In vivo pectoralis muscle force-length behavior during level flight in pigeons (Columba livia)
For the first time, we report in vivo measurements of pectoralis muscle length change obtained using sonomicrometry combined with measurements of its force development via deltopectoral crest strain recordings of a bird in free flight. These measurements allow us to characterize the contractile behavior and mechanical power output of the pectoralis under dynamic conditions of slow level flight in pigeons Columba livia. Our recordings confirm that the pigeon pectoralis generates in vivo work loops that begin with the rapid development of force as the muscle is being stretched or remains nearly isometric near the end of the upstroke. The pectoralis then shortens by a total of 32 % of its resting length during the downstroke, generating an average of 10.33.6 J kg-1 muscle (mean s.d.) of work per cycle for the anterior and posterior sites recorded among the five animals. In contrast to previous kinematic estimates of muscle length change relative to force development, the sonomicrometry measurements of fascicle length change show that force declines during muscle shortening. Simultaneous measurements of fascicle length change at anterior and posterior sites within the same muscle show significant (P<0.001, three of four animals) differences in fractional length (strain) change that averaged 1912 %, despite exhibiting similar work loop shape. Length changes at both anterior and posterior sites were nearly synchronous and had an asymmetrical pattern, with shortening occupying 63 % of the cycle. This nearly 2:1 phase ratio of shortening to lengthening probably favors the ability of the muscle to do work. Mean muscle shortening velocity was 5.381.33 and 4.881.27 lengths s-1 at the anterior and posterior sites respectively. Length excursions of the muscle were more variable at the end of the downstroke (maximum shortening), particularly when the birds landed, compared with highly uniform length excursions at the end of the upstroke (maximum lengthening). When averaged for the muscle as a whole, our in vivo work measurements yield a mass-specific net mechanical power output of 70. 2 W kg-1 for the muscle when the birds flew at 5-6 m s-1, with a wingbeat frequency of 8.7 Hz. This is 38 % greater than the value that we obtained previously for wild-type pigeons, but still 24-50 % less than that predicted by theory.


Mexiletine Shortens the QT Interval in Patients With Potassium Channel-Mediated Type 2 Long QT Syndrome.
Long QT syndrome is a potentially lethal yet highly treatable cardiac channelopathy. Although β-blocker therapy is standard for most patients, concomitant therapy with sodium channel blockers, like mexiletine, is often utilized for patients with sodium channel-mediated type 3 long QT syndrome (LQT3). The potential role of sodium channel blockers in patients with potassium channel-mediated long QT syndrome (ie, LQT1 and LQT2) has not been investigated in detail. We performed a retrospective chart review on 12 patients (5 females; median age at diagnosis 14.1 years (interquartile range [IQR], 7.7-23; range, 0-59, median heart rate-corrected QT interval [QTc] at diagnosis 557 ms (IQR, 529-605) with genetically established LQT2 (10) or a combination of LQT1/LQT2 (1) or LQT2/LQT3 (1), who received mexiletine. Data were collected on symptomatic status, treatments, and breakthrough cardiac events after diagnosis and initiation of treatment. Additionally, 12-lead ECGs were collected at diagnosis, before initiation of mexiletine and following mexiletine to evaluate the drug's effect on QTc. Before diagnosis, 6 patients were symptomatic and, before initiation of mexiletine, 4 patients experienced ≥1 breakthrough cardiac event on β-blocker. Median age at first mexiletine dose was 24.3 years (IQR, 14-32.4). After mexiletine, the median QTc decreased by 65±45 ms from 547 ms (IQR, 488-558) premexiletine to 470 ms (IQR, 409-529) postmexiletine ( P=0.0005) for all patients. In 8 patients (67%), the QTc decreased by ≥ 40 ms with a mean decrease in QTc of 91 ms ( P < 0.008). For the 11 patients maintained on mexiletine therapy, there have been no breakthrough cardiac events during follow-up. Although commonly prescribed in patients with LQT3, mexiletine also shortens the QTc significantly in two-thirds of a small subset of patients with potassium channel-mediated LQT2. In patients with LQT2, pharmacological targeting of the physiological late sodium current may provide added therapeutic efficacy to β-blocker therapy.


The Effect of Pain Neuroscience Education on Sports Therapy and Rehabilitation Students' Knowledge, Attitudes, and Clinical Recommendations Toward Athletes With Chronic Pain.
Context: Pain education is a fundamental part of a holistic approach to athlete injury management. Objective: To investigate the effect of pain neuroscience education (PNE) on sports therapy and rehabilitation students (1) knowledge of persistent pain, (2) attitudes toward athletes with persistent pain, and (3) clinical recommendations for athletes with persistent pain. Design: Parallel groups, single-blind randomized control trial. Setting: A university in the United Kingdom. Participants: Sixty-one undergraduate and postgraduate sports therapy and rehabilitation students. Interventions: The PNE session (intervention group) provided detailed information on the neuroscience of persistent pain, the modulating role of psychosocial factors on pain biology, and how this information could be used to inform clinical practice. The red flags (control group) session provided information on screening patients with persistent pain for serious/sinister pathologies. Each education session lasted 70 minutes. Outcome measures: (1) Knowledge-the Revised Pain Neurophysiology Questionnaire; (2) Attitudes-the Health Care Pain Attitudes and Impairment Relationship Scale; and (3) Clinical recommendations-an athlete case vignette. Results: Posteducation, the PNE group had a greater increase in pain neuroscience knowledge (mean difference 3.2; 95% confidence interval [95% CI], 2.1 to 4.3; P < .01) and improved attitudes (mean difference -10.1; 95% CI, -16.6 to -3.6; P < .01). In addition, students in the PNE group were more likely to make appropriate clinical recommendations (odds ratio [OR]; 95% CI) regarding return-to-work (OR = 6.1; 95% CI, 1.1 to 32.3; P = .03), exercise (OR = 10.7; 95% CI, 2.6 to 43.7; P ≤ 01), and bed rest (OR = 4.3; 95% CI, 1.5 to 12.8; P = 01). Conclusion: A brief PNE session can, in the immediate term, increase sports therapy and rehabilitation students' knowledge of pain neuroscience, improve attitudes toward athletes with pain, and shift their clinical recommendations in line with current guidelines. Such changes could lead to enhanced rehabilitation for athletes with persistent pain.


Modification of the ionizing radiation response in living cells by an scFv against the DNA-dependent protein kinase.
The non-homologous end joining pathway uses pre-existing proteins to repair DNA double-strand breaks induced by ionizing radiation. Here we describe manipulation of this pathway in living cells using a newly developed tool. We generated a single chain antibody variable fragment (scFv) that binds to the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a key enzyme in the pathway. In contrast to existing pharmacologic inhibitors, the scFv binds a newly defined regulatory site outside the kinase catalytic domain. Although the scFv inhibits kinase activity only modestly, it completely blocks DNA end joining in a cell-free system. Microinjection of the scFv sensitizes human cells to radiation, as measured by a reduction in efficiency of colony formation and induction of apoptosis at an otherwise sublethal dose of 1.5 Gy. The scFv blocks non-homologous end joining in situ at a step subsequent to histone gamma-H2AX focus formation but preceding gamma-H2AX dephosphorylation. Blockage occurs in cells exposed to as little as 0.1 Gy, indicating that DNA-PKcs is essential for double-strand break repair even at low radiation doses. The ability to modify the radiation response in situ in living cells provides a link between biochemical, genetic and cytologic approaches to the study of double-strand break repair intermediates.


Calcium regulation by skeletal muscle membranes of horses with recurrent exertional rhabdomyolysis.
To determine whether an alteration in calcium regulation by skeletal muscle sarcoplasmic reticulum, similar to known defects that cause malignant hyperthermia (MH), could be identified in membrane vesicles isolated from the muscles of Thoroughbreds with recurrent exertional rhabdomyolysis (RER). Muscle biopsy specimens from 6 Thoroughbreds with RER and 6 healthy (control) horses. RER was diagnosed on the basis of a history of > 3 episodes of exertional rhabdomyolysis confirmed by increases in serum creatine kinase (CK) activity. Skeletal muscle membrane vesicles, prepared by differential centrifugation of muscle tissue homogenates obtained from the horses, were characterized for sarcoplasmic reticulum (SR) activities, including the Ca2+ release rate for the ryanodine receptor-Ca2+ release channel, [3H]ryanodine binding activities, and rate of SR Ca2+-ATPase activity and its activation by Ca2+. Time course of SR Ca2+-induced Ca2+ release and [3H]ryanodine binding to the ryanodine receptor after incubation with varying concentrations of ryanodine, caffeine, and ionized calcium did not differ between muscle membranes obtained from control and RER horses. Furthermore, the maximal rate of SR Ca2+-ATPase activity and its affinity for Ca2+ did not differ between muscle membranes from control horses and horses with RER. Despite clinical and physiologic similarities between RER and MH, we concluded that RER in Thoroughbreds does not resemble the SR ryanodine receptor defect responsible for MH and may represent a novel defect in muscle excitation-contraction coupling, calcium regulation, or contractility.


Chemotherapy-induced muscle wasting: an update.
The majority of cancers are associated to cachexia, a severe form of weight loss mostly accounted for by skeletal muscle wasting. Cancer patients are often treated with chemotherapy, whose side effects are at times neglected or underestimated. Paradoxically, chemotherapy itself can induce muscle wasting with severe, cancer-independent effects on muscle homeostasis. Since muscle wasting is a primary marker of poor prognosis for cancer patients and negatively affects their quality of life, the systemic consequences of chemotherapy in this context must be fully characterized and taken into account. Ten years ago a precursor study in an animal cancer model was published in the European Journal of Translation Myology (back then, Basic and Applied Myology), highlighting that the side effects of chemotherapy include muscle wasting, possibly mediated by NF-κB activation. This paper, entitled «Chemotherapy-induced muscle wasting: association with NF-κB and cancer cachexia», is now being reprinted for the inaugural issue of the «Ejtm Seminal Paper Series». In this short review we discuss those results in the light of the most recent advances in the study of chemotherapy-induced muscle wasting.


A comparative analysis of Type 2 diabetes and binge eating disorder in a bariatric sample.
An emerging literature has illuminated an important link between Type 2 diabetes mellitus (DM) and binge eating disorder (BED) within obese cohorts. However, prior work has not examined this relationship specifically in a weight loss surgery (WLS) sample or fully explored potential psychosocial factors associated with this co-occurrence. Therefore, the present investigation sought to identify socio-demographic (i.e. age, education, BMI, ethnicity, gender, age of obesity onset) and psychological (i.e. depressive symptoms, hedonic hunger/food locus of control beliefs, severity of binge eating-related cognitions) correlates of the co-occurrence of Type 2 DM and BED among bariatric surgery candidates. An archival sample of 488 patients seeking surgical treatment for clinical obesity completed a standard battery of pre-operative psychosocial measures. The presence of BED was evaluated using a semi-structured clinical interview based on the DSM-IV TR (APA, 2000) and was further corroborated by responses on the Questionnaire on Eating and Weight Patterns-Revised (QEWP-R; Spitzer, Yanovski, & Marcus, 1993). Results indicated that 8.2% of the sample was classified as having both Type 2 DM and BED concurrently. A multivariate logistic regression model revealed that in addition to other psychological (e.g., binge eating-related cognitions, hedonic hunger) and demographic variables (i.e. male gender), African American ethnicity (OR=3.3: 1.41-7.73) was a particularly robust indicator of comorbid status. Findings support and extend previous health disparity research urging greater attention to the needs of traditionally underserved, at-risk populations seeking treatment for obesity complicated by dysregulated eating and metabolism. Additionally, these preliminary results underscore the relevance of considering the potential benefits of providing quality comprehensive pre- and post-operative psychological care among bariatric patients towards optimizing both short- and long-term health and well-being.


Identification of four new mutations in the short-chain acyl-CoA dehydrogenase (SCAD) gene in two patients: one of the variant alleles, 511C-->T, is present at an unexpectedly high frequency in the general population, as was the case for 625G-->A, together conferring susceptibility to ethylmalonic aciduria.
We have shown previously that a variant allele of the short-chain acyl-CoA dehydrogenase ( SCAD ) gene, 625G-->A, is present in homozygous form in 7% of control individuals and in 60% of 135 patients with elevated urinary excretion of ethylmalonic acid (EMA). We have now characterized three disease-causing mutations (confirmed by lack of enzyme activity after expression in COS-7 cells) and a new susceptibility variant in the SCAD gene of two patients with SCAD deficiency, and investigated their frequency in patients with elevated EMA excretion. The first SCAD-deficient patient was a compound heterozygote for two mutations, 274G-->T and 529T-->C. These mutations were not present in 98 normal control alleles, but the 529T-->C mutation was found in one allele among 133 patients with elevated EMA excretion. The second patient carried a 1147C-->T mutation and the 625G-->A polymorphism in one allele, and a single point mutation, 511C-->T, in the other. The 1147C-->T mutation was not present in 98 normal alleles, but was detected in three alleles of 133 patients with elevated EMA excretion, consistently as a 625A-1147T allele. On the other hand, the 511C-->T mutation was present in 13 of 130 and 15 of 67 625G alleles, respectively, of normal controls and patients with elevated EMA excretion, and was never associated with the 625A variant allele. This over-representation of the haplotype 511T-625G among the common 625G alleles in patients compared with controls was significant ( P < 0.02), suggesting that the allele 511T-625G-like 511C-625A-confers susceptibility to ethylmalonic aciduria. Expression of the variant R147W SCAD protein, encoded by the 511T-625G allele, in COS-7 cells showed 45% activity at 37 degrees C in comparison with the wild-type protein, comparable levels of activity at 26 degrees C, and 13% activity when incubated at 41 degrees C. This temperature profile is different from that observed for the variant G185S SCAD protein, encoded by the 511C-625A allele, where higher than normal activity was found at 26 and 37 degrees C, and 58% activity was present at 41 degrees C. These results corroborate the notion that the 511C-625A variant allele is one of the possible underlying causes of ethylmalonic aciduria, and suggest that the 511C-->T mutation represents a second susceptibility variation in the SCAD gene. We conclude that ethylmalonic aciduria, a commonly detected biochemical phenotype, is a complex multifactorial/polygenic condition where, in addition to the emerging role of SCAD susceptibility alleles, other genetic and environmental factors are involved.


Caregiving associated with selected cancer risk behaviors and screening utilization among women: cross-sectional results of the 2009 BRFSS.
Informal caregiving is increasingly common as the U.S. population ages, and there is concern that caregivers are less likely than non-caregivers to practice health-promoting behaviors, including cancer screening. We examined caregiving effects on cancer risk behaviors and breast and cervical cancer screening in the 2009 Behavioral Risk Factor Surveillance System. Women age ≥ 41 with data on breast and cervical cancer screening were included (weighted frequency 3,478,000 women). Cancer screening was classified according to American Cancer Society guidelines. We evaluated the association of caregiving with cancer risk behaviors (obesity, physical activity, alcohol intake, smoking status, and fruit/vegetable consumption) and cancer screening (mammography, clinical breast exam [CBE], and Pap test) using logistic regression overall and with stratification on age (<65, ≥ 65) or race (white, non-white). Caregivers had greater odds of being obese, physically active, and current smokers. Subgroup analyses revealed that caregiving was associated with obesity in younger women and whites, and with less obesity in older women. Also, caregiving was associated with smoking only among younger women and non-whites. Caregivers had greater odds of ever having had a mammogram or CBE, yet there was no association with mammogram, CBE, or Pap test within guidelines. Caregiving was associated with some health behaviors that increase cancer risk, yet not with cancer screening within guidelines. Effects of caregiving by age and race require confirmation by additional studies.


Three-year trajectory of teachers' fidelity to a drug prevention curriculum.
Little is known about the trajectories over time of classroom teachers' fidelity to drug prevention curricula. Using the "Concerns-Based Adoption Model" (C-BAM) as a theoretical framework, we hypothesized that teachers' fidelity would improve with repetition. Participants comprised 23 middle school teachers who videotaped their administration of three entire iterations of the All Stars curriculum. Investigators coded two key curriculum lessons, specifically assessing the proportion of activities of each lesson teachers attempted and whether they omitted, added, or changed prescribed content, or delivered it using new methods. Study findings provided only partial support for the C-BAM model. Considerable variability in teachers' performance over time was noted, suggesting that their progression over time may be nonlinear and dynamic, and quite possibly a function of their classroom and school contexts. There was also evidence that, by their third iteration of All Stars, teachers tended to regress toward the baseline mean. That is, the implementation quality of those that started out with high levels of fidelity tended to degrade, while those that started out with very low fidelity to the curriculum tended to improve. Study findings suggest the need for ongoing training and technical assistance, as well as "just in time" messages delivered electronically; but it is also possible that some prevention curricula may impose unrealistic expectations or burdens on teachers' abilities and classroom time.


Restructuring VA ambulatory care and medical education: the PACE model of primary care.
The Veterans Health Administration (VHA) Western Region and associated medical schools formulated a set of recommendations for an improved ambulatory health care delivery system during a 1988 strategic planning conference. As a result, the Department of Veterans Affairs (VA) Medical Center in Sepulveda, California, initiated the Pilot (now Primary) Ambulatory Care and Education (PACE) program in 1990 to implement and evaluate a model program. The PACE program represents a significant departure from traditional VA and non-VA academic medical center care, shifting the focus of care from the inpatient to the outpatient setting. From its inception, the PACE program has used an interdisciplinary team approach with three independent global care firms. Each firm is interdisciplinary in composition, with a matrix management structure that expands role function and empowers team members. Emphasis is on managed primary care, stressing a biopsychosocial approach and cost-effective comprehensive care emphasizing prevention and health maintenance. Information management is provided through a network of personal computers that serve as a front end to the VHA Decentralized Hospital Computer Program (DHCP) mainframe. In addition to providing comprehensive and cost-effective care, the PACE program educates trainees in all health care disciplines, conducts research, and disseminates information about important procedures and outcomes. Undergraduate and graduate trainees from 11 health care disciplines rotate through the PACE program to learn an integrated approach to managed ambulatory care delivery. All trainees are involved in a problem-based approach to learning that emphasizes shared training experiences among health care disciplines. This paper describes the transitional phases of the PACE program (strategic planning, reorganization, and quality improvement) that are relevant for other institutions that are shifting to training programs emphasizing primary and ambulatory care.


Profitability and occupational injuries in U.S. underground coal mines.
Coal plays a crucial role in the U.S. economy yet underground coal mining continues to be one of the most dangerous occupations in the country. In addition, there are large variations in both profitability and the incidence of occupational injuries across mines. The objective of this study was to examine the association between profitability and the incidence rate of occupational injuries in U.S. underground coal mines between 1992 and 2008. We used mine-specific data on annual hours worked, geographic location, and the number of occupational injuries suffered annually from the employment and accident/injury databases of the Mine Safety and Health Administration, and mine-specific data on annual revenue from coal sales, mine age, workforce union status, and mining method from the U.S. Energy Information Administration. A total of 5669 mine-year observations (number of mines×number of years) were included in our analysis. We used a negative binomial random effects model that was appropriate for analyzing panel (combined time-series and cross-sectional) injury data that were non-negative and discrete. The dependent variable, occupational injury, was measured in three different and non-mutually exclusive ways: all reported fatal and nonfatal injuries, reported nonfatal injuries with lost workdays, and the 'most serious' (i.e. sum of fatal and serious nonfatal) injuries reported. The total number of hours worked in each mine and year examined was used as an exposure variable. Profitability, the main explanatory variable, was approximated by revenue per hour worked. Our model included mine age, workforce union status, mining method, and geographic location as additional control variables. After controlling for other variables, a 10% increase in real total revenue per hour worked was associated with 0.9%, 1.1%, and 1.6% decrease, respectively, in the incidence rates of all reported injuries, reported injuries with lost workdays, and the most serious injuries reported. We found an inverse relationship between profitability and each of the three indicators of occupational injuries we used. These results might be partially due to factors that affect both profitability and safety, such as management or engineering practices, and partially due to lower investments in safety by less profitable mines, which could imply that some financially stressed mines might be so focused on survival that they forgo investing in safety.


Molecular adaptations of Herbaspirillum seropedicae during colonization of the maize rhizosphere.
Molecular mechanisms of plant recognition and colonization by diazotrophic bacteria are barely understood. Herbaspirillum seropedicae is a Betaproteobacterium capable of colonizing epiphytically and endophytically commercial grasses, to promote plant growth. In this study, we utilized RNA-seq to compare the transcriptional profiles of planktonic and maize root-attached H. seropedicae SmR1 recovered 1 and 3 days after inoculation. The results indicated that nitrogen metabolism was strongly activated in the rhizosphere and polyhydroxybutyrate storage was mobilized in order to assist the survival of H. seropedicae during the early stages of colonization. Epiphytic cells showed altered transcription levels of several genes associated with polysaccharide biosynthesis, peptidoglycan turnover and outer membrane protein biosynthesis, suggesting reorganization of cell wall envelope components. Specific methyl-accepting chemotaxis proteins and two-component systems were differentially expressed between populations over time, suggesting deployment of an extensive bacterial sensory system for adaptation to the plant environment. An insertion mutation inactivating a methyl-accepting chemosensor induced in planktonic bacteria, decreased chemotaxis towards the plant and attachment to roots. In summary, analysis of mutant strains combined with transcript profiling revealed several molecular adaptations that enable H. seropedicae to sense the plant environment, attach to the root surface and survive during the early stages of maize colonization.


Expression of emotion in Eastern and Western music mirrors vocalization.
In Western music, the major mode is typically used to convey excited, happy, bright or martial emotions, whereas the minor mode typically conveys subdued, sad or dark emotions. Recent studies indicate that the differences between these modes parallel differences between the prosodic and spectral characteristics of voiced speech sounds uttered in corresponding emotional states. Here we ask whether tonality and emotion are similarly linked in an Eastern musical tradition. The results show that the tonal relationships used to express positive/excited and negative/subdued emotions in classical South Indian music are much the same as those used in Western music. Moreover, tonal variations in the prosody of English and Tamil speech uttered in different emotional states are parallel to the tonal trends in music. These results are consistent with the hypothesis that the association between musical tonality and emotion is based on universal vocal characteristics of different affective states.


Variation at the major histocompatibility complex in Savannah sparrows.
The class I and class II genes of the major histocompatibility complex (Mhc) encode dimeric glycoproteins responsible for eliciting the adaptive immune response of vertebrates. Recent work with birds suggests that the number, size, and arrangement of these genes can differ markedly across species, although the extent of this variation, and its causes and consequences, are poorly understood. We have used a 157-base-pair (bp) portion of the second exon of a class II B gene to probe the Mhc in a free-living population of Savannah sparrows (Passerculus sandwichensis). Segregation analysis of Mhc bands suggests that class II B genes can be found in two independently assorting clusters, as previously described for domestic chickens (Gallus gallus) and ring-necked pheasants (Phasianus colchicus) but unlike gene organization in mammals. The Mhc in Savannah sparrows appears large (with many class II B genes) and variable; we found 42 unique genotypes among 48 adults breeding on Kent Island, New Brunswick, Canada in 1995. Savannah sparrows are long-distance migrants, and these results support recent predictions that migratory birds should show higher levels of Mhc polymorphism and/or a greater number of genes than sedentary species. Savannah sparrows are also socially polygynous with high levels of extra-pair paternity, suggesting that a history of sexual selection might also influence the size and/or structure of the avian Mhc.


DuraSeal Exact Is a Safe Adjunctive Treatment for Durotomy in Spine: Postapproval Study.
A nonrandomized, two-armed prospective study. Water-tight dural closure is paramount to the prevention of cerebrospinal fluid (CSF) leakage and associated complications. Synthetic polyethylene glycol (PEG) hydrogel has been used as an adjunct to sutured dural repair; however, its expansion postoperatively is a concern for neurological complications. A low-swell formulation of PEG sealant was introduced as DuraSeal Exact Spine Sealant System (DESS). A Post-Approval Study was performed primarily to evaluate the safety and efficacy of DESS for spinal dural repair compared to current alternatives, in a large patient population, reflecting a real-world practice. A total of 36 sites in the United States enrolled 429 patients treated with DESS as an adjunct to dural repair in the spinal sealant group and 406 patients treated with all other modalities in the control arm, from October 2011 to June 2016. The primary endpoint was the incidence of CSF leak within 90 days of operation. The secondary endpoints evaluated were deep surgical site infection and neurological serious adverse events. The CSF leakage in the DESS group (6.6%) was not significantly different from the control group (6.5%) (p = .83), and there was no significant difference in the time to first leak. The two groups had no significant differences in deep surgical site infection (1.6% versus control 2.1%, p = .61) or proportion of subjects with neurological serious adverse events (2.9% versus control 1.6%, p = .516). DuraSeal Exact Spinal Sealant is safe when compared to current alternatives for spinal dural repair.


Secondary haemophagocytic lymphohistiocytosis: Experience from the Uppsala University Hospital.
Haemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterized by fever, hepatosplenomegaly, cytopenia, and progressive multiple-organ failure. HLH in adults is often secondary to autoimmune diseases, cancer, or infections in contrast to familial HLH. Treatment of secondary HLH is directed against the triggering disease in addition to immunosuppressive therapy, the latter commonly according to the HLH-2004 protocol. We conducted a retrospective study to identify triggering diseases, disease-specific and immunosuppressive therapy administered, and prognosis in adult patients with secondary HLH. Patient data were collected from October 2010 to January 2015. Ten adult patients with secondary HLH were identified. Seven were men, and the median age at diagnosis was 62 years. Five cases were triggered by malignant disease and five by infection. The median patient fulfilled five of the eight HLH-2004 diagnostic criteria. All patients fulfilled the criteria fever, cytopenia, and ferritin >500 µg/L. Median time from hospital admission to HLH diagnosis was 20 days. Four patients received immunosuppressive therapy according to the HLH-2004 protocol. The prognosis was dismal, especially for the patients with malignancy-associated HLH, of whom all died. HLH should be suspected in patients who present with fever, cytopenia, and ferritin >500 µg/L. Secondary HLH has a dismal prognosis. None of the patients with HLH triggered by malignancy survived. Achieving remission of the triggering disease seems to be important for a favourable outcome as, in all surviving patients, the haemophagocytic syndrome resolved after remission of the underlying infection.


Transcorneal electrical stimulation shows neuroprotective effects in retinas of light-exposed rats.
To examine the effects of transcorneal electrical stimulation (TES) on retinal degeneration of light-exposed rats. Thirty-three Sprague Dawley albino rats were divided into three groups: STIM (n = 15) received 60 minutes of TES, whereas SHAM (n = 15) received identical sham stimulation 2 hours before exposure to bright light with 16,000 lux; healthy animals (n = 3) served as controls for histology. At baseline and weekly for 3 consecutive weeks, dark- and light-adapted electroretinography was used to assess retinal function. Analysis of the response versus luminance function retrieved the parameters Vmax (saturation amplitude) and k (luminance to reach ½Vmax). Retinal morphology was assessed by histology (hematoxylin-eosin [HE] staining; TUNEL assay) and immunohistochemistry (rhodopsin staining). Vmax was higher in the STIM group compared with SHAM 1 week after light damage (mean intra-individual difference between groups 116.06 μV; P = 0.046). The b-wave implicit time for the rod response (0.01 cd.s/m²) was lower in the STIM group compared with the SHAM group 2 weeks after light damage (mean intra-individual difference between groups 5.78 ms; P = 0.023); no other significant differences were found. Histological analyses showed photoreceptor cell death (TUNEL and HE) in SHAM, most pronounced in the superior hemiretina. STIM showed complete outer nuclear layer thickness preservation, reduced photoreceptor cell death, and preserved outer segment length compared with SHAM (HE and rhodopsin). This sham-controlled study shows that TES can protect retinal cells against mild light-induced degeneration in Sprague Dawley rats. These findings could help to establish TES as a treatment in human forms of retinal degenerative disease.


Physical exercise during encoding improves vocabulary learning in young female adults: a neuroendocrinological study.
Acute physical activity has been repeatedly shown to improve various cognitive functions. However, there have been no investigations comparing the effects of exercise during verbal encoding versus exercise prior to encoding on long-term memory performance. In this current psychoneuroendocrinological study we aim to test whether light to moderate ergometric bicycling during vocabulary encoding enhances subsequent recall compared to encoding during physical rest and encoding after being physically active. Furthermore, we examined the kinetics of brain-derived neurotrophic factor (BDNF) in serum which has been previously shown to correlate with learning performance. We also controlled for the BDNF val66met polymorphism. We found better vocabulary test performance for subjects that were physically active during the encoding phase compared to sedentary subjects. Post-hoc tests revealed that this effect was particularly present in initially low performers. BDNF in serum and BDNF genotype failed to account for the current result. Our data indicates that light to moderate simultaneous physical activity during encoding, but not prior to encoding, is beneficial for subsequent recall of new items.


Evidence that transition from health to psychotic disorder can be traced to semi-ubiquitous environmental effects operating against background genetic risk.
In order to assess the importance of environmental and genetic risk on transition from health to psychotic disorder, a prospective study of individuals at average (n = 462) and high genetic risk (n = 810) was conducted. A three-year cohort study examined the rate of transition to psychotic disorder. Binary measures indexing environmental exposure (combining urban birth, cannabis use, ethnicity and childhood trauma) and proxy genetic risk (high-risk sibling status) were used to model transition. The majority of high-risk siblings (68%) and healthy comparison subjects (60%) had been exposed to one or more environmental risks. The risk of transition in siblings (n = 9, 1.1%) was higher than the risk in healthy comparison subjects (n = 2, 0.4%; OR(adj) = 2.2,95%CI:5-10.3). All transitions (100%) were associated with environmental exposure, compared to 65% of non-transitions (p = 0.014), with the greatest effects for childhood trauma (OR(adj) = 34.4,95%CI:4.4-267.4), cannabis use (OR = 4.1,95%CI:1.1, 15.4), minority ethnic group (OR = 3.8,95%CI:1.2,12.8) and urban birth (OR = 3.7,95%CI:0.9,15.4). The proportion of transitions in the population attributable to environmental and genetic risk ranged from 28% for minority ethnic group, 45% for urban birth, 57% for cannabis use, 86% for childhood trauma, and 50% for high-risk sibling status. Nine out of 11 transitions (82%) were exposed to both genetic and environmental risk, compared to only 43% of non-transitions (p = 0.03). Environmental risk associated with transition to psychotic disorder is semi-ubiquitous regardless of genetic high risk status. Careful prospective documentation suggests most transitions can be attributed to powerful environmental effects that become detectable when analysed against elevated background genetic risk, indicating gene-environment interaction.


Premarital sexual behaviour among higher secondary students in Pokhara Sub-Metropolitan City Nepal.
Background Sexual behaviour of young people is one of the major public health issues. This is because adolescent people may involve themselves in risky sexual behaviour such as practising sex at an early age, having multiple sexual partners, having sex while under the influence of alcohol or drugs, and unprotected sexual behaviours. The objective of this study was to explore the premarital sexual behaviours among higher secondary school students in Pokhara Sub-Metropolitan City. This survey adopted a design of an institution-based descriptive cross-sectional study. A pre-tested structured questionnaire sealed in an envelope was distributed among all consenting 522 higher secondary school adolescent students. Nearly twenty-five per cent (24.6%) of study respondents have had premarital sex. Respondents who had discussed sexual matters with friends had a 2.62-fold higher chance of having premarital sex than those who had not. Male respondents were eight-fold more likely to have premarital sex than females. Respondents who were exposed to pornography reported a nine-fold higher possibility of having premarital sex. Study respondents were also involved in unsafe sexual practices; for example, 13.4% of male respondents had sex with female sex workers. Despite the deleterious social and cultural norms and values regarding premarital sexual activities school adolescents are increasingly involved in sexual activities before marriage. Peer groups or friends are major sources of sexual and reproductive health information, which is often insufficient and inaccurate. It is important to design an appropriate and effective intervention to ensure that adolescents get correct and suitable sexual and reproductive information.


What is a run-in phase?
Run-in periods are frequently used when designing a clinical trial. In this paper we analysed the implications of run-in periods for interpreting the results of clinical trials and applying these results in clinical practice. Study reports should indicate in details how run-in periods were carried out.


Delta-9-tetrahydrocannabinol/cannabidiol (Sativex®): a review of its use in patients with moderate to severe spasticity due to multiple sclerosis.
Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) [Sativex®] is an oromucosal spray formulation that contains principally THC and CBD at an approximately 1:1 fixed ratio, derived from cloned Cannabis sativa L. plants. The main active substance, THC, acts as a partial agonist at human cannabinoid receptors (CB1 and CB2), and thus, may modulate the effects of excitatory (glutamate) and inhibitory (gamma-aminobutyric acid) neurotransmitters. THC/CBD is approved in a number of countries, including Germany and the UK, as an add-on treatment for symptom improvement in adult patients with moderate to severe spasticity due to multiple sclerosis who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy. In the largest multinational clinical trial that evaluated the approved THC/CBD regimen in this population, 12 weeks' double-blind treatment with THC/CBD significantly reduced spasticity severity (primary endpoint) compared with placebo in patients who achieved a clinically significant improvement in spasticity after 4 weeks' single-blind THC/CBD treatment, as assessed by a patient-rated numerical rating scale. A significantly greater proportion of THC/CBD than placebo recipients achieved a ≥ 30% reduction (a clinically relevant reduction) in spasticity severity. The efficacy of THC/CBD has been also shown in at least one everyday clinical practice study (MOVE 2). THC/CBD was generally well tolerated in clinical trials. Dizziness and fatigue were reported most frequently during the first 4 weeks of treatment and resolved within a few days even with continued treatment. Thus, add-on THC/CBD is a useful symptomatic treatment option for its approved indication.


SMD-Based Interaction-Energy Fingerprints Can Predict Accurately the Dissociation Rate Constants of HIV-1 Protease Inhibitors.
Recent research has increasingly suggested that the crucial factors affecting drug potencies are related not only to the thermodynamic properties but also to the kinetic properties. Therefore, in silico prediction of ligand-binding kinetic properties, especially the dissociation rate constant ( koff), has aroused more and more attention. However, there are still a lot of challenges that need to be addressed. In this paper, steered molecular dynamics (SMD) combined with residue-based energy decomposition was employed to predict the dissociation rate constants of 37 HIV-1 protease inhibitors (HIV-1 PIs). For the first time, a predictive model of the dissociation rate constant was established by using the interaction-energy fingerprints sampled along the ligand dissociation pathway. On the basis of the key fingerprints extracted it can be inferred that the dissociation rates of 37 HIV-1 PIs are basically determined in the first half of the dissociation processes and that the H-bond interactions with active-site Asp25 and van der Waals interactions with flap-region Ile47 and Ile50 have important influences on the dissociation processes. In general, the strategy established in this paper can provide an efficient way for the prediction of dissociation rate constants as well as the unbinding mechanism research.


Multifocal optical systems and pupil dynamics in birds.
In animal eyes of the camera type longitudinal chromatic aberration causes defocus that is particularly severe in species with short depth of focus. In a variety of vertebrates, multifocal optical systems compensate for longitudinal chromatic aberration by concentric zones of different refractive powers. Since a constricting circular pupil blocks peripheral zones, eyes with multifocal optical systems often have slit pupils that allow light to pass through all zones, irrespective of the state of pupil constriction. Birds have circular pupils and were therefore assumed to have monofocal optical systems. We examined the eyes of 45 species (12 orders) of bird using videorefractometry, and the results are surprising: 29 species (10 orders) have multifocal systems, and only five species (five orders) have monofocal systems. The results from 11 species (four orders) are inconclusive. We propose that pupils 'switching' between being fully opened (multifocal principle) to maximally closed (pinhole principle) can make multifocal optical systems useful for animals with circular pupils. Previous results indicate that mice have both multifocal optical systems and switching pupils. Our results suggest that parrots may use a similar mechanism. By contrast, owl pupils responded weakly to changes in illumination and stayed remarkably wide even in full daylight. Moreover, the parrots opened their pupils at higher light levels than owls, which correlates with the differences in sensitivity between diurnal and nocturnal eyes.


Chimeric study of sodium channels from rat skeletal and cardiac muscle.
Two isoforms of voltage-dependent Na channels, cloned from rat skeletal muscle, were expressed in Xenopus oocytes. The currents of rSkM1 and rSkM2 differ functionally in 4 properties: (i) tetrodotoxin (TTX) sensitivity, (ii) mu-conotoxin (mu-CTX) sensitivity, (iii) amplitude of single channel currents, and (iv) rate of inactivation. rSkM1 is sensitive to both TTX and mu-CTX. rSkM2 is resistant to both toxins. Currents of rSkM1 have a higher single channel conductance and a slower rate of inactivation than those of rSkM2. We constructed (i) chimeras by interchanging domain 1 (D1) between the two isoforms, (ii) block mutations of 22 amino acids in length that interchanged parts of the loop between transmembrane segments S5 and S6 in both D1 and D4, and (iii) point mutations in the SS2 region of this loop in D1. The TTX sensitivity could be switched between the two isoforms by the exchange of a single amino acid, tyrosine-401 in rSkM1 and cysteine-374 in rSkM2 in SS2 of D1. By contrast most chimeras and point mutants had an intermediate sensitivity to mu-CTX when compared with the wild-type channels. The point mutant rSkM1 (Y401C) had an intermediate single-channel conductance between those of the wild-type isoforms, whereas rSkM2 (C374Y) had a slightly lower conductance than rSkM2. The rate of inactivation was found to be determined by multiple regions of the protein, since chimeras in which D1 was swapped had intermediate rates of inactivation compared with the wild-type isoforms.


aDolescents gEnder surVey, rEsponsible coupLes evaluatiOn, and capacity building Project in India (DEVELOP): a study protocol.
Domestic violence and assault (DVA) against women is a serious concern in India. This affects the health and wellbeing of victims and their dependents. Published evidence has documented a variety of reasons for such violence in Indian societies, paving a pathway to design, implement, and evaluate intervention models to address this issue. DEVELOP is a research study designed by UK and Indian research teams to plan future projects to address gender-based discrimination and DVA against women and girls in India. This study protocol provides detailed information on the objectives, research methods, data collection, storage, analysis, and dissemination plans of the DEVELOP phase 1 work (2018-19). The first component is a survey of adolescent boys and girls from rural areas of the Maharashtra state of India to understand their gender equality related knowledge and beliefs. The insight gathered will be used to design interventions targeted at adolescent populations through future research and development programmes. Secondly, an evaluation of the 'Responsible Couples' project will be conducted to assess its success and challenges, and to inform future programme activities and strategy. The 'Responsible Couples' project is implemented in 40 villages of Maharashtra state to improve relationships in married couples, prevent violence against women, intervene during violence, and to provide support services for women and their family members. Research findings will be disseminated though public engagement events in India, international conferences, and peer reviewed publications. Secondly, our two key partners (SWISSAID and HMF) will benefit from such evidence to inform their on-going as well as forthcoming projects on gender equality in India. Research findings will be also useful for local government authorities and non-government agencies striving to advance gender equality.


Analysis of RNA decay factor mediated RNA stability contributions on RNA abundance.
Histone epigenome data determined by chromatin immunoprecipitation sequencing (ChIP-seq) is used in identifying transcript regions and estimating expression levels. However, this estimation does not always correlate with eventual RNA expression levels measured by RNA sequencing (RNA-seq). Part of the inconsistency may arise from the variance in RNA stability, where the transcripts that are more or less abundant than predicted RNA expression from histone epigenome data are inferred to be more or less stable. However, there is little systematic analysis to validate this assumption. Here, we used stability data of whole transcriptome measured by 5'-bromouridine immunoprecipitation chase sequencing (BRIC-seq), which enabled us to determine the half-lives of whole transcripts including lincRNAs, and we integrated BRIC-seq with ChIP-seq to achieve better estimation of the eventual transcript levels and to understand the importance of post-transcriptional regulation that determine the eventual transcript levels. We identified discrepancies between the RNA abundance estimated by ChIP-seq and measured RNA expression from RNA-seq; for number of genes and estimated that the expression level of 865 genes was controlled at the level of RNA stability in HeLa cells. ENCODE data analysis supported the idea that RNA stability control aids to determine transcript levels in multiple cell types. We identified UPF1, EXOSC5 and STAU1, well-studied RNA degradation factors, as controlling factors for 8% of cases. Computational simulations reasonably explained the changes of eventual mRNA levels attributable to the changes in the rates of mRNA half-lives. In addition, we propose a feedback circuit that includes the regulated degradation of mRNAs encoding transcription factors to maintain the steady state level of RNA abundance. Intriguingly, these regulatory mechanisms were distinct between mRNAs and lincRNAs. Integrative analysis of ChIP-seq, RNA-seq and our BRIC-seq showed that transcriptional regulation and RNA degradation are independently regulated. In addition, RNA stability is an important determinant of eventual transcript levels. RNA binding proteins, such as UPF1, STAU1 and EXOSC5 may play active roles in such controls.


Construction of a cDNA library and preliminary analysis of the expressed sequence tags of the earthworm Eisenia fetida (Savigny, 1826).
Earthworms are useful indicator organisms of soil health and Eisenia fetida have been extensively used as test organisms in ecotoxicological studies. In order to gain insight into the gene expression profiles associated with physiological functions of earthworms, a full‑length enriched cDNA library of the Eisenia fetida genome was successfully constructed using Switching Mechanism at 5'End of RNA Template technology. Construction of a cDNA library and analysis of Expressed Sequence Tags (ESTs) are efficient approaches for collecting genomic information and identifying genes important for a given biological process. Furthermore, analysis of the expression abundance of ESTs was performed with the aim of providing genetic and transcriptomic information on the development and regenerative process of earthworms. Phrep and Crossmatch were used to process EST data and a total of 1,140 high‑quality EST sequences were determined by sequencing random cDNA clones from the library. Clustering analysis of sequences revealed a total of 593 unique sequences including 225 contiguous and 368 singleton sequences. Basic Local Alignment Search Tool analysis against the Kyoto Encyclopedia of Genes and Genomes database resulted in 593 significant hits (P‑value <1x10‑8), of which 168 were annotated through Gene Ontology analysis. The STRING database was used to determine relationships among the 168 ESTs, identifying associated genes involved in protein‑protein interactions and gene expression regulation. Based on nucleic acid and protein sequence homology, the mutual relationships between 287 genes could be obtained, which identified a portion of the ESTs as known genes. The present study reports on the construction of a high‑quality cDNA library representative of adult earthworms, on a preliminary analysis of ESTs and on a putative functional analysis of ESTs. The present study is expected to enhance our understanding of the molecular basis underlying the biological development of earthworms.


Hemodynamic and hematologic profile of healthy adults ingesting dietary supplements containing 1,3-dimethylamylamine and caffeine.
1,3-dimethylamylamine (a constituent of geranium), alone and in combination with caffeine, is widely used within dietary supplements. We have recently determined the hemodynamic effects of 1,3-dimethylamylamine and caffeine alone and in combination, using a single ingestion study. However, no study has determined the hemodynamic effects of these ingredients following chronic use. Moreover, no study has determined the effects of these ingredients on bloodborne variables related to health and safety. Therefore, the purpose of this investigation was to assess the hemodynamic and hematologic profile of two different dietary supplements containing 1,3-dimethylamylamine and caffeine (in addition to other ingredients), before and after two weeks of daily intake. 7 men (24.9 ± 4.2 yrs) ingested the dietary supplement Jack3d™, while 4 men and 2 women (22.5 ± 1.8 yrs) ingested the dietary supplement OxyELITE Pro™ once per day for two weeks. On days 1 and 15, resting heart rate (HR), systolic (SBP), and diastolic (DBP) blood pressure were measured and rate pressure product (RPP) was calculated. Fasting blood samples were analyzed for complete blood counts, comprehensive metabolic panel, and lipid panel. These tests were done prior to ingestion of supplement. On days 1 and 15 following blood collection, subjects ingested the assigned supplement (2 servings) and HR, SBP, DBP, and RPP were recorded at 30, 60, 90, and 120 minutes post-ingestion. After 14 days of treatment, resting HR, SBP, DBP, and RPP were not increased (P > 0.05). No significant changes were noted in any measured bloodborne variable, with the exception of an increase in fasting blood glucose with ingestion of Jack3d™ (P = 0.02). In response to acute intake of the supplements, HR, DBP, and RPP were not increased statistically (P > 0.05). SBP was increased with OxyELITE Pro™ (P = 0.03), but not with Jack3d™ (P = 0.09). Compared to pre-ingestion and in general, both supplements resulted in an increase in SBP, DBP, and RPP from 5%-15%, with a peak occurring at the 60 or 90 minute post-ingestion time. Acute ingestion of OxyELITE Pro™, but not Jack3d™, results in an increase in SBP. Chronic intake of two servings per day of OxyELITE Pro™ or Jack3d™ over a 14 day period does not result in an elevation in resting HR, SBP, DBP, or RPP. No significant changes are noted in any measured bloodborne variable following 14 days of ingestion, with the exception of blood glucose with Jack3d™. Longer term intervention studies inclusive of larger sample sizes are needed to extend these findings.


Studies of cell subpopulations mediating mitogen hyporesponsiveness in patients with Hodgkin's disease.
Hodgkin's disease (HD) is associated with a deficit in T-cell immunity characterized by skin test anergy and decreased lymphocyte responses to phytohemagglutinin (PHA). To investigate this mitogen hyporesponsiveness in HD, we separated peripheral blood mononuclear cells on Ficoll-Hypaque gradients and determined their response to various suboptimal concentrations of PHA. As was expected, patients with HD demonstrated marked mitogen hyporesponsiveness relative to normal controls; however, if the cell suspensions were first passed through glass wool columns to remove adherent cells, the PHA responsiveness of the hyporesponsive HD cells was markedly increased. In contrast, the responsiveness of normal controls was decreased so that the responses of nonadherent normal and HD cells were statistically indistinguishable. Evidently, a glass wool-adherent suppressor cell had been removed from patients with HD, while a glass wool-adherent cell which enhanced mitogenic responses had been removed from normal controls during column passage. Previous to column depletion, patients with HD had decreased proportions of E-rosettes and increased proportions of cells with surface alpha-fetoprotein; however, the proportion of these cells was not changed after column passage. Significant changes with column depletion of glass wool-adherent cells in HD were recorded in the proportions of monocytes (13.2 vs 5.8%) and lymphocytes with C-3 receptors (12.6 vs. 7.8%). The only significant change in normal controls was a decrease in the proportion of monocytes (10 vs. 1.7%). To determine if glass-adherent cells would have a suppressor effect, HD-adherent cells were added in progressively increasing numbers to mononuclear cell suspensions depleted of glass wool-adherent cells. PHA responsiveness returned toward predepletion levels. In summary, patients with HD possess a glass wool-adherent suppressor cell which is responsible at least in part for in vitro mitogen hyporesponsiveness.


Interference method for pattern comparison.
A test pattern may be compared with a reference pattern by placing the two side by side in a coherent beam. If the compared patterns are sufficiently similar, regular parallel fringes will modulate the common Fraunhofer diffraction pattern of the compared samples. The regularity of the interference fringes is a measure of the similarity between the compared patterns. The sensitivity of the method is not disturbed by small absolute and relative displacements of test and reference signals. The effect of even small rotations is, however, severe. The effect of random noise is to reduce the contrast of the interference fringes.


The preclinical Alzheimer cognitive composite: measuring amyloid-related decline.
As Alzheimer disease (AD) research moves to intervene in presymptomatic phases of the disease, we must develop outcome measures sensitive to the earliest disease-related changes. To demonstrate the feasibility of a cognitive composite outcome for clinically normal elderly participants with evidence of AD pathology using the ADCS Preclinical Alzheimer Cognitive Composite (ADCS-PACC). The ADCS-PACC combines tests that assess episodic memory, timed executive function, and global cognition. The ADCS-PACC is the primary outcome measure for the first clinical trial in preclinical AD (ie, the Anti-Amyloid Treatment in Asymptomatic Alzheimer's study). With the ADCS-PACC, we derive pilot estimates of amyloid-related decline using data from 2 observational studies conducted in North America and another conducted in Australia. The participants analyzed had normal cognition and mean ages of 75.81, 71.37, and 79.42 years across the 3 studies. For the 2 studies that collected data on Aβ levels (ADNI and AIBL), we estimate decline in a preclinical AD "Aβ-positive" placebo group and compare them with an "Aβ-negative" group. For the study that did not include data on Aβ levels (the ADCS Prevention Instrument [ADCS-PI] study), we grouped participants by the presence of APOE-ε4 and by clinical progression. In ADNI, Aβ-positive participants showed more decline than did Aβ-negative participants with regard to the ADCS-PACC score at 24 months (mean [SE] difference, -1.239 [0.522] [95% CI, -2.263 to -0.215]; P = .02). In AIBL, the mean (SE) difference is significant at both 18 months (-1.009 [0.406] [95% CI, -1.805 to -0.213]; P = .01) and 36 months (-1.404 [0.452] [95% CI, -2.290 to -0.519]; P = .002). In the ADCS-PI study, APOE-ε4 allele carriers performed significantly worse on the ADCS-PACC at 24 months (mean [SE] score, -0.742 [0.294] [95% CI, -1.318 to -0.165]; P = .01) and 36 months (-1.531 [0.469] [95% CI, -2.450 to -0.612]; P = .001). In the ADCS-PI study, cognitively normal participants who progress from a global Clinical Dementia Rating score of 0 are significantly worse on the ADCS-PACC than cognitively normal participants who are stable with a global Clinical Dementia Rating score of 0 at months 12, 24, and 36 (mean [SE] ADCS-PACC score, -4.471 [0.702] [95% CI, -5.848 to -3.094]; P < .001). Using pilot estimates of variance and assuming 500 participants per group with 30% attrition and a 5% α level, we project 80% power to detect effects in the range of Δ = 0.467 to 0.733 on the ADCS-PACC. Analyses of at-risk cognitively normal populations suggest that we can reliably measure the first signs of cognitive decline with the ADCS-PACC. These analyses also suggest the feasibility of secondary prevention trials.


Real-time analysis and selection of methylated DNA by fluorescence-activated single molecule sorting in a nanofluidic channel.
Epigenetic modifications, such as DNA and histone methylation, are responsible for regulatory pathways that affect disease. Current epigenetic analyses use bisulfite conversion to identify DNA methylation and chromatin immunoprecipitation to collect molecules bearing a specific histone modification. In this work, we present a proof-of-principle demonstration for a new method using a nanofluidic device that combines real-time detection and automated sorting of individual molecules based on their epigenetic state. This device evaluates the fluorescence from labeled epigenetic modifications to actuate sorting. This technology has demonstrated up to 98% accuracy in molecule sorting and has achieved postsorting sample recovery on femtogram quantities of genetic material. We have applied it to sort methylated DNA molecules using simultaneous, multicolor fluorescence to identify methyl binding domain protein-1 (MBD1) bound to full-duplex DNA. The functionality enabled by this nanofluidic platform now provides a workflow for color-multiplexed detection, sorting, and recovery of single molecules toward subsequent DNA sequencing.


A comparison of the theory of unpleasant symptoms and the conceptual model of chemotherapy-related changes in cognitive function.
To explore the use of the Theory of Unpleasant Symptoms (TUS) as a model for describing the symptom experience related to the cognitive impairment associated with standard-dose chemotherapy and compare and contrast that use of the TUS with the Conceptual Model of Chemotherapy-Related Changes in Cognitive Function. PubMed database. Retrospective and prospective clinical trials have substantiated the incidence of mild to moderate cognitive impairment. Patients have reported a significant effect on quality of life. Associated factors may include age, anemia, fatigue, depression, anxiety, hormone levels, cytokine release, and genetic makeup. Establishing the appropriateness of a working model to describe the relationships would provide additional structure and focus for empirical research. Both models have utility for describing the relationships of factors associated with chemotherapy-related cognitive impairment. Blending of the TUS and the Conceptual Model of Chemotherapy-Related Changes in Cognitive Function may provide an enhanced framework for further research about the physiologic and psychological aspects of chemotherapy-related cognitive impairment.


Iliac crest histomorphometry and skeletal heterogeneity in men.
The cortical characteristics of the iliac crest in male have rarely been investigated with quantitative histomorphometry. Also it is still unknown how cortical microarchitecture may vary between the iliac crest and fractures related sites at the proximal femur. We studied the microarchitecture of both external and internal cortices within the iliac crest, and compared the results with femoral neck and subtrochanteric femoral shaft sites. Undecalcified histological sections of the iliac crest were obtained bicortically from cadavers (n = 20, aged 18-82 years, males). They were cut (7 μm) and stained using modified Masson-Goldner stain. Histomorphometric parameters of cortical bone were analysed with low (× 50) and high (× 100) magnification, after identifying cortical bone boundaries using our previously validated method. Within cortical bone area, only complete osteons with typical concentric lamellae and cement line were selected and measured. At the iliac crest, the mean cortical width of external cortex was higher than at the internal cortex (p < 0.001). Also, osteon structural parameters, e.g. mean osteonal perimeter, were higher in the external cortex (p < 0.05). In both external and internal cortices, pore number per cortical bone area was higher in young subjects (≤ 50 years) (p < 0.05) while mean pore perimeter was higher in the old subjects (> 50 years) (p < 0.05). Several cortical parameters (e.g. osteon area per cortical bone area, pore number per cortical area) were the lowest in the femoral neck (p < 0.05). The maximal osteonal diameter and mean wall width were the highest in the external cortex of the iliac crest (p < 0.05), and the mean cortical width, osteon number per cortical area were the highest in the subtrochanteric femoral shaft (p < 0.05). Some osteonal structural parameters (e.g. min osteonal diameter) were significantly positively correlated (0.29 ≤ R2 ≤ 0.45, p < 0.05) between the external iliac crest and the femoral neck. This study reveals heterogeneity in cortical microarchitecture between the external and internal iliac crest cortices, as well as between the iliac crest, the femoral neck and the subtrochanteric femoral shaft. Standard iliac crest biopsy does not reflect accurately cortical microarchitecture of other skeletal sites.


CD8+ Tc2 cells: underappreciated contributors to severe asthma.
The complexity of asthma is underscored by the number of cell types and mediators implicated in the pathogenesis of this heterogeneous syndrome. Type 2 CD4+ T-cells (Th2) and more recently, type 2 innate lymphoid cells dominate current descriptions of asthma pathogenesis. However, another important source of these type 2 cytokines, especially interleukin (IL)-5 and IL-13, are CD8+ T-cells, which are increasingly proposed to play an important role in asthma pathogenesis, because they are abundant and are comparatively insensitive to corticosteroids. Many common triggers of asthma exacerbations are mediated via corticosteroid-resistant pathways involving neutrophils and CD8+ T-cells. Extensive murine data reveal the plasticity of CD8+ T-cells and their capacity to enhance airway inflammation and airway dysfunction. In humans, Tc2 cells are predominant in fatal asthma, while in stable state, severe eosinophilic asthma is associated with greater numbers of Tc2 than Th2 cells in blood, bronchoalveolar lavage fluid and bronchial biopsies. Tc2 cells strongly express CRTH2, the receptor for prostaglandin D2, the cysteinyl leukotriene receptor 1 and the leukotriene B4 receptor. When activated, these elicit Tc2 cell chemotaxis and production of chemokines and type 2 and other cytokines, resulting directly or indirectly in eosinophil recruitment and survival. These factors position CD8+ Tc2 cells as important and underappreciated effector cells contributing to asthma pathogenesis. Here, we review recent advances and new insights in understanding the pro-asthmatic functions of CD8+ T-cells in eosinophilic asthma, especially corticosteroid-resistant asthma, and the molecular mechanisms underlying their pathologic effector function.


Visually driven regulation of intrinsic neuronal excitability improves stimulus detection in vivo.
Neurons adapt their electrophysiological properties to maintain stable levels of electrical excitability when faced with a constantly changing environment. We find that exposing freely swimming Xenopus tadpoles to 4-5 hr of persistent visual stimulation increases the intrinsic excitability of optic tectal neurons. This increase is correlated with enhanced voltage-gated Na+ currents. The same visual stimulation protocol also induces a polyamine synthesis-dependent reduction in Ca2+-permeable AMPAR-mediated synaptic drive, suggesting that the increased excitability may compensate for this reduction. Accordingly, the change in excitability was prevented by blocking polyamine synthesis during visual stimulation and was rescued when Ca2+-permeable AMPAR-mediated transmission was selectively reduced. The changes in excitability also rendered tectal cells more responsive to synaptic burst stimuli, improving visual stimulus detection. The synaptic and intrinsic adaptations function together to keep tectal neurons within a constant operating range, while making the intact visual system less responsive to background activity yet more sensitive to burst stimuli.


Axonal guidance signaling pathway interacting with smoking in modifying the risk of pancreatic cancer: a gene- and pathway-based interaction analysis of GWAS data.
Cigarette smoking is the best established modifiable risk factor for pancreatic cancer. Genetic factors that underlie smoking-related pancreatic cancer have previously not been examined at the genome-wide level. Taking advantage of the existing Genome-wide association study (GWAS) genotype and risk factor data from the Pancreatic Cancer Case Control Consortium, we conducted a discovery study in 2028 cases and 2109 controls to examine gene-smoking interactions at pathway/gene/single nucleotide polymorphism (SNP) level. Using the likelihood ratio test nested in logistic regression models and ingenuity pathway analysis (IPA), we examined 172 KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, 3 manually curated gene sets, 3 nicotine dependency gene ontology pathways, 17 912 genes and 468 114 SNPs. None of the individual pathway/gene/SNP showed significant interaction with smoking after adjusting for multiple comparisons. Six KEGG pathways showed nominal interactions (P < 0.05) with smoking, and the top two are the pancreatic secretion and salivary secretion pathways (major contributing genes: RAB8A, PLCB and CTRB1). Nine genes, i.e. ZBED2, EXO1, PSG2, SLC36A1, CLSTN1, MTHFSD, FAT2, IL10RB and ATXN2 had P interaction < 0.0005. Five intergenic region SNPs and two SNPs of the EVC and KCNIP4 genes had P interaction < 0.00003. In IPA analysis of genes with nominal interactions with smoking, axonal guidance signaling $$\left(P=2.12\times 1{0}^{-7}\right)$$ and α-adrenergic signaling $$\left(P=2.52\times 1{0}^{-5}\right)$$ genes were significantly overrepresented canonical pathways. Genes contributing to the axon guidance signaling pathway included the SLIT/ROBO signaling genes that were frequently altered in pancreatic cancer. These observations need to be confirmed in additional data set. Once confirmed, it will open a new avenue to unveiling the etiology of smoking-associated pancreatic cancer.


Surgical Satisfaction, Quality of Life, and Their Association After Gender-Affirming Surgery: A Follow-up Study.
We assessed the outcomes of gender-affirming surgery (GAS, or sex-reassignment surgery) 4 to 6 years after first clinical contact, and the associations between postoperative (dis)satisfaction and quality of life (QoL). Our multicenter, cross-sectional follow-up study involved persons diagnosed with gender dysphoria (DSM-IV-TR) who applied for medical interventions from 2007 until 2009. Of 546 eligible persons, 201 (37%) responded, of whom 136 had undergone GAS (genital, chest, facial, vocal cord and/or thyroid cartilage surgery). Main outcome measures were procedure performed, self-reported complications, and satisfaction with surgical outcomes (standardized questionnaires), QoL (Satisfaction With Life Scale, Subjective Happiness Scale, Cantril Ladder), gender dysphoria (Utrecht Gender Dysphoria Scale), and psychological symptoms (Symptom Checklist-90). Postoperative satisfaction was 94% to 100%, depending on the type of surgery performed. Eight (6%) of the participants reported dissatisfaction and/or regret, which was associated with preoperative psychological symptoms or self-reported surgical complications (OR = 6.07). Satisfied respondents' QoL scores were similar to reference values; dissatisfied or regretful respondents' scores were lower. Therefore, dissatisfaction after GAS may be viewed as indicator of unfavorable psychological and QoL outcomes.


Low-income mothers as "othermothers" to their romantic partners' children: women's coparenting in multiple partner fertility relationships.
In this article, we investigated low-income mothers' involvement in multiple partner fertility (MPF) relationships and their experiences as "othermothers" to their romantic partners' children from previous and concurrent intimate unions. Othermothering, as somewhat distinct from stepmothering, involves culturally-scripted practices of sharing parenting responsibilities with children's biological parents. We framed this investigation using this concept because previous research suggests that many low-income women practice this form of coparenting in their friend and kin networks. What is not apparent in this literature, however, is whether women unilaterally othermother their romantic partners' children from different women. How often and under what circumstances do women in nonmarital MPF intimate unions with men coparent their partners' children from other relationships? We explored this question using a modified grounded theory approach and secondary longitudinal ethnographic data on 256 low-income mostly unmarried mothers from the Three-City Study. Results indicated that 78% of the mothers had been or were involved in MPF unions and while most had othermothered the children of their friends and relatives, 89% indicated that they did not coparent their partners' children from any MPF relationship. Mothers' reasons for not doing so were embedded in: (a) gendered scripts around second families, or "casa chicas"; (b) the tenuous nature of pass-through MPF relationships; and (c) mothers' own desires for their romantic partners to child-swap. Implications of this research for family science and practice are discussed.


Surgical and Non-surgical Treatment Options for Piriformis Syndrome: A Literature Review.
Piriformis syndrome is a solely clinical diagnosis that often eludes the practitioner and goes underdiagnosed. PS is a pain syndrome and for those it affects, causes persistent pain and limits daily activity and work capacity. It is a form of deep gluteal syndrome that needs to be considered on the differential of low back pain as it comprises between 0.3% - 6% of all low back pain cases and is frequently underdiagnosed. Piriformis syndrome may be primary due anatomic anomalies or secondary, though the majority of cases are secondary to some insult. The objective of this manuscript is to provide a description of the epidemiology and presentation of piriformis as well as both non-operative and operative treatment options. We review all of the recent clinical evidence regarding the aforementioned therapies. Literature searches were performed using the below MeSH Terms using Mendeley version 1.19.4. Search fields were varied until further searches revealed no new articles. All articles were screened by title and abstract. Decision was made to include an article based on its relevance and the list of final articles was approved three of the authors. This included reading the entirety of the article. Any question regarding the inclusion of an article was discussed by all authors until an agreement was reached. Medical management and physical therapy show some promise; however, when conservative treatment fails minimally invasive methods such as steroid injections, botulinum toxin injections, dry needling are all efficacious and there is substantial clinical evidence regarding these therapies. In those patients in which minimally invasive techniques do not result in an adequate relief of pain and return of function, endoscopic release can be considered. Endoscopic release is far superior to open release of the piriformis syndrome given the higher success and lower rate of complications. Piriformis syndrome is an important differential diagnosis in the work up of lower back pain and should not be ruled out with proper examination and testing. Clinicians should consider medical management and conservative management in the initial treatment plan for piriformis syndrome. There are many options within the conservative management and the literature shows much promise regarding these. Physical therapy, steroid injections, botulinum toxin injections, and dry needling are all potentially effective therapies with few adverse effects. Surgical options remain as gold standard, but only when conservative management has failed and the symptoms are significant to affect daily living activities. Endoscopic decompression of the sciatic nerve with or without release of the piriformis muscle has a reported high likelihood of success and a low complication rate. Current literature supports the preference of the endoscopic approach over the open approach due to improved outcomes and decreased complications. Further research is to well define the metrics for the diagnosis of piriformis syndrome and may include a need to develop diagnostic criteria.


An ADAMTS3 missense variant is associated with Norwich Terrier upper airway syndrome.
In flat-faced dog breeds, air resistance caused by skull conformation is believed to be a major determinant of Brachycephalic Obstructive Airway Syndrome (BOAS). The clinical presentation of BOAS is heterogeneous, suggesting determinants independent of skull conformation contribute to airway disease. Norwich Terriers, a mesocephalic breed, are predisposed to Upper Airway Syndrome (UAS), a disease whose pathological features overlap with BOAS. Our health screening clinic examined and scored the airways of 401 Norwich terriers by laryngoscopy. Genome-wide association analyses of UAS-related pathologies revealed a genetic association on canine chromosome 13 (rs9043975, p = 7.79x10-16). Whole genome resequencing was used to identify causal variant(s) within a 414 kb critical interval. This approach highlighted an error in the CanFam3.1 dog assembly, which when resolved, led to the discovery of a c.2786G>A missense variant in exon 20 of the positional candidate gene, ADAM metallopeptidase with thrombospondin type 1 motif 3 (ADAMTS3). In addition to segregating with UAS amongst Norwich Terriers, the ADAMTS3 c.2786G>A risk allele frequency was enriched among the BOAS-susceptible French and (English) Bulldogs. Previous studies indicate that ADAMTS3 loss of function results in lymphoedema. Our results suggest a new paradigm in the understanding of canine upper airway disease aetiology: airway oedema caused by disruption of ADAMTS3 predisposes dogs to respiratory obstruction. These findings will enhance breeding practices and could refine the prognostics of surgical interventions that are often used to treat airway obstruction.


Assessment of procalcitonin to predict outcome in hypothermia-treated patients after cardiac arrest.
Objective. Determine the potential of procalcitonin (PCT) to predict neurological outcome after hypothermia treatment following cardiac arrest. Methods. Retrospective analysis of patient data over a 2-year period. Mortality and neurological outcome of survivors were determined 6 months after cardiac arrest using the Cerebral Performance Category (CPC) score. Results. Data from 53 consecutive patients were analyzed. Median age was 63 (54-71) and 79% were male. Twenty-seven patients had good outcome (CPC ≤ 2) whereas 26 had severe neurological sequelae or died (CPC 3-5). At 48 h, after regaining normothermia, PCT was significantly higher in patients with bad outcome compared to those with good outcome: 3.38 (1.10-24.48) versus 0.28 (0-0.75) ng/mL (P < 0.001). PCT values correlated with bad neurological outcome (r = 0.54, P = 0.00004) and predicted outcome with an area under the curve of 0.84 (95% CI 0.73-0.96). A cutoff point of 1 ng/mL provided a sensitivity of 85% and a specificity of 81%. Above a PCT level of 16 ng/mL, no patient regained consciousness. PCT provided an additive value over simplified acute physiology score II. Conclusions. PCT might be an ancillary marker for outcome prediction after cardiac arrest treated by induced hypothermia.


Impact of KChIP2 on Cardiac Electrophysiology and the Progression of Heart Failure.
Electrophysiological remodeling of cardiac potassium ion channels is important in the progression of heart failure. A reduction of the transient outward potassium current (I(to)) in mammalian heart failure is consistent with a reduced expression of potassium channel interacting protein 2 (KChIP2, a K(V)4 subunit). Approaches have been made to investigate the role of KChIP2 in shaping cardiac I(to), including the use of transgenic KChIP2 deficient mice and viral overexpression of KChIP2. The interplay between I(to) and myocardial calcium handling is pivotal in the development of heart failure, and is further strengthened by the dual role of KChIP2 as a functional subunit on both K(V)4 and Ca(V)1.2. Moreover, the potential arrhythmogenic consequence of reduced I(to) may contribute to the high relative incidence of sudden death in the early phases of human heart failure. With this review, we offer an overview of the insights into the physiological and pathological roles of KChIP2 and we discuss the limitations of translating the molecular basis of electrophysiological remodeling from animal models of heart failure to the clinical setting.


Weight-based victimization, eating behaviors, and weight-related health in Sexual and Gender Minority Adolescents.
Weight-based victimization (WBV) is a common form of bullying associated with maladaptive eating, and poor weight-related health. Although sexual and gender minority (SGM) youth experience a number of eating and weight-related health disparities, the link between WBV and these outcomes has not been investigated in this vulnerable population. Data came from the LGBTQ Teen Study, a national survey of SGM adolescents. Participants provided data to assess body mass index (BMI), WBV, sexual identity, gender identity, dieting, binge eating, eating to cope with stress, weight control behaviors, exercise, and stress (N = 9679). The sample was 66% White, with a mean age of 15.6 years; 58.5% had healthy weight, and 37.2% had overweight or obesity. Over half of participants reported WBV from family members and peers. WBV from family members was associated with maladaptive eating (i.e., binge-eating, unhealthy weight-control behaviors), dieting, and poor weight-related health (i.e., stress, exercise avoidance, less physical activity and poorer sleep); relationships remained significant after accounting for participants' age, BMI percentile for age and sex, race, gender identity, and sexual identity. Higher frequency of WBV at school, but not history of peer weight-based victimization, was associated with more maladaptive eating, dieting, and poorer weight-related health on all outcomes except physical activity. This is the first large-scale study that examined links between WBV, maladaptive eating behaviors, and weight-related health in SGM adolescents. These results suggest the need for increased awareness that WBV may play a role in maladaptive eating, and weight-related health of SGM youth, and may contribute to both elevated levels of eating disorders and obesity in this population.


Identification of a cDNA encoding an active asparaginyl endopeptidase of Schistosoma mansoni and its expression in Pichia pastoris.
Asparaginyl endopeptidases, or legumains, are a recently identified family of cysteine-class endopeptidases. A single gene encoding a Schistosoma mansoni asparaginyl endopeptidase (a.k.a. Sm32 or schistosome legumain) has been reported, but by sequence homology it would be expected to yield an inactive product as the active site C197 had been replaced by N. We now describe a new S. mansoni gene in which C197 is present. Both gene products were expressed in Pichia pastoris. Autocatalytic processing to fully active C197 Sm32 occurred at acid pH. In contrast, N197 Sm32 was not processed and this is consistent with the hypothesis that C197 is essential for catalysis. This was confirmed by mutation of N197 to C and re-expression in Pichia. The availability of recombinant active Sm32 allows detailed analysis of its catalytic mechanism and its function(s) in the biology of this important human parasite.


Level crossing statistics for optical beam wander in a turbulent atmosphere with applications to ground-to-space laser communications.
Level crossing statistics is applied to the complex problem of atmospheric turbulence-induced beam wander for laser propagation from ground to space. A comprehensive estimate of the single-axis wander angle temporal autocorrelation function and the corresponding power spectrum is used to develop, for the first time to our knowledge, analytic expressions for the mean angular level crossing rate and the mean duration of such crossings. These results are based on an extension and generalization of a previous seminal analysis of the beam wander variance by Klyatskin and Kon. In the geometrical optics limit, we obtain an expression for the beam wander variance that is valid for both an arbitrarily shaped initial beam profile and transmitting aperture. It is shown that beam wander can disrupt bidirectional ground-to-space laser communication systems whose small apertures do not require adaptive optics to deliver uniform beams at their intended target receivers in space. The magnitude and rate of beam wander is estimated for turbulence profiles enveloping some practical laser communication deployment options and suggesting what level of beam wander effects must be mitigated to demonstrate effective bidirectional laser communication systems.


Effect of allelic heterogeneity on the power of the transmission disequilibrium test.
Due in part to an influential paper by Risch and Merikangas [(1996) Science 273:1516-1517], which suggested that disequilibrium tests would have greater power to detect genes of small effect than would linkage tests, interest in the use of the Transmission Disequilibrium Test (TDT) as an analysis tool for genomewide studies is steadily growing. However, the paper by Risch and Merikangas made several simplifying assumptions. One such assumption was that the underlying gene showed allelic homogeneity, and another was that the allele being measured was the actual susceptibility allele. Here we investigate the effect of allelic heterogeneity on the power of the TDT using multiplicative, additive, dominant, and recessive modes of inheritances in the context of a genomewide study. We further distinguish two cases: first, that the marker alleles are the actual susceptibility alleles, and second, that alleles are measured at a marker linked to the disease gene with zero recombination. We consider two family structures, either a single affected offspring (SAO) and two parents, or an affected sib-pair (ASP) and two parents. We find that, as expected, the power of the TDT declines as the number of susceptibility alleles at the locus being tested increases and the effect on power can be substantial. When a linked marker is measured rather than a susceptibility allele itself, sample sizes reach unattainable levels when as few as two susceptibility alleles are present. Across all the models we consider, the required number of families for a TDT with ASP sampling varies from 19 to over a million families. Thus, the TDT may not be an optimal test in the context of genomic screens under more biologically realistic assumptions.


Neurons of the olfactory epithelium in adult rats contain vimentin.
In the developing nervous system, the intermediate filament protein vimentin is found in the proliferating neuroepithelium and neural crest. As development proceeds, postmitotic neurons cease vimentin expression and neurofilament proteins begin to accumulate. We have shown that olfactory receptor neurons deviate from the general pattern of neuronal intermediate filament expression, in that they continue to express vimentin or a highly vimentin-like protein rather than neurofilament proteins in the adult rat. With light-microscopic immunohistochemistry, three independently derived antibodies to vimentin label all portions of the primary olfactory projection, including the sensory neuron cell bodies in the olfactory epithelium, the fascicles of the olfactory nerve, and their axonal arbors in the glomeruli of the olfactory bulb. In contrast, anti-neurofilament antisera stain only rare scattered receptor cells and a small number of axons in the olfactory nerve. Electron-microscopic immunohistochemistry shows dense staining of olfactory axons with anti-vimentin. The vimentin-like immunoreactive material in the olfactory nerve layer was characterized by SDS-PAGE and by immunoblotting. On immunoblots of homogenates of the olfactory nerve, the anti-vimentin monoclonal antibody SBV-21 (Blose et al., 1984) stains only a single protein of Mr = 55 kDa. This band comigrates with vimentin in crude cytoskeletal material from the neonatal rat brain prepared according to the method of Dahl et al. (1981). SBV-21 does not stain neurofilament triplet proteins or glial fibrillary acidic protein, which are also present in these blots. These results demonstrate that the vast majority of olfactory receptor neurons and their axons contain vimentin or a protein of similar immunological character and electrophoretic mobility, while identifiable expression of neurofilament proteins is confined to a very small subpopulation. Hence, the switch in intermediate filament proteins that normally accompanies neuronal maturation is arrested in most olfactory neurons, and a "juvenile" biochemical marker is retained. This population of neurons is also unique among mammalian neurons in several other respects, including that olfactory neurons die during normal adult life or following injury and then are replaced from a proliferating pool of stem cells.


A randomized trial of three novel regimens for recurrent acute myeloid leukemia demonstrates the continuing challenge of treating this difficult disease.
To improve the outcome of relapsed/refractory acute myeloid leukemia (AML), a randomized phase II trial of three novel regimens was conducted. Ninety patients were enrolled and were in first relapse or were refractory to induction/re-induction chemotherapy. They were randomized to the following regimens: carboplatin-topotecan (CT), each by continuous infusion for 5 days; alvocidib (formerly flavopiridol), cytarabine, and mitoxantrone (FLAM) in a timed sequential regimen; or sirolimus combined with mitoxantrone, etoposide, and cytarabine (S-MEC). The primary objective was attainment of a complete remission (CR). A Simon two-stage design was used for each of the three arms. The median age of the patients in the FLAM arm was older at 62 years compared with 55 years for the CT arm and the S-MEC arm. The overall response was 14% in the CT arm (5/35, 90% CI 7%-35%), 28% in the FLAM arm (10/36, 90% CI, 16%-43%), and 16% in the S-MEC arm (3/19, 90% CI, 4%-36%). There were nine treatment-related deaths, seven of which occurred in the FLAM arm with four of these in elderly patients. We conclude that the FLAM regimen had an encouraging response rate and should be considered for further clinical development but should be used with caution in elderly patients.


Rescue and Stabilization of Acetylcholinesterase in Skeletal Muscle by N-terminal Peptides Derived from the Noncatalytic Subunits.
The vast majority of newly synthesized acetylcholinesterase (AChE) molecules do not assemble into catalytically active oligomeric forms and are rapidly degraded intracellularly by the endoplasmic reticulum-associated protein degradation pathway. We have previously shown that AChE in skeletal muscle is regulated in part post-translationally by the availability of the noncatalytic subunit collagen Q, and others have shown that expression of a 17-amino acid N-terminal proline-rich attachment domain of collagen Q is sufficient to promote AChE tetramerization in cells producing AChE. In this study we show that muscle cells, or cell lines expressing AChE catalytic subunits, incubated with synthetic proline-rich attachment domain peptides containing the endoplasmic reticulum retrieval sequence KDEL take up and retrogradely transport them to the endoplasmic reticulum network where they induce assembly of AChE tetramers. The peptides act to enhance AChE folding thereby rescuing them from reticulum degradation. This enhanced folding efficiency occurs in the presence of inhibitors of protein synthesis and in turn increases total cell-associated AChE activity and active tetramer secretion. Pulse-chase studies of isotopically labeled AChE molecules show that the enzyme is rescued from intracellular degradation. These studies provide a mechanistic explanation for the large scale intracellular degradation of AChE previously observed and indicate that simple peptides alone can increase the production and secretion of this critical synaptic enzyme in muscle tissue.


Validity and reliability of a 1500-m lap-time collection method using public videos.
The collection of retrospective lap times from video footage is a potentially useful research tool to analyze the pacing strategies in any number of competitive events. The aim of this study was to validate a novel method of obtaining running split-time data from publically available video footage. Videos of the 1500-m men's final from the 2004 and 2008 Olympics, 2005 and 2009 World Championships, and 2010 European Championships were obtained from the YouTube Web site, and split times were collected from all competitors using frame-by-frame playback. The typical error of video split times ranged between 0.02 s and 0.11 s for the 4 laps when compared with official split times. Video finishing times were also similar to official finishing times (typical error of 0.04 s). The method was shown to be highly reliable with a typical error of 0.02 s when the same video was analyzed on 2 occasions separated by 8 mo. Video data of track races are widely available; however, camera angles are not always perpendicular to the start/finish line, and some slower athletes may cross the line after the camera has panned away. Nevertheless, the typical errors reported here show that when appropriate camera angles are available this method is both valid and reliable.


ACCF/SCCT/ACR/AHA/ASE/ASNC/NASCI/SCAI/SCMR 2010 Appropriate Use Criteria for Cardiac Computed Tomography. A Report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the Society of Cardiovascular Computed Tomography, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the American Society of Nuclear Cardiology, the North American Society for Cardiovascular Imaging, the Society for Cardiovascular Angiography and Interventions, and the Society for Cardiovascular Magnetic Resonance.
The American College of Cardiology Foundation (ACCF), along with key specialty and subspecialty societies, conducted an appropriate use review of common clinical scenarios where cardiac computed tomography (CCT) is frequently considered. The present document is an update to the original CCT/cardiac magnetic resonance (CMR) appropriateness criteria published in 2006, written to reflect changes in test utilization, to incorporate new clinical data, and to clarify CCT use where omissions or lack of clarity existed in the original criteria (1). The indications for this review were drawn from common applications or anticipated uses, as well as from current clinical practice guidelines. Ninety-three clinical scenarios were developed by a writing group and scored by a separate technical panel on a scale of 1 to 9 to designate appropriate use, inappropriate use, or uncertain use. In general, use of CCT angiography for diagnosis and risk assessment in patients with low or intermediate risk or pretest probability for coronary artery disease (CAD) was viewed favorably, whereas testing in high-risk patients, routine repeat testing, and general screening in certain clinical scenarios were viewed less favorably. Use of noncontrast computed tomography (CT) for calcium scoring was rated as appropriate within intermediate- and selected low-risk patients. Appropriate applications of CCT are also within the category of cardiac structural and functional evaluation. It is anticipated that these results will have an impact on physician decision making, performance, and reimbursement policy, and that they will help guide future research.


Effects of mental task on heart rate variability during graded head-up tilt.
In this study, we used spectral analysis of heart rate variability (HRV) to estimate the changes in autonomic control in response to disparate stimuli produced by mental task and graded head-up tilting. The low frequency (LF) component of HRV provided a quantitative index of the sympathetic and parasympathetic (vagal) activities controlling the heart rate (HR), while the high frequency (HF) component of HRV provided an index of the vagal tone. We studied 17 healthy male subjects (21-25 yr of age) who were placed on a tilt-table and the graded tilt-protocol involved tilted sine angles 0.0, 0.2, 0.4, 0.6, 0.8, and 1.0. These tilt-protocols were repeated with or without the mental task, which consisted of auditory distinctive reaction-time tasks. The basal autonomic mode against the graded head-up tilt was characterized by reciprocal changes in sympathetic and vagal tones. There were significant increases of HR corresponding to the mental task with lower tilt-angle, albeit the changes with higher tilt angles were not significant. Furthermore, there were increases and decreases of the LF component induced by the mental task at lower and higher tilt-angles, respectively. These results revealed that the different responses of HR and LF component against the same tasks could be derived from the alterations of autonomic mode during gradual changes in autonomic control.


The eye in bone marrow transplantation. VI. Retinal complications.
To evaluate the posterior segment ocular complications of patients undergoing bone marrow transplantation (BMT). Retrospective analysis. Academic ophthalmology department at a tertiary care hospital with a BMT unit. Patients undergoing BMT were seen by an ophthalmologist for clinical care and enrolled in a long-term follow-up study, during which they were seen 6 and 12 months after the transplantation and annually thereafter. Of 397 patients undergoing BMT, 51 (12.8%) developed posterior segment complications. Fourteen patients (3.5%) developed hemorrhagic complications with either intraretinal and/or vitreous hemorrhages and 17 patients (4.3%) developed cotton-wool spots in the fundus of both eyes. Eleven patients (2.8%) had bilateral optic disc edema, with eight cases attributed to the toxic effects of cyclosporine and three to other causes. Two patients (0.5%) developed serious retinal detachments. Eight patients (2.0%) developed infectious retinitis and/or endophthalmitis. Fungal infections with Candida or Aspergillus usually occurred within 120 days after BMT, while viral infections with herpes zoster or cytomegalovirus and parasitic infections with Toxoplasma occurred later. Intraocular lymphoma occurred in one patient (0.2%). Severe, potentially vision-threatening, posterior segment complications following BMT occur due to a variety of causes.