Expression of plant cyclic nucleotide-gated cation channels in yeast.
The functional properties of inwardly conducting plant cyclic nucleotide-gated cation channels (CNGCs) have not been thoroughly characterized due in part to the recalcitrance of their functional expression in heterologous systems. Here, K+ uptake-deficient mutants of yeast (trk1,2) and Escherichia coli (LB650), as well as the Ca2+-uptake yeast mutant mid1,cch1, were used for functional characterization of Arabidopsis thaliana CNGCs, with the aim of identifying some of the cultural and physiological conditions that impact on plant CNGC function in heterologous systems. Use of the Ca2+-uptake yeast mutant provided the first evidence consistent with Ca2+ conduction by the A. thaliana CNGC AtCNGC1. Expression of AtCNGC1 in LB650 demonstrated that mutants of Escherichia coli (which has no endogenous calmodulin) can also be used to study functional properties of CNGCs. Expression of AtCNGC2 and AtCNGC4 enhanced growth of trk1,2 in the presence of hygromycin; AtCNGC1 has less of an effect. Deletion of the AtCNGC1 calmodulin-binding domain enhanced growth of trk1,2 at low external K+ but not of LB650, suggesting that yeast calmodulin may bind to, and down-regulate this plant channel. In vitro binding studies confirmed this physical interaction. Northern analysis, green fluorescent protein:AtCNGC1 fusion protein expression, as well as an antibody raised against a portion of AtCNGC1, were used to monitor expression of AtCNGC1 and deletion constructs of the channel in the heterologous systems. In the presence of the activating ligand cAMP, expression of the AtCNGC1 channel with the calmodulin-binding domain deleted increased intracellular [K+] of trk1,2. Trk1,2 is hypersensitive to the toxic cations spermine, tetramethylamine, and NH4+. These compounds, as well as amiloride, inhibited trk1,2 growth and thereby improved the efficacy of this yeast mutant as a heterologous expression system for CNGCs. In addition to characterizing mutants of yeast and E. coli as assay systems for plant CNGCs, work presented in this report demonstrates, for the first time, that a plant CNGC can retain ion channel function despite (partial) deletion of its calmodulin-binding domain and that yeast calmodulin can bind to and possibly down-regulate a plant CNGC.


Immune complex glomerulonephritis in mice infected with Escherichia coli.
C57Bl/6 mice were injected intraperitoneally with 10(8) to 2 x 10(8) living K 38 Escherichia coli (E. coli) and serological changes and kidney involvement were studied. E. coli were found in the blood 45 min to 24 hr after injection. In serum, large amounts of deoxyribonucleic acid (DNA) were present 24 hr after E. coli injection, and thereafter disappeared. Seven days after infection, antibodies directed against E. coli, anti-DNA antibodies and C1q-binding substances were found in serum and the kinetics of the variations of these parameters were studied until day 35. Kidney lesions were evaluated immunochemically and by optical and electron microscopy. In the glomeruli, heavy granular deposits of IgG and IgM were constantly found in mesangium and along capillary walls. In most kidneys slight granular deposits of IgG and IgM were also found in the tubules. Histological studies revealed in the glomeruli mild endocapillary cell proliferation, focal thickening of glomerular basement membrane and dense deposits in mesangial and subendothelial areas and inside the glomerular basement membrane; in the tubules dense deposits were focally observed inside the tubular basement membrane.


Amyloid-β₄₂ activates the expression of BACE1 through the JNK pathway.
The sequential endoproteolytic cleavages operated by the γ-secretase and the β-secretase (BACE1) on the amyloid-β protein precursor (AβPP) result in the production of the amyloid-β (Aβ) species, with two C-terminal variants, at residue 40 or at residue 42. Accumulation in brain tissue of small, soluble aggregates of Aβ42 is the major pathogenic event of Alzheimer's disease (AD). However, the physiologic activity of Aβ peptides is still elusive. Here, we show that expression of BACE1 is regulated by Aβ42, which augments BACE1 gene transcription through the JNK/c-jun signaling pathway. Of note, Aβ40 has much less effect on BACE1 expression. These findings unveil a positive feedback loop in which γ-secretase cleavage of AβPP releases a functionally-active peptide, Aβ42, that promotes BACE1 transcription. Thus, gene expression induced by Aβ42 may have implications in the neuronal dysfunction and degeneration that occurs in AD.


Use of stroma-supported cultures of leukemic cells to assess antileukemic drugs. I. Cytotoxicity of interferon alpha in acute lymphoblastic leukemia.
Leukemic cells from most cases of acute lymphoblastic leukemia (ALL) rapidly die by apoptosis in vitro, unless they are cultured onto bone marrow-derived stromal layers. We have recently established a stroma-supported tissue culture technique that allows long-term culture of leukemic lymphoblasts. In this study, we used this technique to examine interferon alpha (IFN alpha) cytotoxicity to ALL blasts. In 16 ALL cases tested (14 B-lineage ALL, 2 T-ALL), the number of cells recovered after 7 days of culture on stromal feeder layers was 60-178% (median, 108%) of those originally seeded. The percentage of lymphoblasts killed by 2000 U/ml IFN alpha 2b after 7 days of culture, ranged from < 1% to 91% (median, 56%). Cytotoxicity was (i) dose-dependent, (ii) eliminated by a neutralizing antibody to IFN alpha, and (iii) accompanied by tyrosine phosphorylation of a 135 kDa protein, which was detectable after 5 minutes of treatment. Numbers of residual normal lymphoid cells in the cultures remained low and conditioned medium prepared from IFN alpha-stimulated T, NK, and stromal cells was not cytotoxic to ALL blast cells. In contrast to results in freshly isolated ALL cells, six ALL cell lines tested were completely resistant to IFN alpha cytotoxicity. We conclude that IFN alpha is directly cytotoxic in most ALL cases but that the intensity of its effects varies widely among cases. The method used in this study may be applied to evaluate leukemic blast cell sensitivity to compounds with potential antileukemic activity, and to select patients to be entered in to clinical trials.


Exendin-4 potentiates insulinotropic action partly via increasing beta-cell proliferation and neogenesis and decreasing apoptosis in association with the attenuation of endoplasmic reticulum stress in islets of diabetic rats.
Exendin-4, a long-acting glucagon-like peptide-1-receptor agonist, is known to enhance beta-cell function, but the active mechanism by which it modulates beta-cell mass still remains unclear. We investigated what the long-term effects of exendin-4 (300 pmol/kg body weight per day) on beta-cell function and mass would be in 90% pancreatectomized (Px) Sprague Dawley rats; half of whom were intraperitoneally injected with streptozotocin (STZ, 20 mg/kg body weight) and half of whom were not. Exendin-4 improved glucose tolerance by elevating serum insulin levels in both STZ-treated and untreated Px rats. At hyperglycemic clamp, STZ attenuated both first and second phase insulin secretion in STZ- and saline-treated Px rats, but exendin-4 incompletely reversed the attenuation. Since STZ mostly removed the remaining beta-cells by increasing apoptosis after Px, their regeneration was initiated through neogenesis, which was determined by the number of beta-cells budding from pancreatic duct layers and small clusters. Exendin-4 enhanced beta-cell proliferation and neogenesis in STZ-treated and -untreated Px rats and reduced beta-cell apoptosis partly by attenuating the expression of endoplasmic reticulum stress-response genes such as X-box-binding protein-1, activating transcription factor (ATF)-4, ATF6, and C/EBP-homologous protein. In conclusion, exendin-4 improved glycemic control by potentiating beta-cell function and increasing beta-cell mass by increasing beta-cell neogenesis and proliferation and by decreasing apoptosis in diabetic rats.


Initiation of network bursts by Ca2+-dependent intrinsic bursting in the rat pilocarpine model of temporal lobe epilepsy.
Chronically epileptic rats, produced by prior injection of pilocarpine, were used to investigate whether changes in intrinsic neuronal excitability may contribute to the epileptogenicity of the hippocampus in experimental temporal lobe epilepsy (TLE). Paired extra-/intracellular electrophysiological recordings were made in the CA1 pyramidal layer in acute hippocampal slices prepared from control and epileptic rats and perfused with artificial cerebrospinal fluid (ACSF). Whereas orthodromic activation of CA1 neurons evoked only a single, stimulus-graded population spike in control slices, it produced an all-or-none burst of population spikes in epileptic slices. The intrinsic firing patterns of CA1 pyramidal cells were determined by intrasomatic positive current injection. In control slices, the vast majority (97%) of the neurons were regular firing cells. In epileptic slices, only 53% the pyramidal cells fired in a regular mode. The remaining 47% of the pyramidal cells were intrinsic bursters. These neurons generated high-frequency bursts of three to six spikes in response to threshold depolarizations. A subgroup of these neurons (10.1% of all cells) also burst fired spontaneously even after suppression of synaptic activity. In epileptic slices, burst firing in most cases (ca 70%) was completely blocked by adding the Ca2+ channel blocker Ni2+ (1 mM) to, or removing Ca2+ from, the ACSF, but not by intracellular application of the Ca2+ chelater 1,2-bis(o-aminophenoxy)ethane-N,N,N ',N '-tetra-acetic acid (BAPTA), suggesting it was driven by a Ca2+ current. Spontaneously recurring population bursts were observed in a subset of epileptic slices. They were abolished by adding 2 M 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) to the ACSF, indicating that synaptic excitation is critical for the generation of these events. All sampled pyramidal cells fired repetitively during each population burst. The firing of spontaneously active bursters anteceded the population discharge, whereas most other pyramidal cells began to fire conjointly with the first population spike. Thus, spontaneous bursters are likely to be the initiators of spontaneous population bursts in epileptic slices. The dramatic up-regulation of intrinsic bursting in CA1 pyramidal cells, particularly the de novo appearance of Ca2+-dependent bursting, may contribute to the epileptogenicity of the hippocampus in the pilocarpine model of TLE. These findings have important implications for the pharmacological treatment of medically refractory human TLE.


Biomaterials Based on Carbon Nanotube Nanocomposites of Poly(styrene-b-isobutylene-b-styrene): The Effect of Nanotube Content on the Mechanical Properties, Biocompatibility and Hemocompatibility.
Nanocomposites based on poly(styrene-block-isobutylene-block-styrene) (SIBS) and single-walled carbon nanotubes (CNTs) were prepared and characterized in terms of tensile strength as well as bio- and hemocompatibility. It was shown that modification of CNTs using dodecylamine (DDA), featured by a long non-polar alkane chain, provided much better dispersion of nanotubes in SIBS as compared to unmodified CNTs. As a result of such modification, the tensile strength of the nanocomposite based on SIBS with low molecular weight (Mn = 40,000 g mol-1) containing 4% of functionalized CNTs was increased up to 5.51 ± 0.50 MPa in comparison with composites with unmodified CNTs (3.81 ± 0.11 MPa). However, the addition of CNTs had no significant effect on SIBS with high molecular weight (Mn~70,000 g mol-1) with ultimate tensile stress of pure polymer of 11.62 MPa and 14.45 MPa in case of its modification with 1 wt% of CNT-DDA. Enhanced biocompatibility of nanocomposites as compared to neat SIBS has been demonstrated in experiment with EA.hy 926 cells. However, the platelet aggregation observed at high CNT concentrations can cause thrombosis. Therefore, SIBS with higher molecular weight (Mn~70,000 g mol-1) reinforced by 1-2 wt% of CNTs is the most promising material for the development of cardiovascular implants such as heart valve prostheses.


Response of prolactin to different photoperiods after surgical disconnection of the hypothalamus and pituitary in sheep fetuses.
The aim of this study was to determine the impact of surgical disconnection of the fetal hypothalamus and pituitary on the fetal prolactin response to different photoperiods. Disconnection of the hypothalamus (HPD) or a sham operation was carried out at around day 110 of gestation (term = 145 +/- 3 days). Before surgery, pregnant ewes were maintained under a photoperiod of 12 h light:12 h dark. After surgery, ewes carrying HPD fetuses (n = 10) or intact fetuses (n = 13) were exposed to either a long day (16 h light:8 h dark) or a short day (8 h light:16 h dark) regimen until day 143 of gestation. Thyrotrophin-releasing hormone (50 micrograms) was administered intrafetally at days 130-135 of gestation and chlorpromazine (a dopaminergic antagonist) was administered to all sheep fetuses at days 141-142 of gestation. Mean fetal prolactin concentrations were significantly higher in the long day group (HPD: 37.3 +/- 11.3 ng ml-1; intact: 71.0 +/- 16.2 ng ml-1) than in the short day group (HPD: 9.0 +/- 4.8 ng ml-1; intact: 34.2 +/- 16.0 ng ml-1). In the intact group, fetal prolactin concentrations increased significantly between day 6 and day 30 of exposure to either photoperiod. However, in the HPD group, fetal prolactin increased with increasing exposure to the long day photoperiod and decreased with increasing exposure to the short day photoperiod.(ABSTRACT TRUNCATED AT 250 WORDS)


A Web-Based Mobile App With a Smartwatch to Support Social Engagement in Persons With Memory Loss: Pilot Randomized Controlled Trial.
It is estimated that the number of individuals living with dementia worldwide will increase from 50 million in 2017 to 152 million by 2050. Assistive technology has been recognized as a promising tool to improve the lives of persons living with memory loss and their caregivers. The use of assistive technology in dementia care is expanding, although it is most often intended to manage care and promote safety. There is a lack of assistive technology designed to aid persons with memory loss in participating in meaningful activities. The Social Support Aid (SSA) is a mobile phone-based app that employs facial recognition software. It was designed to assist persons with memory loss remember the names and relationships of the people they interact with to promote social engagement. This study uses a pilot randomized controlled trial (RCT) design to evaluate the SSA. The objectives were to ascertain (1) the feasibility and utility of the SSA, (2) whether the outcomes of SSA use suggest potential benefits for persons living with memory loss and their care partners, and (3) how study design components could inform subsequent RCTs. Persons with memory loss were randomized to the SSA (n=20) or the usual care control group (n=28). Quantitative data were collected at three timepoints (baseline, 3 months, and 6 months). Participants in the intervention group participated in qualitative interviews following completion of their 6-month survey. Participant eligibility, willingness to be randomized, and retention were not barriers to conducting a full-scale RCT; however, recruitment strategies should be addressed before doing so. Feasibility and utility scores indicated that participants felt neutral about the technology. Use of the SSA was not significantly associated with changes in quality of social interactions or quality of life measures over the 6 months of follow-up (P>.05). The qualitative analysis revealed three themes that described how and why the SSA worked or not: (1) outcomes, (2) reasons why it was or was not useful, and (3) recommendations. There is a need to develop effective assistive technology that improves the quality of life of persons with memory loss. Assistive technology that allows persons living with memory loss to maintain some level of autonomy should be a priority for future research. This study suggests reasons why the SSA facial recognition software did not appear to improve the quality of social interaction and quality of life of people with memory loss. Results also provide recommendations for future assistive technology development and evaluation. ClinicalTrials.gov NCT03645694; https://clinicaltrials.gov/ct2/show/NCT03645694 (Archived by WebCite at http://www.webcitation.org/78dcVZIqq).


Triazolylthioacetamide: A Valid Scaffold for the Development of New Delhi Metallo-β-Lactmase-1 (NDM-1) Inhibitors.
The metallo-β-lactamases (MβLs) cleave the β-lactam ring of β-lactam antibiotics, conferring resistance against these drugs to bacteria. Twenty-four triazolylthioacetamides were prepared and evaluated as inhibitors of representatives of the three subclasses of MβLs. All these compounds exhibited specific inhibitory activity against NDM-1 with an IC50 value range of 0.15-1.90 μM, but no activity against CcrA, ImiS, and L1 at inhibitor concentrations of up to 10 μM. Compounds 4d and 6c are partially mixed inhibitors with K i values of 0.49 and 0.63 μM using cefazolin as the substrate. Structure-activity relationship studies reveal that replacement of hydrogen on the aromatic ring by chlorine, heteroatoms, or alkyl groups can affect bioactivity, while leaving the aromatic ring of the triazolylthiols unmodified maintains the inhibitory potency. Docking studies reveal that the typical potent inhibitors of NDM-1, 4d and 6c, form stable interactions in the active site of NDM-1, with the triazole bridging Zn1 and Zn2, and the amide interacting with Lys 211 (Lys224).


Clinical outcomes after closed, staged, and open forefoot amputations.
Surgical approaches for forefoot osteomyelitis include amputation with immediate wound closure or resection followed by either staged re-resection and wound closure or local care of the open wound for secondary healing. This study evaluated the effectiveness of closed, staged, and open forefoot amputations in preventing major leg amputation and identified those variables that are associated with successful limb preservation. From July 2002 to June 2004, 208 patients with forefoot osteomyelitis or gangrene underwent minor amputation according to a standard treatment algorithm. Wounds with limited cellulitis underwent immediate wound closure (CLOSED), wounds with marginally viable soft tissue underwent open amputation followed by wound closure at 2 to 7 days (STAGED), and wounds with tenosynovitis or extensive necrosis underwent débridement with no attempt at wound closure (OPEN). Patient demographics, need for further operative interventions, time to complete healing, and progression to major amputation were recorded. With four subjects lost to follow-up, 204 patients (98%) (94 CLOSED, 56 STAGED, and 54 OPEN) were monitored to complete healing, major amputation, or death. OPEN amputations had a significantly reduced initial healing rate (37%, P < .001) and a frequent need for repeat operative intervention (43%), although successful limb salvage was ultimately achieved in 70% of the cases. Initial healing in the CLOSED and STAGED amputation groups was similar (71% and 78%, respectively), leading to excellent early limb salvage (86% and 91%). The median time to healing for closed, staged, and open amputations was 1.2, 1.6, and 4.6 months, respectively (P < .001). Follow-up evaluation demonstrated the initial improvements in limb salvage with the CLOSED and STAGED groups were lost, resulting in similar amputation rates among the three groups of 30% to 35% over 36 months. Although open amputation of extensive forefoot infections frequently requires repeat operative interventions and a prolonged time to complete healing, this approach provides limb salvage rates approaching those observed for less invasive infections amenable to immediate closure. Staged closure offers an improved time to healing without negatively impacting the risk of major limb amputation. Independent of their initial operative approach, these patients frequently progress to early leg amputation.


Kinetics of platelet 5-hydroxytryptamine uptake in headache patients.
Platelet 5-hydroxytryptamine (5-HT) uptake was measured in asymptomatic headache patients attending a specialist migraine clinic, and in hospital staff who did not suffer from regular or severe headache. Current levels of anxiety and depression were assessed in all subjects using the Hospital Anxiety and Depression (HAD) scale and their possible influence on the uptake kinetics taken into account during the analysis of results. The Michaelis-Menten constant (Km) was significantly raised in common migraine and tension headache compared with controls (p less than 0.001 and p less than 0.01, respectively), but not in classical migraine or cluster headache. The increase remained significant after adjusting for differences in age, sex, presence of anxiety or depression (HAD sub-scale score greater than or equal to 8), drug intake during the week before testing, time elapsed since last attack and time of assay (am or pm). No differences were observed between patients and controls in the maximal rate of uptake (Vmax) or platelet count, and previous reports of a reduction in Vmax in patients experiencing attack within 5 days prior to testing could not be confirmed. The cause and significance of an increased Km are not clear, but plasma factors acting as competitive inhibitors for the uptake site or an alteration in the configuration of the uptake site are possible explanations. If confirmed, the shared biochemical abnormality may suggest that common migraine and tension headache have a common pathogenesis.


A Boron Delivery Antibody (BDA) with Boronated Specific Residues: New Perspectives in Boron Neutron Capture Therapy from an In Silico Investigation.
Boron Neutron Capture Therapy (BNCT) is a tumor cell-selective radiotherapy based on a nuclear reaction that occurs when the isotope boron-10 (10B) is radiated by low-energy thermal neutrons or epithermal neutrons, triggering a nuclear fission response and enabling a selective administration of irradiation to cells. Hence, we need to create novel delivery agents containing 10B with high tumor selectivity, but also exhibiting low intrinsic toxicity, fast clearance from normal tissue and blood, and no pharmaceutical effects. In the past, boronated monoclonal antibodies have been proposed using large boron-containing molecules or dendrimers, but with no investigations in relation to maintaining antibody specificity and structural and functional features. This work aims at improving the potential of monoclonal antibodies applied to BNCT therapy, identifying in silico the best native residues suitable to be substituted with a boronated one, carefully evaluating the effect of boronation on the 3D structure of the monoclonal antibody and on its binding affinity. A boronated monoclonal antibody was thus generated for specific 10B delivery. In this context, we have developed a case study of Boron Delivery Antibody Identification Pipeline, which has been tested on cetuximab. Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor used in the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer, and head and neck cancer.


Stereo and scanning electron microscopy of in-shell Brazil nut (Bertholletia excelsa H.B.K.): part two-surface sound nut fungi spoilage susceptibility.
This work reports the in-shell Brazil nut spoilage susceptible morpho-histological characteristics and fungi infection (shell, edible part, and brown skin) through stereo and scanning electron microscopies (SEM). The following characteristics related to shell (a) morphology-that allow fungi and insects' entrance to inner nut, and (b) histology-that allow humidity absorption, improving environment conditions for living organisms development, were identified. (a.1) locule in testae-the nut navel, which is a cavity formed during nut detaching from pods (located at 1.0 to 2.0/4th of the shell B&C nut faces linkage). It allows the nut brown skin (between shell and edible part) first contact to the external environment, through the (a.2) nut channel-the locule prolongation path, which has the water/nutrients cambium function for their transport and distribution to the inner seed (while still on the tree/pod). Both, locule followed by the channel, are the main natural entrance of living organisms (fungi and insects), including moisture to the inner seed structures. In addition, the (a.3) nut shell surface-which has a crinkled and uneven surface morphology-allows water absorption, thus adding to the deterioration processes too. The main shell histological characteristic, which also allows water absorption (thus improving environment conditions for fungi proliferation), is the (b.1) cell wall porosity-the multilayered wall and porous rich cells that compose the shell faces double tissue layers and the (b.2) soft tissue-the mix of tissues 2 faces corner/linkage. This work also shows in details the SEM nut spoilage susceptible features highly fungi infected with hyphae and reproductive structures distribution.


[Effect of the Antiemetic Drug Olanzapine on Blood Sugar Levels in Patients Treated with Adjuvant or Neoadjuvant Chemotherapy for Breast Cancer].
This retrospective study aimed to evaluate the effect of the antiemetic drug olanzapine(OLZ)on blood sugar levels in patients treated with adjuvant or neoadjuvant chemotherapy(AC: doxorubicin plus cyclophosphamide or CEF: cyclophosphamide plus epirubicin plus fluorouracil) for breast cancer. Here, we evaluated the frequency of diabetes(postprandial blood sugar: PBS≥200 mg/dL)and the change in PBS in 149 patients who were prescribed OLZ between September 2016 and August 2017 at our hospital. No diabetic patients were identified during the observation period(median: 3 cycles of chemotherapy). Among the 95 patients with more than 2 PBS readings, no difference was observed in the incidence of increased PBS, regardless of the diabetic risk, before and after OLZ administration. This study therefore found that the short term use of OLZ as an antiemetic had little effect on PBS, suggesting that it can be used safely during treatment with AC or CEF.


The impact of health insurance on out-of-pocket expenditure on delivery in Indonesia.
In this study, we estimate the effects of health insurance on the out-of-pocket expenditure on health care for maternal delivery in Indonesia. Distinguishing between the types of health insurance, we explore heterogeneity in the size of the impact of noncontributory insurance for poor households vis-à-vis contributory insurance for nonpoor households. We find that noncontributory insurance and contributory insurance reduce the average out-of-pocket expenditure by 1,136,966 IDR ([Formula: see text]) and 676,402 IDR ([Formula: see text]), respectively. Also, larger impacts of noncontributory insurance and contributory insurance are found at the right tail of the distribution.


[Level of functional mitochondrial activity of the preserved kidney].
The authors investigated the activity of mitochondria from cells of the cortical and of the medullar structures of the dog kidney perfused in pulsatile flow and under hypothermia for a duration of 12 hours, as well as for 24 hours. The swelling-contraction process was determined, and the thiol (T-SH) groups in mitochondrial suspensions. The kinetics of the mitochondrial swelling showed moderate reduction of the activity, differentiated in the medullary and in the cortical areas, and depending on the duration of the perfusion. The energetic processes in the medullary layer were less affected than in the cortical. There was correlation of mitochondrial function and the contents in thiol groups.


Emergence of simple-cell receptive field properties by learning a sparse code for natural images.
The receptive fields of simple cells in mammalian primary visual cortex can be characterized as being spatially localized, oriented and bandpass (selective to structure at different spatial scales), comparable to the basis functions of wavelet transforms. One approach to understanding such response properties of visual neurons has been to consider their relationship to the statistical structure of natural images in terms of efficient coding. Along these lines, a number of studies have attempted to train unsupervised learning algorithms on natural images in the hope of developing receptive fields with similar properties, but none has succeeded in producing a full set that spans the image space and contains all three of the above properties. Here we investigate the proposal that a coding strategy that maximizes sparseness is sufficient to account for these properties. We show that a learning algorithm that attempts to find sparse linear codes for natural scenes will develop a complete family of localized, oriented, bandpass receptive fields, similar to those found in the primary visual cortex. The resulting sparse image code provides a more efficient representation for later stages of processing because it possesses a higher degree of statistical independence among its outputs.


Comparative study on the tensile bond strength and marginal fit of complete veneer cast metal crowns using various luting agents: An in vitro study.
Several commercially available luting agents are used to cement the dental restorations such as intra-coronal, extra-coronal, and fixed partial dentures. Tensile bond strength (TBS) and accurate marginal fit are the essential factors to determine the good clinical results in fixed prosthesis. The retentivity of the luting cements is assessed by their adhesive capacity over the tooth surface and metal surface. Generally, the adhesive ability has been evaluated with in vitro testing, with tensile bond tests. The failure of fixed prosthesis may be happened as a result of incomplete seating during cementation. Most research on cementation of crowns relates seating failure to the thickness of the cement film. The study is divided into four groups with 10 samples for each of the luting cement taken up for testing TBS and four groups with 5 samples for each luting agent chosen for assessing marginal fit. The results were tabulated and statistically analyzed. In this in vitro study, the TBS of luting cements, and marginal fit in relation to luting cements were tested by using appropriate testing devices. The TBS of cement is measured using universal testing machine, and the results are tabulated. The marginal gap that exists between the margin of the cast metal crown, and the finish line is measured using travelling microscope before and after cementation. The difference between these two values gives the discrepancy that is due to the film thickness of cement used for luting the restoration. The TBS value of zinc phosphate cement and glass ionomer cement were found to be almost same. The chemical adhesiveness of the glass ionomer with calcium ions of enamel and dentin may be the attributed reason (ionic bonding). In this study, the polycarboxylate is the one that showed low TBS, and it may be attributed to the weakness of the cement due to reduced film thickness, though this cement has a chemical bonding nature. The observation of results of marginal fit in this study is the increased gap found in zinc phosphate cement followed by resin cement, zinc polycarboxylate, and glass ionomer cement. It is agreeable to estimate the marginal fit of the restoration, which could be affected by the film thickness of the luting cement along with other factors.


Acquired personality disturbances associated with bilateral damage to the ventromedial prefrontal region.
Personality changes in 7 participants with bilateral ventromedial prefrontal lesions (PF-BVM), 14 participants with prefrontal lesions but not bilateral ventromedial involvement (PF-NBVM), and 36 with nonprefrontal lesions (NPF) were investigated with the Iowa Rating Scales of Personality Change. Informants rated 30 specific characteristics for degree of disturbance and change from premorbid personality. PF-BVM participants showed a higher rate of acquired disturbances than NPF participants in blunted emotional experience, apathy, low emotional expressiveness, inappropriate affect, poor frustration tolerance, irritability, lability, indecisiveness, poor judgment, social inappropriateness, lack of planning, lack of initiation and persistence, and lack of insight. Differences between the PF-BVM and PF-NBVM groups were significant for several of these characteristics. All 7 PF-BVM participants developed a syndrome, including general dampening of emotional experience; poorly modulated emotional reactions; defective decision making, especially in the social realm; impaired goal-directed behavior; and striking lack of insight. Similarities between this syndrome of "acquired sociopathy" and developmental psychopathy in characteristic personality disturbances and psychophysiological abnormalities suggest that diminished emotionality, impaired decision making, and psychosocial dysfunction may be related to ventromedial prefrontal dysfunction in both groups.


Impaired natural killing activity in patients with rheumatoid arthritis. Clinical characteristics and a study of defective mechanisms.
We have studied NK activity against K562 cells of peripheral blood mononuclear cells (PBMC) from 83 patients affected with RA and searched for correlations with some clinical and laboratory parameters. In 65 patients T lymphocyte subsets were investigated by laser flow cytometry using monoclonal antibodies against OKT3, OKT4 and OKT8 antigens and in 25 patients also HNK-1+ cells were enumerated. NK activity in patients with RA resulted significantly decreased compared with controls (relative cytotoxic index = 0.68 +/- 0.74 versus 1.00 +/- 0.60, p less than 0.01). Decreased NK activity was not correlated with sex, age, duration of disease, ESR, haemoglobin, serum alpha-2-globulin, serum gamma-globulin, rheumatoid factor titre. The only clinical parameter correlated with decreased NK activity was the anatomical stage of the disease. NK activity depression resulted to be significantly correlated with OKT3+ cell percentage and at a lesser extent with OKT4+ and OKT8+ cell percentages. HNK-1+ cell percentage resulted only slightly reduced in patients with RA (13.1 +/- 8.7 versus 15.0 +/- 7.0) and there was only a modest correlation (p approximately equal to 0.10) between NK activity and HNK-1+ cell percentage. In order to elucidate the mechanisms of impaired NK activity in RA, experiments in vitro were carried out on PBMC of 23 patients to investigate the effects of the depletion of cells adherent to plastic, incubation with beta-interferon (1000 IU/ml) and incubation with indomethacin (10 -6M). Our data suggest that decreased NK activity in RA is mainly due to functional immaturity of NK cells and sometimes to inhibition by monocytes in some cases probably through prostaglandin release.


Why consent may not be needed for organ procurement.
Most people think it is wrong to take organs from the dead if the potential donors had previously expressed a wish not to donate. Yet people respond differently to a thought experiment that seems analogous in terms of moral relevance to taking organs without consent. We argue that our reaction to the thought experiment is most representative of our deepest moral convictions. We realize not everyone will be convinced by the conclusions we draw from our thought experiment. Therefore, we point out that the state ignores consent in performing mandatory autopsies in some cases. If readers are willing to give up the permissibility of mandatory autopsies, we then offer some metaphysical arguments against posthumous harm. Drawing upon claims about bodies ceasing to exist at death and Epicurean-inspired arguments against posthumous interests, we make a case for an organ conscription policy which respects fundamental liberal principles of autonomy, bodily integrity, and property.


Preparation and Use of Turn-on Fluorescent Probe for Detection and Live Cell Imaging of Vitamin D Receptor as a Target Protein.
Turn-on fluorescent probe mediated by conjugate addition and cyclization (TCC probe) is a small molecule that reacts with a protein of interest in cells. TCC probe is applicable to various types of proteins by exchanging the ligand unit for target proteins. TCC probes are a potent tool for molecular imaging and chemical proteomics. This protocol describes the synthesis of a TCC probe via unstable intermediate and how to use this probe to visualize vitamin D receptor as a target protein. For complete details on the use and execution of this protocol, please refer to Kojima et al. (2020).


The role of HER3, the unpretentious member of the HER family, in cancer biology and cancer therapeutics.
Many types of human cancer are characterized by deregulation of the human epidermal growth factor receptor (HER) family of tyrosine kinase receptors. In some cancers, genomic events causing overactivity of individual HER family members are etiologically linked with the pathogenesis of these cancers, and constitute the driving signaling function underlying their tumorigenic behavior. HER3 stands out among this family as the only member lacking catalytic kinase function. Cancers with driving HER3 amplifications or mutations have not been found, and studies of its expression in tumors have been only weakly provocative. However, substantial evidence, predominantly from experimental models, now suggest that its non-catalytic functions are critically important in many cancers driven by its' HER family partners. Furthermore, new insights into the mechanism of activation in the HER family has provided clear evidence of functionality in the HER3 kinase domain. The convergence of structural, mechanistic, and experimental evidence highlighting HER3 functions that may be critical in tumorigenesis have now led to renewed efforts towards identification of cancers or subtypes of cancers wherein HER3 function may be important in tumor progression or drug resistance. It appears now that its failure to earn the traditional definition of an oncogene has allowed the tumor promoting functions of HER3 to elude the effects of cancer therapeutics. But experimental science has now unmasked the unpretentious role of HER3 in cancer biology, and the next generation of cancer therapies will undoubtedly perform much better because of it.


Intragenic allele pyramiding combines different specificities of wheat Pm3 resistance alleles.
Some plant resistance genes occur as allelic series, with each member conferring specific resistance against a subset of pathogen races. In wheat, there are 17 alleles of the Pm3 gene. They encode nucleotide-binding (NB-ARC) and leucine-rich-repeat (LRR) domain proteins, which mediate resistance to distinct race spectra of powdery mildew. It is not known if specificities from different alleles can be combined to create resistance genes with broader specificity. Here, we used an approach based on avirulence analysis of pathogen populations to characterize the molecular basis of Pm3 recognition spectra. A large survey of mildew races for avirulence on the Pm3 alleles revealed that Pm3a has a resistance spectrum that completely contains that of Pm3f, but also extends towards additional races. The same is true for the Pm3b and Pm3c gene pair. The molecular analysis of these allelic pairs revealed a role of the NB-ARC protein domain in the efficiency of effector-dependent resistance. Analysis of the wild-type and chimeric Pm3 alleles identified single residues in the C-terminal LRR motifs as the main determinant of allele specificity. Variable residues of the N-terminal LRRs are necessary, but not sufficient, to confer resistance specificity. Based on these data, we constructed a chimeric Pm3 gene by intragenic allele pyramiding of Pm3d and Pm3e that showed the combined resistance specificity and, thus, a broader recognition spectrum compared with the parental alleles. Our findings support a model of stepwise evolution of Pm3 recognition specificities.


Mirror adaptation in sensory-motor simultaneity.
When one watches a sports game, one may feel her/his own muscles moving in synchrony with the player's. Such parallels between observed actions of others and one's own has been well supported in the latest progress in neuroscience, and coined "mirror system." It is likely that due to such phenomena, we are able to learn motor skills just by observing an expert's performance. Yet it is unknown whether such indirect learning occurs only at higher cognitive levels, or also at basic sensorimotor levels where sensorimotor delay is compensated and the timing of sensory feedback is constantly calibrated. Here, we show that the subject's passive observation of an actor manipulating a computer mouse with delayed auditory feedback led to shifts in subjective simultaneity of self mouse manipulation and auditory stimulus in the observing subjects. Likewise, self adaptation to the delayed feedback modulated the simultaneity judgment of the other subjects manipulating a mouse and an auditory stimulus. Meanwhile, subjective simultaneity of a simple visual disc and the auditory stimulus (flash test) was not affected by observation of an actor nor self-adaptation. The lack of shift in the flash test for both conditions indicates that the recalibration transfer is specific to the action domain, and is not due to a general sensory adaptation. This points to the involvement of a system for the temporal monitoring of actions, one that processes both one's own actions and those of others.


The Contradictions of Liminal Legality: Economic Attainment and Civic Engagement of Central American Immigrants on Temporary Protected Status.
This study examines how Temporary Protected Status (TPS) may shape immigrants' integration trajectories. Building on core themes identified in the immigrant incorporation scholarship, it investigates whether associations of educational attainment with labor market outcomes and with civic participation, which are well established in the general population, hold for immigrants who live in the "liminal legality" of TPS. Conducted in 2016 in five U.S. metropolitan areas, the study is based on a unique survey of Salvadoran and Honduran TPS holders, the majority of immigrants on this status. The analyses find that TPS holders with higher levels of educational attainment do not derive commensurate significant occupational or earnings premiums from their education. In contrast, the analysis of the relationship between educational attainment and civic engagement detects a positive association: more educated TPS holders are more likely to be members of community organizations and to participate in voluntary community service, compared to their less educated counterparts. These findings illustrate the contradictions inherent to TPS as it may hinder certain aspects of immigrant integration but not others. This examination contributes to our understanding of the implications of immigrants' legal statuses and of immigration law and policy for key aspects of immigrant integration trajectories.


TYMP Variants Result in Late-Onset Mitochondrial Myopathy With Altered Muscle Mitochondrial DNA Homeostasis.
Biallelic TYMP variants result in the mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), a juvenile-onset disorder with progressive course and fatal outcome. Milder late-onset (>40 years) form has been rarely described. Gene panel sequencing in a cohort of 60 patients featuring muscle accumulation of mitochondrial DNA (mtDNA) deletions detected TYMP defects in three subjects (5%), two of them with symptom onset in the fifth decade. One of the patients only displayed ptosis and ophthalmoparesis. Biochemical and molecular studies supported the diagnosis. Screening of TYMP is recommended in adult patients with muscle mtDNA instability, even in the absence of cardinal MNGIE features.


[Study on mechanisms of interleukin-17A regulating the expressions of interleukin-1β and interleukin-23 in mouse keratinocytes].
Objective: To investigate the mechanisms of interleukin-17A (IL-17A) regulating the expressions of IL-1β and IL-23 in mouse keratinocytes (KCs). Methods: Primary KCs were isolated from the skin of 400 newborn male and female wild type C57BL/6 mice and cultured in 24-well plates with Roswell Park Memorial Institute 1640 medium containing fetal bovine serum in the volume fraction of 10% for the following experiments. (1) The cells were divided into phosphate buffer solution (PBS) control group and IL-17A stimulation group according to the random number table (the same grouping method below), which were cultured with 10 μL PBS or 10 μL IL-17A in the mass concentration of 100 ng/mL for 6 hours, respectively. The expression levels of IL-1β and IL-23 mRNA in cells were detected by real-time fluorescence quantitative reverse transcription polymerase chain reaction (RT-PCR), with 3 samples in each group. (2) The cells were divided into dimethyl sulfoxide (DMSO) control group, IL-17A+ DMSO group, IL-17A+ nuclear factor κB (NF-κB) inhibitor group, IL-17A+ signal transduction and activator of transcription 3 (STAT3) inhibitor group, IL-17A+ extracellular signal-regulated kinase 1 (ERK1) inhibitor group, IL-17A+ ERK2 inhibitor group, and IL-17A+ c-Jun N-terminal kinase (JNK) inhibitor group. The reagents were added to cells in corresponding groups respectively and cultured for 6 hours. The volume of each reagent was 10 μL, the mass concentration of IL-17A was 100 ng/mL, and the molarity concentrations of NF-κB, STAT3, ERK1, ERK2, JNK signal pathway inhibitors PDTC, S3I-201, SCH772984, SCH772984, SP600125 were 5 μmol/L, 100 μmol/L, 4 nmol/L, 1 nmol/L, and 10 μmol/L, respectively. The expression levels of IL-1β mRNA and IL-23 mRNA in cells were detected by real-time fluorescence quantitative RT-PCR, with 3 samples in each group. (3) The cells were grouped and treated the same as those in experiment (1). The levels of NF-κB phosphorylation, STAT3 phosphorylation, ERK phosphorylation, and JNK phosphorylation were detected by Western blotting, with 3 samples in each group. Data were statistically analyzed with two-tailed Student t test, one-way analysis of variance, t test, and Bonferroni correction. Results: (1) After culture of 6 hours, compared with those in PBS control group, the expression levels of IL-1β and IL-23 mRNA in cells in IL-17A stimulation group were significantly increased (t=13.46, 6.72, P<0.01). (2) After culture of 6 hours, the expression levels of IL-1β and IL-23 mRNA in cells in DMSO control group, IL-17A+ DMSO group, IL-17A+ NF-κB inhibitor group, IL-17A+ STAT3 inhibitor group, IL-17A+ ERK1 inhibitor group, IL-17A+ ERK2 inhibitor group, and IL-17A+ JNK inhibitor group were 1.00±0.11, 4.01±0.32, 0.32±0.06, 1.76±0.43, 3.62±0.24, 3.80±0.43, 4.26±0.74 and 1.03±0.29, 4.08±0.34, 4.76±0.38, 4.70±0.21, 1.06±0.42, 0.92±0.21, 0.39±0.05, respectively. Compared with those in DMSO control group, the expression levels of IL-1β and IL-23 mRNA in cells in IL-17A+ DMSO group were significantly increased (t=9.24, 12.60, P<0.01). Compared with that in IL-17A+ DMSO group, the expression level of IL-1β mRNA was significantly decreased in cells in IL-17A+ NF-κB inhibitor group and IL-17A+ STAT3 inhibitor group (t=11.34, 6.91, P<0.01). Compared with that in IL-17A+ DMSO group, the expression level of IL-23 mRNA was significantly decreased in cells in IL-17A+ ERK1 inhibitor group, IL-17A+ ERK2 inhibitor group, and IL-17A+ JNK inhibitor group (t=12.44, 13.03, 15.21, P<0.01). (3) After culture of 6 hours, compared with those in PBS control group, the levels of NF-κB phosphorylation, STAT3 phosphorylation, ERK phosphorylation, and JNK phosphorylation in cells in IL-17A stimulation group were significantly increased. Conclusions: IL-17A promotes the transcription of IL-1β in mouse KCs through the phosphorylation of NF-κB and STAT3 pathways and IL-23 through the phosphorylation of ERK and JNK pathways.


Ghrelin modulates fatty acid synthase and related transcription factor mRNA levels in a tissue-specific manner in neonatal broiler chicks.
The endogenous ligand for the growth hormone (GH) secretagogue receptor ghrelin is a peptide secreted by the stomach of mammals and stimulates food intake and enhances adiposity. In avian species, ghrelin is mainly produced by the proventriculus but reduces food intake whereas its effect on lipogenesis in different tissues is unknown. We therefore investigated the effects of a single intravenous injection of 2.8 microg (1 nmol per chick) recombinant chicken ghrelin in neonatal broiler chicks. Besides food intake and plasma corticosterone levels, mRNA levels of the key lipogenic enzyme fatty acid synthase (FAS) and its related transcription factors sterol regulatory element binding protein-1 (SREBP-1) and peroxisome proliferator-activated receptor-gamma (PPARgamma) were determined in diencephalon, liver and quadriceps femoris muscle before, and 15, 30, and 60 min after injection. Chicken ghrelin administration induced a significant short-term (<30 min) reduction in food intake and markedly elevated plasma corticosterone levels. In diencephalon, FAS, SREBP-1 and PPARgamma mRNA levels were significantly increased within 15 min after ghrelin injection. These observations suggest that central fatty acid metabolism is involved in the anorectic effects of ghrelin. In contrast, hepatic mRNA levels of FAS and both transcription factors were significantly reduced within 30 min after ghrelin injection. In muscle, FAS and transcription factor gene expression was very low and not affected by ghrelin. Overall, our results indicate that ghrelin has opposite effects on FAS and transcription factor mRNA amounts with increased levels in diencephalon (central anorectic effect) and decreased levels in liver (peripheral anti-lipogenic effect) in chickens.


The Caenorhabditis elegans XPA homolog of human XPA.
The Xeroderma pigmentosum complementation group A (XPA) protein that is indispensable for nucleotide excision repair of DNA damage in eukaryotes participates in photoproduct recognition. A search of the current Caenorhabditis elegans database allowed us to identify a good candidate for the XPA protein homolog. We cloned a complete cDNA of C. elegans XPA (Ce-XPA) by using RT-PCR. Northern blot analysis showed that the Ce-xpa gene is expressed in all of the stages, including embryos. Ce-XPA encodes a 241-amino acid protein that is homologous to all known eukaryotic XPA. Ce-XPA RNAi caused embryonic lethality and survival lethality to UV radiation. This result suggests that Ce-XPA is involved in the repair of UV-damaged DNA in C. elegans.


Ileal impaction in 245 horses: 1995-2007.
The objective of this study was to identify parameters that would assist in determining the probability of a successful outcome with medical management versus surgical intervention in horses with ileal impaction. Medical records of 245 horses admitted for ileal impaction were reviewed and placed into 2 groups: medical (med) and surgical (sx) treatment. Persistence of abdominal pain, gastric reflux, frequency of analgesic administration, and 1-year survival were evaluated. There were no differences in signalment, abdominal pain, or heart rate among groups; however, significantly more sx horses had peritoneal fluid abnormalities (51%) and produced gastric reflux (62%) than did med horses (38% and 15%, respectively). Eighty-nine percent of med horses required repeated analgesic administration for successful resolution. One-year survival was 91% for sx horses and 92% for med horses. Horses with ileal impaction responsive to analgesic therapy with minimal gastric reflux are likely to be managed successfully with medical treatment. Horses with persistent abdominal pain and gastric reflux are candidates for surgery.


The French Epidemic Intelligence System: comparing disease surveillance at the national and international level using data from the Program for Monitoring Emerging Diseases.
In a context of globalisation and climate change, the risk of emerging infectious diseases spreading around the world has significantly increased in the past decades. In response to this growing threat, an epidemic intelligence team has been set up within the framework of the French animal health epidemiological surveillance platform (ESA platform). The French Epidemic Intelligence System (FEIS) monitors animal health risks in Europe and beyond that threaten animal populations in France (emerging and exotic diseases not yet present). The FEIS expert network covers all 53 category 1 health hazards identified as priority diseases by the French authorities. From January 2016 to December 2017, the FEIS published 126 reports on animal health events related to infectious diseases, of which 76.2% were related to events in Europe. When comparing FEIS reports to posts from the Program for Monitoring Emerging Diseases (ProMED), an FEIS report was produced for 52.6% of ProMED themes (combinations of disease and country) posted in 2016-2017 on events in Europe. The remaining European ProMED themes did not meet the criterion for the production of an FEIS report because either the disease was already present in France, the risk of introduction into France was considered low or negligible, or the introduction of the pathogen would have low or negligible economic and societal impacts. The FEIS efficiently detected and reported on all health hazards identified by ProMED to alert health authorities and stakeholders when needed (according to the criterion). Compared with international epidemic intelligence systems such as ProMED, which provide general information, the FEIS adds another layer of filtering and interpretation to available information on animal health threats tailored to France's specific needs, in order to communicate only essential information to health authorities.


Pharmaceutical regulation in France 1980-2003.
This paper provides an overview of French pharmaceutical policy between 1980 and 2003, which was dominated by price control and management of the positive list during the 1980s, with new policy instruments being introduced in the 1990s. The development and diffusion of prescription guidelines has been used to promote more appropriate use of medicines, and some measures aimed at developing the generic market have been implemented. In parallel, attempts have been made to set expenditure caps for physicians' prescriptions and for pharmaceutical companies' turnover. This second option seems to be more durable and effective, although its effectiveness in controlling increases in pharmaceutical expenditure remains limited. Pharmaceutical regulation is now more transparent than it used to be, and the monitoring of prescriptions is steadily improving. However, some areas remain problematic, for example over-prescription of certain classes of medicines such as antibiotics and probably psycholeptics.


Protective effect of quercetin on cadmium-induced renal apoptosis through cyt-c/caspase-9/caspase-3 signaling pathway.
Cadmium (Cd), a heavy metal, has harmful effects on animal and human health, and it can also obviously induce cell apoptosis. Quercetin (Que) is a flavonoid compound with antioxidant and other biological activities. To investigate the protective effect of Que on Cd-induced renal apoptosis in rats. 24 male SD rats were randomly divided into four groups. They were treated as follows: control group was administered orally with normal saline (10 ml/kg); Cd group was injected with 2 mg/kg CdCl2 intraperitoneally; Cd + Que group was injected with 2 mg/kg CdCl2 and intragastric administration of Que (100 mg/kg); Que group was administered orally with Que (100 mg/kg). The experimental results showed that the body weight of Cd-exposed rats significantly decreased and the kidney coefficient increased. In addition, Cd significantly increased the contents of Blood Urea Nitrogen, Creatinine and Uric acid. Cd also increased the glutathione and malondialdehyde contents in renal tissues. The pathological section showed that Cd can cause pathological damages such as narrow lumen and renal interstitial congestion. Cd-induced apoptosis of kidney, which could activate the mRNA and protein expression levels of Cyt-c, Caspase-9 and Caspase-3 were significantly increased. Conversely, Que significantly reduces kidney damage caused by Cd. Kidney pathological damage was alleviated by Que. Que inhibited Cd-induced apoptosis and decreased Cyt-c, Caspase-9 and Caspase-3 proteins and mRNA expression levels. To sum up, Cd can induce kidney injury and apoptosis of renal cells, while Que can reduce Cd-induced kidney damage by reducing oxidative stress and inhibiting apoptosis. These results provide a theoretical basis for the clinical application of Que in the prevention and treatment of cadmium poisoning.


Association of Acute Kidney Injury During Diabetic Ketoacidosis With Risk of Microalbuminuria in Children With Type 1 Diabetes.
Diabetic kidney disease is among the most important causes of end-stage kidney disease worldwide. Risk factors for diabetic kidney disease remain incompletely defined. Recent studies document a high frequency of acute kidney injury (AKI) during diabetic ketoacidosis (DKA) in children, raising the question of whether these AKI episodes might contribute to future risk of diabetic kidney disease. To determine whether episodes of AKI occurring during DKA in children are associated with increased risk of development of microalbuminuria. This retrospective review of medical records included children with type 1 diabetes with 1 or more urine albumin levels measured during routine diabetes care from 2 university-affiliated urban tertiary children's hospitals in the United States from January 2006 to December 2019. Age at diagnosis of diabetes, hemoglobin A1c levels, episodes of DKA, pH and creatinine levels during DKA, and urine albumin and creatinine measurements were analyzed. Cox proportional hazards regression models were used to identify variables affecting the hazard rate for microalbuminuria development. Analyses began January 2021 and ended May 2021. Episodes of DKA and episodes of AKI occurring during DKA. AKI occurrence and AKI stage were determined from serum creatinine measurements during DKA using Kidney Disease: Improving Global Outcomes criteria. Microalbuminuria was defined as urine albumin-to-creatinine ratio of 30 mg/g or more or excretion of 30 mg or more of albumin in 24 hours. Of 2345 children, the mean (SD) age at diagnosis was 9.4 (4.4) years. One or more episodes of DKA occurred in 963 children (41%), and AKI occurred during DKA in 560 episodes (47%). In multivariable models adjusting for the associations of age at diagnosis and mean hemoglobin A1c level since diagnosis, each episode of AKI during DKA was associated with a hazard ratio of 1.56 (95% CI, 1.3-1.87) for development of microalbuminuria. Four or more episodes increased the hazard rate by more than 5-fold. DKA episodes without AKI did not significantly increase the hazard rate for microalbuminuria development after adjusting for other covariates. These data demonstrate that episodes of AKI occurring during DKA in children with type 1 diabetes are significantly associated with risk of developing microalbuminuria. Greater efforts are necessary to reduce the frequency of DKA.


Impact of socio-economic factors on Tuberculosis treatment outcomes in north-eastern Uganda: a mixed methods study.
Tuberculosis (TB) is a major public health problem and at 48%, Karamoja in North-Eastern Uganda has the lowest treatment success rate nationally. Addressing the social determinants of TB is crucial to ending TB. This study sought to understand the extent and ways in which socio-economic factors affect TB treatment outcomes in Karamoja. We conducted a convergent parallel mixed methods study in 10 TB Diagnostic and Treatment Units. The study enrolled former TB patients diagnosed with drug-susceptible TB between April 2018 and March 2019. Unit TB and laboratory registers were reviewed to identify pre-treatment losses to follow-up. Four focus group discussions with former TB patients and 18 key informant interviews with healthcare workers were conducted. Principle component analysis was used to generate wealth quintiles that were compared to treatment outcomes using the proportion test. The association between sociodemographic characteristics and TB treatment outcomes was evaluated using the chi-square test and multiple logistic regression. A total of 313 participants were randomly selected from 1184 former TB patients recorded in the unit TB registers. Of these, 264 were contacted in the community and consented to join the study: 57% were male and 156 (59.1%) participants had unsuccessful treatment outcomes. The wealthiest quintile had a 58% reduction in the risk of having an unsuccessful treatment outcome (adj OR = 0.42, 95% CI 0.18-0.99, p = 0.047). People who were employed in the informal sector (adj OR = 4.71, 95% CI 1.18-18.89, p = 0.029) and children under the age of 15 years who were not in school or employed (adj OR = 2.71, 95% CI 1.11-6.62, p = 0.029) had significantly higher odds of unsuccessful treatment outcome. Analysis of the pre-treatment loss to follow-up showed that 17.2% of patients with pulmonary bacteriologically confirmed TB did not initiate treatment with a higher proportion among females (21.7%) than males (13.5%). Inadequate food, belonging to migratory communities, stigma, lack of social protection, drug stock-outs and transport challenges affected TB treatment outcomes. This study confirmed that low socio-economic status is associated with poor TB treatment outcomes emphasizing the need for multi- and cross-sectoral approaches and socio-economic enablers to optimise TB care.


Digest: Study associates squamate rates, traits, and climates.
The large variation in evolutionary rates across species remains unexplained. A new many-species multivariate study of evolutionary rates in skinks found that environmental temperature explains 45% of rate variation. These results, together with previous studies highlighting different determinants in other organisms, urge a pluralistic understanding of the determinants of evolutionary rate, in contrast to reductive models.


Postabortion Contraception Acceptance and Associated Factors in Dessie Health Center and Marie Stopes International Clinics, South Wollo Northeast, Amhara Region, 2017.
Abortion is termination of pregnancy before the viability of the pregnancy. It is one of the major causes for maternal mortality in the world and in Ethiopia. Unintended pregnancies which end up in abortion occur due to contraception method nonuse or misuse. To limit unintended pregnancies and avoid repeated abortions promoting immediate postabortion contraception is crucial. To assess the proportion of postabortion contraception acceptance among women who got abortion care service and factors associated with it in Marie stopes international clinic and Dessie health center, Dessie, North eastern Amhara, 2017. An institutional based cross-sectional study design was conducted from May 1 to May 30, 2017, at Marie stopes international clinics and Dessie health center. A sample of 125 women were selected by means of systematic sampling techniques and 118 abortion clients were interviewed in Marie stopes international clinic and Dessie on the use/acceptance of postabortion family planning (PAFP). Data were collected through pretested structured questionnaire. Data was cleaned and checked. Chi-square test was done to assess the association between dependent and independent variables. Odds ratio was done to assess the strength of association. Frequency tables, pie chart, and graphs were used to present the finding of the study. From a total of 125 participants recruited, 118 participated in the study while 7 were unwilling to participate in the study, yielding the response rate of 94.4%. Among the 118 study participants, 79 (66.9%) were within the age group 25-34. This study found a strong positive association between Postabortion contraception acceptance and age [P = 0.007 [X2 test= 9.989, COR=2.625)]. Study subjects aged 15-24 years were 3 times more likely to accept postabortion family planning as compared with those aged >35 years. This study revealed that the acceptance of postabortion family planning method was 84%. Age of women, marital status, ever use of history family planning, involvement of others in decision making, and family planning counseling were significantly associated with postabortion family planning acceptance. Therefore it is better to give emphasis on health education about family planning.


Activation-induced cytidine deaminase links between inflammation and the development of colitis-associated colorectal cancers.
Activation-induced cytidine deaminase (AID) was originally identified as an inducer of somatic hypermutations in the immunoglobulin gene. We recently revealed that ectopic AID expression serves as a link between the cellular editing machinery and high mutation frequencies, leading to human cancer development. In the current study, we investigated whether AID might contribute to the development of colitis-associated colorectal cancers. The expression and regulation of AID in association with proinflammatory cytokine stimulation were investigated in cultured colonic cells. Genotoxic activity of AID in colonic cells was analyzed using retroviral system. Immunohistochemistry for AID was carried out on various human colonic tissues specimens. Tumor necrosis factor-alpha induced aberrant AID expression via IkappaB kinase-dependent nuclear factor (NF)-kappaB-signaling pathways in human colonic epithelial cells. Moreover, AID expression was also induced in response to the T helper cell 2-driven cytokines interleukin-4 and interleukin-13, which are activated in human inflammatory bowel disease. Aberrant activation of AID in colonic cells preferentially induced genetic mutations in the TP53 gene, whereas there were no nucleotide alterations of the APC gene. Immunohistochemistry revealed enhanced expression of endogenous AID protein not only in the inflamed colonic mucosa of ulcerative colitis patients but also in tumor lesions of colitis-associated colorectal cancers. Our findings indicate that proinflammatory cytokine-mediated aberrant expression of AID in colonic epithelial cells is a genotoxic factor linking inflammation, somatic mutations, and colorectal cancer development.


The changing outlook of psychedelic drugs: The importance of risk assessment and occupational exposure limits.
Serotonergic psychedelics, such as lysergic acid diethylamide (LSD), psilocybin, dimethyltryptamine (DMT), and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), are currently being investigated for the treatment of psychiatric disorders such as depression and anxiety. Clinical trials with psilocybin and LSD have shown improvement in emotional and psychological scores. Although these drugs are reported to be safe in a controlled environment (such as clinical trials), exposure to low doses of these drugs can result in psychedelic effects, and therefore, occupational safety is an important consideration to prevent adverse effects in the workplace from low daily exposure. This article will discuss the factors involved in the derivation of occupational exposure limits (OELs) and risk assessment of these psychedelic drugs. To support the OEL derivations of psychedelic drugs, information regarding their mechanism of action, adverse effect profiles, pharmacokinetics, clinical effects, and nonclinical toxicity were considered. Additionally, psilocybin and LSD, which are the most extensively researched psychedelic substances, are employed as illustrative examples in case studies. The OELs derived for psilocybin and for LSD are 0.05 and 0.002 μg/m3 , respectively, which indicates that these are highly hazardous compounds, and it is important to take into account suitable safety measures and risk-management strategies in order to minimize workplace exposure.


Micro-enterprise development schemes as effective reintegration assistance programs for voluntarily-repatriated Vietnamese asylum seekers.
"From the creation of the Comprehensive Plan of Action (CPA) in 1989 through December 1994, about sixty-eight thousand asylum seekers have voluntarily repatriated to Vietnam. In response to this reverse migration, the international community has funded numerous reintegration assistance programs to facilitate the asylum seekers' return. This article examines reintegration assistance programs currently operating in Vietnam and presents an argument that small scale income generation projects constitute the most effective and efficient use of scarce repatriation funding."


Normative data in women aged 85 and older: verbal fluency, digit span, and the CVLT-II short form.
Individuals aged 85 years and above (i.e., the oldest old) represent the fastest growing segment of the US population and are at increased risk of developing dementia. This represents an important challenge for the clinical neuropsychologist, as the extant normative data on neuropsychological measures remain relatively limited for this age group. Therefore the aim of the present study was to characterize the performance effects of age and education in a large, well-characterized sample of women between the ages of 85 and 95 years on the California Verbal Learning Test-II (CVLT-II) Short Form (Delis, Kramer, Kaplan, & Ober, 2000), verbal fluency tasks, and the WAIS-III Digit Span Test (Wechsler, 1997 ). In order to minimize the likelihood that women with an incipient neurodegenerative process were included in the final normative sample, we applied regression-based change scores to identify and exclude women who evidenced a statistically significant decline on a global cognitive screening measure over a 20-year interval. The results of our analysis indicate varying influence of age and education on these measures and we provide tables with descriptive statistics stratified by both age and education. Findings from the present normative study are discussed within the context of "robust" longitudinal normative data.


Inhibitory Effect of Coenzyme Q0 on the Growth of Staphylococcus aureus.
Coenzyme Q0 (CoQ0), one of benzoquinone compounds, has been demonstrated to possess antineoplastic, anti-inflammatory and antioxidant activities. However, its antimicrobial effect has not been extensively reported. In this study, antimicrobial activity of CoQ0 against Staphylococcus aureus was evaluated by measurement of inhibition zone, minimum inhibitory concentration (MIC), and growth curves. Time-kill assay was performed to assess the bactericidal activity of CoQ0 against S. aureus in tryptone soya broth and pasteurized milk. The possible mechanism of action was explored through measuring changes in intracellular ATP concentrations, membrane potential, and cell morphology. Furthermore, propidium iodide (PI) staining assay was performed to evaluate the effect of CoQ0 on cell membrane integrity. The MIC of CoQ0 against tested strains ranged from 7.8 to 62.5 μg/mL. CoQ0 at 2 × MIC showed bactericidal effect on S. aureus in tryptic soy broth (TSB) and pasteurized milk. Decrease in intracellular ATP concentration and membrane potential were detected when cells were treated with CoQ0. PI staining demonstrated destruction of bacterial cell membrane. CoQ0 also induced abnormal cell morphological changes, as confirmed by field emission scanning electron microscopy. These findings suggested that CoQ0 exhibited antimicrobial effect on S. aureus, which was partly because of its ability to damage cell membrane.


[Limited evidence for negative pressure wound treatment of skin transplants and closed surgical wounds].
The indications for negative pressure wound treatment (NPWT) are increasing, e.g. for fixation of skin transplant and primary closed surgical wounds. The evidence for indications and positive effects are limited. NPWT should exclusively be used for fixation of split thickness skin transplants when immobilisation is otherwise difficult and for primary closed surgical wounds in selected patients at risk. Future high-quality investigations are necessary to pinpoint indications for topical negative pressure therapy, the effect of the different NPWT-modalities, and the overall economy compared to conventional bandages.


Critical interplay between parasite differentiation, host immunity, and antigenic variation in trypanosome infections.
Increasing availability of pathogen genomic data offers new opportunities to understand the fundamental mechanisms of immune evasion and pathogen population dynamics during chronic infection. Motivated by the growing knowledge on the antigenic variation system of the sleeping sickness parasite, the African trypanosome, we introduce a mechanistic framework for modeling within-host infection dynamics. Our analysis focuses first on a single parasitemia peak and then on the dynamics of multiple peaks that rely on stochastic switching between groups of parasite variants. A major feature of trypanosome infections is the interaction between variant-specific host immunity and density-dependent parasite differentiation to transmission life stages. In this study, we investigate how the interplay between these two types of control depends on the modular structure of the parasite antigenic archive. Our model shows that the degree of synchronization in stochastic variant emergence determines the relative dominance of general over specific control within a single peak. A requirement for multiple-peak dynamics is a critical switch rate between blocks of antigenic variants, which implies constraints on variant surface glycoprotein (VSG) archive genetic diversification. Our study illustrates the importance of quantifying the links between parasite genetics and within-host dynamics and provides insights into the evolution of trypanosomes.


[Molecular pathogenesis of haemophilia A].
Haemophilia A is one of the most common inherited bleeding disorders. Bleeding phenotype is caused by mutations within factor VIII gene, which result in deficient activity of the factor VIII in plasma. Various genetic defects have been described to affect factor VIII transcription, translation or its amino acid composition. Utilisation of 3D-model of the factor VIII helped to identify amino acid substitutions which adversely affect the protein folding and those which disturb various factor VIII interactions. Genetic defects have been stratified with respect to the relative risk of factor VIII inhibitor formation and a mechanism by which the antibody inhibits its function has been described. The knowledge has been utilised in current diagnostic practice and developement of future therapeutic strategies.


Genetic Distances for Intra- and Between-Group of Scapharca subcrenata from Yeosu of the Korea.
The oligonucleotides polymers (ON-polymers) were used producing a total of 110 loci unique to each clam population (LUECP) in group one and 132 in group two, respectively, varying in amount of DNA fragments (FRs) from greater than near 50 to a smaller quantity than 1,050 bp. The larger FR amounts (>1,050 bp) are not noticed in the two Scapharca subcrenata groups. The ON-polymer OPD-01 produced 33 LUECP, which were defining each group, almost 300 bp, 450 bp, and 500 bp, in the group one. The OPD-15 recognized 22 loci shared by the two clam populations (Loci shared by the two clam populations, LSTCP), a variety of FRs of sizes 300 bp that were equivalent in all specimens. The mean number of LUECP was varied and 1.2-fold greater in the shellfish group two than in the group one. Respecting mean bandsharing (BS) grade outcomes, entities in the shellfish group one (0.779±0.011) had a little higher BS grades than did entities from the group two (0.756±0.009) (p<0.05). The entities of the shellfish group one are not tightly gathered with other entities of the group two. The genetic distance (GD) (0.422) of this invertebrate (SUBCRENATA 02 and 01) is 7.41-fold hereditarily distinct to the GD (0.057) of the other invertebrate (SUBCRENATA 22 and 19). The polar dendrogram (PDG) procured by the five ON-polymers underlines two characteristic groups.


Mechanical properties of the lateral cortex of mammalian auditory outer hair cells.
Mammalian auditory outer hair cells generate high-frequency mechanical forces that enhance sound-induced displacements of the basilar membrane within the inner ear. It has been proposed that the resulting cell deformation is directed along the longitudinal axis of the cell by the cortical cytoskeleton. We have tested this proposal by making direct mechanical measurements on outer hair cells. The resultant stiffness modulus along the axis of whole dissociated cells was 3 x 10(-3) N/m, consistent with previously published values. The resultant axial and circumferential stiffness moduli for the cortical lattice were 5 x 10(-4) N/m and 3 x 10(-3) N/m, respectively. Thus the cortical lattice is a highly orthotropic structure. Its axial stiffness is small compared with that of the intact cell, but its circumferential stiffness is within the same order of magnitude. These measurements support the theory that the cortical cytoskeleton directs electrically driven length changes along the longitudinal axis of the cell. The Young's modulus of the circumferential filamentous components of the lattice were calculated to be 1 x 10(7) N/m2. The axial cross-links, believed to be a form of spectrin, were calculated to have a Young's modulus of 3 x 10(6) N/m2. Based on the measured values for the lattice and intact cell cortex, an estimate for the resultant stiffness modulus of the plasma membrane was estimated to be on the order of 10(-3) N/m. Thus, the plasma membrane appears to be relatively stiff and may be the dominant contributor to the axial stiffness of the intact cell.


Interpretations of education about gene-environment influences on health in rural Ethiopia: the context of a neglected tropical disease.
Misunderstandings of the role of genetics in disease development are associated with stigmatizing behaviors and fatalistic attitudes about prevention. This report describes an evaluation of community understanding of an educational module about genetic and environmental influences on the development of podoconiosis, a neglected tropical disease endemic in highland Ethiopia. A qualitative process assessment was conducted as part of a large prospective intervention trial in August 2013, in Wolaita Zone, southern Ethiopia. Sixty five participants were purposively selected from 600 households randomized to receive the inherited susceptibility module. The educational module used pictorial representations and oral explanations of the interaction of inherited sensitivity and soil exposure and was delivered by lay health educators in participants' homes. Data were collected using semi-structured individual interviews (IDIs) or focus group discussions (FGDs). Qualitative analyses showed that most participants improved their understanding of inherited soil sensitivity and susceptibility to podoconiosis. Participants linked their new understanding to decreased stigma-related attitudes. The module also corrected misconceptions that the condition was contagious, again diminishing stigmatizing attitudes. Lastly, these improvements in understanding increased the perceived value of foot protection. Taken together, these improvements support the acceptability, feasibility and potential benefits of implementing gene-environment education in low and middle income countries.


Genetics of social behaviour in fire ants.
A recent study is the first to sequence a gene known to underlie a complex social phenotype. In the fire ant, Solenopsis invicta, a single allelic difference at the Gp-9 locus specifies the number of queens a colony has, and hence the social structure of the colony. Gp-9 appears to encode a protein implicated in chemical recognition of nestmates, consistent with workers determining queen number by selectively executing queens as a function of workers' and queens' Gp-9 genotypes. Other Solenopsis species exhibit the same social and genetic polymorphism. This study pioneers the integrated understanding of the evolution of social behaviour at molecular, individual and social levels.


Expression of the subtype 2 angiotensin (AT2) receptor protein in rat kidney.
In situ hybridization studies have suggested that the subtype 2 angiotensin (AT2) receptor gene is expressed in fetal and newborn rat kidney but is undetectable in the adult animals. In the present study, we investigated the expression of AT2 receptor protein in the fetal (days 14 and 19 of fetal life), newborn (day 1 postpartum), and adult (4-week-old and 3-month-old) rat kidney. Polyclonal anti-peptide antiserum was raised against the amino terminus of the native AT2 receptor. The selectivity of the antiserum was validated by recognition of the AT2 receptor in a stably transfected COS-7 cell line by Western blot and immunocytochemical analysis. As a positive control, the AT2 receptor signal was detected strongly in the adrenal gland. Positive immunohistochemical staining was observed in the mesenchymal cells and ureteric buds of the 14-day fetal kidney and in the glomeruli, tubules, and vessels in the 19-day fetal and newborn kidney. Glomeruli expressing the AT2 receptor were localized mainly in the outer layer of the renal cortex. In the young (4-week-old) and mature (3-month-old) adult rat on normal sodium intake, renal AT2 receptor immunoreactivity was present in glomeruli but substantially diminished compared with that of newborn rats. In both young and mature adult rats, dietary sodium depletion increased the renal AT2 receptor signal, mainly in the glomeruli and interstitial cells. Preimmune and preadsorption controls were negative. Western blot analysis detected a single 44-kD band in the fetal and newborn rat kidney and in the young and mature adult rat kidney. Dietary sodium depletion increased the density of the AT2 receptor band in mature adult rat kidneys. These data provide evidence that the AT2 receptor protein is expressed in the fetal and newborn rat kidney, diminishes in adult life, and is reexpressed in the adult in response to sodium depletion.


Surgical timing in neonatal brachial plexus palsy: A PRISMA-IPD systematic review.
Neonatal brachial plexus palsy (NBPP) is a serious complication of high-risk deliveries with controversy surrounding timing of corrective nerve surgery. This review systematically examines the existing literature and investigates correlations between age at time of upper trunk brachial plexus microsurgery and surgical outcomes. A systematic screening of PubMed, Cochrane, Web of Science, and CINAHL databases using PRISMA-IPD guidelines was conducted in January 2020 to include full-text English papers with microsurgery in upper trunk palsy, pediatric patients. Spearman rank correlation analysis and two-tailed t-tests were performed using individual patient data to determine the relationship between mean age at time of surgery and outcome as determined by the Mallet, Medical Research Council (MRC), or Active Movement Scale (AMS) subscores. Two thousand nine hundred thirty six papers were screened to finalize 25 papers containing individual patient data (n = 256) with low to moderate risk of bias, as assessed by the ROBINS-I assessment tool. Mallet subscore for hand-to-mouth and shoulder abduction, AMS subscore for elbow flexion and external rotation, and MRC subscore for elbow flexion were analyzed alongside the respective age of patients at surgery. Spearman rank correlation analysis revealed a significant negative correlation (ρ = -0.30, p < .01, n = 89) between increasing age (5.50 ± 2.09 months) and Mallet subscore for hand-to-mouth (3.43 ± 0.83). T-tests revealed a significant decrease in Mallet hand-to-mouth subscores after 6 months (p < .05) and 9 months (p < .05) of age. No significant effects were observed for Mallet shoulder abduction, MRC elbow flexion, or AMS elbow flexion and external rotation. The cumulative evidence suggests a significant negative correlation between age at microsurgery and Mallet subscores for hand-to-mouth. However, a similar correlation with age at surgery was not observed for Mallet shoulder abduction, MRC elbow flexion, AMS external rotation, and AMS elbow flexion subscores.


Phosphatase inhibitors promote ICAM-1 and LFA-1 mediated homotypic aggregation of Jurkat and U937 cells.
Here we investigated the role of cellular phosphatases in activation of homotypic aggregation in leukocytes by adding the phosphatase inhibitors okadaic acid (OA) and calyculin A (CA) to cultures of the human monocytic U937 cell line and the human T-lymphocytic Jurkat cell line. We found that OA produces a 120-fold increase of homotypic aggregation with Jurkat cells and a 200-fold increase with U937 cells. Calyculin A increased aggregation of Jurkat cells 10-fold and U937 cells 88-fold. Monoclonal antibodies to LFA-1 completely inhibited the OA and CA induced aggregation in both cell lines, whereas the monoclonal antibody to ICAM-1 only inhibited U937 cell aggregation. These data suggest that phosphatase activity is important in the regulation of ICAM-1 and LFA-1 mediated homotypic aggregation in leukocytes.


[The logopenic variant of primary progressive aphasia].
The logopenic variant of primary progressive aphasia [also referred to as logopenic progressive aphasia (LPA)] is the most recently identified variant of primary progressive aphasia (PPA). This disorder, characterized by a unique speech and language profile, occurs due to damage to specific anatomical areas. An international panel of experts has established a set of diagnostic criteria for PPA and its clinical variants. The clinical diagnostic criteria for the logopenic variant include core features such as impaired single-word retrieval in spontaneous speech and impaired repetition of sentences and phrases. Additional features, of which at least 3 are essential for diagnosing the logopenic variant, include phonological errors in speech, spared single-word comprehension and object knowledge, spared motor speech, and lack of frank agrammatism. For a next imaging-supported diagnosis, the aforementioned clinical features must be accompanied by imaging findings revealing atrophy, hypoperfusion, or hypometabolism in the left temporo-parietal junction area. Finally, a pathology-confirmed case of the logopenic variant requires a clinical diagnosis of the syndrome accompanied by histopathological data or the presence of a known pathogenic mutation. Studies have clarified the clinical phenotype of this disorder, suggesting a prominent impairment of the phonological working memory. Several studies have provided evidences of a possible link between the logopenic phenotype and the specific pathological and genetic correlates. The diagnostic guidelines will enable a more accurate identification of the individuals with the logopenic variant, thus facilitating the documentation of the course of illness and, ultimately, the underlying pathological substrate in this patient group via the pathology-confirmed series.


[Intercellular communication within the anterior pituitary].
Paracrine and autocrine interactions within the anterior pituitary have been studied in the last few years. The adaptation of novel methodology to the study of the physiology of the anterior pituitary has yielded convincing evidence for cell-cell communication. Another reason for expanded interest in this field is the discovery of a growing member of substances that likely play a role in cell-cell communication. The various types of secretory cells within the anterior pituitary, gonadotroph, thyrotroph, somatotroph, lactotroph and corticotroph, have been addressed as sources, and then targets of intercellular factors. We need have more a collection of observations than a system of delineated pathways. Moreover, care must be exercised in interpretations of these observations.


The use of in vitro expanded erythroid cells in a model system for the isolation of fetal cells from maternal blood.
The development of a non-invasive prenatal diagnostic test using fetal nucleated red blood cells (NRBCs) isolated from the maternal circulation is hampered by the low frequency of these cells in maternal blood, requiring extensive enrichment procedures before any analytical procedure can be performed. In order to improve and simplify these procedures, we have used in vitro expanded erythroid cells derived from male umbilical cord blood in a model system for the isolation of fetal NRBCs from maternal blood. Erythroblast cells were expanded in vitro to high cell numbers and were immunophenotypically identical to fetal NRBCs isolated from maternal blood. Magnetic activated cell sorting (MACS) isolation procedures were optimized using in vitro expanded male NRBCs diluted up to 1 in 400,000 with female peripheral blood mononucleated cells. The number of recovered male cells was determined using two-colour fluorescence in situ hybridization with X and Y chromosomal probes. Using this model system, an NRBC isolation technique is described. It is based on a one-step MACS enrichment protocol for CD71 positive cells, which showed a significant (Wilcoxon signed ranks test, p<0.05) two-fold higher yield of male NRBCs than previously described MACS methodologies, in which CD71 positive cells were enriched after depletion of other cell types. Application of these isolation strategies to maternal blood samples resulted in a similar improved enrichment of male fetal cells after the direct enrichment of CD71 positive cells.


Prediction of outcome in infants with congenital diaphragmatic hernia or severe diaphragmatic eventration.
Congenital diaphragmatic hernia (CDH) and severe congenital diaphragmatic eventration (SDE) still have high mortality. Our aims were to identify clinical prognostic factors for CDH and SDE, and to determine whether the size or area of the proximal bilateral pulmonary arteries (PA) correlate with the clinical outcome. We retrospectively analyzed medical charts of 26 patients--20 with CDH and 6 with SDE, but no obvious other associated anomalies--admitted over a 12-year period. We compared prenatal history, clinical manifestations, blood gas, and echocardiography before surgery in the survivors and the non-survivors. Ten patients (8 CDH, 2 SDE) died 2 to 16 days after birth, including 2 patients without surgery due to progressive hypoxemia. The survivors had significantly higher 1- and 5-min Apgar scores, higher the worst preductal arterial blood gas pH levels, lower oxygen indices, and lower PaCO2 (P < 0.05). The McGoon index of PA size measured by echocardiography was higher in survivors, but not statistically significant. Nakada PA index results, however, were statistically significant (93.07 +/- 32.02 vs. 121.07 +/- 27.08, P < 0.05) In conclusion, Apgar scores, preductal PaCO2, oxygen index, and pH level can predict prognosis in infants with CDH and SDE. The Nakada PA index, however, might be a useful prognostic marker for patients with CDH and SDE.


Recognition physical activities with optimal number of wearable sensors using data mining algorithms and deep belief network.
Daily physical activities monitoring is benefiting the health care field in several ways, in particular with the development of the wearable sensors. This paper adopts effective ways to calculate the optimal number of the necessary sensors and to build a reliable and a high accuracy monitoring system. Three data mining algorithms, namely Decision Tree, Random Forest and PART Algorithm, have been applied for the sensors selection process. Furthermore, the deep belief network (DBN) has been investigated to recognise 33 physical activities effectively. The results indicated that the proposed method is reliable with an overall accuracy of 96.52% and the number of sensors is minimised from nine to six sensors.


Effect of the Heart At Work program on awareness of risk factors, self-efficacy, and health behaviors.
This study evaluates the effects of the American Heart Association's Heart At Work program on cardiovascular disease risk factor awareness, self-efficacy, and health behaviors. A prospective, quasi-experimental research design was used to assess the impact of the program at two factory sites (one intervention and one control). A total of 633 employees participated. Intervention site respondents significantly improved their knowledge of blood pressure management, the relationship between nutrition and cardiovascular disease, and heart attack risk factors. They also were more likely to begin treatment for hypertension, to report fewer sick days, and to have plans to improve their diet and lose weight. These findings suggest that the Heart At Work program had a favorable overall impact.


Advances in studies of ncRNAs in the pathophysiology and treatment of spinal disease.
Symptoms of spinal disease frequently accompany altered or damaged spine and vertebral structures resulting from endogenous and exogenous factors. Back braces, therapeutic agents, and surgery remain the main treatments for spinal diseases. However, the efficacy of currently available therapeutic agents is limited due to their side effects, whereas back braces and surgeries are less effective for certain patients. The significant effect of spinal disease on patients' morbidity and mortality emphasizes the necessity to develop novel and more effective therapeutic agents that mitigate the consequences of spinal disease. Accumulating research acknowledges that non-coding RNAs (ncRNAs), including miRNAs, lncRNAs, circRNAs, etc., are involved in the pathogenesis of spinal disease, their pronounced therapeutic potential and significant regulatory functions in spinal diseases. Hence, this review focuses on summarizing the latest advances in studies of ncRNAs in the progression and recovery of spinal diseases, as well as highlighting the collaboration of ncRNA networks in treating spinal disease.


Formulation design, in vitro characterizations and anti-malarial investigations of artemether and lumefantrine-entrapped solid lipid microparticles.
Poor aqueous solubility of artemether and lumefantrine makes it important to seek better ways of enhancing their oral delivery and bioavailability. To formulate and carry out in vitro and anti-malarial pharmacodynamic evaluations of solidified reverse micellar solutions (SRMS)-based solid lipid microparticles (SLMs) of artemether and lumefantrine for oral delivery and improved bioavailability. Rational blends of Softisan(®)154 and Phospholipon(®)90H lipid matrices, and different concentrations of artemether and lumefantrine were used to formulate several batches of SLMs. Drug-free SLMs were also formulated. Morphology, particle size, encapsulation efficiency (EE%) and pH studies were performed. In vitro release studies were performed in alcoholic buffer, simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) without enzymes. Anti-malarial pharmacodynamic studies were conducted in mice. Stable, smooth and spherical particles with sizes ranging from 4.2 ± 0.02 to 9.3 ± 0.8 µm were formed. EE% of 92.2-97.3% and 30.2-84.7% and pH of 3.0 ± 0.02 to 4.9 ± 0.12 and 3.0 ± 0.02 to 5.8 ± 0.05 were obtained for artemether and lumefantrine SLMs, respectively. Release of 100, 88.28 and 75.49%, as well as 63.26, 34.31 and 56.17% were recorded for artemether and lumefantrine in alcoholic buffer, SGF and SIF, respectively. Pharmacodynamic studies indicated very significant (p < 0.05) clearance of parasitaemia in plasmodium-infected mice by the drug-loaded SLMs. Oral delivery and bioavailability of artemether and lumefantrine could be improved using SRMS-based SLMs.


Comparison and recalculation of the very different QTc interval durations in young healthy women.
The aim was to use some simple way for easier comparison, other expression or recalculation of the QTc duration from one formula to another in order to remove the large QTc differences. The QT interval duration in 138 young healthy women was taken from our archive. The measured QT interval was corrected for heart rate (QTc) according to nine published regression equations (Bazett, Fridericia, Hodges, Sarma, Lecocq, Rautaharju, Sagie=Framingham, Arrowood, Malik) and compared mathematically by the Pearson correlation coefficient R and graphically by linear correlation.Correlation between two different QTc durations can be of three kinds: small (e.g. Bazett's versus Malik's formulas, R=0.0525, p=0.5405, the QTc values are much dispersed in the graph), larger (Malik's versus Sarma's formulas, R=0.939, p<0.01, the values are less dispersed), and identical (the Rautaharju's versus Arrowood's formulas, R=1.000, p<0.01, all QTc points are situated on one line). The linear correlation QTc1 = a+b·QTc2 enables recalculation from one QTc formula into another, if necessary.In conclusion, the QTc interval durations are differently long according to the QTc formula used. The correlations with the large Pearson R coefficient indicate the QTc pairs inappropriate for recalculation, the small R values indicate the appropriate pairs for recalculation.