Effect of Humeral Component Version on Outcomes in Reverse Shoulder Arthroplasty.
Although reverse shoulder arthroplasty provides excellent clinical results in appropriately selected patients, loss of external and internal rotation may occur. Component selection, design, and placement affect postoperative results. Recent studies considered the effect of humeral component version on functional results. The current study investigated whether humeral stem retroversion affects the outcomes of reverse shoulder arthroplasty with a retrospective review of a multisurgeon, industry-sponsored, prospectively gathered database of a single reverse shoulder arthroplasty implant. All patients had at least 2-year follow-up. Clinical outcomes, including American Shoulder and Elbow Surgeons score, visual analog scale pain score, Short Form-12 Mental and Physical Component scores, range of motion, and internal rotation function, were compared between patients with humeral retroversion of 10° or less (group A) and those with humeral retroversion of 20° or greater (group B). Radiographic outcomes were compared. The analysis included 64 patients (group A, 29 patients; group B, 35 patients). No clinical or statistically significant difference was found in American Shoulder and Elbow Surgeons scores. Both groups showed statistical and clinical improvement vs preoperative scores, with group A averaging 77.8 and group B averaging 79.2 at final follow-up. No differences were found between groups in range of motion or ability to perform tasks that require shoulder internal rotation. Patients can expect good clinical improvement after reverse shoulder arthroplasty. No difference was found in clinical or radiologic outcomes based on humeral component retroversion. Despite the theoretical increase in external rotation when the humeral component is placed closer to native retroversion, the results did not show this effect. [Orthopedics. 2017; 40(3):179-186.].


The protooncogene c-myb increases the expression of insulin-like growth factor 1 and insulin-like growth factor 1 receptor messenger RNAs by a transcriptional mechanism.
The protooncogene c-myb is the cellular equivalent of the viral transforming oncogene v-myb. When human c-myb is constitutively expressed in Balb/c3T3 cells it abrogates their absolute requirement for insulin-like growth factor 1 (IGF-1). We show now, in two different cell lines, that the constitutive expression of the protooncogene c-myb causes an increase in both IGF-1 and IGF = 1 receptor mRNA levels. This increase in mRNA levels is due, at least in part, to an increase in the rate of transcription since, by run-on assay, cells carrying the human c-myb cDNA show a 3-fold increase in transcriptional rates in comparison to the control parent cell lines. The increased expression of IGF-1 receptor mRNA also results in an increased number of IGF-1 binding sites per cell. Although some oncogenes have been described that are homologous to growth factors, or growth factor receptors, c-myb seems to represent a novel way of oncogene action inasmuch as it increases the expression of both a growth factor receptor and its ligand, thus establishing a quasi-autocrine mechanism which modifies the growth factor requirements of the cell and its growth regulation.


Impact of molecular structure of starch on the glutinous taste quality of cooked chestnut kernels.
Chestnuts are a starchy food with a characteristic glutinous taste that is often used to assess their quality. In this study, our findings indicated that chestnuts with higher glutinous taste quality had lower amylose content and microcrystalline structures, as well as higher subcrystalline structures and relative crystallinity in both the raw and steamed starches. In the leached starch, chestnuts with higher glutinous taste quality had lower amylopectin B1 chains and microcrystalline structure, but higher amylopectin B2 chains, subcrystalline structure and relative crystallinity. These results suggest that amylose content, relative crystallinity, and amylopectin chain length distribution are important factors determining the glutinous taste quality of chestnuts. To further enhance our understanding of these factors, an sensory evaluation model was developed based on textural profile analysis parameters. This study provides valuable insights into the relationship between molecular structure of starch and the glutinous taste quality of starchy foods.


Paclitaxel Inhibits KCNQ Channels in Primary Sensory Neurons to Initiate the Development of Painful Peripheral Neuropathy.
Cancer patients undergoing paclitaxel infusion usually experience peripheral nerve degeneration and serious neuropathic pain termed paclitaxel-induced peripheral neuropathy (PIPN). However, alterations in the dose or treatment schedule for paclitaxel do not eliminate PIPN, and no therapies are available for PIPN, despite numerous studies to uncover the mechanisms underlying the development/maintenance of this condition. Therefore, we aimed to uncover a novel mechanism underlying the pathogenesis of PIPN. Clinical studies suggest that acute over excitation of primary sensory neurons is linked to the pathogenesis of PIPN. We found that paclitaxel-induced acute hyperexcitability of primary sensory neurons results from the paclitaxel-induced inhibition of KCNQ potassium channels (mainly KCNQ2), found abundantly in sensory neurons and axons. We found that repeated application of XE-991, a specific KCNQ channel blocker, induced PIPN-like alterations in rats, including mechanical hypersensitivity and degeneration of peripheral nerves, as detected by both morphological and behavioral assays. In contrast, genetic deletion of KCNQ2 from peripheral sensory neurons in mice significantly attenuated the development of paclitaxel-induced peripheral sensory fiber degeneration and chronic pain. These findings may lead to a better understanding of the causes of PIPN and provide an impetus for developing new classes of KCNQ activators for its therapeutic treatment.


Lack of associations between thyroid dysfunction and obstructive sleep apnea-hypopnea syndrome: A meta-analysis.
Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a comprehensive syndrome with endocrine and metabolic complications. This review aims to explore the correlation between thyroid hormone levels and the severity of OSAHS in patients. The protocol for this meta-analysis has been registered on PROSPERO. Searches were carried out from the inception of the databases to July 18, 2023, utilizing 6 databases (PubMed, CNKI, EMBASE, Web of Science, Cochrane Library, China Biology Medicine, and Wanfang). Standardized mean difference (SMD) and correlation coefficients were used as the effect size measures. Additionally, random effects or fixed effects models were used for pooled analysis. Moreover, data were statistically evaluated with the help of STATA 11.0 and R 4.1.3. This study included 23 articles that satisfied the pre-defined criteria. The prevalence of hypothyroidism and subclinical hypothyroidism in OSAHS patients was 6% and 8%, whereas hyperthyroidism had a prevalence of 2%. Moreover, thyroid hormone levels in OSAHS individuals exhibited no significant difference relative to healthy subjects. Subgroup analysis based on disease severity also established no significant changes in thyroid hormone levels between OSAHS individuals and controls. There was no significant correlation between the Apnea-Hypopnea Index (AHI) and free triiodothyronine (FT3), serum thyroid stimulating hormone (TSH), and free thyroxine (FT4) levels. The prevalence of thyroid dysfunction is relatively low in OSAHS individuals. Thyroid hormone levels show no significant difference between OSAHS patients and healthy subjects. Furthermore, there is no significant correlation between AHI and serum TSH, FT3, and FT4 levels. Based on existing data, the relationship between OSAHS and thyroid function remains controversial, and further in-depth research is warranted to validate the connection and elucidate the underlying mechanisms.


[The evaluation of heterosexual transmission of the human immunodeficiency virus by nucleic acid amplification technics].
Heterosexual couples of individuals infected by HIV represent a group of high risk of virus infection. We have investigated the presence of fragments of the HIV genome with a new nucleic acid amplification technique (PCR or polymerase chain reaction) in lymphocytes from 33 seronegative couples with anti-HIV antibodies, most of which were heroin addicts. 12 of the 33 couples (36%) had positive PCR for a gag HIV amplimer in the absence of antibodies. 4 of them (12%) also showed reactivity for sequences from an env amplimer. A control group of 7 patients with AIDS and 4 seropositive couples showed reactivity to gag and env in all. It is concluded that silent HIV infection may frequently develop in heterosexual couples of infected individuals.


When is a tumor marker ready for prime time? A case study of c-erbB-2 as a predictive factor in breast cancer.
c-erbB-2 (HER-2, c-neu) might play a role as a predictive factor in breast cancer. However, the clinical utility of the marker in this disease is still not established. We conducted a critical analysis of the literature, in which we reviewed the factors that contribute to the lack of acceptance of c-erbB-2 for clinical use and attempted to determine the predictive role of c-erbB-2 for response to specific therapies. We conducted a MEDLINE literature search using the keywords c-erbB-2, HER2, neu, and breast cancer, reviewed the references included in each publication, and reviewed abstracts that have been reported in the 1997-2000 proceedings to the American Association of Cancer Research and American Society for Clinical Oncology annual meetings. The preclinical and clinical data reported to date suggest that amplification or overexpression of c-erbB-2 is a weak to moderate negative pure prognostic factor. c-erbB-2 seems to be a weak to moderate negative predictive factor for response to endocrine therapy. The marker is also a moderate negative predictive factor for response to alkylating agents and a moderate positive predictive factor for response to anthracyclines. The data regarding response to taxanes or radiotherapy are not sufficient to make recommendations regarding treatment decision making. Finally, c-erbB-2 is a strong predictive factor for response to trastuzumab. We conclude that, in the adjuvant setting, c-erbB-2 status should not be used to determine whether a woman should receive adjuvant systemic therapy (weak prognostic factor). In addition, c-erbB-2 status should not be used to determine whether a patient should receive endocrine therapy. When adjuvant chemotherapy is recommended, anthracycline-based therapy should be the preferred regimen for c-erbB-2-positive patients. However, when anthracyclines are contraindicated, alkylating agent-based therapy should not be withheld. To determine the true predictive role and strength of the marker for response to each therapy, prospective randomized clinical trials or formal meta-analyses are required.


Are they really lost? "true" status and reasons for treatment discontinuation among HIV infected patients on antiretroviral therapy considered lost to follow up in Urban Malawi.
Patients who are lost to follow-up (LTFU) while on antiretroviral therapy (ART) pose challenges to the long-term success of ART programs. We describe the extent to which patients considered LTFU are misclassified as true disengagement from care when they are still alive on ART and explain reasons for ART discontinuation using our active tracing program to further improve ART retention programs and policies. We identified adult ART patients who missed clinic appointment by more than 3 weeks between January 2006 and December 2010, assuming that such patients would miss their doses of antiretroviral drugs. Patients considered LTFU who consented during ART registration were traced by phone or home visits; true ART status after tracing was documented. Reasons for ART discontinuation were also recorded for those who stopped ART. Of the 4,560 suspected LTFU cases, 1,384 (30%) could not be traced. Of the 3,176 successfully traced patients, 952 (30%) were dead and 2,224 (70%) were alive, of which 2,183 (99.5%) started ART according to phone-based self-reports or physical verification during in-person interviews. Of those who started ART, 957 (44%) stopped ART and 1,226 (56%) reported still taking ART at the time of interview by sourcing drugs from another clinic, using alternative ART sources or making brief ART interruptions. Among 940 cases with reasons for ART discontinuations, failure to remember (17%), too weak/sick (12%), travel (46%), and lack of transport to the clinic (16%) were frequently cited; reasons differed by gender. The LTFU category comprises sizeable proportions of patients still taking ART that may potentially bias retention estimates and misdirect resources at the clinic and national levels if not properly accounted for. Clinics should consider further decentralization efforts, increasing drug allocations for frequent travels, and improving communication on patient transfers between clinics to increase retention and adherence.


Effects of leg blood flow restriction during walking on cardiovascular function.
Exercise with limb blood flow restriction (BFR) is a very popular exercise modality in Japan and is spreading widely to the rest of the world. The underlying principle of this training modality is that under the conditions of restricted blood flow, even low-intensity exercise can provide significant muscle strength and hypertrophy. One concern, however, is that BFR during exercise may place unnecessary burden on those with compromised cardiac function. We determined the impact of leg BFR during walking on cardiovascular function in 17 young (26 ± 1 yr) healthy volunteers. Each subject underwent five bouts of 2-min treadmill walking at 2 miles·h(-1) with 1-min interval either with or without tourniquet cuffs inflated on both thighs. Heart rate increased more during the BFR session, whereas stroke volume decreased greater during the BFR session. Blood pressure increased significantly and substantially during the BFR session. Consequently, an increase in double product, an index of myocardial oxygen demand, was more than threefold higher in the BFR condition. Systemic arterial compliance evaluated by stroke volume/pulse pressure ratio significantly increased during the control session by 14% but reduced during the BFR condition by 19%. Popliteal artery flow-mediated vasodilation decreased significantly after the exercise with BFR but not after the control session. Even at low intensity, the aerobic exercise with BFR requires a greater cardiac work and decreases endothelial function. Limb BFR during exercise may need to be more cautiously prescribed to those with compromised cardiac conditions.


[Periportal hyperechogenicity of the liver. Clinical aspects and pathology of the so-called fixed star heaven phenomenon of the liver].
The clinical significance of the sonographic finding "periportal hyperechogenicity", which is characterized by hard periportal echoes, is largely undetermined. This phenomenon has been reported in a large number of disorders, as well as in healthy persons. A prospective study of 1853 patients revealed this finding in 12 cases. These 12 patients were followed up after two to four months. Only four cases were seen to still have diffuse periportal accentuation in the follow-up, while five patients showed a partially and three a completely normal liver. The laboratory values of these 12 patients were largely normal at the time of diagnosis and follow-up. Periportal accentuation was not correlated with any hepatological disorders. Examination using two different ultrasound devices revealed no major differences. Overall, these findings confirm the earlier assumption that this sonographic picture designated as periportal hyperechogenicity or accentuation is not diagnostic of any hepatological disorder, nor is it even a sign of disease, because most patients with this phenomenon can be termed hepatologically "healthy".


Coproporphyrin I and 3 excretion in bile and urine.
The excretion of coproporphyrin isomers I and III was studied in the rat. Both isomers were found to bind equally to rat plasma and liver cytosol in vitro and to disappear from plasma at equal rates after single injections in vivo. During equimolar infusions of isomers into bile fistula animals, both the I and III isomers were excreted in bile in a concentration ratio of 2:1, respectively. Pretreatment of animals with ethinylestradiol or simultaneous infusions of phenoldibromophthalein disulfonate caused a reduction in total hepatic excretion with no change in the 2:1 ratio in bile. As hepatic excretion fell, excretion of both isomers in urine rose, with an increase in the proportion of the I isomer. The findings mimic those reported to occur in man and can be explained by inhibition of a common carrier which requires a stereospecific configuration that statistically favors the hepatic transport of the symmetrical coproporphyrin I isomer.


Bisalbuminemia in chronic kidney disease.
Hereditary and acquired bisalbuminemia, in which the serum contains an albumin variant differing from albumin A by single amino-acid substitutions, have been reported in different races or ethnic groups and in association with various pathologic states. The importance of this rare condition in the pathophysiology of established diseases is uncertain. We evaluated a 68-year-old woman with chronic kidney disease who presented with worsened serum creatinine concentration despite lack of dietary or medical changes. Serum protein electrophoresis was performed with an automated rapid electrophoresis system. Bisalbuminemia was noted as an incidental finding on serum protein electrophoresis. The serum creatinine level stabilized with dietary protein restriction and a beta-blocking agent/diuretic combination for blood pressure control. Although the possibility that some physiologic or pharmacologic substances may not bind to abnormal albumin variants as well as they bind to normal albumin should not be discounted, the finding of bisalbuminemia did not influence the diagnosis, management, course, or prognosis of chronic kidney disease. The role of persistent bisalbuminemia in renal disease is uncertain.


Contributions of Fat and Carbohydrate Metabolism to Glucose Homeostasis in Childhood Change With Age and Puberty: A 12-Years Cohort Study (EARLYBIRD 77).
Puberty-a period when susceptibility to the onset of Type 2 diabetes (T2D) increases-is marked with profound physiological and metabolic changes. In the EarlyBird cohort, children who developed impaired fasting glycemia in adolescence already exhibited higher fasting blood glucose at 5 years of age, independent of their body mass index (BMI), suggesting that pubertal factors may modify existing predisposition. Understanding how the physiological changes during childhood influence glucose homeostasis and how the central energy metabolism may help deciphering the mechanisms that underlie the risk of developing T2D in children and adults. We investigated these associations by analyzing glycemic variations with molecular markers of central energy metabolism, substrate oxidation status and pubertal stages in the EarlyBird cohort. The EarlyBird study is a non-interventional, prospective cohort study, that recruited 307 healthy UK children at age 5, and followed them annually throughout childhood for 12 years. Longitudinal data on blood biochemistry, respiratory exchange ratio, and anthropometry, available from 150 children were integrated with fasting glycemia. The gradual rise in blood glucose during childhood associates with age-dependent changes in molecular processes and substrate oxidation status, namely (i) greater pre-pubertal fat utilization, ketogenesis, and fatty acid oxidation, and (ii) greater pubertal carbohydrate oxidation and glycolytic metabolism (Cori and Cahill Cycles) associated with different amino acid exchanges between muscle and other tissues (proline, glutamine, alanine). Since children's metabolic and nutritional requirements evolve during childhood, this study has potential clinical implications for the development of nutritional strategies for disease prevention in children.


Characterization and Comparison of Intestinal Bacterial Microbiomes of Euschistus heros and Piezodorus guildinii Collected in Brazil and the United States.
Background: Herbivorous insects are one of the main biological threats to crops. One such group of insects, stink bugs, do not eat large amounts of tissue when feeding on soybean, but are damaging to the quality of the seed yield as they feed on green developing seeds leading to poorly marketable harvests. In addition to causing physical damage during sucking-feeding activities, the insects can also transmit microbial pathogens, leading to even greater yield loss. Conducting surveys of the insect intestinal microbiome can help identify possible pathogens, as well as detail what healthy stink bug digestive systems have in common. Methods: We used the conserved V4 region of the 16S rRNA gene to characterize the bacterial microbiome of the red-banded stink bug Piezodorus guildinii collected in Brazil and the United States, as well as the neotropical brown stink bug Euschistus heros collected in Brazil. Results: After quality filtering of the data, 192 samples were kept for analyses: 117 samples from P. guildinii covering three sites in Brazil and four sites in the United States, and 75 samples for E. heros covering 10 sites in Brazil. The most interesting observations were that the diversity and abundance of some bacterial families were different in the different ecoregions of Brazil and the United States. Conclusion: Some families, such as Acetobacteraceae, Bacillaceae, Moraxellaceae, Enterobacteriaceae, and Rhodocyclaceae, may be related to the better adaptation in some localities in providing nutrients, break down cellulose, detoxify phytochemicals, and degrade organic compounds, which makes it difficult to control these species.


Low Prevalence of Colon Polyps in Chronic Inflammatory Conditions of the Colon.
Previous studies have reported a low prevalence of colon polyps in patients with microscopic colitis. The aim of the study was to test whether such inverse associations applied to other inflammatory diseases of the colon. In a case-control study among 130,204 patients undergoing colonoscopy for the work-up of diarrhea, we compared the prevalence of colon polyps in a case population of patients with inflammatory bowel disease (IBD), microscopic colitis, histologic signs of active colitis, diverticulitis, or ischemic colitis, and in a control population with normal colon mucosa. Case and control subjects were compared using odds ratios and their 95% confidence intervals adjusted for age and sex. In 11,176 patients with microscopic colitis, the prevalence of hyperplastic polyps, serrated adenomas, and tubular adenomas were all reduced: odds ratios=0.46 (95% confidence intervals=0.43-0.49), 0.24 (0.19-0.30), and 0.35 (0.33-0.38), respectively. In 4,435 patients with IBD, the corresponding values were: 0.18 (0.15-0.21), 0.24 (0.16-0.35), and 0.18 (0.15-0.21), respectively. In 6,501 patients with histologically active colitis, the corresponding values were: 0.58 (0.53-0.63), 0.57 (0.46-0.70), and 0.63 (0.58-0.68), respectively. No such consistent reduction in polyp prevalence was found in patients with diverticulitis or ischemic colitis. Chronic inflammatory conditions of the colon are associated with a decreased prevalence of colon polyps.


MRCP evaluation of biliary system following vagotomy and gastric surgery.
The aim of this study was to show the usefulness of MR cholangiopancreatography (MRCP) in demonstrating biliary system pathologies in patients with a history of vagotomy and Billroth II operations. The hepatobiliary system of eight patients with a history of vagotomy and Billroth II operations was evaluated with MRCP. Three-dimensional fast spin-echo technique was used at a 1.0-T scanner with following parameters: TR=2857-4615 ms, TE=850-1117 ms, BW=31.2, FOV=40, 21-28 slices, NEX=0.5, scan time = 90 s. Eight patients were evaluated with MRCP. Three patients had cholecystectomy. In one patient the gall bladder wall was thickened, accompanied with an irregular, unknown filling defect at the level of the fundus. Four of these patients had common bile duct stones. Two patients had gallstones and one patient had a stone in the common hepatic duct. A capping deformity of the distal common bile duct was observed in all of the patients. We conclude that MRCP can be used effectively for evaluation of biliary system of patients with previous history of biliary or gastric operations.


Volume of Interest Analysis of Spatially Normalized PRESTO Imaging to Differentiate between Parkinson Disease and Atypical Parkinsonian Syndrome.
Various magnetic resonance imaging (MRI) techniques including T2*-weighted imaging, susceptibility-weighted imaging, and MR relaxometry had been performed to evaluate different patterns of brain iron depositions in Parkinsonian syndrome. The aim of the present study was to evaluate the diagnostic value of a volume of interest (VOI) analysis on the principles of echo shifting with a train of observations (PRESTO) imaging using the statistical parametric mapping (SPM) 8 and the WFU PickAtlas program for the diagnosis of Parkinsonian syndrome.,Methods: Fifty subjects, including 13 with the Parkinsonian variant of multiple system atrophy (MSA-P), 12 with progressive supranuclear palsy (PSP), 12 with Parkinson's disease (PD) and 13 controls were evaluated in this study. After the spatial normalization of PRESTO images on SPM8, the WFU PickAtlas program was performed to create target VOIs in the putamen, red nucleus, substantia nigra, subthalamic nucleus, and dentate nucleus. The signal intensity ratio (SIR) was calculated by normalizing the signal of each VOI to that of the cerebrospinal fluid space. These SIRs were used as determinants in receiver operating characteristic (ROC) analyses. SIR of the putamen was significantly lower in MSA-P than in PSP (P = 0.0051) and controls (P = 0.0004). In contrast, SIR of the red nucleus was significantly lower in PSP than in MSA-P (P = 0.0003), PD (P = 0.0029), and controls (P = 0.0011). In ROC analyses, SIR of the putamen exhibited the highest areas under the curves (AUCs) of 0.83 (vs. PSP) and 0.91 (vs. controls) in the diagnosis of MSA-P. On the other hand, SIR of the red nucleus exhibited the highest AUCs of 0.87 (vs. MSA-P), 0.90 (vs. PD), and 0.89 (vs. controls) in the diagnosis of PSP. The VOI analysis based on spatially normalized PRESTO images may be useful for depicting hypointensity, indicative of abnormal iron depositions, of the putamen and red nucleus in the diagnosis of MSA-P and PSP.


β3-Adrenergic receptor-dependent modulation of the medium afterhyperpolarization in rat hippocampal CA1 pyramidal neurons.
Action potential firing in hippocampal pyramidal neurons is regulated by generation of an afterhyperpolarization (AHP). Three phases of AHP are recognized, with the fast AHP regulating action potential firing at the onset of a burst and the medium and slow AHPs supressing action potential firing over hundreds of milliseconds and seconds, respectively. Activation of β-adrenergic receptors suppresses the slow AHP by a protein kinase A-dependent pathway. However, little is known regarding modulation of the medium AHP. Application of the selective β-adrenergic receptor agonist isoproterenol suppressed both the medium and slow AHPs evoked in rat CA1 hippocampal pyramidal neurons recorded from slices maintained in organotypic culture. Suppression of the slow AHP was mimicked by intracellular application of cAMP, with the suppression of the medium AHP by isoproterenol still being evident in cAMP-dialyzed cells. Suppression of both the medium and slow AHPs was antagonized by the β-adrenergic receptor antagonist propranolol. The effect of isoproterenol to suppress the medium AHP was mimicked by two β3-adrenergic receptor agonists, BRL37344 and SR58611A. The medium AHP was mediated by activation of small-conductance calcium-activated K+ channels and deactivation of H channels at the resting membrane potential. Suppression of the medium AHP by isoproterenol was reduced by pretreating cells with the H-channel blocker ZD7288. These data suggest that activation of β3-adrenergic receptors inhibits H channels, which suppresses the medium AHP in CA1 hippocampal neurons by utilizing a pathway that is independent of a rise in intracellular cAMP. This finding highlights a potential new target in modulating H-channel activity and thereby neuronal excitability. NEW & NOTEWORTHY The noradrenergic input into the hippocampus is involved in modulating long-term synaptic plasticity and is implicated in learning and memory. We demonstrate that activation of functional β3-adrenergic receptors suppresses the medium afterhyperpolarization in hippocampal pyramidal neurons. This finding provides an additional mechanism to increase action potential firing frequency, where neuronal excitability is likely to be crucial in cognition and memory.


Pre-sleep feeding, sleep quality, and markers of recovery in division I NCAA female soccer players.
Pre-sleep nutrition habits in elite female athletes have yet to be evaluated. A retrospective analysis was performed with 14 NCAA Division I female soccer players who wore a WHOOP, Inc. band - a wearable device that quantifies recovery by measuring sleep, activity, and heart rate metrics through actigraphy and photoplethysmography, respectively - 24 h a day for an entire competitive season to measure sleep and recovery. Pre-sleep food consumption data were collected via surveys every 3 days. Average pre-sleep nutritional intake (mean ± sd: kcals 330 ± 284; cho 46.2 ± 40.5 g; pro 7.6 ± 7.3 g; fat 12 ± 10.5 g) was recorded. Macronutrients and kcals were grouped into high and low categories based upon the 50th percentile of the mean to compare the impact of a high versus low pre-sleep intake on sleep and recovery variables. Sleep duration (p = 0.10, 0.69, 0.16, 0.17) and sleep disturbances (p = 0.42, 0.65, 0.81, 0.81) were not affected by high versus low kcal, PRO, fat, CHO intake, respectively. Recovery (p = 0.81, 0.06, 0.81, 0.92), RHR (p = 0.84, 0.64, 0.26, 0.66), or HRV (p = 0.84, 0.70, 0.76, 0.93) were also not affected by high versus low kcal, PRO, fat, or CHO consumption, respectively. Consuming a small meal before bed may have no impact on sleep or recovery.


Delayed construction of the bilio-digestive anastomosis in right living donor liver transplantation.
We describe a two-step procedure in the transplantation of a right lobe liver graft obtained from a living donor, in which the biliary anastomosis is delayed until the day after the actual implantation of the graft. The purpose of the two-step procedure is to minimize the factors that might contribute to biliary complications in living donor liver transplantation (LDLT). Three patients who received a graft with two hepatic ducts underwent Roux-en-Y hepatico-jejunostomies during a separate procedure the day after the implantation of the graft. Length of intubation, recovery of enteral alimentation, and hospital stay were similar to the patients who underwent one-step transplant. No biliary or infectious complications occurred. Delaying the hepatico-jejunostomy when two ducts are present and a bilio-digestive anastomosis is planned has no negative impact on the postoperative course of the patients but can ameliorate the conditions under which the anastomoses must be performed.


Respiratory function in a large cohort of treatment-naïve adult spinal muscular atrophy patients: a cross-sectional study.
Due to poor data in literature, we aimed to investigate the respiratory function in a large cohort of naïve Italian adult (≥18 years) SMA patients in a multi-centric cross-sectional study. The following respiratory parameters were considered: forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and need for non-invasive ventilation (NIV). We included 145 treatment-naïve adult patients (SMA2=18, SMA3=125; SMA4=2), 58 females (40 %), with median age at evaluation of 37 years (range 18-72). Fifty-six (37 %) and 41 (31 %) patients had abnormal (<80 %) values of FVC and FEV1, respectively. Fourteen (14 %) patients needed NIV, started at median age of 21 (range 4-68). Motor function, measured by Hammersmith Functional Motor Scale Expanded and Revised Upper Limb Module as well as SMA2, loss of walking ability, surgery for scoliosis, use of NIV, and cough assisting device (CAD) were all significantly associated to lower FVC and FEV1 values, while no association with age at baseline, disease duration, gender or 6 min walking test was observed, except for a correlation between FVC and age in SMA3 walkers (p < 0.05). In conclusion, respiratory function in adult SMA patients is relatively frequently impaired, substantially stable, and significantly correlated with motor function and disease severity.


Independent assessment of the growth and aggregation of calcium oxalate crystals using the Coulter counter.
The growth and aggregation of calcium oxalate seed crystals in a metastable solution of this salt were assessed separately by using the Coulter counter to measure the net increase in total crystal volume and the percentage change in total crystal number respectively. The value of assessing crystal growth and aggregation in these terms was shown by using these parameters to measure the inhibitory effect of a normal human urine. Independent assessment of growth and aggregation enabled a more accurate interpretation of experimental events than was possible by considering the two processes in combination. The method therefore has the potential of improving the discrimination between the inhibitory activities of different urines.


Cross Sectional Association between Spatially Measured Walking Bouts and Neighborhood Walkability.
Walking is the most popular choice of aerobic physical activity to improve health among U.S. adults. Physical characteristics of the home neighborhood can facilitate or hinder walking. The purpose of this study was to quantify neighborhood walking, using objective methods and to examine the association between counts of walking bouts in the home neighborhood and neighborhood walkability. This was a cross-sectional study of 106 adults who wore accelerometers and GPS devices for two weeks. Walking was quantified within 1, 2, and 3 km Euclidean (straight-line) and network buffers around the geocoded home location. Walkability was estimated using a commercially available index. Walking bout counts increased with buffer size and were associated with walkability, regardless of buffer type or size (p < 0.001). Quantification of walking bouts within (and outside) of pre-defined neighborhood buffers of different sizes and types allowed for the specification of walking locations to better describe and elucidate walking behaviors. These data support the concept that neighborhood characteristics can influence walking among adults.


Immunolocalization and tissue-specific splicing of AE2 anion exchanger in mouse kidney.
In this study, an epitope-unmasking technique was used to immunolocalize AE2 anion exchanger polypeptide to basolateral plasma membranes of tubular epithelial cells in mouse kidney. Kidney AE2 immunostaining in mouse kidney was less prominent than in rat, consistent with the relative levels of AE2 mRNA and polypeptide in these two species. Glomeruli showed faint but consistent AE2 immunostaining, whereas proximal tubules were generally unstained. Macula densa epithelial cells displayed bright AE2 immunostaining, and cortical thick limbs were stained at a lower intensity. AE2 immunostaining was weak or absent in type B intercalated cells and principal cells of the cortical collecting duct, but increased in intensity in principal cells of the inner stripe of the outer medulla. AE2 staining in medullary thick limbs was also of greater intensity than in cortical thick limbs. AE2 staining was strong and uniform in the epithelial cells of the inner medullary collecting duct, and in epithelial cells of the papillary surface, the ureter, and the urinary bladder. Extratubular and epithelial cells of the inner medulla also showed punctate intracellular AE2 staining in a Golgi-like distribution that, in contrast to cell surface staining, was sodium dodecyl sulfate-sensitive. Golgi localization of AE2 epitope was confirmed by immunoperoxidase electron microscopy. Reverse transcription-PCR analysis of mouse kidney RNA detected AE2a, AE2b, and an AE2c2 transcript, but an AE2c1 transcript was absent. Unlike in rat, the mouse AE2c2 mRNA splice variant encoded a polypeptide with a novel predicted N-terminal amino acid sequence.


Assisted reproductive technology and the incidence of ovarian cancer: a meta-analysis.
To systematically evaluate the available literature regarding the relationship between assisted reproductive technology and ovarian cancer. Computerized search of 6 databases from 1966 (or closest) to present: Cochrane Controlled Trials Register, Cancerlit, CINHAL, Current Contents, PubMed in process (formerly called PreMEDLINE), and MEDLINE. We collected references from the bibliographies of reviews, original research articles, content experts, and conference proceedings to find published and unpublished literature. Case-control and cohort studies are included. The population of interest is treated infertile women, the control population is untreated infertile women, and the intervention or exposure of interest includes the following fertility medications: clomiphene citrate, gonadotropins, human chorionic gonadotropin, and gonadotropin releasing hormone agonists. The primary outcome is incident, primary ovarian cancer. Three cohort and 7 case-control studies were included in the quantitative analyses. The Newcastle-Ottawa Quality Assessment Scales were used. Two investigators independently extracted study methods, sources of bias, and outcomes. The following information was recorded: publication information, subject characteristics, intervention information and outcomes. Studies combined were sufficiently homogeneous for quantitative summary. Case-control and cohort data showed a significantly elevated risk for exposure of infertility medications and ovarian cancer in subjects who underwent assisted reproductive technology compared with general population controls (1.52; 95% confidence interval [CI] 1.18 to 1.97). When cases of ovarian cancer were compared with infertile controls for exposure to infertility medications, the odds ratio (0.99; 95% CI 0.67, 1.45) was not elevated. However, cohort data comparing outcome in treated infertile patients with untreated infertile patients suggests that treated patients may tend to a lower incidence of ovarian cancer-odds ratio = 0.67 (95% CI 0.32, 1.41). Ovarian cancer does not appear to be increased in treated infertile patients versus untreated infertile patients. Treated infertile patients may have a lower incidence of ovarian cancer than untreated infertile patients.


IFNγ Production Profile in Turkeys of Different Immunological Status after TRT Vaccination.
Despite vaccination against avian metapneumoviruses (aMPV), cases of turkey rhinotracheitis (TRT) caused by aMPV field strains are frequently reported. Differences have been shown in the level of immune system stimulation after aMPV vaccination between turkeys that do and do not possess specific anti-aMPV maternally derived antibodies (MDA). The article describes the influence of MDA on the production of IFNγ in the spleen of aMPV-vaccinated turkeys. MDA+ or MDA- turkeys were vaccinated against TRT after hatching or on the 14th day of life. Spleen samples were collected 3, 7, and 14 days post vaccination for mononuclear cell isolation. Real-time PCR, flow cytometry, and the enzyme-linked immunospot assay were used to evaluate the levels of IFNγ gene expression, production, and secretion by cells within the spleen samples. Increased IFNγ gene expression was noticed after vaccination only in birds that did not possess MDA or possessed MDA at relatively low level (MDA+ birds vaccinated at 14 DOL). In all birds, an increased percentage of T lymphocytes producing IFNγ was recorded. The proportion of anti-aMPV IFNγ-secreting cells was increased only in MDA- birds. Besides having a protective role, MDA are known to interfere with vaccination efficacy. The analysis of our results confirms that MDA can decrease the level of immune system stimulation after aMPV vaccination of turkeys.


Feasibility of dried blood spots for HIV viral load monitoring in decentralized area in North Vietnam in a test-and-treat era, the MOVIDA project.
Access to HIV viral load is crucial to efficiently monitor patients on antiretroviral treatment (ART) and prevent HIV drug resistance acquisition. However, in some remote settings, access to viral load monitoring is still complex due to logistical and financial constraints. Use of dried blood spots (DBS) for blood collection could overcome these difficulties. This study aims to describe feasibility and operability of DBS use for routine viral load monitoring. From June 2017 to April 2018, HIV-infected adults who initiated ART were enrolled in a prospective cohort in 43 clinical sites across 6 provinces in North Vietnam. Following national guidelines, the first viral load monitoring was planned 6 months after ART initiation. DBS were collected at the clinical site and sent by post to a central laboratory in Hanoi for viral load measurement. Of the 578 patients enrolled, 537 were still followed 6 months after ART initiation, of which DBS was collected for 397 (73.9%). The median (inter quartile range) delay between DBS collection at site level and reception at the central laboratory was 8 (6-19) days and for 70.0% viral load was measured ≤30 days after blood collection. The proportion of patients with viral load ≥1000 copies/mL at the 6 month evaluation was 15.9% (n = 59). Of these, a DBS was collected again to confirm virological failure in 15 (24.4%) of which virological failure was confirmed in 11 (73.3%). Delay of DBS transfer to the central laboratory was acceptable and most viral loads were measured in ≤30 days, in-line with routine follow-up. However, the level of DBS coverage and the proportion of patients in failure for whom a confirmatory viral load was available were suboptimal, indicating that integration of viral load monitoring in the field requires, among other things, careful training and strong involvement of the local teams. The proportion of patients experiencing virological failure was in line with other reports; interestingly those who reported being non-adherent and those with a low BMI were more at risk of failure.


Ursodeoxycholic acid ingestion after ileal resection. Effect on biliary bile acid and lipid composition.
The effect of ursodeoxycholic acid ingestion on biliary bile acids and biliary lipids was studied in six patients after ileal resection. All patients had bile acid malabsorption, as documented by increased breath and fecal excretion of 14C after oral administration of [1-14C] cholylglycine. Fasting duodenal bile was collected by intubation before and seven days after ursodeoxycholic acid administration (4 g/day), and biliary bile acid and lipid composition were determined. Ursodeoxycholic acid ingestion increased the percentage of ursodeoxycholic acid in bile tenfold (3.6 +/- 2.6% vs 38.6 +/- 12.0%) and decreased chenodeoxycholic acid in bile by approximately 40%. Before ursodeoxycholic acid ingestion, bile was supersaturated in all patients. After ursodeoxycholic acid ingestion, cholesterol saturation decreased in all six patients by an average of 43%, and bile became unsaturated in five. Ursodeoxycholic acid ingestion had no effect on stool frequency. We conclude that, as in subjects with an intact enterohepatic circulation, ursodeoxycholic acid therapy has litholytic potential in patients after ileal resection.


Monitoring of viral cancer progression using FTIR microscopy: a comparative study of intact cells and tissues.
Fourier transform infrared microspectroscopy (FTIR-MSP) is an analytical method with a promising potential for detecting the spectral changes due to cancerous changes in cells. The purpose of the present study is monitoring biochemical spectral changes accompanying viral cancer progression in cells and tissues using FTIR-MSP. As a model system, we used cells in culture which were transformed to malignant cells by infection with murine sarcoma virus (MuSV) and cervical tissues at different neoplastic stages. In order to devise a systematic follow-up of the cancer progression, it was essential first to determine and validate consistent and significant spectral biomarkers, which can evidently discriminate between normal and cancerous cells/tissues. Then these biomarkers were used for the characterization and classification of early stages of malignant transformation utilizing discriminant classification function techniques. Our study points out that malignancy progression can be eminently graded for both cell lines and tissues. For example, using the array of four biomarkers: A(2958)A(2852)+A(2923),A(1121)/A(1015),A(1171)/A(1152)and|A(1082)-A(1056)|A(1028), we attained that the classification accuracies of different premalignant stages of cell lines and tissues were varied between 89.5 and 97.4%. These results strongly support the potential of developing FTIR microspectroscopy as a simple, reagent free method for early detection and accurate differentiation of premalignant stages.


Localization of the appendix at MR imaging during pregnancy: utility of the cecal tilt angle.
To determine whether the cecal tilt angle on sagittal magnetic resonance (MR) images in pregnant patients correlates with the location of the appendix and gestational age and whether the cecal tilt angle can help predict the location of the appendix. This HIPAA-compliant retrospective study was approved by the institutional review board. Informed consent was waived. Of 146 consecutive pregnant patients suspected of having appendicitis (mean age, 29 years) who underwent MR imaging, 143 had MR images in which the appendix and cecum were identifiable in the sagittal plane. Two observers reviewed the MR images; findings were agreed upon by consensus. With use of sagittal single-shot fast spin-echo MR images, the cecal tilt angle was calculated as the angle between the imaging table and a line drawn between the cecal tip and the luminal center of the most proximal inflection point in the ascending colon. The location of the appendiceal base relative to the lumbosacral spine was recorded. Statistical analyses were performed by using Spearman and Pearson correlation coefficients to evaluate the relationship among gestational age, appendiceal base location, and cecal tilt angle. Receiver operating characteristic curve analysis was performed to assess the ability of the cecal tilt angle to help differentiate between a high and low appendiceal base level. Cecal tilt angles showed moderate correlation with appendiceal base levels (Spearman correlation coefficient, 0.44; P < .001) and poor correlation with gestational age (Pearson correlation coefficient, 0.25; P = .002). Regardless of gestational age, cecal tilt angles of at least 90 degrees were predictive of a high appendiceal base level with a specificity of 98% (95% confidence interval: 92%, 100%). The cecal tilt angle is useful for localizing the appendix in pregnant patients at MR imaging and helps predict the location of the appendix within the right upper quadrant of the abdomen with high specificity, irrespective of gestational age.


Retinoic acid inhibits monocyte to macrophage survival and differentiation.
Vitamin A metabolites are potent differentiation-inducing agents for myelomonocytic cell lines in vitro and are successfully used for the treatment of patients with acute promyelocytic leukemia. However, little is known about the effects of vitamin A on normal hematopoietic cells. Therefore, we investigated the effect of vitamin A on differentiation and activation of human blood monocytes (MO). Culturing MO for up to 4 days with 9-cis retinoic acid (RA) and all-trans RA but not retinol reduced MO survival, with the remaining cells being morphologically comparable to control cells. Because macrophage colony-stimulating factor (M-CSF) is a well-known survival factor for MO, we measured the M-CSF content of MO culture supernatants using enzyme-linked immunosorbent assay and found that RA suppressed the constitutive secretion of M-CSF. Northern analysis showed that the M-CSF mRNA expression was only slightly reduced by RA treatment, suggesting regulation on the posttranscriptional level. In contrast to MO, M-CSF secretion by MO-derived macrophages (MAC) was not altered by RA, suggesting a differentiation-dependent switch in the responsiveness of MO/MAC to RA. Because M-CSF is not only a survival-promoting but also a differentiation-promoting factor for myeloid cells, we analyzed the effect of RA on MO to MAC maturation. RA suppressed the expression of the maturation-associated antigen carboxypeptidase M (CPM)/MAX.1 at both the protein and mRNA levels and modulated the lipopolysaccharide-stimulated cytokine secretion of MO/MAC. The addition of exogenous M-CSF to RA-containing MO cultures fails to overcome the RA-induced inhibition of MO differentiation. However, the survival rate was improved by exogenous M-CSF. We conclude that RA acts via two different mechanisms on monocyte survival and differentiation: posttranscriptionally by controlling M-CSF secretion, which decreases MO survival, and transcriptionally regulating the expression of differentiation-associated genes. The regulation of M-CSF production may contribute to the antileukemic effect of RA in vivo by reducing autocrine M-CSF production by leukemic cells.


The Preterm Clinical Network (PCN) Database: a web-based systematic method of collecting data on the care of women at risk of preterm birth.
Despite much research effort, there is a paucity of conclusive evidence in the field of preterm birth prediction and prevention. The methods of monitoring and prevention strategies offered to women at risk vary considerably around the UK and depend on local maternity care provision. It is becoming increasingly recognised that this experience and knowledge, if captured on a larger scale, could be a utilized as a valuable source of evidence for others. The UK Preterm Clinical Network (UKPCN) was established with the aim of improving care and outcomes for women at risk of preterm birth through the sharing of a wealth of experience and knowledge, as well as the building of clinical and research collaboration. The design and development of a bespoke internet-based database was fundamental to achieving this aim. Following consultation with UKPCN members and agreement on a minimal dataset, the Preterm Clinical Network (PCN) Database was constructed to collect data from women at risk of preterm birth and their children. Information Governance and research ethics committee approval was given for the storage of historical as well as prospectively collected data. Collaborating centres have instant access to their own records, while use of pooled data is governed by the PCN Database Access Committee. Applications are welcomed from UKPCN members and other established research groups. The results of investigations using the data are expected to provide insights into the effectiveness of current surveillance practices and preterm birth interventions on a national and international scale, as well as the generation of ideas for innovation and research. To date, 31 sites are registered as Data Collection Centres, four of which are outside the UK. This paper outlines the aims of the PCN Database along with the development process undertaken from the initial idea to live launch.


Atmospheric concentrations and sources of trace metals at the South pole.
The chemical composition of atmospheric particulate material collected at the geographic South Pole indicates that Al, Sc, Th, Sm, V, Mn, Eu, Fe, La, Ce, Co, Cr, Na, K, Mg, and Ca are derived from either crustal weathering or the ocean. The relatively volatile elements Zn, Cu, Sb, Se, Pb, and Br are apparently derived from other sources. Because of their volatility, vapor-phase condensation or a high-temperature dispersion source is suspected for these elements or their compounds.


The structure of Apo R268A human aldose reductase: hinges and latches that control the kinetic mechanism.
Aldose reductase (AR) catalyzes the NADPH-dependent reduction of glucose and other sugars to their respective sugar alcohols. The NADP+/NADPH exchange is the rate-limiting step for this enzyme and contributes in varying degrees to the catalytic rates of other aldo-keto reductase superfamily enzymes. The mutation of Arg268 to alanine in human recombinant AR removes one of the ligands of the C2-phosphate of NADP+ and markedly reduces the interaction of the apoenzyme with the nucleotide. The crystal structure of human R268A apo-aldose reductase determined to a resolution of 2.1 A is described. The R268A mutant enzyme has similar kinetic parameters to the wild-type enzyme for aldehyde substrates, yet has greatly reduced affinity for the nucleotide substrate which greatly facilitates its crystallization in the apoenzyme form. The apo-structure shows that a high temperature factor loop (between residues 214 and 226) is displaced by as much as 17 A in a rigid body fashion about Gly213 and Ser226 in the absence of the nucleotide cofactor as compared to the wild-type holoenzyme structure. Several factors act to stabilize the NADPH-holding loop in either the 'open' or 'closed' conformations: (1) the presence and interactions of the nucleotide cofactor, (2) the residues surrounding the Gly213 and Ser226 hinges which form unique hydrogen bonds in the 'open' or 'closed' structure, and (3) the Trp219 "latch" residue which interacts with an arginine residue, Arg293, in the 'open' conformation or with a cysteine residue, Cys298, in the 'closed' conformation. Several mutations in and around the high temperature factor loop are examined to elucidate the role of the loop in the mechanism by which aldose reductase binds and releases its nucleotide substrate.


The myth of plant species saturation.
Plant species assemblages, communities or regional floras might be termed 'saturated' when additional immigrant species are unsuccessful at establishing due to competitive exclusion or other inter-specific interactions, or when the immigration of species is off-set by extirpation of species. This is clearly not the case for state, regional or national floras in the USA where colonization (i.e. invasion by exotic species) exceeds extirpation by roughly a 24 to 1 margin. We report an alarming temporal trend in plant invasions in the Pacific Northwest over the past 100 years whereby counties highest in native species richness appear increasingly invaded over time. Despite the possibility of some increased awareness and reporting of native and exotic plant species in recent decades, historical records show a significant, consistent long-term increase in exotic species (number and frequency) at county, state and regional scales in the Pacific Northwest. Here, as in other regions of the country, colonization rates by exotic species are high and extirpation rates are negligible. The rates of species accumulation in space in multi-scale vegetation plots may provide some clues to the mechanisms of the invasion process from local to national scales.


NRG1 is required for glucose repression of the SUC2 and GAL genes of Saccharomyces cerevisiae.
Glucose repression of transcription in the yeast, Saccharomyces cerevisiae, has been shown to be controlled by several factors, including two repressors called Mig1 and Mig2. Past results suggest that other repressors may be involved in glucose repression. By a screen for factors that control transcription of the glucose-repressible SUC2 gene of S. cerevisiae, the NRG1 gene was identified. Analysis of an nrg1Delta mutant has demonstrated that mRNA levels are elevated at both the SUC2 and of the GAL genes of S. cerevisiae when cells are grown under normally glucose-repressing conditions. In addition, genetic interactions have been detected between nrg1Delta and other factors that control SUC2 transcription. The analysis of nrg1Delta demonstrates that Nrg1 plays a role in glucose repression of the SUC2 and GAL genes of S. cerevisiae. Thus, three repressors, Nrg1, Mig1, and Mig2, are involved as the downstream targets of the glucose signaling in S. cerevisiae.


Melanopsin-dependent persistence and photopotentiation of murine pupillary light responses.
To determine the relative contributions of inner and outer retinal photoreception to the pupillary light response. Wild-type, retinal degenerate (rd/rd), and melanopsin mutant (opn4(-/-)) mice were tested for pupillary light responsiveness by video pupillometry before, during, and after exposure to supersaturating light intensities. Similar lighting protocols were used to probe responses of intrinsically photosensitive retinal ganglion cells (ipRGCs) recorded with multielectrode arrays ex vivo. Both outer retinal photoreceptors (rods and cones) and inner retinal photoreceptors (intrinsically photosensitive retinal ganglion cells [ipRGCs]) are sufficient to drive the pupillary light response in mice. After supersaturating light exposure, rather than bleaching or adapting, rd/rd mice showed paradoxical potentiation of responses to subsaturating light exposure. opn4(-/-) mice, in contrast, could not sustain pupillary constriction under continuous bright illumination, and showed desensitization after bright-light exposure. Both the intensity of light necessary to induce potentiation and the spectral sensitivity for sustained and potentiated responses differed from that necessary to trigger pupillary constriction, suggesting that photopotentiation is dependent on a pigment-state distinct from that triggering the pupillary light response itself. Multielectrode array recordings of ipRGCs from rd/rd retinas demonstrated persistent cell firing under continuous light exposure but did not show potentiation. Unique photoreceptive properties of intrinsically photosensitive RGCs confer resistance to bleaching and/or adaptation under continuous bright illumination to the pupillary light response and suggest the presence of a photopigment with multiple absorption states.


MKP1 regulates the induction of MUC5AC mucin by Streptococcus pneumoniae pneumolysin by inhibiting the PAK4-JNK signaling pathway.
Mucosal epithelial cells in the respiratory tract act as the first line of host innate defense against inhaled microbes by producing a range of molecules for clearance. In particular, epithelial mucins facilitate the mucociliary clearance by physically trapping the inhaled microbes. Up-regulation of mucin production thus represents an important host innate defense response against invading microbes. Excess mucin production, however, overwhelms the mucociliary clearance, resulting in defective mucosal defenses. Thus, tight regulation of mucin production is critical for maintaining an appropriate balance between beneficial and detrimental outcomes. Among various mechanisms, negative regulation plays an important role in tightly regulating mucin production. Here we show that the PAK4-JNK signaling pathway acted as a negative regulator for Streptococcus pneumoniae pneumolysin-induced MUC5AC mucin transcription. Moreover pneumolysin also selectively induced expression of MKP1 via a TLR4-dependent MyD88-TRAF6-ERK signaling pathway, which inhibited the PAK4-JNK signaling pathway, thereby leading to up-regulation of MUC5AC mucin production to maintain effective mucosal protection against S. pneumoniae infection. These studies provide novel insights into the molecular mechanisms underlying the tight regulation of mucin overproduction in the pathogenesis of airway infectious diseases and may lead to development of new therapeutic strategies.


In vivo administration of TNF-alpha prevents EMC-M virus induced viral encephalitis.
EMC-M virus causes a monophasic paralytic syndrome characterized by encephalitic lesions in the brain and patchy demyelinating lesions in the spinal cord and nerve roots of BALB/c mice. Since the replication of EMC virus in vitro is inhibited by tumor necrosis factor (TNF)-alpha we have studied the effect of in vivo administration of this cytokine on the acute disease. Our studies show that periodic administration of TNF-alpha to animals infected with EMC-M reduces viral titers in the brain, and decreases the degree of clinical paralysis and the severity of the inflammatory lesions in the brain.


[Effect of Long Non-Coding RNA LINC01268 on the Malignant Biological Behaviors of Acute Myeloid Leukemia Cells].
To investigate the effect of long non-coding RNA LINC01268 on apoptosis of acute myeloid leukemia (AML) cells and related mechanisms. The expression levels of LINC01268 and miR-217 in peripheral blood samples from AML patients and AML cell lines HL-60 and KG-1 were detected by qRT-PCR. HL-60 cells were divided into pcDNA3.1-NC, pcDNA3.1-LINC01268, si-NC, si-LINC01268, miR-NC, miR-217 mimics, si-LINC01268 + inhibitor-NC and si-LINC01268+ miR-217 inhibitor groups. The mRNA expressions of LINC01268 and miR-217 were detected by qRT-PCR. The targeting relationship between LINC01268 and miR-217 was detected by dual-luciferase reporter assay. Cell viability was detected by CCK-8 assay. Cell cycle distribution and apoptosis were detected by flow cytometry. The expression of cell cycle and apoptosis-related proteins p21, Bcl-2, Bax, caspase-3 and PI3K/AKT signaling pathway-related proteins were detected by Western blot. The expression of LINC01268 in peripheral blood samples of AML patients and AML cell lines HL-60 and KG-1 was increased (P < 0.05), and the expression of miR-217 was decreased (P < 0.05). Compared with si-NC group and miR-NC group, the viability of HL-60 cells was decreased in si-LINC01268 group and miR-217 mimics group (P < 0.05), the proportion of cells in G1 phase and apoptosis rate were increased (P < 0.05), the protein expression levels of p21, Bax and caspase-3 were increased (P < 0.05), while the protein expression level of Bcl-2 was decreased (P < 0.05). LINC01268 targeted and negatively regulated the expression of miR-217, and inhibiting the expression of miR-217 partially reversed the effects of LINC01268 interference on the viability, cell cycle and apoptosis of HL-60 cells. Interference with LINC01268 could inhibit the activity of PI3K/AKT signaling pathway. Inhibiting the expression of miR-217 could partially reverse the inhibition of LINC01268 interference on PI3K/AKT signaling pathway. LINC01268 is highly expressed and miR-217 is lowly expressed in AML cells. LINC01268 can promote the activity of PI3K/AKT signaling pathway, increase the survival rate and inhibit the apoptosis of AML cells by targeting miR-217 expression.


Sulforaphane Attenuates AOM/DSS-Induced Colorectal Tumorigenesis in Mice via Inhibition of Intestinal Inflammation.
Sulforaphane (SFN) is a compound derived from cruciferous plants. It has received considerable attention in recent years due to its effectiveness in cancer prevention and anti-inflammatory properties. The purpose of this study was to evaluate the antitumor potential of sulforaphane on colitis-associated carcinogenesis (CAC) through the establishment of a mouse model with AOM/DSS. First, AOM/DSS and DSS-induced model were established and administered SFN for 10 wk, and then the severity of colitis-associated colon cancer was examined macroscopically and histologically. Subsequently, immune cells and cytokines in the tumor microenvironment (TME) were quantified. Finally, the influence of sulforaphane was also investigated using different colon cell lines. We found that sulforaphane treatment decreased tumor volume, myeloid-derived suppressor cells (MDSC) expansion, the expression of the proinflammatory cytokine IL-1β, and the level of IL-10 in serum. Also, it enhanced the antitumor activities of CD8+ T cells and significantly reduced tumorigenesis as induced by AOM/DSS. SFN also attenuated intestinal inflammation in DSS-induced chronic colitis by reshaping the inflammatory microenvironment. This work demonstrates that sulforaphane suppresses carcinogenesis-associated intestinal inflammation and prevents AOM/DSS-induced intestinal tumorigenesis and progression.


Very rapid phosphorylation kinetics suggest a unique role for Lhcb2 during state transitions in Arabidopsis.
Light-harvesting complex II (LHCII) contains three highly homologous chlorophyll-a/b-binding proteins (Lhcb1, Lhcb2 and Lhcb3), which can be assembled into both homo- and heterotrimers. Lhcb1 and Lhcb2 are reversibly phosphorylated by the action of STN7 kinase and PPH1/TAP38 phosphatase in the so-called state-transition process. We have developed antibodies that are specific for the phosphorylated forms of Lhcb1 and Lhcb2. We found that Lhcb2 is more rapidly phosphorylated than Lhcb1: 10 sec of 'state 2 light' results in Lhcb2 phosphorylation to 30% of the maximum level. Phosphorylated and non-phosphorylated forms of the proteins showed no difference in electrophoretic mobility and dephosphorylation kinetics did not differ between the two proteins. In state 2, most of the phosphorylated forms of Lhcb1 and Lhcb2 were present in super- and mega-complexes that comprised both photosystem (PS)I and PSII, and the state 2-specific PSI-LHCII complex was highly enriched in the phosphorylated forms of Lhcb2. Our results imply distinct and specific roles for Lhcb1 and Lhcb2 in the regulation of photosynthetic light harvesting.


[Efficacy of various types of femoropopliteal crural bypass grafting].
Over the period from 1997 to 2007 a total of 132 patients presenting with chronic lower-limb ischaemia underwent reconstructive bypass grafting operations performed at the Department of Cardiovascular Surgery of the Murmansk Regional Clinical Hospital named after P.A. Bayandin. Depending on the method of formation of the distal anastomosis the patients were subdivided into two groups: Group I with endarterectomy in the zone of the distal anastomosis, including 39 patients, and Group II without endarterectomy, comprising 93 patients. As the plastic material for bypass grafting we used autoveins in the "reverse" and "in situ" positions, allografts made of polytetrafluoroethylene (PTFE) or woven fabric, combined grafts. In the both groups prevailing were patients with critical ischaemia of the lower limbs. Thus, 20 (51.3%) patients had degree III ischaemia in Group One and 60 (64.5%) patients in Group Two, and 18 (46.2%) patients had ischaemia degree IV and 20 (21.5%), respectively. In order to evaluate the state of the distal bed we calculated the average score according to the Rutherford classification (Rutherford, et al., 1997), which amounted to 7.56 ±1.5 and 6.2±1.43 for Group I and II, respectively. The best patency and limb salvage rate were observed in autovenous bypass grafting according to the "in situ" technique without endarterectomy. Thus, the cumulative patency amounted to 21% and limb salvage to 29.4% after 5 years.


Formulation design of self-microemulsifying drug delivery systems for improved oral bioavailability of celecoxib.
Celecoxib is a hydrophobic and highly permeable drug belonging to class II of biopharmaceutics classification system. Low aqueous solubility of celecoxib leads to high variability in absorption after oral administration. Cohesiveness, low bulk density and compressibility, and poor flow properties of celecoxib impart complications in it's processing into solid dosage forms. To improve the solubility and bioavailability and to get faster onset of action of celecoxib, the self-microemulsifying drug delivery system (SMEDDS) was developed. Composition of SMEDDS was optimized using simplex lattice mixture design. Dissolution efficiency, t(85%), absorbance of diluted SMEDDS formulation and solubility of celecoxib in diluted formulation were chosen as response variables. The SMEDDS formulation optimized via mixture design consisted of 49.5% PEG-8 caprylic/capric glycerides, 40.5% mixture of Tween20 and Propylene glycol monocaprylic ester (3:1) and 10% celecoxib, which showed significantly higher rate and extent of absorption than conventional capsule. The relative bioavailability of the SMEDDS formulation to the conventional capsule was 132%. The present study demonstrated the suitability of mixture design to optimize the compositions for SMEDDS. The developed SMEDDS formulations have the potential to minimize the variability in absorption and to provide rapid onset of action of celecoxib.


GRAND ROUNDS: an atypical progressive dementia in a male carrier of the fragile X premutation: an example of fragile X-associated tremor/ataxia syndrome.
This case study describes a 65-year-old man initially diagnosed with an atypical rapidly progressive dementia who subsequently participated in a research project at the MIND Institute at the University of California-Davis, where he was diagnosed with a recently identified neurodegenerative syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS). He was a carrier of the fragile X premutation and in later life developed tremor, gait ataxia, parkinsonism, and cognitive deficits that progressed very rapidly. This case study provides a detailed description of the individual's history, presenting symptoms, neuropsychological test results, and postmortem neuropathological analysis. Pathological findings showed diagnostic features of both FXTAS and Alzheimer's disease, which might help to explain the rapid progression of his dementia.


Inhibitors and promoters of stone formation.
The understanding of the formation of urinary stones centers around three main mechanisms: the urinary concentration of stone-forming ions, the role of promoters, and the role of inhibitors of crystal formation and crystal aggregation. With respect to the promoting activity, lately emphasis has shifted from the role of the organic matrix to that of one salt inducing by epitaxy the precipitation of another salt. Among the inhibitors, it has become necessary to distinguish between those affecting crystal formation and those affecting crystal aggregation. For measuring the inhibitory activity, the various techniques and their relevance have been reviewed. It has been found that the main inhibitors for calcium phosphate and calcium oxalate precipitation are citrate, pyrophosphate, and perhaps magnesium. Those for calcium phosphate and calcium oxalate aggregation are glycosaminoglycans, pyrophosphate, and citrate. Among the synthetic inhibitors, the diphosphonates are the most powerful for both processes. The role and the therapeutic implications of these various concepts have been discussed.


Practical induction system for dopamine-producing cells from bone marrow stromal cells using spermine-pullulan-mediated reverse transfection method.
Introduction of various kinds of exogenous genes is an important step for control of differentiation in stem cell biology and regenerative medicine. However, some kinds of cells are vulnerable to manipulations such as gene delivery. In this context, a gene introduction method with higher efficiency and safety is required. Bone marrow stromal cells (BMSCs) offer possibilities for clinical application because of their potential for expandability and ability to be auto-transplanted. In this study, we established an efficient induction system of dopamine-producing neuronal cells from BMSCs in several species using the spermine-pullulan-mediated reverse transfection technique. In this system, introduced exogenous plasmid genes were successfully transcribed and expressed as proteins in the cytoplasm of BMSCs with the smallest number of cell death. Microtubule-associated protein 2 and anti-beta-tubulin class III+ neurons were successfully delivered from human, monkey, and mouse BMSCs, and further treatment with trophic factors promoted differentiation of induced neuronal cells into dopamine-producing cells that were positive for tyrosine hydroxylase and secreted dopamine after high K+ stimulation in high-performance liquid chromatography analysis. Our study indicates the availability of the reverse transfection method for the induction of dopamine-producing neuronal cells from BMSCs, which is expected to apply to cell-based therapy in Parkinson's disease.


Role of NAD+ and ADP-ribosylation in the maintenance of the Golgi structure.
We have investigated the role of the ADP- ribosylation induced by brefeldin A (BFA) in the mechanisms controlling the architecture of the Golgi complex. BFA causes the rapid disassembly of this organelle into a network of tubules, prevents the association of coatomer and other proteins to Golgi membranes, and stimulates the ADP-ribosylation of two cytosolic proteins of 38 and 50 kD (GAPDH and BARS-50; De Matteis, M.A., M. DiGirolamo, A. Colanzi, M. Pallas, G. Di Tullio, L.J. McDonald, J. Moss, G. Santini, S. Bannykh, D. Corda, and A. Luini. 1994. Proc. Natl. Acad. Sci. USA. 91:1114-1118; Di Girolamo, M., M.G. Silletta, M.A. De Matteis, A. Braca, A. Colanzi, D. Pawlak, M.M. Rasenick, A. Luini, and D. Corda. 1995. Proc. Natl. Acad. Sci. USA. 92:7065-7069). To study the role of ADP-ribosylation, this reaction was inhibited by depletion of NAD+ (the ADP-ribose donor) or by using selective pharmacological blockers in permeabilized cells. In NAD+-depleted cells and in the presence of dialized cytosol, BFA detached coat proteins from Golgi membranes with normal potency but failed to alter the organelle's structure. Readdition of NAD+ triggered Golgi disassembly by BFA. This effect of NAD+ was mimicked by the use of pre-ADP- ribosylated cytosol. The further addition of extracts enriched in native BARS-50 abolished the ability of ADP-ribosylated cytosol to support the effect of BFA. Pharmacological blockers of the BFA-dependent ADP-ribosylation (Weigert, R., A. Colanzi, A. Mironov, R. Buccione, C. Cericola, M.G. Sciulli, G. Santini, S. Flati, A. Fusella, J. Donaldson, M. DiGirolamo, D. Corda, M.A. De Matteis, and A. Luini. 1997. J. Biol. Chem. 272:14200-14207) prevented Golgi disassembly by BFA in permeabilized cells. These inhibitors became inactive in the presence of pre-ADP-ribosylated cytosol, and their activity was rescued by supplementing the cytosol with a native BARS-50-enriched fraction. These results indicate that ADP-ribosylation plays a role in the Golgi disassembling activity of BFA, and suggest that the ADP-ribosylated substrates are components of the machinery controlling the structure of the Golgi apparatus.


Sharps Disposal Practices Among People With Diabetes in a Community Care Clinic.
The primary objective of this study was to determine sharps disposal practices among people with diabetes in a community care clinic. Secondary objectives were to identify patterns of sharps use and barriers to proper use. Surveys were distributed to patients at a community care clinic in person and via mail. Survey questions focused on how sharps are used and disposed of, the frequency of sharps changes, sharps disposal training, sharps identification, and confidence in sharps disposal. Participant demographics and diabetes profiles were also collected. Among 89 respondents, mean age was 60 years (range 29-93 years), 61.8% were Caucasian, 88.8% had type 2 diabetes, and 60.7% had had a diabetes diagnosis for ≤10 years, with diverse diabetes management methods; 57.3% did not receive or were unsure of sharps training, 25.8% discarded used sharps without a designated sharps container, and 37.1% properly disposed of sharps containers at sharps disposal facilities. Barriers to proper sharps practices included perceived safety of reusing sharps and waste with single use, cost, and the hassle of disposal. Those with prior sharps training were more likely to properly use and discard sharps; however, gaps in knowledge were still evident in this population. Results indicate gaps in proper sharps use and disposal knowledge among people with diabetes. Responses revealed sharps practices that are inconsistent with current federal and state regulations and are potentially dangerous for those handling improperly discarded sharps. Targeted sharps usage and disposal education resources are needed for individuals with and without prior sharps training.


Amino acid transport by prosthecae of Asticcacaulis biprosthecum: evidence for a broad-range transport system.
Prosthecae purified from cells of Asticcaulis biprosthecum possess active transport systems that transport all 20 amino acids tested. Using ascorbate-reduced phenazine methosulphate in the presence of oxygen, all 20 amino acids are accumulated against a concentration gradient by isolated prosthecae. Results of experiments testing the inhibition of transport of one amino acid by another, and of experiments testing the exchange of exogenous amino acids with those preloaded in prosthecae, along with characteristics of mutants defective in amino acid transport, suggest the presence in prosthecae of three amino acid transport systems. One, the general or G system, transports at least 18 of the 20 amino acids tested. Another system, referred to as the proline or P system, transports seven amino acids (including proline) that are also transported by the G system. The third system transports only glutamate and aspartate, and is referred to as the acidic amino acid transport system or A system.


[Evaluation of dynamic left ventricular outflow tract obstruction by dobutamine stress echocardiography].
This study was planned to evaluate the dynamic left ventricular outflow tract (LVOT) obstruction by using dobutamine stress echocardiography (DSE) in patients with asymmetric septal hypertrophy and/or septal bulging, who have no signs of LVOT gradient detected by conventional echocardiography, with symptoms mimicking hypertrophic obstructive cardiomyopathy (HOCM). In sixty-one consecutive patients referred to our echocardiography laboratory with HOCM pre-diagnosis, exercise dyspnea and limitation of exercise capacity were evaluated. DSE was performed in 31 patients who fulfilled the inclusion criteria. Patients were divided into two groups according to the degree of dynamic gradient increase above baseline values during stress-test (Group 1 < 30 mmHg, Group 2 > 30 mmHg). Left ventricular diameters, septum and posterior wall thicknesses, ejection fraction, LVOT and aortic root diameters, presence of septal bulging and systolic anterior motion (SAM) and degree of septal angulation were sought. There were no significant differences between groups by means of LV diameters, septum and posterior wall thicknesses, EF, LVOT and aortic root diameters, presence of septal bulging (p > 0.05); whereas there were significant differences in SAM and degree of septal angulation (p < 0.05 and p < 0.0001, respectively). Systolic anterior motion (r = 0.61, p < 0.0001) and degree of septal angulation (r = -0.71, p < 0.001) correlated significantly with the dynamic gradient increase. Presence of SAM and degree of septal angulation obtained by DSE are reliable parameters to determine dynamic LVOT obstruction in patients who have asymmetric septal hypertrophy and septal bulging with no gradient on LVOT by conventional echocardiography.


Formation of porous crystals via viscoelastic phase separation.
Viscoelastic phase separation of colloidal suspensions can be interrupted to form gels either by glass transition or by crystallization. With a new confocal microscopy protocol, we follow the entire kinetics of phase separation, from homogeneous phase to different arrested states. For the first time in experiments, our results unveil a novel crystallization pathway to sponge-like porous crystal structures. In the early stages, we show that nucleation requires a structural reorganization of the liquid phase, called stress-driven ageing. Once nucleation starts, we observe that crystallization follows three different routes: direct crystallization of the liquid phase, the Bergeron process, and Ostwald ripening. Nucleation starts inside the reorganized network, but crystals grow past it by direct condensation of the gas phase on their surface, driving liquid evaporation, and producing a network structure different from the original phase separation pattern. We argue that similar crystal-gel states can be formed in monatomic and molecular systems if the liquid phase is slow enough to induce viscoelastic phase separation, but fast enough to prevent immediate vitrification. This provides a novel pathway to form nanoporous crystals of metals and semiconductors without dealloying, which may be important for catalytic, optical, sensing, and filtration applications.


Efficacy of a fixed combination of indomethacin, prochlorperazine, and caffeine versus sumatriptan in acute treatment of multiple migraine attacks: a multicenter, randomized, crossover trial.
To compare the efficacy of a fixed combination of indomethacin, prochlorperazine, and caffeine suppositories with sumatriptan suppositories in the treatment of 2 consecutive migraine attacks of moderate or severe intensity in a multicenter, randomized, crossover study. A fixed combination of indomethacin, prochlorperazine, and caffeine is the most commonly used drug for the acute treatment of migraine in Italy. No studies have been published comparing the efficacy of this combination with sumatriptan, the most widely prescribed of the triptans. One hundred twelve patients with migraine with or without aura according to the diagnostic criteria of the International Headache Society were randomized to treat 2 migraine attacks with a fixed combination of indomethacin, prochlorperazine, and caffeine and 2 migraine attacks with sumatriptan. Both drugs were rectally administered in a single dose for each attack. Patients were asked to take study medication as soon as possible at the onset of a headache. Of the 112 patients, 88 were compliant to the protocol. More attacks became pain-free at 2 hours postdose (primary end point) on the combination than on sumatriptan (49% versus 34%; P<.01), while there was no difference in the relief of headache at 2 hours postdose (71% versus 65%). The combination was statistically superior to sumatriptan in the time to a pain-free response (a higher percentage of attacks became pain-free from 0.5 hours postdose to 5 hours postdose), in alleviation of nausea, and in a sustained pain-free response (pain-free at 2 hours postdose with no use of rescue medication or relapses within 48 hours). Moreover, a significant consistent response was achieved for the combination compared with sumatriptan across (higher percentage of patients pain-free at 2 hours postdose in the first, second, third, and fourth treated attack) and within patients (pain-free in 2 of 2 treated attacks in 35% of patients taking the combination and 20% of patients on sumatriptan). Both drugs were well-tolerated. This study, analyzed according to the more recent guidelines for controlled trials in migraine, showed that a fixed combination of indomethacin, prochlorperazine, and caffeine is significantly more effective than sumatriptan in the acute treatment of migraine attacks. It is notable that the combination is less expensive than sumatriptan per unit dose.


Solid-phase immune electron microscopy-double-antibody technique for rapid detection of papovaviruses.
The solid-phase immune electron microscopy-double-antibody technique, which takes less than 1 h to perform, was applied as a rapid, sensitive, and specific diagnostic tool in the demonstration of papovavirus particles. BK virus propagated in 82C human skin fibroblasts and a monospecific high-titer immune serum to BK virus were used to establish the test procedure. When Formvar-carbon-coated grids were treated with appropriately diluted antibody, a 28-fold increase of virus particles per square micrometer was observed. Viewing of the virus particles was facilitated by the addition of a second "decorator" antibody. BK virus preparations at concentrations of 10(2) to 10(3) PFU/ml could be detected by this technique. There was no cross-reaction with mouse polyomavirus.


7-monohydroxyethylrutoside protects against chronic doxorubicin-induced cardiotoxicity when administered only once per week.
Doxorubicin is a very effective antitumor agent, but its clinical use is limited by the occurrence of a cumulative dose-related cardiotoxicity, resulting in congestive heart failure. 7-Monohydroxyethylrutoside (monoHER), a flavonoid belonging to the semisynthetic hydroxyethylrutoside family, has been shown to protect against doxorubicin-induced cardiotoxicity when administered i.p. at a dose of 500 mg/kg five times/week in combination with a weekly i.v. dose of doxorubicin. Such a dosing schedule would be very inconvenient in clinical practice. We therefore investigated a dosing schedule of one administration of monoHER just before doxorubicin. The electrocardiogram was measured telemetrically in mice after the combined treatment of doxorubicin (4 mg/kg, i.v.) with one dose of monoHER (500 mg/kg, i.p., administered 1 h before doxorubicin) for 6 weeks. These data were compared with the five times/week schedule (500 mg/kg, i.p., administered 1 h before doxorubicin and every 24 h for 4 days). The increase of the ST interval was used as a measure for cardiotoxicity. It was shown that 500 mg/kg monoHER administered only 1 h before doxorubicin provided complete protection against the cardiotoxicity. This protection was present for at least 10 weeks after the last treatment. Because of the short half-life of monoHER, these results suggest that the presence of monoHER is only necessary during the highest plasma levels of doxorubicin.


Type 2 diabetes, skin autofluorescence, and brain atrophy.
Type 2 diabetes mellitus (T2DM) is associated with brain atrophy, but the mechanisms underlying this link are unknown. Advanced glycation end products (AGEs) accumulate in T2DM, resulting in inflammation, oxidative stress, and protein cross-linking, which are known contributors to neurodegeneration. We aimed to study whether tissue AGE accumulation is associated with T2DM-related brain atrophy. We performed brain magnetic resonance imaging, cognitive tests, and noninvasive skin autofluorescence (SAF; a measure of tissue AGE levels) on people aged >55 years with and without T2DM. Multivariable linear regression was used to study the relationships among T2DM, SAF, and gray matter volume (GMV). There were 486 people included in the study. T2DM was associated with greater SAF. Greater SAF, T2DM, and cognitive impairment were each associated with lower GMV independently of age, sex, and total intracranial volume. SAF partially mediated the association between T2DM and GMV. Longitudinal studies may help confirm whether tissue AGE accumulation is associated with brain atrophy in T2DM.


Identification of novel isomeric pectic oligosaccharides using hydrophilic interaction chromatography coupled to traveling-wave ion mobility mass spectrometry.
Separation and characterization of complex mixtures of pectic oligosaccharides still remains challenging and often requires the use of multiple analytical techniques, especially when isomeric structures are present. In this work, it is demonstrated that the coupling of hydrophilic interaction chromatography (HILIC) to traveling-wave ion mobility mass spectrometry (TWIMMS) enabled the simultaneous separation and characterization of complex mixtures of various isomeric pectic oligosaccharides. Labeling of oligosaccharides with 3-aminoquinoline (3-AQ) improved MS-ionization efficiency of the oligosaccharides and reduced the complexity of the product ion mass spectra, without losing resolution of the HILIC separation. In addition, labeling enabled quantification of oligosaccharides on molar basis using in-line fluorescence detection. Isomeric structures were distinguished using TWIMMS. The 3-AQ-HILIC-TWIMMS method was used to characterize a series of isomeric sugar beet rhamnogalacturonan I derived oligosaccharides carrying a glucuronic acid substituent. Thereby, some novel structural features were identified for the first time: glucuronic acid was attached to O-3 or to O-2 of galacturonic acid residues and a single galacturonic acid residue within an oligomer could contain both an acetyl group and a glucuronic acid substituent.


Noncontact Layer Stabilization of Azafullerene Radicals: Route toward High-Spin-Density Surfaces.
We deposit azafullerene C59N• radicals in a vacuum on the Au(111) surface for layer thicknesses between 0.35 and 2.1 monolayers (ML). The layers are characterized using X-ray photoemission (XPS) and X-ray absorption fine structure (NEXAFS) spectroscopy, low-temperature scanning tunneling microscopy (STM), and by density functional calculations (DFT). The singly unoccupied C59N orbital (SUMO) has been identified in the N 1s NEXAFS/XPS spectra of C59N layers as a spectroscopic fingerprint of the molecular radical state. At low molecular coverages (up to 1 ML), films of monomeric C59N are stabilized with the nonbonded carbon orbital neighboring the nitrogen oriented toward the Au substrate, whereas in-plane intermolecular coupling into diamagnetic (C59N)2 dimers takes over toward the completion of the second layer. By following the C59N• SUMO peak intensity with increasing molecular coverage, we identify an intermediate high-spin-density phase between 1 and 2 ML, where uncoupled C59N• monomers in the second layer with pronounced radical character are formed. We argue that the C59N• radical stabilization of this supramonolayer phase of monomers is achieved by suppressed coupling to the substrate. This results from molecular isolation on top of the passivating azafullerene contact layer, which can be explored for molecular radical state stabilization and positioning on solid substrates.


Improving immunization of programmable logic controllers using weighted median filters.
This paper addresses the problem of improving immunization of programmable logic controllers (PLC's) to electromagnetic interference with impulsive characteristics. A filtering structure, based on weighted median filters, that does not require additional hardware and can be implemented in legacy PLC's is proposed. The filtering operation is implemented in the binary domain and removes the impulsive noise presented in the discrete input adding thus robustness to PLC's. By modifying the sampling clock structure, two variants of the filter are obtained. Both structures exploit the cyclic nature of the PLC to form an N-sample observation window of the discrete input, hence a status change on it is determined by the filter output taking into account all the N samples avoiding thus that a single impulse affects the PLC functionality. A comparative study, based on a statistical analysis, of the different filters' performances is presented.


Granulocyte colony-stimulating factor- and chemotherapy-induced large-vessel vasculitis: six patient cases and a systematic literature review.
Patients receiving chemotherapy are prone to neutropoenic infections, presenting with non-specific symptoms such as a high fever and elevated inflammatory parameters. Large-vessel vasculitis (LVV) may have a similar clinical presentation and should be included in differential diagnostics. A few published case reports and adverse event reports suggest a causal association between LVV and the use of granulocyte colony-stimulating factor (G-CSF) and chemotherapy. Our objective was to evaluate the relationship between LVV, G-CSF and chemotherapy. Between 2016 and 2018, we identified six patients in Finland with probable drug-induced LVV associated with G-CSF and chemotherapy. All six patients had breast cancer. A systematic literature review was performed according to PRISMA guidelines using comprehensive search terms for cancer, chemotherapy, G-CSF and LVV. The literature search identified 18 similar published case reports, of which most were published after 2014. In all patients combined (n = 24), the time delay from the last drug administration to the LVV symptoms was on average 5 days with G-CSF (range = 1-8 days) and 9 days with chemotherapy (range = 1-21 days). Common symptoms were fever (88%), neck pain (50%) and chest pain (42%). Based on imaging, 17/24 (71%) had vascular inflammation in the thoracic aorta and supra-aortic vessels, but 5/24 (21%) reportedly had inflammation limited to the carotid area. This review suggests that LVV may be a possible serious adverse event associated with G-CSF and chemotherapy. Successful management of drug-induced LVV requires early identification, through diagnostic imaging, and discontinuation of the drug.


Epistatic interaction between two nonstructural loci on chromosomes 7 and 3 influences hepatic lipase activity in BSB mice.
BSB mice exhibit a wide range of obesity despite being produced by a backcross of lean C57BL/6J (B) x lean Mus spretus (SPRET/Pt) F1 animals x B. Previous linkage studies identified a quantitative trait locus (QTL) on mouse chromosome 7 with coincident peaks for hepatic lipase activity, obesity, and plasma cholesterol. However, these mice were not analyzed for gene x gene epistasis. Hepatic lipase activity is correlated with obesity and plasma cholesterol levels. In this study, we identified QTLs for plasma hepatic lipase activity with three statistical mapping methods: maximum likelihood interval mapping, Bayesian nonepistatic mapping, and Bayesian epistatic mapping. Bayesian epistatic mapping detected not only the QTL on chromosome 7 but also an additional QTL on chromosome 3, which has a weak main effect but a strong interaction with chromosome 7. SPRET/Pt alleles of the QTL on each chromosome promote hepatic lipase activity. The proportion of phenotypic variance explained by the epistatic effect is higher than that explained by the main effect of the QTL on chromosome 7.


Adding the temporal domain to PET radiomic features.
Radiomic features, extracted from positron emission tomography, aim to characterize tumour biology based on tracer intensity, tumour geometry and/or tracer uptake heterogeneity. Currently, radiomic features are derived from static images. However, temporal changes in tracer uptake might reveal new aspects of tumour biology. This study aims to explore additional information of these novel dynamic radiomic features compared to those derived from static or metabolic rate images. Thirty-five patients with non-small cell lung carcinoma underwent dynamic [18F]FDG PET/CT scans. Spatial intensity, shape and texture radiomic features were derived from volumes of interest delineated on static PET and parametric metabolic rate PET. Dynamic grey level cooccurrence matrix (GLCM) and grey level run length matrix (GLRLM) features, assessing the temporal domain unidirectionally, were calculated on eight and sixteen time frames of equal length. Spearman's rank correlations of parametric and dynamic features with static features were calculated to identify features with potential additional information. Survival analysis was performed for the non-redundant temporal features and a selection of static features using Kaplan-Meier analysis. Three out of 90 parametric features showed moderate correlations with corresponding static features (ρ≥0.61), all other features showed high correlations (ρ>0.7). Dynamic features are robust independent of frame duration. Five out of 22 dynamic GLCM features showed a negligible to moderate correlation with any static feature, suggesting additional information. All sixteen dynamic GLRLM features showed high correlations with static features, implying redundancy. Log-rank analyses of Kaplan-Meier survival curves for all features dichotomised at the median were insignificant. This study suggests that, compared to static features, some dynamic GLCM radiomic features show different information, whereas parametric features provide minimal additional information. Future studies should be conducted in larger populations to assess whether there is a clinical benefit of radiomics using the temporal domain over traditional radiomics.


Specificity and heregulin regulation of Ebp1 (ErbB3 binding protein 1) mediated repression of androgen receptor signalling.
Although ErbB receptors have been implicated in the progression of prostate cancer, little is known about proteins that may mediate their interactions with the androgen receptor (AR). Ebp1, a protein cloned via its association with the ErbB3 receptor, binds the AR and inhibits androgen-regulated transactivation of wild-type AR in COS cells. As the complement of coregulators in different cells are important for AR activity, we determined the effect of Ebp1 on AR function in prostate cancer cell lines. In addition, we examined the regulation of Ebp1 function by the ErbB3/4 ligand heregulin (HRG). In this study, we demonstrate, using several natural AR-regulated promoters, that Ebp1 repressed transcriptional activation of wild-type AR in prostate cancer cell lines. Downregulation of Ebp1 expression in LNCaP cells using siRNA resulted in activation of AR in the absence of androgen. Ebp1 associated with ErbB3 in LNCaP cells in the absence of HRG, but HRG induced the dissociation of Ebp1 from ErbB3. In contrast, HRG treatment enhanced both the association of Ebp1 with AR and also the ability of Ebp1 to repress AR transactivation. These studies suggest that Ebp1 is an AR corepressor whose biological activity can be regulated by the ErbB3 ligand, HRG.