The interaction of catalytic metal ions and ionizing groups in equilibrium studies and in transient intermediates of metal-substituted alcohol dehydrogenases.
The step of ternary complex interconversion in the reaction catalyzed by horse liver alcohol dehydrogenase has been resolved into five distinct molecular species with the aid of metal-substitution studies in combination with rapid-scanning spectrophotometry. A correlation with electronic absorption spectra at equilibrium provides structural insights into these intermediates. In contrast to NADH, NAD+ only leads to a conformational change of the protein when a negative charge has been created in the vicinity of the catalytic metal ion. This paper presents also a reevaluation of previous assignments of catalytically important groups in the light of some recent results.


Phenotypic and genetic characterisation of bacteriocin-producing strains of Staphylococcus aureus involved in bovine mastitis.
Fifty strains of Staphylococcus spp. isolated from bovine mastitis cases in several herds from different Argentinian provinces were screened for antimicrobial substances. Twelve strains exhibited a high antagonistic activity against the indicator strain (Corynebacterium fimi) and were chosen for further characterisation. The antimicrobial substances were sensitive to proteolytic enzymes suggesting that they might be bacteriocins (Bac). These strains were identified as S. aureus by the amplification of the femA gene. Plasmid profile analysis of these strains revealed the presence of at least one plasmid. Eleven strains carried a plasmid with a size similar to that of pRJ6 (8.0kb), which encodes aureocin A70, a bacteriocin produced by the Brazilian S. aureus strain A70 isolated from commercial milk. The other strain harboured a much larger plasmid. PCR experiments, using specific primers for amplification of the bacteriocin operon found in pRJ6, showed that all strains had the expected 525bp amplicon, suggesting that the bacteriocin produced may be related to aureocin A70. The genomic DNA of all Bac(+) strains was then analysed by pulsed-field gel electrophoresis (PFGE) in order to investigate clonal relationships amongst strains. Based on the results of PFGE experiments, 10 out of the 12 Bac(+) strains belonged to the same clone. The remaining two strains are possibly related to the prevalent clone. The aureocin A70 producer-strain belonged to a distinct clone.


4-aminomethylbenzoic acid is a non-translocated competitive inhibitor of the epithelial peptide transporter PepT1.
1. 4-Aminomethylbenzoic acid, a molecule which mimics the special configuration of a dipeptide, competitively inhibits peptide influx in both Xenopus Laevis oocytes expressing rabbit PepT1 and through PepT1 in rat renal brush border membrane vesicles. 2. This molecule is not translocated through PepT1 as measured both by direct HPLC analysis in PepT1-exp ressing oocytes and indirectly by its failure to trans-stimulate labelle d peptide efflux through PepT1 in oocytes and in renal membrane vessicle s. 3. However 4-aminiomethylbenzoic acid does reverse trans-stimulation through expressed PepT1 of labelled peptid efflux induced by unlabelled peptide. Quantitatively this reversal is compatible with 4-aminomethyl benzoic acid competitively binding to the external surface of PepT1. 4. 4-Aminomethylbenzoic acid (the first molecule discovered to be a non-translocated competitive inhibitor of proton-coupled oligopeptide transport) and its derivatives may thus be particularly useful as experimental tools.


Curative-intent radiotherapy for glottic carcinoma in situ.
The aim of the study was to update our experience treating patients with glottic carcinoma in situ (CIS) with curative radiotherapy (RT). Fifty patients received continuous-course RT using once-daily fractionation. Twenty-eight (56%) had recurrent or persistent CIS after resection. Median total dose was 63.0 Gy; median dose per fraction was 2.25 Gy. Median follow-up was 9.6 years for all patients and 8.4 years for survivors. After RT, 5 patients (10%) recurred locally; salvage surgery was performed in 4 (1 refused). Five-year outcomes were as follows: local control, 91%; ultimate local control (including patients successfully salvaged after local recurrence), 100%; ultimate local control with larynx preservation, 93%; local-regional control, 91%; ultimate local-regional control, 100%; distant metastases-free survival, 100%; cause-specific survival, 100%; and overall survival, 81%. No patient experienced a severe complication. RT is an excellent treatment for patients with CIS recurrent after transoral excision and those with previously untreated CIS who are unsuitable for partial laryngectomy.


Successful treatment by chemotherapy for acromegaly associated with ectopic growth hormone releasing hormone secretion from a carcinoid tumour.
Acromegaly secondary to the secretion of ectopic growth hormone releasing hormone (GHRH) is rare. We have documented the presentation and unusual clinical course of a patient with a disseminated GHRH-secreting bronchial carcinoid tumour associated with acromegaly over a 17-year period. Recurrent widespread metastatic lesions have been treated over a 10-year period by repeated cycles of the nitrosourea CCNU and 5-fluorouracil with evidence of tumour regression and reduction of circulating growth hormone (GH) and urinary 5HIAA excretion. This cytotoxic regimen, which has been well tolerated, may prove valuable in the management of disseminated carcinoid tumours.


Long-term supervised domiciliary EEG monitoring in epileptic patients employing radio telemetry and telephone telemetry. I. Telephone telemetry system.
A PCM system provides digital transmission of 8 EEG channels over conventional voice graded telephone lines. Transmission of the EEG from the patient's residence to the clinical centre enables the use of existing monitoring facilities for carrying out continuously supervised long-term domiciliary EEG monitoring. Secondary channels simultaneously enable exchange of information for quality and performance control. The ease of use and the flexibility of the public telephone system enable recording from almost any place desired.


Genetic associations of in vivo pathology influence Alzheimer's disease susceptibility.
Although the heritability of sporadic Alzheimer's disease (AD) is estimated to be 60-80%, addressing the genetic contribution to AD risk still remains elusive. More specifically, it remains unclear whether genetic variants are able to affect neurodegenerative brain features that can be addressed by in vivo imaging techniques. Targeted sequencing analysis of the coding and UTR regions of 132 AD susceptibility genes was performed. Neuroimaging data using 11C-Pittsburgh Compound B positron emission tomography (PET), 18F-fluorodeoxyglucose PET, and MRI that are available from the KBASE (Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's disease) cohort were acquired. A total of 557 participants consisted of 336 cognitively normal (CN) adults, 137 mild cognitive impairment (MCI), and 84 AD dementia (ADD) groups. We called 5391 high-quality single nucleotide variants (SNVs) on AD susceptibility genes and selected significant associations between variants and five in vivo AD pathologies: (1) amyloid β (Aβ) deposition, (2) AD-signature region cerebral glucose metabolism (AD-Cm), (3) posterior cingulate cortex (PCC) cerebral glucose metabolism (PCC-Cm), (4) AD-signature region cortical thickness (AD-Ct), and (5) hippocampal volume (Hv). The association analysis for common variants (allele frequency (AF) > 0.05) yielded several novel loci associated with Aβ deposition (PIWIL1-rs10848087), AD-Cm (NME8-rs2722372 and PSEN2-rs75733498), AD-Ct (PSEN1-rs7523) and, Hv (CASS4-rs3746625). Meanwhile, in a gene-based analysis for rare variants (AF < 0.05), cases carrying rare variants in LPL, FERMT2, NFAT5, DSG2, and ITPR1 displayed associations with the neuroimaging features. Exploratory voxel-based brain morphometry between the variant carriers and non-carriers was performed subsequently. Finally, we document a strong association of previously reported APOE variants with the in vivo AD pathologies and demonstrate that the variants exert a causal effect on AD susceptibility via neuroimaging features. This study provides novel associations of genetic factors to Aβ accumulation and AD-related neurodegeneration to influence AD susceptibility.


Maternal regulation of fecundity: non-random ovule abortion inCassia fasciculata Michx.
We examined the extent of ovule abortion and the within-fruit pattern of abortion inCassia fasciculata, an annual legume, and tested the hypothesis that abortion can result from competition for limited maternal resources among developing fruits and seeds. In a natural population at Mayview, IL, 53.4% of ovules in mature fruits matured as seeds; 43.4% showed some development but aborted, and 3.1% showed no development over virgin ovules. In a greenhouse experiment in which treatments were applied after most fruits were initiated, nutrient addition and partial root removel had no effect on abortion, but drought reduced the proportion of ovules maturing to 75% of the control mean. A fruit thinning experiment was conducted in which the number of fruits initiated on certain plants was limited. Control plants had more ovule abortion than fruit-thinned plants, suggesting that abortion resulted from competition for limited maternal resources. A "position effect" was observed in both field and greenhouse populations; ovules toward the fruit base (pedicellar end) had higher frequencies of abortion than those at the distal end. Thus, ovule abortion, like fruit abortion in this species, is non-random. Indivisuals regulate fecundity at both the whole fruit and individual seed levels.


A retrospective analysis comparing the safety and efficacy of chemotherapy in elderly and non-elderly non-small-cell lung cancer patients.
The number of elderly patients with non-small-cell lung cancer (NSCLC) is increasing in Japan. We retrospectively analyzed and compared the safety and efficacy of chemotherapy in elderly and non-elderly NSCLC patients who received chemotherapy at Shimane University Hospital. We carried out a retrospective analysis of survival in a series of 112 NSCLC patients treated from 2004 through 2009. We compared the data from the elderly group (≥ 70 years-of-age, 56 patients) with the non-elderly group (< 70 years-of-age, 56 patients) who had similar characteristics, such as sex and Eastern Cooperative Oncology Group performance status. We analyzed the patient characteristics, therapeutic regimen, dose intensity, toxicity and survival time in both groups. The patient characteristics were comparable between the two groups; however, there was a significant difference between the choice of first-line therapeutic regimen. A platinum-doublet regimen was more frequently used in the non-elderly population (39.3% vs 64.3% for the elderly patients vs the non-elderly patients, respectively; P < 0.01), whereas single agents and epidermal growth factor receptor-tyrosine kinase inhibitors were more frequent in the elderly population (26.8% vs 10.7%, 19.6% vs 7.1%; P < 0.05, respectively). The relative dose intensity was approximately 80% or higher for all regimens, and toxicity was acceptable. The median survival time was 24.4 months and 18.6 months in the elderly and non-elderly groups, respectively. This retrospective study suggests that elderly patients can safely receive effective chemotherapy similar to non-elderly patients under careful observation and management.


Flipons and small RNAs accentuate the asymmetries of pervasive transcription by the reset and sequence-specific microcoding of promoter conformation.
The role of alternate DNA conformations such as Z-DNA in the regulation of transcription is currently underappreciated. These structures are encoded by sequences called flipons, many of which are enriched in promoter and enhancer regions. Through a change in their conformation, flipons provide a tunable mechanism to mechanically reset promoters for the next round of transcription. They act as actuators that capture and release energy to ensure that the turnover of the proteins at promoters is optimized to cell state. Likewise, the single-stranded DNA formed as flipons cycle facilitates the docking of RNAs that are able to microcode promoter conformations and canalize the pervasive transcription commonly observed in metazoan genomes. The strand-specific nature of the interaction between RNA and DNA likely accounts for the known asymmetry of epigenetic marks present on the histone tetramers that pair to form nucleosomes. The role of these supercoil-dependent processes in promoter choice and transcriptional interference is reviewed. The evolutionary implications are examined: the resilience and canalization of flipon-dependent gene regulation is contrasted with the rapid adaptation enabled by the spread of flipon repeats throughout the genome. Overall, the current findings underscore the important role of flipons in modulating the readout of genetic information and how little we know about their biology.


Toxicity assessment of sanitary landfill leachate before and after Fenton treatment process.
Sanitary landfills are widely accepted and promoted as the environmentally friendly way to properly dispose of solid waste. However, a harmful aspect is the leachate generation and management, which are currently recognized as one of the greatest challenges in the environmental engineering field. Due to the high leachate recalcitrance, Fenton treatment has been accepted as a viable and efficient treatment process, which significantly reduces the organic matter: 91 % of COD; 72 % of BOD5; and 74 % of DOC. However, the acute toxicity of leachate must be assessed, mainly after the Fenton process, with the view of performing a low-cost biological post-treatment of the effluent. Despite the high redox potential, degrading 185 organic chemicals compounds identified in raw leachate, the present work reports a removal efficiency of almost 84 %, counting 156 organic compounds removed, and almost 16 % of persistent compounds. After Fenton treatment, 109 organic compounds were identified, beyond the persistent fraction of almost 27 %, wherein 29 organic compounds remained unchanged after Fenton treatment, counting 80 new short chain and lower complexity organic compounds formed. Despite the biogas production ratio increase (3-6 times), and significant enhancement of the biodegradable fraction susceptible to oxidation in respirometric test, a higher reduction in the oxygen uptake rate (OUR) was identified after Fenton treatment due to persistent compounds and their bioaccumulation. Additionally, the D. magna bioindicator parameter indicated that treated leachate is three times more toxic than raw leachate.


Investigation of molecular mechanisms of interaction between myofibrillar proteins and 1-heptanol by multiple spectroscopy and molecular docking methods.
In this study, we investigated the interaction between myofibrillar proteins (MPs) and selected alcohols (1-pentanol, 1-hexanol, and 1-heptanol). Only 1-heptanol exhibited the binding ability to MPs, and the binding ability significantly increased with increasing protein concentration (p < 0.05). In addition, both static and dynamic quenching occurred during the interaction, with a red shift of the maximum absorption peak in the synchronous fluorescence spectra indicating a change in the microenvironment of the MPs. The results of circular dichroism measurements suggested that the interaction between MPs and 1-heptanol altered the secondary structure of the MPs. Furthermore, thermodynamic analysis showed that hydrogen bonding and van der Waals forces dominated the interaction between MPs and 1-heptanol, which was confirmed by the results of molecular docking/dynamics simulations. This study provides an in-depth understanding of the interaction between MPs and alcohols, which can help to improve the flavor control in meat.


Stochastic models for heterogeneous DNA sequences.
The composition of naturally occurring DNA sequences is often strikingly heterogeneous. In this paper, the DNA sequence is viewed as a stochastic process with local compositional properties determined by the states of a hidden Markov chain. The model used is a discrete-state, discrete-outcome version of a general model for non-stationary time series proposed by Kitagawa (1987). A smoothing algorithm is described which can be used to reconstruct the hidden process and produce graphic displays of the compositional structure of a sequence. The problem of parameter estimation is approached using likelihood methods and an EM algorithm for approximating the maximum likelihood estimate is derived. The methods are applied to sequences from yeast mitochondrial DNA, human and mouse mitochondrial DNAs, a human X chromosomal fragment and the complete genome of bacteriophage lambda.


A cilium is not a cilium is not a cilium: signaling contributes to ciliary morphological diversity.
Mukhopadhyay and colleagues reveal in this issue of Developmental Cell that signaling mediated by a specialized neuronal cilium in C. elegans affects its structure. The finding that this cilium is modified in response to the cues it transduces suggests that cilia may not be static antennae, but organelles whose functions are shaped by their signaling activities.


Current state of theoretical and experimental studies of the voltage-dependent anion channel (VDAC).
Voltage-dependent anion channel (VDAC), the major channel of the mitochondrial outer membrane provides a controlled pathway for respiratory metabolites in and out of the mitochondria. In spite of the wealth of experimental data from structural, biochemical, and biophysical investigations, the exact mechanisms governing selective ion and metabolite transport, especially the role of titratable charged residues and interactions with soluble cytosolic proteins, remain hotly debated in the field. The computational advances hold a promise to provide a much sought-after solution to many of the scientific disputes around solute and ion transport through VDAC and hence, across the mitochondrial outer membrane. In this review, we examine how Molecular Dynamics, Free Energy, and Brownian Dynamics simulations of the large β-barrel channel, VDAC, advanced our understanding. We will provide a short overview of non-conventional techniques and also discuss examples of how the modeling excursions into VDAC biophysics prospectively aid experimental efforts. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov.


Management of Fusarium Wilt Disease of Maize (Zea mays L.) with Selected Antimycotic Plant Extracts and Inhibitory Bacillus Strains.
Maize (Zea mays L. var. Everta) is an economically significant crop cultivated worldwide. Unfortunately, microbial diseases, especially, mycopathogens such as Fusarium species, militate against the production of maize. Protective microbial species and bioactive plant extracts have been studied in the control of plant pathogens. However, there is a dearth of information on their comparative efficacy and effect on wilt disease of maize caused by Fusarium solani, as investigated in this study. Using the ITS and 16s rDNA primers for fungal pathogen and bacterial strains, respectively, the mycopathogen was confirmed as Fusarium solani FCI20, while biocontrol Bacillus strains were identified as Bacillus velezensis EBs02 and Bacillus thuringiensis EBs04. Fusarium solani FCI20 successfully infected maize seedlings through rhizosphere inoculation, and caused severe leaf chlorosis, necrosis and wilt in maize seedlings. Bacillus thuringiensis EBs04 expressed the highest in vitro mycelial inhibition (85.20%), followed by Gmelina arborea (78.58%), while Milicia excelsa appeared to express the lowest mycelial inhibition potential (49.95%). Bacillus velezensis EBs02 expressed the highest in vivo disease severity reduction in maize seedlings (with percentage disease control of 84.16), while B. thuringiensis-treated plants had the lowest incidence of wilt disease (4.32%). However, contrary to their in vitro mycelial inhibition potential, B. velezensis EBs02, Gmelina arborea, Milicia excelsa and Cola nitida expressed radically different levels of in vivo wilt disease control in maize seedlings. Consequent upon the biocontrol patterns observed in this study, in vivo assay should be considered in the preliminary selection of promising biocontrol agents against phytopathogens, such as Fusarium species.


Is the sentinel lymph node biopsy more sensitive for the identification of positive lymph nodes in breast cancer than the axillary lymph node dissection?
Since the routine clinical use of the sentinel lymph node (SLN) procedure, questions have been raised concerning an increase in the overall percentage of node-positive patients. The goal of our study was to compare the sensitivity of the SLN procedure and the axillary lymph node dissection (ALND) for the identification of positive lymph nodes in breast cancer. The incidence of axillary node metastasis in SLNB and ALND specimens from patients undergoing operative treatment of a primary breast carcinoma was compared retrospectively. Logistic regression models were used to analyze the effect of various predictors on the presence of positive lymph nodes. We constructed a multivariate model including the procedure and these predictors that have shown to be related to lymph node involvement in univariate analysis. The probability of finding positive lymph nodes was thus calculated in both groups correcting for relevant predictors of lymph node involvement. The SLNB group included 830 patients, the ALND group 320. In a multivariate analysis, adjusting for the number of foci, tumor location in the breast, tumor size, LVI, ER, PR, tumor grade and histological subtype, the probability of finding positive lymph nodes was higher with SLNB procedure than with an ALND. However, this difference was not statistically significant (OR 0.7635; CI 0.5334-1.0930, p 0.1404). For comparable tumors, SLNB procedure is at least as sensitive as ALND for detecting positive lymph nodes.


Life-long deficits in social adaptation and the frontal lobes: New evidence, seventy-five years after Ackerly and Benton's landmark case report of JP.
The case of JP, reported by Ackerly and Benton in 1948 with a detailed follow-up by Ackerly in 1964, stands as the index case of developmental prefrontal damage and its impact on social adaptation. Although the 1948 case report included findings from a 1933 pneumoencephalogram and exploratory craniotomy, a definitive cause was never established for JP's prefrontal damage. Etiologies were never determined for the left-sided seizures that occurred when JP was age four, nor for the progressive anterograde amnesia that JP developed in middle age. Given Ackerly's thoroughness and long-term follow-up of his patient, it was hoped that a brain cutting would have been done, though no report of a post-mortem examination was published. The lead author of this paper (SB) set out to discover what had happened to JP after Ackerly's 1964 report and whether a brain cutting had in fact occurred. Using a variety of investigative approaches, it was discovered that a post-mortem brain examination had taken place. Those present at the brain cutting were identified, and the still-living witnesses to the brain cutting were interviewed. Previously unpublished, relevant materials were uncovered from archival sources. A film of the brain cutting, as well as photos, were located. A film of Ackerly interviewing JP prior to JP's death at age sixty-four also was found. The authors studied autopsy findings in the newly discovered video and still images. These findings were judged consistent with massive perinatal hemorrhagic damage to both frontal lobes. JP's left-sided seizures were likely due to activation of a focus from his congenital brain damage. The anterograde amnesia that was documented when JP was twenty-five and that was noted to worsen when he was forty-nine remains unexplained but may have been related to slowly progressive hydrocephalus. This paper expands what is known about the case of JP, making it the only report of a person with congenital frontal injury followed for their entire life including post-mortem brain examination.


Surgery during acute pancreatitis. Observations in 50 patients.
Surgery was performed during the acute phase of illness in 50 of 348 patients with acute pancreatitis. The operative mortality was 40 percent. Analysis of the indications for operation, the operative findings, and the mortality rate revealed that the suspected complications for which operation was planned were not always borne out by the operative findings. In addition, the deterioration of patients while being treated conservatively, or the presence of severe acute pancreatitis preoperatively, were not predictive of the finding of hemorrhagic or necrotizing pancreatitis at operation. In a significant proportion of patients with severe pancreatitis, the diagnosis of pancreatitis was first made at laparotomy. More use should be made of the newer investigative methods to better identify any complications which may have occurred and the necessity for operative intervention.


Patient-selected goal attainment for pessary wearers: what is the clinical relevance?
The purpose of this study was to evaluate whether patient determined goal achievement is associated with pessary continuation. Patients identified goals they wished to achieve from pessary use. Patients were asked whether they continued pessary use and if goals were met 6-12 months later. Goals were divided into 8 categories. Fisher exact test was used to evaluate categorical variables, t tests for continuous variables, and regression methods to calculate odds ratios (OR). Eighty women enrolled in the study. Sixty-four had follow-up data. Goals commonly listed were bladder (36%), activity (20%), general health (13%), and prolapse related (11%). Thirty-four women continued and 30 discontinued pessary use. Women who continued pessary use were more likely to meet 1 or 2 goals (OR 17.5, 21.1 and 95% CI 4.8-64.4, 5.7-78.9, respectively). Patient goals are variable and subjective. However, when assessed for achievement, they are associated with pessary continuation. Women who attain self-determined goals are likely to continue pessary use.


An overview of the sandfly fauna (Diptera: Psychodidae) followed by the detection of Leishmania DNA and blood meal identification in the state of Acre, Amazonian Brazil.
In Acre state, Brazil, the dissemination of cutaneous leishmaniasis has increased in recent years, with limited knowledge of the potential Leishmania spp. vectors involved. Here, data concerning the sandfly fauna of Brasiléia municipality, Leishmania DNA-detection rates and the identification of blood meal sources of insects captured in 2013-2015 are presented. Parasite detection in female sandflies was performed individually by multiplex polymerase chain reaction (PCR) (Leishmania kDNA/sandfly cacophony-gene), with the identification of Leishmania spp. by hsp70-PCR and sequencing. The identification of blood gut-content from fed females was performed by cyt b-PCR and sequencing. A total of 4,473 sandflies were captured. A subgroup of 864 non-blood-fed females evaluated for the presence of Leishmania DNA showed 2.9% positivity for Leishmania (Viannia) braziliensis and L. (V.) guyanensis. The identification of blood meal sources was performed in 96 blood-fed females, allowing the identification of 13 vertebrate species. In nine/96 fed females, DNA from L. (V.) shawi, L. (V.) guyanensis, L. (V.) braziliensis and Endotrypanum sp. was detected. In Brumptomyia sp. and Evandromyia termitophila, the first report of Leishmania DNA-detection is provided in Acre; Nyssomyia shawi is implicated as potential vector of L. (V.) braziliensis and L. (V.) guyanensis for the first time in Brazil.


Age at Parkinson's disease onset modulates the effect of levodopa on response inhibition: Support for the dopamine overdose hypothesis from the antisaccade task.
The antisaccade task is an established eye-tracking paradigm to explore response inhibition. While many studies showed that antisaccade performance is impaired in Parkinson's disease (PD), the effect of dopaminergic medication is still an area of debate. According to the dopamine overdose hypothesis, intrinsic basal dopamine levels in ventral parts of the striatum determine whether levodopa intake has beneficial or detrimental effects on dopamine-dependent cognitive tasks. The objective of this study was therefore to explore the effect of several disease-related factors on changes in antisaccade performance after levodopa intake in PD. Thirty-five individuals with PD (and 30 healthy controls) performed antisaccades in OFF and ON medication state. Multiple linear regressions were calculated to predict the change in antisaccade latency, directive errors and express saccade rate based on age at PD onset, disease duration, levodopa-equivalent daily dose, motor symptom severity and executive functions. Levodopa intake did not alter antisaccade performance on a group level. However, the effect of levodopa was differentially modulated by age at PD onset and motor symptom severity. Earlier disease onset and milder motor symptoms in OFF medication state were associated with reduced response inhibition capacity after levodopa intake measured as increased express saccade and error rates. Our results indicate that levodopa may have opposing effects on oculomotor response inhibition dependent on the age at PD onset and motor disease severity. Assuming less dopaminergic loss in ventral parts of the striatum in early compared to late onset PD, these findings support the dopamine overdose hypothesis.


The Effect of Proximal Row Carpectomy and Trapeziectomy on First Ray Stability: A Cadaveric Study.
Wrist and thumb pathology can coexist leading to potential indications for proximal row carpectomy (PRC) and trapeziectomy. In this setting, the axial stability of the first ray is not known. We sought to evaluate axial subsidence of the first metacarpal in cadavers following trapeziectomy and trapeziectomy with PRC to determine the mechanical effects of the procedures performed concurrently. Eleven fresh-frozen cadaveric distal forearm specimens were used in this study. The specimens were fixed in cement and mounted to a material test system frame. A predetermined force (20 N) was applied to the thumb metacarpal to simulate forces observed with lateral pinch. Axial displacement of the thumb metacarpal was measured. The application of force was repeated following trapeziectomy on each hand and then again following PRC. Analysis was performed to compare thumb metacarpal subsidence of the 3 groups: native, trapeziectomy, and trapeziectomy with PRC. Before trapeziectomy, native cadaver specimens had an average of 5.1 ± 1.9 mm of thumb metacarpal subsidence under the material test system load (20 N), compared to 16.2 ± 3.4 mm following trapeziectomy, and 25.0 ± 5.5 mm for trapeziectomy with PRC. We observed a significant increase in thumb metacarpal subsidence following concurrent trapeziectomy with PRC when compared to trapeziectomy alone. Our results suggest that performing both operations together would lead to a substantial risk of first ray subsidence. When treating concurrent basilar thumb and wrist arthritis, it may be more effective to stage the procedures or use a form of thumb metacarpal suspension or arthrodesis.


Bioactive component analysis and investigation of antidiabetic effect of Jerusalem thorn (Paliurus spina-christi) fruits in diabetic rats induced by streptozotocin.
The extracts of Jerusalem thorn fruits (JT-FE) have been commonly used for the treatment of diabetes mellitus in Turkey. In this study, it is aimed to investigate the effects of the JT-FE, prepared by decoction, on blood glucose, insulin and glycated haemoglobin levels of diabetic rats induced with streptozotocin (STZ). Hypoglycemic activity of the extracts was examined in streptozotocin-induced diabetic rats. For this purpose, pre-prandial blood sugar, insulin and glycated hemoglobin levels were measured. To investigate active substances that were responsible for the antidiabetic activity, phytochemical analysis was carried out with optimized and validated LC-MS/MS method using 53 phytochemicals in JT-FE. In addition, ICP-OES analysis was performed to determine the mineral content. The findings of the study demonstrate that when insulin and JT-FE applied groups were compared with the diabetic control group, their blood sugar and glycated hemoglobin levels were seen to statistically decrease (p < 0,001). Morewer, When JT-FE treated groups were compared with insulin-treated groups, a statistically decrease (p < 0,05) in their levels was observed. On the other hand, it was also found that the increase in extract concentration didn't contribute significantly to antidiabetic activity. As a result of the phytochemical analysis, total of 31 different phenolic compounds were defined in JT-FE. The major components of JT-FE (as analyte/g extract) were; rutin (98753.4 ± 24.39 μg), catechin (58695.3 ± 12.971 μg), hesperidin (47445.2 ± 15.894 μg), quinic acid (38279.5 ± 14.239 μg) and malic acid (17536.8 ± 2.279 μg). In the mineral analysis we made; Sodium, calcium, magnesium and phosphorus elements were found at macro level, Zn and Cr3+ minerals were found at trace level. Our findings show that JT-FE, prepared by decoction, is rich in phenolic and mineral content and strong in antihyperglycemic activity. That's why Jerusalem thorn fruits can be a useful antidiabetic phytotherapy agent.


Natural Therapeutics in Aid of Treating Alzheimer's Disease: A Green Gateway Toward Ending Quest for Treating Neurological Disorders.
The current scientific community is facing a daunting challenge to unravel reliable natural compounds with realistic potential to treat neurological disorders such as Alzheimer's disease (AD). The reported compounds/drugs mostly synthetic deemed the reliability and therapeutic potential largely due to their complexity and off-target issues. The natural products from nutraceutical compounds emerge as viable preventive therapeutics to fill the huge gap in treating neurological disorders. Considering that Alzheimer's disease is a multifactorial disease, natural compounds offer the advantage of a multitarget approach, tagging different molecular sites in the human brain, as compared with the single-target activity of most of the drugs so far used to treat Alzheimer's disease. A wide range of plant extracts and phytochemicals reported to possess the therapeutic potential to Alzheimer's disease includes curcumin, resveratrol, epigallocatechin-3-gallate, morin, delphinidins, quercetin, luteolin, oleocanthal, and other phytochemicals such as huperzine A, limonoids, and azaphilones. Reported targets of these natural compounds include inhibition of acetylcholinesterase, amyloid senile plaques, oxidation products, inflammatory pathways, specific brain receptors, etc. We tenaciously aimed to review the in-depth potential of natural products and their therapeutic applications against Alzheimer's disease, with a special focus on a diversity of medicinal plants and phytocompounds and their mechanism of action against Alzheimer's disease pathologies. We strongly believe that the medicinal plants and phytoconstituents alone or in combination with other compounds would be effective treatments against Alzheimer's disease with lesser side effects as compared to currently available treatments.


Economic development, weak ties, and depression: Evidence from China.
Weak ties are becoming mainstream in daily relationships and play an essential role in the improvement of individuals' mental health. Despite growing concerns on depression, inclusion of weak ties is limited. To address the gap, this study empirically shed light on the role of weak ties on individual depression in the context of economic development. A cross-sectional study was conducted based on 2018 China Health and Retirement Longitudinal Study (CHARLS) with a sample of 16,545 individuals. A moderated mediation model is constructed to evaluate the impact of economic development (GDP) on the degrees of depression, the mediating effect of weak ties, and the moderating effect of residents' residence types (living in urban or rural areas). Economic development exerts a significant direct impact on depression (β=-1.027, p<0.001). Weak ties are significantly negatively correlated with depression (β=-0.574, p<0.001), and act as a mediator between economic development and local individual depression. In addition, the residence type plays a moderating role between economic development and weak ties (β=0.193, p<0.001). That is, living in urban areas would introduce the higher the level of weak ties. Higher economic development is largely conducive to alleviating the degrees of depression, weak ties play a mediating role between economic development and depression, and residence types exert a positive moderating effect on the economic development and weak ties.


Immunohistological study of grumose degeneration of the dentate nucleus in progressive supranuclear palsy.
The grumose degeneration observed in the dentate nuclei of 7 cases of progressive supranuclear palsy (PSP) was studied with a panel of antibodies which included 2 neurofilaments, Tau and ubiquitin. Dentate nucleus neurons were negative with all antibodies except ubiquitin which showed a slightly positive homogeneous pattern of staining. The amorphous material surrounding swollen or normal neurons was strongly positive for neurofilament and subunits and numerous torpedoes were observed in the granular layer of the cerebellar cortex. Our results confirm that grumose degeneration consists in degeneration of terminal axons of Purkinje cells in the dentate nucleus. The positivity of dentate nucleus neurons for ubiquitin may support the concept of synaptic dysfunction between Purkinje cells and dentate nucleus neurons.


Impact of crossflow microfiltration on aroma and sensory profiles of a potential functional citrus-based food.
Citrus juices can be cold-concentrated by crossflow microfiltration (CMF) in order to obtain functional foods enriched in carotenoids, flavonoids and pectins. The work aimed to characterize the organoleptic quality of this type of micronutrient-dense foods through their aroma profile and sensory analysis. Two citrus concentrates with and without a diafiltration step were compared. Both citrus products were very different, linked to aroma compound, sugar and organic acid contents. Due to its sugar/acidity balance and its better aromatic profile responsible for the citrus-floral flavour, the concentrate without diafiltration was preferred by the sensory panel. Thanks to a simple transfer model, we showed that retention of volatiles clearly varied from one aroma compound to another. The terpene hydrocarbons were the most retained by the membrane during CMF, probably because they were strongly associated with insoluble solids by adsorption. Even though the process modified their organoleptic profiles, both citrus-based products were well rated and can be consumed directly as pleasant functional drinks. © 2022 Society of Chemical Industry.


Comparison of quantitative diagnostic tests: type I error, power, and sample size.
For a quantitative laboratory test the 0.975 fractile of the distribution of reference values is commonly used as a discrimination limit, and the sensitivity of the test is the proportion of diseased subjects with values exceeding this limit. A comparison of the estimates of sensitivity between two tests without taking into account the sampling variation of the discrimination limits can increase the type I error to about seven times the nominal value of 0.05. Correct statistical procedures are considered, and the power and required sample size are studied for Gaussian and log-Gaussian distributions of diagnostic test values. The results may be useful for the planning phase of studies to evaluate quantitative diagnostic tests.


Success of microbial genes based transgenic crops: Bt and beyond Bt.
Transgenic technology could hold the key to help farmers to fulfill the ever increasing fast-paced global demand for food. Microbes have always wondered us by their potentials and thriving abilities in the extreme conditions. The use of microorganisms as a gene source in transgenic development is a promising option for crop improvement. The aforesaid approach has already for improving the characteristics of food, industrial, horticulture, and floriculture crops. Many transgenic crops containing microbial genes have been accepted by the farmers and consumers worldwide over the last few decades. The acceptance has brought remarkable changes in the status of society by providing food safety, economic, and health benefits. Among transgenic plants harboring microbial genes, Bacillus thuringiensis (Bt) based transgenic were more focused and documented owing to its significant performance in controlling insects. However, other microbial gene-based transgenic plants have also reserved their places in the farmer's field globally. Therefore, in this review, we have thrown some light on successful transgenic plants harboring microbial genes other than Bt, having application in agriculture. Also, we presented the role of microbial genetic element and product thereof in the inception of biotechnology and discussed the potential of microbial genes in crop improvement.


Position-dependence of retinoic acid receptor-beta gene expression in the chick limb bud.
Retinoic acid and 3,4-didehydroretinoic acid are metabolites of vitamin A that can induce duplications and other malformations when locally applied to the anterior margin of the chick limb bud. There is evidence that they may be natural signaling substances in the limb bud. Both compounds are thought to act by binding to ligand-dependent transcription factors that belong to the steroid/thyroid hormone nuclear receptor superfamily. In situ hybridization analyses show that in the mesenchyme of the chick wing bud between embryonic stages 20 and 27, retinoic acid receptor-beta (RAR-beta) transcripts are restricted to the proximal region of the bud and are present at highest levels in the region of the limb bud mesenchyme that contributes to the shoulder. We have performed grafting experiments in order to examine whether RAR-beta gene expression in limb bud mesenchyme cells is cell-autonomous or whether it is dependent upon the cell's position within the limb bud. When tissue from the proximal region of the stage 22 wing bud, which contains high levels of RAR-beta transcripts, was grafted to the distal tip of the bud, RAR-beta transcripts were undetectable in the graft 6 hr later. When tissue from the distal tip of the bud was grafted to a proximal site, most of the grafts exhibited a slight increase in the level of RAR-beta transcripts, which was detectable 6 hr after grafting. However, the levels of RAR-beta transcripts in these grafts never approached those found in the proximal core of the bud. These data indicate that RAR-beta gene expression in the chick wing bud is position-dependent in that it is repressed at the distal tip of the bud and partially activated by grafting distal tissue to a proximal site. However, accumulation of RAR-beta transcripts to high levels appears to be a characteristic of mesenchyme that was initially specified to form proximal structures.


Saying it with a natural child's voice! When affective auditory manipulations increase working memory in aging.
Working memory functions and their relations with affective auditory factors, have not been extensively investigated in aging yet. In this study, younger and older participants completed a classical working memory test (a running working memory task) pronounced by three different voices. In particular, in Experiment 1 the natural voices of a 3-year-old child, a 26-year-old young adult and an 86-year-old older adult were used for task presentation. In Experiment 2 stimuli were morphed in order to better control for sound properties across the three voices. Results showed that working memory increased for older adults compared to younger adults when the task was presented with natural voices and especially so when the task was presented in a child's voice. However, the child-voice effect disappeared with morphed voices. Data confirm the importance of studying the relationship between auditory features and emotional variations as a possible practical means of reducing typical age-related working memory deficits.


Self-administration of heroin in rats: effects of low-level lead exposure during gestation and lactation.
Developmental lead exposure has been found to produce differential patterns of drug self-administration in adult animals. The present study examined the effects of perinatal (gestation/lactation) lead exposure on adult patterns of heroin self-administration. Female rats were gavaged daily with 0 mg or 16 mg lead for 30 days prior to breeding with non-exposed males. Metal administration continued through pregnancy and lactation and was discontinued at weaning [postnatal day 21 (PND 21)]. Animals born to control or lead-exposed dams received indwelling jugular catheters as adults and were randomly assigned to one of two studies. In experiment 1, animals were tested on a FR-2 schedule in an effort to examine differential sensitivity to heroin in an intravenous self-administration paradigm. Seven doses of heroin were selected ranging from 0.56 microg/kg to 36 microg/kg per infusion. In experiment 2, littermates were tested on a progressive ratio (PR) schedule in order to more explicitly determine the nature of the change in sensitivity to the drug. In experiment 1, lead-exposed animals responded for heroin at significantly lower rates across most doses as evidenced by a downward shift in the inverted-U dose-effect curve. Congruent with these findings, lead-exposed animals in experiment 2 exhibited a decrease in progressive ratio responding (lower breaking points) across all heroin doses, further suggesting that perinatal lead exposure attenuates opiate self-administration in adult animals by altering the rewarding efficacy of the drug. In experiment 2, it was determined further that lead-exposed animals had lower latencies to make the initial lever press for heroin. These results support previous literature suggesting that perinatal exposure to inorganic lead attenuates the effectiveness of opiates as a reinforcer when animals are tested in the adult life cycle.


The mapping competences of the nurse Case/Care Manager in the context of Intensive Care.
Since the recent introduction of the Case/Care Manager's professional figure, it is quite difficult to identify properly his/her own particular features, which could be mainly be found revising mainly in American studies. Therefore, the present study intended to identify the Case/Care Manager's skills and professional profile in an Intensive Care Unit experience, taking into consideration the staff's activities, perception and expectations towards the Case/Care Manager. In particular, it has been compared the experience of an Intensive Care Units where the Case/Care Manager's profile is operational to a different Unit where a Case/Care Manager is not yet in force. a Levati's model was used to map the Case/Care Manager's skills, involving each unit whole working staff, executives and caregivers through semi-structured interviews. It has been taken into consideration the Anaesthesia Unit and Emergency Unit of Cesena's healthcare organisation (AUSL of Romagna) and a Cardiology Intensive Care Unit of Piacenza's healthcare organisation, where the Case/Care Manager's profile has not been experimented yet. Firstly, it a data collection in each healthcare organization has been organised. Subsequently, semi-structured interviews to doctors, unit nurses, caregivers, nurses' coordinators and medical staff have been used to compare each healthcare system. The interviewees' described their expectations in relation to the Case/Care Manager working in a critical area. Then, every data collected during interviews has been organised to map a Case/Care Manager's essential professional profile to work in a critical area together with medical staff. Piacenza's O.U. critical area experience reported a major demand for patients' and patient's families' assistance. On the other hand, the very same aspects seem to have been better achieved in Cesena's O.U., where a Case/Care Manager's recent introduction has actually helped to overcome the void in organising systems. a Case/Care Manager's profile has been drafted on the basis of the comparative analysis conducted. It has been noted how the Case/Care Manager's professional profile can really improve relationships and communications between medical staff and patients, promoting a major unity among the working team. According to the present research, the Case/Care Manager's profile has been proved helpful in positively influencing the team activity and to elicit major satisfaction both in patients and their family.


Phase separation in fluids with many interacting components.
Fluids in natural systems, like the cytoplasm of a cell, often contain thousands of molecular species that are organized into multiple coexisting phases that enable diverse and specific functions. How interactions between numerous molecular species encode for various emergent phases is not well understood. Here, we leverage approaches from random-matrix theory and statistical physics to describe the emergent phase behavior of fluid mixtures with many species whose interactions are drawn randomly from an underlying distribution. Through numerical simulation and stability analyses, we show that these mixtures exhibit staged phase-separation kinetics and are characterized by multiple coexisting phases at steady state with distinct compositions. Random-matrix theory predicts the number of coexisting phases, validated by simulations with diverse component numbers and interaction parameters. Surprisingly, this model predicts an upper bound on the number of phases, derived from dynamical considerations, that is much lower than the limit from the Gibbs phase rule, which is obtained from equilibrium thermodynamic constraints. We design ensembles that encode either linear or nonmonotonic scaling relationships between the number of components and coexisting phases, which we validate through simulation and theory. Finally, inspired by parallels in biological systems, we show that including nonequilibrium turnover of components through chemical reactions can tunably modulate the number of coexisting phases at steady state without changing overall fluid composition. Together, our study provides a model framework that describes the emergent dynamical and steady-state phase behavior of liquid-like mixtures with many interacting constituents.


Comparing conventional flap-less immediate implantation and socket-shield technique for esthetic and clinical outcomes: A randomized clinical study.
The aim of this study was to assess the esthetic and clinical outcomes of immediate implantation using the conventional flap-less approach and the socket-shield technique (SST). This study included 30 adult patients who underwent anterior teeth replacement and fulfilled the pre-defined criteria. Patients were randomly allocated to the SST (n = 15) and conventional flap-less (control, n = 15) groups. The esthetic outcomes were evaluated by assessing the degree of soft-tissue recession and the pink esthetic scores (PESs). Clinical parameters, including the modified plaque index, modified sulcus bleeding index (mSBI), probing depth (PD), and implant stability quotient (ISQ), were assessed. The buccal plate width (BPW) and height (BPH) were also measured. Implantation was clinically successful for all subjects in both groups. With a similar baseline, the SST group exhibited less reduction in the midfacial mucosal margins and the height of the mesial and distal papillae as well as higher BPW and BPH values compared with the control group (p < .001). The ISQ values were 76.01 ± 1.31 for the SST group and 75.56 ± 1.07 for the control group (p > .05), suggesting sufficient initial stability in both groups. At the 24-month follow-up, SST group patients had statistically significant lower values of PD, mSBI, and mPLI compared with the control group. There were no significant differences in the overall and individual PES values for both groups. SST may improve functional and esthetic outcomes by maintaining alveolar bone volume and peri-implant tissues. SST seems to be a promising treatment approach for implants in the esthetic zone.


Synthesis of hydroxyapatite nanotubes for biomedical applications.
Single phase, stoichiometrically pure, hollow nanotubes of hydroxyapatite have been synthesized and single-particle analysis has been performed to successfully prove the sole formation of Ca10(PO4)6(OH)2 phase. The facile synthesis involves a sol-gel process under neutral conditions in the presence of a sacrifical anodic alumina template. The structures formed are hollow nanotubes that have been characterized by XRD, SEM, TEM, SAED, EELS, EDS and BET measurements. The diameter of the resulting tubes is in the range of 140-350 nm, length is on the order of a few microns and the wall thickness of the tubes was found to be ca. 30 nm. Moreover these tubes had a large BET surface area of 115 m(2)/g and were found to be biocompatible. They displayed inertness in the presence of NIH 3T3 mouse fibroblast cells as dictated by an MTT assay.


Selective solid-phase extraction using molecularly imprinted polymer for the analysis of polar organophosphorus pesticides in water and soil samples.
An analytical methodology for the analysis of four polar organophophorus pesticides (monocrotophos, mevinphos, phosphamidon, omethoate) in water and soil samples incorporating a molecularly imprinted solid-phase extraction (MISPE) process using a monocrotophos-imprinted polymer was developed. Binding study demonstrated that the polymer showed excellent affinity and high selectivity to monocrotophos. The MISPE procedure including the clean-up step to remove any interferences was optimized. The accuracy and selectivity of the MISPE process developed were verified using a non-imprinted (blank) polymer and a classical ENVI-18 cartridge as the SPE matrix during control experiments. The use of MISPE improved the accuracy and precision of the GC method and lowered the limit of detection. The recoveries of four polar organophosphorus pesticides (OPPs) extracted from 1 L of river water at a 100 ng/L spike level were in the range of 77.5-99.1%. The recoveries of organophosphorus pesticides extracted from a 5-g soil sample at the 100 microg/kg level were in the range of 79.3-93.5%. The limit of detection varied from 10 to 32 ng/L in water and from 12 to 34 microg/kg in soil samples. The molecularly imprinted polymer (MIP) enabled the selective extraction of four organophosphorus pesticides successfully from water and soil samples, demonstrating the potential of molecularly imprinted solid-phase extraction for rapid, selective, and cost-effective sample pretreatment.


Establishing a new body mass index cutoff value for malnutrition diagnosis using the Global Leadership Initiative on Malnutrition (GLIM) tool in Chinese older adults.
The body weight of the Chinese population rose rapidly over the past two decades. The old 2001 body mass index (BMI) cutoff value for malnutrition may underestimate malnutrition diagnosis. We explored the BMI cutoff value for malnutrition diagnosis based on national BMI data from the past 30 years and applied it to the Global Leadership Initiative on Malnutrition (GLIM) criteria when investigating malnutrition in hospitalized older patients. To explore the BMI cutoff value for malnutrition, we established a linear stepwise model to predict the annual increasing BMI trend based on data from the national BMI data set. The new cutoff value was applied to a large-scale data set from a cross-sectional study pertaining to older hospitalized patients recruited from 30 large hospitals in China. The BMI increased from 21.8 to 23 kg/m2 in two decades. We calculated that the net BMI increase will be 1.49 kg/m2 from 1999 to 2019. We subsequently proposed that the BMI cutoff value for malnutrition should rise to 20 kg/m2 . This cutoff value was applied to the validation data set, containing 8725 patients, and the GLIM-determined malnutrition rate was 24.58% (using the Nutrition Risk Screening 2002 [NRS-2002]) and 23.32% (using the Mini Nutritional Assessment-Short Form [MNA-SF]). The results significantly differed from those obtained using the 2001 Chinese BMI criteria. The GLIM tool has good applicability in Asian populations, especially in Chinese older patients. The BMI cutoff value for malnutrition should be adjusted to 20 kg/m2 for Chinese adults.


Special Issue "Selected Papers from the 8th Asia-Pacific NMR (APNMR) Symposium: Recent Advances in NMR Spectroscopy".
Asia-Pacific NMR (APNMR) has been an important scientific event in the region, engaging a large number of NMR scientists from academia and industries [...].


Direct microbial electron uptake as a mechanism for stainless steel corrosion in aerobic environments.
Shewanella oneidensis MR-1 is an attractive model microbe for elucidating the biofilm-metal interactions that contribute to the billions of dollars in corrosion damage to industrial applications each year. Multiple mechanisms for S. oneidensis-enhanced corrosion have been proposed, but none of these mechanisms have previously been rigorously investigated with methods that rule out alternative routes for electron transfer. We found that S. oneidensis grown under aerobic conditions formed thick biofilms (∼50 µm) on stainless steel coupons, accelerating corrosion over sterile controls. H2 and flavins were ruled out as intermediary electron carriers because stainless steel did not reduce riboflavin and previous studies have demonstrated stainless does not generate H2. Strain ∆mtrCBA, in which the genes for the most abundant porin-cytochrome conduit in S. oneidensis were deleted, corroded stainless steel substantially less than wild-type in aerobic cultures. Wild-type biofilms readily reduced nitrate with stainless steel as the sole electron donor under anaerobic conditions, but strain ∆mtrCBA did not. These results demonstrate that S. oneidensis can directly consume electrons from iron-containing metals and illustrate how direct metal-to-microbe electron transfer can be an important route for corrosion, even in aerobic environments.


Aneuploidy induction in Saccharomyces cerevisiae by two solvent compounds, 1-methyl-2-pyrrolidinone and 2-pyrrolidinone.
A number of solvent compounds that were tested in Saccharomyces cerevisiae were potent inducers of aneuploidy, although they did not induce any other genetic effects. As an extention of these earlier findings, 1-methyl-2-pyrrolidinone was tested and was found to induce aneuploidy. Several structurally related compounds were also tested; 2-pyrrolidinone induced aneuploidy, but succinimide, pyrrolidine, 1-methylpyrrolidine, 1-methyl-3-pyrrolidinol, and 2-pyrrolidineethanol did not. Maleimide and its N-hydroxy, N-methyl, and N-ethyl derivatives were also negative for aneuploidy induction.


Emergent surface superconductivity in the topological insulator Sb2Te3.
Surfaces of three-dimensional topological insulators have emerged as one of the most remarkable states of condensed quantum matter where exotic electronic phases of Dirac particles should arise. Here we report on superconductivity in the topological insulator Sb2Te3 with transition to zero resistance induced through a minor tuning of growth chemistry that depletes bulk conduction channels. The depletion shifts Fermi energy towards the Dirac point as witnessed by a factor of 300 reduction of bulk carrier density and by the largest carrier mobility (≳25,000 cm(2) V(-1) s(-1)) found in any topological material. Direct evidence from transport, the unprecedentedly large diamagnetic screening, and the presence of ∼25 meV gaps detected by scanning tunnelling spectroscopy reveal the superconducting condensate to emerge first in surface puddles, with the onset of global phase coherence at ∼9 K. The rich structure of this state lends itself to manipulation via growth conditions and the material parameters such as Fermi velocity and mean free path.


Imaging of the scrotum in children.
Clinical examination of the scrotum is difficult due to the small size of the testes and the epididymis in infants and young children, and eliciting patients' history is challenging. Therefore imaging of the scrotum in childhood bears great importance. Ultrasound is the standard imaging technique of choice providing the clinicians with a definitive diagnosis in most cases. However, in conditions of testicular torsion and epididymoorchitis--the most common differential diagnosis of scrotal pain--ultrasound findings can be inconclusive and further evaluation is required. Since there is a large overlap between paediatric and adult pathology, differences from adults in anatomy and pathology must be considered when evaluating the paediatric scrotum.


Does the Duncan-Ely test predict abnormal activity of the rectus femoris in stroke survivors with a stiff knee gait?
To determine the diagnostic value of the Duncan-Ely test in predicting abnormal rectus femoris activity during gait in stroke survivors walking with a stiff knee gait. Cross-sectional diagnostic study. A total of 95 patients with chronic stroke. During physical examination, the Duncan-Ely test was performed and scored. Surface electromyography of the rectus femoris was then recorded during dynamic gait. To determine the diagnostic value, the results of the Duncan-Ely test and surface electromyography recordings (gold standard) were compared. The Duncan-Ely test had a sensitivity of 73%, a specificity of 29%, a positive predictive value of 60%, and a negative predictive value of 42%. The area under the curve was 0.488 ([AQ1] CI 0.355-0.621, p = 0.862), showing that the Duncan-Ely test is not better than random guessing. The Duncan-Ely test has no predictive value for determining abnormal activity of the rectus femoris during gait. Using this test can lead to incorrect identification of abnormal rectus femoris activity, which might hamper the selection of optimal treatment options. We recommend stopping use of the Duncan-Ely test to predict rectus femoris overactivity during swing, and instead use surface electromyography.


Characterization of GPCR signaling in hypoxia.
G protein-coupled receptors (GPCRs) signal in response to various external stimuli including stress. GPCR signaling has been shown to play a critical role in the adaptation of cell response to limited oxygen supply. Hypoxia has been implicated in cardiovascular diseases, human pulmonary arterial responses, and persistent pulmonary hypertension in newborns. One of the key GPCRs implicated in hypoxia is the prostanoid receptor, thromboxane A2 receptor (TP). Hypoxia can affect TP localization, stability, and activity both in vivo and in vitro. To elucidate hypoxia-mediated GPCR signaling in vitro, we lay out a general strategy to perform hypoxic experiments using both primary pulmonary artery smooth muscle cells and TP expressed in HEK293T cells. We describe assay for measuring moderate tissue hypoxia using static cell cultures, monitoring pericellular media oxygen content, and signaling of TP.


Simultaneous occurrence of Graves' disease with endocrine ophthalmopathy. Thyroiditis and thyroid carcinoma.
The simultaneous occurrence of Graves' disease with ophthalmopathy lymphocytic and subacute de Quervains' thyroiditis has been observed in two male patients suffering from follicular-type thyroid carcinoma. In one of them Sjögren syndrome and a mild form of diabetes were also diagnosed. It is assumed, on the basis of indirect evidence, that the humoral and cellular lesions determined by genetic factors and influenced by prolonged thyrostatic and steroid treatment are jointly responsible for tumour genesis.


Pulmonary Manifestations of Genetic Disorders in Children.
Congenital bronchopulmonary malformations are relatively common and arise during various periods of morphogenesis. Although some are isolated or sporadic occurrences, others may result from single gene mutations or cytogenetic imbalances. Single gene mutations have been identified, which are etiologically related to primary pulmonary hypoplasia, lung segmentation defects as well as pulmonary vascular and lymphatic lesions. Functional defects in cystic fibrosis, primary ciliary dyskinesias, alpha-1-antitrypsin deficiency, and surfactant proteins caused by gene mutations may result in progressive pulmonary disease. This article provides an overview of pediatric pulmonary disease from a genetic perspective.


Diversity of trypanosome species in small ruminants, dogs and pigs from three sleeping sickness foci of the south of Chad.
Despite considerable data generated on livestock trypanosomoses in tsetse-infested areas, little attention was paid for animal African trypanosomosis (AAT) in sleeping sickness foci. This study aimed to fill this gap by determining the diversity and prevalence of trypanosome species in animals from three Chadian human African trypanosomosis (HAT) foci. Blood samples were collected from 443 goats, 339 sheep, 228 dogs and 98 pigs of the Mandoul, Maro and Moissala HAT foci in the south of Chad. Capillary tube centrifugation (CTC) and specific primers were used to search trypanosomes. The prevalence of trypanosome infections was 6.3% for CTC and 22.7% for PCR. Trypanosomes of the sub-genus Trypanozoon had the highest prevalence (16.6%) while T. congolense savannah (1.9%) was least prevalent. Significant differences were recorded between the prevalence of trypanosome species (χ2 = 8.34; p = 0.04) and HAT foci (χ2 = 24.86; p ≤0.0001). Maro had the highest prevalence (32.7%) and Mandoul the lowest (17.4%). Significant differences were also recorded for T. congolense forest (χ2 = 45.106; p < 0.0001) and all T. congolense (χ2 = 34.992; p < 0.0001). Goats had the highest prevalence (26.9%) and sheep the lowest one (18.6%). Between animals, significant differences were recorded for trypanosomes of the sub-genus Trypanozoon (χ2 = 9.443; p = 0.024), T. congolense forest (χ2 = 10.476; p = 0.015) and all T. congolense (χ2 = 12.152; p = 0.007). Of the 251 animals carrying trypanosome infections, 88.8% had single infections while 11.2% had more than one trypanosome species. The overall prevalence of single and mixed trypanosome infections were respectively 20.1% and 2.6% in animal taxa of all foci. This study highlighted a diversity of trypanosomes in animal taxa of all HAT foci. It showed that AAT constitutes a threat for animal health and animal breeding in Chadian HAT foci. In these tsetse infested areas, reaching the elimination of AAT requires the designing and the implementation of control measures against trypanosome infections.


Nano Wave Plates Structuring and Index Matching in Transparent Hydroxyapatite-YAG: Ce Composite Ceramics for High Luminous Efficiency White Light-Emitting Diodes.
Replacing traditional luminous silicone or resins with phosphor in ceramics (PiCs) as color converters has been proposed as an efficient way to improve thermal stability of high-power white light-emitting diodes (WLEDs). However, excessive light scattering in existing PiCs results in enormous phosphor-converted light losses, which makes the luminosity of current PiCs color converters less efficient and means that they can only be used in devices working in reflective mode. By introducing nano wave plate structuring and Rayleigh scattering, luminous hydroxyapatite (HA)-YAG: Ce ceramics are prepared from mesoporous HA nanorods and YAG: Ce phosphors at 850 °C, enabling for the first time WLEDs equipped with PiC color converters in transmission mode. With low-temperature sintering and a highly transparent matrix, the quantum yield of HA-YAG: Ce retains ≈90% of the raw phosphor, and WLEDs with the color converters exhibit a record luminous efficiency of 170 lm W-1 and a correlated color temperature below 4500 K. A facile and practical strategy of using nano structural modulation to eliminate birefringence-induced light scattering for fabricating high-performance ceramic converters suitable for multiple mode luminaires is demonstrated.


Respiratory biofeedback accuracy in chronic renal failure patients: a method comparison.
To analyse respiratory biofeedback effects on respiratory muscle strengthening in chronic renal failure patients. Randomized controlled study. Nephrology and dialysis centre. Forty-one end-stage renal patients on haemodialysis treatment were allocated into three groups: control (n = 10), G-1 (inspiratory muscle training using Threshold IMT device; n = 16) and G-2 (biofeedback; n = 15) and given respiratory muscle training (three sessions/week for six weeks). Forced vital capacity (FVC), expiratory volume in the first second (FEV(1)), FEV(1)/FVC ratio, maximal voluntary ventilation (MVV) and maximal inspiratory (MIP) and expiratory (MEP) pressures were measured before and after the respiratory muscle training programme. Both training methods were efficient since we found an increase after training in the FVC in the G-1 group (from 2.45 ± 0.17 to 2.85 ± 0.16; P = 0.001) and in the G-2 group (from 2.35 ± 0.19 to 2.55 ± 0.19; P = 0.007), in the FEV(1) in G-1 (from 2.18 ± 0.16 to 2.46 ± 0.14; P = 0.01) and in G-2 (from 1.97 ± 0.17 to 2.20 ± 0.15; P < 0.0001), MIP in G-1 (from 70.63 ± 4.03 to 108.75 ± 7.41; P < 0.0001) and in G-2 (from 67.67 ± 5.02 to 96.33 ± 8.30; P < 0.001) and MEP in G-1 (from 73.13 ± 5.10 to 82.50 ± 6.74; P = 0.007) and in G-2 (from 67.67 ± 5.41 to 76.00 ± 4.29; P = 0.002). Respiratory biofeedback is efficient as a respiratory muscle training modality for patients with chronic renal failure.


Vitamin D-binding protein, total, "nonbioavailable," bioavailable, and free 25-hydroxyvitamin D, and mortality in a large population-based cohort of older adults.
Epidemiological studies consistently find low concentrations of 25-hydroxyvitamin D (25(OH)D) in blood to be associated with increased mortality, and a recent large-scale Mendelian randomization study strongly supports a causal relationship among individuals with low vitamin D status. Evolving evidence suggested that bioavailable or free 25(OH)D may better predict mortality. We aimed to compare the prognostic values of vitamin D-binding protein (VDBP), total, bioavailable, complementary "nonbioavailable", and free 25(OH)D for total and cause-specific mortality in a large population-based cohort study of older adults from Germany. Bioavailable, complementary "nonbioavailable", and free 25(OH)D concentrations were calculated among 5899 participants aged 50-75 years, based on serum concentrations of total 25(OH)D, VDBP, and albumin. The cohort was followed with respect to total and cause-specific mortality from recruitment in 2001-2002 up to the end of 2018. Multivariable Cox proportional hazards regression models were used to assess the associations between various vitamin D biomarkers and mortality, and further stratified by vitamin D status. During a median follow-up of 17.1 years, 1739 participants died, of whom 575, 584, and 94 died of cardiovascular diseases, cancer, and respiratory diseases, respectively. Very similar inverse associations with total mortality (hazard ratio (HR) per standard deviation decrease: 1.17, 95% confidence interval (CI): 1.11, 1.24 for total 25(OH)D; HR: 1.14, 95% CI: 1.08, 1.21 for bioavailable 25(OH)D; HR: 1.12, 95% CI: 1.06, 1.18 for free 25(OH)D) and cause-specific mortalities were seen for all biomarkers of vitamin D status. The strongest associations were consistently seen for respiratory mortality. These inverse associations were strongest among participants with low vitamin D levels (<50 nmol/L). No significant associations were seen between VDBP and mortality. Total, nonbioavailable, bioavailable, and free 25(OH)D showed very similar inverse associations with total and cause-specific mortality, which were strongest among those with low vitamin D status in this large population-based cohort.


Short bowel syndrome: a practical pathway leading to successful enteral autonomy.
Short bowel syndrome is a multisystemic disorder that results from the loss of a significant amount of small bowel. The goal of treatment in these patients is to achieve complete enteral autonomy while minimizing complications. Our unit has 30 years of experience in the management of short gut patients. During the past decade, our results have improved significantly, especially in children with severe short bowel syndrome. This brief communication looks at the algorithm presently used in our unit. In this communication, the principles in management of short bowel syndrome in our unit are discussed. In addition, our algorithm is published for the first time. A brief summary of our results is provided. Twenty-seven children were enrolled from 2000 to 2009. In this cohort, two patients died because of significant liver disease: one after having two liver and bowel transplants. Overall, survival stands at 92%. All had autologous gastrointestinal reconstruction, and 19 patients underwent bowel lengthening (longitudinal intestinal lengthening and tailoring). The median residual length of bowel of this subgroup at first operation was 25 cm in those who had their gut measured. Two patients were lost to follow-up. Two patients remain on supplemental total parenteral nutrition (TPN), with an overall 91% of surviving patients off TPN at a median of 6 months after reconstruction. We believe this improvement is related to the development-over many years-of a structured pathway for managing these patients.


Carbon Nanomaterials for Treating Osteoporotic Vertebral Fractures.
To identify the use of carbon nanomaterials in bone regeneration and present new data on the regenerative capacity of bone tissue in osteopenic rats treated with graphene nanoribbons (GNRs). The results show that the physical and chemical properties of the nanomaterials are suitable for the fabrication of scaffolds intended for bone regeneration. The in vitro tests suggested a non-toxicity of the GNRs as well as improved biocompatibility and bone mineralization activity. Here, for the first time, we evaluated the potential of GNRs in remodeling and repairing bone defects in osteoporotic animal models in vivo. Interestingly, bone mineralization and the initiation of the remodeling cycle by osteoclasts/osteoblasts were observed after the implantation of GNRs, thus implying healthy bone remodeling when using GNRs. This study, therefore, has opened our perspectives and certainly calls for more attention to the use of carbon nanomaterials for a wide range of osteoporosis applications.


Strain-induced reorientation and mobility in nematic liquid-crystalline elastomers as studied by time-resolved FTIR spectroscopy.
Polarized Fourier transform infrared (FTIR) spectroscopy is employed to study the segmental orientation and mobility of liquid-crystalline elastomers (LCEs) with a monodomain structure in response to external mechanical fields parallel and perpendicular to the initial nematic director. The mean orientation and the molecular order parameter of the different molecular moieties referring to the mesogen, the spacer and the network are analyzed in detail. Parallel stretch leaves the mean orientation of the different molecular moieties and its molecular order parameter nearly uninfluenced. Perpendicular stretch results in a threshold-like dependence: for elongation ratios lambda < or = lambda(c) = 1.3 (10 mol% crosslinker density), respectively lambda < or = lambda(c) = 1.6 (5 mol% crosslinker density) no change of the mean orientation and the molecular order parameters is observed, while for lambda > or = lambda(c) all molecular units reorient and their molecular order parameters are strongly decreased. The present studies give no indications that the reorientational dynamics of the network and the mesogens differ as long as the elongation ratio is smaller than lambda(c).


Does speed matter? Revision rates and functional outcomes in TKA in relation to duration of surgery.
Longer operative times may be required in complex total knee arthroplasty (TKA), however little is known about outcomes in procedures performed rapidly. We analysed 58,009 primary TKAs from the New Zealand National Joint Registry. The mean surgical duration was 89 minutes, and 50% of procedures lasted between 60 and 89 minutes. There was no difference in adjusted revision rates for groups lasting between 40 and 120 minutes, however procedures lasting >120 minutes had significantly higher revision rates. There was a higher revision rate in TKAs lasting <40 minutes (0.71 vs 0.48 revisions per 100 component years) but this was not statistically significant (P = 0.1). For primary TKAs lasting less than 120 minutes, further shortening operative time did not improve outcome, and very rapid procedures (<40 minutes) may lead to an increased risk of revision.


RNA-Seq, Bioinformatic Identification of Potential MicroRNA-like Small RNAs in the Edible Mushroom Agaricus bisporus and Experimental Approach for Their Validation.
Although genomes from many edible mushrooms are sequenced, studies on fungal micro RNAs (miRNAs) are scarce. Most of the bioinformatic tools are designed for plants or animals, but the processing and expression of fungal miRNAs share similarities and differences with both kingdoms. Moreover, since mushroom species such as Agaricus bisporus (A. bisporus, white button mushroom) are frequently consumed as food, controversial discussions are still evaluating whether their miRNAs might or might not be assimilated, perhaps within extracellular vesicles (i.e., exosomes). Therefore, the A. bisporus RNA-seq was studied in order to identify potential de novo miRNA-like small RNAs (milRNAs) that might allow their later detection in diet. Results pointed to 1 already known and 37 de novo milRNAs. Three milRNAs were selected for RT-qPCR experiments. Precursors and mature milRNAs were found in the edible parts (caps and stipes), validating the predictions carried out in silico. When their potential gene targets were investigated, results pointed that most were involved in primary and secondary metabolic regulation. However, when the human transcriptome is used as the target, the results suggest that they might interfere with important biological processes related with cancer, infection and neurodegenerative diseases.


Compartmentalized Spherical Collagen Microparticles for Anisotropic Cell Culture Microenvironments.
This paper describes a new fabrication method for obtaining anisotropic spherical hydrogel microparticles with different types of extracellular matrix (ECM) hemispheres for use in 3D cell culture. To fabricate the microparticles, a mixture of an ECM precursor solution and sodium alginate is ejected into a calcium chloride solution under large centrifugal acceleration by a centrifuge-based microfluidic device; the calcium alginate hydrogel plays a significant role as a "sacrificial gelation template" to maintain the ECM molecules in each hemisphere. This fabrication method enables gaining control of the hemispherical volume, density, and type of ECM. Using the microparticles, cells could be successfully encapsulated in each hemisphere selectively with high viability, which are then suitable for culture in the microparticles to form microtissues. It is believed that the proposed anisotropic ECM microparticles will facilitate the coculture of multiple cell types in different ECMs, which is similar to in vivo microenvironments, facilitating control of cell behavior in an anisotropic microenvironment for the benefit of large-scale and quantitative analyses in vitro.


Familial clustering of parotid gland lymphoepithelioma in North America.
To describe genetic susceptibility in the first familial clustering of parotid gland lymphoepithelioma reported in North America. Retrospective study. Tertiary care institution with outreach to northern Quebec. Chart, family history, literature review, and c-kit assay. C-kit assay. Four family members of both sexes over two generations had lymphoepithelioma of the parotid gland, without involvement of the nasopharynx. Two c-kit assays were positive of the three cases that could be done. Association with Epstein-Barr virus has been demonstrated in the oncogenesis of lymphoepithelioma. Genetic susceptibility and common familial environmental factors play a role in the development of parotid gland lymphoepithelioma. A complete family history should be obtained in all cases of lymphoepithelioma of the parotid gland.


Kupffer cells modulate natural killer cell activity in vitro by producing prostaglandins.
The effect of Kupffer cells on natural killer (NK) cell-mediated cytotoxicity was examined. Kupffer cells prepared from rat liver suppressed NK activity against K562 cells and other tumor cell lines through a soluble factor secreted into the culture supernatant. When human peripheral blood mononuclear cells were incubated with the Kupffer cell-culture supernatant, a significant reduction of the cytotoxic activity was observed in the 6-hr chromium-release assay. This activity was dose dependent and was evident at various effector/target cell ratios. Lipopolysaccharide stimulated generation of the suppressive factor released from Kupffer cells in a dose-dependent manner. Suppression of the NK activity was observed when the Kupffer cell-culture supernatant was present in the assay system, whereas pretreatment of effector/target cells with the supernatant had minimal inhibitory effects. Autologous monocytes in human peripheral mononuclear cells were not related to this suppression. The suppressive factor in the fraction had a molecular weight below 10,000. Indomethacin, an inhibitor of prostaglandin synthesis, ameliorated the suppressive effects. These results suggest that Kupffer cells may modulate NK activity by producing PGs (E1, E2, and F2 alpha).


Reduction of E-cadherin by human defensin-5 in esophageal squamous cells.
Barrett's esophagus (BE) is metaplastic columnar epithelium converted from normal squamous epithelia in the distal esophagus that is thought to be a precancerous lesion of esophageal adenocarcinoma. BE is attributed to gastroesophageal reflux disease (GERD), and therefore gastric acid or bile acids are thought to be factors that cause epithelial cell damage and inflammation in the gastro-esophageal junction. The decrease of adherent junction molecules, E-cadherin has been reported to be associated with the progression of the Barrett's carcinoma, but the initiation of BE is not sufficiently understood. BE is characterized by the presence of goblet cells and occasionally Paneth cells are observed at the base of the crypts. The Paneth cells possess dense granules, in which human antimicrobial peptide human defensin-5 (HD-5) are stored and secreted out of the cells. This study determined the roles of HD-5 produced from metaplastic Paneth cells against adjacent to squamous cells in the gastro-esophageal junction. A human squamous cell line Het-1A, was incubated with the synthetic HD-5 peptide as a model of squamous cell in the gastro-esophageal junctions, and alterations of E-cadherin were investigated. Immunocytochemistry, flowcytometry, and Western blotting showed that the expression of E-cadherin protein was decreased. And a partial recovery from the decrease was observed by treatment with a CD10/neprilysin inhibitor (thiorphan). In conclusion, E-cadherin expression in squamous cells was reduced by HD-5 using in vitro experiments. In gastro-esophageal junction, HD-5 produced from metaplastic Paneth cells may therefore accelerate the initiation of BE.


Root and microbial biomass dynamics under the canopy of the desert shrub Zygophyllum dumosum.
A study was done to evaluate the influence of soil moisture and rainfall on root and microbial biomass production under the canopy of the desert shrub Zygophyllum dumosum. During the study period the root biomass production increased following the early rains but subsequently declined, remaining fairly constant thoroughout the season. In contrast microbial biomass and soil organic matter increased during the rainy season and declined with the onset of the dry summer period. Based on our results we suggest that the moisture event and not the amount and the organic matter content regulate root and microbial biomass production at the 0 to 10 cm soil layer.


Treg Cell Differentiation: From Thymus to Peripheral Tissue.
Regulatory T cells (Tregs) are crucial mediators of self-tolerance in the periphery. They differentiate in the thymus, where interactions with thymus-resident antigen-presenting cells, an instructive cytokine milieu, and stimulation of the T cell receptor lead to the selection into the Treg lineage and the induction of Foxp3 gene expression. Once mature, Treg cells leave the thymus and migrate into either the secondary lymphoid tissues, e.g., lymph nodes and spleen, or peripheral nonlymphoid tissues. There is growing evidence that Treg cells go beyond the classical modulation of immune responses and also play important functional roles in nonlymphoid peripheral tissues. In this review, we summarize recent findings about the thymic Treg lineage differentiation as well as the further specialization of Treg cells in the secondary lymphoid and in the peripheral nonlymphoid organs.


Effects of glycosylation on protein conformation and amide proton exchange rates in RNase B.
Assignment of most of the proton NMR resonances of bovine pancreatic RNase B has been achieved using standard NMR techniques and by comparison with the published assignments for RNase A. A comparison of the NMR spectra of RNase B with RNase A shows that glycosylation of the enzyme has little overall effect on the conformation of the protein in solution. Comparisons of hydrogen-deuterium solvent exchange rates for the NH protons of RNase A and RNase B were made using two-dimensional 1H correlation spectroscopy. In the case of the glycosylated enzyme the exchange rates decreased for the NH protons of residues 9-14, 23-24, 32, 34-35, 39-40, 43-44, 48-49, 60, 71, 75-76, 80, 83-85, 100-101, 107, 111 and 122, relative to the unglycosylated RNase A. These results are consistent with the presence of the oligosaccharide inducing enhanced global dynamic stability and consequent changes to the unfolding equilibrium of the enzyme. The enhanced stability is observed not only for residues in the vicinity of the glycosylation site, asparagine-34, but also at residues remote from this site, as much as 30 A away.


Artificial intelligence in radiology: relevance of collaborative work between radiologists and engineers for building a multidisciplinary team.
The use of artificial intelligence (AI) algorithms in the field of radiology is becoming more common. Several studies have demonstrated the potential utility of machine learning (ML) and deep learning (DL) techniques as aids for radiologists to solve specific radiological challenges. The decision-making process, the establishment of specific clinical or radiological targets, the profile of the different professionals involved in the development of AI solutions, and the relation with partnerships and stakeholders are only some of the main issues that have to be faced and solved prior to starting the development of radiological AI solutions. Among all the players in this multidisciplinary team, the communication between radiologists and data scientists is essential for a successful collaborative work. There are specific skills that are inherent to radiological and medical training that are critical for identifying anatomical or clinical targets as well as for segmenting or labelling lesions. These skills would then have to be transferred, explained, and taught to the data science experts to facilitate their comprehension and integration into ML or DL algorithms. On the other hand, there is a wide range of complex software packages, deep neural-network architectures, and data transfer processes for which radiologists need the expertise of software engineers and data scientists in order to select the optimal manner to analyse and post-process this amount of data. This paper offers a summary of the top five challenges faced by radiologists and data scientists including tips and tricks to build a successful AI team.


Parental exome analysis identifies shared carrier status for a second recessive disorder in couples with an affected child.
Consanguinity, commonplace in many regions around the globe, is associated with an increased risk of autosomal recessive (AR) genetic disorders. Consequently, consanguineous couples undergoing preimplantation genetic diagnosis (PGD) for one Mendelian disorder may be at increased risk for a child with a second, unrelated AR genetic disorder. We examined the yield of exome analysis for carrier screening of additional AR disorders, beyond the primary diagnosis, amongst consanguineous vs. non-consanguineous populations. Parental samples from trio exomes of 102 consanguineous families and 105 non-consanguineous controls were evaluated for shared carrier status, after disregarding the primary molecular diagnosis. Results were sub-classified according to disease severity. Secondary shared carrier status for pathogenic and likely pathogenic variants leading to AR disorders of moderate to profound severity was identified in 10/102 (9.8%) consanguineous couples, as compared to 1/105 (0.95%) non-consanguineous couples (χ2 = 8.0565, p value < 0.005). Higher inbreeding coefficient values, calculated from individual exomes, correlated with secondary shared carrier status for diseases of moderate to profound severity (r = 0.17, p value < 0.0125). Our results indicate that consanguineous couples undergoing PGD are at increased risk for a second genetic disease of moderate to profound severity. This study represents an underestimate of the rate of secondary shared carrier status due to inability to detect deep intronic variants, no assessment of copy number variants, and false negative results stemming from stringent variant interpretation. False positive results may result from inaccuracies in public databases. Additional studies in consanguineous populations will determine whether exome-based carrier screening should be recommended to all couples undergoing PGD.


Preoperative beta-blocker use should not be a quality metric for coronary artery bypass grafting.
Preoperative beta-blockade for coronary artery bypass grafting (CABG) has become an accepted hospital quality metric. However, single-institution reports regarding the benefits of beta-blocker (ß-blocker) use are conflicting. The purpose of this study was to evaluate the associations between preoperative beta-blocker use and outcomes within a large, regional cohort. Patient records from a statewide, multi-institutional Society of Thoracic Surgeons (STS) certified database for isolated CABG operations (2001 to 2011) were extracted and stratified by preoperative ß-blocker use. The influence of preoperative ß-blockers on risk-adjusted outcomes was assessed by hierarchical regression modeling with adjustment for preoperative risk using calculated STS predictive risk indices. A total of 43,747 (age, 63 years; ß-blocker 80% versus non ß-blocker 20%) patients were included. Median STS predicted risk of mortality scores for ß-blocker patients were incrementally lower (1.2% vs 1.4%, p < 0.001). Non ß-blocker patients more frequently developed pneumonia (3.5% vs 2.8%, p = 0.001), while ß-blocker patients surprisingly had greater intraoperative blood usage (16% vs 11%, p < 0.001). There was no difference in unadjusted mortality (ß-blocker: 1.9% vs non ß-blocker: 2.2%, p = 0.15). After risk adjustment, preoperative ß-blocker use was not associated with mortality (p = 0.63), morbidity, length of stay (p = 0.79), or hospital readmission (p = 0.97). Preoperative ß-blocker use is not associated with risk-adjusted mortality, several measures of morbidity, or hospital resource utilization after CABG operations. Thus, these data suggest that the routine use of preoperative ß-blockers for CABG operations should not be used as a measure of surgical quality.


Sex differences in solid pseudopapillary neoplasm of the pancreas: A population-based study.
Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare tumor. This study aims to examine the clinicopathological features and surgical treatments of SPN and compare the clinical behavior and prognosis between men and women with SPN. We collected the population data of patients with SPN diagnosed between 2004 and 2017 from the SEER database. The Kaplan-Meier method was used to analyze overall survival (OS) and disease-specific survival (DSS), and log-rank tests were used to evaluate the differences between subgroups. Univariate and multivariate Cox regression analyses were performed to screen out prognostic risk factors of SPN. A total of 378 patients with SPN were included, with 246 (65.1%) female patients. 1-, 3-, and 5-year overall survival rates were 98.9%, 95.7%, and 93.7%, respectively. Survival analysis revealed that regardless of stage, patients with SPN who underwent surgical interventions still had a significantly better prognosis than those without surgical interventions (P < .001). The patients with lymphatic dissection had a significantly better prognosis than those without lymphatic dissection (P < .001). Moreover, compared with female patients, male patients had significantly poorer OS and DSS (P < .001). Female SPN showed a bimodal age-frequency distribution with early-onset incidence at 28 years and late-onset peak incidence at 62 years, while male SPN presented a unimodal distribution with peak incidence at approximately age 64 years. In female patients, the tumor size in premenopausal females (<65 years old) was significantly larger than that in postmenopausal females (≥65 years old) (P < .001). Clinicopathological characteristic profiles were different not only between male SPN and premenopausal female SPN but also between premenopausal and postmenopausal female SPN. SPN presents indolent behavior and predominantly occurs in young women. Regardless of stage, surgical intervention is recommended. Moreover, our study is the first large enough study to demonstrate sex-related discrepancies in SPN. Thus, different treatment strategies should be designed for patients of different sexes at different ages and hormone therapy is a promising approach for SPN.


Identification and impact of hepatitis B virus DNA and antigens in pancreatic cancer tissues and adjacent non-cancerous tissues.
Increasing evidence suggests that a link exists between hepatitis B virus (HBV) serum markers and pancreatic cancer (PC). In this study, HBsAg and HBcAg were expressed in 21.0% (34/162) of PC and 29.0% (47/162) of non-tumor pancreatic tissues, and they were significantly associated with chronic pancreatitis (P=0.000). The HBV S, C and X genes were identified in 20% (6/30) of PC and 26.9% (7/26) of non-tumor tissues by PCR. A serological survey revealed that the prevalence of HBV DNA and anti-HBc was significantly increased in PC patients compared with healthy controls. Our data suggest that HBV infection in the pancreas may play an etiologic role in PC.


Identification of patients with locally advanced rectal cancer eligible for neoadjuvant chemotherapy alone: Results of a retrospective study.
Neoadjuvant chemotherapy (nCT) appears in a few clinical studies as an alternative to neoadjuvant chemoradiation (nCRT) in selected patients with locally advanced rectal cancer (LARC). We aimed to compare the clinical outcomes of nCT with or without nCRT in patients with LARC and to identify patients who may be suitable for nCT alone. A total of 155 patients with LARC who received neoadjuvant treatment (NT) were retrospectively analysed from January 2016 to June 2021. The patients were divided into two groups: nCRT (n = 101) and nCT (n = 54). More patients with locally advanced disease (cT4, cN+ and magnetic resonance imaging-detected mesorectal fascia [mrMRF] positive [+]) were found in the nCRT group. Patients in the nCRT group received a dose of 50 Gy/25 Fx irradiation with concurrent capecitabine, and the median number of nCT cycles was two. In the nCT group, the median number of cycles was four. The median follow-up duration was 30 months. The pathologic complete response (pCR) rate in the nCRT group was significantly higher than that in the nCT group (17.5% vs. 5.6%, p = 0.047). A significant difference was observed in the locoregional recurrence rate (LRR); 6.9% in the nCRT group and 16.7% in the nCT group (p = 0.011). Among patients with initial mrMRF (+) status, the LRR in the nCRT group was significantly lower than that in the nCT group (6.1% vs. 20%, p = 0.007), but not in patients with initial mrMRF negative (-) (10.5% in each group, p = 0.647). Compared with the nCT group, a lower LRR was observed in patients in the nCRT group with initial mrMRF (+) converted to mrMRF (-) after NT (5.3% vs. 23%, p = 0.009). No significant difference was observed between the two groups regarding acute toxicity and overall and progression-free survivals. Multivariate analysis showed that nCRT and ypN stage were independent prognostic factors for the development of LRR. Patients with initial mrMRF (-) may be suitable for nCT alone. However, patients with initial mrMRF (+) converted to mrMRF (-) after nCT are still at high risk of LRR, and radiotherapy is recommended. Prospective studies are required to confirm these findings.


The AT2 receptor--a matter of love and hate.
In 1989, the development of specific angiotensin receptor antagonists which distinguish between two angiotensin receptor subtypes (AT1 and AT2) led to a breakthrough in angiotensin research. It turned out, that the AT1 receptor was almost entirely responsible for the "classical" actions of angiotensin II related to the regulation of blood pressure as well as volume and electrolyte balance. However, actions and signal transduction mechanisms coupled to the AT2 receptor remained enigmatic for a long time. The present review summarizes the current knowledge of AT2 receptor distribution, signaling and function with an emphasis on growth/anti-growth, differentiation and the regeneration of neuronal tissue.