm (OWS) myiases for potential use in screwworm containment and eradication programs. The longevity of protection provided by six insecticidal formulations (subcutaneous ivermectin, doramectin and abamectin, a topically applied aqueous formulation of spinosad, ivermectin controlled-release capsule and a dicyclanil spray-on formulation) was tested using implants of 1st-instar OWS larvae on Javanese thin-tail sheep. Therapeutic efficacy of four formulations (topical ivermectin, chlorfenvinphos/cypermethrin mixture, aerosol spinosad formulation and a formulation containing propetamphos and eucalyptus oil) was tested against 2- and 4-day-old OWS strikes. Both the ivermectin capsule and dicyclanil spray-on formulation gave 100% protection against screwworm implants for the full 12 weeks of the study. Ivermectin, doramectin and abamectin administered SC all gave 100% protection at 3 days post-treatment, but at 2 weeks the protection had become incomplete. Spinosad dipping did not give complete protection at any time. All four therapeutic treatments gave complete resolution of 2-day-old strikes and topical ivermectin, spinosad and chlorfenvinphos/cypermethrin, but not the propetamphos/eucalyptus oil formulation, gave complete resolution of all 4-day-old strikes. Dicyclanil spray-on and ivermectin capsule formulations, both registered for use in sheep, but not for cattle or other livestock species, gave much longer protection against screwworm implants than the currently recommended SC ivermectin. Pre-emptive action to facilitate rapid deployment of these formulations in the event of a screwworm incursion is urgently needed.


Effects of tetracaine on insulin release and calcium handling by rat pancreatic islets.
The effects of tetracaine on insulin release and 45Ca2+ handling by rat pancreatic islets have been studied under basal (2.8 mM glucose), glucose-stimulated (5.6, 8.3, and 16.7 mM glucose), and 3-isobutyl-1-methylxanthine (IBMX)-stimulated conditions. Islets were isolated by the use of collagenase and used either directly (freshly isolated islets) or after a period under tissue culture conditions. Tetracaine was found to stimulate insulin release under basal conditions, to inhibit glucose-stimulated insulin release, and to potentiate insulin release stimulated by IBMX. In studies on the mechanisms underlying these effects, tetracaine was found to decrease glucose-stimulated net retention of 45Ca2+ (by an action to block the voltage-dependent Ca channels) and to mobilize Ca2+ from intracellular stores. These two actions form the basis for the inhibition of glucose-stimulated insulin release, which depends heavily on Ca2+ entry via the voltage-dependent channels and the synergism with IBMX to potentiate release. No inhibition of IBMX-stimulated release occurs because IBMX does not use the voltage-dependent channels to raise intracellular Ca2+.


Compliance in 2017 With Federal Calorie Labeling in 90 Chain Restaurants and 10 Retail Food Outlets Prior to Required Implementation.
To examine early compliance with the delayed federal calorie labeling regulation that requires posting calories on menus and menu boards at retail food chains with 20 or more establishments nationally. We explored implementation of calorie labeling at 90 of the largest US chain restaurants and the 10 highest-grossing supermarket chains from May to December 2017. We contacted corporate offices and at least 2 locations for each chain, made site visits when possible, and supplemented these efforts with targeted Internet searches. Overall, 71 (79%) restaurant chains partially or fully implemented labeling, as did 9 (90%) supermarket chains. Fast-food and fast-casual restaurants fully implemented labeling at a modestly higher rate than did full-service restaurants. Most of the retail food chains we assessed implemented calorie labeling policies in advance of the May 2018 compliance date. Public Health Implications. Although implementation of federal calorie labeling has been delayed repeatedly in the 8 years since the passage of the legislation, retail food chains have demonstrated a high rate of compliance with calorie labeling in advance of the required May 2018 implementation date. Despite reports from some retail food industries that compliance will be difficult, current implementation shows the feasibility of complying.


Use of derived adipose stem cells to reduce complications of cutaneous scarring in smokers. An experimental model in rats.
To evaluate the use of adipose-derived stem cells (ADSC) in reducing the necrosis area in an experimental model of cutaneous ischemic flap in rats submitted to subcutaneous nicotine injection to simulate a smoker patient. In an experimental study, 30 rats were enrolled and divided into two experimental groups of 15 animals all submitted to a subcutaneous nicotine injection to create ischemic cutaneous flaps on their backs. Other 10 animals were used only to obtain adipose tissue derived stem cells (ADSC). The first group (n=15) received ADSC treatment at the end of surgery while the other group, the control (n=15), received no other interventions. After euthanasia, a decal was performed on the whole area of the flap, accurately defining the transition from necrosis to healthy region. Photos of all animals were collected and evaluated by scales standardized by Paint-Autocad- 2015 software to define the area of flap necrosis in each rat. Student T test was performed to compare the groups, considering a p< 0.05 significant. Data were analyzed using SPSS IBM® 18 version. Through the analysis of the images by the program Paint-Autocad-2015 and the area of decal obtained by the transparent sheet, we obtained a mean of 46% necrosis of the total area of the flap in the treatment group and 69.4% in the control group. In the descriptive analysis, a mean of 3.7 cm of necrosis CI 95% (3.2 - 4.2) was evident in the treatment group whereas a mean value of 5.56 CI 95% (5.2 - 5.9) was found in control group, with p value <0.001 for this comparison. The application of adipose-derived stem cells reduces the percentage of necrosis in an experimental model of randomized cutaneous flap in rats submitted to subcutaneous nicotine injection.


Optimizing health care for individuals with Down syndrome in Israel.
Down syndrome is one of the most common chromosomal abnormalities. Children and adults with DS have significant medical problems and require life-long medical follow-up. To determine the adequacy of medical surveillance of individuals with DS as recommended by the American Academy of Pediatrics. The study was conducted at a multidisciplinary center specializing in the care of DS during the period 2004-2006. At their first visit to the Center, caregivers of individuals with DS were questioned about the medical status of their child including previous evaluations. Medical records brought in by the parents were reviewed. The caregivers of 150 individuals with DS (age ranging from newborn to 48-years-old, median age 5 years) were interviewed and the medical records were reviewed. The prevalence of specific medical problems differed between our population and the reported prevalence from other surveys. For example, 39.3% of our population had documented auditory deficits while the reported prevalence is 75%. For gastrointestinal and thyroid disease, the prevalence was higher in the studied population than that reported in the literature. In terms of compliance with the AAP recommendations, most children (94%) underwent echocardiography, but only 42.7% and 63.3% had been tested for auditory or visual acuity respectively. Only 36.3% over the age of 3 years had cervical spine films. Many individuals with DS are not receiving appropriate medical follow-up and the consequences of inadequate surveillance can be serious.


Genetic diseases associated with an increased risk of skin cancer development in childhood.
Childhood skin cancers are relatively rare and may indicate an underlying genetic disorder. The increasing elucidation of genetic pathways is changing the diagnosis and management of genetic skin cancer susceptibility syndromes. In this review, we provide an overview of genetic conditions that predispose to skin cancer development in childhood and signs that providers should assess when evaluating affected individuals. In basal cell nevus syndrome (BCNS), the patched2 (PTCH2) and suppressor of fused (SUFU) genes have been implicated in disease pathogenesis. The sonic hedgehog (SHH) pathway inhibitor vismodegib was shown in a placebo-controlled phase III randomized trial to reduce the tumor burden in patients with BCNS. Epidermolysis bullosa (EB) has been classified into four major types and more than 30 subtypes based partly on specific mutations, and best clinical practice guidelines for the management of cutaneous squamous cell carcinoma in EB have been developed. Oculocutaneous albinism (OCA) has been associated with new mutations in genes named OCA5, OCA6, and OCA7, bringing to the total number of culprit genes to seven (OCA1-OCA7). Advances in our understanding of genetic conditions that predispose to childhood skin cancer include new disease classification systems, management guidelines, and treatment options.


Pharmacokinetics and cerebrospinal fluid bactericidal activity of ceftriaxone in the treatment of pediatric patients with bacterial meningitis.
Single-dose pharmacokinetics of ceftriaxone were determined in 19 patients with proven bacterial meningitis. The dosage was 50 mg of ceftriaxone per kg. The plasma concentration time curve declined in a biexponential manner. The mean peak plasma concentration was 207 micrograms/ml, and the elimination half-life was 4 h. In 12 patients, multiple-dose pharmacokinetics were determined after a loading dose of 75 mg of ceftriaxone per kg, followed by 50-mg/kg doses every 8 h in 5 patients or every 12 h in 7 patients. The mean peak plasma concentration was 230 micrograms/ml after the first dose and 263 micrograms/ml after the last dose. Of 12 patients, 5 had trough values that were larger after multiple doses than after a single dose. Mean penetration of ceftriaxone into cerebrospinal fluid was 3.1%. The median cerebrospinal fluid bactericidal titer against the patients pathogens was greater than 1:1,024 and less than 1:2,048. The drug was well tolerated without adverse effects.


Localization of matrix metalloproteinases, (MMPs) their tissue inhibitors, and vascular endothelial growth factor (VEGF) in growth plates of children and adolescents indicates a role for MMPs in human postnatal growth and skeletal maturation.
Numerous studies have focused on the expression, regulation, and biological significance of matrix metalloproteinases (MMPs) in the growth plate. Findings in mouse knockout models and in vitro data from various species indicate that MMPs not only degrade extracellular matrix components but may regulate the activity of local growth factors. In this study we investigated the presence, distribution, and activity of various MMPs and inhibitors, tissue transglutaminase (tTG or TG2) and vascular endothelial growth factor (VEGF) in the human child and adolescent growth plates by means of immunohistochemistry and gelatin zymography. Tissue was derived during orthopedic surgery (epiphysiodesis) in two prepubertal and four pubertal patients.MMP-2 and MMP-14 were present in reserve cell chondrocytes. MMP-14 was the most prominent MMP within all zones of the growth plate including proliferating chondrocytes. MMP-1 and MMP-13 (collagenases 1 and 3), MMP-9 (gelatinases B), MMP-10, and MMP-11 (stromelysins) and VEGF were positive in hypertrophic chondrocytes and osteoblasts. MMP-2 showed the same expression pattern but was negative in osteoblasts. Osteoclasts stained positive for MMP-9, MMP-2, and TG2. Tissue inhibitor of MMP (TIMP)-1 was present in all zones of the growth plate, osteoblasts, and osteoclasts; TIMP-2 was found in hypertrophic chondrocytes and osteoblasts. In summary, the presence of MMPs, TIMPs, TG2, and VEGF in our study indicated that the MMPs are relevant in growth plate physiology during the postnatal period in humans. The specific location of MMP expression within the growth plate may be the basis for further studies on the role of MMPs in the local regulation of chondrocyte differentiation, proliferation, and ossification at the chondroosseus junction.


Cost-Effectiveness of Palmaz-Schatzª Stenting for Patients with Coronary Artery Disease in Italy.
The increasing use of stent implantation in coronary artery disease raises economic concerns for health care decision-makers. This model analysis, which applies to the Italian health care system and uses the latest clinical and economic data, demonstrates coronary stent implantation (CSI) in single-vessel disease (SVD) to be clinically and economically superior to conventional balloon angioplasty (PTCA). Although the procedural cost for CSI remains higher than for PTCA (Lit. 7.5 million vs. Lit. 4.9 million), this cost difference in the cath lab is decreased to approximately Lit. 1.7 million during the in-hospital period due to avoided procedural complications and associated bail-out treatments. By the end of year one, the incremental cost of CSI is totally recouped through savings in revascularization procedures, and the result is maintained over subsequent years. This favorable cost outcome, combined with a higher rate of event-free patients, also improves the cost-effectiveness of CSI, which has a 30.2%, 31.2%, and 32.9% lower cost per event-free survivor than PTCA at the 1-, 2-, and 3-year follow-ups, respectively. In multi-vessel disease, CSI also appears to be a cost-effective alternative to CABG.


Phospholipase A2 mRNA expression in the nasal mucosa of healthy subjects and patients with seasonal allergic rhinitis.
Phospholipase A2 (PLA2) is a family of enzymes that play different role(s) in inflammation, but their importance in seasonal allergic rhinitis (SAR) has not been clarified. Here, we determined the levels of messenger ribonucleic acid (mRNA) for different PLA2 types in the nasal mucosa of SAR patients (n = 6) and healthy controls (n = 5). Nasal brush samples were taken both during pollen season, when the symptoms of the patients were severe, and off-season, when the patients were free of symptoms. We found that PLA2 IB, IIA, IID, IIE, IIF, III, IVA, IVB, IVC, VIA, VIB, VIIA, VIIB, VIIIA, VIIIB, X, XII and XIII were all expressed in each subject at both occasions. The mRNA levels of PLA2 VIIA (platelet-activating factor (PAF) acetylhydrolase) were lower in SAR patients than controls, both during pollen season (p = 0.03) and off season (p = 0.03). These findings demonstrate that a large number of PLA2 types are expressed in the nasal mucosa, regardless of whether there is ongoing allergic inflammation or not. The observation that PAF acetylhydrolase mRNA expression in the nasal mucosa is lower in SAR patients than in healthy subjects suggests the possibility that impaired ability to inactivate PAF might be of importance in SAR. Further studies are required to clarify whether the decreased PAF acetylhydrolase mRNA expression in SAR is accompanied by decreased enzyme activity and whether aberrations in PAF acetylhydrolase are present in infectious rhinitis patients as well.


Evaluation of harmful algal bloom outreach activities.
With an apparent increase of harmful algal blooms (HABs) worldwide, healthcare providers, public health personnel and coastal managers are struggling to provide scientifically-based appropriately-targeted HAB outreach and education. Since 1998, the Florida Poison Information Center-Miami, with its 24 hour/365 day/year free Aquatic Toxins Hotline (1-888-232-8635) available in several languages, has received over 25,000 HAB-related calls. As part of HAB surveillance, all possible cases of HAB-related illness among callers are reported to the Florida Health Department. This pilot study evaluated an automated call processing menu system that allows callers to access bilingual HAB information, and to speak directly with a trained Poison Information Specialist. The majority (68%) of callers reported satisfaction with the information, and many provided specific suggestions for improvement. This pilot study, the first known evaluation of use and satisfaction with HAB educational outreach materials, demonstrated that the automated system provided useful HAB-related information for the majority of callers, and decreased the routine informational call workload for the Poison Information Specialists, allowing them to focus on callers needing immediate assistance and their healthcare providers. These results will lead to improvement of this valuable HAB outreach, education and surveillance tool. Formal evaluation is recommended for future HAB outreach and educational materials.


Seropositivity to cytomegalovirus, inflammation, all-cause and cardiovascular disease-related mortality in the United States.
Studies have suggested that CMV infection may influence cardiovascular disease (CVD) risk and mortality. However, there have been no large-scale examinations of these relationships among demographically diverse populations. The inflammatory marker C-reactive protein (CRP) is also linked with CVD outcomes and mortality and may play an important role in the pathway between CMV and mortality. We utilized a U.S. nationally representative study to examine whether CMV infection is associated with all-cause and CVD-related mortality. We also assessed whether CRP level mediated or modified these relationships. Data come from subjects ≥ 25 years of age who were tested for CMV and CRP level and were eligible for mortality follow-up on December 31(st), 2006 (N = 14153) in the National Health and Nutrition Examination Survey (NHANES) III (1988-1994). Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for all-cause and CVD-related mortality by CMV serostatus. After adjusting for multiple confounders, CMV seropositivity remained statistically significantly associated with all-cause mortality (HR 1.19, 95% CI: 1.01, 1.41). The association between CMV and CVD-related mortality did not achieve statistical significance after confounder adjustment. CRP did not mediate these associations. However, CMV seropositive individuals with high CRP levels showed a 30.1% higher risk for all-cause mortality and 29.5% higher risk for CVD-related mortality compared to CMV seropositive individuals with low CRP levels. CMV was associated with a significant increased risk for all-cause mortality and CMV seropositive subjects who also had high CRP levels were at substantially higher risk for both for all-cause and CVD-related mortality than subjects with low CRP levels. Future work should target the mechanisms by which CMV infection and low-level inflammation interact to yield significant impact on mortality.


Sex differences in cannabinoid 1 vs. cannabinoid 2 receptor-selective antagonism of antinociception produced by delta9-tetrahydrocannabinol and CP55,940 in the rat.
The purpose of this study was to determine whether sex differences in cannabinoid (CB)-induced antinociception and motoric effects can be attributed to differential activation of CB(1) or CB(2) receptors. Rats were injected intraperitoneally with vehicle, rimonabant [5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (SR141716A), a putative CB(1) receptor-selective antagonist; 0.1-10 mg/kg] or 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]-1H-pyrazole-3-carboxamide (SR144528) (a putative CB(2) receptor-selective antagonist; 1.0-10 mg/kg). Thirty minutes later, Δ(9)-tetrahydrocannabinol (THC; 1.25-40 mg/kg) or 5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol (CP55,940) (0.05-1.6 mg/kg) was injected. Paw pressure and tail withdrawal antinociception, locomotor activity, and catalepsy were measured. Rimonabant dose-dependently antagonized THC and CP55,940 in each test, but was up to 10 times more potent in female than male rats on the nociceptive tests; estimates of rimonabant affinity (apparent pK(B)) for the CB(1) receptor were approximately 0.5 to 1 mol/kg higher in female than male rats. SR144528 partially antagonized THC-induced tail withdrawal antinociception and locomotor activity in females, but this antagonism was not dose-dependent or consistent; no SR144528 antagonism was observed in either sex tested with CP55,940. Neither the time course of rimonabant antagonism nor the plasma levels of rimonabant differed between the sexes. Rimonabant and SR144528 did not antagonize morphine-induced antinociception, and naloxone did not antagonize THC-induced antinociception in either sex. These results suggest that THC produces acute antinociceptive and motoric effects via activation of CB(1), and perhaps under some conditions, CB(2) receptors, in female rats, whereas THC acts primarily at CB(1) receptors in male rats. Higher apparent pK(B) for rimonabant in female rats suggests that cannabinoid drugs bind with greater affinity to CB(1) receptors in female than male rats, probably contributing to greater antinociceptive effects observed in female compared with male rats.


Trends and predictors of radiation exposure in percutaneous coronary intervention: the PROTECTION VIII study.
Percutaneous coronary intervention (PCI) is indispensable in cardiology; however, exposure to potentially harmful ionising radiation remains a concern. This study was designed to assess the PCI-related radiation dose over the last decade and to identify predictors of increased dose exposure. The PROcedural radiaTion dose Exposure in percutaneous Coronary intervenTION (PROTECTION VIII) study included all PCIs reported to a German quality assurance programme between 2008 and 2018. Dose area product (DAP) and radiation time were analysed. Effective dose (ED) was estimated (ED=DAP*k; conversion coefficient k=0.0022 mSv/cGy*cm2). Multivariate linear regression analysis was used to identify predictors associated with a clinically relevant increase of radiation dose (ED ≥1 mSv). We enrolled 3,704,986 patients undergoing PCI (median age 70 years, 30% female). Indications were chronic coronary syndrome (37.5%), unstable angina pectoris and non-ST-segment elevation myocardial infarction (non-STEMI; 33.2%) and STEMI (18.5%). Median DAP was 4,203 (interquartile range [IQR] 2,313-7,300) cGy*cm, ED was 9.2 mSv and median radiation time was 9.2 (IQR 5.8-15.0) min. Within the 10-year period, radiation exposure was reduced by 36% (p<0.001) and resulted in a median DAP of 3,070 cGy*cm (ED 6.8 mSv) in 2018. A significant 5.3-fold variability of median DAP was observed between catheterisation laboratories (p<0.001). We identified patient-related (gender, coronary artery bypass graft surgery, heart failure) and procedure-related (coronary occlusion PCI, ostial lesion PCI, left main PCI, multivessel PCI) predictors of increased radiation dose (all p<0.001). This radiation dose survey demonstrates a considerable reduction of PCI radiation exposure during the last decade. However, large variability between catheterisation laboratories underlines the need for further radiation dose reduction.


Esophageal web associated with Zenker's diverticulum: a possible cause of continuing dysphagia after diverticulectomy.
A 67-year-old man with upper esophageal dysphagia thought to be caused by a large Zenker's diverticulum was found to have esophageal web at the time of diverticulectomy and cricopharyngeal myotomy. The web was divided by sharp dissection. Untreated, this thin web would almost certainly have resulted in dysphagia postoperatively. The authors therefore recommend routine open diverticulectomy for the management of Zenker's diverticulum, to allow inspection of the esophageal lumen for concomitant disease and palpation of the cricopharyngeal muscle at the time of myotomy.


[Genetic-biochemical study of acid phosphatases from Saccharomyces cerevisiae yeasts. IV. Genetic control of acid phosphatase II activity].
Genetic control of exocellular acid phosphatase of yeast Saccharomyces cerevisiae (acph 2) is studied. 64 mutants with the impaired activity of acid phosphatase have been obtained by UV-irradiation. All the mutations have been distributed among 4 genes: ACP1, ACP2, ACP3, ACP4 using functional and recombinational tests for allelism. It is shown that mutations in genes ACP1--ACP3 are recessive, but in the gene ACP4--dominant. The gene ACP4 is found to be located 0.41+/-0.064 in strains from centromere and to have no linkage with ACP1. Possible functions of genes studied are under discussion.