PET imaging of tumor hypoxia using 18F-labeled pimonidazole.
Tumor hypoxia contributes to loco-regional failure, and for optimal treatment planning, knowledge about tumor hypoxia in individual patients is required. Nitroimidazole-based tracers, which are retained in hypoxic cells, allow PET-based assessment of tumor hypoxia, but current tracers are characterized by slow tracer retention and clearance, resulting in low inter-tissue contrast. Pimonidazole is an immune detectable hypoxia marker widely used for detection of hypoxia in tumor samples. Pimonidazole has excellent chemical properties for hypoxia imaging, but labeling for non- invasive assay has not been attempted. Here we labeled pimonidazole with (18)F ([(18)F]FPIMO). [(18)F]FPIMO was produced by fluorination of 1-[2-O-tosyl-3-(2-nitroimidazole-1-yl)-propyl]-piperidine, which resulted in two isomeric interchangeable forms (named "5" and "6") with a radiochemical purity of 91-100%. [(18)F]FPIMO was tested by incubation of two different tumor cell lines at high and low oxygen levels. [(18)F]FPIMO was also administered to tumor-bearing mice and tracer retention in tumors, non-hypoxic reference tissues and tissues involved in drug metabolism/clearance was evaluated by various techniques. Retention of [(18)F]FPIMO was strongly hypoxia-driven in vitro, but isomeric form "5" was particularly promising and reached impressive anoxic-to-oxic retention ratios of 36 and 102, in FaDuDD and SiHa cells, respectively, following three hours of tracer incubation. This was equal to or higher than ratios measured using the established hypoxia tracer [(18)F]FAZA. [(18)F]FPIMO also accumulated in tumors grown in mice, and reached tumor levels that were two to six-fold higher than in muscle three hours post-administration. Furthermore, the intra-tumoral distribution of [(18)F]FPIMO (autoradiography) and unlabeled pimonidazole (immunohistochemistry) was largely identical. Nonetheless, [(18)F]FPIMO proved inferior to [(18)F]FAZA, since absolute tumor signal and intra-tumoral contrast was low, thus compromising PET imaging. Low tumor signal was coupled to extensive tracer accumulation in liver and kidneys, and analysis of blood metabolites revealed that [(18)F]FPIMO was metabolized rapidly, with little parent compound remaining 15 minutes post-administration. Ongoing work focuses on the possibility of labeling pimonidazole in different positions with (18)F to improve tracer stability in vivo.


Biodegradation of conventional plastics: Candidate organisms and potential mechanisms.
With the benefits of coming at low-cost, being light-weight and having a high formability and durability, conventional plastics are widely used in both industry and daily life. However, because of their durability and extensive half-life with poor degradability and the low recycling rate, large amounts of plastic waste are accumulated in various environments, posing a significant threat to organisms and ecosystems. Compared to conventional physical and chemical degradation, biodegradation of plastic might become a promising and environmentally friendly solution for this problem. One of the aims of this review is to briefly describe the impact of plastics (especially microplastics). To facilitate rapid advancements in the area of plastic biodegradation, this paper provides a comprehensive review of the candidate organisms capable of biodegrading plastics and originating from four categories including natural microorganisms, artificially derived microorganisms, algae and animal organisms. In addition, the potential mechanism during plastic biodegradation and associated driving factors are summarized and discussed. Furthermore, the recent biotechnological progress (e.g. synthetic biology, systems biology, etc.) is highlighted as being key for future research. Finally, innovative research avenues for future studies are proposed. Concluding, our review is addressing the practical application of plastic biodegradation and the plastic pollution, thus necessitating more sustainable developments.


Kinetic studies of copper-induced oxidation of urate, ascorbate and their mixtures.
Urate and ascorbate are the major water-soluble low molecular weight antioxidants in serum. Much attention has been devoted to the effect of these antioxidants on lipoprotein peroxidation in vivo and on their effect on copper-induced peroxidation ex vivo. These studies revealed that urate inhibits ascorbate oxidation in vitro, whereas the effect of ascorbate on urate oxidation has not been systematically studied thus far. The present study addresses mechanistic aspects of the kinetics of copper-induced oxidation of both these antioxidants and their mutual effects in aqueous solutions. We found that: (i) ascorbate becomes oxidized much faster than urate. (ii) Urate inhibits the oxidation of ascorbate but, even in the presence of excess urate, ascorbate becomes oxidized much faster than urate. (iii) Ascorbate, as well as the products of its oxidation (and/or hydrolysis) inhibit the copper-induced oxidation of urate. All these results are consistent with the hypothesis that the rate of ascorbate oxidation is determined by the rate of reoxidation of reduced copper (Cu(I)) to Cu(II) by molecular oxygen, whereas the rate of urate oxidation is governed by the rate of oxidation of urate within a 2:1 urate/copper complex. We think that the mutual effects of urate and ascorbate on each other's oxidation are likely to enhance their inhibitory effect on lipid peroxidation in biologically relevant systems including membranes and lipoproteins.


Prevention of aphakic retinal detachment by circumferential cryotherapy.
In a series of ARD'S, the incidence of bilaterality was 35%, as opposed to an incidence of bilaterality of 12% in patients with PRDs. The purpose of this communication is to determine whether the very high incidence of bilaterality in patients with ARDs can be reduced significantly by prophylactic treatment of the fellow eye. The fellow eye of patients who had suffered a unilateral ARDs were treated by prophylactic circumferential equatorial cryopexy irrespective of whether or not predisposing lesions were present. The eyes were treated either prior to lens extraction or following lens extraction. The techniques, complications and results of treatment are discussed.


Editorial Commentary: When Properly Indicated, Combined Tibial Tubercle Osteotomy Reduces Risk of Recurrent Patellofemoral Instability More Than Does Isolated Medial Patellofemoral Ligament Reconstruction.
Clinical recognition and surgical treatment of patellofemoral instability has evolved dramatically over the past 3 decades. However, few patellofemoral patients present with an isolated medial patellofemoral ligament (MPFL) tear. Rather, patients often demonstrate patella alta, increased tibial tubercle to trochlear groove (TT-TG) distance, dysplasia, coronal malalignment, or combinations thereof. Given this, concomitant procedures such as tibial tubercle osteotomy (TTO) have become increasingly popularized, given their ability to anteriorize, medialize, and even distalize the patella to correct tracking. It is generally recommended that concurrent TTO be considered with primary medial patellofemoral ligament reconstruction (MPFLR) in patients with closed physes whose TT-TG distance is larger than 17 to 20 mm. MPFLR + TTO is generally safe and may decrease risk of revision surgery when compared with isolated MPFLR in properly indicated patients. However, it important to measure both knee rotation angle and tibial tubercle lateralization on magnetic resonance imaging, as both factors influence TT-TG. In patients in whom abnormal knee rotation angle is felt to be the primary driver of TT-TG, surgeons should proceed with caution when considering concomitant TTO. The pen may be mightier than the sword, but the osteotome may be mightier yet than the scalpel.


African neurosurgery, the 21st-century challenge.
Two major challenges facing African neurosurgery include quality and quantity, in both recourses and personnel. Discrepancy is noted between the two poles, namely, the north and south of the continent and the sub-Saharan area. Although reasonably advanced in the north and south, neurosurgery remains poorly distributed and has multiple deficiencies. The sub-Saharan region, where the demand is high and services are scarce, suffers from a similar lack of both qualified personnel and well-equipped neurosurgical facilities. Insufficient state funding and research facilities aggravate the situation and discourage the few well-trained African neurosurgeons to practice in their homeland. For those who do return home, cultural, social, economical, and political issues hinder their performance and hence the quality of neurosurgery delivered in Africa. Strategies for rectification of these handicaps are presented, including the need for high-standard local training and support from international organizations.


Total retinal thickness: a neglected factor in the evaluation of inner retinal thickness.
To determine whether macular retinal nerve fibre layer (mRNFL) and ganglion cell-inner plexiform layer (GC-IPL) thicknesses vary by ethnicity after accounting for total retinal thickness. We included healthy participants from the UK Biobank cohort who underwent macula-centred spectral domain-optical coherence tomography scans. mRNFL and GC-IPL thicknesses were determined for groups from different self-reported ethnic backgrounds. Multivariable regression models adjusting for covariables including age, gender, ethnicity and refractive error were built, with and without adjusting for total retinal thickness. 20237 participants were analysed. Prior to accounting for total retinal thickness, mRNFL thickness was on average 0.9 μm (-1.2, -0.6; p<0.001) lower among Asians and 1.5 μm (-2.3, -0.6; p<0.001) lower among black participants compared with white participants. Prior to accounting for total retinal thickness, the average GC-IPL thickness was 1.9 μm (-2.5, -1.4; p<0.001) lower among Asians compared with white participants, and 2.4 μm (-3.9, -1.0; p=0.001) lower among black participants compared with white participants. After accounting for total retinal thickness, the layer thicknesses were not significantly different among ethnic groups. When considered as a proportion of total retinal thickness, mRNFL thickness was ~0.1 and GC-IPL thickness was ~0.2 across age, gender and ethnic groups. The previously reported ethnic differences in layer thickness among groups are likely driven by differences in total retinal thickness. Our results suggest using layer thickness ratio (retinal layer thicknesses/total retinal thickness) rather than absolute thickness values when comparing retinal layer thicknesses across groups.


An imaging evaluation of the simultaneously integrated boost breast radiotherapy technique.
To evaluate in-field megavoltage (MV) imaging of simultaneously integrated boost (SIB) breast fields to determine its feasibility in treatment verification for the SIB breast radiotherapy technique, and to assess whether the current-imaging protocol and treatment margins are sufficient. For nine patients undergoing SIB breast radiotherapy, in-field MV images of the SIB fields were acquired on days that regular treatment verification imaging was performed. The in-field images were matched offline according to the scar wire on digitally reconstructed radiographs. The offline image correction results were then applied to a margin recipe formula to calculate safe margins that account for random and systematic uncertainties in the position of the boost volume when an offline correction protocol has been applied. After offline assessment of the acquired images, 96% were within the tolerance set in the current department-imaging protocol. Retrospectively performing the maximum position deviations on the Eclipse™ treatment planning system demonstrated that the clinical target volume (CTV) boost received a minimum dose difference of 0.4% and a maximum dose difference of 1.4% less than planned. Furthermore, applying our results to the Van Herk margin formula to ensure that 90% of patients receive 95% of the prescribed dose, the calculated CTV margins were comparable to the current departmental procedure used. Based on the in-field boost images acquired and the feasible application of these results to the margin formula the current CTV-planning target volume margins used are appropriate for the accurate treatment of the SIB boost volume without additional imaging.


[Arterial phenomenon of autonomization of vascularized island flaps reviewed by expansion of the vascular pedicle. An experimental study in the rat].
This experimental study performed in rats examined the possible vascular extensions of a periprosthetic membrane neoflap with an axial vascular pedicle towards an adjacent cutaneous angiotome. 22 Wistar rats were operated. After tattooing the superficial iliac circumflex angiotome, the adjacent epigastric pedicle was expanded. After expansion and a two-month rest period, clinical and microangiographic studies were performed. In 50% of cases, the iliac island skin flap raised on the periprosthetic membrane created by the epigastric pedicle was considered to be viable. The microangiographic results were identical. The pathophysiological mechanism is analysed in the light of the literature.


Myelin-associated glycoprotein is the antigen for a monoclonal IgM in polyneuropathy.
Recent studies show that IgM monoclonal antibody from patients with IgM paraproteinemia and peripheral neuropathy reacts with a protein component of human PNS myelin and an analogous component or components of human CNS myelin. We have now demonstrated that the antigen for this antibody is a specific glycoprotein component of myelin, referred to as myelin-associated glycoprotein (MAG). Human PNS and CNS myelin proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis on pore-gradient slabs, and MAG was identified by the immuno-electroblot procedure with rabbit anti-MAG (rat). The identical band(s) were stained by an analogous procedure with patient serum as the first antibody. Human PNS MAG had an apparent molecular weight of 107,000. Human CNS MAG appeared as three bands: 113,000, 107,000, and 92,000. Passage of myelin proteins through a concanavalin A-Sepharose column removed the staining component. Purified patient IgM, added to a lithium diiodosalicylate extract of myelin, immunoprecipitated MAG. This antibody also cross-reacted with MAG from bovine CNS, but not from rabbit, rat, or mouse.


New approaches in pulmonary rehabilitation.
Patients who have mild to severe chronic obstructive pulmonary disease may obtain improvement in dyspnea, exercise capacity, and health-related quality of life as a result of exercise training. The type and intensity of training is of key importance in determining outcomes. High-intensity aerobic training leads to physiologic gains in aerobic fitness. Nevertheless, extreme breathlessness or peripheral muscle fatigue may prevent some patients from performing high-intensity exercise; therefore, new tools are needed to improve the effectiveness of pulmonary rehabilitation.


Grouping with and without attention.
The effects of perceptual grouping on a line discrimination task were investigated using Moore and Egeth's (1997) paradigm. Observers judged which of two lines, presented one above the other over a matrix of spots, was longer. On some trials, larger spots at both ends of the lines formed arrowheads, thereby making possible the Müller-Lyer illusion. When observers attended only to the lines, they were not aware of the arrowheads. Yet their line judgment performance showed that they had succumbed to the illusion. When the observers' attention was directed to the arrowheads but they nevertheless failed to discern the arrowheads' orientation, their line judgments were still influenced by the illusion.


Formation of cartilage in bioprosthetic cardiac valves implanted in sheep: a morphologic study.
Foci of cartilage were found in 12 of 120 bioprostheses implanted in young sheep for 13 to 24 weeks, but in none of 47 bioprostheses implanted for less than 13 weeks. Cartilage was found more frequently (p less than 0.01) in bioprotheses implanted in the tricuspid position than in those implanted in the mitral position. In porcine aortic valvular bioprostheses, the cartilage was preferentially localized in the region of the muscle shelf; in pericardial bioprostheses, it occurred in the fibrous sheaths covering the cusps. In both instances, the cartilage was found to undergo calcification and was considered to be formed by metaplasia of connective tissue cells of host origin.


In-hospital revascularization and one-year outcome of acute coronary syndrome patients stratified by the GRACE risk score.
In the prospective, multicenter Canadian Acute Coronary Syndromes Registry, in-hospital revascularization was independently associated with better 1-year survival only among patients with high-risk non-ST-elevation acute coronary syndromes stratified by the Global Registry of Acute Coronary Events risk score; similar benefits were not observed in the low- and intermediate-risk groups. The Global Registry of Acute Coronary Events risk score appears to be a useful risk stratification tool that identifies high-risk patients for whom more aggressive treatment is warranted.


Preliminary experience with electromagnetic navigation system in TKA.
Accuracy of implant positioning and precise reconstruction of leg alignment offers the best way to achieve good long-term results in total knee arthroplasty. Computer instrumentation was developed to improve the final position of the component and restore the mechanical axis. Current navigation systems use either optical or electromagnetic tracking. The advantage of the Electromagnetic (EM) navigation system is that no line-of-sight issues are present. However, special iron-free instruments are required. This report analyzes the postoperative radiological results of 32 knees treated using an EM system. All the measurements were recorded using software able to subtend angles automatically by five physicians, three radiologist and two orthopedic residents not involved with the surgery. Each radiograph was measured three times, in random order, and at delayed intervals. We found an ideal alignment for the mechanical axis (180+/-3 degrees ) in 30 out of 32 cases, whereas all the patients achieved a value of 90 degrees +/-3 degrees for both femoral and tibial frontal component angles. An apparently over-corrected implant position for the sagittal femoral component was reported, with a mean value of 11.2 degrees +/-3.6. The mean position of the tibial component was 90.6 degrees +/-2.8; just four measurements were outside of the +/-3 degrees of the desired value. EM is safe and there were no complications related to this system. An almost perfect correlation was found between the mechanical axis value of the EM navigation system (179.8 degrees +/-1.8) and the median value of the all reviewers (180.3 degrees +/-1.9) with a difference of 0.5 degrees .


Impact of practicing internal benchmarking on continuous improvement of cataract surgery outcomes: a retrospective observational study at Aravind Eye Hospitals, India.
We aim to assess the effectiveness of a cataract surgery outcome monitoring tool used for continuous quality improvement. The objectives are to study: (1) the quality parameters, (2) the monitoring process followed and (3) the impact on outcomes. In this retrospective observational study we evaluated a quality improvement (QI) method which has been practiced at the focal institution since 2012: internal benchmarking of cataract surgery outcomes (CATQA). We evaluated quality parameters, procedures followed and clinical outcomes. We created tables and line charts to examine trends in key outcomes. Aravind Eye Care System, India. Phacoemulsification surgeries performed on 718 120 eyes at 10 centres (five tertiary and five secondary eye centres) from 2012 to 2020 were included. An internal benchmarking of surgery outcome parameters, to assess variations among the hospitals and compare with the best hospital. Intraoperative complications, unaided visual acuity (VA) at postoperative follow-up visit and residual postoperative refractive error (within ±0.5D). Over the study period the intraoperative complication rate decreased from 1.2% to 0.6%, surgeries with uncorrected VA of 6/12 or better increased from 80.8% to 89.8%, and surgeries with postoperative refractive error within ±0.5D increased from 76.3% to 87.3%. Variability in outcome measures across hospitals declined. Additionally, benchmarking was associated with improvements in facilities, protocols and processes. Internal benchmarking was found to be an effective QI method that enabled the practice of evidence-based management and allowed for harnessing the available information. Continuous improvement in clinical outcomes requires systematic and regular review of results, identifying gaps between hospitals, comparisons with the best hospital and implementing lessons learnt from peers.


A small non-coding RNA of the invasion gene island (SPI-1) represses outer membrane protein synthesis from the Salmonella core genome.
The Salmonella pathogenicity island (SPI-1) encodes approximately 35 proteins involved in assembly of a type III secretion system (T3SS) which endows Salmonella with the ability to invade eukaryotic cells. We have discovered a novel SPI-1 gene, invR, which expresses an abundant small non-coding RNA (sRNA). The invR gene, which we identified in a global search for new Salmonella sRNA genes, is activated by the major SPI-1 transcription factor, HilD, under conditions that favour host cell invasion. The RNA chaperone, Hfq, is essential for the in vivo stability of the approximately 80 nt InvR RNA. Hfq binds InvR with high affinity in vitro, and InvR co-immunoprecipitates with FLAG epitope-tagged Hfq in Salmonella extracts. Surprisingly, deletion/overexpression of invR revealed no phenotype in SPI-1 regulation. In contrast, we find that InvR represses the synthesis of the abundant OmpD porin encoded by the Salmonella core genome. As invR is conserved in the early branching Salmonella bongori, we speculate that porin repression by InvR may have aided successful establishment of the SPI-1 T3SS after horizontal acquisition in the Salmonella lineage. This study identifies the first regulatory RNA of an enterobacterial pathogenicity island, and new roles for Hfq and HilD in SPI-1 gene expression.


Perfusion cooling by pulsatile flow.
Organ temperature changes and the temperature gradient between organs with cooling and rewarming were studied in rabbits using pulsatile flow perfusion. The temperature gradient between organs was within 3 degrees C. At the initial stage of cooling and rewarming, organ temperatures changed rapidly. During circulatory arrest, organ temperatures rose gradually. Brain temperature changes were similar to other organs.


Excision of esophageal duplication cysts with robotic-assisted thoracoscopic surgery.
Esophageal duplication cysts are infrequent anomalies of the gastrointestinal tract that are predominantly found in children. The conventional surgical approach for removal of these cysts is an open surgery one with a posterolateral thoracotomy incision. However, more recently, these cysts have been excised via video-assisted thoracoscopic surgery (VATS). In this article, we present 2 pediatric patients treated with successful excision of an esophageal duplication cyst via robotic-assisted thoracoscopic surgery (RATS) using the da Vinci surgical system. With robotic technology, precise dissection and complete resection of the thoracic mass was achieved without violating the esophageal mucosa. There were no complications, and the patients did not require placement of a postoperative chest tube. Pathological examination of the mass was consistent with an esophageal (foregut) duplication cyst in both cases.


A novel biocatalyst for efficient production of 2-oxo-carboxylates using glycerol as the cost-effective carbon source.
The surplus of glycerol has increased remarkably as a main byproduct during the biofuel's production. Exploiting an alternative route for glycerol utilization is significantly important for sustainability of biofuels. A novel biocatalyst that could be prepared from glycerol for producing 2-oxo-carboxylates was developed. First, Pseudomonas putida KT2440 was reconstructed by deleting lldR to develop a mutant expressing the NAD-independent lactate dehydrogenases (iLDHs) constitutively. Then, the Vitreoscilla hemoglobin (VHb) was heterologously expressed to further improve the biotransformation activity. The reconstructed strain, P. putida KT2440 (ΔlldR)/pBSPPcGm-vgb, exhibited high activities of iLDHs when cultured with glycerol as the carbon source. This cost-effective biocatalyst could efficiently produce pyruvate and 2-oxobutyrate from dl-lactate and dl-2-hydroxybutyrate with high molar conversion rates of 91.9 and 99.8 %, respectively. The process would not only be a promising alternative for the production of 2-oxo-carboxylates, but also be an example for preparation of efficient biocatalysts for the value-added utilization of glycerol.


Involvement of classic and alternative non-homologous end joining pathways in hematologic malignancies: targeting strategies for treatment.
Chromosomal translocations are the main etiological factor of hematologic malignancies. These translocations are generally the consequence of aberrant DNA double-strand break (DSB) repair. DSBs arise either exogenously or endogenously in cells and are repaired by major pathways, including non-homologous end-joining (NHEJ), homologous recombination (HR), and other minor pathways such as alternative end-joining (A-EJ). Therefore, defective NHEJ, HR, or A-EJ pathways force hematopoietic cells toward tumorigenesis. As some components of these repair pathways are overactivated in various tumor entities, targeting these pathways in cancer cells can sensitize them, especially resistant clones, to radiation or chemotherapy agents. However, targeted therapy-based studies are currently underway in this area, and furtherly there are some biological pitfalls, clinical issues, and limitations related to these targeted therapies, which need to be considered. This review aimed to investigate the alteration of DNA repair elements of C-NHEJ and A-EJ in hematologic malignancies and evaluate the potential targeted therapies against these pathways.


Laser-Induced Neocollagenesis in Focal Dermal Hypoplasia Associated With Goltz Syndrome in a Girl.
Current models of Goltz syndrome cannot estimate the overall neocollagenesis and marked shift in collagen types after ablative fractional laser resurfacing (AFR) within treated areas of focal dermal hypoplasia (FDH). To clinically improve FDH by using AFR to characterize the specific ratio of collagen types associated with observed clinical changes. This case report of a girl with Goltz syndrome used extensive laboratory evaluation and multiple observers blinded to the patient's clinical status. Serial samples of clinically unaffected skin constituted internal control specimens, with clinical and histologic evaluations performed as part of a multicenter investigation. The analysis tested the hypothesis that thermal microtrauma caused by AFR created a unique environment that activated latent genes, inducing neocollagenesis and allowing the patient to adaptively produce the collagen subtype that was specifically deficient at baseline. Two AFR treatments were administered within an area of FDH. Histologic comparison of the pretreatment and posttreatment skin was performed using serial internal controls. Histologic changes, including Herovici collagen staining to differentiate between types I and III collagen, within a treated area of mosaically affected FDH compared with clinically unaffected skin. This female patient presented in the second decade of life with self-described red, itchy skin within a large plaque of FDH on her left posterior thigh and calf. After AFR, skin tightening and symptomatic relief were reported. Histologic findings demonstrated objective thickening of the dermal collagen. A marked shift in collagen predominance from type III (fetal/early wound) to type I (adult/mature) was observed. Although further study is needed, this report shows promising results and raises important questions about gene expression and the epigenetics of Goltz syndrome-associated mutations and the local effects of AFR. Coupled with more rigorous investigation, this novel technique may help reveal molecular workarounds permitting innovative therapies that take advantage of the subtly different collagens that exist within the skin.


Genetic Studies on Polycystic Ovary Syndrome.
Polycystic ovary syndrome (PCOS) is a highly heterogeneous reproductive system disorder of which the aetiology is not fully understood. Previous association studies have been conducted on >100 candidate genes, which principally related to reproductive hormones, cellular metabolism and chronic inflammation. Heritable tendencies have long been recognized for pathogeneses of PCOS, and recently a genome-wide association study (GWAS) in PCOS provides new clues to understand the genetic components and pathways in PCOS physiology. However, the current knowledge of the pathogenesis of PCOS is still in its infancy. Further studies using new technologies such as next-generation sequencing (NGS) shall be useful to understand more causal variants for PCOS.


Risdiplam treatment has not led to retinal toxicity in patients with spinal muscular atrophy.
Evaluation of ophthalmologic safety with focus on retinal safety in patients with spinal muscular atrophy (SMA) treated with risdiplam (EVRYSDI®), a survival of motor neuron 2 splicing modifier associated with retinal toxicity in monkeys. Risdiplam was approved recently for the treatment of patients with SMA, aged ≥ 2 months in the United States, and is currently under Health Authority review in the EU. Subjects included patients with SMA aged 2 months-60 years enrolled in the FIREFISH, SUNFISH, and JEWELFISH clinical trials for risdiplam. Ophthalmologic assessments, including functional assessments (age-appropriate visual acuity and visual field) and imaging (spectral domain optical coherence tomography [SD-OCT], fundus photography, and fundus autofluorescence [FAF]), were conducted at baseline and every 2-6 months depending on study and assessment. SD-OCT, FAF, fundus photography, and threshold perimetry were evaluated by an independent, masked reading center. Adverse events (AEs) were reported throughout the study. A total of 245 patients receiving risdiplam were assessed. Comprehensive, high-quality, ophthalmologic monitoring assessing retinal structure and visual function showed no retinal structural or functional changes. In the youngest patients, SD-OCT findings of normal retinal maturation were observed. AEs involving eye disorders were not suggestive of risdiplam-induced toxicity and resolved with ongoing treatment. Extensive ophthalmologic monitoring conducted in studies in patients with SMA confirmed that risdiplam does not induce ophthalmologic toxicity in pediatric or adult patients with SMA at the therapeutic dose. These results suggest that safety ophthalmologic monitoring is not needed in patients receiving risdiplam, as also reflected in the United States Prescribing Information for risdiplam.


Patterns of neuronal loss in the cerebral cortex in chronic alcoholic patients.
A loss of neurones from the frontal cortex of chronic alcoholic patients has recently been documented. In addition to this loss of neurones there was found to be a reduction in the mean size of the neuronal soma in both the superior frontal and motor cortices. This could be explained on the basis of a selective loss of larger neurones rather than a general shrinkage of all neurones. This population of large neurones (greater than 90 microns 2) has been recognised as being more vulnerable in both Alzheimer's disease and the normal ageing process. Neurones in 2 size categories (41-90 microns 2 and greater than 90 microns 2) were counted in the superior frontal and motor cortices of age- and sex-matched controls and alcoholics. There was found to be a significant reduction in the number of large neurones in the superior frontal cortex, whilst no change in number was seen in the motor cortex. The possibility that neurones in particular layers of the cortex are more severely affected in alcohol abuse was also considered. The cortex was divided into 3 layers and the number of neurones and glia in each determined. No pattern of regional neuronal loss could be distinguished.


The involvement of orbitofrontal cerebrum in cognitive tasks.
Although the frontal lobes are frequently associated with high-level cognitive functions, patients with significant frontal damage often maintain normal "intelligence". While recent research has clarified some aspects of this enigma, specific questions remain concerning the nature of the deficit in these patients and its relation to lesion localization within the frontal lobes. A group of psychiatric patients who had undergone prefrontal leucotomy 25 years earlier and whose frontal lesions were bilateral and maximal orbitofrontally were evaluated. Sixteen leucotomized schizophrenics, divided into three groups based upon recovery after psychosurgery, were compared to two control groups: (1) non-leucotomized chronic schizophrenics; (2) normal subjects. Four tests were administered: Wechsler Adult Intelligence Scale, Wisconsin Card Sorting test, Visual Metaphor test, and the Visual Verbal test of abstraction. The results suggest that orbitofrontal pathology does cause impaired performance on certain cognitive tests, which appeared independent of IQ measures.


The oracle of Delphi 2.0: considering artificial intelligence as a challenging tool for the treatment of eating disorders.
In this editorial, we discuss how the diffusion of Artificial Intelligence (AI)-based tools-such as the recently available conversational AIs-could impact and transform eating disorders (EDs) care. We try to envision the possible use of AI by individuals affected by EDs and by clinicians, in terms of prevention, support to treatment, and development of new and actually personalized treatment strategies. We then focus on how the introduction of AI into psychotherapy could either represent an element of disruption for the therapeutical relationship or be positively and creatively integrated into session and inter-sessional dynamics. As technological advancements open scenarios where anyone could have access to a personal and all-knowing "oracle", the ability to formulate questions, individuals' experiences, and the scientific rigor with which clinicians study them must remain at the center of our work. Ethical and legal issues about the use of AI are also considered.


Development of activity-based probes for the protein deacylase Sirt1.
Sirtuins are NAD+-dependent protein deacylases that remove acyl modifications from acyl-lysine residues, resulting in essential cellular signaling. Recognized for their role in lifespan extension, humans encode seven sirtuin isoforms (Sirt1-7), and loss of sirtuin deacylase activity is implicated in many aging-related diseases. Despite being intriguing therapeutic targets, cellular studies of sirtuins are hampered by the lack of chemical probes to measure sirtuin activity independent of sirtuin protein levels. Here, we use a modular, peptide-based approach to develop activity-based probes (ABPs) that directly measure Sirt1 activity in vitro and in cell lysates. ABPs were synthesized containing four elements: (1) thioacetyl-lysine for mechanism-based affinity towards only active sirtuins, (2) either histone H3 lysine-14 (H3K14) or p53 sequences for Sirt1 specificity, (3) a diazirine for covalent labeling upon UV irradiation, and (4) an alkyne for bioorthogonal conjugation to a fluorophore for gel-based detection of active Sirt1. Compared to the H3K14 ABP, the p53 ABP showed increased sensitivity and selective labeling of active Sirt1. Acyl-lysine peptide competition, pharmacological inhibition, and inhibitory post-translational modification of Sirt1 resulted in the loss of p53 ABP labeling both in vitro and in HEK293T cell lysates, consistent with the ABP measuring decreased Sirt1 activity. Furthermore, the p53 ABP measured subcellular Sirt1 activity in MCF7 breast cancer cells. The development of a Sirt1-selective ABP that detects Sirt1 activity with an order of magnitude increased sensitivity compared to previous approaches demonstrates the utility of a modular, peptide-based approach for selective-targeting of the sirtuin protein family and provides a framework for further development of sirtuin-selective chemical probes.


Stereological analysis of three-dimensional structure organization of surfaces in multiphase specimens: statistical methods and model-inferences.
In a multiphase material the structural components or phases are everywhere in contact with each other. The relative area of surface contact between various phases is an important aspect of the short-range ordering or organization of the structure. The stereological quantitation of such specific interfaces is a simple and well-known technique. The proper statistical definition of realistic models for the frequency of contact and the quantitative estimation of phase-specific affinities is studied. The meaningful interpretation of sets of estimated affinities poses a major problem of statistical inference which is dealt with in detail and illustrated by a worked-out biological example.


Serum-sickness-like disease is a common cause of acute arthritis in children.
Among 283 children in a prospective study of arthritis we found 15 patients with a self-limited serum-sickness-like disease consisting of urticaria or joint erythema and mostly polyarticular arthritis. The mean duration of joint symptoms was 5.9 days. A preceding infection was reported in 12 patients and 12 had received drugs, the therapy starting on average 12.8 days before the onset of joint symptoms. In 9 cases the drug was penicillin. Four patients had recurrent attacks. Circulating immune complexes were detected in the serum of 12 patients, but specific IgE antibodies to penicillin only in 3 patients. The estimated annual incidence of the condition was 4.7/100,000 children under age 16.


Retracted: The Impact of Tax Reduction and Fee Reduction Based on Big Data Algorithm on the High-Quality Development of the Real Economy under the Action of Coupling Effect or Substitution Effect.
[This retracts the article DOI: 10.1155/2022/2828687.].


De novo brain arteriovenous malformation after tumor resection: case report and literature review.
The congenital origin of brain arteriovenous malformations (bAVMs) has been increasingly challenged by reports of de novo bAVMs in patients previously confirmed to have no vascular malformation. We describe the oldest patient reported in the English language literature harboring a de novo bAVM. An uneventful frontal convexity meningioma resection was performed for a 60-year-old woman, and at 67 years of age, a bAVM was detected by MRI and confirmed by digital subtraction angiography at the site of the previous meningioma resection. This case adds to the growing literature that the etiology of bAVMs is most likely multifactorial.


Evaluative conditioning is a qualitatively distinct form of classical conditioning: a reply to Davey (1994).
Based on a critical review of the literature, Davey (1994) [Behaviour Research and Therapy, 32, 291-299] concludes that there is no sufficient evidence to support the theoretical position that evaluative conditioning is a qualitatively different form of classical conditioning. In the present manuscript, we will try to show that Davey's conclusion is biased by: (a) an overemphasis on what he believes to be problematic procedural aspects of previous evaluative conditioning studies; and (b) a selective reading of the available evidence. Finally, an attempt is made to characterize evaluative conditioning phenomena as the output of a Referential Learning System, which can be distinguished from an Expectancy Learning System.


Care burden and depression in caregivers caring for patients with intractable neurological diseases at home in Japan.
The aims of this study are to describe the care burden on caregivers of individuals with intractable neurological diseases and to clarify the prevalence of depression in caregivers and factors related to the presence of depression. A cross-sectional survey was conducted among caregivers who provide home care to patients with neurological diseases such as Parkinson disease (PD), spinocerebellar degeneration (SCD), multiple system atrophy (MSA), and amyotrophic lateral sclerosis (ALS), using a mailed, self-administered questionnaire. We used the Burden Index of Caregivers to measure multi-dimensional care burden and the Center for Epidemiologic Studies Depression scale to determine the presence of depression among caregivers. A total of 418 questionnaires were analyzed. Although several domains of care burden for caregivers were significantly different among the four diseases, the intensity of caregiving and hours spent caregiving were the main definitive variables. In addition, we described different aspects of the care burden using the multi-dimensional care burden scale. The prevalence of depression in caregivers was high (PD, 46%; SCD, 42%; MSA, 63%; ALS, 61%). Hours required for close supervision of the patient (P=0.015), intensity of caregiving (P=0.024), and low household income (P=0.013) were independently-related variables for depression in caregivers. The care burden of caregivers was mainly explained by the intensity of caregiving and hours spent caregiving per day, not only according to the disease. The high prevalence of depression indicates the need for effective interventions, especially for caregivers of patients with MSA and ALS.


Metabolic and morphological changes of the heart in Chinese hamsters (CHAD strain) with spontaneous long-term diabetes.
We studied the effect of spontaneous long-term (9-10 months) diabetes on the heart of Chinese hamsters (CHAD strain) to elucidate the relationship between diabetes mellitus and cardiomyopathy. The diabetic hamsters, aged approximately 11 months, showed body weight loss, hyperglycemia (mean fasting plasma glucose 402 mg/dl), hypoinsulinemia, hyperlipidemia and ketonemia. The diabetic hamsters showed reduced activities of cytoplasmic glycolytic key enzymes; hexokinase, pyruvate kinase and phosphofructokinase, increases in cardiac glycogen and glucose-6-phosphate contents and a 40% decrease in cardiac ATP content, indicating decreased energy production. An accumulation of myocardial triglyceride and cholesterol was found in the diabetic hamsters. In addition, the cardiac norepinephrine content was increased in the diabetic hamsters, suggesting the presence of autonomic nervous disorder. Increased heart weight and thickening of the septum and both ventricular walls were found in the diabetic hamsters. Light-microscopic analysis revealed that 42.9% of the diabetic hamsters had myocardial degeneration without any vascular lesion of extramural large and intramural small vessels, whereas the non-diabetic controls had no myocardial or vascular lesions. These data suggest that the diabetic Chinese hamsters had cardiomyopathy, which is possibly caused by extravascular factors such as metabolic or autonomic nervous disorder although conclusive evidence is lacking.


[Short-term antibiotic prophylaxis with ceftriaxone in general surgery].
The authors report their own experience on the efficacy of a short term antimicrobial prophylaxis involving a long-acting cephalosporin, ceftriaxone (Rocefin), in surgical patients. A study was carried out to evaluate the efficacy of a single dose of 1 or 2 g by i.v. administered 1 h. before elective surgery. 100 patients were admitted to study. Therapeutic success was achieved in 92 cases (92%).


Amino acid incorporation in a cell-free system derived from rat liver studied with the aid of selenodiglutathione.
Selenodiglutathione (GSSeSG), a potent inhibitor of elongation factor 2 (EF2) has been used to study amino acid incorporation in a rat liver cell-free system. While translocation of the ribosomes was inhibited by GSSeSG, ribosomes with a free acceptor site were still capable of incorporating one amino acid residue. From this the average number of amino acids incorporated per ribosomes was calculated to be 2--5. In this respect virtually no difference has been observed between ribosomes present on small or large aggregates. The time required for one translocation by all active ribosomes, and the time required for the incorporation of one amino acid (starting with aminoacyl-tRNA or amino acids) has also been determined. By incubation under conditions for amino acid incorporation, part of the ribosomes were completely inactivated whereas the rest remained as active as at the start of the incubation.


High Frequency Acceleration: A New Tool for Alveolar Bone Regeneration.
A common problem in clinical dentistry is the significant and rapid bone loss that occurs after periodontitis, osteoporosis, tooth extractions, lack of function, or any other pathologic condition that target the alveolar bone. Currently there is no stable solution for the long-term preservation or rehabilitation of alveolar bone. In this article, we review the latest concepts on bone response to mechanical stimulation, and summarize the results of our studies on the effect of high frequency acceleration (HFA) on healthy alveolar bone and on healing alveolar bone after extractions. In both studies, we used adult Sprague Dawley rats to test the response of alveolar bone to different frequencies and accelerations applied to the maxillary molars. Once we determined which parameters of HFA induced a higher osteogenic response, we tested the effect of this mechanical stimulation during bone healing after molar extraction. Our studies strongly show that HFA can stimulate bone formation in the healthy alveolar bone surrounding the tooth/point of application as well as the distant bone surrounding the neighboring teeth. When HFA was applied to the second molar, after extraction of the third molar, it accelerated bone healing and prevented alveolar bone resorption in and around the extraction socket. HFA is a noninvasive safe treatment that can be used to prevent alveolar bone loss, accelerate bone healing and to improve the quality and quantity of alveolar bone under both physiological and pathological conditions.


Impact of chronic comorbidities on hospitalization, intensive care unit admission and death among adult vaccinated and unvaccinated COVID-19 confirmed cases during the Omicron wave.
Comorbidities are important risk factors of severe COVID-19 complications. Their impact during the Omicron wave among vaccinated and unvaccinated COVID-19 cases is not well documented. The objective of this study was to estimate the association between the number of comorbidities and the risk of hospitalization, intensive care unit (ICU) admission, and death among vaccinated and unvaccinated confirmed adult COVID-19 cases during the Omicron wave. We performed a cohort study of COVID-19 adult cases of primo-infection occurring during the Omicron wave, from December 5, 2021 to January 9, 2022 using surveillance database of the province of Québec, Canada. The database included all laboratory-confirmed cases in the province and the related information on 21 pre-existing comorbidities, hospitalization, ICU admission, death related to COVID-19 and vaccination status. We performed a robust Poisson regression model to estimate the impact of the number of comorbidities on each complication by vaccination status adjusted for age, sex, socioeconomic status, and living environment. We observed that the risk of complication increased for each additional comorbidity in both vaccinated and unvaccinated individuals and that this risk was systematically higher among unvaccinated individuals. Compared with vaccinated individuals without comorbidities (reference group), the risks of hospitalization, ICU admission, and death were respectively: 9X (95% CI [7.77-12.01]), 13X (95% CI [8.74-18.87]), and 12X (95% CI [7.57-18.91]) higher in vaccinated individuals with ≥3 comorbidities; 22X (95% CI [19.07-25.95]), 45X (95% CI [29.06-69.67]) and 38X (95% CI [23.62-61.14]) higher in unvaccinated individuals with ≥3 comorbidities. Our results support the importance of promoting vaccination in all individuals, and especially those with pre-existing medical conditions, to reduce severe complications, even during the Omicron wave.


Phase I clinical trial of parenteral hydroxyurea in combination with pelvic and para-aortic external radiation and brachytherapy for patients with advanced squamous cell cancer of the uterine cervix.
Oral hydroxyurea (HU) is a potent radiation sensitizer, but in vitro studies have suggested that prolonged exposure to HU by way of continuous parenteral infusion would enhance clinical efficacy. The objective of this study was to determine the maximal tolerated dose and identify the toxicities of continuous infusion HU in combination with pelvic and para-aortic external beam radiotherapy (RT) and intrauterine brachytherapy in patients with locally advanced carcinoma of the uterine cervix. This Phase I study of concomitant RT was designed with an escalating dose schedule of HU administered by continuous infusion. HU was administered parenterally as a continuous infusion, 5 d/wk, during the first 21 days of external radiation, during the final 5 days of external beam RT, followed by another 5-day infusion schedule bracketing the single fraction of brachytherapy. The maximal tolerated dose was defined as the highest dose level at which 3 of 3 or 5 of 6 patients could be treated without dose-limiting toxicity. At dose level 1 (0.25 mg/m(2)/min), 0 of 4 patients experienced Grade 4 toxicities and 2 patients experienced Grade 3 hematologic toxicities that were not considered dose-limiting. One of the first 4 patients at level 2 (0.375 mg/m(2)/min) had Grade 3 diarrhea, but the 3 subsequent patients tolerated the dose. At level 3 (0.5 mg/m(2)/min), 4 of 5 patients failed to complete therapy without a >7-day interruption in HU. The maximal tolerated dose of parenteral HU was 0.375 mg/m(2)/min when administered with concomitant RT. The most common toxicities were hematologic. A new trial, incorporating concurrent cisplatin, HU, and RT is planned.


Effects of a Robot-Assisted Arm Training Plus Hand Functional Electrical Stimulation on Recovery After Stroke: A Randomized Clinical Trial.
To compare the effects of unilateral, proximal arm robot-assisted therapy combined with hand functional electrical stimulation with intensive conventional therapy for restoring arm function in survivors of subacute stroke. This was a single-blinded, randomized controlled trial. Inpatient rehabilitation university hospital. Patients (N=40) diagnosed as having ischemic stroke (time since stroke <8wk) and upper limb impairment were enrolled. Participants randomized to the experimental group received 30 sessions (5 sessions/wk) of robot-assisted arm therapy and hand functional electrical stimulation (RAT+FES). Participants randomized to the control group received a time-matched intensive conventional therapy. The primary outcome was arm motor recovery measured with the Fugl-Meyer Motor Assessment. Secondary outcomes included motor function, arm spasticity, and activities of daily living. Measurements were performed at baseline, after 3 weeks, at the end of treatment, and at 6-month follow-up. Presence of motor evoked potentials (MEPs) was also measured at baseline. Both groups significantly improved all outcome measures except for spasticity without differences between groups. Patients with moderate impairment and presence of MEPs who underwent early rehabilitation (<30d post stroke) demonstrated the greatest clinical improvements. RAT+FES was no more effective than intensive conventional arm training. However, at the same level of arm impairment and corticospinal tract integrity, it induced a higher level of arm recovery.


Dominant role of local dipolar interactions in phosphate binding to a receptor cleft with an electronegative charge surface: equilibrium, kinetic, and crystallographic studies.
Stringent specificity and complementarity between the receptor, a periplasmic phosphate-binding protein (PBP) with a two-domain structure, and the completely buried and dehydrated phosphate are achieved by hydrogen bonding or dipolar interactions. We recently found that the surface charge potential of the cleft between the two domains that contains the anion binding site is intensely electronegative. This novel finding prompted the study reported here of the effect of ionic strength on the equilibrium and rapid kinetics of phosphate binding. To facilitate this study, Ala197, located on the edge of the cleft, was replaced by a Trp residue (A197W PBP) to generate a fluorescence reporter group. The A197W PBP-phosphate complex retains wild-type Kd and X-ray structure beyond the replacement residue. The Kd (0.18 microM) at no salt is increased by 20-fold at greater than 0.30 M NaCl. Stopped-flow fluorescence kinetic studies indicate a two-step binding process: (1) The phosphate (L) binds, at near diffusion-controlled rate, to the open cleft form (Po) of PBP to produce an intermediate, PoL. This rate decreases with increasing ionic strength. (2) The intermediate isomerizes to the closed-conformation form, PcL. The results indicate that the high specificity, affinity, and rate of phosphate binding are not influenced by the noncomplementary electronegative surface potential of the cleft. That binding depends almost entirely on local dipolar interactions with the receptor has important ramification in electrostatic interactions in protein structures and in ligand recognition.


Intermittent fasting associated with aerobic exercise improves oxidative parameters and causes muscle damage without compromising the performance of Wistar rats.
The aim of this study was to` investigate the effects of intermittent fasting (IF) and the possible association with aerobic exercise on performance, oxidative, biochemical, and somatic parameters of Wistar rats. Forty rats were randomized into the following groups: sedentary (SC) and trained (TC) controls, sedentary intermittent fasting (SIF), and trained intermittent fasting (TIF). The rats were subjected to IF for 15 h every day and aerobic exercise lasting 30 min, five times a week, at a speed of 15 m/min for 4 wk. Performance tests were performed at the beginning and end of the protocol. Glucose and insulin tolerance, somatic parameters, lipidogram, leptin, insulin, malondialdehyde, antioxidant capacity, C-reactive protein, alpha acid glycoprotein, creatine kinase, lactate dehydrogenase, and muscle histology were analyzed. The trained groups had similar performance and significantly improved performance at the end of the experiment. TIF showed lower body weight (-16 g), lean mass (22.49%), homeostatic model assessment for insulin resistance (29%), and lactate dehydrogenase (48%), and higher malondialdehyde (53%) and antioxidant capacity (75%) than the TC group. The SIF and TIF groups showed a fiber area reduction and positivity marking for tumor necrosis factor-α in the muscles. Although IF associated with aerobic exercise improved antioxidant capacity caused damage to muscle fibers and lean mass loss, it did not change the performance of the rats.


Engineering Electrodes with Robust Conducting Hydrogel Coating for Neural Recording and Modulation.
Coating conventional metallic electrodes with conducting polymers has enabled the essential characteristics required for bioelectronics, such as biocompatibility, electrical conductivity, mechanical compliance, and the capacity for structural and chemical functionalization of the bioelectrodes. However, the fragile interface between the conducting polymer and the electrode in wet physiological environment greatly limits their utility and reliability. Here, a general yet reliable strategy to seamlessly interface conventional electrodes with conducting hydrogel coatings is established, featuring tissue-like modulus, highly-desirable electrochemical properties, robust interface, and long-term reliability. Numerical modeling reveals the role of toughening mechanism, synergy of covalent anchorage of long-chain polymers, and chemical cross-linking, in improving the long-term robustness of the interface. Through in vivo implantation in freely-moving mouse models, it is shown that stable electrophysiological recording can be achieved, while the conducting hydrogel-electrode interface remains robust during the long-term low-voltage electrical stimulation. This simple yet versatile design strategy addresses the long-standing technical challenges in functional bioelectrode engineering, and opens up new avenues for the next-generation diagnostic brain-machine interfaces.


Density of imaginary multiplicative chaos via Malliavin calculus.
We consider the imaginary Gaussian multiplicative chaos, i.e. the complex Wick exponential μ β : = : e i β Γ ( x ) : for a log-correlated Gaussian field Γ in d ≥ 1 dimensions. We prove a basic density result, showing that for any nonzero continuous test function f, the complex-valued random variable μ β ( f ) has a smooth density w.r.t. the Lebesgue measure on C . As a corollary, we deduce that the negative moments of imaginary chaos on the unit circle do not correspond to the analytic continuation of the Fyodorov-Bouchaud formula, even when well-defined. Somewhat surprisingly, basic density results are not easy to prove for imaginary chaos and one of the main contributions of the article is introducing Malliavin calculus to the study of (complex) multiplicative chaos. To apply Malliavin calculus to imaginary chaos, we develop a new decomposition theorem for non-degenerate log-correlated fields via a small detour to operator theory, and obtain small ball probabilities for Sobolev norms of imaginary chaos.


miR-423-3p activates FAK signaling pathway to drive EMT process and tumor growth in lung adenocarcinoma through targeting CYBRD1.
Lung adenocarcinoma (LUAD) is a malignant tumor with a high fatality rate and poor overall survival, while molecular targets diagnosing and alleviating lung cancer remain inadequate. In this article, we highlighted the upregulation of microRNA-423-3p (miR-423-3p) in LUAD, especially in smokers aged over 40, and revealed that the high expression of miR-423-3p was significantly associated with smoker, age, and pathologic stage of LUAD patients. Moreover, overexpressing miR-423-3p could facilitate LUAD cell proliferation, invasion, adhesion, and epithelial-mesenchymal transition (EMT) process, while depleted miR-423-3p caused repressive influence upon it. Mechanically, we identified that miR-423-3p could activate FAK signaling pathway through binding to the 3'-UTR of cytochrome B reductase 1 (CYBRD1). Furthermore, we demonstrated that CYBRD1 was lowly expressed in LUAD, and miR-423-3p overexpression could rescue the impairment of LUAD cell proliferation, invasion, adhesion, and EMT caused by CYBRD1 depletion. Noticeably, miR-423-3p depletion efficiently hindered LUAD tumor growth in vivo. Collectively, our findings demonstrated that miR-423-3p/CYBRD1 axis could be regarded as a promising biomarker to alleviate the poor LUAD prognosis.


Effect of dermorphin and morphine on the sympathetic and cardiovascular system of the pithed rat.
Dermorphin is a recently discovered opioid peptide which is unique in having a D-amino acid in its sequence. Dermorphin binding sites have been shown in central and peripheral organs and central administered dermorphin produces profound autonomic responses. The purpose of this study was to examine the effect of intravenous dermorphin on heart rate and blood pressure of the pithed rat in basal condition and in response to controlled sympathetic stimulation. Also, since dermorphin is a selective mu-receptor agonist, its effects were compared to morphine, an opiate selective for mu receptors. Dermorphin (0.0001-10 mumol/kg, i.v) or morphine (1-10 mg/kg) had no effect on basal heart rate or blood pressure and failed to modify sympatho-adreno-medullary evoked pressor and tachycardic responses. Furthermore, dermorphin or morphine did not affect the increase in plasma norepinephrine and epinephrine in response to spinal cord stimulation. It is concluded that the dermorphin and morphine have no direct peripheral effects on heart rate or blood vessel tone nor do these mu-receptor agonists have any effect on norepinephrine and epinephrine release from the sympathetic nerves and the adrenal medulla in the rat.


Circulating adiponectin and carotid intima-media thickness: A systematic review and meta-analysis.
Adiponectin (APN) is an adipokine with insulin-sensitizing, anti-inflammatory, and vasculoprotective properties. Hypoadiponectinemia has been linked with disease states, such as obesity, type 2 diabetes, and cardiovascular disease. Carotid intima-media thickness (cIMT) is a strong and independent predictor of both coronary and cerebrovascular events, and has been used as a surrogate marker of subclinical atherosclerosis. The aim of this report is to systematically review the evidence on the relationship between APN and cIMT in a wide range of individuals. Medline, Embase, Biosis, Scopus, Web of Science, and Pubmed were searched for published studies and conference abstracts. The "sign test" and "vote count" methods were used to estimate the direction and significance of the relationship between APN and cIMT. The quality of the eligible studies was evaluated using an adapted version of the New Castle Ottawa quality assessment scale. Fifty-five articles fulfilled the inclusion criteria, comprised of only cross-sectional studies, including healthy subjects, general population, and individuals with metabolic, inflammatory, or other chronic diseases. Most associations between APN and cIMT followed a negative direction in the healthier and general populations, and also in cohorts with metabolic disorders and other chronic diseases, but not in those with inflammatory diseases (sign test). These associations were generally found to be weak or non-significant among all cohort groups studied (vote count). Our results are suggestive but not conclusive for an inverse association between APN levels and cIMT in diseased and non-diseased populations.


Early pain after laparoscopic inguinal hernia repair. A qualitative systematic review.
Early post-operative pain after laparoscopic groin hernia repair may, as in other laparoscopic operations, have its own individual pain pattern and patient-related predictors of early pain. The purpose of this review was to characterise pain within the first post-operative week after transabdominal pre-peritoneal repair (TAPP) and total extraperitoneal repair (TEP), and to identify patient-related predictors of early pain. A qualitative systematic review was conducted. Pubmed, Embase, CINAHL, and the Cochrane database were searched for studies on early pain (first week) after TAPP or TEP. We included 71 eligible studies with 14,023 patients. Post-operative pain is most severe on day 0 and mainly on a level of 13-58 mm on a visual analogue scale and decreases to low levels on day 3. There seems to be no difference in pain intensity and duration when TEP and TAPP are compared. Deep abdominal pain (i.e. groin pain/visceral pain) dominates over superficial pain (i.e. somatic pain) and shoulder pain (i.e. referred pain) after TAPP. Predictors of early pain are young age and pre-operative high pain response to experimental heat stimulation. Furthermore, evidence supported early pain intensity as a predictive risk factor of chronic pain after laparoscopic groin hernia repair. Early pain within the first week after TAPP and TEP is most severe on the first post-operative day, and the pain pattern is dominated by deep abdominal pain. Early post-operative pain is most intense in younger patients and can be predicted by pre-operative high pain response to experimental heat stimulation.


Spiculated periosteal response induced by intraosseous injection of 22Rv1 prostate cancer cells resembles subset of bone metastases in prostate cancer patients.
Prostate cancer bone metastasis is distinguished by the predominance of osteoblastic lesions. This phenotype has been difficult to reproduce in animal models. Here, we describe a model utilizing the 22Rv1 human prostate cancer cell line that generates osteolytic lesions and a prominent spiculated periosteal osteoblastic response following intraosseous injection in scid mice. We injected 22Rv1-luciferase prostate cancer cells directly into the tibiae of C.B-17 scid mice. We analyzed tumor growth and pathology every 2 weeks using radiographic and histologic techniques. X-ray analysis revealed that 22Rv1 tumors elicit a mixed-type lesion including some osteolysis and a robust induction of periosteal bone formation, in contrast to PC3M-luciferase intraosseous tumors which induce only extensive osteolysis. Micro-computerized tomographic imaging shows that 22Rv1 tumors exhibit both osteolytic and osteoblastic features which become apparent between 4 and 6 weeks post injection. There is initial disruption of the cortex and corresponding invasion of the periosteum which is associated with a vigorous osteoblastic response. Histological analysis of late stage tumors shows that the tumor has grown outside of the medullary cavity and surrounds the tibia underneath the periosteum and intermixed with spicules of woven bone which is detected in the radiographic analysis. The overall pattern of this model is suggestive of clinical cases of prostate cancer metastasis in which periosteal responses are noted, often in association with rapidly progressive disease. We expect that intraosseous injection of 22Rv1 cells will provide a new experimental model for the study of osteoblastic prostate cancer metastasis.


Cerebral ventricles are smaller in Hispanic than non-Hispanic patients with Alzheimer's disease.
MRI scans were compared between 71 Hispanic and 73 white non-Hispanic patients with National Institute of Neurological Disorders and Stroke probable AD. Analysis of covariance controlled for age, sex, education, and Mini-Mental State Examination scores indicated that ventricular size was smaller in Hispanic than white non-Hispanic patients (p = 0.0003). There was no difference in cortical atrophy and T2-weighted white matter hyperintense signals between groups.


NADPH Selective Depletion Nanomedicine-Mediated Radio-Immunometabolism Regulation for Strengthening Anti-PDL1 Therapy against TNBC.
Anti-PD(L)1 immunotherapy recently arises as an effective treatment against triple-negative breast cancer (TNBC) but is only applicable to a small portion of TNBC patients due to the low PD-L1 expression and the immunosuppressive tumor microenvironment (TME). To address these challenges, a multifunctional "drug-like" copolymer that possesses the auto-changeable upper critical solution temperature and the capacity of scavenging reduced nicotinamide adenine dinucleotide phosphate (NADPH) inside tumor cells is synthesized and employed to develop a hypoxia-targeted and BMS202 (small molecule antagonist of PD-1/PD-L1 interactions)-loaded nanomedicine (BMS202@HZP NPs), combining the anti-PD-L1 therapy and the low-dose radiotherapy (LDRT) against TNBC. In addition to the controlled release of BMS202 in the hypoxic TNBC, BMS202@HZP NPs benefit the LDRT by upregulating the pentose phosphate pathway (PPP, the primary cellular source for NADPH) of TME whereas scavenging the NADPH inside tumor cells. As a result, the BMS202@HZP NPs-mediated LDRT upregulate the PD-L1 expression of tumor to promote anti-PD-L1 therapy response while reprogramming the immunometabolism of TME to alleviate its immunosuppression. This innovative nanomedicine-mediated radio-immunometabolism regulation provides a promising strategy to reinforce the anti-PD-L1 therapy against TNBC.


C-wave versus electrooculogram in diseases of the retinal pigment epithelium.
The c-wave and the electrooculogram (EOG) are retinal potentials predominantly generated by the pigment epithelium. In most diseases both parameters show a parallel decrease in amplitude. However, in patients with dominant drusen, and cone dystrophies, and in clinically nonaffected members of families suffering from vitelliform macula degeneration, the EOG is close to normal whereas the c-wave shows a reduced amplitude. These findings suggest a higher sensitivity of the generators of the c-wave compared with those responsible for the EOG. Thus the direct current electroretinogram provides additional diagnostic information.


Monte Carlo simulation of a beta particle detector for food samples.
The accident at the Fukushima Daiichi Nuclear Power Plant in March 2011 released radionuclides into the environment. There is concern that (90)Sr will be concentrated in seafood. To measure the activities of (90)Sr in a short time without chemical processes, we have designed a new detector for measuring activity that obtains count rates using 10 layers of proportional counters that are separated by walls that absorb beta particles. Monte Carlo simulations were performed to confirm that its design is appropriate.


Variability in emotional/behavioral problems in boys with oppositional defiant disorder or conduct disorder: the role of arousal.
It is often reported that children with oppositional defiant disorder (ODD) or conduct disorder (CD) are under-aroused. However, the evidence is mixed, with some children with ODD/CD displaying high arousal. This has led to the hypothesis that different profiles of arousal dysfunction may exist within children with ODD/CD. This knowledge could explain variability within children with ODD/CD, both in terms of specific types of aggression as well as comorbid symptoms (e.g., other emotional/behavioral problems). We measured heart rate variability (HRV), heart rate (HR) and skin conductance level (SCL) during rest and stress, and obtained parent and teacher reports of aggression, anxiety, attention problems and autism traits in a sample of 66 ODD/CD and 36 non-clinical boys (aged 8-12 years). The ODD/CD group scored significantly higher on aggression, anxiety, attention problems and autism traits than the controls; boys with ODD/CD also had higher resting HRs than controls, but HR stress, HRV and SCL did not differ. Hierarchical regressions showed different physiological profiles in subgroups of boys with ODD/CD based on their type of aggression; a pattern of high baseline HR and SCL, but low stress HRV was related to reactive aggression, whereas the opposite physiological pattern (low HR, low stress SCL, high stress HRV) was related to proactive aggression. Furthermore, high stress SCL was related to anxiety symptoms, whereas low stress SCL was related to attention problems. These findings are important because they indicate heterogeneity within boys with ODD/CD and highlight the importance of using physiology to differentiate boys with different ODD/CD subtypes.


Estimating and minimizing movement artifacts in surface electromyogram.
While recording surface electromyography [sEMG], it is possible to record the electrical activities coming from the muscles and transients in the half-cell potential at the electrode-electrolyte interface due to micromovements of the electrode-skin interface. Separating the two sources of electrical activity usually fails due to the overlapping frequency characteristics of the signals. This paper aims to develop a method that detects movement artifacts and suggests a minimization technique. Towards that aim, we first estimated the frequency characteristics of movement artifacts under various static and dynamic experimental conditions. We found that the extent of the movement artifact depended on the nature of the movement and varied from person to person. Our study's highest movement artifact frequency for the stand position was 10 Hz, tiptoe 22, walk 32, run 23, jump from box 41, and jump up and down 40 Hz. Secondly, using a 40 Hz highpass filter, we cut out most of the frequencies belonging to the movement artifacts. Finally, we checked whether the latencies and amplitudes of reflex and direct muscle responses were still observed in the highpass-filtered sEMG. We showed that the 40 Hz highpass filter did not significantly alter reflex and direct muscle variables. Therefore, we recommend that researchers who use sEMG under similar conditions employ the recommended level of highpass filtering to reduce movement artifacts from their records. However, suppose different movement conditions are used. In that case, it is best to estimate the frequency characteristics of the movement artifact before applying any highpass filtering to minimize movement artifacts and their harmonics from sEMG.


Immediate skin-to-skin contact after birth ensures stable thermoregulation in very preterm infants in high-resource settings.
To investigate the impact of immediate skin-to-skin contact with a parent after birth on thermal regulation in very preterm infants. This clinical trial was conducted in three neonatal intensive care units in Scandinavia from 2018 to 2021. Infants born between 28 + 0 and 32 + 6 weeks and days of gestation were randomised to immediate skin-to-skin contact or conventional care in an incubator during the first 6 postnatal hours. We report on a secondary outcome: serial measurements of axillary temperature. Ninety-one infants were randomised to skin-to-skin contact or conventional care. Mean (range) gestational ages were 31 + 2 (28 + 6, 32 + 5) and 31 + 0 (28 + 4, 32 + 6) weeks and days, mean birth weights were 1572 (702, 2352) and 1495 (555, 2440) grams, respectively. Mean (95%CI, p-value) temperatures were within the normal range in both groups, 0.2°C (-0.29, -0.14, p < 0.001) lower in the skin-to-skin contact group. The skin-to-skin contact group had a lower relative risk (95%CI, p-value) of developing events of hyperthermia, RR = 0.70 (0.50, 0.99, p = 0.04). Very preterm infants, irrespective of clinical stability, do not develop hypothermia during immediate skin-to-skin contact after birth. Immediate skin-to-skin contact did protect against events of hyperthermia. Concerns about thermal regulation should not limit implementation of immediate skin-to-skin contact in high-resource settings.


Electronic modification of an aminotroponiminate zinc complex leading to an increased reactivity in the hydroamination of alkenes.
The electronically modified zinc complex 5-phenylsulfanyl-N-isopropyl-2-(isopropylamino)troponiminate zinc methyl, [(PhS-ATI(iPr)2)ZnMe], was synthesized. It showed an increased reactivity in the intramolecular hydroamination reaction of non-activated alkenes compared to a previously-reported, non-substituted complex.


Effects of acute CS2 intoxication on protein metabolism in rat brain.
The effect of acute CS2 exposure on the rat brain protein metabolism was studied with control and phenobarbitone pretreated adult male rats 1, 4 and 46 h after exposure. Increased activity of acid proteinase was detected in both test groups 1 and 4 h after exposure and it was accompanied by changes in 14C-labelled leucine turnover as well as in RNA content. The changes were more conspicuous in cerebellum than in brain in both test groups while phenobarbitone pretreatment modified the brain response towards intoxication. This modification probably represents inherent effects of barbiturate on brain protein metabolism as well as altered metabolism of CS2. The activities of creatine kinase and nonspecific cholinesterase displayed only subtle changes as assayed in cerebral homogenate and serum. Thus a single acute CS2 intoxication apparently causes definitive transient changes in brain protein metabolism; serum enzyme determinations may not reflect the magnitude of these changes.


Continuous Inferior Vena Cava Diameter Tracking through an Iterative Kanade-Lucas-Tomasi-Based Algorithm.
Ultrasound assessment of the respiratory-induced change in size of the inferior vena cava is a useful technique in the evaluation and management of critically ill patients. We have developed an automated technique based on the Kanade-Lucas-Tomasi feature tracker and pyramidal segmentation to continuously track the diameter of the inferior vena cava during ultrasound. To test the accuracy of this automated process, the inferior vena cava of 47 spontaneously breathing patients were measured by trained ultrasound physicians and compared against the results obtained via the automated tracking. Good agreement between the techniques was found, with intra-class correlation coefficients for maximum vessel diameter, minimum diameter and caval index of 0.897, 0.967 and 0.975, respectively. More than 95% of the difference between physicians and automated measurements agreed to within 10% of the inferior vena cava collapse. Furthermore a phenomenon of cardiac collapsibility index variability was observed and reported. The accuracy and precision of this algorithmic technique provide a foundation for future automated measures for critical care ultrasound.


Functional properties of the R154X HNF-4alpha protein generated by a mutation associated with maturity-onset diabetes of the young, type 1.
Mutations in the hepatocyte nuclear factor 4alpha (HNF-4alpha) gene are associated with one form of maturity-onset diabetes of the young (MODY1). The R154X mutation generates a protein lacking the E-domain which is required for normal HNF-4alpha functions. Since pancreatic beta-cell dysfunction is a feature of MODY1 patients, we compared the functional properties of the R154X mutant in insulin-secreting pancreatic beta-cells and non-beta-cells. The R154X mutation did not affect nuclear localisation in beta-cells and non-beta-cells. However, it did lead to a greater impairment of HNF-4a function in beta-cells compared to non-beta-cells, including a complete loss of transactivation activity and a dominant-negative behaviour. .


Separating the chemical and microbial factors of oat harvested at two growth stages to determine the main factor on silage fermentation.
This work evaluated the effects of epiphytic microbiota and chemical components on fermentation quality and microbial community of ensiled oat. Oat harvested at the heading stage (HS) and the milk stage (MS) was sterilized by gamma-ray irradiation and inoculated as the following: (1) HS epiphytic microbiota + sterilized HS (H-H); (2) MS epiphytic microbiota + sterilized HS (M-H); (3) MS epiphytic microbiota + sterilized MS (M-M); and (4) HS epiphytic microbiota + sterilized MS (H-M). After 60-day fermentation, silages inoculated with the epiphytic microbiota of HS had higher acetic acid content than those inoculated with MS. Silage made from sterilized MS had lower pH, ammonia nitrogen and butyric acid contents and higher dry matter, water-soluble carbohydrates and lactic acid contents than that made from sterilized HS. The microbial communities of oat silages were similar, and they were mainly Lactobacillus. The chemical component rather than the epiphytic microbiota at harvest exerted more effects on oat silages. This work reveals the different effects of chemical and microbial factors on the fermentation of silage, which is instructive for us to produce quality silage.


The experimental infection of calves with a British strain of Haemophilus somnus.
Intravenous inoculation of a British strain of Haemophilus somnus resulted either in fatal peracute or chronic forms of H somnus disease. Pleuritis, pericarditis and arthritis were prominent post mortem findings. Intratracheal inoculation led to severe cellulitis and abscess formation in the neck with acute suppurative bronchopneumonia in one calf, while in another, encapsulated abscesses and pleural adhesions were seen. Intraperitoneal inoculation resulted in fatal fibrinous peritonitis in one calf. The organism was readily recovered from the lesions except when overgrown by post mortem contaminants. Rising antibody titres were detected in two calves 12 days after inoculation by a micro-complement fixation test, and the organism was demonstrated in synovial fluid by an indirect fluorescent antibody test. No organisms were recovered from and no lesions were seen in the nervous tissues of the calves in contrast to studies of this disease in the USA.


Humility in medicine.
Becoming a physician comes with privilege and exciting opportunities. The rigor of academic medicine can be challenging. The ability to have humility as a physician is not only a sign of a good doctor, but it can be one of the most challenging attributes to maintain. My surgeon, Dr. Steven Kopits, embodied what it means to be a humble, yet accomplished physician.


Prevalence of temporomandibular disorders (TMD) in bleeding disorders: A systematic review with meta-analysis.
Haemophilia A, B and von Willebrand disease are the most common bleeding disorders. There is an increased tendency of spontaneous bleeding into joints resulting in intra-articular infection. It is believed that Temporomandibular Joint (TMJ) can be affected in a similar manner which can further lead to limited mouth opening and ankylosis. The association between bleeding disorders (BD) and development of temporomandibular disorders (TMD) is poorly understood. This systematic review intends to evaluate the association of TMD in individuals with inherited bleeding disorders as compared to healthy controls. PubMed, Ovid SP and Google Scholar were searched for articles published between the times of inception to 1 May 2023. All the articles were subjected to Population, Exposure, Comparison and Outcome model (PECO) based on which inclusion and exclusion criteria were applied. Participants (P) is children, adults or adolescents; Exposure (E) is children, adults or adolescents with a diagnosis of Haemophilia or bleeding disorder (BD); Comparator (C) is age and gender-matched healthy controls who do not have Haemophilia or bleeding disorder; Outcome (O) is prevalence of any signs or symptoms (clinical, radiographic) that is suggestive of temporomandibular disorder (TMD). Studies showing the prevalence of TMD are included for qualitative analysis. Only the studies which provided data of the prevalence of TMD in both the groups (BD and healthy controls) were included in the quantitative analysis. TMD diagnosis can be by clinical signs and symptoms, radiographic criteria, Diagnostic Criteria for Temporomandibular Disorders (DC/TMD), The Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) or any other imaging criteria (MRI). We have set the exclusion criteria as articles without a control group, diagnostic sensitivity studies, case reports and systematic reviews and narrative reviews. The software Review Manager version 5.4 (Cochrane Collaboration) was used to perform the pooled analysis. We measured the risk ratio (RR) between the two groups (BD and healthy controls) for the outcome TMD. A total of seven studies are included for qualitative analysis of data. The age of the population (BD and control) in the included studies ranged between 2 and 57 years. The prevalence of TMD in individual studies varied from 2% to 77%, and controls in the individual studies varied from 2% to 14%. Among the included studies, only clinical signs, symptoms and history were taken into consideration in four studies. Four studies were included for meta-analysis, the pooled result of the four studies suggests there is no significant difference in the prevalence of TMD in BD and control group (p value = .11, RR 2.19; 95% CI [0.84, 5.73]). This systematic review and meta-analysis elicits no association between bleeding disorders and increased prevalence of TMD.


Influenza A replication and host nuclear compartments: many changes and many questions.
It is over 40 years since investigations showed that influenza A, one of the rare nuclear replicating RNA viruses, induces marked remodeling of the host nuclear architecture. Influenza modifies and/or hijacks host nuclear machinery in order to replicate, express viral proteins and interfere with host antiviral response. Numerous interactions between constitutive nuclear proteins and viral factors are now characterized but less is known concerning their functional significance and their connection with viral-induced modifications of nuclear ultrastructure. Therefore, the purpose of this review is to summarize data and hypotheses about functional interplays between host nuclear compartments and influenza A during viral replication.


Avoid Oversimplifications in Machine Learning: Going beyond the Class-Prediction Accuracy.
Class-prediction accuracy provides a quick but superficial way of determining classifier performance. It does not inform on the reproducibility of the findings or whether the selected or constructed features used are meaningful and specific. Furthermore, the class-prediction accuracy oversummarizes and does not inform on how training and learning have been accomplished: two classifiers providing the same performance in one validation can disagree on many future validations. It does not provide explainability in its decision-making process and is not objective, as its value is also affected by class proportions in the validation set. Despite these issues, this does not mean we should omit the class-prediction accuracy. Instead, it needs to be enriched with accompanying evidence and tests that supplement and contextualize the reported accuracy. This additional evidence serves as augmentations and can help us perform machine learning better while avoiding naive reliance on oversimplified metrics.


Isolation and characterization of a ribonuclease from human leukemic blood cells specific for ribonucleic acid of ribonucleic acid-deoxyribonucleic acid hybrid molecules.
A ribonuclease that specifically hydrolyzes RNA in RNA. DNA hybrids has been purified more than 100-fold from human acute leukemic white blood cells. The molecular weight of this enzyme has been estimated as 80,000 by glycerol gradient centrifugation. It requires Mg-2plus for activity and is inhibited by N-ethylmaleimide. The optimum activity is observed at pH 8 (37 DEGREES). It is a heat-labile protein, t 1/2 at 50 degrees being 2 min. Among the substrates examined, (A)n X (dT)m, (I)n X (DC)m, and PHIX-174 DNA X RNA were hydrolyzed efficiently. (U)n X (dA)m showed a slight substrate activity, while (c) n X (dG) m and (G)n X (dC)m were not significantly hydrolyzed. The enzyme is an endonuclease and does not require RNA ends in the substrate molecule. It is capable of converting more than 95% of the RNA portions in hybrid substrates into acid-soluble products which are mono- and oligonucleotides terminated in 3'-OH and 5'-phosphate.


Video Game Play Does Not Improve Spatial Skills When Controlling for Speed-Accuracy Trade-Off: Evidence From Mental-Rotation and Mental-Folding Tasks.
Researchers have been divided on the efficacy of computerized cognitive training (CCT) for enhancing spatial abilities, transfer of training, and improving malleability of skills. In this study, we assessed the effects of puzzle video game training on subsequent mental rotation (MR) and mental folding (MF) performance among adults with no cognitive impairment. We assessed participants at baseline with the Shepard-Metzler MR test followed by the differential aptitude test: space relations MF test (i.e., far transfer). We ranked participants' skills on these pre-tests and used a matching technique to form two skill groups from which we then randomly assigned members of each skill group either to an experimental group or a wait-list control group. The experimental group played two puzzle video games closely related to two-dimensional and three-dimensional MR tasks during 4-week training sessions (total of 12 hour of video games). Post-training, participants completed the MR and MF tests again. Two months later, we re-assessed only the experimental group's spatial skills to explore the sustainability of the trained performance. In addition to response times (RT) and error scores (ES), reported separately, we combined these variables into rate correct scores (RCS) to form an integrated measure of potential speed-accuracy trade-offs (SAT). As a result, we did not find significant improvements in MR performance from CCT engagement, nor did participants show a transfer of skills obtained by practicing MR-related puzzle games to a MF task. Based on the current findings, we urge caution when proposing a game-based intervention as a training tool to enhance spatial abilities. We argue that separately interpreting individual test measures can be misleading, as they only partially represent performance. In contrast, composite scores illuminate underlying cognitive strategies and best determine whether an observed improvement is attributable to enhanced capacities or individual heuristics and learned cognitive shortcuts.


Regional enteritis in children: small bowel disease with normal terminal ileum.
Regional enteritis in children may affect the small bowel without involvement of the terminal ileum. We have noted this distribution of disease in 4 of 20 consecutive cases of Crohn's disease. The clinical and radiologic features of these 4 patients are reported together with a review of similar observations in the literature.


Tooth pulp stimulation advances both medullary off-cell pause and tail flick.
It has been postulated that the so-called off-cells of nucleus raphe magnus and adjacent structures in the rat are the output elements of a system which inhibits nociceptive transmission at the spinal cord. Off-cells stop firing about 0.4 s before the tail flick reflex (TF) elicited by the application of noxious heat to the tail. When continuous off-cell activity is induced by either morphine injection or periaqueductal gray stimulation, the TF is delayed. The present results show that electrical stimulation of the tooth pulp (TP) causes the off-cells to stop firing. Furthermore, when TP is stimulated during tail heating and before the expected time for TF, off-cells stop firing earlier and the TF occurs also earlier. This supports the notion that off-cells inhibit nociceptive transmission.


Self-Assembled Polydiacetylene Vesicle and Helix with Chiral Interface for Visualized Enantioselective Recognition of Sulfinamide.
An l-glutamic acid terminated amphiphilic diacetylene was designed and found to self-assemble into vesicles in water and supramolecular gel with helical structures in mixed methanol/water solvent. Both the vesicles and the helices underwent topochemical photopolymerization under UV irradiation and changed to a blue color. During the self-assembly and photopolymerization, the chirality of localized l-glutamic acid was successfully transferred to polydiacetylene (PDA), which resulted in obvious CD signals in the PDA blue phase. Interestingly, the CD signals for PDA vesicles and helices were opposite due to the different packing modes in the PDA skeleton. However, although these two assembly systems own opposite supramolecular chirality, both of them showed the same enantioselective recognition of sulfinamide enantiomers, in which the assemblies with S-enantiomer turned red while the other remained blue in the presence of the R-enantiomer. It is suggested that the chiral interface composed of l-glutamic acid played an important role in the enantioselective recognition. This work revealed the function of molecular and supramolecular chirality in the supramolecular self-assembly system.


Treatment of type II symptomatic ulnar styloid nonunions with reinsertion of the triangular fibrocartilage complex.
The purpose of this retrospective study was to introduce an alternative technique for the treatment of type II symptomatic ulnar styloid nonunion by the reinsertion of the triangular fibrocartilage complex and the ulnar collateral ligament. Between March 2009 and May 2017, 45 patients (34 males and 11 females) suffering from the nonunion of type II ulnar styloid fractures all underwent the subperiosteal resection of the avulsed fragments and the reinsertion of the TFCC and ulnar collateral ligament. Outcome assessments included the ranges of motion of the wrist, grip strength, pain, and Mayo wrist score. The preoperative and postoperative parameters were compared. A P-value less than 0.05 was considered to be statistically significant. The mean follow-up period was 21.66 ± 7.93 months (range, 12 to 26 months). At the final follow-up, the mean preoperative flexion and extension were 79.32 ± 4.52° and 74.40 ± 4.36° respectively. The mean preoperative pain score, grip strength, and Mayo wrist score were 32.48 ± 4.00; 23.88 ± 8.38 kg, and 77.72 ± 8.31 respectively. The mean postoperative flexion and extension of the wrist were 80.56 ± 6.32° and 75.43 ± 3.12° respectively. The mean postoperative pain score, grip strength, and Mayo wrist score were 12.41 ± 3.27, 26.31 ± 8.30 kg, and 90.71 ± 7.97 respectively. There were significant differences in pain, grip strength, and Mayo wrist score (P < 0.05), but no significant differences concerning the range of motion of the wrist. In the treatment of the nonunion of type II ulnar styloid fractures, the resection of the avulsed fragments followed by the reinsertion of the TFCC and the ulnar collateral ligament with an anchor was a reliable alternative technique, bringing the satisfactory function of the wrist.


Fabrication and characterization of microfluidic devices based on boron-modified epoxy resin using CO2 laser ablation for bio-analytical applications.
CO2 laser ablation is a rapid and precise technique for machining microfluidic devices. And also, low-cost epoxy resin (ER) proved the great feasibility of fabricating these devices using the CO2 laser ablation technique in our previous studies. However, such a technique has shown negative impacts on such ER-based microfluidics as rough surface microchannels, and thermal defects. Therefore, incorporating different proportions of boric acid (BA) into epoxy resin formulation was proposed to obviate the genesis of these drawbacks in ER-based microfluidics. The structural and optical properties of plain ER- and B-doped ER-based chips were characterized by Fourier transform infrared (FT-IR) and UV/Vis spectral analyses. Furthermore, their thermal properties were studied by thermo-gravimetric (TGA) and differential scanning calorimetric (DSC) analysis. A CO2 laser ablation machine was used in vector mode to draw the designed micro-channel pattern onto plain ER- and B-doped ER-based chips. The quality of microchannels engraved onto these chips was assessed using 3D laser microscopy. This microscopic examination showed a noticeable reduction in the surface roughness and negligible bulge heights in the laser-ablated micro-channels. On the other hand, overall and specific migration using gravimetric methods and gas chromatography-mass spectrometry (GC-MS), respectively, and PCR compatibility test were performed to explore the convenience of these micro-plates for the biological reactions. These findings validated the applicability of B-doped ER-based microfluidics in bio-analytical applications as a result of the effective role of boric acid in enhancing the thermal properties of these chips leading to get micro-channels with higher quality with no effect on the biological reactions.


The role of GTPase-activating protein ARHGAP26 in human cancers.
Rho GTPases are molecular switches that play an important role in regulating the behavior of a variety of tumor cells. RhoA GTPase-activating protein 26 (ARHGAP26) is a GTPase-activating protein and inhibits the activity of Rho GTPases by promoting the hydrolytic ability of Rho GTPases. It also affects tumorigenesis and progression of various tumors through several methods, including formation of abnormal fusion genes and circular RNA. This review summarizes the biological functions and molecular mechanisms of ARHGAP26 in different tumors, proposes the potential clinical value of ARHGAP26 in cancer treatment, and discusses current issues that need to be addressed.


The missense mutation in Abcg5 gene in spontaneously hypertensive rats (SHR) segregates with phytosterolemia but not hypertension.
Sitosterolemia is a recessively inherited disorder in humans that is associated with premature atherosclerotic disease. Mutations in ABCG5 or ABCG8, comprising the sitosterolemia locus, STSL, are now known to cause this disease. Three in-bred strains of rats, WKY, SHR and SHRSP, are known to be sitosterolemic, hypertensive and they carry a missense 'mutation' in a conserved residue of Abcg5, Gly583Cys. Since these rat strains are also know to carry mutations at other genetic loci and the extent of phytosterolemia is only moderate, it is important to verify that the mutations in Abcg5 are causative for phytosterolemia and whether they contribute to hypertension. To investigate whether the missense change in Abcg5 is responsible for the sitosterolemia we performed a segregation analysis in 103 F2 rats from a SHR x SD cross. Additionally, we measured tail-cuff blood pressure and measured intestinal lipid transport to identify possible mechanisms whereby this mutation causes sitosterolemia. Segregation analysis showed that the inheritance of the Gly583Cys mutation Abcg5 segregated with elevated plant sterols and this pattern was recessive, proving that this genetic change is responsible for the sitosterolemia in these rat strains. Tail-cuff monitoring of blood pressure in conscious animals showed no significant differences between wild-type, heterozygous and homozygous mutant F2 rats, suggesting that this alteration may not be a significant determinant of hypertension in these rats on a chow diet. This study shows that the previously identified Gly583Cys change in Abcg5 in three hypertension-susceptible rats is responsible for the sitosterolemia, but may not be a major determinant of blood pressure in these rats.


Transcription factor levels in medullary thyroid carcinoma cells differentiated by Harvey ras oncogene: c-jun is increased.
In the TT cell line of human medullary thyroid carcinoma, the viral Harvey ras (v-rasH) oncogene induces differentiation, marked by morphological changes, diminution of growth, and increased expression of the calcitonin gene. Here, we show that the transcriptional factor c-jun is increased during v-rasH induced differentiation of TT cells both at the mRNA and functional protein levels. In contrast, nuclear proteins with binding activities related to AP2, AP3, NF1/CTF, and Sp1 were unchanged in v-rasH differentiated TT cells.