Evaluating effect of metallic ions on aggregation behavior of β-amyloid peptides by atomic force microscope and surface-enhanced Raman Scattering.
Excessive aggregation of β-amyloid peptides (Aβ) is regarded as the hallmark of Alzheimer's disease. Exploring the underlying mechanism regulating Aβ aggregation remains challenging and investigating aggregation events of Aβ in the presence and absence of metallic ions at molecular level would be meaningful in elucidating the role of metal cations on interactions between Aβ molecules. In this study, chemical self-assembled monolayer (SAM) method was employed to fabricate monolayer of β-amyloid peptides Aβ42 on gold substrate with a bolaamphiphile named 16-Mercaptohexadecanoic acid (MHA). Firstly, the samples of gold substrate (blank control), the MHA-modified substrate, and the Aβ42-modified substrate were detected by X-ray photoelectron spectroscopy (XPS) to track the self-assembly process. Aggregation behaviors of Aβ42 before and after metallic ions (Zn2+, Ca2+, Al3+) treatment were monitored by atomic force microscopy (AFM) and the interaction between Aβ42 and metallic ions (Zn2+, Ca2+, Al3+) was investigated by surface-enhanced Raman Scattering (SERS). The XPS spectra of binding energy of gold substrate (blank control), the MHA-modified substrate, and the Aβ42-modified substrate are well fitted with the corresponding monolayer's composition, which indicates that Aβ42 monolayer is well formed. The recorded surface morphology of different experimental groups obtained by AFM showed markedly different nanostructures, indicating occurrence of aggregation events between Aβ42 molecules after adding metal ions to the solution. Compared to the control group, the presence of metallic ions resulted in the increased size of surface structures on the observed 3D topography. Besides, the intermolecular rupture force of Aβ42 increased with the addition of metallic ions. Further study by SERS showed that the Raman strength of Aβ42 changes significantly after the metal cation treatment. A considerable part of the amide bonds interacts with metal cations, leading to a structural change, which is characterized by the weakened β-fold Raman peak. The AFM imaging results suggest that aggregation events occurred between Aβ42 molecules with the addition of metal cations. In addition, the results of force tests indicate that the presence of metallic ions could promote adhesion between Aβ42 molecules, which is likely to be the trigger for aggregation behavior of Aβ42. Furthermore, the effect of metallic cations on the conformational change of Aβ42 studied by SERS supported the results obtained by AFM. Taken together, the results showed that the presence of substoichiometric metal cations promotes aggregation behavior between Aβ42 molecules on the substrate at pH 7.4.


Growth performance and carcass characteristics of feedlot Thai native × Lowline Angus crossbred steer fed with fermented cassava starch residue.
Ten Thai native × Lowline Angus crossbred (50:50) steers were used in a completely randomized design to receive two treatments including concentrate containing cassava chips (Control) and fermented cassava starch residue (FCSR) as major carbohydrate sources. FCSR was prepared as yeast (Saccharomyces cerevisiae) inoculates with exogenous enzyme addition. All steers received ad libitum rice straw and concentrate in equal proportions (1:1). Replacement of cassava chip with FCSR increased neutral detergent fiber and acid detergent fiber intakes but decreased non-protein nitrogen intake of steers. Digestibility of dry matter, organic matter, and crude protein were decreased with replacement of cassava chip by FCSR; however, digested nutrients were similar between groups. Replacement of cassava chip in the concentrate with FCSR resulted in comparable growth performance and feed efficiency of the feedlot steers. Moreover, carcass characteristics in terms of yield and meat quality of the steers were not affected by cassava chips replaced by FCSR as a major carbohydrate source in the concentrate. In conclusion, replacement of cassava chip in the concentrate with FCSR decreased feed digestibility; however, it did not impact negatively on growth performance and carcass traits of feedlot Thai native × Lowline Angus crossbred steers.


Unsuccessful in vitro fertilization: a follow-up study.
Results from a follow-up questionnaire completed by 28 women who had unsuccessfully completed one or more trials of in vitro fertilization (IVF) are reported. The mean time lapse since completing IVF was 8.4 months. During that period, 33% of the respondents had applied for adoption and 11% had secured an adoptive child. More than half the respondents had abandoned biological attempts to conceive and 52% felt as though they had "resolved" the infertility crisis. Nevertheless, 93% of the respondents indicated that they would participate in any new reproductive options that would enhance the likelihood of a biological pregnancy! The results and implications of this study are discussed.


Oral administration of transgenic biosafe microorganism containing antimicrobial peptide enhances the survival of tilapia fry infected bacterial pathogen.
To develop an alternative to conventional antibiotics used in the aquaculture and livestock industries, we employed Bacillus subtilis, considered a biosafe microorganism, to express the degradable antimicrobial peptide lactoferricin. An expression plasmid pP43-6LFBII-GFP, in which reporter GFP cDNA was fused downstream of lactoferricin cDNA driven by an endogenous constitutive P43 promoter was electroporated into B. subtilis, followed by regeneration and cultivation. The putative colonies harboring plasmids were primarily screened by PCR-amplification of lactoferricin cDNA. Four transformants which were stable inheritance of plasmid containing lactoferricin cDNA included strains T1, T4, T7 and T13. Based on Western blot and Southern blot analyses, we found that transgenic strains T1 and T13 not only highly expressed exogenous recombinant lactoferricin, but also exhibited more stable inheritance of plasmids with 931 and 647 copies per cell, respectively. In the antibacterial in vitro experiment, the bactericidal activity of each microliter of cell lysate from transgenic strains T1 and T13 (5 × 108 CFU) for Escherichia coli was equivalent to 56 and 53 ng of Ampicillin dosage, respectively, while for Staphylococcus epidermidis, the equivalency T1 and T13 was 154 and 130 ng of Ampicillin dosage, respectively. Equivalencies of bacterial activity for Vibrio parahaemolyticus and Edwardsiella tarda followed suit. In the antibacterial in vivo experiment, we oral-in-tube fed tilapia fry (Oreochromis mossambicus X O. niloticus) with cell lysate from transgenic strain T1 and T13 individually. After 1-h of incubation, we immersed these treated fish fry in a water tank containing E. tarda (5 × 1011 CFU) for a 5-hr bacterial challenge. After one month cultivation, an average survival rate of 63 and 67% was observed after having fed the fish fry with transgenic strains T1 and T13, respectively. However, the average survival rate of fish fry fed with B. subtilis WT strain and transgenic strain T19 without expressing recombinant lactoferricin reached only 5 and 9%, respectively. These data indicate that the survival of fish fry infected by the intestinal pathogen tested could be significantly enhanced by feeding transgenic B. subtilis containing antibacterial peptide. Therefore, we suggest that this strategy could be applied to both aquaculture and livestock industries to (i) reduce the dependency on conventional antibiotics during seasonal outbreaks and (ii) eliminate the problem of antibiotic resistance.


Long-Term Outcomes of Biceps Rerouting for Flexible Supination Contractures in Children With Brachial Plexus Birth Injuries.
Forearm supination contractures occur in 7% of children with brachial plexus birth injuries (BPBI). Biceps rerouting is proposed when pronation has deteriorated but is passively correctable to at least 0° (neutral). The purpose of this investigation was to evaluate long-term outcomes of biceps rerouting for this indication, including magnitude and maintenance of correction, complications, and subsequent osteotomy. We conducted a retrospective review of all children with BPBI and forearm supination contractures treated with biceps rerouting alone, for the above indications, from 1993 to 2017 with at least 2 years follow-up. Demographic information, BPBI characteristics, surgical details, and ranges of motion were obtained from medical records. Pre- and postoperative active pronation (AP) and supination (AS), elbow flexion contracture, and arc of forearm rotation (Arc) were analyzed using linear mixed-effect models. Twenty-five children (13 females; 13 left forearms; 15 global BPBI) underwent biceps rerouting at age 7 ± 3 years and were followed for 6 ± 3 years. Before surgery, the mean AP and AS were 6° ± 29° and 62° ± 27°, respectively. At the final follow-up, the mean AP, AS, and Arc were 39° ± 36°, 18° ± 34°, and 57° ± 42°, respectively. AP was significantly improved and AS was significantly decreased by 2 years after surgery and at the final follow-up. Neither Arc nor elbow flexion contracture changed significantly. Two of 25 (8%) children underwent subsequent forearm osteotomy. Biceps rerouting in children with BPBI improves the forearm position when pronation is deteriorating by shifting the arc from supination to pronation without decreasing the arc of motion or worsening elbow flexion contractures. There is a low risk of complications and a limited need for subsequent forearm osteotomy. These results are maintained over time. When performed before passive pronation is reduced beyond neutral, this procedure may prevent severe supination contractures and reduce the need for forearm osteotomy. Therapeutic IV.


Surgeon error in performing intraoperative estimation of stem anteversion in cementless total hip arthroplasty.
To examine the accuracy of intraoperative estimation of stem anteversion in total hip arthroplasty (THA), we compared the intraoperatively estimated stem anteversion (estimated prosthetic anteversion) to stem anteversion measured by postoperative computed tomography (true anteversion) in 73 hips in 73 patients. Estimated prosthetic anteversion was significantly greater than true anteversion by 5.8°, and the mean absolute value of surgeon error was 7.3° ranging from 11° underestimation to 25° overestimation. Surgeons tended to overestimate when the true anteversion was smaller. A multivariate analysis showed that advanced knee osteoarthritis significantly increased surgeon error. These results indicated that estimated prosthetic anteversion was generally larger than true anteversion and that the grade of knee osteoarthritis affected the degree of surgeon error.


Nucleotide-resolution DNA double-strand break mapping by next-generation sequencing.
We present a genome-wide approach to map DNA double-strand breaks (DSBs) at nucleotide resolution by a method we termed BLESS (direct in situ breaks labeling, enrichment on streptavidin and next-generation sequencing). We validated and tested BLESS using human and mouse cells and different DSBs-inducing agents and sequencing platforms. BLESS was able to detect telomere ends, Sce endonuclease-induced DSBs and complex genome-wide DSB landscapes. As a proof of principle, we characterized the genomic landscape of sensitivity to replication stress in human cells, and we identified >2,000 nonuniformly distributed aphidicolin-sensitive regions (ASRs) overrepresented in genes and enriched in satellite repeats. ASRs were also enriched in regions rearranged in human cancers, with many cancer-associated genes exhibiting high sensitivity to replication stress. Our method is suitable for genome-wide mapping of DSBs in various cells and experimental conditions, with a specificity and resolution unachievable by current techniques.


A randomised, controlled, single-blinded study on the impact of a single rhythmical massage (anthroposophic medicine) on well-being and salivary cortisol in healthy adults.
Rhythmical massage (RM) has evolved from classical massage and is based on the principles of Anthroposophic medicine. The goal of this randomized, single-blinded study was to assess the efficacy of a single RM intervention with either aroma oil (RA) or a neutral oil (RM) compared to a sham massage (SM) on several dimensions of well-being and salivary cortisol in a laboratory setting. 118 healthy adults (mean age: 25.2 years; SD: 4.7) were randomized to one of three groups (RM, RA or SM). After baseline measurements, all subjects were exposed to an experimental stressful situation (Trier Social Stress Test, TSST), before receiving a single massage intervention of about 60 min including a 20-minute rest period. Well-being as the main outcome parameter was assessed by standardized questionnaires (MDBF, Bf-S, B-L) and visual analogue scales (VAS) prior to the beginning of the massage and subsequently. Salivary cortisol and heart rate variability (data are shown elsewhere) were also measured. Participants who received RM or RA showed no statistically significant improvements (MDBF, Bf-S, B-L) compared to the SM group after adjusting for baseline differences observed between the treatment groups. Furthermore, no statistically significant differences were found between the RM and RA groups in any of the analyses. Within a follow-up survey all participants from the RA and 82% from the RM group described the intervention as "relaxing" compared with 42% in the SM group. Salivary cortisol did not differ statistically significantly between the three groups over time. We found no significant effect within this trial. This may be due to the methodological complexity of massage research and especially the sham-controlled design with only one single intervention examined. The influence of the setting, and the expectations of and interaction between participant and practitioner seem to play a role that needs to be verified. Therefore the true potential of rhythmical massage intervention still needs to be validated.


Regulation and rate of the hexose monophosphate shunt in Rana ridibunda erythrocytes.
1. Resting rates of Rana ridibunda erythrocyte glucose consumption and 14CO2 production from 1-14C-glucose were found to be significantly lower than the respective values in human erythrocytes. 2. In the presence of 1-14C-glucose Methylene Blue stimulated 14CO2 production 7-fold, while in the presence of 6-14C-glucose Methylene Blue stimulated 14CO2 production 1.2-fold. 3. The Km of G-6-PD for G-6-P and NADP were 29 and 12 microM, respectively while the Km of 6-PGD for 6-PG and NADP were 83 and 32 microM, respectively. The Ki of G-6-PD and 6-PGD for NADPH were 80 and 12 microM, respectively. 4. Excess amounts of NADP resulted in a significant decrease of 14CO2 production from 1-14C-glucose in total haemolysates. 5. ATP, ADP and fructose diphosphate inhibited both G-6-PD and 6-PGD, the latter being more sensitive than G-6-PD to their inhibitory effect, 2,3-DPG and reduced and oxidized glutathione showed a marked inhibitory effect on 6-PGD, while the phosphorylated trioses inhibited only G-6-PD. 6. Physiological concentrations of oxidized glutathione decreased the inhibition exercised by NADPH on G-6-PD. 7. The possible role of the two dehydrogenases in the regulation of the HMS is discussed.


Increased risk of diseases of the basal ganglia and cerebellum in patients with a history of attention-deficit/hyperactivity disorder.
Attention-deficit/hyperactivity disorder (ADHD) is marked by an ongoing pattern of inattention and/or hyperactivity and involves dysregulated dopaminergic pathways. Dopaminergic agents (i.e., amphetamine and methylphenidate) are thus prescribed to treat ADHD. As little is known regarding long-term consequences of either ADHD or its treatment, the objective of this study was to determine if either alters the risk of diseases of the basal ganglia and cerebellum, including Parkinson's disease. Statewide medical records from 1996 to 2016 were retrieved from the Utah Population Database to conduct a retrospective cohort study. Participants included ADHD patients (International Classification of Diseases, 9th revision (ICD-9) diagnosis codes 314.0-314.2, 314.8, 314.9) and 5:1 random sex-matched and age-matched subjects with no ADHD diagnosis history. Both patients and non-ADHD subjects met the following eligibility criteria: (1) no prior diagnosis of Parkinson's disease, secondary parkinsonism, basal ganglia disease, or essential tremor (ICD-9 codes 332.0, 332.1, 333.0, 333.1), (2) born in 1950 or later and age ≥20 years at last follow-up, and (3) no history of substance abuse (illicit drugs or alcohol). Outcomes were measured as time to diagnosis of diseases of the basal ganglia and cerebellum, death, or study-end. A Cox model incorporating a competing risk of death was used to provide hazard ratio estimates. Patients with ADHD (N = 31,769) had a 2.4-fold increased risk of basal ganglia and cerebellum diseases (95% confidence interval (CI): 2.0-3.0; P < 0.0001) compared with 158,790 non-ADHD persons, after controlling for sex and age and adjusting for tobacco use and psychotic conditions. In 4960 ADHD patients prescribed psychostimulants, risk of basal ganglia and cerebellum diseases between ages 21 and 49 years was especially pronounced, at 8.6-fold (95% CI: 4.8-15.6; P < 0001). The association of ADHD patients prescribed psychostimulants with higher risk of diseases of the basal ganglia and cerebellum may reflect a more severe ADHD phenotype rather than a direct association between prescribed stimulant use and basal ganglia or cerebellum disorders. Future studies to assess and stratify patient risk so as to inform treatment are warranted.


Absorption of copper and copper-histidine complexes across the apical surface of freshwater rainbow trout intestine.
Bioavailability is integral in mediating the delicate balance between nutritive and potentially toxic levels of copper in fish diets. Brush-border membrane vesicles isolated from freshwater rainbow trout intestine were used to characterise apical copper absorption, and to examine the influence of the amino acid histidine on this process. In the absence of histidine, a low affinity, high capacity copper uptake mechanism was described. However, when expressed as a function of ionic copper (Cu(2+)), absorption was linear, rather than saturable, suggesting that the saturable curve was an artifact of copper speciation. Conversely, in the presence of L: -histidine (780 microM) saturable uptake was characterised. The uptake capacity discerned (J (max) of 354 +/- 81 nmol mg protein(-1) min(-1)) in the presence of histidine indicated a significantly reduced capacity for copper transport than that in the absence of histidine. To determine if copper uptake was achievable through putative histidine uptake pathways, copper and histidine were incubated in the presence of tenfold greater concentrations of amino acids proposed to block histidine transporters. Accounting for changes in copper speciation, significant inhibition of uptake by glycine and lysine were noted at copper levels of 699 and 1,028 microM. These results suggest that copper-histidine complexes may be transportable via specific amino acid-transporters in the brush-border membrane.


Minimum acceptable diet intake and its associated factors among children age at 6-23 months in sub-Saharan Africa: a multilevel analysis of the sub-Saharan Africa demographic and health survey.
Only one in five children aged below 24 months in the low-income countries feed the minimum recommended diet, and significantly varied across socio-economic classes. Though sub-saharan Africa (SSA) shares the huge burden of children under nutrition, as to our search of literature there is limited evidence on the pooled magnitude and factors associated with minimum acceptable diet (MAD) intake among children aged 6 to 23 months in the region. This study aimed to assess the pooled magnitude and associated factors of MAD intake among children aged 6-23 months in SSA using recent 2010-2020 DHS data. Demographic and Health Survey datasets of SSA countries were used for this study with a total of 78,542 weighted samples. The data were cleaned using MS excel and extracted and analyzed using STATA V.16 software. A multilevel binary logistic regression model was fitted. The adjusted odds ratio (AOR) with P-value < 0.05 was taken to declare statistical significance. The pooled magnitude of MAD intake among children aged 6-23 months in SSA was 9.89% [95%CI: 8.57, 11.21%] ranging from 3.10% in Guinea to 20.40% in Kenya. Individual level factors such as; secondary &above women educational status [AOR = 1.41; 95%CI; 1.29, 1.53], having employed women [AOR = 1.25;95%CI;1.17,1.33], having media exposure [AOR = 1.55;95%CI;1.45,1.66], richest household wealth [AOR = 1.93; 95%CI; 1.73, 2.15], plural birth [AOR = 0.68;95%CI; 0.56, 0.82] and breastfed child [AOR = 2.04; 95%CI; 1.89, 2.21], whereas, community level factor such as rural residence [AOR = 0.74; 95%CI; 0.69, 0.79] and living in upper middle income country [AOR = 1.62; [95%CI; 1.41,1.87] were significantly associated with MAD intake. Minimum acceptable diet intake in SSA is relatively low. Variables such as; secondary &above maternal education, having employed mother, exposure to media, richest wealth, breast feeding child, and upper middle income country have a significant positive association, whereas having plural birth and living in rural residence have a significant negative association with MAD intake. These findings highlight that policymakers and other stakeholders had better give prior attention to empowering women, enhance household wealth status and media exposure to increase the MAD intake in the region.


Discrete Supramolecular Stacks Based on Multinuclear Tweezer-Type Rhodium Complexes.
By taking advantage of self-complementary π-π stacking and CH-π interactions, a series of discrete quadruple stacks were constructed through the self-aggregation of U-shaped dirhodium metallotweezer complexes featuring various planar polyaromatic ligands. By altering the conjugate stacking strength and bridging ligands, assemblies with a range of topologies were obtained, including a binuclear D-shaped macrocycle, tetranuclear open-ended cagelike frameworks, and duplex metallotweezer stacking structures. Furthermore, a rare stacking interaction resulting in selective C-H activation was observed during the self-assembly process of these elaborate architectures.


Antiretroviral regimens for treatment-experienced patients with HIV-1 infection.
A significant number of treatment-experienced patients with HIV-1 infection develop drug-resistant virus. To define strategies for managing the antiretroviral-experienced patient and summarize current data with commonly used drugs for this population. This review incorporated data from most recent antiretroviral treatment guidelines, published papers on related topics, and peer-reviewed publications or presentations at research meetings on the safety and efficacy of agents commonly used in this patient population. The patient experiencing virologic failure on treatment must be evaluated for their ability to adhere with therapy and to define the number of available active drugs. A viable regimen should include at least two fully active agents, with the goal being to achieve complete virologic suppression.


Identification of novel predictive factors for post surgical corneal haze.
Molecular factors altered in corneas that develop haze post refractive surgery have been described, but pre-existing factors that predispose clinically normal corneas to aberrant fibrosis post surgery and the role of the corneal epithelium remains unknown. We analyzed the global gene expression in epithelium collected intraoperatively from subjects undergoing photorefractive keratectomy. Subjects were grouped into those that developed haze 12 months post surgery (n = 6 eyes; haze predisposed) and those that did not develop haze in a similar follow up duration (n = 11 eyes; controls). Ontological analysis of 1100 upregulated and 1780 downregulated genes in the haze predisposed group revealed alterations in pathways associated with inflammation, wnt signaling, oxidative stress, nerve functions and extra cellular matrix remodeling. Novel factors such as PREX1, WNT3A, SOX17, GABRA1and PXDN were found to be significantly altered in haze predisposed subjects and those with active haze(n = 3), indicating their pro-fibrotic role. PREX1 was significantly upregulated in haze predisposed subjects. Ectopic expression of PREX1 in cultured human corneal epithelial cells enhanced their rate of wound healing while its ablation using shRNA reduced healing compared to matched controls. Recombinant TGFβ treatment in PREX1 overexpressing corneal cells led to enhanced αSMA expression and Vimentin phosphorylation while the converse was true for shPREX1 expressing cells. Our data identify a few novel factors in the corneal epithelium that may define a patient's risk to developing post refractive corneal haze.


Posterior Vertebral Column Resection Through Unilateral Osteotomy Approach for Old Lumbar Fracture Combined with Kummell Disease.
Kummell disease is a clinical syndrome characterized by minor spinal trauma with a symptom-free period from months to years, followed by progressive painful kyphosis. Many surgical options for Kummell disease have been reported in the previous literature; however, no study has mentioned the surgical strategy for patients whose fractured vertebrae were severely compressed and only a slice of superior and inferior end plate was left. Here we report the case of a 69-year-old woman who suffered persistent severe back pain since she slipped and fell 1 year before medical consult. The patient presented with constrained body posture and pressure pain on the thoracolumbar region. Visual analog scale pain under weight bearing was 90/100, and her Oswestry Disability Index score was 74%. Kummell disease was diagnosed on the basis of clinical presentation, trauma history, radiograph, computed tomography, and magnetic resonance imaging. We performed the posterior vertebral column resection through the unilateral osteotomy approach for the patient, and the clinical outcome and radiologic restoration were recorded. One year after the surgery, outpatient follow-up review revealed that the visual analog scale reduced to 10/100 and Oswestry Disability Index reduced to 13%. The posteroanterior and lateral radiograph in the standing position showed bony fusion was achieved at the osteotomy site. No pseudarthrosis or instrumentation-related failure occurred. Posterior vertebral column resection through unilateral osteotomy approach is an effective method for patients with Kummell disease, especially when the fractured vertebrae compressed severely and only a slice of superior and inferior end plate was left.


Comparison of analgesic effect, knee joint function recovery, and safety profiles between pre-operative and post-operative administrations of meloxicam in knee osteoarthritis patients who underwent total knee arthroplasty.
This study aimed to compare the efficacy and safety of pre-operative and post-operative meloxicam administration regarding post-operative pain control and knee joint function recovery in knee osteoarthritis (KOA) patients who underwent total knee arthroplasty (TKA). Totally, 196 KOA patients who underwent TKA were consecutively enrolled and randomly assigned into pre-operative (N = 98) and post-operative administration group (N = 98) as 1:1 ratio. Pre-operative administration group received meloxicam 15 mg at 24 h pre-operation and 7.5 mg at 4 h, 24 h, 48 h, and 72 h post-operation, respectively. Post-operative administration group received meloxicam 15 mg at 4 h post-operation and 7.5 mg at 24 h, 48 h, and 72 h post-operation, respectively. Pain visual analog scale (VAS) at rest and at flexion, patient's global assessment (PGA), patient-controlled analgesia (PCA) consumption, hospital for special surgery (HSS), knee score, and adverse events were assessed. Pre-operative meloxicam administration attenuated pain VAS score at rest at 6 h, 12 h, and 24 h; and pain VAS score at flexion at 6 h, 12 h, 24 h, and 48 h; as well as PGA score at 6 h, 12 h, 48 h post-TKA compared with post-operative meloxicam administration. Additional and total consumption of PCA were both decreased in pre-operative meloxicam administration group than post-operative meloxicam administration group, while HSS knee score at 3 months post-TKA was similar between pre-operative and post-operative meloxicam administration groups. Regarding safety, the incidence of adverse events was of no difference between the two groups. Pre-operative administration of meloxicam might assist the post-operative pain management and care in KOA patients who underwent TKA.


Newborns' neural processing of native vowels reveals directional asymmetries.
Prenatal learning of speech rhythm and melody is well documented. Much less is known about the earliest acquisition of segmental speech categories. We tested whether newborn infants perceive native vowels, but not nonspeech sounds, through some existing (proto-)categories, and whether they do so more robustly for some vowels than for others. Sensory event-related potentials (ERP), and mismatch responses (MMR), were obtained from 104 neonates acquiring Czech. The ERPs elicited by vowels were larger than the ERPs to nonspeech sounds, and reflected the differences between the individual vowel categories. The MMRs to changes in vowels but not in nonspeech sounds revealed left-lateralized asymmetrical processing patterns: a change from a focal [a] to a nonfocal [ɛ], and the change from short [ɛ] to long [ɛ:] elicited more negative MMR responses than reverse changes. Contrary to predictions, we did not find evidence of a developmental advantage for vowel length contrasts (supposedly most readily available in utero) over vowel quality contrasts (supposedly less salient in utero). An explanation for these asymmetries in terms of differential degree of prior phonetic warping of speech sounds is proposed. Future studies with newborns with different language backgrounds should test whether the prenatal learning scenario proposed here is plausible.


Longitudinal Associations between Inflammatory Markers and Fatigue up to Two Years after Colorectal Cancer Treatment.
Fatigue is often reported by colorectal cancer survivors and largely impacts their quality of life. Inflammation has been linked to fatigue mainly in patients with breast cancer. Therefore, we investigated how inflammation is longitudinally associated with fatigue in colorectal cancer survivors, up to 2 years posttreatment. A total of 257 patients from the ongoing Energy for life after ColoRectal cancer cohort study were included in the analysis. Plasma levels of IL6, IL8, IL10, TNFα, high-sensitivity C-reactive protein (hsCRP), and fatigue were measured at 6 weeks, 6, 12, and 24 months posttreatment. Fatigue was measured through the validated Checklist Individual Strength (CIS; total, 20-140), consisting of four subscales - subjective fatigue (8-56), motivation (4-28), physical activity (3-21), and concentration (5-35), and the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 fatigue subscale (0-100). Linear mixed-models were used to assess the confounder-adjusted longitudinal associations between inflammatory markers and overall fatigue along with the subscales. Mean levels of CIS fatigue decreased from 62.9 at 6 weeks to 53.0 at 24 months. In general, levels of inflammatory markers also decreased over time. No statistically significant longitudinal associations were found between IL6, IL8, IL10, TNFα, and fatigue. Higher levels of hsCRP were associated with more CIS fatigue (β per SD 3.21, 95% confidence interval (CI), 1.42-5.01) and EORTC fatigue (β 2.41, 95% CI, 0.72-4.10). Increased levels of hsCRP are longitudinally associated with more posttreatment fatigue in colorectal cancer survivors. These findings suggest that low-grade inflammation may play a role in fatigue reported by colorectal cancer survivors up to 2 years posttreatment.


The periplasmic coiled coil formed by the assembly platform proteins PulL and PulM is critical for function of the Klebsiella type II secretion system.
Bacteria use type II secretion systems (T2SS) to secrete to their surface folded proteins that confer diverse functions, from nutrient acquisition to virulence. In the Klebsiella species, T2SS-mediated secretion of pullulanase (PulA) requires assembly of a dynamic filament called the endopilus. The inner membrane assembly platform (AP) subcomplex is essential for endopilus assembly and PulA secretion. AP components PulL and PulM interact with each other through their C-terminal globular domains and transmembrane segments. Here, we investigated the roles of their periplasmic helices, predicted to form a coiled coil, in assembly and function of the PulL-PulM complex. PulL and PulM variants lacking these periplasmic helices were defective for interaction in the bacterial two-hybrid (BACTH) assay. Their functions in PulA secretion and assembly of PulG subunits into endopilus filaments were strongly reduced. Interestingly, deleting the cytoplasmic peptide of PulM nearly abolished the function of variant PulMΔN and its interaction with PulG, but not with PulL, in the BACTH assay. Nevertheless, PulL was specifically proteolyzed in the presence of the PulMΔN variant, suggesting that PulM N-terminal peptide stabilizes PulL in the cytoplasm. We discuss the implications of these results for the T2S endopilus and type IV pilus assembly mechanisms.


Lessons learned through the 20-year development of a national fatal drowning database in Australia.
Co-ordinated, evidence-based policy and programmatic efforts are needed to respond to complex drowning prevention problems. Comprehensive, current, and robust data are vital for agenda setting, burden and risk factor identification, intervention design and evaluation, as well as setting policy. We aim to record methods used in, and identify impacts of, the development of a national fatal drowning database (NFDD) in Australia, including lessons learned across research, policy, and practice. We employ a case study method using process mapping and document review to explore the evolution, drivers and impacts of the NFDD. We analyse methodological approaches including those relating to data definitions, drowning case collection, and management, as well as tracking the various outputs of the NFDD. We describe a development timeline that presents impact of drowning prevention policy, and research agendas on database development, and research investments more specifically. Our study identified that the collected variables grew 20-fold from 2002 to 2022, reaching 259 variables, and 5,692 unique cases of fatal drowning. The NFDD employs data triangulation methodology, combining keyword and targeted searches of coronial files, media report monitoring, and organisational data provision. Database development is influenced by the Australia Water Safety Strategy, policymaker and practitioner-initiated research agendas, and identification of knowledge gaps. We identified numerous outputs spanning publications, media, intervention development, and legislative submissions. A comprehensive and robust NFDD informed by policymaker and practitioner input can enhance surveillance, policy, and intervention development for drowning prevention. Employing mixed data collection and validation methods can supplement weaknesses in official data sources. There is a need for the NFDD to continue to evolve in its application while maintaining rigorous case identification and data quality assurance processes. Despite significant investment, the outputs and influence on drowning prevention practice in Australia has been extremely valuable and contributed to sizeable reductions in Australia's fatal drowning rate.


Persistence of Natural Killer (NK) cell lymphocytosis with hyposplenism without development of leukaemia.
Natural killer (NK) cell lymphocytosis usually has an indolent course and can progress into massive lymphocytosis with development of cytopenias and neoplastic diseases. NK-cells usually express one or more "NK-associated" antigens (CD16, CD56, CD57). Reactive expansions are seen in autoimmune diseases, viral infections, solid tumours and non-Hodgkin's lymphoma. We report a lady with a benign clinical course over 10 years and persistent CD8+/CD3-/CD57+/CD16+ LGL proliferation with presence of Howell-Jolly bodies (functional hyposplenism), an association not previously described. We discuss the possible causes of clonal expansion and conclude that this may be part of the spectrum of immune dysregulation associated with NK-cell lymphocytosis.


Tumor incidence was not related to the thickness of visceral pleural in female Syrian hamsters intratracheally administered amphibole asbestos or manmade fibers.
Histological observations were performed on female Syrian hamsters 2 years after the intratracheal administration of amphibole asbestos, amosite, and crocidolite to evaluate the tumorigenicity of six types of fine manmade fibers (reported previously). A mesothelioma and a lung tumor were induced in 20 animals administered amosite, but no tumors were found in the crocidolite group. Because this incidence is not higher than that of manmade fibers, such as basic magnesium sulfate fiber [9 tumor-bearing hamsters in 20 hamsters (9/20)], metaphosphate fiber (5/20), calcium sulfate fiber (3/20), and fiberglass (2/20), it is suggested that some types of manmade fibers have a greater ability than asbestos to induce tumors. Moreover, as a specific observation in manmade fiber groups, tumors were induced at intracelial organs rather than at the pleural cavity. On the other hand, the average thickness of visceral pleura was higher in all asbestos and manmade fiber groups than in the control (2.9 microns), for instance, 36.95 microns in potassium titanate fiber group, 15.90 microns crocidolite group, 13.00 microns basic magnesium sulfate fiber group, and 10.45 microns in the rockwool group. Although both pleural thickening and mesothelioma are known as peculiar lesions in asbestos-exposed people, it might also be suggested that these lesions could be induced by different mechanisms from the result that there was no relation between the pleural thickening and mesothelioma incidence in hamsters.


Reduction in occupational and patient radiation exposure from myocardial perfusion imaging: impact of stress-only imaging and high-efficiency SPECT camera technology.
Recently introduced high-efficiency SPECT cameras have demonstrated the ability to reduce radiation exposure to patients undergoing myocardial perfusion imaging studies, especially when combined with stress-only imaging protocols. To date there have been no relevant studies examining the reduced occupational radiation exposure to medical staff. We sought to determine whether changes in stress myocardial perfusion imaging protocols and camera technology can reduce the occupational radiation exposure to the staff of a nuclear cardiology laboratory. Monthly radiation dosimeter readings from 4 nuclear technologists, 4 nurses, and 2 administrative employees were analyzed from two 12-mo periods: October 2007-September 2008 (period 1), before the use of high-efficiency SPECT, and October 2010-September 2011 (period 2), after high-efficiency SPECT was introduced. The average monthly dose equivalent in millirems (1 mrem = 0.01 mSv) was recorded from personal dosimeters worn on laboratory coats. The total activity of (99m)Tc used per month, mean (99m)Tc administered activity per patient, average number of patients per month, patient time spent in the laboratory, and proportion of stress-only studies were determined. There were 3,539 patients in period 1 and 3,898 in period 2. An approximately 40% reduction in the dose equivalent across all staff members occurred during this time (-16.9 and -16.2 mrem for nuclear technologists and nurses, respectively; P < 0.0001). During period 2, the total activity of (99m)Tc used per month decreased (10,746 vs. 7,174 mCi [1 mCi = 37 MBq], P < 0.0001), as did the mean (99m)Tc administered activity per patient (36.5 vs. 23.8 mCi, P < 0.0001). The percentage of patients having stress-only imaging increased (35% vs. 56%, P < 0.0001), and the total patient time spent in the laboratory decreased. Radiation dose equivalent levels were reduced in period 2 to 1%-7% of the allowed annual occupational dose equivalent. The combination of the use of high-efficiency SPECT technology and stress-only protocols resulted in a 34.7% reduction in mean total (99m)Tc administered activity between time periods, with camera technology being responsible for 39.2% of the reduction and stress-only protocols for 60.8%. A combination of high-efficiency SPECT technology and selective use of stress-only protocols significantly reduces the occupational radiation dose equivalent to the staff of a nuclear cardiology laboratory.


Endodermal sinus tumor in pregnancy: report of a case and review of the literature.
The endodermal sinus tumor is a rare germ cell tumor characterized by extremely rapid growth and grave prognosis. The case of a 17-year-old black primigravida with a 19-week intrauterine gestation and concurrent endodermal sinus tumor of the ovary is presented. This case is the eighth reported case of this tumor during pregnancy. alpha-Fetoprotein and other oncofetal antigens are postulated as agents of rapid growth of this tumor. It is suggested that immunotherapy with antibodies against alpha-fetoprotein and other oncofetal antigens might change the unfavorable outcome of this tumor.


Larry Steinman.
Larry Steinman divides his time between the neurology clinic and the lab where his team helped develop the first antibody therapy for multiple sclerosis. In this interview with Neuron, he talks about his family and upbringing, his team strategy as a principal investigator, and his long trajectory in translational medicine.


Early experience of the quality improvement award program in federally funded health centers.
To describe the Health Resources and Services Administration's Quality Improvement Award (QIA) program, award patterns, and early lessons learned. 1413 health centers were eligible for QIA from 2014 to 2018. We assessed cumulative QIA funding earned and modified funding excluding payments for per-patient bonuses, electronic health record (EHR) use, patient-centered medical home (PCMH) accreditation, and health information technology. We compared health centers on rural/urban location, PCMH accreditation, EHR reporting, and size. Organizational and quality measures are reported in the Uniform Data System, QIA program data. Average cumulative funding was higher for health centers that were not rural (USD 380,387 [± USD 233,467] vs. USD 303,526 [± USD 164,272]), had PCMH accreditation (USD 401,675 [± USD 218,246] vs. USD 250,784 [± USD 144,404]), used their EHR for quality reporting (USD 374,214 (± USD 222,866) vs. USD 331,150 (± USD 198,689)), and were large (USD 435,473 (± USD 238,193) vs. USD 270,681 (± USD 114,484) an USD 231,917 (± USD 97,847) for small and medium centers, respectively). There were similar patterns, with smaller differences, for average modified payments. QIA is an important feasible initiative to introduce value-based payment principles to health centers. Early lessons for program design include announcing award criteria in advance and focusing on a smaller number of priority targets.


The structure of ([W3Q4X3(dmpe)3]+, Y-) ion pairs (Q = S, Se; X = H, OH, Br; Y = BF4, PF6, dmpe = Me2PCH2CH2PMe2) in dichloromethane solution and the effect of ion-pairing on the kinetics of proton transfer to the hydride cluster [W3S4H3(dmpe)3]+.
The 1H,19F HOESY spectra of the title compounds in CD2Cl2 solution indicate that the cluster cations form ion pairs with the BF4- and PF6- anions with a well-defined interionic structure that appears to be basically determined essentially by the nature of the X- ligand. For the clusters with X = H and OH, the structure of the ion pairs is such that the counteranion (Y-) and the X- ligands are placed close to each other. However, when the size and electron density of X- increase (X = Br), Y- is forced to move to a different site, far away from X-. The relevance of ion-pairing on the chemistry of these compounds is clearly seen through a decrease in the rate of proton transfer from HCl to the hydride cluster [W3S4H3(dmpe)3]+ in the presence of an excess of BF4-. The kinetic data for this reaction can be rationalized by considering that the ([W3S4H3(dmpe)3]+, BF4-) ion pairs are unproductive in the proton-transfer process. Theoretical calculations indicate that the real behavior can be more complex. Although the cluster can still form adducts with HCl in the presence of BF4-, the structures of the most-stable BF4--containing HCl adducts show H...H distances too large to allow the subsequent release of H2. In addition, the effective concentration of HCl is also reduced because of the formation of adducts as ClH...BF4-. As a consequence of both effects, the proton transfer takes place more slowly than for the case of the dihydrogen-bonded HCl adduct resulting from the unpaired cluster.


Young Age on Starting Prostate-specific Antigen Testing Is Associated with a Greater Reduction in Prostate Cancer Mortality: 24-Year Follow-up of the Göteborg Randomized Population-based Prostate Cancer Screening Trial.
The risk of death from prostate cancer (PC) depends on age, but the age at which to start prostate-specific antigen (PSA) screening remains uncertain. To study the relationship between risk reduction for PC mortality and age at first PSA screening. The randomized Göteborg-1 trial invited men for biennial PSA screening between the ages of 50 and 70 yr (screening, n = 10 000) or no invitation but exposure to opportunistic PSA testing (control, n = 10 000). Regular versus opportunistic PSA screening or no PSA. We modeled the nonlinear association between starting age and the absolute risk reduction in PC mortality in three settings: (1) intention-to-screen (randomized arms); (2) historical control (screening group and 1990-1994 registry data); and (3) attendees only (screening attendees and matched controls). We tested whether the effect of screening on PC mortality depends on the age at starting screening by comparing survival models with and without an interaction between trial arm and age (intention-to-screen and attendees only). Younger age on starting PSA testing was associated with a greater reduction in PC mortality. Starting screening at age 55 yr approximately halved the risk of PC death compared to first PSA at age 60 yr. The test of association between starting age and the effect of screening on PC mortality was slightly greater than the conventional level of statistical significance (p = 0.052) for the entire cohort, and statistically significant among attendees (p = 0.002). This study is limited by the low number of disease-specific deaths for men starting screening before age 55 yr and the difficulty in discriminating between the effect of starting age and screening duration. Given that prior screening trials included men aged up to 70 yr on starting screening, our results suggest that the effect size reported in prior trials underestimates that of currently recommended programs starting at age 50-55 yr. In this study from the Göteborg-1 trial, we looked at the effect of prostate-specific antigen (PSA) screening in reducing men's risk of dying from prostate cancer given the age at which they begin testing. Starting at a younger age reduced the risk of prostate cancer death by a greater amount. We recommend that PSA screening should start no later than at age 55 yr.


Chlorophenoxy acetic acid derivatives as hemoglobin modifiers and tumor radiosensitizers.
We have studied the influence of the antilipidemia drug, clofibrate, and several structurally related analogs on the binding affinity of hemoglobin for oxygen and the radiation sensitivity of the SCCVII/St carcinoma in the mouse. Several compounds in this class reduced hemoglobin affinity in vivo; and two of these, ML1024 (etophyline clofibrate) and ML1037, were at least as effective as clofibrate at reducing hemoglobin affinity and much less toxic. When given orally at a dose of 4.1 m mole/Kg, 1/2-2 hrs before 20 Gy X rays, clofibrate gave radiosensitization in the SCCVII/St tumor equivalent to a 40-fold reduction in hypoxic fraction. ML1024 and ML1037 at a dose (3.0 m mole/Kg), which had a similar effect on hemoglobin, gave much less sensitization of the tumor. Only ML1024 produced a statistically significant effect, equivalent to a four-fold reduction in hypoxic fraction. We conclude that there are several clofibrate analogs which in relation to their toxicity are much better hemoglobin modifiers than the parent compound. They do not, however, show the same radiosensitizing effects, leading us to believe that mechanisms other than changes in hemoglobin/oxygen binding must also be involved.


Systemic administration of the antisense oligonucleotide NS-089/NCNP-02 for skipping of exon 44 in patients with Duchenne muscular dystrophy: Study protocol for a phase I/II clinical trial.
The purpose of this study is to evaluate the safety and pharmacokinetics of the novel morpholino oligomer NS-089/NCNP-02 which can induce exon 44 skipping, in patients with DMD. Additionally, we aimed to identify markers predictive of therapeutic efficacy and determine the optimal dosing for future studies. This is an open-label, dose-escalation, two-center phase I/II trial in ambulant patients with DMD, presence of an out-of-frame deletion, and a mutation amenable to exon 44 skipping. Part 1 is a stepwise dose-finding stage (4 weeks) during which NS-089/NCNP-02 will be administered intravenously at four dose levels once weekly (1.62, 10, 40, and 80 mg/kg); Part 2 is a 24-week evaluation period based on the dosages determined during Part 1. The primary (safety) endpoints are the results of physical examinations, vital signs, 12-lead electrocardiogram and echocardiography tests, and adverse event reporting. Secondary endpoints include expression of dystrophin protein, motor function assessment, exon 44 skipping efficiency, plasma and urinary NS-089/NCNP-02 concentrations, and changes in blood creatine kinase levels. Exon-skipping therapy using ASOs shows promise in selected patients, and this first-in-human study is expected to provide critical information for subsequent clinical development of NS-089/NCNP-02.


Imaging Subcellular AMPK Activity Using an Excitation-Ratiometric AMPK Activity Reporter.
Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a master regulator of cellular metabolism, phosphorylating a variety of downstream targets throughout the cell. Subcellular AMPK activity results in regulation of glycolysis, lipid and protein biosynthesis, mitochondrial function, and gene expression. But how AMPK senses and responds to stimuli in a compartment-specific manner is not well understood, leaving an incomplete picture of compartmentalized AMPK activity. Key tools for studying subcellular AMPK activity are genetically encoded AMPK activity reporters (AMPKARs), which allow for the quantitative visualization of subcelluar AMPK activity. However, many AMPKARs suffer from poor dynamic range and sensitivity, limiting their application. I recently reported the development of a new excitation-ratiometric (ExRai) AMPKAR, a single-fluorophore AMPKAR with enhanced dynamic range for detection of subtle, subcellular AMPK activity. I used ExRai AMPKAR to study subcellular AMPK activity at several locations, including the lysosome and mitochondria, identifying new mechanisms for the regulation of AMPK activity. Here, I describe the use of ExRai AMPKAR to image subcellular AMPK activity in mouse embryonic fibroblasts using both widefield and confocal microscopy. I also describe the culture of mouse embryonic fibroblasts. Through the use of ExRai AMPKAR, subcellular AMPK activity can be illuminated to better understand how this central kinase regulates cellular metabolism. © 2023 The Author. Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Imaging subcellular AMPK activity using ExRai AMPKAR Support Protocol 1: Culturing of mouse embryonic fibroblasts for live-cell imaging Support Protocol 2: Live-cell imaging of ExRai AMPKAR using confocal microscopy.


The brachioradialis: anatomy, properties, and value for tendon transfer in the tetraplegic.
We have studied the brachioradialis muscle both physiologically and clinically for its suitability for tendon transfer in the tetraplegic. Intraoperative measurements have shown that the muscle is strong, provides excellent excursion, and is commonly available for transfer in the absence of other candidate muscles. The anatomic features that limit its use can be overcome during the operation. Postsurgical assessment of the muscle using electromyography and muscle-force measurement have shown that the muscle is voluntarily activated and provides strength for the intended function. Our experience with transfer of the brachioradialis to the hand of a tetraplegic patient has been highly positive.


Current imaging of PE and emerging techniques: is there a role for artificial intelligence?
Acute pulmonary embolism (PE) is a critical, potentially life-threatening finding on contrast-enhanced cross-sectional chest imaging. Timely and accurate diagnosis of thrombus acuity and extent directly influences patient management, and outcomes. Technical and interpretive pitfalls may present challenges to the radiologist, and by extension, pose nuance in the development and integration of artificial intelligence support tools. This review delineates imaging considerations for diagnosis of acute PE, and rationale, hurdles and applications of artificial intelligence for the PE task.


What North Carolina's Health Workforce Data Can-and Can't-Tell Us.
North Carolina has some of the country's best health workforce supply data through cooperation with licensing boards, but the data don't encompass all health care workers. Workforce demand data are more difficult to track, and it's even harder to know how many health care workers are truly needed to improve the state's health.


Corrigendum: Study on characteristic of epileptic multi-electroencephalograph base on Hilbert-Huang transform and brain network dynamics.
[This corrects the article DOI: 10.3389/fnins.2023.1117340.].


High-energy pelvic ring disruptions.
High energy pelvic ring disruptions are associated with numerous primary organ system injuries. Early, accurate pelvic reduction and stable fixation optimize patient outcome. A variety of fixation techniques have been advocated. A multispecialty team approach is advantageous when managing these patients and their pelvic injuries.


Noxious stimulation during orthopaedic surgery results in EEG 'arousal' or 'paradoxical arousal' reaction in isoflurane-anaesthetised sheep.
The effects of surgical stimuli on haemodynamic and electroencephalographic (EEG) variables were determined in 25 adult ewes undergoing an experimental orthopaedic procedure in isoflurane anaesthesia. Data were recorded after 15 min of constant end-tidal concentration of approximately 2.2% isoflurane (SS: steady state=baseline), during skin disinfection (DIS), incision (INC), drilling of the first hole through the tibia (DRI) and insertion of a threaded pin (PIN) for external fixation. Stimulation resulted in a significant increase in systolic and mean arterial pressure above SS at INC, DRI and PIN. Haemodynamic changes were accompanied by either significant increases or decreases in EEG median frequency (MF) and 80% spectral edge frequency (SEF80) above or below SS at all four stimulation time points suggesting 'arousal' or 'paradoxical arousal' reaction, respectively. We conclude, that either type of EEG activation pattern could be elicited dependent on stimulation intensity and level of anaesthetic depth.


The effect of humeral avulsion of the glenohumeral ligaments and humeral repair site on joint laxity: a biomechanical study.
The aims of this cadaveric study were to assess the effect of different sizes of humeral avulsion of the glenohumeral ligament (HAGL) lesions on joint laxity and to investigate any difference between repairs with anchors placed in a juxtachondral position and repairs with anchors placed in the humeral neck. Glenohumeral specimens were tested on a shoulder laxity testing system with translations applied anteriorly up to 30 N, with the joint in 60° of glenohumeral abduction. Testing was conducted in neutral rotation and under 1-Nm external rotation for 5 specimen states: intact, medium HAGL lesion (4:30 to 5:30 clock-face position), large HAGL lesion (3:30 to 6:30 clock-face position), repair with juxtachondral suture anchors, and repair with humeral neck suture anchors. Significant increases in translation were observed between the intact and large HAGL lesion states for neutral rotation (1.46 mm [SD, 2.33 mm] at 30 N; P = .049) and external rotation (0.81 mm [SD, 0.72 mm] at 30 N; P = .005). Significant reductions in translation were also observed between the large HAGL lesion and humeral neck repair states for neutral rotation (-1.78 mm [SD, 2.23 mm] at 30 N; P = .022) and external rotation (-0.33 mm [SD, 0.37 mm] at 30 N; P = .015). Large HAGL lesions can increase the passive motion of the glenohumeral joint in both neutral and external rotation, although these differences are small and may be difficult to measure clinically. A repair using anchors placed in the humeral neck is more likely to restore the normal restraint to anterior translation than a juxtachondral repair. Medium HAGL lesions are unlikely to show significant increases in joint translation, and repair of large HAGL lesions should be achieved with anchors placed in the humeral neck if possible.


Dentin bond optimization using the dimethyl sulfoxide-wet bonding strategy: A 2-year in vitro study.
This study evaluated a new approach, named dimethyl sulfoxide (DMSO)-wet bonding, to produce more desirable long-term prospects for the ultrafine interactions between synthetic polymeric biomaterials and the inherently hydrated dentin substrate. Sound third molars were randomly restored with/without DMSO pretreatment using a total-etch (Scocthbond Multipurpose: SBMP) and a self-etch (Clearfil SE Bond: CF) adhesive systems. Restored teeth (n=10)/group were sectioned into sticks and submitted to different analyses: micro-Raman determined the degree of conversion inside the hybrid layer (DC); resin-dentin microtensile bond strength and fracture pattern analysis at 24h, 1year and 2 years of aging; and nanoleakage evaluation at 24h and 2 years. DMSO-wet bonding produced significantly higher 24h bond strengths for SBMP that were sustained over the two-year period, with significantly less adhesive failures. Similarly, DMSO-treated CF samples presented significantly higher bond strength than untreated samples at two years. Both adhesives had significant less adhesive failures at 2 years with DMSO. DMSO had no effect on DC of SBMP, but significantly increased the DC of CF. DMSO-treated SBMP samples presented reduced silver uptake compared to untreated samples after aging. Biomodification of the dentin substrate by the proposed strategy using DMSO is a suitable approach to produce more durable hybrid layers with superior ability to withstand hydrolytic degradation over time. Although the active role of DMSO on dentin bond improvement may vary according to monomer composition, its use seems to be effective on both self-etch and etch-and-rinse bonding mechanisms.


The genesis of human hematopoietic stem cells.
Developmental hematopoiesis consists of multiple, partially overlapping hematopoietic waves that generate the differentiated blood cells required for embryonic development while establishing a pool of undifferentiated hematopoietic stem cells (HSCs) for postnatal life. This multilayered design in which active hematopoiesis migrates through diverse extra and intraembryonic tissues has made it difficult to define a roadmap for generating HSCs vs non-self-renewing progenitors, especially in humans. Recent single-cell studies have helped in identifying the rare human HSCs at stages when functional assays are unsuitable for distinguishing them from progenitors. This approach has made it possible to track the origin of human HSCs to the unique type of arterial endothelium in the aorta-gonad-mesonephros region and document novel benchmarks for HSC migration and maturation in the conceptus. These studies have delivered new insights into the intricate process of HSC generation and provided tools to inform the in vitro efforts to replicate the physiological developmental journey from pluripotent stem cells via distinct mesodermal and endothelial intermediates to HSCs.


Design, synthesis, biological evaluation and docking study of 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors.
A series of novel 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors have been designed and synthesized. The screening results showed that most of the compounds exhibited potent anti-AChE activity in the range of nM concentrations. The 1-(4-fluorobenzyl) substituted derivative 9d exhibited the most potent anti-AChE activity with IC50 value of 8.9 nM and high AChE/BuChE selectivity (SI>230). Kinetic and molecular modeling studies suggested that compound 9d was mixed-type inhibitor, binding simultaneously to CAS and PAS of AChE. Besides, the preliminary structure-activity relationships were discussed.


Comparison of usefulness of plasma procalcitonin and C-reactive protein measurements for estimation of severity in adults with community-acquired pneumonia.
Although procalcitonin (PCT) measurement has been performed in patients with infectious diseases, there are few reports on its usefulness in community-acquired pneumonia (CAP) associated with systemic inflammatory response syndrome (SIRS). We investigated 88 patients who visited the internal medicine departments of Nagasaki University Hospital, Nagasaki, Japan, and its 11 affiliated hospitals in Japan because of CAP with or without SIRS. Of the 88 patients, 15 (17.0%), 43 (48.9%), and 30 (34.1%) were judged to have severe, moderate, and mild CAP, respectively. Although 87 patients (98.9%) had C-reactive protein (CRP) levels exceeding 0.3 mg/dL, only 30 patients (34.1%) had PCT levels more than 0.5 ng/mL. In addition, 93.3% (28/30) of patients with mild CAP had negative PCT, and 48.3% (28/58) of patients positive for PCT had moderate or severe CAP. Our findings suggest that PCT level might be more useful for estimating CAP severity than CRP level at the 1st visit.


Effect of gas composition during Pt sputtering on structural and magnetic properties of CoFeB thin films.
Ultrathin Ta/CoFeB/Pt trilayer structures are relevant to a wide range of spintronic applications, from magnetic tunnel junctions to skyrmionics devices. Controlling the perpendicular magnetic anisotropy, Gilbert damping and Dzyaloshinskii-Moriya interaction in the CoFeB layer is key for these applications. We examine the role of sputter gas composition during the Pt overlayer deposition of a Ta/CoFeB/Pt trilayer in Ar, Kr and Xe working gas environments during direct current magnetron sputtering. Decreasing density of the Pt layer (from 21 g/cm3 to 15 g/cm3) was apparent in specular x-ray reflectivity measurements of the trilayer films when increasing the molecular weight of the sputtering gas from Ar to Kr to Xe. Significant effects on the Gilbert damping and the interfacial Dzyaloshinskii-Moriya interaction (DMI) energy were observed, with increases in the damping from 0.037(1) to 0.042(1) to 0.048(1), and reductions in the interfacial DMI from 0.47(4) mJ/m2 to 0.45(5) mJ/m2 to 0.39(4) mJ/m2. The ability to control the perpendicular magnetization and DMI strength of these materials through judicious interfacial control is a means toward magnetic devices with better stability at smaller lateral dimension, key to device scaling for spintronic device arrays.


Protective action of amiodarone against ventricular fibrillation in the isolated perfused rat heart.
The pretreatment of rats with amiodarone for 2 minutes to 3 weeks before the excision of their hearts caused a dose-related decrease in heart rate and an increase in the ventricular fibrillation threshold both before and after coronary arterial ligation. Similarly, amiodarone decreased the incidence of ventricular premature extrasystoles, ventricular tachycardia and fibrillation during the period of regional ischemia after coronary arterial ligation and also after reperfusion of the ischemic myocardium. There was no evidence of a metabolic protective effect on ischemic myocardium because tissue high energy phosphate content decreased to a similar extent in ischemic myocardium from control and amiodarone-treated rats. Instead, the protective effect of amiodarone against fibrillation was accompanied by attenuation of the increase in tissue cyclic adenosine monophosphate in ischemic myocardium after coronary arterial ligation. It is proposed that amiodarone exerts a potent antifibrillatory effect by decreasing tissue cyclic adenosine monophosphate in ischemic myocardium.


Measurements of target volumes and organs at risk using DW‑MRI in patients with central lung cancer accompanied with atelectasis.
Accurate imaging-based tumor delineation is crucial for guiding the radiotherapy treatments of various solid tumors. Currently, several imaging procedures, including diffusion-weighted magnetic resonance imaging (DW-MRI), intensified computed tomography and positron emission tomography are routinely used for targeted tumor delineation. However, the performance of these imaging procedures has not yet been comprehensively evaluated. In order to address this matter, the present study was conducted in an aim to assess the use of DW-MRI in guiding radiotherapy treatments, by comparing its performance to that of other imaging procedures. Specifically, the exposure dosages to organs at risk, including the lungs, heart and spinal mencord, were evaluated using various radiotherapy regimes. The findings of the present study demonstrated that DW-MRI is a non-invasive and cost-effective imaging procedure that can be used to reduce lung exposure doses, minimizing the risk of radiation pneumonitis. The data further demonstrate the immense potential of the DW-MRI procedure in the precision radiotherapy of lung cancers.


Deletion of kif3a in CK19 positive cells leads to primary cilia loss, biliary cell proliferation and cystic liver lesions in TAA-treated mice.
Loss of primary cilia in epithelial cells is known to cause cystic diseases of the liver and kidney. We have previously shown that during experimental and human cirrhosis that primary cilia were predominantly expressed on biliary cells in the ductular reaction. However, the role of primary cilia in the pathogenesis of the ductular reaction is not fully understood. Primary cilia were specifically removed in biliary epithelial cells (BECs) by the administration of tamoxifen to Kif3af/f;CK19CreERT mice at week 2 of a 20-week course of TAA treatment. Biliary progenitor cells were isolated and grown as organoids from gallbladders. Cells and tissue were analysed using histology, immunohistochemistry and Western blot assays. At the end of 20 weeks TAA administration, primary cilia loss in liver BECs resulted in multiple microscopic cystic lesions within an unaltered ductular reaction. These were not seen in control mice who did not receive TAA. There was no effect of biliary primary cilia loss on the development of cirrhosis. Increased cellular proliferation was seen within the cystic structures associated with a decrease in hepatocyte lobular proliferation. Loss of primary cilia within biliary organoids was initially associated with reduced cell passage survival but this inhibitory effect was diminished in later passages. ERK but not WNT signalling was enhanced in primary cilia loss-induced cystic lesions in vivo and its inhibition reduced the expansion of primary cilia deficient biliary progenitor cells in vitro. TAA-treated kif3a BEC-specific knockout mice had an unaltered progression to cirrhosis, but developed cystic lesions that showed increased proliferation.


Vestibular perception of passive whole-body rotation about horizontal and vertical axes in humans: goal-directed vestibulo-ocular reflex and vestibular memory-contingent saccades.
This study was aimed at complementing the existing knowledge about vestibular perception of self-motion in humans. Both goal-directed vestibulo-ocular reflex and vestibular memory-contingent saccade (VMCS) tasks were used, respectively as concurrent and retrospective magnitude estimators for passive whole-body rotation. Rotations were applied about the earth-vertical and earth-horizontal axes to study the effect of the otolith signal in self-rotation evaluation, and both in yaw and pitch to examine the horizontal and vertical semi-circular canals. Two different magnitudes of constant angular acceleration (50 degrees/s2 and 100 degrees/s2) were used. The main findings were (1) strong correlation between both oculomotor responses of both tasks, (2) greater accuracy with rotations about the earth-vertical than the earth: -horizontal axis, (3) greater accuracy for yaw than for pitch rotations, (4) greater accuracy for high acceleration than for low, and (5) no effect of the delay (2 s or 12 s) in the VMCS task. Adequacy of both tasks as subjective magnitude estimators of vestibular perception of self-motion is discussed.


Medial orbitofrontal cortical regulation of different aspects of Pavlovian and instrumental reward seeking.
The medial subregion of the orbitofrontal cortex (mOFC) is thought to play an important role representing the expected outcome of a given course of action, as lesioning or inactivating this cortical region results in the adoption of choice strategies based more on observable (rather than previously learned) information. Despite this, its role in mediating basic associative learning remains to be fully clarified. The present series of experiments examined the role of the mOFC in (1) Pavlovian conditioned approach, (2) conditioned reinforcement, (3) extinction, and (4) cue-induced reinstatement of food-seeking behavior. Separate cohorts of rats went through Pavlovian or instrumental training. Intra-mOFC infusions of either saline or GABA agonists (to temporarily inactivate neural activity) were given prior to Pavlovian approach, conditioned reinforcement, first or second day of instrumental extinction training, or cue-induced reinstatement test days. mOFC inactivation increased lever-CS contacts in Pavlovian conditioned approach and (2) had no effect on conditioned reinforcement. These manipulations (3) accelerated within-session instrumental extinction during the initial extinction session, but impaired subsequent extinction learning on drug-free days. (4) mOFC inactivation induced differential effects on reinstatement that depended on baseline performance. mOFC inactivation abolished reinstatement in "Reinstater" rats (who displayed robust responding under control conditions) and robustly increased reinstatement in "Non-Reinstater" rats (who showed little reinstatement under control conditions) suggesting that individual differences in reinstatement may be supported by differences in mOFC mediated representations of expected outcomes. These findings have important implications for understanding how the mOFC uses stimulus-outcome and action-outcome expectancies to guide behavior, and how dysfunction within this region may contribute to pathological patterns of reward seeking.


Understanding the Organizational Implementation Context of Schools: A Qualitative Study of School District Administrators, Principals, and Teachers.
Key features of the school environment can have a significant impact on teachers' effective use of evidence-based practices (EBP), yet implementation-specific organizational constructs have rarely been studied in the education sector. This study examined three aspects of the organizational implementation context (implementation leadership, climate, and citizenship behavior), which have been conceptualized and validated in other service settings. Focus groups with central office administrators, principals, and teachers were conducted to understand the applicability and conceptual boundaries of these organizational constructs in schools. Focus group transcripts were coded, and the results indicated both similarities and differences in their conceptualizations of implementation leadership, climate, and citizenship behavior in school. The data indicated that: (1) implementation leadership was largely present in schools with the addition of Distributed Leadership; (2) two implementation climate constructs were most clearly present (i.e., Focus on EBP and Educational Support for EBP) and two additional constructs (i.e., Existing Support to Deliver EBP and Prioritization of EBP) emerged as part of this construct; and (3) implementation citizenship behavior (Helping Others and Keeping Informed) was consistently acknowledged across schools and two new components emerged (i.e., Information Sharing and Observation/Feedback). Recommendations to researchers and community stakeholders are discussed.


Kinesin-Binding Protein Controls Microtubule Dynamics and Cargo Trafficking by Regulating Kinesin Motor Activity.
Kinesin motor proteins play a fundamental role for normal neuronal development by controlling intracellular cargo transport and microtubule (MT) cytoskeleton organization. Regulating kinesin activity is important to ensure their proper functioning, and their misregulation often leads to severe human neurological disorders. Homozygous nonsense mutations in kinesin-binding protein (KBP)/KIAA1279 cause the neurological disorder Goldberg-Shprintzen syndrome (GOSHS), which is characterized by intellectual disability, microcephaly, and axonal neuropathy. Here, we show that KBP regulates kinesin activity by interacting with the motor domains of a specific subset of kinesins to prevent their association with the MT cytoskeleton. The KBP-interacting kinesins include cargo-transporting motors such as kinesin-3/KIF1A and MT-depolymerizing motor kinesin-8/KIF18A. We found that KBP blocks KIF1A/UNC-104-mediated synaptic vesicle transport in cultured hippocampal neurons and in C. elegans PVD sensory neurons. In contrast, depletion of KBP results in the accumulation of KIF1A motors and synaptic vesicles in the axonal growth cone. We also show that KBP regulates neuronal MT dynamics by controlling KIF18A activity. Our data suggest that KBP functions as a kinesin inhibitor that modulates MT-based cargo motility and depolymerizing activity of a subset of kinesin motors. We propose that misregulation of KBP-controlled kinesin motors may represent the underlying molecular mechanism that contributes to the neuropathological defects observed in GOSHS patients.


Selective and sensitive speciation analysis of Cr(VI) and Cr(III) in water samples by fiber optic-linear array detection spectrophotometry after ion pair based-surfactant assisted dispersive liquid-liquid microextraction.
A simple ion pair based-surfactant assisted dispersive liquid-liquid microextraction (IP-SA-DLLME) was evaluated for extraction and preconcentration of Cr(VI) and Cr(III) in aqueous samples. In this method, which was used for the first time for chromium speciation analysis, sodium dodecyl sulfate (SDS) was used as both ion-pairing and disperser agent. Cr(VI) ions were converted into their cationic complex with 1,5-diphenylcarbazide (DPC) and then extracted into 1-octanol dispersed in aqueous solution. Cr(III) ion also can be determined by this procedure after oxidation to Cr(VI). After extraction and phase separation, upper organic phase was transferred to a micro cell of a fiber optic-linear array detection spectrophotometry (FO-LADS). The effects of various parameters on the extraction recovery were investigated. Under the optimized conditions and preconcentration of 10 mL of sample, the enrichment factor of 159 and the detection limit of 0.05 μgL(-1) were obtained. Validation of the method was performed by spiking-recovery method and comparison of results with those obtained by ET-AAS method.


An integrated spectroscopic strategy to trace the geographical origins of emblic medicines: Application for the quality assessment of natural medicines.
Emblic medicine is a popular natural source in the world due to its outstanding healthcare and therapeutic functions. Our preliminary results indicated that the quality of emblic medicines might have an apparent regional variation. A rapid and effective geographical traceability system has not been designed yet. To trace the geographical origins so that their quality can be controlled, an integrated spectroscopic strategy including spectral pretreatment, outlier diagnosis, feature selection, data fusion, and machine learning algorithm was proposed. A featured data matrix (245 × 220) was successfully generated, and a carefully adjusted RF machine learning algorithm was utilized to develop the geographical traceability model. The results demonstrate that the proposed strategy is effective and can be generalized. Sensitivity (SEN), specificity (SPE) and accuracy (ACC) of 97.65%, 99.85% and 97.63% for the calibrated set, as well as 100.00% predictive efficiency, were obtained using this spectroscopic analysis strategy. Our study has created an integrated analysis process for multiple spectral data, which can achieve a rapid, nondestructive and green quality detection for emblic medicines originating from seventeen geographical origins.


Use of pneumatic nebulization and laser ablation-inductively coupled plasma-mass spectrometry to study the distribution and bioavailability of an intraperitoneally administered Pt-containing chemotherapeutic drug.
Quadrupole-based inductively coupled-mass spectrometry (ICP-MS) with pneumatic nebulization as a means of sample introduction was employed for quantification of platinum in blood and tissue samples of rats with peritoneal carcinomatosis, receiving intraperitoneal treatment with the Pt-containing chemotherapeutic drug oxaliplatin, and in the perfusate solution used for this purpose. The Pt levels were measured for various treatment conditions, i.e., with and without supporting treatment with the drug bevacizumab and at two different temperatures. Limits of detection obtained for platinum in blood and tissue samples were 0.3 and 2.0 pg g(-1) respectively. Evaluation of drug penetration into the tumor, under different conditions of treatment, was carried out via laser ablation-ICP-MS. Quantitative mapping of the Pt distribution in tissue sections of rat was attempted relying on gelatin standards. The results show an influence of the temperature at which the treatment is carried out, while supporting administration of the drug bevacizumab did not seem to affect the results.


Randomized phase II trial of gemcitabine plus irinotecan or docetaxel in stage IIIB or stage IV NSCLC.
To evaluate the activity and tolerability of gemcitabine plus irinotecan or docetaxel as first-line chemotherapy for advanced non-small cell lung cancer (NSCLC). Eligible patients with chemotherapy-naïve stage IIIB or IV NSCLC were randomized to receive gemcitabine 1000 mg/m2 on days 1 and 8, plus either irinotecan 100 mg/m2 or docetaxel 40 mg/m2 on days 1 and 8. Treatment was administered every 3 weeks. Of the 80 enrolled patients with stage IIIB or IV NSCLC, 78 were evaluable for activity and safety. Overall response rates, consisting of partial responses, were 12.8% [95% confidence interval (CI) 4% to 35%] for gemcitabine-irinotecan and 23.1% (95% CI 10% to 42%) for gemcitabine-docetaxel. Median overall survival was 7.95 months (95% CI 5.2-10.2) and 12.8 months (95% CI 7.9-17.1) for gemcitabine-irinotecan and gemcitabine-docetaxel, respectively. The corresponding estimated 1-year survivals were 23% and 51%, respectively. The 2-year survival rate in arm A (gemcitabine-irinotecan) is not currently estimable. The 2-year survival rate for arm B (gemcitabine-docetaxel) is 22% (95% CI 6% to 37%). Both combinations were well tolerated; the most common hematological toxicity was neutropenia, which occurred in 26% of patients in each treatment arm. These results suggest that gemcitabine plus docetaxel or irinotecan is well tolerated in patients with chemotherapy-naïve advanced NSCLC. The survival data with the combination gemcitabine-docetaxel are promising. Gemcitabine-docetaxel combination therapy may be particularly useful for patients who have experienced toxicities with a platinum regimen or in patients who may be more susceptible to platinum-related toxicity.


Thiel-embalmed cadavers as a novel training model for ultrasound-guided supine endoscopic combined intrarenal surgery.
To evaluate Thiel-embalmed cadavers (TEC) as a training model for percutaneous nephrolithotomy (PCNL), more specifically for ultrasound (US)-guided supine endoscopic combined intrarenal surgery (ECIRS). Thirteen urologists (nine experienced endourologists, four fellows/residents) performed an US-guided supine ECIRS procedure on a TEC. The model was evaluated by way of a questionnaire (5-point Likert scale). Descriptive statistical analysis was performed and results were graphically presented using divergent bar graphs. US images were appreciated as lifelike in all aspects. Although distention of the collecting system was not ideal in one out of three TEC, US visualisation of the distended calyces during puncture was good. Skin penetration was more difficult and less realistic in TEC, while kidney puncture and dilatation were deemed very realistic. Ureteric and collecting system anatomy and consistency were similar to real life, although the mucosa appeared paler. US needle guidance was perceived as excellent. Overall, needle puncture assessment was realistic and useful as a training tool. Overall quality and satisfaction of TEC in US-guided supine ECIRS was good to excellent and comparable to a real-life procedure. Overall appropriateness of the TEC model was considered excellent for both initial and advanced supine PCNL training. Despite the minor drawbacks of tough skin and non-ideal collecting system dilatation during ureteroscopy, the TEC model was considered good to excellent as a training model for US-guided PCNL, in particular, US-guided needle puncture of the kidney during supine ECIRS.


10-Phenyl-10H-phenoxazine-4,6-diol tetra-hydro-furan monosolvate.
In the crystalline state of the title solvate, C18H13NO3·C4H8O, hydrogen-bonding inter-actions between hydroxyl groups on a phenoxazine backbone and the tetra-hydro-furan solvent are observed that suggest the ability for this compound to act as a chelating ligand. The O⋯O donor-acceptor distances for this hydrogen bonding are 2.7729 (15) and 2.7447 (15) Å. The three-ring backbone of the phenoxazine bends out of planarity by 18.92 (3)°, as computed using mean planes that encompass each half of the three-ring structure, with the central N and O atoms forming the line of flexion. In the crystal, a π-π stacking arrangement exists between inversion-related mol-ecules, with a centroid-to-centroid distance of 3.6355 (11) Å. In the disordered tetra-hydro-furan solvate, all atoms except oxygen were modeled over two positions, with occupancies of 0.511 (8) and 0.489 (8).


Letter to the editor regarding "spatiotemporal association of low birth weight with Cs-137 deposition at the prefecture level in Japan after the Fukushima nuclear power plant accidents".
In the previous report, association between increased low birth weight prevalence and radiocesium deposition after 2011 Fukushima nuclear disaster was found. However, the statistical analyses therein raised several questions. First, ecological variables are not justified enough to adjust potential confounding. Second, the spatiotemporal regression model does not consider temporal reduction in radiation dose rate. Third, dose-response plot between dose rates and odds ratios overestimates R2 and underestimates p value.


[What has become of preliminary transfusion protocols in kidney transplantation?].
Many studies have demonstrated that pretransplant blood transfusions improved cadaver kidney graft outcome. The nature and the frequency of transfusions-induced lymphocytotoxic antibodies depends of sex, previous pregnancies and kidney grafts, and transfusional patterns. This provoked immunisation is not a hindrance to beneficial effects of transfusions. Numerous reports have investigated the responsible mechanism for this effect. Controversial data concern the optimum number of blood units. In a previous prospective study in patients who received anti-lymphocyte globulins as part of immunosuppressive therapy, we have shown that a multiple transfusions policy does not give better results than only one. Recently, the beneficial effect of transfusions has been questioned, either entirely, or for particular patients according to age, sex, immunosuppressive treatment including cyclosporin or not. This leaded us to reassess benefits of transfusions.


A recombinant anti-carcinoembryonic antigen immunoreceptor with combined CD3zeta-CD28 signalling targets T cells from colorectal cancer patients against their tumour cells.
The prognosis of metastatic colorectal cancer is still poor, raising the need for alternative therapeutic approaches, particularly by manipulating the antitumour immune response. Advanced tumour stages, however, are frequently accompanied by functional T cell defects which may be critical for a T cell based anticancer immunotherapy. The aim of this study was to address whether T cells from colorectal cancer patients with advanced tumour stages can be specifically antigen activated against their autologous tumour cells. T cells were isolated from colorectal cancer patients and retrovirally transduced to express a recombinant immunoreceptor that has an extracellular binding domain for carcinoembryonic antigen (CEA) and an intracellular CD3zeta signalling domain with and without CD28 costimulation for T cell activation. Peripheral blood T cells from colorectal cancer patients were successfully engineered to express the anti-CEA immunoreceptor on the cell surface. On coincubation with autologous CEA(+) tumour cells, T cells with anti-CEA immunoreceptor are specifically activated to secrete interferon gamma (IFN-gamma) and to lyse autologous tumour cells whereas T cells without immunoreceptor are not. T cells equipped with combined CD3zeta-CD28 signalling receptor are more efficiently activated to secrete IFN-gamma compared with T cells with CD3zeta signalling receptor. Induction of interleukin 2 secretion on targeting towards autologous tumour cells requires triggering of T cells by the CD3zeta-CD28 costimulatory receptor. T cells from advanced colorectal cancer patients can be tumour specifically activated with high efficiency by engraftment with a combined CD3zeta-CD28 immunoreceptor to break tolerance against autologous tumour cells.


Carcinogenic chemicals enhance mouse leukemia virus infection in contact-inhibited culture: a new simple method of screening carcinogens.
Carcinogenic chemicals enhanced infection in contact-inhibited cells with mouse leukemia virus. A correlation was found between the enhancing effects and the carcinogenicities of the 40 chemicals tested. The tumor promoter 12-O-tetradecanoylphorbol-13-acetate did not enhance viral infection.


Retained primary teeth in STAT3 hyper-IgE syndrome: early intervention in childhood is essential.
STAT3 hyper-IgE syndrome (STAT3-HIES) is a rare primary immunodeficiency that clinically overlaps with atopic dermatitis. In addition to eczema, elevated serum-IgE, and recurrent infections, STAT3-HIES patients suffer from characteristic facies, midline defects, and retained primary teeth. To optimize dental management we assessed the development of dentition and the long-term outcomes of dental treatment in 13 molecularly defined STAT3-HIES patients using questionnaires, radiographs, and dental investigations. Primary tooth eruption was unremarkable in all STAT3-HIES patients evaluated. Primary tooth exfoliation and permanent tooth eruption was delayed in 83% of patients due to unresorbed tooth roots. A complex orthodontic treatment was needed for one patient receiving delayed extraction of primary molars and canines. Permanent teeth erupted spontaneously in all patients receiving primary teeth extraction of retained primary teeth during average physiologic exfoliation time. The association of STAT3-HIES with retained primary teeth is important knowledge for dentists and physicians as timely extraction of retained primary teeth prevents dental complications. To enable spontaneous eruption of permanent teeth in children with STAT3-HIES, we recommend extracting retained primary incisors when the patient is not older than 9 years of age and retained primary canines and molars when the patient is not older than 13 years of age, after having confirmed the presence of the permanent successor teeth by radiograph.


A nationwide study of the epidemiology, treatment and survival of oropharyngeal carcinoma in The Netherlands.
Seven head and neck oncology cooperative groups in the Netherlands have reviewed the epidemiology, staging, treatment and survival of oropharyngeal carcinoma patients treated between 1986 and 1990. In all, 640 patients with squamous cell carcinoma (628, 98%) or undifferentiated carcinoma (12, 2%) referred for primary treatment were analyzed. The total group included 441 males (69%) and 199 females (31%), with a median age of 59 years (range, 30-92). Tumor distribution by subsite was the tonsillar region (372 patients, 58%), base of the tongue/vallecula (179, 28%), soft palate/uvula (62, 10%) and posterior oropharyngeal wall (27, 4%). Forty-four patients (7%) had stage I disease, 106 (17%) had stage II disease, 157 (24%) stage III, and 319 (50%) stage IV. Staging was unknown in 14 patients (2%). Radiotherapy was given to the primary tumor in 408 patients (64%), surgery and radiotherapy to 147 (23%), surgery alone to 42 (7%), other treatments to 14 (2%) and no treatment to 29 patients (4%). The 5-year overall survival was 28% and the 5-year disease-specific survival was 41%. This latter survival was 35% in males and 51% in females (P = 0.003). Five-year survival by subsite was 54% in the soft palate/uvula, 42% in the tonsillar region, 33% in the base of the tongue and 32% in the posterior oropharyngeal wall (P = 0.003). When analyzing survival by stage, 5-year survival in patients with stage I disease was 68% and decreased significantly to 27% in stage IV disease (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)


Evidence for two insulin-like growth factor I receptors with distinct primary structure that are differentially expressed during development.
We have previously presented evidence for two IGF I receptor species in rat skeletal muscle. One form of IGF I receptor is selectively expressed in fetal and early postnatal life, and the second is present in both fetal and adult animals. These two IGF I receptors were shown to have similar tryptic phosphopeptide maps but to differ in beta subunit molecular weight (105,000 for the fetal vs. 95,000 for the adult type receptor). In this study, we have used specific antibodies to investigate the structural relationships between the two IGF I receptors. Anti-IGF I receptor beta subunit antibodies were generated against synthetic peptides corresponding to residues 1284-1293 and 1308-1318 of the cloned human IGF I receptor, and the capacity of these antibodies to interact with the two IGF I receptors was investigated. Both anti-peptide antibodies selectively immunoprecipitated the higher molecular weight fetal receptor and not the adult receptor from rat muscle. Human placenta and muscle were shown to contain two receptors similar to those observed in rat muscle. In human muscle, the anti-peptide antibodies and the human-specific monoclonal alpha subunit antibody alpha-IR3 also selectively immunoprecipitated the fetal type receptor. The presence of a 95,000 M(r) IGF I receptor beta subunit distinct from the insulin receptor beta subunit in human muscle was confirmed by the demonstration of an IGF I sensitive receptor with a beta subunit of this size after insulin receptor immunodepletion. These data strongly support the conclusion that the fetal and adult type IGF I receptors differ in primary structure. The fetal receptor corresponds to the cloned and sequenced IGF I receptor, and the primary structure of the adult type receptor has not yet been established.


Substance Abuse Screening and Treatment.
One of the more prevalent and often undiagnosed problems seen by primary care clinicians is substance misuse. Resulting in increased morbidity and mortality, loss of productivity, and increased health care costs, substance misuse in our society remains a significant public health issue. Primary care physicians are on the front lines of medical care, and as such, are in a distinctive position to recognize potential problems in this area and assist. This article outlines office-based screening approaches and strategies for managing and treating this complex issue confronting primary care.


Phosphorus adsorption characteristics of oyster shells and alum sludge and their application for nutrient control in constructed wetland system.
This research aimed to evaluate the feasibility of employing some locally available oyster shells (OS) and alum sludge (AS) as the P adsorption media of constructed wetland beds. The batch and column tests were conducted with different sizes of OS and AS to observe the P adsorption characteristics and breakthrough, while P adsorption rates were determined from jar test. From the batch test, the ability to adsorb the amount of added P was different considerably between OS and AS media and sizes. At the same size, the P adsorption capacities of OS were higher than those of alum sludge. The P adsorption capacities of AS with 0.3-0.6 mm and > 0.6 mm sizes were similar, but those of 0.3-0.6 mm OS was higher than > 0.6 mm OS. Jar test results revealed the first-order P removal rates (k) to be 11.4, 4.5, 1.7 and 1.0 d(- 1) for the 0.3-0.6 mm AS, > 0.6 mm AS, 0.3-0.6 mm OS, and > 0.6 mm OS, respectively. From the column tests, the adsorption capacities were found to be more than 26 and 24.5 g/kg for the OS media sizes of 0.3-0.6 and > 0.6 mm, respectively, and 12 g/kg for the AS media. The column tests revealed that AS was able to adsorb P faster than the oyster shells, but due to its low adsorption capacity, the periods of P breakthrough in the effluent of the alum sludge columns were shorter than those of the oyster shell columns. Experiments with a pilot-scale vertical-flow subsurface constructed wetland unit packed with > 0.6 mm OS media demonstrated the high P removal efficiencies of more than 96.2% during the 210 days of operation.


Attempts to isolate virus from human trigeminal and facial ganglions.
Herpes virus hominis type 1 was isolated from the trigeminal ganglion (ganglion semilunare, gasservian) in three out of 20 randomly selected autopsies. Two of the three patients had been treated with immunosuppressive or cytostatic agents. Clinical signs of herpes infection were not observed during the previous 6 months. No virus was isolated from the facial ganglion (geniculate ganglion) in the same 20 cases. The findings are discussed in relation to the viral etiology of acute peripheral facial palsy.


Significance of pacing cycle lengths in manifest entrainment of orthodromic circus movement tachycardia by ventricular pacing.
The physiology of entrainment of orthodromic circus movement tachycardia (CMT) was studied using ventricular pacing during 18 episodes of induced CMT in 7 patients with atrioventricular (AV) accessory pathways. The first paced impulse was delivered as late as possible in the tachycardia cycle (mean 88 +/- 5% of the spontaneous cycle length [CL]). Entrainment was demonstrated by the following criteria: 1:1 retrograde conduction via the accessory pathway; capture of atrial, ventricular and His bundle electrograms at the pacing rate; and resumption of tachycardia at its previous rate after cessation of pacing. The number of ventricular paced impulses ranged from 5 to 14 (mean 8 +/- 3), and entrainment occurred in 2 to 7 paced cycles (mean 4 +/- 2). Orthodromic activation of a major part of the reentry circuit (manifest entrainment) was demonstrated during 9 episodes by the occurrence of His bundle electrogram preceding the first CMT QRS at the time anticipated from the last paced beat. In the 9 other episodes, persistent retrograde His bundle activation and AV nodal penetration by each paced impulse caused a delay (mean 79 +/- 25 ms) in activation of the His bundle preceding the first CMT QRS after the last paced beat. The mean pacing CL achieving manifest entrainment was 92 +/- 3% of the tachycardia CL, compared with 84 +/- 3% for retrograde AV nodal penetration (p less than 0.01). In conclusion, manifest entrainment of orthodromic CMT can be demonstrated by ventricular pacing at very long CLs; shorter CLs may cause CMT termination due to retrograde AV nodal penetration.


A mechanism for interference between stream predators: responses of the stonefly Agnetina capitata to the presence of sculpins.
Mottled sculpins (Cottus bairdi) have a strong negative effect on the ability of the stonefly Agnetina capitata to capture some types of mayfly prey. To determine the mechanism for this interference effect, behavior of Agnetina in the presence and absence of sculpins was observed over 24 h periods (12 h light, 12 h dark), using an infra-red sensitive camera and a time-lapse video recorder. Agnetina larvae reacted to the presence of sculpins by significantly reducing the time they spent off the bottom of the substrate, and by significantly decreasing the amount of time spent moving on the substrate. These experiments suggest that in the presence of fish, stonefly diets may contain a smaller proportion of prey that tend to frequent tops and sides of stones. This behavioral flexibility may be important in streams in that it allows stoneflies to advantageously shift their diets when fish population densities are low.