Novel protective effects of histone deacetylase inhibition on stroke and white matter ischemic injury.
Understanding how epigenetics influences the process and progress of a stroke could yield new targets and therapeutics for use in the clinic. Experimental evidence suggests that inhibitors of zinc-dependent histone deacetylases can protect neurons, axons, and associated glia from the devastating effects of oxygen and glucose deprivation. While the specific enzymes involved have yet to be clearly identified, there are hints from somewhat selective chemical inhibitors and also from the use of specific small hairpin RNAs to transiently knockdown protein expression. Neuroprotective mechanisms implicated thus far include the upregulation of extracellular glutamate clearance, inhibition of p53-mediated cell death, and maintenance of mitochondrial integrity. The histone deacetylases have distinct cellular and subcellular localizations, and discrete substrates. As a number of chemical inhibitors are already in clinical use for the treatment of cancer, repurposing for the stroke clinic should be expedited.


Towards a top-domain ontology for linking biomedical ontologies.
In this paper we present the ongoing development and extension work on BioTop--a top-domain ontology for linking biomedical domain ontologies. We start by making the case for the application of a common ontology to interface independent biomedical domain ontologies by introducing a set of more general classes. Then we briefly depict the relation of BioTop to the GENIA ontology as starting point of its initial developement. Afterwards we propose our distinction of ontologies into top, top-domain and domain ones and describe our approach to the integration of the top ontology BFO into BioTop. Then we present our plans to join the OBO and OBO Foundry repository of ontologies and list its admission principles in relation to our ontology. Some actual BioTop interface classes are shown subsequently. We conclude by detailing on some planned BioTop usages in the area of BioNLP and cancer research and show some further intended improvements.


Adjuvant therapy in patients with ductal carcinoma in situ of the breast: The Pandora's box.
Most patients with ductal carcinoma in situ of the breast (DCIS) are eligible for breast conservation treatment. The key management decision is whether to add radiotherapy and/or endocrine therapy to minimize the risk of a subsequent recurrence. Recent analyses indicating a lack of benefit in terms of breast cancer-associated mortality have suggested that more conservative approaches, omitting adjuvant therapy or even surgery, may be advisable in selected patients. These mortality observations are directly influenced by widespread use of mammographic screening which has opened a Pandora's box of subclinical DCIS and early invasive lesions. Confusion as to how aggressively such possibly indolent lesions should be treated has led to misunderstandings among patients and medical professionals. While awaiting further prospective evidence from clinical trials, we endorse an active treatment of DCIS as the standard of care. Our rationale is twofold: invasive recurrences are associated with an increase in breast cancer mortality, which is not the only relevant endpoint for DCIS. The benefit of complete surgical excision, adjuvant radiotherapy and endocrine treatment in preventing recurrence and invasive progression has been demonstrated in DCIS. The challenge now is how to identify DCIS patients who will not progress to invasive carcinoma even without complete excision and, at the other extreme, those patients at the highest risk who require mastectomy for local control. The current controversies over whether and which adjuvant therapy should be implemented can at least in part be addressed by developing effective doctor-patient communications that enable mutual understanding about the management of this biologically heterogeneous disease.


[Effectiveness of treatment of elderly patients with traumatic brain injury complicated by subdural hematoma.]
The work is based on the results of a retrospective analysis of the medical records of 56 patients with traumatic brain injury complicated by acute subdural hematoma with a volume of 60-100 cm3. The patients were divided into 2 groups according to their age: the 1st group included 29 patients aged 22-29 years, the 2nd group consisted of 27 patients aged 61-69 years. The degree of impaired consciousness in the victims at admission to the clinic was evaluated on the Glasgow scale, the effectiveness of the treatment at discharge from the hospital was performed on the Rankin scale, assessing the degree of independence and disability. Elderly patients were found to have a more severe condition upon admission to the clinic. Upon discharge from the hospital, the assessment of the degree of independence and disability on the Rankin scale revealed a statistically significant predominance of scores in the group of elderly patients (p<0,01), which indicates less effective treatment in comparison with young patients. The results of this study can serve as a basis for the development of additional recommendations in outpatient practice for the care and care of patients in the older age group and a personalized approach to neurosurgical patients taking into account their age.


Improved conditions for isolation and quantification of RNA in urine specimens.
There is clear evidence that the occurrence of specific mRNAs in plasma and serum is associated with cancer, while the usefulness of other body fluids for nucleic acid-based cancer detection remains to be elucidated. Nevertheless, due to the principal advantages of urine (large sample quantities, easy to acquire), several attempts were made to use quantitative reverse transcriptase polymerase chain reaction (RT-PCR)-based detection of putative RNA tumor markers from urine as a tool for noninvasive tumor detection. Because most of the commercially available RNA isolation systems do not accommodate larger sample volumes, the majority of experiments were performed using urine pellets. During the centrifugation step, putative extracellular nucleic acids of low molecular weight as well as complexes containing nucleic acids with low density are lost. Furthermore, cells may be destroyed during this procedure, and the subsequently released nucleic acids will quickly be degraded by nucleases in the urine, which may give rise to inconsistent results. Therefore, we established an improved protocol for the isolation of RNA from urine and subsequent quantification steps. The isolation procedure was tested using a quantitative RT-PCR specific for Ki-67 RNA as well as a radioactive-based reverse transcription approach.


Husbands' and wives' stressful work, couple BMI dynamics, and later-life physical health.
Previous research has not adequately investigated the persistent influence of stressful work experiences, particularly person-work mismatch (PWM), on later-life physical health outcomes of working husbands and wives. Using prospective data collected from 235 working husbands and wives over a period of 27 years (1991-2017), this study examined PWM in early middle years (40-50 years of age) and body mass index (BMI) trajectories in mid-later years (50-65 years of age) in a dyadic actor-partner interdependence modelling framework. Results showed PWM in early middle years was related to BMI trajectories in mid-later years, which contributed to multiple physical health outcomes in later life. Spouses' PWM influenced not only their BMI trajectories but also their partners' BMI trajectories, providing evidence for partner effects. This couple-level BMI process over the mid-later years was related to spouses' physical health in later years. Husbands' elevated BMI level resulted in adverse physical health outcomes. In contrast, for wives, it was the change in BMI over time that resulted in adverse physical health outcomes in their later years. These findings are particularly important for couple-focused family interventions as they highlight the need to consider couple-level lifestyle and behavioural factors that can safeguard spouses from the negative health consequences of PWM.


Resistance to artemisinin in falciparum malaria parasites: A redox-mediated phenomenon.
Malaria remains a major public health disease due to its high yearly mortality and morbidity. Resistance to the gold standard drug, artemisinin, is worrisome and needs better understanding in order to be overcome. In this work, we sought to study whether redox processes are involved in artemisinin resistance. As artemisinin is known to act among others via production of reactive species, we first compared the production of reactive oxygen species and concomitant protein oxidation in artemisinin-sensitive and artemisinin-resistant parasites when treated with artemisinin. The results undoubtedly demonstrated, using different original methods, that the level of ROS, including superoxide production, and oxidized protein were lower in the resistant strain. Interestingly, the major in-between strain difference was reported at the earlier ring stages, which are the forms able to enter in a quiescence state according to the ART resistance phenomenon. Moreover, we demonstrated a better homeostasis regulation in relation with higher expression of antioxidants in the artemisinin-resistant parasites than their sensitive counterparts after artemisinin exposure, notably, superoxide dismutase and the glutathione (GSH) system. These findings enrich the body of knowledges about the multifaceted mechanism of artemisinin resistance and will help in the design and development of newer antimalarials strategies active against resistant parasites.


Introduction to Deep Brain Stimulation.
It is estimated that over 160,000 patients worldwide have received deep brain stimulation (DBS) to date predominantly for Parkinson's disease and other movement disorders. With the success of this therapy, a greater appreciation of the clinical benefits and adverse effects is being realized. Neurosurgeons are increasingly paying attention to the technical details of these procedures and optimizing targeting, surgical techniques, and programming to improve outcomes. In this issue, the nuances of surgical techniques for DBS are covered by Dr. House. Dr. Toda et al. and Mr. Chartrain et al. tackle the approach to treating tremors, either essential tremor or Holmes tremor, using either a single target or, in cases of difficult-to-treat tremors, using more than one target and interleaving the stimulation. These abstracts and videos will be appreciated by both those who are being initiated to DBS and the more seasoned practitioners who are looking for helpful hints to tackle challenging cases.


Molecular biology of brain tumors.
Through the technical advances in molecular biology during the past decade, important new insights into the fundamental chromosomal changes associated with brain tumors have been gained. The pace of such research is accelerating, and most of the published reports have appeared outside the neurosurgical literature. Furthermore, many neurosurgeons may not be sufficiently familiar with the terminology and techniques involved to remain abreast of the field. In this review, we discuss through specific examples of recent work on brain tumors the basic techniques of molecular biology, including the Southern and Northern blots, restriction enzyme digestion of DNA, molecular cloning of genes, and mapping of chromosomal deletions. Gene amplification and rearrangements are discussed through review of recent work on the N-myc gene in neuroblastoma and the epidermal growth factor receptor (EGFR) gene in glioblastoma. The molecular cloning of the gli gene from a glioblastoma illustrates the powerful analytic nature of these laboratory techniques and the investigative potential of a cloned gene. The concept of the "recessive oncogene" is discussed through a summary of recent work analyzing restriction fragment length polymorphisms (RFLPs) in families of patients with meningioma, acoustic neurinoma, and bilateral acoustic neurofibromatosis (BANF; NF-2). Throughout this article, emphasis is placed on ways in which molecular biology may soon affect clinical practice.


Outcomes of salvage high-dose-rate brachytherapy with or without external beam radiotherapy for isolated vaginal recurrence of endometrial cancer.
This study was designed to retrospectively analyze outcomes of high-dose-rate (HDR) brachytherapy, with or without external beam radiotherapy (EBRT), in patients with vaginal recurrence of endometrial carcinoma, and to identify factors prognostic of patient outcomes. The medical records of all patients who underwent HDR brachytherapy for initial recurrence in the vagina of endometrial cancer after definitive surgery between 1992 and 2014 were retrospectively reviewed. All patients underwent either intracavitary brachytherapy (ICBT) or interstitial brachytherapy (ISBT) with or without EBRT. Late toxicity was graded using the EORTC (LENT/SOMA) scale, revised in 1995. Thirty-seven patients were identified. The median follow-up time was 48 months (range: 6-225 months). Of these 37 patients, 23 underwent ICBT, 14 underwent ISBT, and 26 underwent EBRT. Tumor size at first examination of initial relapse was significantly larger in the ISBT than in the ICBT group. The 4-year respective overall survival (OS), local control (LC), and progression-free survival (PFS) rates in the entire cohort were 81.0%, 77.9%, and 56.8%, respectively. The interval between diagnosis of first recurrence and radiotherapy (< 3 months, ≥ 3 months) was a significant predictor of LC and PFS. OS and LC rates did not differ significantly in the ICBT and ISBT groups. Two patients experienced grade 2 rectal bleeding, and four experienced grade 2 hematuria. No grade 3 or higher late complications were observed. Salvage HDR brachytherapy is an optimal for treating vaginal recurrence of endometrial carcinoma with acceptable morbidity. Early radiotherapy, including brachytherapy, should be considered for women who experience vaginal recurrence of endometrial cancer.


Complications of hand-assisted laparoscopic urologic surgery.
Since the first urologic case was reported in 1997, hand-assisted laparoscopic surgery (HALS) has proven to be useful for both the experienced and the inexperienced laparoscopic surgeon. In a recent series of 196 cases at three major medical institutions, 18 patients (9.2%) suffered 32 major complications, and 28 patients (14.3%) had 31 minor complications. The most common major complications were small-bowel injury, requirement for open conversion to control bleeding, and need for reintubation. The most frequent minor complications were urinary retention, splenic capsular injury, and prolonged ileus. The author discusses ways of recognizing and managing the complications of HALS, including physiologic, access-related, intraoperative, and post-operative problems.


Toward maximizing immunotherapy in metastatic castration-resistant prostate cancer - rationale for combinatorial approaches using chemotherapy.
Prostate cancer is particularly suited for active immunotherapy because of the expression of a distinctive number of antigens which are overexpressed on prostate cancer cells and cell lines. There is evidence in this disease that tumors promote immune tolerance starting early in the disease course. As such, chemotherapy, by suppressing tumors and activating immune system homeostatic mechanisms, may help overcome this tumor-induced immune tolerance. Sipuleucel-T which has recently been approved in the US, is an autologous cellular product immunotherapy that induces immune activity likely through activation of dendritic cells. This was associated with a survival benefit in the absence of significant toxicity. However, a post hoc analysis of phase III trial participants found a substantial survival benefit to receiving docetaxel some months after sipuleucel-T. However, another phase III immunotherapy trial combining a prostate cancer therapeutic vaccine GVAX plus docetaxel versus standard docetaxel therapy in advanced prostate cancer, observed a lower overall survival with the vaccine regimen. These trials highlight major unresolved questions concerning the optimum choice, dosing, and timing of chemotherapy relative to active immunotherapy and the overall merits of considering this approach. The ideal treatment approach remains unclear; advances in biomarker validation and trial design may likely improve our ability to assess biologic benefit irrespective of the development of true antitumor immunity.


[Perceptual analysis of dysarthria: presentation and validation of a clinical scale. Preliminary study].
Perceptual analysis is widely used in clinical practice to assess motor speech disorders such as dysarthria. Unfortunately, there is no standardised tool available in French. The purpose of this study was first to develop a perceptual rating system modelled after systems currently used in the English literature and second to determine its reliability. We evaluated 33 dimensions using a 5-point scale. The production of 10 dysarthric patients were rated by 9 clinicians during both spontaneous speech and a reading task. Intra judge reliability (at 1-point) was about 90 percent, while inter judge reliability was about 80 percent. Ratings were comparable for the spontaneous speech and the reading task. Perceptual analysis of dysarthria is an easy and reproducible approach that can be used for the initial evaluation and for the follow up of dysarthric patients.


Counting animal species with DNA barcodes: Canadian insects.
Recent estimates suggest that the global insect fauna includes fewer than six million species, but this projection is very uncertain because taxonomic work has been limited on some highly diverse groups. Validation of current estimates minimally requires the investigation of all lineages that are diverse enough to have a substantial impact on the final species count. This study represents a first step in this direction; it employs DNA barcoding to evaluate patterns of species richness in 27 orders of Canadian insects. The analysis of over one million specimens revealed species counts congruent with earlier results for most orders. However, Diptera and Hymenoptera were unexpectedly diverse, representing two-thirds of the 46 937 barcode index numbers (=species) detected. Correspondence checks between known species and barcoded taxa showed that sampling was incomplete, a result confirmed by extrapolations from the barcode results which suggest the occurrence of at least 94 000 species of insects in Canada, a near doubling from the prior estimate of 54 000 species. One dipteran family, the Cecidomyiidae, was extraordinarily diverse with an estimated 16 000 species, a 10-fold increase from its predicted diversity. If Canada possesses about 1% of the global fauna, as it does for known taxa, the results of this study suggest the presence of 10 million insect species with about 1.8 million of these taxa in the Cecidomyiidae. If so, the global species count for this fly family may exceed the combined total for all 142 beetle families. If extended to more geographical regions and to all hyperdiverse groups, DNA barcoding can rapidly resolve the current uncertainty surrounding a species count for the animal kingdom. A newly detailed understanding of species diversity may illuminate processes important in speciation, as suggested by the discovery that the most diverse insect lineages in Canada employ an unusual mode of reproduction, haplodiploidy.This article is part of the themed issue 'From DNA barcodes to biomes'.


FDA Approval Summary: Tivozanib for Relapsed or Refractory Renal Cell Carcinoma.
On March 10, 2021, the FDA granted regular approval to tivozanib for treatment of patients with relapsed or refractory (R/R) advanced renal cell carcinoma (RCC) following two or more prior systemic therapies. Approval was based on the TIVO-3 study, a randomized trial of tivozanib versus sorafenib in patients with R/R advanced RCC. In TIVO-3, patients were randomized to receive either tivozanib 1.34 mg orally once daily for 21 consecutive days of every 28-day cycle or sorafenib 400 mg orally twice daily continuously. The primary endpoint was progression-free survival (PFS) per RECIST v1.1. Tivozanib demonstrated efficacy compared with sorafenib with an improvement in PFS [HR, 0.73; 95% confidence interval (CI), 0.56-0.95; P = 0.016]. The estimated median PFS was 5.6 months and 3.9 months in the tivozanib and sorafenib arms, respectively. There was no evidence of a detrimental effect on overall survival: HR, 0.97 (95% CI, 0.75-1.24). The most common grade 3 to 4 adverse reaction on the tivozanib arm was hypertension (24%). Compared with sorafenib, tivozanib was associated with lower rates of grade 3 to 4 diarrhea, rash, and palmar-plantar erythrodysesthesia. Patients receiving tivozanib in TIVO-3 had lower rates of dose reduction, interruption, or permanent discontinuation than those receiving sorafenib.


Unusual Enterobacteriaceae: lactose-positive Salmonella typhimurium which is endemic in São Paulo, Brazil.
Since 1971 a lactose-positive (lac+) Salmonella typhimurium variety Copenhagen has been endemic in the city of Sao Paulo. The strain is a strong lactose fermenter and resembles Escherichia coli on primary plating media and in triple sugar iron agar. Although most isolates of the strain have uniform properties, some have slightly different antigens, antibiograms, phage types, or fermentation patterns. Most isolates have come from stools of infants under 1 year of age and are probably hospital acquired; however, other isolates are probably community acquired. Eighteen other lac+ Salmonella isolated in the United States were also studied. Most of these strains resembled E. coli on primary plates and triple sugar iron agar; thus their identification would pose a problem for most clinical laboratories. A simple procedure for detecting lac+ Salmonella mixed with lac+ E. coli consists of touching 12 colonies in succession with a straight wire and then inoculating a peptone iron agar tube. H2S production is apparent from lac+ Salmonella even if 11 E. coli and one Salmonella colony are picked. If a positive peptone iron agar tube is observed, then individual colonies are tested to rule out other strong H2S producers. The true incidence of lac+ Salmonella is unknown because they are not isolated and identified in most laboratories.


[Therapy-resistant lumbago].
The 71-year-old female patient was hospitalized owing to a therapy-resistant lumbo-spondylogenic syndrome. Radiology with increased infection parameters gave rise to the suspicion of a bacterial spondylodiscitis L1/L2. Puncture of the vertebral body as well as blood cultures established proof of yersinia enterocolitica. In spite of immediate adequate antibiosis, by means of "Ciprofloxacin" i.v. spondylodesis of the lumbar spine had to be carried out in order meet the threat of instability. Spondylodiscitis is an extremely rare manifestation of a yersinia infection, only few cases have been described so far in medical literature.


[Establishment of a FVB/N mouse model of cardiac hypertrophy by isoprenaline].
To investigate the condition of isoprenaline (ISO)-induced cardiac hypertrophy in the FVB/N mouse. ISO (30 mg/kg/d) was administered either by daily subcutaneous injection, or by continuous infusion via an implanted osmotic minipump. The mice in each mode of administration were randomly divided into two groups. For subcutaneous injection: the mice received ISO or saline through daily subcutaneous injection for 2 weeks. The mice for minipump: the mice received continuous infusion of ISO via an implanted osmotic minipump for 2 weeks, or received sham operation as the control to mimipump. The ratio of heart weight to tibia length (HW/TI), the diastolic left ventricular posterior wall thickness (dLVPW) were used to indicate cardiac hypertrophy. Interstitial fibrosis was examined with picrosirius red staining. ISO (30 mg/kg/d) administered by daily subcutaneous injection did not lead to cardiac hypertrophy or fibrosis in the FVB/N mice, and 50% of the mice died before the end point. The mice receiving ISO via minipumps showed significant increase in HW/TI [(10.60±0.40 ) mg/mm vs. (7.93±0.19) mg/mm,P<0.001] and dLVPW [(0.87±0.03) mm vs. (0.68±0.06)mm,P=0.0116]. ISO administered via minipumps did not induce cardiac fibrosis. All the mice in this group survived to the end point. ISO (30 mg/kg/d) administered by continuous infusion via a minipump for 2 weeks can lead to significant cardiac hypertrophy.


Successful outcome after massive bleeding in a heart transplant recipient with mycotic aortitis. Case report.
Sudden mediastinal haemorrhage one month after heart transplantation in an 18-year-old youth was found to originate from a rupture of the ascending aorta associated with mycotic aortitis. Aortic continuity was restored with a Dacron graft. Cultures from the resected vessel wall showed Candida albicans. The patient recovered, and 11 months later is well.


Predictions and Outcomes of Atrial Fibrillation in the Patients with Acute Myocardial Infarction.
The large epidemiological studies demonstrated that atrial fibrillation is correlated with high mortality and adverse events in patients with acute myocardial infarction. The aim of this study was to determinate predictors of atrial fibrillation develop during the hospital period in patients with acute myocardial infarction as well as short- and long-term mortality depending on the atrial fibrillation presentation. The 600 patients with an acute myocardial infarction were included in the study and follow-up 84 months. Atrial fibrillation develops during the hospital period was registered in 48 patients (8%). After adjustment by logistic regression model the strongest predictor of atrial fibrillation develop during the hospital period was older age, particularly more than 70 years (odds ratio 2.37, CI 1.23-4.58, p=0.010), followed by increased of Body Mass Index (odds ratio 1.17, CI 1.04-1.33, p=0.012), enlarged diameter of left atrium (LA) (odds ratio 1,18, CI 1,03-1,33, p=0,015) presentation of mitral regurgitation (odds ratio 3.56, CI 1.25-10.32, p=0.018) and B-type natriuretic peptide (odds ratio 2.12, CI 1.24-3.33, p=0.048).Patients with atrial fibrillation develop during the hospital period had a higher mortality during the hospital course (10.4% vs. 5.6%) p=0.179. as well as follow-up period of 84 months than patients without it (64.6% vs. 39.1%) p=0.569, than patients without it, but without statistically significance. Patients with AF develop during the hospital period had higher mortality during the hospital course as well as follow up period of 84 months than patients without it, but without statistically significance.


Combined landscape of single-nucleotide variants and copy number alterations in clonal hematopoiesis.
Clonal hematopoiesis (CH) in apparently healthy individuals is implicated in the development of hematological malignancies (HM) and cardiovascular diseases. Previous studies of CH analyzed either single-nucleotide variants and indels (SNVs/indels) or copy number alterations (CNAs), but not both. Here, using a combination of targeted sequencing of 23 CH-related genes and array-based CNA detection of blood-derived DNA, we have delineated the landscape of CH-related SNVs/indels and CNAs in 11,234 individuals without HM from the BioBank Japan cohort, including 672 individuals with subsequent HM development, and studied the effects of these somatic alterations on mortality from HM and cardiovascular disease, as well as on hematological and cardiovascular phenotypes. The total number of both types of CH-related lesions and their clone size positively correlated with blood count abnormalities and mortality from HM. CH-related SNVs/indels and CNAs exhibited statistically significant co-occurrence in the same individuals. In particular, co-occurrence of SNVs/indels and CNAs affecting DNMT3A, TET2, JAK2 and TP53 resulted in biallelic alterations of these genes and was associated with higher HM mortality. Co-occurrence of SNVs/indels and CNAs also modulated risks for cardiovascular mortality. These findings highlight the importance of detecting both SNVs/indels and CNAs in the evaluation of CH.


Congenital cholesteatoma together with ossicular chain anomaly.
Cholesteatomas that occur under an intact tympanic membrane in the absence of prior surgical procedures or perforation are defined as congenital cholesteatomas. These entities are rarely seen, because they do not cause any major symptoms unless they touch the ossicular chain. Likewise, isolated congenital ossicular anomalies that occur independently of external ear anomalies and craniofacial dysplasia are also rarely seen. Here, we report a patient who presented with congenital cholesteatoma associated with anomalies of the ossicular chain and discuss its pathogenesis.


Chemical synthesis of the RGD-protein decorsin: Pro-->Ala replacement reduces protein thermostability.
Decorsin is a 39-residue polypeptide chain, crosslinked by three disulfide bridges, that strongly inhibits platelet aggregation. We report the chemical synthesis and characterization of analogs of decorsin with the aim of investigating the role of proline residues in protein structure, stability and biological activity. Decorsin analogs have been synthesized in which one (P23A and P24A decorsin) or two (P23,24A decorsin) proline residues have been substituted by alanine. The crude synthetic polypeptides were purified by reversed-phase HPLC in their reduced form and allowed to refold oxidatively to their disulfide-crosslinked species. The homogeneity of the synthetic mini-proteins, and also the correct pairing of the three disulfide bridges, were established by a number of analytical criteria, including fingerprinting analysis of the refolded synthetic analogs by using thermolysin and proteinase K as proteolytic enzymes. Replacement of proline by alanine results in a significant and cumulative decrease of the high thermal stability (Tm 74 degrees C) of native decorsin. The mono-substituted analogs display a Tm of 66-67 degrees C, while the double-substituted analog a Tm of 50 degrees C. On the other hand, the overall secondary and tertiary structures were not affected by the Pro-->Ala exchanges, as judged from circular dichroism measurements. Platelet aggregation assays established that the proline substitutions do not impair significantly the biological activity of decorsin. The results of this study clearly indicate that proline residues contribute significantly to the protein thermal stability. Our results are in line with the 'proline rule', previously advanced for explaining the unusual thermal stability of thermophilic enzymes, which usually show an enhanced content of proline residues with respect to their mesophilic counterparts.


Multi-wavelength Yb:YAG/Nd3+:YVO4 continuous-wave microchip Raman laser.
Multi-wavelength continuous-wave (CW) Raman lasers in a laser diode pumped Yb:YAG/Nd3+:YVO4 microchip Raman laser have been demonstrated for the first time to our best knowledge. The multi-wavelength laser of the first Stokes radiation around 1.08 μm has been achieved with a Raman shift of 261 cm-1 for a-cut Nd:YVO4 crystal corresponding to the fundamental wavelength at 1.05 μm. Multi-wavelength laser operation simultaneously around 1.05 and 1.08 μm has been achieved under the incident pump power between 1.5 and 1.7 W. Multi-wavelength Raman laser with frequency separation of 1 THz around 1.08 μm has been obtained when the incident pump power is higher than 1.7 W. The maximum Raman laser output power of 260 mW at 1.08 μm is obtained and the corresponding optical-to-optical conversion efficiency is 4.2%. Elliptically polarized fundamental laser and linearly polarized Raman laser were observed in an Yb:YAG/Nd:YVO4 CW microchip Raman laser. The experimental results of linearly polarized, multi-wavelength Yb:YAG/Nd:YVO4 CW microchip Raman laser with adjustable frequency separation provide a novel approach for developing potential compact laser sources for Terahertz generation.


Meningitis retention syndrome.
A 50-year-old Caucasian woman presented with signs and symptoms of meningitis preceded by a 3 day history of flu-like symptoms and progressive difficulty with urination. Cerebrospinal Fluid (CSF) analysis was consistent with aseptic meningitis. She was found to have a significant urinary retention secondary to atonic bladder. MRI of the brain and spine were normal and CSF-PCR (polymerase chain reaction) was positive for HSV-2. Urinary retention in the context of meningitis and CSF pleocytosis is known as Meningitis Retention Syndrome (MRS). MRS is a rare but important complication of meningitis most commonly associated with HSV-2. Involvement of central pathways may have a role in the pathogenesis of MRS but this is poorly documented. MRS is different from Elsberg syndrome wherein patients display features of lumbosacral polyradiculitis or radiculomyelitis. Early treatment with antiviral therapy was associated with a favorable outcome in our patient.


Band-limited double-phase method for enhancing image sharpness in complex modulated computer-generated holograms.
Herein, we propose a band-limited double-phase method to improve the quality of reconstructed images encoded by double-phase holograms (DPHs) derived from complex-amplitude light waves. Although the quality of images produced by DPHs was improved compared to that of conventional holographic images, it still suffered from degradation because of the spatial shifting noise generated during the conversion from complex-amplitude holograms to phase-only holograms. The proposed method overcomes this shortcoming by defining a band-limiting function according to the spatial distribution of DPHs in the frequency domain to remove the specific spatial frequency components severely affected by the spatial shifting of DPHs. The sharpness of images reconstructed from band-limited DPHs with appropriate optical filtering showed an improvement of 36.84% in simulations and 51.67% in experiments evaluated by 10-90% intensity variation.


[Is the frequency of pre-seasonal manifestation in patients with Japanese cedar pollinosis so high?].
Based on subjective symptom, it has been documented that so high as 21 to 62% of patients with Japanese cedar pollinosis has pollinosis symptom before the start of pollen season. Since this is not objectively evidenced, we aimed to clarify whether or not it is true. We quantified intranasal pollen by means of our nasal lavage method in patients with Japanese cedar pollinosis shortly after the onset of symptom during pre-, mid- and post-season from 1997 to 2005. Significant differences in intranasal pollen count were revealed among mid- and pre- and post-season. Intra-nasal pollens, so few as 1 or less, were found in 67.8% of patients having pre-seasonal symptom, while in 12.5% during the mid-season. The majority of patients had not sufficient number of intra-nasal pollen to induce pollinosis. However, the intranasal pollen counts in preseason were related well with total airborne pollen amount in next spring. Pollens other than Japanese cedar pollen were also detected in lavages. Many factors such as method of pollen survey, personal nasal hyper-reactivity and irritation by cold air, or with pollens other than Japanese cedar may cause the pre-seasonal pollinosis symptom. High frequencies of pre-seasonal onset in previous reports may be over-estimated due to inaccurate diagnosis of Japanese cedar pollinosis.


Transferrin receptor 1-mediated iron uptake plays an essential role in hematopoiesis.
Transferrin receptor 1 (Tfr1) mediates the endocytosis of diferric transferrin in order to transport iron, and Tfr1 has been suggested to play an important role in hematopoiesis. To study the role of Tfr1 in hematopoiesis, we generated hematopoietic stem cell (HSC) specific Tfr1 knockout mice. We found that Tfr1 conditional knockout mice reached full term but died within one week of birth. Further analyses revealed that Tfr1-deficient HSC had impaired development of all hematopoietic progenitors except thrombocytes and B lymphocytes. In addition, Tfr1-deficient cells had cellular iron deficiency, which blocked the proliferation and differentiation of hematopoietic precursor cells, attenuated the commitment of hematopoietic lineages, and reduced the regeneration potential of HSC. Notably, hemin rescued the colony-forming capacity of Tfr1-deficient HSC, whereas expressing a mutant Tfr1 that lacks the protein's iron-transporting capacity failed to rescue hematopoiesis. These findings provide direct evidence that Tfr1 is essential for hematopoiesis through binding diferric transferrin to supply iron to cells.


Empowering Nurses to Lead Interprofessional Collaborative Practice Environments Through a Nurse Leadership Institute.
A year-long Nurse Leadership Institute (NLI) for emerging leaders in primary care clinics and acute care environments was developed, implemented, and evaluated. The NLI's goal was to foster empowerment in interprofessional collaborative practice environments for nurses in the three cohorts of NLIs. The NLI was framed around the Five Leadership Practices of modeling the way, inspiring a shared vision, challenging the process, enabling others to act, and encouraging the heart. To create a professional learning environment, foster community, and enhance leadership skills, the Lean In Circle materials developed by Sandberg were adapted for content reorganization and discussion. Minimal literature exists specifically addressing nursing leadership professionals' development based on Sandberg's Circle materials. The findings of the three NLI cohorts reported in this article begin to fill this existing knowledge gap. Participants reported a significant increase in leadership skills. Recommendations for refinement of future NLI offerings are provided. J Contin Educ Nurs. 2018;49(2):61-71.


[Prevalence of diabetic retinopathy among the elderly in rural southern Shuangcheng city, Heilongjiang province].
The purpose of this study was to understand the awareness, prevalence of diabetic retinopathy and treatment status of people aged over 50 and living in the rural areas of Shuangcheng city, Heilongjiang province, China. Cluster sampling was used in randomly selected 5504 survey for ophthalmic clinical examination, in patients with diabetic retinopathy. A questionnaire in the state of knowledge about prevention and treatment was developed. Among the 5504 persons entering in the project, 5053 were examined on their eyes (91.8%). In this selected population, 56 persons (112 eyes) were diagnosed as diabetic retinopathy (1.108%), with 95% confidence interval (CI) as: 0.819% to 1.397%. Of 56 patients, 49 cases were non-proliferative diabetic retinopathy, accounting for 87.50% of the total number of patients with diabetic retinopathy; proliferative diabetic retinopathy 7 cases, accounting for 12.50% of the 112 eyes, 6.25% (7/112) having vitreous hemorrhage, 8.04% (9/112) having macular edema. For diabetic retinopathy prevalence rates, there was no significant difference in males and females. Between the per differential 10-year-old division, the difference was significant. Among the 60 to 69 group, a significantly higher prevalence rate was seen. Of the 112 eyes with diabetic retinopathy, 34 eyes (30.4%) were low vision [visual acuity < 20/60 (0.3) to ≥ 20/400 (0.05)]; 6 eyes (5.4%) were blind [visual acuity < 20/400 (0.05) to NLP]. The rate in the patients with PDR and fasting blood glucose was above 11.1 mmol/L was higher than having NPDR and fasting blood glucose below 11.1 mmol/L. Having fasting blood glucose 11.1 mmol/L and above with the course over five years among patients with PDR, the proportion of fasting blood glucose was higher than those with less than 11.1 mmol/L and diabetic retinopathy duration of less than five years. Of 56 patients with diabetic retinopathy, 38 cases (67.9%) did not receive any treatment. Among 18 cases (32.1%) with insulin or oral drug therapy, regularly using insulin or other medication (14.3%), only 1 (1.8%) case was given the treatment for diabetic retinopathy. Results from our survey showed that patients with diabetic retinopathy had a poor understanding about prevention and treatment of the disease. Long duration and high blood glucose in patients with diabetic retinopathy seemed to be the important risk factor. Early systematic drug use for prevention and blood glucose control was the key to prevent diabetic retinopathy. Patients with diabetic retinopathy in China had poor understanding about the prevention measures of the disease and lack of knowledge.


Applications of Epsilon Radial Networks in Neuroimage Analyses.
"Is the brain 'wiring' different between groups of populations?" is an increasingly important question with advances in diffusion MRI and abundance of network analytic tools. Recently, automatic, data-driven and computationally efficient framework for extracting brain networks using tractography and epsilon neighborhoods were proposed in the diffusion tensor imaging (DTI) literature [1]. In this paper we propose new extensions to that framework and show potential applications of such epsilon radial networks (ERN) in performing various types of neuroimage analyses. These extensions allow us to use ERNs not only to mine for topo-physical properties of the structural brain networks but also to perform classical region-of-interest (ROI) analyses in a very efficient way. Thus we demonstrate the use of ERNs as a novel image processing lens for statistical and machine learning based analyses. We demonstrate its application in an autism study for identifying topological and quantitative group differences, as well as performing classification. Finally, these views are not restricted to ERNs but can be effective for population studies using any computationally efficient network-extraction procedures.


The Institute of Medicine's report on non-heart-beating organ transplantation.
In December 1997, the Institute of Medicine (IOM) released a report on medical and ethical issues in the procurement of non-heart-beating organ donors. This report had been requested in May 1997 by the Department of Health and Human Services (DHHS). We will here describe the genesis of the IOM report, the medical and moral concerns that led the DHHS to sponsor it, the process of producing it, and its conclusions. The analyses, findings, and recommendations of the report are also reviewed, in particular the central issues that led to suggestions for policy changes.


Loss of beta cell function as fasting glucose increases in the non-diabetic range.
Our aim was to define the level of glycaemia at which pancreatic insulin secretion, particularly first-phase insulin release, begins to decline. Plasma glucose and insulin concentrations were measured during an IVGTT in 553 men with non-diabetic fasting plasma glucose concentrations. In 466 of the men C-peptide was also estimated. IVGTT insulin secretion in first and late phases was assessed by: (i) the circulating insulin response; (ii) population parameter deconvolution analysis of plasma C-peptide concentrations; and (iii) a combined model utilising both insulin and C-peptide concentrations. Measurements of insulin sensitivity and elimination were also derived by modelling analysis. As fasting plasma glucose (FPG) increased, IVGTT first-phase insulin secretion declined by 73%, 71% and 68% for the three methods respectively. The FPG values at which this decline began, determined by change point regression, were 4.97, 5.16 and 5.42 mmol/l respectively. The sensitivity of late-phase insulin secretion to glucose declined at FPG concentrations above 6.0 mmol/l. Insulin elimination, but not insulin sensitivity, varied with FPG. The range of FPG over which progressive loss of the first-phase response begins may be as low as 5.0 to 5.4 mmol/l, with late-phase insulin responses declining at FPG concentrations above 6.0 mmol/l.


Antibody-mediated rejection after lung transplantation.
Antibody-mediated rejection (AMR) has been identified as a significant form of acute allograft dysfunction in lung transplantation. The development of consensus diagnostic criteria has created a uniform definition of AMR; however, significant limitations of these criteria have been identified. Treatment modalities for AMR have been adapted from other areas of medicine and data on the effectiveness of these therapies in AMR are limited. AMR is often refractory to these therapies, and graft failure and death are common. AMR is associated with increased rates of chronic lung allograft dysfunction (CLAD) and poor long-term survival. In this review, we discuss the history of AMR and describe known mechanisms, application of the consensus diagnostic criteria, data for current treatment strategies, and long-term outcomes. In addition, we highlight current gaps in knowledge, ongoing research, and future directions to address these gaps. Promising diagnostic techniques are actively being investigated that may allow for early detection and treatment of AMR. We conclude that further investigation is required to identify and define chronic and subclinical AMR, and head-to-head comparisons of currently used treatment protocols are necessary to identify an optimal treatment approach. Gaps in knowledge regarding the epidemiology, mechanisms, diagnosis, and treatment of AMR continue to exist and future research should focus on these aspects.


The Relationship Between Coat Color and Aggressive Behaviors in the Domestic Cat.
The authors explored a possible relationship between coat color and aggressive behaviors in the domestic cat. This study used an Internet-based survey to collect information on coat color, affiliative behaviors toward cats/humans, agonistic behaviors toward cats/humans, other "problem" behaviors, and cat and guardian demographic data. A total of 1,432 cat guardians completed the online survey; after exclusions based on study protocol, data analysis included 1,274 completed surveys. Guardians reported sex-linked orange female (tortoiseshells, calicos, and "torbies"), black-and-white, and gray-and-white cats to be more frequently aggressive toward humans in 3 settings: during everyday interactions, during handling, and during veterinary visits. Kruskal-Wallis 1-way analysis of variance was used to compare possible differences between the 2 sexes and among different coat colors. Analyses of aggression due to handling, as well as aggression displayed during veterinarian visits, showed little difference among coat colors in these settings.


Vision health care providers' attitudes and experiences with preschool vision screening in Ontario.
The validity of preschool vision screening has been questioned in the light of the World Health Organization's criteria for determining the validity of screening programs. However, recommendations toward preschool screening have been made by a number of organizations. Given the contrasting views of screening, the purpose of this study was to examine visual health care provider experiences and attitudes toward preschool screening. Optometrists, public health administrators, pediatric ophthalmologists, and orthoptists were surveyed about opinions of, recommendations for, and experiences with preschool vision screening in Ontario. The survey focused on four areas, including general opinion of preschool screening, screening standards and practices, provider experience with preschool screening, and barriers to preschool screening. In addition, survey responses were broken down by regional access to health care. Overall, strong support for preschool vision screening and movement toward standardization of screening practice was found among all surveyed groups. Although support for vision screening in low health care access areas was strong, providers estimated that parent compliance to screening was weaker in low access areas. Providers also reported considerable variability in vision screening practices. In addition, although the majority of providers had been involved in a screening program, the majority was no longer involved because of lack of program organization, structure, and funding. Lack of sufficient funding, public education, organization of screening, training, and government support were listed as barriers to preschool vision screening. Providers are interested in the development of structured screening programs. However, although screening may be a way to offer some level of vision care service to low health care access areas, a number of factors need to be addressed in discussions of vision screening program standards or screening best practice. In general, preschool screening programs need to be structured, be supported, have quality control, and be evaluated.


Prevention of contamination after endotracheal intubation using a dedicated sleeve.
Contamination of work surfaces by used laryngoscopes after endotracheal intubation is a serious infection control concern but no strategies are available to address it. We assessed if contamination of the surfaces after endotracheal intubation would be reduced when providers used a dedicated, self-erected, disposable plastic sleeve (BladePouch) to store the used laryngoscope as compared to using single gloves or double gloves and sheathing the laryngoscope with the outer gloves. Twenty participants were recruited including attending physicians, trainees and allied health care professionals. They performed endotracheal intubation on a mannequin with oral cavity coated with a dye and stored the used laryngoscope blade using single gloves, double gloves or BladePouch. Each participant used both direct and video laryngoscopes. Following intubation, dye contamination of gloves, gown and work surface was evaluated. There was no difference in the contamination of gloves or gowns between the single gloves, double gloves or BladePouch groups. However, work surface contamination was significantly reduced when using BladePouch compared to single or double gloves (13% vs. 100% vs. 80% respectively, P<0.001). The odds of work surface contamination were significantly lower with BladePouch vs. single or double gloves, even when adjusted for intubation device, role and experience of participants with an adjusted odds ratio of 0.0054 (95% confidence interval: 0.0009-0.0314), P<0.001. In conjunction with standard precautions, the use of a dedicated plastic sleeve to store contaminated laryngoscope blade after endotracheal intubation may reduce the work surface contamination, independent of intubation device, role and experience of providers.


Pattern of pediatric poisoning and accident in Patan Hospital.
Kerosene, drugs, pesticides are chemicals used in home and farms. But because of parents' or caretakers' negligence, accidents and poisoning in children may take life of a child. To study the common causes and outcome of pediatric accident and poisoning cases admitted in Patan Hospital. A prospective (2068-69) and retrospective (2066-67) studies of pediatric accident and poisoning cases admitted in Patan Hospital (2066-chaitra 2069) were done. Out of 44 registered cases total 35 cases were collected in last 4 years. Twenty one in prospective and 14 in retrospective study. Male female ratio was 1.2:1. Most vulnerable age group was 1-5 years (21) and 11-15 yrs (8). Most common poison was pesticide (11), kerosene (9) and drugs (7). Twenty percent were suicidal, 3% were homicidal and rest was accidental. Suicidal poisoning was common in 11-14 years. Accidental poisoning was: taking kerosene from mineral water bottle for water. Small children took drugs and pesticides due its easy availability or careless storing. Five common accidents were near drowning (2), hot water scald, hanging and fall from height. Outcome was 2 expired; 1 Organo-phosphorous and 1 food poisoning. Mortality was 6%. One hanging survived as vegetation. Accident and poisoning are preventable. We need to make our home and surrounding poison and accident proof. Small children should never be left unattended. Drugs, pesticides, hot things, and sharp instruments should be kept out of reach of children and in child proof container in separate places. Pesticide should not be sold to children.


Hole Hopping through Tryptophan in Cytochrome P450.
Electron-transfer kinetics have been measured in four conjugates of cytochrome P450 with surface-bound Ru-photosensitizers. The conjugates are constructed with enzymes from Bacillus megaterium (CYP102A1) and Sulfolobus acidocaldarius (CYP119). A W96 residue lies in the path between Ru and the heme in CYP102A1, whereas H76 is present at the analogous location in CYP119. Two additional conjugates have been prepared with (CYP102A1)W96H and (CYP119)H76W mutant enzymes. Heme oxidation by photochemically generated Ru3+ leads to P450 compound II formation when a tryptophan residue is in the path between Ru and the heme; no heme oxidation is observed when histidine occupies this position. The data indicate that heme oxidation proceeds via two-step tunneling through a tryptophan radical intermediate. In contrast, heme reduction by photochemically generated Ru+ proceeds in a single electron tunneling step with closely similar rate constants for all four conjugates.


Plutonium transport in the environment.
The recent estimated global stockpile of separated plutonium (Pu) worldwide is about 500 t, with equal contributions from nuclear weapons and civilian nuclear energy. Independent of the United States' future nuclear energy policy, the current large and increasing stockpile of Pu needs to be safely isolated from the biosphere and stored for thousands of years. Recent laboratory and field studies have demonstrated the ability of colloids (1-1000 nm particles) to facilitate the migration of strongly sorbing contaminants such as Pu. In understanding the dominant processes that may facilitate the transport of Pu, the initial source chemistry and groundwater chemistry are important factors, as no one process can explain all the different field observations of Pu transport. Very little is known about the molecular-scale geochemical and biochemical mechanisms controlling Pu transport, leaving our conceptual model incomplete. Equally uncertain are the conditions that inhibit the cycling and mobility of Pu in the subsurface. Without a better mechanistic understanding for Pu at the molecular level, we cannot advance our ability to model its transport behavior and achieve confidence in predicting long-term transport. Without a conceptual model that can successfully predict long-term Pu behavior and ultimately isolation from the biosphere, the public will remain skeptical that nuclear energy is a viable and an attractive alternative to counter global warming effects of carbon-based energy alternatives. This review summarizes our current understanding of the relevant conditions and processes controlling the behavior of Pu in the environment, gaps in our scientific knowledge, and future research needs.


Effectiveness and safety of massage for athletic injuries: A protocol for systematic review and meta-analysis.
Athletic injuries have been a major area of interest in the field of sports and clinical medicine. Implemented on people's skin, muscles, and joints as an important part of complementary and alternative medicine (CAM), massage therapy has a positive effect on athletic injuries. This protocol is to provide the methods used to evaluate the effectiveness and safety of massage therapy for patients with athletic injuries. A systematic search will be performed in the following electronic databases for randomized controlled trials (RCTs) to evaluate the effectiveness and safety of massage therapy in treating athletic injuries: PubMed, the Cochrane Library, EMBASE and four Chinese databases (CNKI, Wan Fang, CBMdisc and VIP). Each database will be searched from inception to July 2021. The entire process will include study selection, data extraction, risk of bias assessment and meta-analysis. A high-quality synthesis of current evidence of massage therapy for patients with athletic injuries will be provided. This systematic review will provide evidence for assessing the credibility of massage therapy for patients with athletic injuries. The results of this review will be disseminated through peer-reviewed publication. This review does not require ethical approval because all the data used in this systematic review and meta-analysis have already been published. Furthermore, all of these data will be analyzed anonymously during the review process. INPLASY202170066.


[Meta-analysis in medicine].
Systematic reviews are widely used in medicine as a method of decision making based on evidences. The systematic review is a method of locating and evaluation of a synthesising evidence. Meta-analysis refers to quantitative synthesis of the results of clinical trials or other primary studies. Simple introductory account about meta-analysis is given. We describe two examples of meta-analysis application and strengths and weaknesses of this research method.


European comparison of costs and quality in the treatment of acute myocardial infarction (2000-2001).
To compare the inpatient costs and process quality in the treatment of acute myocardial infarction in France, Germany, Italy, The Netherlands, Sweden, Switzerland, and the U.K. A total of 208 European hospitals assessed services for one hypothetical average patient with acute myocardial infarction (cost evaluation) and prospectively followed up one or two real acute myocardial infarction patients (quality evaluation) in 2000/2001. The following cost modules were evaluated: general medicine ward, critical care unit (both personnel costs only), and reperfusion therapy. The following process quality indicators were evaluated: reperfusion therapy; and prescription of aspirin, lidocaine, beta-blockers, and ACE inhibitors. Switzerland, Germany, and France had the highest reperfusion costs due to a relatively high percentage of patients receiving percutaneous transluminal coronary angioplasties, stents, and glycoprotein IIb/IIIa blockers. Personnel costs for general medicine wards and critical care units were highest in Italy and Germany due to relatively long hospital stays. Average quality ratings ranged from 89% in the U.K. and France to 96% in Germany. There was little variation in the process quality of care for treating acute myocardial infarction. Differences in resource use may result from differences in the types of reimbursement and in the rates of diffusion of new technology.


Non-invasive monitoring of subclinical and clinical actinic keratosis of face and scalp under topical treatment with ingenol mebutate gel 150 mcg/g by means of reflectance confocal microscopy and optical coherence tomography: New perspectives and comparison of diagnostic techniques.
Actinic keratosis (AK) corresponds to the earliest stage of in situ squamous cell carcinoma and arises on chronically sun-exposed skin. Around the clinically evident AKs, the apparently healthy epidermis may contain different grades of atypia that can be detected by noninvasive imaging techniques such as reflectance confocal microscopy (RCM) and optical coherence tomography (OCT). Subclinical actinic keratosis (sAK) has captured increasing interest as a potential target of field therapies. The aim of this study was to evaluate in vivo the changes in the field cancerization undergoing treatment with topical ingenol mebutate by combining RCM and OCT. Twenty patients with field cancerization of the face and scalp were treated with ingenol mebutate gel (150 mcg/g) for three consecutive days on an area of 25 cm2 containing at least two AKs, two sAKs and two apparently healthy sites. About 120 lesions were evaluated through clinical investigation and clinical, dermoscopical, RCM and OCT images at day 0, 4, 14 and 56 based on the diagnostic criteria for AKs. Main pathological features improved in both AKs and sAKs, in particular the epidermal thickness measured by OCT and the epidermal atypia graded by RCM. Local skin reactions (LSR) arose predominantly in the lesional area compared with healthy skin. A complete clearance was detected in 58% for AKs, and in 55% and 72% for sAKs measured by RCM and OCT, respectively. Both OCT and RCM allow the morphological representation of field cancerization including subclinical lesions and provide complementary information. Ingenol mebutate is effective not only in clinically evident but also in sAKs. The differences in LSR highlight the potential selectivity of the treatment.


[Magnetic resonance tomography as a localization method in hyperparathyroidism].
Magnetic Resonance Imaging (MRT) was performed in 36 consecutive patients with hyperparathyroidism. MR tomograms of 31 patients were evaluated and compared with the results of operation and histology (n = 29). In the remaining 5 patients MR examination was not completed, due to claustrophobia or motion artefacts. MR examinations were performed in 2 superconductive magnets (0.5 and 1.5 Tesla). A surface coil with following spinecho sequences was used: SE: TR/TE: 550-700/15-30; 2000/22-100. All patients were subjected to additional sonography. Out of 28 parathyroid adenomas 25 were identified on MR tomograms (sensitivity: 73%, specificity: 90%). However, only 2 out of 6 hyperplastic parathyroid glands were localized on MR tomograms. Lesions missed on MR tomograms measured 15 mm and less in diameter. It is characteristic that parathyroid adenomas showed isointense MR signal to the thyroid (SE 550/30 and hyperintense MR signal to fat (SE 2000/100). Different signal intensities of the adenomas were observed in 25% of the cases. MR imaging is a valuable diagnostic method for preoperative localisation of parathyroid adenomas. We think that MR imaging should be performed when sonography and subtraction scintigraphy are not able to identify a suspected adenoma in the same location.


Cutting edge: induction of the antigen-processing enzyme IFN-gamma-inducible lysosomal thiol reductase in melanoma cells Is STAT1-dependent but CIITA-independent.
Presentation and CD4(+) T cell responses to Ag in the context of MHC class II molecules require processing of native proteins into short peptide fragments. Within this pathway, IFN-gamma-inducible lysosomal thiol reductase (GILT) functions to catalyze thiol bond reduction, thus unfolding native protein Ag and facilitating further processing via cellular proteases. In contrast with professional APCs such as B cells, class II-positive human melanomas expressed relatively little to no GILT protein or mRNA. Tumor cell GILT expression was partially restored with IFN-gamma treatment but unlike other genes required for class II Ag presentation, GILT was not regulated by CIITA. Rather, studies revealed STAT1 plays a direct role in IFN-gamma-inducible GILT expression. These results define a molecular mechanism for the uncoupled regulation of MHC class II genes and the processing enzyme GILT in human melanomas.


Experience with peritoneal mesothelioma at the Milan National Cancer Institute.
Diffuse malignant peritoneal mesothelioma (DMPM) is an uncommon and rapidly fatal tumor. Therapeutic options have traditionally been limited and ineffective. The biologic and molecular events correlated with poor responsiveness to therapy are still poorly understood. In recent years, an innovative treatment approach involving aggressive cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy has reportedly resulted in improved outcome, as compared to historical controls. Since 1995, at the National Cancer Institute (NCI) of Milan (Italy), patients with DMPM have been treated with CRS and hyperthermic intra-peritoneal chemotherapy (HIPEC). In the present paper, clinical experiences and basic science investigations on DMPM at Milan NCI are reviewed. Peri-operative and long-term outcome results with CRS and HIPEC are presented. Clinico-pathological prognostic factors were investigated by multivariate analysis. The pathologic features and immunohistochemical markers related to DMPM biologic behavior were assessed in a large case-series uniformly treated at our institution. The prevalence and prognostic role of telomere maintenance mechanisms, which account for the limitless cell replicative potential of many malignancies, were studied. The dysregulation of the apoptotic pathways may play a role in the relative chemo-resistance of DMPM and a better understanding of apoptosis-related mechanisms could result in novel targeted therapeutic strategies. On this basis, the expression of survivin and other IAP family members (IAP-1, IAP-2, and X-IAP), the pro-apoptotic protein Smac/DIABLO, and antigens associated with cell proliferation (Ki-67) and apoptosis (caspase-cleaved cytokeratin-18) were analyzed. Finally, analyses of EGFR, PDGFRA and PDGFRB were performed to ascertain if deregulation of RTK could offer useful alternative therapeutic targets.


The distribution and the antimicrobial susceptibility features of microorganisms isolated from the burn wounds; a ten-year retrospective analysis.
In this study we aimed to evaluate the distribution features and antimicrobial susceptibility test results of the microorganisms isolated from the wounds of pediatric and adult burn patients. The culture and susceptibility test results of the microorganisms isolated from the wound swabs of the patients hospitalised in a tertiary burn care center in 10-years period, were retrospectively screened on the microbiology department databases. Their distribution of isolated microorganisms regarding species and susceptibility test results were compared with previous studies. A total of 367 microorganisms isolated from the burn wounds of 293 patients (13± 18.9 years, F/M: 0.93) (73 adult and 220 pediatric patients), were included in this study. A solitary agent was isolated in 239 (81.6%) patients, while two were isolated in 43 (14.7%) and three or more agents in 11 (3.8%). From these, 33% of the isolated microorganisms were gram positive cocci, 61% were gram negative bacteria and 6% were Candida spp. The most common isolated microorganisms were Staphylococcus aureus (18.5%), Pseudomonas spp. (16.9) and Escherichia coli (%11.2), while the least common was Streptococcus spp. (2.5%). Methicillin resistance was 15% among the S. aureus strains. No resistance was observed against levofloxacin, vancomycin, teicoplanin, linezolid, daptomycin, fusidic acid and tigecycline in S. aureus strains. The highest resistance rates were observed against levofloxacin (64%), tobramycin (64%), pip/tazobactam (63%), imipenem (63%), and the lowest against colistin (5%) and ceftazidime (29%), among Pseudomonas spp. The most common causative agents in burn wound infections and their current antimicrobial susceptibility features should be well identified, in order for prevention of serious complications and optimal management the condition to occur.


Treatment of Denture Stomatitis Using Modified Tissue Conditioners: A Systematic Review.
The most common sequela of wearing removable dentures is denture stomatitis. This review article uses a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) format to collect data regarding articles that report on the treatment of denture stomatitis using tissue conditioners modified with antifungal drugs, inorganic compound, and phytomedicines. Their advantages, disadvantages, and mechanism of action are discussed.


The critical period for darkness-induced recovery of the vision of the amblyopic eye following early monocular deprivation.
Exposure of kittens to complete darkness for 10 days has been shown (Duffy & Mitchell, 2013) to reverse the loss of visual acuity that follows a prior period of monocular deprivation (MD). In that study, recovery of acuity in the previously deprived eye was fast despite the fact that darkness was imposed 2 months after the period of MD when kittens were 3 months old. In a later study (Holman, Duffy, & Mitchell, 2018), it was demonstrated that the same period of darkness was ineffective when it was imposed on cats about 1 year old, suggesting that dark exposure may only promote recovery when applied within an early critical period. To determine the profile of this critical period, the identical period of darkness (10 days) was imposed on kittens at various ages that had all received the same 7-day period of MD from postnatal day 30 (P30). Recovery of the acuity of the deprived eye as measured by use of a jumping stand was complete when darkness was imposed prior to P186 days, but thereafter, darkness induced progressively smaller acuity improvements and was ineffective in kittens when it began at or beyond P191 days of age. These data indicate a critical period for darkness-induced recovery with an abrupt end over a 5-day period.


Arthroscopy-assisted combined external and internal fixation of a pilon fracture of the tibia.
There are serious problems with existing methods of treating pilon fractures of the tibia caused by high-energy trauma. The method chosen to treat these fractures should not raise the risk of infection while effectively restoring the joint surface. We successfully treated a 42-year-old male patient with a pilon fracture caused by high-energy trauma using an arthroscopy-assisted unilateral external fixator and minimally invasive internal osteosynthesis. We used arthroscopy to reposition the fracture fragments and restore the joint surface. The fracture fragments were fixed with screws immediately after being repositioned. We believe that arthroscopy-assisted combined external and minimally invasive internal fixation is the treatment of choice for these fractures. We used external fixation to improve the fracture alignment, arthroscopy for restoring the joint surface, and minimally invasive screws to ensure fragment stability.


Contextual factors determine the use of allocentric information for reaching in a naturalistic scene.
Numerous studies have demonstrated that humans incorporate allocentric information when reaching toward visual targets. So far, it is unclear how this information is integrated into the movement plan when multiple allocentric cues are available. In this study we investigated whether and how the extent of spatial changes and the task relevance of allocentric cues influence reach behavior. To this end, we conducted two experiments where we presented participants three-dimensional-rendered images of a naturalistic breakfast scene on a computer screen. The breakfast scene included multiple objects (allocentric cues) with a subset of objects functioning as potential reach targets (i.e., they were task-relevant). Participants freely viewed the scene and after a short delay, the scene reappeared with one object missing (target) and other objects being shifted left- or rightwards. Afterwards, participants were asked to reach toward the target position on a gray screen while fixating the screen center. We found systematic deviations of reach endpoints in the direction of object shifts which varied with the number of objects shifted, but only if these objects served as potential reach targets. Our results suggest that the integration of allocentric information into the reach plan is determined by contextual factors, in particular by the extent of spatial cue changes and the task-relevance of allocentric cues.


The potential of pharmacogenetics in optimizing the use of methotrexate for psoriasis.
The study of pharmacogenetics will optimize the use of systemic therapies in dermatology. Directed prescription of azathioprine dependent on phenotypic expression of the thiopurine methyltransferase gene is now accepted practice. To some extent other, older drugs have been neglected. We look at the role that pharmacogenetics could play in the use of methotrexate for psoriasis, focusing on known polymorphisms in the folate metabolic pathway.


Design, synthesis, DFT calculations, molecular docking and antimicrobial activities of novel cobalt, chromium metal complexes of heterocyclic moiety-based 1,3,4-oxadiazole derivatives.
A Schiff base, 5-(4-methylphenyl)-4-[(pyridin-2-ylmethylidene)amino]-4H-1,2,4-oxadiazole as a bidentate ligand has been synthesized by the reaction between the 4-amino-5-(4-methylphenyl)-4H-1,3,4-oxadiazole and aromatic aldehyde. The Schiff base reacted with CoCl3·6H2O and CrCl3·6H2O in ethanol to yield 1,3,4-oxadiazole complexes. The structures of synthesized ligand and their complexes have been established on the basis of their IR, Mass and 1H-NMR spectra. Electronic and geometric structures of both cobalt and chromium complexes were investigated by density functional theory (DFT) and quantum theory of atoms in molecules (QTAIM) calculations. DFT-based reactivity calculations estimated the studied system as strong electrophile and/or strong nucleophile in polar organic reactions. Moreover, most reactive sites were predicted theoretically based on the delocalized and localized indexes. The nature of Ligand-Metal chemical bonding is discussed in terms of the natural bond orbital (NBO) and QTAIM analysis. Accordingly, the metal ions such as cobalt and chromium are bidentate coordinated with the Schiff base by nitrogen atoms of imine function and pyridine, to form stable complexes. Furthermore, the chromium ions have an affinity superior to the cobalt ions towards Schiff base ligand. In addition, the results of the antibacterial activity in-vitro show that the metal complexation confers an increase in the antibacterial activity of the complexed ligand compared to the free ligand against both Gram-positive and Gram-negative bacteria with broad spectrum activity. In silico molecular docking studies of the ligands and their complexes were applied to describe the probable binding modes into the active site of Escherichia coli (E. coli) FabH and Salmonella typhimurium LT2 neuraminidase (STNA) receptors. The increase in biological activity could be attributed to the high stability of the complexes and strong affinities to bacterial enzyme receptors.Communicated by Ramaswamy H. Sarma.


Coarse-graining methods for computational biology.
Connecting the molecular world to biology requires understanding how molecular-scale dynamics propagate upward in scale to define the function of biological structures. To address this challenge, multiscale approaches, including coarse-graining methods, become necessary. We discuss here the theoretical underpinnings and history of coarse-graining and summarize the state of the field, organizing key methodologies based on an emerging paradigm for multiscale theory and modeling of biomolecular systems. This framework involves an integrated, iterative approach to couple information from different scales. The primary steps, which coincide with key areas of method development, include developing first-pass coarse-grained models guided by experimental results, performing numerous large-scale coarse-grained simulations, identifying important interactions that drive emergent behaviors, and finally reconnecting to the molecular scale by performing all-atom molecular dynamics simulations guided by the coarse-grained results. The coarse-grained modeling can then be extended and refined, with the entire loop repeated iteratively if necessary.


[Supervised bimonthly quadruple chemotherapy in 72 paucibacillary leprosy patients in French Guyana].
In French Guyana we have treated 72 paucibacillary leprosy with an association of Rifadine + Lamprene + Trecator + Disulone given twice monthly under supervision during 6 months. Results have been satisfying and side effects rare. The sequential character of treatment shows a substantial advantage on the operational side but may appear to be favorable to bacterial resistance.


N,N-dialkylated leucine enkephalins as potential delta opioid receptor antagonists.
A series of N,N-dialkylated leucine enkephalins were prepared in order to study the effect of substitution on antagonist activity at the delta opioid receptor. The target peptides 1-7 were evaluated in the mouse vas deferens (MVD) and guinea pig ileum (GPI) at 1 microM. All of the compounds except [N,N-di-2-phenethyl,Leu5]enkephalin (7) showed antagonist activity in the MVD against the delta receptor agonist [D-Ala2,D-Leu5]enkephalin. The most potent congener, [N,N-dibenzyl,Leu5]enkephalin (3), was 2.5-fold more potent than [N,N-diallyl,Leu5]enkephalin (1). None of the compounds at 1 microM showed any antagonist activity against agonists for other receptor types. The N,N-di-2-phenethyl (7) and N,N-dioctyl (6) analogues showed significant agonist activity at 1 microM in the MVD.


Complex arteriovenous fistula of the brain in an infant. Case report.
A rare case of complex cerebral arteriovenous fistula in an infant is reported. An 8-month-old boy first presented with a syndrome of increased intracranial pressure. Neuroradiological assessment showed a direct intracerebral arteriovenous shunt with marked venous engorgement. No hemorrhage was evident. Direct surgical treatment was decided. Clinical and radioanatomical cure was achieved. The main angiographic and pathophysiologic features of this unusual entity, as well as the available therapeutic options, are reviewed and discussed.


Arm Contouring: Review and Current Concepts.
Arm contour improvement is a desired goal of the massive weight loss and the aging population who want to maintain the arm aesthetics. Brachioplasty is a growing and safe procedure to improve the arm contour and different approaches and innovative treatment options have been described since the 1930s. This paper reviews the relevant literature in arm contouring including surgical and nonsurgical procedures used to aesthetically improve the arm. A comprehensive literature review was performed using the words "brachioplasty," "arm lift," "arm contouring," "arm liposuction," "noninvasive arm lift," "minimally invasive arm lift." Commonly used techniques, classification systems, and procedure outcomes are described. The review demonstrated that there are several methods to accomplish good arm contouring. There is no consensus about the best incision type and location, but the classification systems help guide treatment. Assessment of fat excess, skin excess, and location of the deformity (proximal, entire arm, arm and chest) help determine the best approach including liposuction only, skin resection only, a combination of liposuction and excision, or even the use of nonsurgical devices. Infection, hematoma, and unsatisfactory scars are the most commonly reported complications. Brachioplasty is a growing procedure and can be performed with low complication rates and good patient satisfaction. Classification systems stratify deformities to the ideal treatment but no studies have shown the superiority of any technique. Nonsurgical fat removal and skin tightening of the arms are promising procedures for selected patients and higher levels of evidence are needed to show clear indication for different technologies and devices.


Microsporogenesis in Brachiaria dictyoneura (Fig. & De Not.) Stapf (Poaceae: Paniceae).
Microsporogenesis was analyzed in five accessions of Brachiaria dictyoneura presenting x = 6 as the basic chromosome number. All accessions were tetraploid (2n = 4x = 24) with chromosome pairing in bi-, tri-, and quadrivalents. The recorded meiotic abnormalities were those typical of polyploids, including precocious chromosome migration to the poles, laggard chromosomes, and micronucleus formation. The frequency of these abnormalities, however, was lower than those reported for other polyploid accessions previously analyzed for other Brachiaria species. Cell fusion and absence of cytokinesis were also recorded in some accessions, leading to restitutional nucleus formation in some cells. Genetically unbalanced microspores, binucleate, and 2n microspores were found among normal meiotic products as results from these abnormalities. The limitation in using these accessions as pollen donor in interspecific crosses with sexual species with x = 7 or x = 9 in breeding programs is discussed.


Transcriptional silencing of ETS-1 abrogates epithelial-mesenchymal transition resulting in reduced motility of pancreatic cancer cells.
v-ets erythroblastosis virus E26 oncogene homolog 1 (ETS-1) plays crucial roles in a spectrum of malignancies. ETS-1 has gained attention in cancer research for its importance in cell migration, invasion and proliferation. In the present study, we focused on the effect of ETS-1 on epithelial-mesenchymal transition (EMT), which is characterized by reduced E-cadherin expression and increased N-cadherin expression. We found that ETS-1 mRNA expression was positively correlated with N-cadherin and negatively correlated with E-cadherin mRNA expression in five pancreatic cancer cell lines. To elucidate the functionality of ETS-1 on EMT in pancreatic cancer cells, we constructed a green fluorescent protein (GFP)-expressing plasmid carrying ETS-1 short hairpin RNA (shRNA), and transfected Panc-1 cells with the plasmid. We detected reduced N-cadherin and vascular endothelial growth factor yet higher E-cadherin expression in the ETS-1-silenced cells compared with the control group. In addition, we observed reduced cell migration and increased adhesion in these cells. Our data showed that ETS-1 actively functioned as a regulator of EMT in Panc-1 cells, and provide additional evidence supporting a fundamental role for ETS-1 in metastatic pancreatic cancer cells. These results suggest that analysis of ETS-1 expression levels may provide an avenue for evaluating prognosis in pancreatic cancer.


Statins in chronic kidney disease: cardiovascular risk and kidney function.
Chronic kidney disease (CKD) represents a serious public health concern. It has been associated with a significant burden of cardiovascular disease and studies have linked decreases in estimated glomerular filtration rate to higher incidences of cardiovascular events and mortality. Evidence from randomized clinical trials have shown that statins are a safe and effective treatment for improving cardiovascular outcomes in primary and secondary cardiovascular disease prevention in patients with CKD; despite this, statins are often underutilized in these patients. In addition to cardiovascular benefits, statin therapy may be associated with improvements in renal function in patients with kidney disease. Some statin treatment regimens have been shown to slow decline in kidney function, and some trials have found that intensive statin therapy improved kidney function. This review examines improved cardiovascular outcomes with statin treatment in patients with CKD (excluding end-stage renal disease) and investigates the effects of statin therapy on kidney function.


In Situ Detection and Imaging of Telomerase Activity in Cancer Cell Lines via Disassembly of Plasmonic Core-Satellites Nanostructured Probe.
The label-free localized surface plasmon resonance (LSPR) detection technique has been identified as a powerful means for in situ investigation of biological processes and localized chemical reactions at single particle level with high spatial and temporal resolution. Herein, a core-satellites assembled nanostructure of Au50@Au13 was designed for in situ detection and intracellular imaging of telomerase activity by combining plasmonic resonance Rayleigh scattering spectroscopy with dark-field microscope (DFM). The Au50@Au13 was fabricated by using 50 nm gold nanoparticles (Au50) as core and 13 nm gold nanoparticles (Au13) as satellites, both of them were functionalized with single chain DNA and gathered proximity through the highly specific DNA hybridization with a nicked hairpin DNA (O1) containing a telomerase substrate (TS) primer as linker. In the presence of telomerase, the telomeric repeated sequence of (TTAGGG)n extended at the 3'-end of O1 would hybridized with its complementary sequences at 5'-ends. This led the telomerase extension product of O1 be folded to form a rigid hairpin structure. As a result, the Au50@Au13 was disassembled with the releasing of O1 and Au13-S from Au50-L, which dramatically decreased the plasmon coupling effect. The remarkable LSPR spectral shift was observed accompanied by a detectable color change from orange to green with the increase of telomerase activity at single particle level with a detection limit of 1.3 × 10-13 IU. The ability of Au50@Au13 for in situ imaging intracellular telomerase activity, distinguishing cancer cells from normal cells, in situ monitoring the variation of cellular telomerase activity after treated with drugs were also demonstrated.


Neural voting machines.
A "Winner-take-all" network is a computational mechanism for picking an alternative with the largest excitatory input. This choice is far from optimal when there is uncertainty in the strength of the inputs, and when information is available about how alternatives may be related. For some time, the Social Choice community has recognized that many other procedures will yield more robust winners. The Borda Count and the pair-wise Condorcet tally are among the most favored. If biological systems strive to optimize information aggregation, then it is of interest to examine the complexity of networks that implement these procedures. We offer two biologically feasible implementations that are relatively simple modifications of classical recurrent networks.


Intestinal secretion is a major route for parent ivermectin elimination in the rat.
The transepithelial intestinal elimination of ivermectin was studied using the intestinal closed-loop model in the rat. The common bile duct was cannulated, and duodenum, jejunum, and ileum were isolated in situ with their intact blood supplies. Following administration of 100, 200, or 400 microg/kg b.wt. ivermectin via the carotid artery, the elimination of parent ivermectin into the small intestinal lumen over 90 min was approximately 5-fold higher than in bile. The major amount of secreted ivermectin was recovered in the jejunum, but the duodenum showed a higher intestinal elimination capacity than the other intestinal segments with respect to the intestinal length. Systemic coadministration of the P-glycoprotein blocker verapamil significantly reduced the elimination capacity of jejunum by 50%, which resulted in a 30% decrease of ivermectin overall elimination by the small intestine. In contrast, verapamil did not significantly affect ivermectin secretion in duodenum, ileum, or bile in the same animals. Ivermectin small intestinal and biliary clearances were estimated to account for 27 and 5.5% of the total drug clearance, which was evaluated from a parallel in vivo experiment in which rats were given 200 microg/kg b.wt. ivermectin intra-arterially. In conclusion, intestinal secretion plays a greater role than biliary secretion in the overall elimination of ivermectin in the rat, providing major amounts of active drug to the intestinal lumen and to feces. This is discussed in terms of therapeutic efficacy against intestinal parasites in humans and animals and of ecotoxicity resulting from the contamination of livestock dung with parent drug.


RNA tertiary interactions mediate native collapse of a bacterial group I ribozyme.
Large RNAs collapse into compact intermediates in the presence of counterions before folding to the native state. We previously found that collapse of a bacterial group I ribozyme correlates with the formation of helices within the ribozyme core, but occurs at Mg2+ concentrations too low to support stable tertiary structure and catalytic activity. Here, using small-angle X-ray scattering, we show that Mg2+-induced collapse is a cooperative folding transition that can be fit by a two-state model. The Mg2+ dependence of collapse is similar to the Mg2+ dependence of helix assembly measured by partial ribonuclease T1 digestion and of an unfolding transition measured by UV hypochromicity. The correspondence between multiple probes of RNA structure further supports a two-state model. A mutation that disrupts tertiary contacts between the L9 tetraloop and its helical receptor destabilized the compact state by 0.8 kcal/mol, while mutations in the central triplex were less destabilizing. These results show that native tertiary interactions stabilize the compact folding intermediates under conditions in which the RNA backbone remains accessible to solvent.


Cardiac manifestations of neurologic disorders.
The cardiac complications of certain neurologic diseases have been well recognized for over 50 years and are mostly evident for cerebrovascular accidents. Although these complications are frequent and in most circumstances benign, detrimental cardiac side effects, such as serious arrhythmias and myocardial infarctions, may occur. The link to most of these cardiac derangements is a transient or chronic autonomic dysfunction, depending on the specific neurologic disease. Myocardial infarcts, left ventricular dysfunction, and arrhythmias are well-recognized complications of subarachnoid hemorrhage, intracranial bleed, and ischemic strokes. Seizures may present with atonia or sudden death from asystole. Degenerative brain disorders, namely the synucleinopathies, may affect the central control areas or peripheral ganglia of the autonomic nervous system, causing autonomic dysfunction. In addition, cardiac conduction defects and cardiomyopathy are common in certain neuromuscular disorders, namely the dystrophies and mitochondrial myopathies.


Metabolism of proline in a human leukemic lymphoblastoid cell line.
Amino acid analysis of the culture medium was carried out in a human leukemic lymphoblastoid cell line (REH) established from the lymphoblasts of a patient with acute lymphoid leukemia. The results are compared with those of a reference cell line (LHN13) established from normal human lymphocytes. The most striking difference between these two cell lines concerns proline. In LHN13 the concentration of this amino acid in the culture medium increases by 40 microgram/ml/10(6) cells during a 72-hr incubation. In REH there is a decrease under the same culture conditions. In both cell lines proline is derived from glutamic acid and from arginine, as found with the use of 14C-labeled precursors. Synthesis of proline in the REH line represents approximately 26% of the value measured in LHN13 when the precursor is glutamic acid and 15% when the precursor is arginine. The radioisotopic assay for delta1-pyrroline-5-carboxylate reductase showed that there is a deficiency of this enzyme in the REH cells. The defect in proline synthesis of REH was found at the establishment of this line and constitutes a metabolic marker that has persisted for more than 2 years.


A Comprehensive Research on the Prevalence and Evolution Trend of Orthopedic Surgeries in Romania.
Accurate knowledge of the prevalence and trends of orthopedic surgeries can facilitate the design of medical plans for effective treatments. The National Endoprosthetic Registry (NER) in Romania provides statistics on endoprosthetic activity (hip, knee), cases of fractures and bone tumors as a result of the legal obligations to report interventions performed by all orthopedic traumatology hospitals/wards in the country. The aim of this study is to describe the annual volumes of orthopedic surgeries between 2001 and 2022 in Romania and analyze the current and future evolution trends of the studied surgeries, gender differences and regional differences based on a complete survey carried out at a national level. For the period 2001-2022, we extracted from the NER the annual volumes of orthopedic interventions performed. With these data, we studied the prevalence and estimated, with the support of an original calculation methodology, the variation trends of orthopedic surgeries in two situations: over the entire 21-year period, respectively, and over the period 2001-2020, which does not include the pandemic period. For hip replacement surgery and knee replacement surgery, we showed the prevalence by subcategory of interventions, gender distribution, regional prevalence and regional density calculated by the annual averages of the total number of cases reported per 100,000 people in the 40 counties of the country and the capital, Bucharest. We also determined the variations in hip and knee arthroplasty revision burdens, calculated as a percentage between the number of revisions and the number of primary interventions in the same period. We determined the regional densities of revision burdens. The total number of orthopedic surgeries in the period 2001-2022 was 1,557,247, of which 189,881 were hip replacement surgeries; 51,035 were knee replacement surgeries; 11,085 were revision hip arthroplasty; 1497 were revision knee arthroplasty; 541,440 were operated fractures; and 16,418 were operated bone tumors. The growth rates of surgical interventions are hip replacement surgery, +8.19%; knee replacement surgery, +19.55%; revision hip arthroplasty, +9.43%; and revision knee arthroplasty, +28.57%. With these data, we have estimated a doubling of the volume of primary and revision interventions of the hip until 2034 and the knee until 2027, respectively. Operated bone tumors register an annual decrease of -4.52% thanks to modern treatments. There are clear gender differences; for primary hip interventions, the proportion of women is 58.82%, and for knee interventions, the proportion of women is 76.42%. This is the first research that, with the support of exhaustive data from the NER, analyzes for the period 2001-2022 the annual number of orthopedic surgeries in Romania. It allows knowledge of the large, anticipated increases in orthopedic surgery and provides a quantitative basis for future policy decisions related to the need for medical personnel and material resources.


Urine Metabonomics Reveals Early Biomarkers in Diabetic Cognitive Dysfunction.
Recently, increasing attention has been paid to diabetic encephalopathy, which is a frequent diabetic complication and affects nearly 30% of diabetics. Because cognitive dysfunction from diabetic encephalopathy might develop into irreversible dementia, early diagnosis and detection of this disease is of great significance for its prevention and treatment. This study is to investigate the early specific metabolites biomarkers in urine prior to the onset of diabetic cognitive dysfunction (DCD) by using metabolomics technology. An ultra-high performance liquid-chromatography-quadrupole time-of-flight-mass spectrometry (UPLC-Q/TOF-MS) platform was used to analyze the urine samples from diabetic mice that were associated with mild cognitive impairment (MCI) and nonassociated with MCI in the stage of diabetes (prior to the onset of DCD). We then screened and validated the early biomarkers using OPLS-DA model and support vector machine (SVM) method. Following multivariate statistical and integration analysis, we found that seven metabolites could be accepted as early biomarkers of DCD, and the SVM results showed that the prediction accuracy is as high as 91.66%. The identities of four biomarkers were determined by mass spectrometry. The identified biomarkers were largely involved in nicotinate and nicotinamide metabolism, glutathione metabolism, tryptophan metabolism, and sphingolipid metabolism. The present study first revealed reliable biomarkers for early diagnosis of DCD. It provides new insight and strategy for the early diagnosis and treatment of DCD.


Mechanisms of allergic diseases in Otorhinolaryngology.
Allergic Rhinitis (AR) is an IgE-mediated hypersensitivity disease caused by inhalation of an allergen to which the patients is sensitized. Etiopathogenesis of AR comprises a sensitization phase, an immediate phase and a late phase. In the sensitization phase, inhaled allergens are processed in peptides and come into contact with the nasal mucosa cells. Antigen-Presenting Cells (APCs), especially represented by Dendritic Cells (DCs), capture them through the interaction with their own MHC class II complexes and migrate to lymph nodes. Then, allergenic peptides are presented to naïve CD4+ T lymphocytes and a differentiation of T cells in Th2 subset takes place. After Th2 lymphocyte induction due to allergen exposure, the most relevant cytokines that are produced are represented by IL-3, IL-4, IL-5, IL-9, IL-10, and IL-13 that are able to promote IgE synthesis and mast cell proliferation. The allergen reaction, when allergen meets its specific IgEs on mast cells surface, causes an early inflammatory reaction determined by mast cells and basophils degranulation with release of preformed mediators from the intracellular granules, resulting in symptoms such as rhinorrhea, itching and sneezing. This phase is followed by a late phase characterized by the release of newly formed mediators, like leukotrienes, chemokines and adhesion molecules, and by the recruitment of eosinophils, neutrophils, macrophages, mast cells, lymphocytes B and T in the nasal mucosa. Such mechanism is responsible for continuing inflammation sustained by chemoattractants, cytokines and adhesion receptors that induce cellular infiltration of eosinophils, basophils, Th2 lymphocytes and mast cells and is clinically mirrored by the prevalence of nasal congestion over sneezing, itching and rhinorrhea.


Inverse Design of Next-Generation Superconductors Using Data-Driven Deep Generative Models.
Finding new superconductors with a high critical temperature (Tc) has been a challenging task due to computational and experimental costs. We present a diffusion model inspired by the computer vision community to generate new superconductors with unique structures and chemical compositions. Specifically, we used a crystal diffusion variational autoencoder (CDVAE) along with atomistic line graph neural network (ALIGNN) pretrained models and the Joint Automated Repository for Various Integrated Simulations (JARVIS) superconducting database of density functional theory (DFT) calculations to generate new superconductors with a high success rate. We started with a DFT data set of ∼1000 superconducting materials to train the diffusion model. We used the model to generate 3000 new structures, which along with pretrained ALIGNN screening results in 61 candidates. For the top candidates, we performed DFT calculations for validation. Such approaches go beyond funnel-like materials screening approaches and allow for the inverse design of next-generation materials.