Onychoscopy in a Colombian population with a diagnosis of toenail onychomycosis: an evaluation study for this diagnostic test.
Onychoscopy is a technique that uses a dermatoscope for the evaluation of specific features of different skin conditions that are not visible to the naked eye. There are few studies establishing parameters for the diagnosis of onychomycosis based on onychoscopy. Determining the sensitivity and specificity of a potentially new diagnostic test for onychomycosis requires an evaluation study of this new diagnostic test, as there are limited studies reporting onychoscopy results. To determine the sensitivity, specificity, positive predictive value and negative predictive value of onychoscopy findings in a Colombian population with onychomycosis. We assessed outpatients with a diagnosis of toenail onychomycosis confirmed by potassium hydroxide preparation or fungal culture. Onychoscopy was performed using a dermatoscope, and digital images collected using a smartphone. The onychoscopy findings were: longitudinal striae, distal spiked pattern, distal irregular termination, linear edge and ruins aspect, while some patients were confirmed as having traumatic onycholysis. A statistically significant association was found between the clinical symptoms of onychomycosis and both the clinical feature of dyschromia and the onychoscopy feature of longitudinal striae. We suggest that this technique is an alternative method that should be used in patients with onychopathies because it has the potential to differentiate onychomycosis from traumatic onycholysis and another nail involvement.


A critical review on the synthesis of NH2-MIL-53(Al) based materials for detection and removal of hazardous pollutants.
Nowadays, emerging hazardous pollutants have caused many harmful effects on the environment and human health, calling for the state of the art methods for detection, qualification, and treatment. Metal-organic frameworks are porous, flexible, and versatile materials with unique structural properties, which can solve such problems. In this work, we reviewed the synthesis, activation, and characterization, and potential applications of NH2-MIL-53(Al). This material exhibited intriguing breathing effects, and obtained very high surface areas (182.3-1934 m2/g) with diverse morphologies. More importantly, NH2-MIL-53(Al) based materials could be used for the detection and removal of various toxic pollutants such as organic dyes, pharmaceuticals, herbicides, insecticides, phenols, heavy metals, and fluorides. We shed light on plausible adsorption mechanisms such as hydrogen bonds, π-π stacking interactions, and electrostatic interactions onto NH2-MIL-53(Al) adsorbents. Interestingly, NH2-MIL-53(Al) based adsorbents could be recycled for many cycles with high stability. This review also recommended that NH2-MIL-53(Al) based materials can be a good platform for the environmental remediation fields.


The Infant Microbiome and Its Impact on Development of Food Allergy.
The prevalence of food allergy (FA) has been increasing over the past few decades; recent statistics suggest that FA has an impact on up to 10% of the population and 8% of children. Although the pathogenesis of FA is unclear, studies suggest gut microbiome plays a role in the development of FA. The gut microbiome is influenced by infant feeding method, infant diet, and maternal diet during lactation. Breastfeeding, Mediterranean diet, and probiotics are associated with commensal gut microbiota that protect against FA. This area of research is essential to discovering potential preventive methods or therapeutic targets against FA.


Noninvasive breath tests can detect alterations in gastric emptying in the mouse.
Noninvasive breath tests may have significant utility for the measurement of gastric emptying in mice, but the tests' sensitivity for detection of changes in gastric emptying has not been evaluated. Hydroxypropyl methyl cellulose was incorporated into a liquid meal to delay gastric emptying, and mice were injected with erythromycin to accelerate emptying of a liquid or solid meal. All test meals were labelled with (13)C-acetic acid or (13)C-octanoic acid. Breath samples collected at intervals were analysed for (13)CO(2) content, and gastric emptying rates were calculated from the resultant (13)CO(2) excretion curves. As predicted, hydroxypropyl methyl cellulose slowed emptying compared with water (14.21 +/- 0.94 min vs. 9.17 +/- 0.47 min, P < 0.001), while erythromycin treatment accelerated emptying of liquids (10.96 +/- 0.78 min vs. 16.41 +/- 1.94 min, P < 0.05) and solids (108.81 +/- 18.06 vs. 157.95 +/- 12.01 min, P < 0.05) compared with the saline injected controls. These data indicate that in mice the breath test is sensitive enough to detect differences in gastric emptying induced by meal composition and pharmacological agents. Noninvasive measurement of gastric emptying in mice will be useful as a method to evaluate the effect of nutrients or drugs on the motility of the gastrointestinal tract.


Behavior and physiology of social stress and depression in female cynomolgus monkeys.
The hypothesis that social subordination is stressful, and results in a depressive response in some individuals, was examined in socially housed female cynomolgus monkeys. Social status was manipulated such that half of the previously subordinate females became dominant and half of the previously dominant females became subordinate. Current subordinates hypersecreted cortisol, were insensitive to negative feedback, and had suppressed reproductive function. Current subordinates received more aggression, engaged in less affiliation, and spent more time alone than dominants. Furthermore, they spent more time fearfully scanning the social environment and displayed more behavioral depression than dominants. Current subordinates with a history of social subordination were preferentially susceptible to a behavioral depression response. The results of this experiment suggest that the stress of social subordination causes hypothalamic-pituitary-adrenal and ovarian dysfunction, and support the hypothesis that chronic, low-intensity social stress may result in depression in susceptible individuals.


Opportunities and challenges for assigning cofactors in cryo-EM density maps of chlorophyll-containing proteins.
The accurate assignment of cofactors in cryo-electron microscopy maps is crucial in determining protein function. This is particularly true for chlorophylls (Chls), for which small structural differences lead to important functional differences. Recent cryo-electron microscopy structures of Chl-containing protein complexes exemplify the difficulties in distinguishing Chl b and Chl f from Chl a. We use these structures as examples to discuss general issues arising from local resolution differences, properties of electrostatic potential maps, and the chemical environment which must be considered to make accurate assignments. We offer suggestions for how to improve the reliability of such assignments.


Catalytic pyrolysis of car tire waste using expanded perlite.
In this study, the non-catalytic and catalytic pyrolysis experiments were conducted on the sample of tire waste using expanded perlite as an additive material to determine especially the effect of temperature and catalyst-to-tire ratio on the products yields and the compositions and qualities of pyrolytic oils (NCPO and CPO). Non-catalytic studies, which were carried out under the certain conditions (a nitrogen flow of 100mL/min and a heating rate of 10°C/min), showed that the highest yield of pyrolytic oil (NCPO) was 60.02wt.% at 425°C. Then, the catalytic pyrolysis studies were carried out at catalyst-to-tire ratio range of 0.05-0.25 and the highest catalytic pyrolytic oil (CPO) yield was 65.11wt.% at the ratio of 0.10 with the yield increase of 8.48wt.% compared with the non-catalytic pyrolysis. Lastly, the pyrolytic oils were characterized with applying a various techniques such as elemental analyses and various chromatographic and spectroscopic techniques (GC-MS, (1)H NMR, FT-IR, etc.). The characterization results revealed that the pyrolytic oils which were complex mixtures of C(5)-C(15) organic compounds (predominantly aromatic compounds) and also the CPO compared to the NCPO was more similar to conventional fuels in view of the certain fuel properties.


Cubital tunnel syndrome caused by ganglion cysts: a review of 59 cases.
Cubital tunnel syndrome caused by ganglion cysts is rare and reports are few. This study aimed to review a patient cohort with ganglion cysts in the cubital tunnel and identify prognostic factors. Fifty-seven patients (59 extremities; McGowan grade I, 4; IIa, 4; IIb, 3; III, 48) were evaluated retrospectively with a minimum follow-up of 2 years. Extraneural cysts were excised completely, while intraneural cysts were incised and drained. All cases underwent subcutaneous transposition. Spearman's rank correlation and the ordinal logistic regression model were used to assess the effect of independent variables on the postoperative McGowan grade. VAS pain and weakness, 2-PD, key-pinch strength, grip strength, first dorsal interosseous muscle strength, Wartenberg sign, and claw hand all improved significantly. DASH scores improved from an average of 43.8 points preoperatively to 10.7 points postoperatively. According to the modified Bishop scoring system, 55 extremities (93.2%) were graded good or excellent. At the last follow-up, 29 hands (49.2%) returned to normal, and improvement by at least one McGowan grade was reached in 51 cases (86.4%). Older age, smoking, and shorter postoperative follow-up were associated with a higher postoperative McGowan grade. Satisfactory surgical outcomes could be expected in these patients following subcutaneous transposition with excision of extraneural cysts and draining of intraneural cysts. Older age, smoking, and shorter postoperative follow-up were found to be independent risk factors for poor outcomes.


[The pronator teres syndrome. Clinical aspects, pathogenesis and therapy of a non-traumatic median nerve compression syndrome in the space of the elbow joint].
The proximal compression neuropathy of the median nerve is described by 11 personal cases and a review of literature. The most reliable diagnostic sign is "pronation-pain", discomfort in the forearm localised under the pronator teres, produced by passive supination of the wrist, by active pronation from this position against resistance, okr by local pressure. A nearly constant finding is weakness of grip and paraesthesia or hypaesthesia of the fingers, not always following the normal median nerve distribution. Three different anatomic points of possible compression are described: 1. The supracondylar process of the humerus, or Struthers' ligament, a rare compression mechanism. 2. The passing of the nerve through the two variable heads of the pronator teres muscle. 3. The sharp edged superficialis bridge. Apart from compression of the entire median nerve single branches of the median nerve can be entrapped seperately (the anterior interosseus nerve, the Martin-Gruber-anastomosis to the ulnar nerve) Conservative treatment with immobilisation and local electric interference current application may be satisfactory. If clinical improvement is insufficient, surgical decompression is indicated.


Effects of Lactococcus lactis subsp. cremoris YRC3780 daily intake on the HPA axis response to acute psychological stress in healthy Japanese men.
Lactococcus lactis subsp. cremoris (YRC3780), which is isolated from kefir, has been associated with anti-allergic effects in humans. However, it remains unknown whether daily intake of YRC3780 attenuates the response to psychological stress in humans in parallel with changes to the gut microbiome. We examined the fundamental role of YRC3780 in the gut microbiome, stress response, sleep, and mental health in humans. Effects of daily intake of YRC3780 on the hypothalamic-pituitary-adrenal (HPA) axis response to acute psychological stress were investigated in a double-blind, placebo-controlled clinical trial involving 27 healthy young men (mean age and body mass index: 23.5 years and 21.5 kg/m2) who were randomly assigned to placebo (n = 13) or YRC3780 (n = 14) groups. The HPA axis response to acute psychological stress, the diurnal rhythm of HPA axis activity, and gut microbiome were assessed and compared between the two groups. The results showed that daily intake of YRC3780 significantly lowered morning salivary cortisol levels compared with placebo. In addition, salivary cortisol levels following a social stress test significantly decreased +40 min after beginning the TSST in the YRC3780-treated group compared to placebo. There were no significant differences between the two groups in terms of actigraphy-based sleep quality, but the subjective sleep quality and mental health were significantly improved in the YRC3780-treated group compared to placebo. Our study suggests that daily intake of YRC3780 improves the HPA axis response to acute psychological stress, which might be associated with a decrease in morning cortisol levels.


Clinical trial facilitators: A novel approach to support the execution of clinical research at the study site level.
In the summer of 2020, multiple efforts were undertaken to establish safe and effective vaccines to combat the spread of the coronavirus disease (COVID-19). In the United States (U.S.), Operation Warp Speed (OWS) was the program designated to coordinate such efforts. OWS was a partnership between the Department of Health and Human Services (HHS), the Department of Defense (DOD), and the private sector, that aimed to help accelerate control of the COVID-19 pandemic by advancing development, manufacturing, and distribution of vaccines, therapeutics, and diagnostics. The U.S. Department of Veterans Affairs' (VA) was identified as a potential collaborator in several large-scale OWS Phase III clinical trial efforts designed to evaluate the safety and efficacy of various vaccines that were in development. Given the global importance of these trials, it was recognized that there would be a need for a coordinated, centralized effort within VA to ensure that its medical centers (sites) would be ready and able to efficiently initiate, recruit, and enroll into these trials. The manuscript outlines the partnership and start-up activities led by two key divisions of the VA's Office of Research and Development's clinical research enterprise. These efforts focused on site and enterprise-level requirements for multiple trials, with one trial serving as the most prominently featured of these studies within the VA. As a result, several best practices arose that included designating clinical trial facilitators to study sites to support study initiation activities and successful study enrollment at these locations in an efficient and timely fashion.


The CRF₁ receptor antagonist SSR125543 prevents stress-induced long-lasting sleep disturbances in a mouse model of PTSD: comparison with paroxetine and d-cycloserine.
The selective CRF₁ (corticotropin releasing factor type 1) receptor antagonist SSR125543 has been previously shown to attenuate the long-term behavioral and electrophysiological effects produced by traumatic stress exposure in mice. Sleep disturbances are one of the most commonly reported symptoms by people with post-traumatic stress disorder (PTSD). The present study aims at investigating whether SSR125543 (10 mg/kg/day/i.p. for 2 weeks) is able to attenuate sleep/wakefulness impairment induced by traumatic stress exposure in a model of PTSD in mice using electroencephalographic (EEG) analysis. Effects of SSR125543 were compared to those of the 5-HT reuptake inhibitor, paroxetine (10 mg/kg/day/i.p.), and the partial N-methyl-d-aspartate (NMDA) receptor agonist, d-cycloserine (10 mg/kg/day/i.p.), two compounds which have demonstrated clinical efficacy against PTSD. Baseline EEG recording was performed in the home cage for 6h prior to the application of two electric foot-shocks of 1.5 mA. Drugs were administered from day 1 post-stress to the day preceding the second EEG recording session, performed 14 days later. Results showed that at day 14 post-stress, shocked mice displayed sleep fragmentation as shown by an increase in the occurrence of both non-rapid eye movement (NREM) sleep and wakefulness bouts. The duration of wakefulness, NREM and REM sleep were not significantly affected. The stress-induced effects were prevented by repeated administration of SSR125543, paroxetine and D-cycloserine. These findings confirm further that the CRF₁ receptor antagonist SSR125543 is able to attenuate the deleterious effects of traumatic stress exposure.


The utility of surveillance CT scans in a cohort of survivors of colorectal cancer.
Colorectal cancer (CRC) is the third most common cancer worldwide. After curative intent treatment, international guidelines recommend surveillance protocols which include annual CT chest, abdomen and pelvis (CAP) and serum carcinoembryonic antigen (CEA) monitoring which aim to improve overall survival by early detection of recurrence. Despite the widespread recommendations, robust evidence of an overall survival benefit is lacking. Our study aimed to quantify the utility of annual CT CAP as a surveillance modality in comparison to the rate of potentially harmful false-positive and incidental findings. High-risk stage II and stage III CRC patients were retrospectively identified from the Sydney Cancer Survivorship Centre database. Findings on surveillance CT were classified into confirmed recurrence or the potentially harmful findings of (a) false-positive or (b) clinically significant incidental finding. A total of 376 surveillance CT CAPs were performed in 174 survivors between 12 September 2013 and 30 June 2020. The recurrence rate during the study period was 23/174 (13.2%) with the majority of recurrences detected by abnormal CEA (14/23, 60.9%) versus surveillance CT (4/23, 17.4%), with the remainder identified on non-surveillance CT (5/23, 21.7%). Curative intent surgery was performed in 12/23 people with CRC recurrence. Surveillance CT was shown to result in high levels of false-positive (31/174, 17.8% of patients) or clinically significant incidental findings (30/174, 17.2% of patients). The risk of identifying these potentially harmful findings was ongoing with each year of surveillance CT. Surveillance CT was associated with low detection rates and high rates of potentially harmful findings bringing this surveillance modality under further scrutiny. An increased emphasis should be placed on educating survivors on the benefits of surveillance CT weighed against the risk of potentially harmful findings.


Intracranial neurosurgical treatment of occlusive cerebrovascular disease.
Anastomosis of the extracranial superficial temporal artery to the intracranial middle cerebral artery offers an additional source of blood to the cerebral circulation in patients with transient ischemic episodes. Fourteen cases are reported. Two representative cases with three anastomoses demonstrate the use of this technique in occlusion of the internal carotid artery, occlusion of the middle cerebral artery and stenosis of the middle cerebral artery. Indications and contraindications of the procedure are discussed.


Comparative study of liponucleosides in Langmuir monolayers as cell membrane models.
Liponucleosides may assist the anchoring of nucleic acid nitrogen bases into biological membranes for tailored nanobiotechnological applications. To this end precise knowledge about the biophysical and chemical details at the membrane surface is required. In this paper, we used Langmuir monolayers as simplified cell membrane models and studied the insertion of five lipidated nucleosides. These molecules varied in the type of the covalently attached lipid group, the nucleobase, and the number of hydrophobic moieties attached to the nucleoside. All five lipidated nucleosides were found to be surface-active and capable of forming stable monolayers. They could also be incorporated into dipalmitoylphosphatidylcholine (DPPC) monolayers, four of which induced expansion in the surface pressure isotherm and a decrease in the surface compression modulus of DPPC. In contrast, one nucleoside possessing three alkyl chain modifications formed very condensed monolayers and induced film condensation and an increase in the compression modulus for the DPPC monolayer, thus reflecting the importance of the ability of the nucleoside molecules to be arranged in a closely packed manner. The implications of these results lie on the possibility of tuning nucleic acid pairing by modifying structural characteristics of the liponucleosides.


Role of ATP-bound divalent metal ion in the conformation and function of actin. Comparison of Mg-ATP, Ca-ATP, and metal ion-free ATP-actin.
The fluorescence of N-acetyl-N'-(sulfo-1-naphthyl)ethylenediamine (AEDANS) covalently bound to Cys-374 of actin is used as a probe for different conformational states of G-actin according to whether Ca-ATP, Mg-ATP, or unchelated ATP is bound to the nucleotide site. Upon addition of large amounts (greater than 10(2)-fold molar excess) of EDTA to G-actin, metal ion-free ATP-G-actin is obtained with EDTA bound. Metal ion free ATP-G-actin is characterized by a higher AEDANS fluorescence than Mg-ATP-G-actin, which itself has a higher fluorescence than Ca-ATP-G-actin. Evidence for EDTA binding to G-actin is shown using difference spectrophotometry. Upon binding of EDTA, the rate of dissociation of the divalent metal ion from G-actin is increased (2-fold for Ca2+, 10-fold for Mg2+) in a range of pH from 7.0 to 8.0. A model is proposed that quantitatively accounts for the kinetic data. The affinity of ATP is weakened 10(6)-fold upon removal of the metal ion. Metal ion-free ATP-G-actin is in a partially open conformation, as indicated by the greater accessibility of -SH residues, yet it retains functional properties of polymerization and ATP hydrolysis that appear almost identical to those of Ca-ATP-actin, therefore different from those of Mg-ATP-actin. These results are discussed in terms of the role of the ATP-bound metal ion in actin structure and function.


[Factors influencing formation of dinitrosyl complexes of non-heme iron in vitro preparations of mouse liver and yeasts].
Total content of Fenh and its amounts incorporated into paramagnetic dinitrozyl complexes of Fenh (complexes 2.03) which are formed in vitro in homogenates of mouse liver and yeast preparations treated with nitrogen oxide was determined by means of chemical and ESR methods. Formation of the complexes 2.03 in the liver homogenate is limited by the content of easily dyalized weakly bound Fenh, in yeasts--by the content of pair RS-groups. It is suggested that in the liver preparation Fenh incorporated into the complexes 2.03 is determined by the interaction of reduction cytoplasm agents with ferritin. A change in the content of Fenh may affect the appearance and disappearance of the complexes 2.03 in animal tissues in vivo.


Physicochemical parameters affecting liposomal bisphosphonates bioactivity for restenosis therapy: internalization, cell inhibition, activation of cytokines and complement, and mechanism of cell death.
Partial inactivation and transient depletion of monocytes/macrophages by liposomal bisphosphonates (LIP-BPs) is widely experimented in various inflammatory disorders including restenosis. Previous studies on activation of cytokines by LIP-BPs are limited to certain cell lines. Moreover, the correlation between in vitro and in vivo studies and complement (C) activation has not been reported. We report here a comprehensive study on the bioactivity of LIP-BPs on various cells' internalization and proliferation, mechanism of cell death, cytokines (in vitro and in vivo) and C activation (in the rat, rabbit and pig). The role of the following parameters has been determined i) drug type (clodronate/alendronate); ii) vesicles size (60-800nm); iii) charge (neutral/negative/ positive); and iv) cell culture type (various cell lines and primary cultures). It was found that monocyte/macrophage inhibition and cytokine activation depend on the cell type, with a limited correlation to the bioactivity obtained in the rat and rabbit models of restenosis. Negatively charged liposomes (85+/-20nm) effectively depleted rabbit's monocytes (67% depletion), with a minor activation of cytokines and no C activation. It is concluded that cell culture studies are insufficient for assessing cytokine activation, and that by controlling LIP-BP properties (size, charge and drug type) optimal bioactivity could be achieved.


Progresses in lignin, cellulose, starch, chitosan, chitin, alginate, and gum/carbon nanotube (nano)composites for environmental applications: A review.
Water sources are becoming increasingly scarce, and they are contaminated by industrial, residential, and agricultural waste-derived organic and inorganic contaminants. These contaminants may pollute the air, water, and soil and invade the ecosystem. Because carbon nanotubes (CNTs) can undergo surface modification, they can combine with other substances to create nanocomposites (NCs), including biopolymers, metal nanoparticles, proteins, and metal oxides. Furthermore, biopolymers are significant classes of organic materials that are widely used for various applications. They have drawn attention due to their benefits, such as environmental friendliness, availability, biocompatibility, safety, etc. As a result, the synthesis of a composite made of CNT and biopolymers can be very effective for various applications, especially those involving the environment. In this review, we reported environmental applications (including removal of dyes, nitro compounds, hazardous materials, toxic ions, etc.) of composites made of CNT and biopolymers such as lignin, cellulose, starch, chitosan, chitin, alginate, and gum. Also, the effect of different factors such as the medium pH, the pollutant concentration, temperature, and contact time on the adsorption capacity (AC) and the catalytic activity of the composite in the reduction or degradation of various pollutants has been systematically explained.


Late potentials in progressive muscular dystrophy of the Duchenne type.
This study describes the late potentials (LPs) obtained by signal-averaged electrocardiography (SAECG) in 66 patients with Duchenne's progressive muscular dystrophy (DMD). It also assesses the possible relationships between LPs and the severity of DMD, and the findings of two-dimensional echocardiography, as well as ventricular arrhythmias examined with the Holter system. SAECGs were performed with a Marquette MAC-1 unit. Based on Swinyard-Deaver's system of stages, ranging from the mildest, S1, to the most severe, S8, one patient each could be assigned to S2 and S4, 6 to S5, 20 to S6, 21 to S7, and 17 to S8. LPs were observed in 21 of the 66 patients (32%), including 3 of the 20 assigned to S6 (15%), 10 of the 21 in S7 (48%), and 8 of the 17 in S8 (47%). The total wall motion index evaluated by the method of Hegar was significantly greater in the patients with LPs (8.4 +/- 4.4) than in those without LPs (5.8 +/- 3.1) (p less than 0.05). The incidence of LPs was found to be higher in the dilated cardiomyopathy (DCM) type (8 of 12;67%) than in the normal type (9 of 41;22%) (p less than 0.01). The incidence of ventricular premature complexes (VPCs) was significantly higher in patients with LPs (13 of 21;62%) than in those without LPs (13 of 45;29%) (p less than 0.05). No sustained ventricular tachycardia (VT) was observed, although nonsustained VT was noted in three patients with LPs. The LPs in patients with DMD were thus associated with left ventricular dysfunction, and the presence of LPs might be correlated with the extent of myocardial derangement in DMD.


Systemic bevacizumab for end-stage juvenile recurrent respiratory papillomas: A case report.
We report on two cases of severe recurrent respiratory papillomatosis (RRP) involvement where the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab IV has been administered for treatment. Notably, there have not been any episodes of urgent transfer to the hospital for obstructive events since the bevacizumab was started. It is important to note however, that the disease has not been eliminated. While some pulmonary nodules continue to grow, they have become cavitated. Overall, the number and size of pulmonary lesions has decreased. Therefore, VEGF-targeted therapies, Bevacizumab, could prove to be a promising novel approach for long-term treatment of severe RRP.


A neuropeptide-mediated stretch response links muscle contraction to changes in neurotransmitter release.
Although Caenorhabditis elegans has been utilized extensively to study synapse formation and function, relatively little is known about synaptic plasticity in C. elegans. We show that a brief treatment with the cholinesterase inhibitor aldicarb induces a form of presynaptic potentiation whereby ACh release at neuromuscular junctions (NMJs) is doubled. Aldicarb-induced potentiation was eliminated by mutations that block processing of proneuropeptides, by mutations inactivating a single proneuropeptide (NLP-12), and by those inactivating an NLP-12 receptor (CKR-2). NLP-12 expression is limited to a single stretch-activated neuron, DVA. Analysis of a YFP-tagged NLP-12 suggests that aldicarb stimulates DVA secretion of NLP-12. Mutations disrupting the DVA mechanoreceptor (TRP-4) decreased aldicarb-induced NLP-12 secretion and blocked aldicarb-induced synaptic potentiation. Mutants lacking NLP-12 or CKR-2 have decreased locomotion rates. Collectively, these results suggest that NLP-12 mediates a mechanosensory feedback loop that couples muscle contraction to changes in presynaptic release, thereby providing a mechanism for proprioceptive control of locomotion.


In vitro mutagenicity and cell-transformation screening of N-(2,3-epoxy-propyl)-phthalimide.
N-(2,3-Epoxy-propyl)-phthalimide (EPP) was tested for genetic activity in the Salmonella/microsome mutagenicity test. Concentration-dependent mutagenicity was demonstrated in S. typhimurium strains TA1535, TA1537 and TA100 with and without rat S9. It was inactive in strain TA1538, and active without rat S9 in TA98 at the high dose. EPP induced 6-thioguanine-resistant mutants of Chinese hamster ovary cells in the absence of an exogenous activating system. EPP produced dose-dependent enhancement of SA7 virus transformation of primary hamster-embryo cells, and transformed secondary hamster-embryo cells in a non-dose-related fashion. At a dose of 5 g/kg p.o. or i.m., EPP was inactive in the host-mediated assay using C57Bl/6XC3H mice and S. typhimurium strain TA1535. Murine testicular DNA synthesis was not inhibited by oral administration of EPP at 1000 mg/kg.


Highly sensitive and specific detection of P-glycoprotein function for haematological and solid tumour cells using a novel nucleic acid stain.
Progress in our understanding of the contribution of P-glycoprotein (P-gp)-mediated resistance to chemotherapy failure in haematological as well as solid tumours has been hampered by the lack of highly sensitive, reliable methods for the detection of P-gp function in fresh human tumour cells. The present study identifies the novel nucleic acid stain SYTO16 as a highly sensitive and specific dye to assess P-gp function. The effect of P-gp is expressed here as the ratio of dye fluorescence (RF) from cells incubated with dye with or without 2 microM of the P-gp inhibitor PSC 833. Using flow cytometric analysis, an RF of 0.9 was found for SYTO16 in the KB3-1 (P-gp-) and 1.6 in KB8 (P-gp+) cells. Three types of patients' cells were studied: (1) in haematopoietic CD34+ cells, which are known to express P-gp, the RF was 6.0 for SYTO16 compared with 2.5 for rhodamine 123 and 1.3 for daunorubicin (mean of five individuals); (2) in acute myeloid leukaemia cells, the RF for SYTO16 was 1.0 in P-gp- and 4.5 in P-gp+ samples; (3) for the first time, we have quantitated P-gp function in fresh human solid tumour (sarcoma) cells. We found, in a P-gp+ leiomyosarcoma, an RF of 16 for SYTO16 and 2.7 for daunorubicin. This means that complete inhibition of P-gp function in these sarcoma cells would lead to an increase of daunorubicin accumulation with 170% compared with 30% in the CD34+ cells. Next, we showed that SYTO16 could be fixed in nuclei by 3.6% formaldehyde treatment, allowing quantification of the nuclear fluorescence on cytospins by laser scanning microscopy. In conclusion, SYTO16 proved to have a combination of favourable properties: it can be excited at 488 nm and has large fluorescence enhancement upon binding to nucleic acids, allowing the use of low, nontoxic (< 10 nM) concentrations. Because the RF for SYTO16 is much higher than for daunorubicin, it can be applied for the determination of P-gp function in relatively small numbers of low-P-gp-expressing tumour cells by laser scanning microscopy. Individual sarcomas were found to have high P-gp function compared with CD34+ cells. This assay may be used to select patients for P-gp modulation protocols.


Implications of oil price shocks on net oil-importing African countries.
The study examines the implications of oil price shocks on developing net oil-importing countries. The study considers the casual relationship, impulse response function, and vector decomposition between oil prices and macroeconomic variables using an unrestricted vector autoregressive (VAR) model. In addition, other robust econometric techniques were applied to the time series of oil prices, GDP per capita (GDPC), and energy consumption from 1980 to 2015. Mix results were obtained for the selected African countries - Cape Verde, Liberia, Sierra Leone, and The Gambia. Evidence from the granger test shows that oil prices cause GDPC in Liberia and Sierra Leone. Furthermore, analyses from the VAR model and Impulse response indicate that oil price increase will temporarily increase GDP per capita in the short run for the selected countries. The study recommends policies that can effectively mitigate the adverse effect of the oil price increase.


How predictable is genome evolution?
Similar patterns of genomic divergence have been observed in the evolution of plant species separated by oceans.


aFGF alleviates diabetic endothelial dysfunction by decreasing oxidative stress via Wnt/β-catenin-mediated upregulation of HXK2.
Vascular complications of diabetes are a serious challenge in clinical practice, and effective treatments are an unmet clinical need. Acidic fibroblast growth factor (aFGF) has potent anti-oxidative properties and therefore has become a research focus for the treatment of diabetic vascular complications. However, the specific mechanisms by which aFGF regulates these processes remain unclear. The purpose of this study was to investigate whether aFGF alleviates diabetic endothelial dysfunction by suppressing mitochondrial oxidative stress. We found that aFGF markedly decreased mitochondrial superoxide generation in both db/db mice and endothelial cells incubated with high glucose (30 mM) plus palmitic acid (PA, 0.1 mM), and restored diabetes-impaired Wnt/β-catenin signaling. Pretreatment with the Wnt/β-catenin signaling inhibitors IWR-1-endo (IWR) and ICG-001 abolished aFGF-mediated attenuation of mitochondrial superoxide generation and endothelial protection. Furthermore, the effects of aFGF on endothelial protection under diabetic conditions were suppressed by c-Myc knockdown. Mechanistically, c-Myc knockdown triggered mitochondrial superoxide generation, which was related to decreased expression and subsequent impaired mitochondrial localization of hexokinase 2 (HXK2). The role of HXK2 in aFGF-mediated attenuation of mitochondrial superoxide levels and EC protection was further confirmed by si-Hxk2 and a cell-permeable form of hexokinase II VDAC binding domain (HXK2VBD) peptide, which inhibits mitochondrial localization of HXK2. Taken together, these findings suggest that the endothelial protective effect of aFGF under diabetic conditions could be partly attributed to its role in suppressing mitochondrial superoxide generation via HXK2, which is mediated by the Wnt/β-catenin/c-Myc axis.


Sex Differences in the Incidence and Outcomes of COPD Patients Hospitalized with Ischemic Stroke in Spain: A Population-Based Observational Study.
To compare the incidence, clinical characteristics and outcomes of patients admitted with ischemic stroke (IS) according to the presence of COPD and sex in Spain (2016-2018). We selected all admissions with IS (≥35 years) included in the Spanish National Hospital Discharge Database. We matched each patient suffering COPD with a non-COPD patient with identical age, sex, IS type and year of hospitalization. IS was coded in 92,524 men and 79,731 women (8.67% with COPD). The incidence of IS was higher in COPD men than in non-COPD men (IRR 1.04; 95% CI 1.03-1.06), although the differences were not significant among women. COPD men had twice higher incidence of IS than COPD women (IRR 2.00; 95% CI 1.93-2.07). After matching, COPD men had a higher in-hospital mortality (IHM) than non-COPD men (11.48% vs 9.80%; p<0.001), and the same happened among women (14.09% vs 11.96%; p=0.002). COPD men received thrombolytic therapy less frequently than non-COPD men. For men and women, the risk of dying in the hospital increased with age, some comorbidities and mechanical ventilation use. After multivariable adjustment, COPD increased the risk of IHM in men (OR 1.16; 95% CI 1.06-1.28) and women (OR 1.12; 95% CI 1.01-1.27). Finally, among COPD patients, being women increased the risk of dying during the hospitalization with IS by 15% (OR 1.15; 95% CI 1.03-1.28). Incidence of IS was higher in COPD patients, although the difference was only significant for men. COPD was associated with an increased risk of IHM. Among COPD patients, women had higher IHM.


Bactericidal proteins and neutral proteases in diabetes neutrophils.
Reduced bacterial killing by polymorphonuclear leucocytes has been reported in patients with diabetes mellitus. Whether this is due to reduced content of bactericidal granular proteins has not been determined. We therefore immunochemically measured the content of myeloperoxidase, lactoferrin, lysozyme, cathepsin G and elastase in polymorphonuclear leucocytes from 50 insulin-treated diabetic patients. The peroxidase activity was also measured. Normal contents of myeloperoxidase and lactoferrin as well as normal peroxidase activity were found. The average contents of cathepsin G, elastase and lysozyme were 2.5, 3.2 and 2.6 micrograms/10(6) polymorphonuclear leucocytes, respectively, and thus 14, 45 and 18% higher than the contents of normal polymorphonuclear leucocytes. The results indicate that reduced intracellular killing of bacteria demonstrated in previous studies in diabetic patients does not appear to be related to a reduction in the content of bactericidal proteins.


In vitro activity of a Combretum micranthum extract against herpes simplex virus types 1 and 2.
The authors demonstrate in vitro antiviral activity of a methanolic extract of Combretum micranthum leaves against HSV-1 and HSV-2. This activity is present only in the extract dissolved 7 days before the assay, but not in the freshly prepared extract, thus indicating the presence of inactive precursors which undergo spontaneous transformations into active compounds. The alkaline autooxidation of the methanolic extract promotes this rapid transformation. The precursors have been identified as condensed catechinic tannins, which, under alkaline conditions, suffer rapid cleavage, intramolecular rearrangement to catechinic acid and autooxidation. The alkaline autooxidation products of the methanolic extract of C. micranthum and those of the synthetic catechinic acid show similar I.R. and U.V. absorption curves, as well as similar anti-HSV-1 and -HSV-2 activities. EC50s of catechinic acid autooxidation products against HSV-1 and HSV-2 replication were 2 micrograms/ml and 4 micrograms/ml, respectively, when cell cultures were treated with the compound during virus infection.


Environmental exposures and rheumatoid arthritis risk.
In addition to rapidly burgeoning data regarding novel genetic risk factors, a growing list of environmental exposures have been implicated in rheumatoid arthritis (RA) susceptibility. Cigarette smoking is chief among the many environmental exposures implicated in disease risk, accounting for approximately one in six new cases of RA, with recent results underscoring the central importance of select gene-smoking interactions in RA development. In this review, we examine data linking several environmental exposures with RA risk, including cigarette smoking, other air pollutants and occupational exposures, reproductive/hormonal influences, alcohol consumption, select infections leading to periodontal disease, and dietary factors. Where applicable, we review the current understanding of biologic mechanisms linking these environmental factors to disease risk.


Huge craniopharyngioma: diffusion MRI and contrast-enhanced FLAIR imaging.
Craniopharyngiomas are most commonly located extraaxially in the suprasellar area. They are benign but aggressive neoplasms. An adult patient is reported to have a huge craniopharyngioma with gross extensions to the surroundings. In diffusion MRI, it had high signal for b=1000 mm(2)/s (true diffusion) images, and at the same time, high ADC values (=2.12 and 2.27 x 10(-3)mm(2)/s, compared to that of normal cerebellar parenchyma 0.85 x 10(-3)mm(2)/s). In FLAIR images, obtained after administration of intravenous contrast medium, an intense, diffuse enhancement pattern was seen involving the viable tumor portions as well as the intratumoral fluid.


Oral squamous cell carcinoma in a 7-year-old Brazilian boy.
Squamous cell carcinomas (SCCs) are amongst the commonest malignancies in adults but in paediatric patients are exceptionally rare, particularly those involving the oral mucosa. The aim of the present report is to describe the features of a gingival well-differentiated SCC in a 7-year-old Brazilian boy. Immunostaining for p53, Ki-67 and Mcm2 showed increased cellular proliferation compared with normal epithelium. In situ hybridization failed to identify human papilloma virus infection. Correct diagnosis of well-differentiated squamous carcinoma can be difficult in children and differentiation from pseudoepitheliomatous hyperplasia is essential to establish proper treatment.


A Contemporary Review of Smart Phone Applications in Bariatric and Metabolic Surgery: an Underdeveloped Support Service.
This study aims to be a contemporary review of mHealth apps in bariatric and metabolic surgery (BMS) to assess their quality using the Silberg scale as well as features, themes, usability, and medical/allied health professional involvement (MAPI). Apps were identified using search terms in the Android and Apple app stores. 52 apps were included. 42 (80.7%) apps main target users were patients. More than half, 27 (52%), targeted US based users. 29 (56%) had payment-restricted content. 42 (81%) had MAPI and the mean Silberg score was 5.2. Compared to previous studies the quality of BMS apps is improving with more MAPI and useful functionality. Wider use of mHealth apps for patient centred follow-up, management and care are yet to be widely implemented and explored.


Bony stress in the lumbar spine is associated with intervertebral disc degeneration and low back pain: a retrospective case-control MRI study of patients under 25 years of age.
Abnormal stress in the lumbar vertebra, also known as bony stress, can be a precursor to degenerative changes which may manifest as low back pain (LBP). However, the prevalence of bony stress in the lumbar spine and its relationship with degenerative changes and LBP is unclear. The purpose of this study was to evaluate the prevalence of bony stress in the lumbar spine and its relationship with intervertebral disc (IVD) degeneration, facet osteoarthritis and LBP in patients under 25 years of age. A retrospective case-control study of 130 patients under 25 years of age was conducted from a population of 493 patients who had lumbar MRI across three imaging centres over three years. A cohort of 55 consecutive patients with bony stress was identified. A control group of consecutive patients (n = 75) without bony stress was also selected from the population. Bony stress was prevalent in 11% (95% CI [8.4-14.5%]) of patients and was not diagnosed in 36% (95% CI [22-55%]) of these cases. Patients with bony stress had over twofold (OR 2.3, 95% CI [1.1-4.8]) and fivefold (OR 5.3, 95% CI [2.11-13.3]) higher likelihood of having IVD degeneration and LBP, respectively, when compared with the control group. Bony stress was not found to be associated with facet osteoarthritis. Bony stress in the lumbar spine was prevalent in 11% of patients under 25 years of age. It was commonly undiagnosed in radiology reports (not reported in 36% of the cases). Being significantly associated and with an increased likelihood of IVD degeneration and LBP, we posit that bony stress is likely a symptomatic and clinically meaningful diagnostic entity in the assessment of LBP. These slides can be retrieved under Electronic Supplementary Material.


Chemotherapy versus chemoradiotherapy for FIGO stages IB1 and IIA1 cervical squamous cancer patients with lymphovascular space invasion: a retrospective study.
To evaluate the impact of different adjuvant therapy on IB1 and IIA1 stage cervical squamous cell cancer patients with lymphovascular space invasion. It also aimed to analyze the relationship between lymphovascular space invasion and other clinical pathological characteristics on IB1 and IIA1 stage cervical squamous cell cancer patients. This retrospective observational study collected data of FIGO stages IB1 and IIA1 squamous cervical cancer patients at the First Affiliated Hospital of Chongqing Medical University between 2014 and 2018. A correlation analysis between lymphovascular space invasion and other clinical or pathological factors was conducted. Prognosis analysis of patients with lymphovascular space invasion were performed to assess associations between clinical-pathological characteristics and survival. A total of 357 women were identified including 110 (30.8%) with lymphovascular space invasion, 247 (69.2%) without lymphovascular space invasion. Both middle 1/3 cervical stromal invasion (p = 0.000) and deep 1/3 cervical stromal invasion (p = 0.000) were independently associated with lymphovascular space invasion. Among lymphovascular space involved women, tumor differentiation (P = 0.001) and postoperative therapy (P = 0.036) had a significant influence on disease recurrence. Multivariate analysis showed that lymph node metastasis (P = 0.017), poorer tumor differentiation (P = 0.036) and postoperative chemotherapy alone (P = 0.021) can increase the risk of tumor relapse. Our study suggested that the presence of deep stromal invasion independently increases the risk of lymphovascular space invasion. Compared with chemotherapy, chemoradiotherapy seems to improve progression-free survival in squamous cervical cancer patients with lymphovascular space invasion.


A Case of in utero Transmission of Drug-resistant HIV in the United States.
Thanks to the development of antiretroviral drugs and the implementation of routine perinatal prophylaxis, primarily containing zidovudine, modern-day rates of perinatal transmission of HIV are very low in developed countries. We present a case of perinatal transmission of HIV with extensive nucleoside reverse transcriptase inhibitor resistance as a reminder that perinatal transmission of resistance mutations can occur. This case calls for further investigation into the utility of using genotype to determine neonatal prophylaxis in the setting of maternal HIV drug resistance.


[Demographic change and the need for prioritization in health care: position of the German Medical Association].
The German health care system will face major challenges in the near future. Progress in medicine as well as demographic change will combine to drastically exacerbate the scarcity of resources in the health care system. The word scarcity in this case not only refers to the availability of funds. Other resources, e.g., staff, attention, time, and organs for transplantation, are also becoming scarce. It is conceivable that, in the future, it will no longer be possible to provide medical services for all patients to the same extent as in the past. If the necessary resources are not available in the health care system, if the potential for saving resources has been more or less exhausted, and if rationing shall not be an option, the only option to resort to will be prioritization. Prioritization in the health care sector denotes a supply of services according to specific, predetermined criteria. A broad and open public debate, which would have to be accompanied as well as moderated by the Health Council ("Gesundheitsrat"), is essential for determining such criteria.


Volumes and numbers of intervillous pores and villous domains in placentas associated with intrauterine growth restriction and/or pre-eclampsia.
The intrauterine environment has an important influence on placental development. In pre-eclampsia (PE) and intrauterine growth restriction (IUGR), early remodelling of spiral arteries has repercussions for uteroplacental blood flow. The IUGR placenta exhibits compromised growth of villous trees, a smaller intervillous space and a lower diffusive conductance. Here, we test whether or not term placentas associated with PE or IUGR also exhibit changes in structural quantities (notably, sizes and numbers of intervillous pores and villous domains) pertinent to uteroplacental haemodynamics. Paraffin wax sections were sampled at random locations and orientations and structural quantities obtained by combining design-based stereological estimates of total and star volumes with model-based estimates of pore hydraulic diameters. Total volumes of intervillous pores and villi were estimated by point counting, total villous surface by intersection counting and star volumes by measuring point-sampled intercept lengths. Other quantities were derived secondarily and group estimates compared by two-way analysis of variance. We found significant main effects of IUGR but no main or interaction effects involving PE. In IUGR, there were fewer intervillous pores and these had larger hydraulic diameters. IUGR also produced fewer villous domains but these were constant in star volume and villi had a constant mean diameter and volume fraction. We concluded that IUGR compromises placental development by producing intervillous pores and villous trees different in size and shape from those in control and PE pregnancies. Calculations suggest that Darcian conductances in the intervillous space improve in IUGR but, in reality, placental performance is compromised by other physiological and structural constraints including the known decline in diffusive conductances.


Identification of Type A Influenza Viruses from Wild Birds on the Delmarva Peninsula, 2007-10.
Wild waterfowl and shorebirds in the Delaware-Maryland-Virginia (Delmarva) Peninsula region within the Atlantic Flyway were sampled as part of the Early Detection of Highly Pathogenic H5N1 Avian Influenza (AI) in Wild Migratory Birds program. The U.S. Department of Agriculture (USDA) and state wildlife agencies submitted 7858 samples for AI virus (AIV) testing by real-time reverse transcription PCR (rRT-PCR) to the University of Delaware Poultry Health System from April 2007 to March 2011. Virus isolation attempts were performed on samples with matrix gene cycle threshold (Ct) values ≤33.9. Using rRT-PCR, AIV was detected in 14% (1091/7857) of the samples. In species with sample sizes >100, American black duck ( Anas rubripes ; 28%), ruddy turnstone ( Arenaria interpres ; 27%), American green-winged teal ( Anas crecca ; 21%), semipalmated sandpiper ( Calidris pusilla ; 27%), greater snow goose ( Chen caerulescens atlanticus; 12%), mallard ( Anas platyrhynchos ; 10%), and northern pintail ( Anas acuta ; 14%) showed the highest rates of AIV detection. Forty-two AIVs were recovered from eight species: American black duck, mallard, ruddy turnstone, American green-winged teal, greater snow goose, Canada goose ( Branta canadensis ), ring-necked duck ( Aythya collaris ), and mallard × American black duck ( Anas platyrhynchos × Anas rubripes ). Recovered H5 (n = 2) and H7 (n = 2) viruses were found to be low pathogenicity by the USDA National Veterinary Services Laboratory. Additional AIVs represented a diversity of subtype combinations: H1-H4, H6, and H10 and H11 and N subtypes N1-N9 and N6-N9. The rate of AIV recovery from swabbings was inversely related to Ct value, ranging from 50% for Ct values of 16.0-18.9 to 5.1% for Ct values of 31-33.9.


Development and application of a fiber2 protein-based indirect ELISA for detection of duck adenovirus 3.
Duck adenovirus 3 (DAdV-3) is a newly identified duck adenovirus that has recently emerged in China. The incidence of duck infection caused by this virus is very high, with very large economic losses to the poultry industry. Thus, there is an urgent need for a serological assay for the specific detection of DAdV-3. To this end, prokaryotic expression of the fiber2 protein of DAdV-3 was used as a coating antigen to establish an indirect enzyme linked immunosorbent assay (ELISA) method for the specific detection of antibodies against DAdV-3. The method was found to be specific, repeatable and more sensitive than the agarose gel precipitation test (AGP). This indirect ELISA method based on the recombinant fiber2 protein may be used for the clinical detection of DAdV-3 infection and for monitoring antibody levels after vaccine immunization and is of great significance for the effective prevention and control of the disease.


Differential vasodilatory action of 2-octynyladenosine (YT-146), an adenosine A2 receptor agonist, in the isolated rat femoral artery and vein.
The vasodilatory action of 2-octynyladenosine (YT-146), an adenosine A2 receptor agonist, was investigated in the isolated rat femoral artery and vein. Exposure to YT-146 resulted in preferential vasodilatation; the vein was completely dilated at YT-146 concentrations as low as 10(-7) M; in contrast, a concentration of YT-146 greater than 10(-4) M was necessary to induce complete relaxation in the femoral artery. 2-[p-(2-Carboxyethyl)-phenethylamine]-5'-N-ethylcarboxamidoadenosine (CGS 21680) also evoked stronger dilation in the vein than in the artery. The vasodilatory action of N6-cyclopentyladenosine (CPA) was much weaker in the vein than that of YT-146. YT-146-induced vasodilation in the artery was antagonized by neither 10(-7) M 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) nor 3 x 10(-6) M (E)-8-(3,4-dimethoxystylyl)-1,3-dipropyl-7-methylxanthine (KF17837), while the vasodilation in the vein was only antagonized by KF17837, suggesting that the vasodilation may involve adenosine A2 receptor activation in the vein. However, the present study did not provide evidence of a link between adenosine agonist-induced vasodilation and adenosine A2 receptor activation in the artery. The addition of 10(-4) M N omega-nitro-L-arginine partially reversed YT-146-induced vasodilation in the artery, but not in the vein. The reversal of YT-146-induced vasodilation by N omega-nitro-L-arginine in the artery was attenuated by the addition of 10(-3) M L-arginine. Removal of the endothelium decreased YT-146-induced vasodilation in the artery, but not in the vein.(ABSTRACT TRUNCATED AT 250 WORDS)


Ovalbumin lipid core peptide vaccines and their CD4(+) and CD8(+) T cell responses.
The lipid core peptide (LCP) system has successfully been used in development of peptide-based vaccines against cancer and infectious diseases (such as group A streptococcal infection). CD8(+) T cells are important targets for vaccines, however developing a vaccine that activates long-lasting immunity has proven challenging. The ability of LCP vaccines to activate antigen-specific CD8(+) and/or CD4(+) T cell responses was tested using compounds that contained two or four copies of OVA257-264 and/or OVA323-339 peptides conjugated to LCP, which are recognised by OTI (CD8(+) specific) and OTII (CD4(+) specific) T cells, respectively. The LCP-ovalbumin vaccines developed in this study were synthesised in 30% yields and showed no significant haemolytic effect on red blood cells (below 4% haemolysis when tested with compounds at up to 100μM concentrations). Promising in vivo data in mice suggested that this LCP-ovalbumin vaccine system could act as a novel and potent vehicle for the stimulation of robust antigen-specific CD8(+) T cell responses.


A Recurrent Variant in POLR1B, c.3007C>T; p.Arg1003Cys, Associated with Atresia of the External Canal and Microtia in Treacher Collins Syndrome Type 4.
Treacher Collins syndrome (TCS) is a heterogenous malformation syndrome characterized by a distinct facial appearance including downslanting palpebral fissures, malar hypoplasia, conductive hearing loss, and mandibular hypoplasia. Recently, a new causative gene, POLR1B, encoding DNA-directed RNA polymerase I subunit RPA2, was identified as a fourth type of TCS (TCS4). We describe another patient with TCS4 caused by a recurrent POLR1B variant, c.3007C>T; p.Arg1003Cys. Including our patient, all 4 patients with p.(Arg1003Cys) had atresia of the external auditory canal and microtia. All of the reported pathogenic variants in POLR1B were clustered at only 2 residues. Our patient highlights the genotype-phenotype correlation in TCS4 associated with POLR1B.


Characterisation of rubella virus hemagglutinin rosettes.
Purified rubella virus treated with Triton X-100 was subjected to centrifugation in a sucrose density gradient containing nonionic detergent beta-D-octylglucoside. The result of this treatment was the formation of hemagglutinating rosettes containing viral glycoproteins VP2 (50,000 mol. wt.) and VP3 (63,000 mol. wt.). The rosettes have a 26 S sedimentation coefficient and a density of 1.2 g/cm3 in sucrose. Electron microscopy revealed 15 nm rosettes with a hollow center. The molecular weight of the rosettes was extrapolated at 850,000.


Comorbidities, multimorbidity and COVID-19.
The influence of comorbidities on COVID-19 outcomes has been recognized since the earliest days of the pandemic. But establishing causality and determining underlying mechanisms and clinical implications has been challenging-owing to the multitude of confounding factors and patient variability. Several distinct pathological mechanisms, not active in every patient, determine health outcomes in the three different phases of COVID-19-from the initial viral replication phase to inflammatory lung injury and post-acute sequelae. Specific comorbidities (and overall multimorbidity) can either exacerbate these pathological mechanisms or reduce the patient's tolerance to organ injury. In this Review, we consider the impact of specific comorbidities, and overall multimorbidity, on the three mechanistically distinct phases of COVID-19, and we discuss the utility of host genetics as a route to causal inference by eliminating many sources of confounding. Continued research into the mechanisms of disease-state interactions will be crucial to inform stratification of therapeutic approaches and improve outcomes for patients.


Rapid identification, by use of the LTQ Orbitrap hybrid FT mass spectrometer, of antifungal compounds produced by lactic acid bacteria.
Fungal contamination of food causes health and economic concerns. Several species of lactic acid bacteria (LAB) have antifungal activity which may inhibit food spoilage fungi. LAB have GRAS (generally recognised as safe) status, allowing them to be safely integrated into food systems as natural food preservatives. A method is described herein that enables rapid screening of LAB cultures for 25 known antifungal compounds associated with LAB. This is the first chromatographic method developed which enables the rapid identification of a wide range of antifungal compounds by a single method with a short analysis time (23 min). Chromatographic separation was achieved on a Phenomenex Gemini C18 100A column (150 mm × 2.0 mm; 5 μm) by use of a mobile-phase gradient prepared from (A) water containing acetic acid (0.1%) and (B) acetonitrile containing acetic acid (0.1%), at a flow rate of 0.3 µL min(-1). The gradient involved a progressive ramp from 10-95% acetonitrile over 13 min. The LC was coupled to a hybrid LTQ Orbitrap XL fourier-transform mass spectrometer (FTMS) operated in negative ionisation mode. High mass accuracy data (<3 ppm) obtained by use of high resolution (30,000 K) enabled unequivocal identification of the target compounds. This method allows comprehensive profiling and comparison of different LAB strains and is also capable of the identification of additional compounds produced by these bacteria.


Novel impedance-pH parameters are associated with proton pump inhibitor response in patients with inconclusive diagnosis of gastro-oesophageal reflux disease according to Lyon Consensus.
The Lyon Consensus delineates impedance-pH parameters that can demonstrate/exclude gastro-oesophageal reflux disease (GERD). In patients with acid exposure time between 4% and 6%, GERD diagnosis has been considered inconclusive. In these cases, mean nocturnal baseline impedance (MNBI) and post-reflux swallow-induced peristaltic wave (PSPW) index may either confirm or refute GERD diagnosis and represent predictors of proton pump inhibitor (PPI) response. To investigate the diagnostic yield of MNBI and PSPW index and their relationship with PPI response in patients with inconclusive GERD diagnosis. Review of impedance-pH tracings from PPI responder/non-responder patients with typical reflux symptoms. Multivariate regression analysis was performed to determine the association of MNBI and PSPW index to PPI response. Among 233 patients evaluated, 145/233 (62.2%) were PPI responders; 62 had conclusive and 65 inconclusive evidence of GERD, 46 had reflux hypersensitivity, and 60 functional heartburn. Abnormal MNBI and PSPW index were significantly more frequent in inconclusive GERD as compared to the functional heartburn group (P < 0.001). Within the inconclusive GERD group, 35/65 (54%) patients were PPI responders and displayed a significantly higher proportion of cases with pathological MNBI or PSPW index as compared to non-responders (32/35 [91.4%] and 30/35 [85.7%] vs 9/30 [30%] and 7/30 [23.3%], P < 0.001). By multivariate analysis, pathological PSPW index and/or MNBI values were significantly associated with PPI response in all groups. The present study highlights the value of MNBI and PSPW index as adjunctive metrics in characterising patients with inconclusive evidence of GERD and identifying those responsive to PPI treatment.


Routine hematological values in term newborns.
Routine hematological parameters were investigated in 240 term normal neonates, 40 neonates in the first week of life and 49 infants between 3 and 6 months of age. Term normal neonates were selected on the basis of well defined criteria. Cord blood Hb values of 16.2 +/- 1.5 g/dl compared well with some of the recent Indian studies and Caucasian figures. Cord blood hemoglobin was lower in the presence of low maternal hemoglobin and in newborns delivered by Cesarean section. A wide variation existed in the total and differential leucocyte counts, thus limiting the clinical utility of white cell counts in the newborn period. Platelet counts were within the adult normal range.


Dengue Fever and Severe Dengue in Barbados, 2008-2016.
Analysis of the temporal, seasonal and demographic distribution of dengue virus (DENV) infections in Barbados was conducted using national surveillance data from a total of 3994 confirmed dengue cases. Diagnosis was confirmed either by DENV-specific real time reverse transcriptase polymerase chain reaction (rRT-PCR), or non-structural protein 1 (NS1) antigen or enzyme linked immunosorbent assay (ELISA) tests; a case fatality rate of 0.4% (10/3994) was observed. The prevalence rate of dengue fever (DF) varied from 27.5 to 453.9 cases per 100,000 population among febrile patients who sought medical attention annually. DF cases occurred throughout the year with low level of transmission observed during the dry season (December to June), then increased transmission during rainy season (July to November) peaking in October. Three major dengue epidemics occurred in Barbados during 2010, 2013 and possibly 2016 with an emerging three-year interval. DF prevalence rate among febrile patients who sought medical attention overall was highest among the 10-19 years old age group. The highest DF hospitalisation prevalence rate was observed in 2013. Multiple serotypes circulated during the study period and Dengue virus serotype 2 (DENV-2) was the most prevalent serotype during 2010, whilst DENV-1 was the most prevalent serotype in 2013. Two DENV-1 strains from the 2013 DENV epidemic were genetically more closely related to South East Asian strains, than Caribbean or South American strains, and represent the first ever sequencing of DENV strains in Barbados. However, the small sample size (n = 2) limits any meaningful conclusions. DF prevalence rates were not significantly different between females and males. Public health planning should consider DENV inter-epidemic periodicity, the current COVID-19 pandemic and similar clinical symptomology between DF and COVID-19. The implementation of routine sequencing of DENV strains to obtain critical data can aid in battling DENV epidemics in Barbados.


A tumor-targeting p53 nanodelivery system limits chemoresistance to temozolomide prolonging survival in a mouse model of glioblastoma multiforme.
Development of temozolomide (TMZ) resistance contributes to the poor prognosis for glioblastoma multiforme (GBM) patients. It was previously demonstrated that delivery of exogenous wild-type tumor suppressor gene p53 via a tumor-targeted nanocomplex (SGT-53) which crosses the blood-brain barrier could sensitize highly TMZ-resistant GBM tumors to TMZ. Here we assessed whether SGT-53 could inhibit development of TMZ resistance. SGT-53 significantly chemosensitized TMZ-sensitive human GBM cell lines (U87 and U251), in vitro and in vivo. Furthermore, in an intracranial GBM tumor model, two cycles of concurrent treatment with systemically administered SGT-53 and TMZ inhibited tumor growth, increased apoptosis and most importantly, significantly prolonged median survival. In contrast TMZ alone had no significant effect on median survival compared to a single cycle of TMZ. These results suggest that combining SGT-53 with TMZ appears to limit development of TMZ resistance, prolonging its anti-tumor effect and could be a more effective therapy for GBM. Using human glioblastoma multiforma cell lines, this research team demonstrated that the delivery of exogenous wild-type tumor suppressor gene p53 via a tumor-targeted nanocomplex limited the development of temozolomide resistance and prolonged its anti-tumor effect, which may enable future human application of this or similar techniques.


Size distributions and health risks of particle-bound toxic elements in the southeast coastland of China.
Size-fractionated samples were collected at five coastal urban sites in Fujian Province, southeast China, in 2016 and 2017 to determine the trace elements using ICP-MS. Ca, Fe, Al, Mg, and K were the most abundant elements among the studied elements in TSP, much higher than those of heavy metals. The annual mean concentrations of Pb, As, V, Ni, Cd, and Mn were within the acceptable limits of the World Health Organization and the Ministry of Ecology and Environment of China while Cr(VI) exceeded the limits. Most elements exhibited clear seasonal patterns with maxima over the cold season and minima over the warm season. The spatial variabilities in concentrations of the measured elements were not significant except Ni and V. However, the size distribution pattern of each element was quite similar across the region. Characteristic size distributions of elements allowed identification of three main groups: (a) unimodal distribution in the coarse fraction for Ca, Al, Mg, and Ba; (b) unimodal distribution in the fine fraction for Pb, Se, As, Ag, V, Ni, Zn, and Cd; and (c) bimodal or multimodal distribution for Fe, Mn, Cr, K, and Cu. The combination of the size-fractionated concentrations, enrichment factors, correlation coefficients, and factor analysis offered the identification of mixed sources such as vehicular exhaust and wear, heavy fuel oil combustion, and resuspension of road dust. Non-carcinogenic health risks associated with inhalable exposure to airborne metals were higher than the safety threshold (hazard index > 1) across the region, suggesting non-carcinogenic health risks via inhalation. Mn, V, and Ni contributed 74-83% of the total non-carcinogenic risk. The assessment investigation of carcinogenic health risks revealed V and Cr(VI) as elements with the largest carcinogenic risks, accounting for more than 95% of the overall inhalation risk. Nevertheless, the carcinogenic risks for children and adults were between 10-6 and 10-4, within the range considered acceptable by the US EPA. In terms of the size-fractionated risk, PM2.5 contributed 43-50% and 39-44% of the total non-carcinogenic and carcinogenic risks, respectively, indicating the potential health hazard of coarse particle-bound toxic metals was not negligible.


Transcriptional expression changes of glucose metabolism genes after exercise in thoroughbred horses.
Physical exercise induces gene expression changes that trigger glucose metabolism pathways in organisms. In the present study, we monitored the expression levels of LDHA (lactate dehydrogenase) and GYS1 (glycogen synthase 1) in the blood, to confirm the roles of these genes in exercise physiology. LDHA and GYS1 are related to glucose metabolism and fatigue recovery, and these processes could elicit economically important traits in racehorses. We collected blood samples from three retired thoroughbred racehorses, pre-exercise and immediately after 30 min of exercise. We extracted total RNA and small RNA (≤ 200 nucleotide-long) from the blood, and assessed the expression levels of LDHA, GYS1, and microRNAs (miRNAs), by using qRT-PCR. We showed that LDHA and GYS1 were down-regulated, whereas eca-miR-33a and miR-17 were up-regulated, after exercise. We used sequences from the 3' UTR of LDHA and GYS1, containing eca-miR-33a and miR-17 binding sites, to observe the down-regulation activity of each gene expression. We observed that the two miRNAs, namely, eca-miR-33a and miR-17, inhibited LDHA and GYS1 expression via binding to the 3' UTR sequences of each gene. Our results indicate that eca-miR-33a and miR-17 play important roles in the glucose metabolism pathway. In addition, our findings provide a basis for further investigation of the exercise metabolism of racehorses.


Application of group smoothly clipped absolute deviation method in identifying correlates of psychiatric distress among college students.
College students are at an increased risk of psychiatric distress. So, identifying its important correlates using more reliable statistical models, instead of inefficient traditional variable selection methods like stepwise regression, is of great importance. The objective of this study was to investigate correlates of psychiatric distress among college students in Iran; using group smoothly clipped absolute deviation method (SCAD). A number of 1259 voluntary college students participated in this cross-sectional study (Jan-May 2016) at Hamadan University of Medical Sciences, Iran. The data were collected using a self-administered questionnaire consisting of demographic information, a behavioral risk factors checklist and the GHQ-28 questionnaire (with a cut-off of 23 to measure psychiatric distress, recommended by the Iranian version of the questionnaire). Penalized logistic regression with a group-SCAD regularization method was used to analyze the data (α = 0.05). The majority of students were aged 18-25 (87.61%), and 60.76% of them were female. About 41% of students had psychiatric distress. Significant correlates of psychiatric distress among college students selected by group-SCAD included the average grade, educational level, being optimistic about future, having a boy/girlfriend, having an emotional breakup, the average daily number of cigarettes, substance abusing during previous month and having suicidal thoughts ever (P < 0.05). Penalized logistic regression methods such as group-SCAD and group-Adaptive-LASSO should be considered as plausible alternatives to stepwise regression for identifying correlates of a binary response. Several behavioral variables were associated with psychological distress which highlights the necessity of designing multiple factors and behavioral changes in interventional programs.


Outstanding clinical efficacy of PD-1/PD-L1 inhibitors for pulmonary pleomorphic carcinoma.
We evaluated programmed death ligand 1 (PD-L1) expression and efficacy of PD-1/PD-L1 inhibitors in patients with pulmonary pleomorphic carcinoma (PC). We created two cohorts of patients diagnosed with pulmonary PC from 2016 to 2019, PD-L1 expression and programmed death 1 (PD-1)/PD-L1 inhibitor efficacy cohorts. The PD-L1 expression cohort included all patients evaluated for PD-L1 expression, irrespective of PD-1/PD-L1 inhibitor therapy. High PD-L1 expression was defined as ≥50% positive tumour cells (TC) for 22C3, ≥25% for SP263 or ≥10%/5% TC/immune cell (IC) for SP142. The PD-1/PD-L1 efficacy cohort included patients treated with PD-1/PD-L1 inhibitors, irrespective of PD-L1 tests. One hundred twenty-five of 175 patients diagnosed with pulmonary PCs were included in the PD-L1 expression cohort. Among them, 112 patients (89.6%) had PD-L1-positive (≥1%) tumours and 100 (80.0%) had tumours with high PD-L1 expression. A total of 49 patients were included in the efficacy cohort: 40 received pembrolizumab, 7 nivolumab and 2 atezolizumab. The objective response rate was 49.0%, with a median progression-free survival (PFS) of 7.2 months and a median overall survival of 22.2 months. In the efficacy cohort, high PD-L1 expression (n = 41) was associated with longer PFS (median: 7.2 versus 1.5 months, hazard ratio [HR]: 0.53 [0.22-1.29], p = 0.16) and overall survival (median: 22.2 versus 3.5, HR: 0.21 [0.08-0.57], p = 0.001) than low/negative/unknown PD-L1 expression (n = 8). PD-1/PD-L1 inhibitors show outstanding efficacy for pulmonary PCs, and this is possibly attributable to high PD-L1 expression in these tumours.


A global dataset for prevalence of Salmonella Gallinarum between 1945 and 2021.
Pullorum disease and fowl typhoid are among the most significant poultry diseases worldwide. However, the global burden of these diseases remains unknown. Most importantly, the parameters contributing to the prevalence of Salmonella Gallinarum variants are not well documented. Therefore, in this study, we present a systematic review and meta-analysis of the global prevalence of Salmonella Gallinarum during 1945-2021. In total, 201 studies were identified for qualitative analysis (>900 million samples). The meta-analysis was subjected to over 183 screened studies. The global prevalence of S. Gallinarum (percentage of positive samples in total samples) was 8.54% (95% CI: 8.43-8.65) and showed a V-shaped recovery over time. Pullorum disease is most common in Asia, particularly in eastern China. Further investigations on chicken origin samples revealed significant differences in S. Gallinarum prevalence by gender, breed, raising mode, economic use, and growth stage, indicating a critical role of vertical transmission. Together, this study offered an updated, evidence-based dataset and knowledge regarding S. Gallinarum epidemics, which might significantly impact decision-making policy with targeted interventions.


Association study of UGT1A9 promoter polymorphisms with DILI based on systematically regional variation screen in Chinese population.
Drug-induced liver injury (DILI) is caused by unpredictable adverse drug reaction due mainly to the accumulation of hepatotoxic compounds in the liver resulting in significant damage. Drug-metabolizing enzymes have been prime targets for molecular studies relevant to DILI. The gene UGT1A9 mainly expresses in the liver and has an important role in drug metabolism. The Han Chinese has a very long and complex demographic history, and the population stratification arising from the interplay of different geographic areas may influence the polymorphism pattern. We selected 260 healthy subjects in three different geographic areas (including Xian, Shanghai and Liuzhou) for systemic screening and analysis of single-nucleotide polymorphisms (SNPs) in the promoter region of UGT1A9. Eight SNPs were identified and no regional disparity exists among the three populations. Based on these results, 213 DILI patients from all over the Chinese mainland were further recruited to investigate possible association between UGT1A9 and DILI. We observed statistically significant associations between SNP rs2741045 and DILI at both allele and genotype levels (allele: P=0.032; genotype: P=0.029; after Bonferroni correction). Also, multivariate interaction analysis discovered the interaction between rs2741045 and age associated with DILI significantly. This is the first such screening study to investigate the association between UGT1A9 promoter polymorphisms and DILI in the Chinese population and it could provide the basis for further study of DILI mechanisms.


[Pancreatic necrosis: pro-endoscopic therapy].
The transmural endoscopic debridement and other minimally invasive therapies of infected postpancreatic necroses have been developed over the last decade as alternatives to open surgery. In several clinical centers the endoscopic approach has become standard therapy. The mortality rate in published series is in the range 0-15% and additional surgery is needed in 0-40%.Out of 73 own patients treated endoscopically between 2006 and 2010, 4 were operated because of bleeding, 2 with an acute abdomen and 3 with sepsis. Of the patients 6 died because of multi-organ failure and in 3 cases despite surgery. Main complications such as bleeding (n=20) and acute abdomen (n=7) were mostly treated conservatively. There was no procedure-related mortality. The endoscopic therapy was successful in 59 patients (80%) of whom 7 required further transmural endoscopic interventions for cystic relapses.At present, finding the best combination of endoscopic-transmural, percutaneous, laparoscopic and sometimes finally open surgical therapy remains an interdisciplinary challenge. The only randomized study published in this context clearly indicates that such a step-up approach is the most favorable.


Inverse identification of pollution source release information for surface river chemical spills using a hybrid optimization model.
To evaluate the liability of the spilled contaminant and to design comprehensive emergency response schemes, it is essential to estimate the contaminant source characteristic and identify where, when and how much the spilled contaminant is injected into a surface river. In this study, an effective pollution source inverse method is developed to reconstruct the release history of the injection location, time, and quantity, and provide appropriate emergency response schemes for dealing with surface river environmental pollution. The pollution source inverse method IGSAA is developed by an integration of genetic algorithm (IGA) and simulated annealing algorithm (SAA) in order to guarantee both the global searching ability and convergence speed. The pollution source inverse method IGSAA is then applied to a hypothetical study, comparing with the traditional GA-based and SAA-based methods, to verify the accuracy and efficiency of the contaminant source inverse, and to a trace study of Truckee River in west America to identify the contaminant source release history and characteristic under different scenarios. The pollution source inversion results can help decision-makers (DMs) to identify the contaminant source characteristics of a chemical spill, and carry out emergency disposal scheme for an emergency rescue in a quick response, and enhance the supervision and management ability for a real surface river system.


Distinctive roles of different beta-amyloid 42 aggregates in modulation of synaptic functions.
To determine how endogenously secreted beta-amyloid 42 (Abeta42) aggregates regulate synaptic functions, we examined effects of Abeta42 at the neuromuscular junction of Drosophila larvae. Voltage-clamp recordings of synaptic transmission and optical analysis of vesicle recycling at presynaptic terminals show that expression of Abeta42 in neurons leads to a reduction of neurotransmitter release. However, expression of Abeta42 in postsynaptic muscle cells enhanced neurotransmitter release. Both effects are neutralized by Abeta antibody, suggesting a role for secreted Abeta42 peptides. Application of exogenously prepared Abeta42 oligomers leads to a reduction in synaptic responses, whereas mixed Abeta42 aggregates with mainly fibrils elicit an opposite effect by increasing synaptic transmission. Further analysis of long-term depression (LTD) confirms differential effects of different Abeta42 aggregates. Taken together, our data suggest that Abeta42 is secreted from neurons primarily as oligomers that inhibit neurotransmitter release and exert no effect on LTD. Whereas larger-sized aggregates, possibly fibrils, are major components secreted from muscle cells, which enhance synaptic transmission and LTD. Thus, different types of cells may secrete distinct forms of Abeta42 aggregates, leading to different modulation of synaptic functions.


The ALS/PDC syndrome of Guam: potential biomarkers for an enigmatic disorder.
The ALS/parkinsonism-dementia complex of Guam is a long latency disease with a diverse phenotypic expression characteristic of classical ALS, parkinsonism and dementia. It is remarkably similar to a syndrome localized to the Kii Peninsula of Japan. There are as yet no identified pathological features that will clearly distinguish the Guam or Kii ALS/PDC syndrome from other degenerative neurological disorders. At present, ALS/PDC of Guam and the Kii Peninsula can be confirmed only by postmortem examination. The most prominent pathological hallmark is the widespread occurrence of neurofibrillary tangles which express the same balance of 3R and 4R tau that is found in Alzheimer disease. They both show an increased prevalence of a peculiar retinal disorder termed linear retinal pigmentary epitheliopathy. The disorders are both highly familial. Several environmental factors have been proposed but no supportive evidence for an environmental or dietary factor has been found. Genome searches have so far failed to identify causative genes although two single nuclear polymorphisms related to MAPT that increase the risk of the Guam syndrome have been located. The two syndromes are clearly unique, and clues as to their causation could be beneficial in understanding the etiology of similar, but much more prevalent disorders in North America, Europe and Asia. Identification of biomarkers for premortem diagnosis would be helpful in management as well as in revealing the true etiology.


Uptake prediction of nine heavy metals by Eichhornia crassipes grown in irrigation canals: A biomonitoring approach.
The principal objective of this study is to generate mathematical regression equations that facilitate the estimation of the extent to which Eichhornia crassipes (C. Mart.) Solms, water hyacinth, absorbs heavy metals (HMs) into four plant organs (laminae, petioles, roots, and stolons). This study considers the absorption of nine HMs (Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, and Zn), and the E. crassipes evaluated in this study were located in three irrigation canals in the North Nile Delta in Egypt, with sampling being conducted in both monospecific and homogenous E. crassipes. Samples of both E. crassipes and water were collected on a monthly basis during one growing season. Analysis of the water samples showed that the HM concentrations ranged from 1.1 μg/l for Cd to 2079.8 μg/l for Fe. All HMs were more concentrated in the E. crassipes roots than in any other organ. Typically, there was a significant correlation between the HM levels in the water and the HM levels in the E. crassipes organs. E. crassipes was documented by a bioconcentration factor > 1.0 for all HMs. The translocation factor in this study was <1.0 for all HMs. The t-values that referred to the discrepancies between the measured and predicted values of the HMs in the four E. crassipes organs were not significant. This finding can be considered to be an indication of the goodness of fit with respect to the ability of the equations to forecast HM uptake. Therefore, the developed equations will benefit the prediction of HM uptake by E. crassipes grown in irrigation canals in the Nile Delta. The efficacy of E. crassipes as a metric for gauging the aggregate impact of environmental pollution in water sources and its potential application in biomonitoring are confirmed in this study.


Comparison of characteristics and survival of colorectal cancer between Japanese-Americans in Hawaii and native Japanese in Japan.
This study was designed to investigate whether characteristics, prognostic risk factors, and survival of colorectal cancer of Japanese-Americans in Hawaii are different from those of native Japanese in Japan. A retrospective review of patients with colorectal cancer surgically resected in single institutions in Hawaii and Japan from 1996 to 2002. A total of 410 Japanese-American patients (218 males; median age, 73 years) and 621 native Japanese patients (382 males; median age, 65 years) were included. There were significant differences in age (P < 0.001), age distribution (P < 0.001), gender (P = 0.008), preoperative carcinoembryonic antigen (P < 0.001), and anatomic site distribution (P < 0.001). The tumor characteristics of Japanese-American patients were close to the general American population compared with the Surveillance, Epidemiology, and End Results data. There were no differences in tumor size, histologic grade, each of T, N, M status and TNM stage between the two groups. The overall five-year survival rates (Japanese-Americans, 75.5 percent; native Japanese, 76.2 percent; P = 0.55) and survival rates in each of four stratified stages were similar. Risk factors associated with survival were not different, except for carcinoembryonic antigen (P = 0.036). In patients with colorectal cancer in Japanese-Americans in Hawaii, some of tumor characteristics have changed from those of native Japanese in Japan. However, there are no remarkable differences in prognostic factors and survival between the two groups. The present study suggests that certain changes of colorectal cancer characteristics that were seen in Japanese-American may occur in native Japanese in Japan in the near future, although the survival outcome of colorectal cancer may remain the same.


Assessment for chronic kidney disease service in high-risk patients at community health clinics.
Chronic kidney disease (CKD) poses significant public health concerns. Early identification and interventions can help prevent or slow progression to end-stage renal disease. To characterize CKD in high-risk indigent patients in a primary care setting and evaluate opportunities for pharmacists to work collaboratively with physicians to improve medication use and CKD patient outcomes. Medical records of 200 patients with diabetes mellitus and/or hypertension were reviewed by the clinical pharmacist. Estimated glomerular filtration rate (creatinine clearance [Cl(cr)]) and urinalysis were used to identify and stage CKD according to published guidelines. Glycosylated hemoglobin concentrations and blood pressures were recorded. The pharmacist evaluated medications for possible drug-related problems (DRPs), made therapeutic recommendations, and evaluated the acceptance rate by physicians. One hundred nineteen patients met inclusion criteria, and a total of 68.9% met CKD criteria: stage 1, 16.0%; stage 2, 20.2%; stage 3, 25.2%; stage 4, 1.7%; stage 5, 0.8%; and not stageable, 5.0%. A total of 381 DRPs were identified, averaging 3.2 (1.7) per patient (range 0-11). The number of DRPs correlated with Cl(cr) (r = -0.25; p = 0.007). Therapeutic recommendations included change of drug, dose and/or interval adjustment of the current drug, discontinuation of nonsteroidal antiinflammatory drugs, additional laboratory monitoring, meeting goal blood pressure and glycosylated hemoglobin, adding renoprotective drug and/or low-dose aspirin, and nephrologist referral. Fewer than half (40.9%) of the recommendations were accepted or accepted with modifications, and an approximately equal percentage were not accepted by the physicians. CKD prevalence was high among the patients evaluated here. New guidelines are available to assist in managing CKD ambulatory patients. Pharmacist collaboration with physicians may optimize CKD screening in high-risk patients and improve medication usage.


Management of mesh complications following surgery for stress urinary incontinence or pelvic organ prolapse: a systematic review.
Mesh surgery for stress urinary incontinence or pelvic organ prolapse can result in complications such as mesh exposure, mesh extrusion, voiding dysfunction, dyspareunia, and pain. There is limited knowledge or guidance on the effective management for mesh-related complications. To determine the best management of mesh complications; a systematic review was conducted as part of the national clinical guideline 'Urinary incontinence (update) and pelvic organ prolapse in women: management'. Search strategies were developed for each indication for referral. Relevant interventions included complete or partial mesh removal, mesh division, and non-surgical treatments such as vaginal estrogen. Characteristics and outcome data were extracted, and as a result of the heterogeneous nature of the data a narrative synthesis was conducted. Twenty-four studies were included; five provided comparative data and four studies stated the indication for referral. Reported outcomes (including pain, dyspareunia, satisfaction, quality of life, incontinence, mesh exposure, and recurrence) and the reported incidences of these varied widely. The current evidence base is limited in quantity and quality and does not permit firm recommendations to be made on the most effective management for mesh-related complications. Robust data are needed so that mesh complications can be managed effectively in the future. Systematic review demonstrates that the outcomes following mesh revision surgery are highly variable.


Oral corticosteroid-dependent asthma: a 30-year review.
To identify novel aspects of the pathogenesis, therapeutic options, and prophylaxis measures of corticosteroid-dependent asthma. PubMed searches were undertaken of studies published between 1966 and 2006 on the pathogenesis of and corticosteroid-sparing therapies for corticosteroid-dependent asthma. Identified review articles were surveyed for additional and earlier citations. Recent American Academy of Asthma, Allergy, and Immunology meeting abstracts were also searched to identify other recently published and unpublished studies. Inclusion of studies in the review was decided by simple agreement of both reviewers, who independently read the "Methods" and "Discussion" sections of articles identified using the search strategy. Quality assessment was performed by the 2 reviewers. High-dose inhaled corticosteroids are the first-line option for corticosteroid-dependent asthmatic patients with clear efficacy. Omalizumab is effective in reducing oral corticosteroid requirements in allergic asthma. Methotrexate, gold, and cyclosporine have corticosteroid-sparing effects clinically that must be weighed against a serious adverse effect profile. Nebulized diuretics and lidocaine, with a low adverse effect profile, offer promising results but require further study. Clarithromycin and telithromycin seem to have an independent mechanism of inflammatory modulation, but their effect on corticosteroid-dependent asthma remains to be seen. Etanercept offers only early clinical evidence of a role in corticosteroid-dependent asthma. With no clear consensus on corticosteroid-sparing treatment in corticosteroid-dependent asthmatic patients, systemic glucocorticoids remain the foremost therapy, with adverse effects that require monitoring and prophylaxis.


The pretreatment lymphocyte to monocyte ratio predicts clinical outcome for patients with hepatocellular carcinoma: A meta-analysis.
The lymphocyte-to-monocyte ratio (LMR) has been reported to predict clinical outcomes in multiple malignancies. The aim of this study was to assess the prognostic role of pretreatment LMR in hepatocellular carcinoma (HCC). A total of seven studies comprising 2,738 patients were included in the meta-analysis. Pooled results showed that elevated LMR was significantly associated with increased overall survival (OS) (HR: 0.31, 95% CI: 0.20-0.47, p < 0.001), disease-free survival (DFS)/recurrence-free survival (RFS) (HR: 0.57, 95% CI: 0.49-0.67, p < 0.001). The favorable prognostic impact of high LMR on OS was observed in all subgroup with different sample size, type of publication, NOS score, and the cut-off value of LMR. In addition, low LMR was significantly correlated with TNM stage and BCLC stage. We therefore conclude that elevated pretreatment LMR could be a favorable prognostic factor for clinical outcomes in patients with HCC.


Optimization of Deep Eutectic Solvents Enables Green and Efficient Cryopreservation.
Cryopreservation presents significant opportunities for biomedical applications including cell therapy, tissue engineering, and assisted reproduction. Dimethyl sulfoxide (DMSO), the most commonly used cryoprotectant (CPA), can be added to cells to prevent cryogenic damage. However, the toxicity of cryoprotectants restrains its further development in many areas with safety concerns such as clinical treatment. Therefore, the development of low-toxicity cryoprotectants is essential for medical research. This work reports deep eutectic solvents (DES) as naturally biocompatible osmoprotectants for green and efficient cryopreservation of human umbilical cord mesenchymal stem cells (HuMSC), which may be an ideal alternative to DMSO. The six types of DESs were explored for thermal properties, toxicity, and permeability in cells. Raman spectroscopy and viscosity studies showed that DES exhibited an improved hydrogen-bonding system as the temperature decreased. By optimizing the freezing process (cooling rate, incubation time, and loading procedure) of DES, the viability of mouse embryonic fibroblast cells (NIH-3T3) after thawing was significantly improved. The HuMSC were successfully preserved with no significant difference (p > 0.05) in cell viability (94.65%) after thawing compared with DMSO, which preserved the cell differentiation function and improved the cell proliferation rate. The mechanism of DES in cryopreservation was investigated, and it was found that DES could bind water molecules and effectively inhibit the growth of ice crystals during ice recrystallization, reducing mechanical damage to cells. This study highlights the excellent performance of DES as a low-toxicity CPA for stem cell preservation, which may be a significant advance for future clinical cell therapy.


Evidence that elevation of maternal somatic cell count could lead to production of offspring with inferior reproductive and productive performance in dairy cows during the first lactation period.
Although the effect of mastitis on reproduction and production of lactating dairy cows has been vastly studied, little information is available about the association of maternal udder health status with offspring reproduction and production. Therefore, the present research was conducted to study the association between maternal average monthly somatic cell count (SCC) with reproduction, anti-Müllerian hormone (AMH) concentration, udder health status and milk production in the offspring. Based on maternal average monthly SCC (MSCC), offspring were classified into five categories including MSCC1 (SCC <200,000; n = 3005), MSCC2 (200,000 ≤ SCC <400,000; n = 252), MSCC3 (400,000 ≤ SCC <600,000; n = 103), MSCC4 (600,000 ≤ SCC <800,000; n = 40) and MSCC5 (SCC ≥800,000; n = 61). Data associated with reproduction, production and udder health status of offspring were retrieved from the herd database. In addition, blood samples were collected from a subset of offspring (n = 136) for measurement of serum AMH, as a reliable marker of ovarian reserves. Offspring in MSCC5 category had more services per conception and longer calving to conception interval than offspring in MSCC1 and MSCC2 categories (P < 0.05). The average number of SCC and risk of clinical mastitis in the offspring were not associated with MSCC (P > 0.05). But offspring in MSCC5 category produced less milk, fat and protein than offspring in MSCC1 category (P < 0.05). In addition, AMH concentration was lower in MSCC5 than MSCC1 category (P < 0.05). In conclusion, the present study showed that elevated maternal average monthly SCC could culminate in birth of offspring with inferior reproductive performance, smaller size of ovarian reserves and lower level of milk production during the first lactation period.


Intraflagellar transport molecules in ciliary and nonciliary cells of the retina.
The assembly and maintenance of cilia require intraflagellar transport (IFT), a process mediated by molecular motors and IFT particles. Although IFT is a focus of current intense research, the spatial distribution of individual IFT proteins remains elusive. In this study, we analyzed the subcellular localization of IFT proteins in retinal cells by high resolution immunofluorescence and immunoelectron microscopy. We report that IFT proteins are differentially localized in subcompartments of photoreceptor cilia and in defined periciliary target domains for cytoplasmic transport, where they are associated with transport vesicles. IFT20 is not in the IFT core complex in photoreceptor cilia but accompanies Golgi-based sorting and vesicle trafficking of ciliary cargo. Moreover, we identify a nonciliary IFT system containing a subset of IFT proteins in dendrites of retinal neurons. Collectively, we provide evidence to implicate the differential composition of IFT systems in cells with and without primary cilia, thereby supporting new functions for IFT beyond its well-established role in cilia.