Zika virus non-structural protein 4B interacts with DHCR7 to facilitate viral infection.
Zika virus (ZIKV) evolves non-structural proteins to evade immune response and ensure efficient replication in the host cells. Cholesterol metabolic enzyme 7-dehydrocholesterol reductase (DHCR7) was recently reported to impact innate immune responses in ZIKV infection. However, the vital non-structural protein and mechanisms involved in DHCR7-mediated viral evasion are not well elucidated. In this study, we demonstrated that ZIKV infection facilitated DHCR7 expression. Notably, the upregulated DHCR7 in turn facilitated ZIKV infection and blocking DHCR7 suppressed ZIKV infection. Mechanically, ZIKV non-structural protein 4B (NS4B) interacted with DHCR7 to induce DHCR7 expression. Moreover, DHCR7 inhibited TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) phosphorylation, which resulted in the reduction of interferon-beta (IFN-β) and interferon-stimulated genes (ISGs) productions. Therefore, we propose that ZIKV NS4B binds to DHCR7 to repress TBK1 and IRF3 activation, which in turn inhibits IFN-β and ISGs, and thereby facilitating ZIKV evasion. This study broadens the insights on how viral non-structural proteins antagonize innate immunity to facilitate viral infection via cholesterol metabolic enzymes and intermediates.


Radiation prophylaxis of heterotopic bone formation following total hip arthroplasty: current status.
Differentiation of pluripotential stem cells into osteogenic precursors is exquisitely sensitive to ionizing radiation. Radiation prophylaxis effectively prevents ectopic ossification if delivered to the operative site within 5 days following total hip arthroplasty. Continued efforts at dose reduction over the last decade have demonstrated efficacy with as little as 6,000 to 8,000 rad; no soft tissue sarcomas have been reported in this low dose range following treatment of malignant disease. Precise limitation of the treatment field is necessary for application of this modality to cementless implants dependent on bony ingrowth for stable fixation. Trochanteric nonunion is reported in 25% of hips following radiation prophylaxis, but this is as likely related to the high proportion of revision surgery in these series as it is a direct consequence of the radiation.


Elevated osteopontin and thrombospondin expression identifies malignant human breast carcinoma but is not indicative of metastatic status.
Our previous characterization of a human breast tumor metastasis model identified several candidate metastasis genes. The expression of osteopontin (OPN) correlated with the metastatic phenotype, whereas thrombospondin-1 (TSP-1) and tyrosinase-related protein-1 (TYRP-1) correlated with the nonmetastatic phenotype of independent MDA-MB-435 cell lines implanted orthotopically into athymic mice. The aim of the present study was to examine the cellular distribution of these molecules in human breast tissue and to determine whether the relative expression level of these three genes is associated with human breast tumor metastasis. Sixty-eight fresh, frozen specimens including 31 primary infiltrating ductal carcinomas, 22 nodal metastases, 10 fibroadenomas, and five normal breast tissues were evaluated for OPN expression, TSP-1 expression and TYRP-1 expression. Immunohistochemistry was performed to monitor the cellular distribution and to qualitatively assess expression. Quantitative analysis was achieved by enrichment of breast epithelial cells using laser-capture microdissection and subsequent real-time, quantitative PCR. The epithelial components of the breast tissue were the source of OPN and TSP-1 expression, whereas TYRP-1 was present in both the epithelial and stromal components. Both OPN and TSP-1 expression were significantly higher in malignant epithelial sources over normal and benign epithelial sources, but no difference in expression levels was evident between primary tumors with or without metastases, nor between primary and metastatic carcinomas. Elevated expression of OPN and TSP-1 may play a role in the pathogenesis of breast cancer. The multiplex analysis of these molecules may enhance our ability to diagnose and/or prognosticate human breast malignancy.


[Determinants of perinatal and infant mortality in Italy 1980-1983].
Determinants of stillbirth, perinatal and infant mortality in Italy have been analyzed using information collected routinely by the Italian Central Institute of Statistics on more than 2,400,000 births and 33,000 infant deaths in the period 1980-1983. Individual records include data on maternal (for example age, education, obstetric history) and fetal (sex, birth weight, gestational week at birth) characteristics. The Italian stillbirth, perinatal and infant (1st-365th day of life) mortality rates were respectively 7.7/1000 births, 16.4/1000 births and 13.5/1000 livebirths for the considered period. Perinatal and infant mortality was impressive in very low birth weight. About 90% of livebirths weighing less than 1000g died within the first year of life, but this percentage decreased to about 45% in babies weighing 1000-1499g. As a whole, low birth weight explained more than 70% of deaths. Further, stillbirth, perinatal and infant mortality rates were higher in male babies, in older women and in higher birth rank. These findings persist, although less markedly, after adjustment for weight. Mortality rates were about 60-70% higher in less educated women. Stillbirth, perinatal and infant mortality rates were 20 to 30% higher in Southern Italy, as compared to the North of the country. This finding was not markedly changed after adjustment for birth weight and maternal age and education, suggesting that socio-economic factors are per se important determinants of perinatal and infant mortality in Italy, and explain in terms of population attributable risk, about 15% of stillbirths or deaths within the first year of life.


Tensor factorization toward precision medicine.
Precision medicine initiatives come amid the rapid growth in quantity and variety of biomedical data, which exceeds the capacity of matrix-oriented data representations and many current analysis algorithms. Tensor factorizations extend the matrix view to multiple modalities and support dimensionality reduction methods that identify latent groups of data for meaningful summarization of both features and instances. In this opinion article, we analyze the modest literature on applying tensor factorization to various biomedical fields including genotyping and phenotyping. Based on the cited work including work of our own, we suggest that tensor applications could serve as an effective tool to enable frequent updating of medical knowledge based on the continually growing scientific and clinical evidence. We encourage extensive experimental studies to tackle challenges including design choice of factorizations, integrating temporality and algorithm scalability.


Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study.
Liver biopsy is thought mandatory for management of patients with hepatitis C virus (HCV) infection, especially for staging fibrosis. We aimed, in our prospective study, to assess the predictive value of a combination of basic serum biochemical markers for diagnosis of clinically significant fibrosis (including early stages). We assessed liver-biopsy patients with detectable HCV by PCR, for eligibility, and took a blood sample on the day of the procedure. The analysis was done in a first-year period for 205 patients and then tested in a second period on 134 patients. We devised a fibrosis index that included the most informative markers (combined with age and sex) for the first-year group. 11 serum markers were assessed as well as fibrosis stage: F0=no fibrosis and F1=portal fibrosis; and for clinically significant fibrosis, F2=few septa, F3=many septa, and F4=cirrhosis. Statistical analysis was by logistic regression, neural connection, and receiver-operating characteristic (ROC) curves. First-year and second-year patient-group characteristics and biochemical markers did not differ. The overall frequency of clinically significant fibrosis was 40% (138 patients). The most informative markers were: alpha2 macroglobulin, alpha2 globulin (or haptoglobin), gamma globulin, apolipoprotein A1, gamma glutamyltranspeptidase, and total bilirubin. The areas (SD) under the ROC curves for the first-year (0.836 [0.430]) and second-year groups (0.870 [0.340]) did not differ (p=0.44). With the best index, a high negative predictive value (100% certainty of absence of F2, F3, or F4) was obtained for scores ranging from zero to 0.10 (12% [41] of all patients), and high positive predictive value (>90% certainty of presence of F2, F3, or F4) for scores ranging from 0.60 to 1.00 (34% [115] of all patients). A combination of basic serum markers could be used to substantially reduce the number of liver biopsies done in patients with chronic HCV infection.


Systematic review of nutrition screening and assessment in inflammatory bowel disease.
Malnutrition is prevalent in inflammatory bowel disease (IBD). Multiple nutrition screening (NST) and assessment tools (NAT) have been developed for general populations, but the evidence in patients with IBD remains unclear. To systematically review the prevalence of abnormalities on NSTs and NATs, whether NSTs are associated with NATs, and whether they predict clinical outcomes in patients with IBD. Comprehensive searches performed in Medline, CINAHL Plus and PubMed. Included: English language studies correlating NSTs with NATs or NSTs/NATs with clinical outcomes in IBD. Excluded: Review articles/case studies; use of body mass index/laboratory values as sole NST/NAT; age < 16. Of 16 studies and 1618 patients were included, 72% Crohn's disease and 28% ulcerative colitis. Four NSTs (the Malnutrition Universal Screening Tool, Malnutrition Inflammation Risk Tool (MIRT), Saskatchewan Inflammatory Bowel Disease Nutrition Risk Tool (SaskIBD-NRT) and Nutrition Risk Screening 2002 (NRS-2002) were significantly associated with nutritional assessment measures of sarcopenia and the Subjective Global Assessment (SGA). Three NSTs (MIRT, NRS-2002 and Nutritional Risk Index) were associated with clinical outcomes including hospitalizations, need for surgery, disease flares, and length of stay (LOS). Sarcopenia was the most commonly evaluated NAT associated with outcomes including the need for surgery and post-operative complications. The SGA was not associated with clinical outcomes aside from LOS. There is limited evidence correlating NSTs, NATs and clinical outcomes in IBD. Although studies support the association of NSTs/NATs with relevant outcomes, the heterogeneity calls for further studies before an optimal tool can be recommended. The NRS-2002, measures of sarcopenia and developments of novel NSTs/NATs, such as the MIRT, represent key, clinically-relevant areas for future exploration.


Computational modeling and molecular imprinting for the development of acrylic polymers with high affinity for bile salts.
This work has focused on the rational development of polymers capable of acting as traps of bile salts. Computational modeling was combined with molecular imprinting technology to obtain networks with high affinity for cholate salts in aqueous medium. The screening of a virtual library of 18 monomers, which are commonly used for imprinted networks, identified N-(3-aminopropyl)-methacrylate hydrochloride (APMA.HCl), N,N-diethylamino ethyl methacrylate (DEAEM) and ethyleneglycol methacrylate phosphate (EGMP) as suitable functional monomers with medium-to-high affinity for cholic acid. The polymers were prepared with a fix cholic acid:functional monomer mole ratio of 1:4, but with various cross-linking densities. Compared to polymers prepared without functional monomer, both imprinted and non-imprinted microparticles showed a high capability to remove sodium cholate from aqueous medium. High affinity APMA-based particles even resembled the performance of commercially available cholesterol-lowering granules. The imprinting effect was evident in most of the networks prepared, showing that computational modeling and molecular imprinting can act synergistically to improve the performance of certain polymers. Nevertheless, both the imprinted and non-imprinted networks prepared with the best monomer (APMA.HCl) identified by the modeling demonstrated such high affinity for the template that the imprinting effect was less important. The fitting of adsorption isotherms to the Freundlich model indicated that, in general, imprinting increases the population of high affinity binding sites, except when the affinity of the functional monomer for the target molecule is already very high. The cross-linking density was confirmed as a key parameter that determines the accessibility of the binding points to sodium cholate. Materials prepared with 9% mol APMA and 91% mol cross-linker showed enough affinity to achieve binding levels of up to 0.4 mmol g(-1) (i.e., 170 mg g(-1)) under flow (1 mL min(-1)) of 0.2 mM sodium cholate solution.


Is the prediction of pKa values by constant-pH molecular dynamics being hindered by inherited problems?
In this study, we investigate two factors that can hinder the performance of constant-pH molecular dynamics methods in predicting protein pK(a) values, using hen egg white lysozyme as a test system. The first factor is related to the molecular definition and pK(a) value of model compounds in the Poisson-Boltzmann framework. We address this by defining the model compound as a molecular fragment with an associated pK(a) value that is calibrated against experimental data, which results in a decrease of 0.12 units in pK(a) errors. The second addressed factor is the possibility that detrimental structural distortions are being introduced in the simulations by the underlying molecular mechanics force field. This issue is investigated by analyzing how the gradual structural rearrangements affect the predicted pK(a) values. The two GROMOS force fields studied here (43A1 and 53A6) yield good pK(a) predictions, although a time-dependent performance is observed: 43A1 performs better after a few nanoseconds of structural reorganization (pK(a) errors of ~0.45), while 53A6 gives the best prediction right at the first nanosecond (pK(a) errors of 0.42). These results suggest that the good performance of constant-pH molecular dynamics methods could be further improved if these force field limitations were overcome.


The Use of Combined Magnetic Field Treatment for Fracture Nonunions: A Prospective Observational Study.
This study evaluated the effectiveness and safety of bone growth stimulation using combined magnetic field (CMF) for the treatment of fracture nonunions. In this prospective multicenter study, patients were assessed monthly for 9 mo, or until they demonstrated a healed nonunion, and were assessed at a final follow-up 3 mo after treatment completion. The primary outcome was the presence or absence of fracture healing at the nonunion site, determined by clinical and radiographic assessment. Enrolled in this study were 112 patients with 116 fracture nonunions. Fifty-two (44.8%) patients demonstrated a healed nonunion between treatment initiation and 12-mo- posttreatment initiation (9 mo of treatment plus 3 mo posttreatment follow-up). Tibial nonunions had a higher percentage of healed fractures compared to other fracture types (78% vs. 46.5%, respectively; p = 0.004). This study demonstrated that noninvasive CMF technology healed 78% of tibial fracture nonunions and 45% of all fracture nonunions (p = 0.004). Additionally, pain at rest, with stress, and on weight bearing all decreased following treatment with CMF, with no adverse events reported. These results indicate that CMF is a beneficial noninvasive treatment modality for nonunions.


In vivo evaluation of tumour acidosis for assessing the early metabolic response and onset of resistance to dichloroacetate by using magnetic resonance pH imaging.
Dichloroacetate (DCA) can reverse the glycolytic phenotype that is responsible of increased lactate production and extracellular pH acidification in cancer cells. Magnetic resonance imaging-chemical exchange saturation transfer (MRI-CEST) pH mapping is a novel non-invasive imaging approach that can measure in vivo extracellular tumour pH. We examined whether MRI-CEST pH mapping can monitor in vivo changes in tumour acidosis for assessing treatment response to DCA. Cell viability and extracellular pH were assessed in TS/A breast cancer cells treated with 1-10 mM DCA for 24 h in normoxia or hypoxia (1% O2) conditions. Extracellular tumour pH values were measured in vivo by MRI-CEST pH mapping of TS/A tumour-bearing mice before, three days and fifteen days after DCA or saline treatment. Reduced extracellular acidification and vitality were observed in DCA-treated TS/A cells. Tumour-bearing mice showed a marked and significant increase of tumour extracellular pH at 3 days post-DCA treatment, reflecting DCA-induced glycolysis inhibition, as confirmed by reduced lactate production. After 15 days of DCA treatment, the onset of resistance to DCA was observed, with recover of tumour extracellular acidification and lactate levels that returned to baseline values. A significant correlation was observed between tumour extracellular pH values and lactate levels (r= -0.97, P<0.05). These results suggest that MRI-CEST pH imaging is a promising tool to monitor the early response and efficacy of cancer metabolic targeting drugs.


0.1% triamcinolone acetonide ointment and patch test responses.
The effect of topical steroids on patch test responsiveness was investigated in 15 subjects. A 0.1% triamcinolone acetonide ointment and a control preparation were applied three times daily to opposing sites on the upper part of the inner arms prior to patch testing. From a total of 18 pairs of patch tests applied to the 15 patients, substantial differences in the paired reactions were seen in only three patients after 96 hours. Of these, two had the more intense reaction on the control side, and the third had a greater reaction on the triamcinolone-pretreated side. Previously applied, intermediate-strength topical steroids are unlikely to prevent the detection of contact allergy by patch testing.


Local Adaptation Interacts with Expansion Load during Range Expansion: Maladaptation Reduces Expansion Load.
The biotic and abiotic factors that facilitate or hinder species range expansions are many and complex. We examine the impact of two genetic processes and their interaction on fitness at expanding range edges: local maladaptation resulting from the presence of an environmental gradient and expansion load resulting from increased genetic drift at the range edge. Results from spatially explicit simulations indicate that the presence of an environmental gradient during range expansion reduces expansion load; conversely, increasing expansion load allows only locally adapted populations to persist at the range edge. Increased maladaptation reduces the speed of range expansion, resulting in less genetic drift at the expanding front and more immigration from the range center, therefore reducing expansion load at the range edge. These results may have ramifications for species being forced to shift their ranges because of climate change or other anthropogenic changes. If rapidly changing climate leads to faster expansion as populations track their shifting climatic optima, populations may suffer increased expansion load beyond previous expectations.


In search of zebras: Critical analysis of the rarity of perineural breast cancer spread to the brachial plexus in men.
Perineural spread (PNS) of breast cancer to the brachial plexus is rare, with reports limited to cases only in female patients. This study aimed to determine the incidence of PNS in male compared with female patients. Adult breast cancer patients referred to a single institution between 1994 and 2022 were retrospectively reviewed for imaging or biopsy-confirmed cases of PNS to the brachial plexus. Two independent reviewers of articles published in any language between 1990 and 2022 in PubMed, Scopus, Embase, and Google Scholar performed a systematic literature review. Of the 10,466 patients with breast cancer (10,355 female, 111 male) referred to a single institution, there were 42 female patients with PNS to the brachial plexus for an estimated incidence of 0.4%. In the same time period, there were 111 male patients treated for breast cancer, including 88 patients with Klinefelter's syndrome (KS); however, there were no cases of male patients with PNS. A systematic review of the world's literature did not identify male patients with PNS to the brachial plexus. There is a lack of any reported cases of PNS of breast cancer to the brachial plexus in men or patients with KS, who have a much higher incidence of breast cancer. This may reflect either the compounding rarity of these two events or point toward a distinct hormonally-driven link between breast cancer and PNS, highlighted by the disparity in PNS incidence in men and women.


Surgical interventions for the management of chronic pelvic pain in women.
Chronic pelvic pain (CPP) is a common gynaecological condition accounting for 20% of all gynaecological referrals. There are wide ranges of causes with overlapping symptomatology, therefore the management of the condition is a formidable challenge for clinicians. The aetiology of CPP is heterogeneous and in many cases, no clear diagnosis can be reached. It is in this scenario that the label of chronic pelvic pain syndrome (CPPS) can be applied. We defined women with CPPS as having a minimum duration of pain of at least 6 months, including with a diagnosis of pelvic congestion syndrome, but excluding pain caused by a condition such as endometriosis. Many surgical interventions have been tried in isolation or in conjunction with non-surgical interventions in the management with variable results. Surgical interventions are invasive and carry operative risks. Surgical interventions must be evaluated for their effectiveness prior to their prevalent use in the management of women with CPPS. To review the effectiveness and safety of surgical interventions in the management of women with CPPS. We searched the Cochrane Gynaecology and Fertility Group (CGF) Specialised Register of Controlled Trials, CENTRAL, MEDLINE, Embase and PsycINFO, on 23 April 2021 for any randomised controlled trials (RCT) for surgical interventions in women with CPPS. We also searched the citation lists of relevant publications, two trial registries, relevant journals, abstracts, conference proceedings and several key grey literature sources. RCTs with women who had CPPS. The review authors were prepared to consider studies of any surgical intervention used for the management of CPPS. Outcome measures were pain rating scales, adverse events, psychological outcomes, quality of life (QoL) measures and requirement for analgesia. Two review authors independently evaluated studies for inclusion and extracted data using the forms designed according to Cochrane guidelines. For each included trial, we collected information regarding the method of randomisation, allocation concealment, blinding, data reporting and analyses. We reported pooled results as mean difference (MDs) or odds ratios (OR) and 95% confidence interval (CI) by the Mantel-Haenszel method. If similar outcomes were reported on different scales, we calculated the standardised mean difference (SMD). We applied GRADE criteria to judge the overall certainty of the evidence. Four studies met our inclusion criteria involving 216 women with CPP and no identifiable cause. Adhesiolysis compared to no surgery or diagnostic laparoscopy We are uncertain of the effect of adhesiolysis on pelvic pain scores postoperatively at three months (MD -7.3, 95% CI -29.9 to 15.3; 1 study, 43 participants; low-certainty evidence), six months (MD -14.3, 95% CI -35.9 to 7.3; 1 study, 43 participants; low-certainty evidence) and 12 months postsurgery (MD 0.00, 95% CI -4.60; 1 study, 43 participants; very low-certainty evidence). Adhesiolysis may improve both the emotional wellbeing (MD 24.90, 95% CI 7.92 to 41.88; 1 study, 43 participants; low-certainty evidence) and social support (MD 23.90, 95% CI -1.77 to 49.57; 1 study, 43 participants; low-certainty evidence) components of the Endometriosis Health Profile-30, and both the emotional component (MD 32.30, 95% CI 13.16 to 51.44; 1 study, 43 participants; low-certainty evidence) and the physical component of the 12-item Short Form (MD 22.90, 95% CI 10.97 to 34.83; 1 study, 43 participants; low-certainty evidence) when compared to diagnostic laparoscopy. We are uncertain of the safety of adhesiolysis compared to comparator groups due to low-certainty evidence and lack of structured adverse event reporting. No studies reported on psychological outcomes or requirements for analgesia. Laparoscopic uterosacral ligament ablation or resection compared to diagnostic laparoscopy/other treatment We are uncertain of the effect of laparoscopic uterosacral ligament/nerve ablation (LUNA) or resection compared to other treatments postoperatively at three months (OR 1.26, 95% CI 0.40 to 3.93; 1 study, 51 participants; low-certainty evidence) and six months (MD -2.10, 95% CI -4.38 to 0.18; 1 study, 74 participants; very low-certainty evidence). At 12 months post-surgery, we are uncertain of the effect of LUNA on the rate of successful treatment compared to diagnostic laparoscopy. One study of 56 participants found no difference in the effect of LUNA on non-cyclical pain (P = 0.854) or dyspareunia (P = 0.41); however, there was a difference favouring LUNA on dysmenorrhea (P = 0.045) and dyschezia (P = 0.05). We are also uncertain of the effect of LUNA compared to vaginal uterosacral ligament resection on pelvic pain at 12 months (MD 2.00, 95% CI 0.47 to 3.53; 1 study, 74 participants; very low-certainty evidence). We are uncertain of the safety of LUNA or resection compared to comparator groups due to the lack of structured adverse event reporting. Women undergoing LUNA may require more analgesia postoperatively than those undergoing other treatments (P < 0.001; 1 study, 74 participants). No studies reported psychological outcomes or QoL. We are uncertain about the benefit of adhesiolysis or LUNA in management of pain in women with CPPS based on the current literature. There may be a QoL benefit to adhesiolysis in improving both emotional wellbeing and social support, as measured by the validated QoL tools. It was not possible to synthesis evidence on adverse events as these were only reported narratively in some studies, in which none were observed. With the inadequate objective assessment of adverse events, especially long-term adverse events, associated with adhesiolysis or LUNA for CPPS, there is currently little to support these interventions for CPPS.


Thyroid carcinoma in children and adolescents: diagnostic implications of analysis of the tumor genome.
To update information about pediatric thyroid cancer. This review of thyroid nodules in children indicates that the incidence of thyroid cancer has been steadily increasing over the last 30 years. Knowledge of factors which predispose to the development of thyroid cancer--radiation exposure and family history of thyroid cancer or personal or family history of familial syndromes associated with thyroid cancer--can help determine the aggressiveness with which the diagnostic studies of thyroid nodules should be pursued. Presence of thyroid nodules should prompt measurement of circulating thyroid-stimulating hormone. Thyroid nodules should generally be studied with thyroid ultrasonography; those greater than 0.5-1 cm in diameter which are not simple cysts should be studied with fine-needle aspiration (FNA). When cytologic analysis is indeterminate, a number of molecular techniques may assist in determining which patients should undergo thyroid surgery. The relative frequency of indeterminate cytology on FNA could necessitate surgery in a large number of patients who will be found to have benign lesions. A number of molecular techniques are available to identify patients with indeterminate cytology who can confidently be followed without surgery as the probability of malignancy is low.


Environmental response patterns in commercial classes of common bean (Phaseolus vulgaris L.).
The yield data of 39 cultivars of diverse commercial classes of beans (Phaseolus vulgaris L.) planted in seven locations in Michigan were subjected to cluster and canonical variate analyses. The essential findings and conclusions can be summarized as follows: (1) Cluster analysis classified the cultivars into sub-sets or clusters almost identically coinciding with their commercial class designation. Canonical variate analysis completely confirmed the sub-groupings. Within class similarities were attributed to a narrow genetic base resulting from a common genetic relationship, or at least sharing of a common gene pool. (2) It was found that two clusters could possess almost identical mean (cluster mean) yields, and deviate in opposite directions over the same range of environments. (3) When total genotype × environmental interaction variance was partitioned into between and within clusters, the cluster × environment portion constituted 80% of the total. (4) These results imply that if the behavior of a given cultivar across a series of environments is known, the behavior of all other members of the class across a similar range of environments would be predictable.


Usefulness of serum thyrotropin for risk prediction of differentiated thyroid cancers does not apply to microcarcinomas: results of 1,870 Chinese patients with thyroid nodules.
The objectives of this study were to investigate whether preoperative serum thyrotropin (TSH) concentrations can be used for risk prediction of differentiated thyroid cancers (DTC), in particular, microcarcinomas (DTMC), which may be in an early stage of development of DTC. The cohort of this retrospective study consisted of 1,870 patients who underwent surgery on thyroid nodules at a single hospital in an iodine-sufficient region in China. Serum TSH and anti-thyroid antibodies were measured and diagnoses were based on surgical pathology reports. Of 1,870 patients, 14.4% (n=269) had DTC. Eighty-nine DTCs were DTMC. As TSH increased, the prevalence of DTC rose clearly. The odds ratio in favor of having DTC with a serum TSH 1.9-4.8 mIU/L and > 4.8 mIU/L, compared with having a serum TSH 1.0-1.9 mIU/L were 1.57 (95% CI 1.03-2.40, P=0.038) and 5.71 (95% CI 2.31-14.14, P=0.0002), respectively. A similar pattern was yielded when excluding subjects with high thyroid autoantibodies. Higher TSH was also associated with lymph node metastasis and advanced disease (stage III and IV). However, preoperative TSH was 1.17 mIU/L in patients with DTMC vs. 1.08 mIU/L in patients with benign pathology (P = 0.80). The pattern of escalating prevalence with higher TSH did not apply to DTMC. In conclusion, serum TSH is not a good risk predictor of DTMCs. Elevated TSH level may be related to advanced stage, that is, progression of thyroid cancer, but not with the development of thyroid cancer, since microcarcinomas do not have any relation with TSH level.


The KEAP1-NRF2 System in Healthy Aging and Longevity.
Aging is inevitable, but the inherently and genetically programmed aging process is markedly influenced by environmental factors. All organisms are constantly exposed to various stresses, either exogenous or endogenous, throughout their lives, and the quality and quantity of the stresses generate diverse impacts on the organismal aging process. In the current oxygenic atmosphere on earth, oxidative stress caused by reactive oxygen species is one of the most common and critical environmental factors for life. The Kelch-like ECH-associated protein 1-NFE2-related factor 2 (KEAP1-NRF2) system is a critical defense mechanism of cells and organisms in response to redox perturbations. In the presence of oxidative and electrophilic insults, the thiol moieties of cysteine in KEAP1 are modified, and consequently NRF2 activates its target genes for detoxification and cytoprotection. A number of studies have clarified the contributions of the KEAP1-NRF2 system to the prevention and attenuation of physiological aging and aging-related diseases. Accumulating knowledge to control stress-induced damage may provide a clue for extending healthspan and treating aging-related diseases. In this review, we focus on the relationships between oxidative stress and aging-related alterations in the sensory, glandular, muscular, and central nervous systems and the roles of the KEAP1-NRF2 system in aging processes.


Phase 2 study of nilotinib in pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia.
Chronic myeloid leukemia (CML) is rare in children and accounts for ≤15% of all myeloid leukemia cases. When we initiated this study with nilotinib, imatinib was the only tyrosine kinase inhibitor indicated for pediatric patients with Philadelphia chromosome-positive (Ph+) CML in chronic phase (CP); alternative treatment options were needed, particularly for patients who developed resistance or intolerance (R/I) to imatinib. This phase 2 study enrolled pediatric patients with either Ph+ CML-CP R/I to imatinib or dasatinib or newly diagnosed Ph+ CML-CP. Data presented are from analyses with minimum follow-up of up to 24 cycles (1 cycle is 28 days). Fifty-nine patients with Ph+ CML-CP were enrolled, and 58 were treated (R/I, n = 33; newly diagnosed, n = 25). Major molecular response (MMR) rate at cycle 6 in the R/I cohort was 39.4% (primary end point); 57.6% of patients achieved or maintained MMR and 81.8% achieved or maintained complete cytogenetic response (CCyR) by 24 cycles. In patients with newly diagnosed disease, rates of MMR by cycle 12 and CCyR at cycle 12 were 64.0% each (primary end points); by cycle 24, cumulative MMR and CCyR rates were 68.0% and 84.0%, respectively. The safety profile of nilotinib in pediatric patients was generally comparable with the known safety profile in adults, although cardiovascular events were not observed in this study, and hepatic laboratory abnormalities were more frequent; no new safety signals were identified. In summary, nilotinib demonstrated efficacy and a manageable safety profile in pediatric patients with Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov as #NCT01844765.


Amino acid substitutions sufficient to convert the nontransforming p60c-src protein to a transforming protein.
We have previously shown that Rous sarcoma virus variants that carry the cellular homolog (c-src) of the viral src gene (v-src) do not transform chicken embryo fibroblasts. We also have shown that replacement of sequences upstream or downstream from the BglI site of the cellular src gene with the corresponding regions of v-src restored transforming activity to the hybrid genes. Since there are only six amino acid changes between p60c-src and p60v-src within the sequences upstream from BglI, we constructed chimeric molecules involving v-src and c-src to determine the effect of each amino acid substitution on the biological activities of the gene product. We found that the change from Thr to Ile at position 338 or the replacement of a fragment of c-src containing Gly-63, Arg-95, and Thr-96 with a corresponding fragment of v-src containing Asp-63, Trp-95, and Ile-96 converted p60c-src into a transforming protein by the criteria of focus formation, anchorage-independent growth, and tumor formation in newborn chickens. These mutations also resulted in elevation of the protein kinase activity of p60c-src.


Unacylated ghrelin suppresses ghrelin-induced neuronal activity in the hypothalamus and brainstem of male rats [corrected].
Ghrelin, the endogenous growth hormone secretagogue, has an important role in metabolic homeostasis. It exists in two major molecular forms: acylated (AG) and unacylated (UAG). Many studies suggest different roles for these two forms of ghrelin in energy balance regulation. In the present study, we compared the effects of acute intracerebroventricular administration of AG, UAG and their combination (AG+UAG) to young adult Wistar rats on food intake and central melanocortin system modulation. Although UAG did not affect food intake it significantly increased the number of c-Fos positive neurons in the arcuate (ARC), paraventricular (PVN) and solitary tract (NTS) nuclei. In contrast, UAG suppressed AG-induced neuronal activity in PVN and NTS. Central UAG also modulated hypothalamic expression of Mc4r and Bmp8b, which were increased and Mc3r, Pomc, Agrp and Ucp2, which were decreased. Finally, UAG, AG and combination treatments caused activation of c-Fos in POMC expressing neurons in the arcuate, substantiating a physiologic effect of these peptides on the central melanocortin system. Together, these results demonstrate that UAG can act directly to increase neuronal activity in the hypothalamus and is able to counteract AG-induced neuronal activity in the PVN and NTS. UAG also modulates expression of members of the melanocortin signaling system in the hypothalamus. In the absence of an effect on energy intake, these findings indicate that UAG could affect energy homeostasis by modulation of the central melanocortin system.


Surgical anatomy of the conduction system of the heart in anomalies of the membranous part of the ventricular septum with orifice in it.
Specific features of surgical anatomy of the atrioventricular conduction system (AVCS) in true and false aneurysms of the membranous part of the ventricular septum were studied on 126 heart specimens. The authors succeeded in localisation and dissection of the CS with the aid of an original method of anatomical microdissection which they prefer to the histologic method in studying the surgical anatomy of CS. The advantage of the authors' method consists in an objective anatomical identification of CS while preserving the integrity of adjacent structures.


Evaluation of Different Gene Prediction Tools in Coccidioides immitis.
Gene prediction is required to obtain optimal biologically meaningful information from genomic sequences, but automated gene prediction software is imperfect. In this study, we compare the original annotation of the Coccidioides immitis RS genome (the reference strain of C. immitis) to annotations using the Funannotate and Augustus genome prediction pipelines. A total of 25% of the originally predicted genes (denoted CIMG) were not found in either the Funannotate or Augustus predictions. A comparison of Funannotate and Augustus predictions also found overlapping but not identical sets of genes. The predicted genes found only in the original annotation (referred to as CIMG-unique) were less likely to have a meaningful functional annotation and a lower number of orthologs and homologs in other fungi than all CIMG genes predicted by the original annotation. The CIMG-unique genes were also more likely to be lineage-specific and poorly expressed. In addition, the CIMG-unique genes were found in clusters and tended to be more frequently associated with transposable elements than all CIMG-predicted genes. The CIMG-unique genes were more likely to have experimentally determined transcription start sites that were further away from the originally predicted transcription start sites, and experimentally determined initial transcription was less likely to result in stable CIMG-unique transcripts. A sample of CIMG-unique genes that were relatively well expressed and differentially expressed in mycelia and spherules was inspected in a genome browser, and the structure of only about half of them was found to be supported by RNA-seq data. These data suggest that some of the CIMG-unique genes are not authentic gene predictions. Genes that were predicted only by the Funannotate pipeline were also less likely to have a meaningful functional annotation, be shorter, and express less well than all the genes predicted by Funannotate. C. immitis genes predicted by more than one annotation are more likely to have predicted functions, many orthologs and homologs, and be well expressed. Lineage-specific genes are relatively uncommon in this group. These data emphasize the importance and limitations of gene prediction software and suggest that improvements to the annotation of the C. immitis genome should be considered.


Natural attenuation of volatile organic compounds (VOCs) in the leachate plume of a municipal landfill: using alkylbenzenes as process probes.
More than 70 individual VOCs were identified in the leachate plume of a closed municipal landfill. Concentrations were low when compared with data published for other landfills, and total VOCs accounted for less than 0.1% of the total dissolved organic carbon. The VOC concentrations in the core of the anoxic leachate plume are variable, but in all cases they were found to be near or below detection limits within 200 m of the landfill. In contrast to the VOCs, the distributions of chloride ion, a conservative tracer, and nonvolatile dissolved organic carbon, indicate little dilution over the same distance. Thus, natural attenuation processes are effectively limiting migration of the VOC plume. The distribution of C2-3-benzenes, paired on the basis of their octanol-water partition coefficients and Henry's law constants, were systematically evaluated to assess the relative importance of volatilization, sorption, and biodegradation as attenuation mechanisms. Based on our data, biodegradation appears to be the process primarily responsible for the observed attenuation of VOCs at this site. We believe that the alkylbenzenes are powerful process probes that can and should be exploited in studies of natural attenuation in contaminated ground water systems.


Pharmacokinetics of ciprofloxacin after intravenous and increasing oral doses.
The pharmacokinetics of ciprofloxacin were evaluated after increasing single oral doses of 100, 250, 500 and 1000 mg, and an intravenous dose of 100 mg given to each of 12 healthy volunteers (6 females and 6 males). Concentrations in serum and urine were determined by microbiological assay. The rise in peak serum concentrations and the values of the total area under the serum concentration curve were proportional to the increase in the oral doses. As the oral dose increased a slight increase was observed in the apparent time lag before absorption from 0.34 h after 100 mg to 0.53 h after 1000 mg. The serum half-life after the intravenous dose was 3.2 h. After the oral doses shorter apparent half-life values were observed. The intravenous dose showed an elimination phase distribution volume of 2.76 l/kg and total body clearance of 40.7 l/h. The total urinary excretion was 42.2 +/- 15.6% of the dose after the intravenous dose; the figure was lower after the oral doses. The bioavailability of the 100 mg oral dose was 83.7% as calculated from the value of the total area under the serum curve after the same oral and intravenous dose in all 12 subjects. Ciprofloxacin thus demonstrates normal linear pharmacokinetics, the rise in serum concentrations being proportional to the dose.


Faster Cortical Thinning and Surface Area Loss in Presymptomatic and Symptomatic C9orf72 Repeat Expansion Adult Carriers.
C9orf72 expansion is the most common genetic cause of frontotemporal dementia (FTD). We examined aging trajectories of cortical thickness (CTh) and surface area in C9orf72 expansion adult carriers compared to healthy controls to characterize preclinical cerebral changes leading to symptoms. Data were obtained from the Genetic Frontotemporal Dementia Initiative. T1-weighted magnetic resonance imaging scans were processed with CIVET 2.1 to extract vertex-wide CTh and cortical surface area (CSA). Symptomatic and presymptomatic subjects were compared to age-matched controls using mixed-effects models, controlling for demographic variables. Aging trajectories were compared between carriers and noncarriers by testing the "age by genetic status" interaction. False discovery rate corrections were applied to all vertex-wide analyses. The sample included 640 scans from 386 subjects, including 54 symptomatic C9orf72 carriers (72.2% behavioral variant FTD), 83 asymptomatic carriers, and 249 controls (age range = 18-86 years). Symptomatic carriers showed fairly symmetric reduction in CTh/CSA in most of the frontal lobes, in addition to large temporoparietal areas. Presymptomatic subjects had reduced CTh/CSA in more restricted areas of the medial frontoparietal lobes, in addition to scattered lateral frontal, parietal, and temporal areas. These differences were explained by faster cortical thinning linearly throughout adulthood in a similar anatomical distribution, with differences emerging in the early 30s. CSA reduction was also faster in mutation carriers predominantly in the ventrofrontal regions. C9orf72 mutation carriers have faster cortical thinning and surface loss throughout adulthood in regions that show atrophy in symptomatic subjects. This suggests that the pathogenic effects of the mutation lead to structural cerebral changes decades prior to symptoms. ANN NEUROL 2020 ANN NEUROL 2020;88:113-122.


To protect or to kill: A persisting Darwinian immune dilemma.
The immune system, which evolved as a protective system, can paradoxically mediate lethal effects when it is over-activated. These effects can be traced back to infected insects and are mainly mediated by phylogenetically old cytokines that have been found already in starfishes and sponges. We hypothesize that these anti-homeostatic effects are important for restricting the cumulative risk of transmission of highly mutating environmental pathogens that may endanger species, particularly when they start to originate and expand. Considering the Darwinian view that evolution is a permanent process, this anti-homeostatic program is preserved and expressed even when there is no risk for the species. Here, we review these aspects and discuss how evolutionary-imposed anti-homeostatic immune programs are expressed during acute and chronic human diseases, which can be further aggravated in the absence of medical interventions. The relevance of early identification of ancestral biomarkers that predict a shift from protective to deleterious immune outcomes is emphasized.


Postsynaptic effects of magnesium and calcium at the mouse neuromuscular junction.
The effects of elevated magnesium and calcium concentrations on height and time course of miniature endplate currents (MEPCs) at the mouse neuromuscular junction were studied. With both ions, MEPC height was decreased; the rate of decay of MEPCs was reduced in high magnesium and was unchanged in high calcium. Raised Mg2+ or Ca2+ both acted to modify the effects on MEPC time course of procaine, scopolamine, atropine, lidocaine, and quinidine, all of which act to cause biphasic decay of MEPCs in a manner consistent with reversible "plugging" of endplate channels, with rate constants for blocking and unblocking that are sensitive to postsynaptic transmembrane potential. Both the blocking and unblocking rate constants were decreased by increasing divalent ion concentration. No such reduction of rate constants was observed using menthol or pentobarbital, which appear to block channels in a voltage-independent manner. It is concluded that the divalent ions act to alter the channel environment via interactions with charged groups in or near the endplate channels.


Comparative study of the cellular pharmacodynamics of tacrolimus in renal transplant recipients treated with and without basiliximab.
Basiliximab is a recently developed immunosuppressive agent for the prevention of acute allograft rejection in renal transplant recipients. The combination use of basiliximab and a calcineurin inhibitor was suggested to be more effective in comparison to immunosuppressive therapy using calcineurin inhibitor without basiliximab. Cyclosporine has been generally administered with basiliximab for renal transplant recipients. However, in cases of tacrolimus-based immunosuppressive regimen, the clinical efficacy and safety of combined use of tacrolimus and basiliximab remains to be elucidated. This study evaluated the tacrolimus pharmacological efficacy using a lymphocyte immunosuppressant sensitivity test (LIST) with MTT assay procedures in 16 cases of renal transplant recipients treated by tacrolimus without basiliximab and in 13 cases treated by tacrolimus in combination with basiliximab. The rate of acute rejection episodes in the recipients treated with tacrolimus plus basiliximab was 1/13 (7.7%), whereas the rate in the recipients treated with tacrolimus without basiliximab was 6/16 (37.5%). The recipients were divided into two groups according to their peripheral blood mononuclear cell (PBMC) sensitivity to tacrolimus [i.e., including a tacrolimus high sensitivity group (IC(50) <1.0 ng/ml) and a low sensitivity group (IC(50) >1.0 ng/ml). In the recipients treated with tacrolimus without basiliximab, the rate of acute rejection episodes in the tacrolimus high sensitivity group was 1/10 (10.0%), which was significantly lower than the rate in the low sensitivity group of 5/6 (83.3%; p = 0.008). The incidence of cytomegalovirus infection was not significantly different between the tacrolimus high and the low sensitivity groups of the recipients treated with tacrolimus with and without basiliximab. Therefore, in the case of selected tacrolimus-based immunosuppressive therapy for renal transplant recipients, the tacrolimus pharmacological efficacy should be evaluated using LIST at a time just before the transplant procedure in order to accurately predict allograft rejection. The data also suggested that low tacrolimus sensitivity recipients should be treated with tacrolimus-based immunosuppressive therapy in combination with basiliximab.


Event-related potentials: search for positive and negative child-related schemata in individuals at low and high risk for child physical abuse.
The present investigation used event-related potentials (ERPs, N400 and N300) to determine the extent to which individuals at low and high risk for child physical abuse (CPA) have pre-existing positive and negative child-related schemata that can be automatically activated by ambiguous child stimuli. ERP data were obtained from individuals at low (n=13) and high risk (n=12) for CPA and used in a procedure check, from which a sub-group of low-risk (n=7) and high-risk (n=7) individuals were selected for inclusion in the main study. ERP data were collected during the presentation of a priming paradigm consisting of non-child pictures (primes) and congruent and incongruent word descriptors (targets). ERP data also were collected during a second priming paradigm consisting of ambiguous child pictures (primes) and positive and negative word descriptors (targets). Data from this second paradigm were used to test the hypothesis that low-risk and high-risk individuals' putative pre-existing child-related schemata (i.e., positive schemata in low-risk individuals and negative schemata in high-risk individuals) provide a context that influences whether targets (positive or negative word descriptors) are congruent or incongruent with ambiguous child picture primes. Analyses revealed the expected larger N400 waves in response to non-child picture, incongruent word pairs. There were no N400 differences between risk groups nor were there any risk group interactions, indicating that all participants responded in a similar manner to the non-child picture, congruent/incongruent word presentations. However, when ambiguous child picture primes were used with positive and negative word descriptors, low-risk individuals showed greater N400 and N300 responses to negative, relative to positive, word descriptors; whereas high-risk individuals showed no ERP differences with respect to positive and negative word descriptors. ERP evidence supports the view that low-risk individuals have greater accessibility to pre-existing positive (relative to negative) child-related schemata, which may reduce the likelihood of negative child-related evaluations. In contrast, high-risk individuals have pre-existing positive and negative child-related schemata that are equally accessible. Hence, high-risk, relative to low-risk, individuals appear to have greater accessibility to negative child-related schemata that may increase the likelihood of negative child-related evaluations and attributions that have been linked to CPA risk.


Atypical strain of Toxoplasma gondii causing fatal reactivation after hematopoietic stem cell transplantion in a patient with an underlying immunological deficiency.
In immunocompromized patients, including hematopoietic stem cell transplant (HSCT) recipients, life-threatening toxoplasmosis may result from reactivation of previous infection. We report a case of severe disseminated toxoplasmosis that developed early after allogeneic HSCT for T-cell lymphoblastic leukemia/lymphoma in a 15-year-old Toxoplasma gondii-seropositive boy with Nijmegen breakage syndrome, a rare genetic DNA repair disorder associated with immunodeficiency. The donor was the patient's HLA-identical brother. Prophylaxis with cotrimoxazole was discontinued a day before the HSCT procedure. Signs of lung infection appeared as early as day 14 post-HSCT. The presence of tachyzoite-like structures on Giemsa-stained bronchoalveolar lavage (BAL) fluid smears suggested toxoplasmosis. Real-time PCR targeted at the T. gondii AF146527 gene revealed extremely high parasite burdens in both blood and BAL fluid. Although immediate introduction of specific treatment resulted in a marked reduction of the parasite load and transient clinical improvement, the patient deteriorated and died of multiple organ failure on day 39 post-HSCT. Direct genotyping of T. gondii DNA from blood and BAL fluid with the PCR-restriction fragment length polymorphism method revealed type II alleles with SAG1, SAG2, and GRA6 markers but alleles of both type I and type II with GRA7. Additional analysis with 15 microsatellite markers showed that the T. gondii DNA was atypical and genetically divergent from that of the clonal type I, II, and III strains. This is the first report of increased clinical severity of toxoplasmosis associated with an atypical strain in the setting of immunosuppression, which emphasizes the need to diagnose and monitor toxoplasmosis by quantitative molecular methods in cases of reactivation risk.


Source, Synthesis, and Biological Evaluation of Natural Occurring 2,2'-Bipyridines.
Molecules containing bipyridine scaffold are fascinating and versatile compounds in the field of natural product chemistry and drug discovery, and these molecules have possible therapeutic applications due to possession of potent biological activities such as antimicrobial, immunomodulatory, antitumor, and phytotoxic. Significant efforts have been devoted to isolating various 2,2' bipyridine compounds from natural sources, with antimicrobial, anti-cancer, and immunosuppressive properties. This review describes recent developments in isolation from different microbial origins, synthesis, and investigation of different kinds of biological activities of 2,2' bipyridines, with a particular emphasis on caerulomycins, collismycins, and related derivates thereof in detail.


Profile of toll-like receptor-positive cells in septic and aseptic loosening of total hip arthroplasty implants.
Distinction between the two major complications of total hip replacement surgery, septic bacterial culture-positive and aseptic bacterial culture-negative osteolysis and loosening, is difficult due to the eventual role of bacterial remnants and biofilms, which are recognized by cells provided by toll-like receptors (TLRs) of the innate immune system. It was hypothesized that cell typing and TLR mapping might provide new information on the pathomechanisms of loosening. To test this hypothesis, septic (n = 10) and aseptic (n = 5) interface tissue as well as mildly inflamed osteoarthritic synovial membrane (n = 5) samples were characterized and compared using antibodies against several cell line-specific markers, including fibroblast, monocyte/macrophage, T cell, B cell, plasma cell and neutrophil markers, and TLRs. In osteoarthritic synovium, TLR-positive cells were restricted to surface tissues and only few inflammatory cells were detected, whereas aseptic interface was heavily infiltrated with monocyte/macrophages, which were also the major TLR-positive cell type rendering the tissue reactive to TLR ligands. Interestingly, septic cases contained also neutrophil and lymphocyte infiltrates of which especially B-cell infiltrates might be clinically useful in discriminating the two major complications of the joint replacement surgery. (c) 2010 Wiley Periodicals, Inc. J Biomed Mater Res, 2010.


Trigeminal neuropathy.
Trigeminal neuropathies (TNs) are well recognized disorders characterized and manifesting as skin and mucosal numbness in the region innervated by the trigeminal nerve. Facial numbness indicates trigeminal sensory alteration affecting the trigeminal system. TNs always pose differential location difficulties as multiple diseases are capable of producing them: they can be the result of traumatism, tumors, or diseases of the connective tissue, infectious or demyelinating diseases, or may be of idiopathic origin. Their importance is explained by the fact that TN may represent the first manifestation of tumor disease, or of relapse in patients with prior neoplastic processes. As such, these manifestations are ominous, and patient life expectancy is often short. The clinical exploration reveals a loss of sensitivity in the cutaneous territory corresponding to the affected nerve, which can be partial (hypoesthesia) or complete (anesthesia). The sensory defect is occasionally associated with hyperesthesia (i.e., the patient suffers a decrease in sensory perception, but when sensation is perceived, it may cause considerable discomfort). Complementary studies are needed to establish the etiologic diagnosis, with laboratory tests to discard the possible causative diseases underlying the trigeminal neuropathy, and the opportune radiographic examinations in the form of plain X-rays or a routine cranial computed tomography scan.


Possibilities of modern x-ray examination methods for diagnostics of hidden dental caries of approximal localization.
Introduction: In case of hidden carious cavities development on the approximal teeth surfaces, the clinical diagnostics of this process is difficult. Then, the diagnostics of carious lesion is not possible without carrying out X-ray examination. The aim of the study was a comparative analysis of the effectiveness of clinical and X-ray diagnostics for hidden caries of approximal teeth surfaces. Materials and methods: Condition of 2 963 teeth of 115 people aged from 19 to 55 was analysed. Additionally, a digital panoramic 2D diagnostics (Planmeca ProSensor, Finland) and Cone Beam Computed Tomography 3D Diagnostics (Morita, Japan) were used for clinical examination of patients. Results: In both variants of diagnostics, the number of caries defects in the upper jaw was higher than in the lower one, and the frequency of caries lesion of various teeth groups had the following sequence in descending order: molar teeth, premolar teeth, incisor teeth and canine teeth. Hidden carious cavities of average depth and deep were detected with almost the same frequency in both variants of the study, which by 1.9 - 2.0 times respectively exceeded the frequency of superficial carious cavities detection (p = 0.0001). According to the results of clinical studies, hidden superficial carious cavities occurred in single cases and X-ray examination improved their diagnostics by 9.6 times (p = 0.0000). Conclusions: X-ray examination allows increasing the effectiveness of diagnostics of hidden carious cavities of approximal localization by 1.2 times on the whole (p <0,05). In such cases orthopantomography (OPG) has reasonably sufficient diagnostic capabilities. Definitely, 3D Cone Beam Computed Tomography (CBCT) has much more diagnostic capabilities, but its use can not be justified for the diagnostics of caries only.


Association of EPCR Polymorphism rs867186-GG With Severity of Human Malaria.
Cerebral malaria (CM) is characterized by the sequestration of Plasmodium-infected erythrocytes (pRBCs) to host brain microvasculature beds via P. falciparum erythrocyte membrane protein 1 (PfEMP1). Under normal conditions, activated protein C (APC) bound to endothelial protein C receptor (EPCR) has cytoprotective properties via the activation of protease-activated receptor 1 (PAR1). During malaria infection, pRBCs transports PfEMP1 to the membranes to bind EPCR in the same region as APC. As a result, APC is less capable of inducing cytoprotective effects via PAR1. Two studies involving adult malaria patients revealed that EPCR rs867186-GG allele is associated with protection against severe malaria, while three other studies involving child malaria patients could not show association between EPCR rs867186-GG genotype and severe malaria or increased mortality among children with CM. We examined the association between the EPCR rs867186-GG genotype and the protection against cerebral malaria. Peripheral blood samples were collected from 47 malaria patients and 34 healthy individuals from a study conducted from 2004 to 2007 at the NSCB Medical College Hospital in India. CM and malaria-associated complications were defined based on WHO criteria. Genomic DNA was isolated from the peripheral blood mononuclear cells. Primer sequences were designed to contain rs867186 of the PROCR gene (NM 006404) and were used to amplify a 660 bp product as described before. PCR products were purified, and DNA sequences were determined by Sanger Sequencing (Genewiz, NJ). Nonparametric tests were used to compare the groups. To analyze differences in allele frequencies, we used chi-squared or Fisher's exact tests for categorical variables if the expected values were less than 5. P-value <0.05 was considered statistically significant. Our results showed significantly higher rates of AG and GG genotypes in CM patients compared to mild malaria (P = 0.0034). Our results indicate that rs867186-GG or rs867186-AG genotypes are not associated with protection against HCM.


Ki-67 "hot spot" digital analysis is useful in the distinction of hepatic adenomas and well-differentiated hepatocellular carcinomas.
This study aims to investigate the utility of digital protocols for Ki-67 immunohistochemistry quantitative analysis ("hot spot" method) in the setting of well-differentiated hepatocellular neoplasms. Resection cases of typical hepatic adenomas (HAs) (n = 40), atypical HAs (n = 9), and well-differentiated hepatocellular carcinomas (WD HCCs) (n = 56) were selected. HAs were further classified by immunohistochemistry using antibodies against liver fatty acid binding protein, glutamine synthetase, B-catenin, hepatic serum amyloid A, and C-reactive protein. Ki-67 proliferative index by immunohistochemistry was evaluated in all cases by digital analysis using a modified neuroendocrine tumor "hot spot" protocol. The proliferative rate of HAs (typical, median 1.2% (range 0-7.4%) and atypical, median 1.0% (range 0.3-3%)) was significantly lower than that of WD HCCs (median 4.5%, range 0-49.8%) (P < 0.0001). Only a few (7.5%) of the adenomas (all inflammatory/telangiectatic type) had proliferative rates higher than 4%, compared to most (51%) of HCCs. Ki-67 is a potentially useful adjunct marker in the evaluation of WD hepatocellular neoplasms, as "hot spot" proliferative rates are consistently very low in HAs but vary significantly in WD HCCs.


Refolding of native and recombinant chicken riboflavin carrier (or binding) protein: evidence for the formation of non-native intermediates during the generation of active protein.
Riboflavin carrier (or binding) protein (RCP) is a phosphoglycoprotein originally purified from the egg white, yolk and serum of laying hens. The 18 cysteine residues present in RCP form nine disulfide bridges, allowing the protein to form a compact structure to generate a hydrophobic pocket in which riboflavin sits. We studied the refolding of totally reduced and denatured egg white RCP and found that the protein initially folded to generate a molecule that did not possess riboflavin-binding activity, despite near-complete oxidation of the cysteine residues. Riboflavin-binding activity was then slowly regained, but the final refolded form of the protein was less compact in structure than the native molecule, due to incomplete oxidation of all the cysteine residues. Denatured and reduced dephosphorylated RCP refolded as efficiently as the native protein, with similar rates of disulfide-bond oxidation and generation of riboflavin binding, showing that the phosphoserine stretch of RCP has little role to play during refolding. In order to study the role of glycosylation in the refolding process, the cDNA for full-length RCP was expressed in Escherichia coli and purified. Recombinant RCP refolded only in the presence of redox buffers, demonstrating that glycosylation of RCP could allow the formation of high yields of productive intermediates in the folding pathway. Using a panel of conformation-specific monoclonal antibodies to RCP, it appeared that the folding intermediates of RCP possessed a structure distinctly different to the native protein, indicating that the correct folding pathway of RCP passed through conformation(s) generated by non-native disulfide bridges.


Analysis of papaya cell wall-related genes during fruit ripening indicates a central role of polygalacturonases during pulp softening.
Papaya (Carica papaya L.) is a climacteric fleshy fruit that undergoes dramatic changes during ripening, most noticeably a severe pulp softening. However, little is known regarding the genetics of the cell wall metabolism in papayas. The present work describes the identification and characterization of genes related to pulp softening. We used gene expression profiling to analyze the correlations and co-expression networks of cell wall-related genes, and the results suggest that papaya pulp softening is accomplished by the interactions of multiple glycoside hydrolases. The polygalacturonase cpPG1 appeared to play a central role in the network and was further studied. The transient expression of cpPG1 in papaya results in pulp softening and leaf necrosis in the absence of ethylene action and confirms its role in papaya fruit ripening.


[Determination of the initial rate of antimutagenic repair in UV-irradiated WP2 Escherichia coli cells].
The initial rates of antimutagenic dark repair were measured in Escherichia coli WP2 trpE65 cells irradiated by UV-light (11 J/m2) and then incubated in liquid media of various compositions. Samples were taken from suspension of incubated bacteria every 5 min following irradiation, mixed with acriflavine to block further repair and plated onto the selective medium containing acriflavine (1 micrograms/ml) to score the Trp+ mutations. The initial rate of antimutagenic repair was estimated from the kinetics of disappearance of mutations in several successive probes. It appeared to depend on the composition of a medium, to establish just after placing irradiated bacteria onto the medium and to decrease significantly in irradiated cells incubated under conditions favourable for growth. The decrease was not due to inhibition of postreplicative repair and was not caused by casaminoacids as such, but by combination of growth factors that provided the intensive protein synthesis. The decrease could be responsible for a strong mutational response of bacteria to irradiation because it secures the survival of premutagenic lesions in DNA till mutation fixation. It is suggested that metabolic regulation of the antimutagenic repair activity exists, based on an active switch of the energy flows required for several parallel metabolic pathways that proceed in irradiated cells.


CFD modeling of turbulent flow and particle deposition in human lungs.
Understanding transport and deposition of inhaled particles in the human airways plays a crucial role in the targeted therapy of pulmonary diseases, and the administration of inhaled medicines. Numerous researchers have studied the inhalation of particles using experiments or computer models. Even though experiments have shown that the airflow in the trachea and the upper branches of the lung is turbulent, the flow is taken to be laminar in most computer models. Only few recently published papers have looked at the turbulent transport of air in the human airways. Even fewer results have been published on the effect of the upper airway structures on the turbulent airflow in the lungs or on the effect of the turbulence on particle deposition. The previously published turbulent models have also mainly used RANS methods to predict the flow. To study the unsteady flow and particle deposition in a human lung, an LES model with a dynamic Smagorinsky sub-grid scale model was used. The model equations were solved to study steady inspirational flow at different flow rates for different particle sizes. Results indicate that the upper airway geometry produces turbulence in the flow and the deposition of particles is mainly affected by the particle size and Stokes number.


Disease progression in paediatric- and adult-onset sclerosing cholangitis: Results from two independent Dutch registries.
Sclerosing cholangitis (SC) is a severe liver disease leading to destruction of bile ducts. It is believed to run a milder course in children than in adults. To test this assumption, we evaluated time-to-complication curves in two independent paediatric-onset cohorts from the same geographical area. Short-term disease outcomes were evaluated with an online clinical registry that was filled with data on children with SC diagnosed between 2000 and 2017 and who were followed bi-annually thereafter. Long-term disease outcomes were evaluated in a paediatric-onset subcohort derived from a previously published population-based study from the Netherlands. Time-to-complication in the first cohort was defined as the time from diagnosis until portal hypertension, biliary obstructions and infections, development of malignancy, or liver transplantation, whichever came first. In the second cohort time-to-complication was defined as the time until liver transplantation or PSC-related death. Median age at diagnosis in the first cohort (n = 86) was 12.3 years. In the first 5 years post-diagnosis 23% of patients developed complications. The patients in the population-based study (n = 683) were stratified into those diagnosed before the age of 18 years ('paediatric-onset' subcohort, n = 43) and those diagnosed after the age of 18 years ('adult-onset' subcohort, n = 640). Median age at diagnosis was 14.6 and 40.2 years, respectively. Median time-to-complication in the paediatric-onset and adult-onset subcohorts was not statistically different. Paediatric and adult-onset SC run a similar long-term disease course. Paediatricians who treat children with SC should monitor them closely to recognize early complications and control long-term sequelae.


Macrophages on the Peritoneum are involved in Gastric Cancer Peritoneal Metastasis.
Tumor-associated macrophages (TAM) have been shown to support tumor growth and progression by various mechanisms. However, the roles of TAM in gastric cancer (GC) peritoneal metastasis remain elusive. To explore the roles of macrophages in the process of GC peritoneal metastasis, we performed the present study. Samples from the primary GC tumor beds, surgical margins, peritoneal metastatic lesions and surrounding tissue, and the Pouch of Douglas, were collected, fixed by formalin, and embedded with paraffin. Immunohistochemistry staining for macrophages markers was performed. The peritoneal lavage was obtained from a fraction of patients to analyze the ratios of epidermal growth factor (EGF)- and vascular endothelial growth factor (VEGF)-secreting macrophages in the peritoneal cavity. GC patients with peritoneal metastasis had increased levels of macrophages and alternatively activated macrophages in the peritoneum compared to those without dissemination. Patients bearing more macrophages in the peritoneum had a poorer prognosis. GC patients bearing peritoneal metastasis harbored an increased level of angiogenesis. Macrophages in the peritoneal cavity were a source of EGF and VEGF. Macrophages in the peritoneum of GC patients play a supportive role for peritoneal metastasis by producing EGF and VEGF. Macrophages in the peritoneum might be a therapeutic target in the future.


Cryohaemorrhoidectomy-preliminary experience.
Twenty patients had their haemorrhoids treated by cryosurgery and were followed up for periods ranging from 6 to 18 months. The main advantages of this technique were that the periods of hospitalization and convalescence were short, reliance on an anesthetists was less, the major symptom of bleeding was eliminated and the period of postoperative discharge not as long as in other reported series. However, patients with third degree haemorrhoids tended to have a persistent skin tag and depigmentation of the perianal skin was not uncommon.


[A simple method of selecting Saccharomyces cerevisiae ade1 and ade2 mutants].
A simple technique of selection for spontaneous red mutants of yeast Saccharomyces cerevisiae is proposed. It is based on incubation of yeast cells carrying a deletion in the GCN4 gene on a solid selective medium containing 3-amino-1, 2, 4-triazole (3AT). After incubation for three weeks at 30 degrees C, the 3 AT-resistant mutants ade2 and ade1 were easily visualized due to the pink or red colony color; they were then selected and analyzed by genetic and biochemical methods. The frequency of these colored mutants was approximately 10-9. The method proposed is shown to be suitable for selection and analysis of both spontaneous mutants ade2 and ade1 and those induced by various mutagens. The possible molecular mechanism of 3AT-resistance of red mutants is discussed. This mechanism involves GCN4-independent activation of expression of genes of purine and histidine metabolism. This activation results from purine starvation caused by arrest of purine biosynthesis the ade2 and ade2 mutations.


[ Air embolism during carotid dilatation with a stent].
We presented the case of endovascular treatment of the restenosis of the carotid artery occuring after carotid endarterectomy. We have shown the need of applying the protection systems during the endovascular procedure, in order to prevent the distal embolisation cused by ahterosclerotic debris and/or air.


Targeted silencing of MLL5β inhibits tumor growth and promotes gamma-irradiation sensitization in HPV16/18-associated cervical cancers.
We previously identified a novel MLL5 isoform, MLL5β, which was essential for E6 and E7 transcriptional activation in HPV16/18-associated cervical cancers. In this report, we investigated the potential of RNAi-mediated silencing of MLL5β through the use of MLL5β-siRNA as a novel therapeutic strategy for HPV16/18-positive cervical cancer. We observed concurrent downregulation of E6 and E7 after MLL5β silencing, leading to growth inhibition via the activation of apoptosis and senescence in the HeLa cell model. This corresponded with the enhanced antitumor effects of MLL5β-siRNA compared with E6- or E7-siRNA single treatments. Significant reduction in tumor size after MLLβ-siRNA treatment in the HeLa xenograft tumor model further emphasized the importance of MLL5β in HPV16/18-associated tumor growth and the potential of RNAi therapeutics that target MLL5β. We also identified MLL5β as a modulator of gamma-irradiation (IR) sensitization properties of cisplatin. We observed that while MLL5β silencing alone was enough to evoke cisplatin-like IR sensitization in tumor cells in vitro, overexpression of MLL5β inhibited the ability of cisplatin to sensitize HeLa cells to IR-induced cytotoxicity. MLL5β-siRNA-IR cotreatment was also observed to enhance tumor growth inhibition in vivo. Taken together, our findings highlight the potential of targeted silencing of MLL5β via the use of MLL5β-siRNA as a novel therapeutic strategy and propose that MLL5β-siRNA could be a viable alternative for cisplatin in the current cisplatin-based chemotherapeutics for HPV16/18-associated cervical cancers.


Absence of ABCG2-mediated mucosal detoxification in patients with active inflammatory bowel disease is due to impeded protein folding.
Xenotoxic damage in inflammatory diseases, including IBD (inflammatory bowel disease), is compounded by reduced activity of the xenobiotic transporter ABCG2 (ATP-binding-cassette G2) during the inflammatory state. An association between the activation of the unfolded protein response pathway and inflammation prompted us to investigate the possibility that reduced ABCG2 activity is causally linked to this response. To this end, we correlated expression of ABCG2 and the unfolded protein response marker GRP78 (glucose-regulated protein of 78 kDa) in colon biopsies from healthy individuals (n=9) and patients with inactive (n=67) or active (n=55) IBD, ischaemic colitis (n=10) or infectious colitis (n=14). In addition, tissue specimens throughout the small bowel from healthy individuals (n=27) and from patients with inactive (n=9) or active (n=25) Crohn's disease were co-stained for ABCG2 and GRP78. In all biopsies from patients with active inflammation, irrespective of the underlying disease, an absolute negative correlation was observed between epithelial ABCG2 expression and GRP78 expression, suggesting that inflammation-dependent activation of the unfolded protein response is responsible for suppression of ABCG2 function. The link between the unfolded protein response and functional ABCG2 expression was further corroborated by live imaging of ABCG2-expressing cells, which showed that various inflammatory mediators, including nitric oxide, activate the unfolded protein response and concomitantly reduce plasma membrane localization as well as transport function of ABCG2. Thus a novel mechanism for explaining xenobiotic stress during inflammation emerges in which intestinal inflammation activates the unfolded protein response, in turn abrogating defences against xenobiotic challenge by impairing ABCG2 expression and function.


Receptor Tyrosine Kinases as Candidate Prognostic Biomarkers and Therapeutic Targets in Meningioma.
Meningioma (MGM) is the most common type of intracranial tumor in adults. The validation of novel prognostic biomarkers to better inform tumor stratification and clinical prognosis is urgently needed. Many molecular and cellular alterations have been described in MGM tumors over the past few years, providing a rational basis for the identification of biomarkers and therapeutic targets. The role of receptor tyrosine kinases (RTKs) as oncogenes, including those of the ErbB family of receptors, has been well established in several cancer types. Here, we review histological, molecular, and clinical evidence suggesting that RTKs, including the epidermal growth factor receptor (EGFR, ErbB1), as well as other members of the ErbB family, may be useful as biomarkers and therapeutic targets in MGM.


Database screening and in vivo efficacy of antimicrobial peptides against methicillin-resistant Staphylococcus aureus USA300.
Natural antimicrobial peptides (AMPs) are promising candidates for developing a generation of new antimicrobials to meet the challenge of antibiotic-resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA). To facilitate the search for new candidates, we have utilised the Antimicrobial Peptide Database (APD), which contains natural AMPs from bacteria, fungi, plants and animals. This study demonstrates the identification of novel templates against MRSA by screening 30 peptides selected from the APD. These peptides are short (<25 residues), cysteine-free, cationic and represent candidates from different biological sources such as bacteria, insects, arachnids, tunicates, amphibians, fish and mammals. Six peptides, including ascaphin-8, database-screened antimicrobial peptide 1 (DASamP1), DASamP2, lycotoxin I, maculatin 1.3 and piscidin 1, were found to exert potent antimicrobial activity against an MRSA USA300 isolate. Although five of the six peptides showed broad-spectrum antibacterial activity, DASamP1 displayed killing of MRSA in vitro but not of Escherichia coli, Bacillus subtilis or Pseudomonas aeruginosa. In addition, DASamP1 suppressed early biofilm formation in a mouse model of catheter-associated MRSA infection. DASamP1 is a novel, short and potent peptide that will be a useful starting template for further developing novel anti-MRSA peptides.


[Evaluating the effectiveness of "open lung" maneuvre].
The purpose of this study--a comparative evaluation of the treatment of postoperative acute respiratory insufficiency in cardio surgical patients with lung opening maneuver and conventional mechanical ventilation. The study included 81 patients operated on the heart and magistral vessels in which the immediate postoperative period was complicated by the development of acute lung injury. Patients were divided into 2 groups: 1 (main) group (48 patients), on which the open lung technique was used, 2 (control) group (33 patients) who underwent a standard respiratory support. The initial values of the partial oxygen pressure in arterial blood and the oxygenation index in patients of both groups were significantly reduced, and the fraction of intrapulmonary shunting - significantly increased. Starting with 1 day sharp increase in PaO2 and IE in patients with the first group was noticed, which coincides with the beginning of the opening of the alveoli. At the same time, the dynamics of these indicators in the second group had the reverse tendency. After the recruiting maneuver in all patients significant improvements in the mechanics of breathing were noticed. As a result of the recruiting maneuver in the first group sustained improvement of arterial oxygenation was achieved in 35 patients. In patients with acute postoperative respiratory failure recruiting maneuver led to a significant increase in arterial oxygenation and reduce the fraction of intrapulmonary shunt. Application of "open lung" maneuver leads to the resolution of respiratory failure, which greatly reduces the timing of mechanical ventilation and length of stay of patients in intensive care units in comparison with traditional methods of respiratory therapy.


Retrospective review of pars plana versus anterior chamber placement of Baerveldt glaucoma drainage device.
To evaluate outcomes of pars plana (PP) versus anterior chamber (AC) placement of Baerveldt glaucoma drainage device (GDD). This study is a nonrandomized, retrospective case series evaluating 63 eyes that underwent GDD insertion with Baerveldt 350 device under the supervision of 2 surgeons at 5 centers. The drainage tube was either inserted into the AC or through the PP into the vitreous cavity where eyes had been vitrectomized. Surgery was conducted between 2003 and 2010 with minimum patient follow-up of 6 months. Data on postoperative intraocular pressure (IOP), visual acuity, number of hypotensive medications, and surgical complications were recorded. Of the 63 drainage device surgeries, 34 tubes were placed in the AC and 29 were placed into the posterior segment through the PP. Preoperative mean IOP was 32.3±20.3 mm Hg in the AC group and 32.8±18.4 mm Hg in the PP group. Postoperative mean IOP was reduced at all follow-up time points in both the groups. Postoperative mean IOP in the anterior tube group was 14.0, 12.9, and 14.0 mm Hg and in the PP group was 14.2, 14.2, and 14.0 mm Hg, at the 1-, 2-, and 3-year follow-up, respectively. The qualified success rate at 2 years was 94% for the PP group and 91% for the AC group, whereas absolute success was 35% for the PP group and 27% for the AC group at 2-year follow-up. Insertion of the tube of the Baerveldt GDD into the PP is a safe and effective method for IOP control in aphakic, pseudophakic, and vitrectomized eyes where there is a need to avoid anterior tube placement such as coexisting corneal pathology. IOP control results appear comparable to conventional AC placement.


Weight loss and African-American women: a systematic review of the behavioural weight loss intervention literature.
The excess burden of obesity among African-American women is well documented. However, the behavioural weight loss intervention literature often does not report results by ethnic group or gender. The purpose of this article is to conduct a systematic review of all behavioural weight loss intervention trials published between 1990 and 2010 that included and reported results separately for African-American women. The criteria for inclusion included (i) participants age ≥18 years; (ii) a behavioural weight loss intervention; (iii) weight as an outcome variable; (iv) inclusion of African-American women; and (v) weight loss results reported separately by ethnicity and gender. The literature search identified 25 studies that met inclusion criteria. Our findings suggest that more intensive randomized behavioural weight loss trials with medically at-risk populations yield better results. Well-designed and more intensive multi-site trials with medically at-risk populations currently offer the most promising results for African-American women. Still, African-American women lose less weight than other subgroups in behavioural weight loss interventions. It is now critical to expand on individual-level approaches and incorporate the biological, social and environmental factors that influence obesity. This will help enable the adoption of healthier behaviours for this group of women disproportionately affected by obesity.


Writing Impairments in Spanish Children With Developmental Dyslexia.
This study investigated which components of the writing production process are impaired in Spanish children with developmental dyslexia (DD) aged 8 to 12 years. Children with and without dyslexia (n = 60) were assessed in their use of the lexical and the sublexical routes of spelling as well as the orthographic working memory system by manipulating lexical frequency, phonology-to-orthography (P-O) consistency, and word length in a copying task and a spelling-to-dictation task. Results revealed that children with dyslexia produced longer written latencies than chronological age-matched (CA) controls, more errors than CA and reading age-matched (RA) controls, and writing durations similar to CA controls. Latencies were more affected by frequency, consistency, and length in the DD group and the RA group than in CA controls. Children in the DD and RA groups produced longer written latencies in the copying than in the spelling-to-dictation task, while controls in the CA group were not affected by the task. Results indicate that spelling impairments in Spanish children with dyslexia affect the relative involvement of lexical and sublexical information during handwriting. Meanwhile, effects on writing speed seem to be related to deficits in reading ability, and accuracy scores seem to be poorer than expected by children's reading skill.


Broad Range Eubacterial Polymerase Chain Reaction of Cerebrospinal Fluid Reduces the Time to Exclusion of and Costs Associated with Ventriculostomy-Related Infection in Hemorrhagic Stroke.
Patients with hemorrhagic stroke and an external ventricular drain in situ are at risk for ventriculostomy-related-infections (VRI). Because of the contamination of the cerebrospinal fluid (CSF) with blood and the high frequency of false negative CSF culture, the diagnosis of VRI remains challenging. This study investigated the introduction of CSF broad range eubacterial polymerase chain reaction (ePCR) and its effect on frequency and duration of antibiotic therapy for VRI, neurocritical care unit (NCCU) length of stay, related costs, and outcome. Between 2020 and 2022, we prospectively included 193 patients admitted to the NCCU of the University Hospital of Zürich with hemorrhagic stroke and an external ventricular drain for more than 48 h. Patient characteristics, serum inflammatory markers, white blood cell count in CSF, use and duration of antibiotic treatment for VRI, microbiological findings (CSF cultures and ePCR tests), and NCCU length of stay were compared in patients with no infection, noncerebral infection, suspected VRI, and confirmed VRI. Data of patients with suspected VRI of this cohort were compared with a retrospective cohort of patients with suspected VRI treated at our NCCU before the introduction of CSF ePCR testing (2013-2019). Out of 193 patients, 12 (6%) were diagnosed with a confirmed VRI, 66 (34%) with suspected VRI, 90 (47%) with a noncerebral infection, and 25 (13%) had no infection at all. Compared with the retrospective cohort of patients, the use of CSF ePCR resulted in a reduction of patients treated for suspected VRI for the whole duration of 14 days (from 51 to 11%). Furthermore, compared with the retrospective group of patients with suspected VRI (n = 67), after the introduction of CSF ePCR, patients with suspected VRI had shorter antibiotic treatment duration of almost 10 days and, hence, lower related costs with comparable outcome at 3 months. The use of CSF ePCR to identify VRI resulted in shorter antibiotic treatment duration without changing the outcome, as compared with a retrospective cohort of patients with suspected VRI.


Double-Row Arthroscopic Rotator Cuff Repair Is More Cost-Effective Than Single-Row Repair.
The optimal technique for arthroscopic rotator cuff repair is controversial, and both single and double-row techniques are commonly used. In the current era of increasing costs, health-care delivery models are focusing on the value of care. In this study, we compared the cost-effectiveness of single-row and double-row reconstructions in patients undergoing arthroscopic rotator cuff repair. A cost-utility analysis was performed from the perspective of a publicly funded health-care system. Health-care costs, probabilities, and utility values were derived from the published literature. Efficacy data were obtained from a previous randomized controlled trial comparing the effect of single-row (n = 48) or double-row (n = 42) reconstruction among 90 surgical patients. Unit cost data were obtained from a hospital database and the Ontario Schedule of Benefits and Fees. Results are presented as an incremental cost per quality-adjusted life year (QALY) gained. All costs are presented in 2015 Canadian dollars. A series of 1-way and probabilistic sensitivity analyses were performed. Double-row fixation was more costly ($2,134.41 compared with $1,654.76) but was more effective than the single-row method (4.073 compared with 4.055 QALYs). An incremental cost-effectiveness ratio (ICER) was estimated to be $26,666.75 per QALY gained for double-row relative to single-row fixation. A subgroup analysis demonstrated that patients with larger rotator cuff tears (≥3 cm) had a lower ICER, suggesting that double-row fixation may be more cost-effective for larger tears. Based on the willingness-to-pay threshold of $50,000 per QALY gained, double-row fixation was found to be more cost-effective than single-row. Furthermore, a double-row reconstruction was found to be more economically attractive for larger rotator cuff tears (≥3 cm). Economic and Decision Analysis Level IV. See Instructions for Authors for a complete description of levels of evidence.


Outcomes After Primary Infliximab Treatment Failure in Inflammatory Bowel Disease.
Primary infliximab treatment failure is common in patients with inflammatory bowel disease and represents a challenge to clinicians. Treatment options are limited. This study assessed the prognosis, defined as surgery-free survival, in patients with primary infliximab treatment failure as compared to patients without primary failure (initial responders). Furthermore, this study assessed the specter of medical therapies used after primary infliximab treatment failure along with treatment outcomes. Retrospective, observational, cohort study of patients with inflammatory bowel disease treated with infliximab as first-line anti-tumor necrosis factor treatment at a tertiary center. Primary infliximab treatment failure was defined as no clinical improvement during infliximab induction therapy resulting in discontinuation of infliximab therapy. A total of 560 patients (Crohn's disease n = 353 and ulcerative colitis n = 207) were treated with infliximab. Among these, 81 (15%) had primary infliximab treatment failure after a median of 3 infusions (weeks 0, 2, and 6) (interquartile range 2-4). The median surgery-free survival was 196 days from first infusion. One year after primary infliximab treatment failure, the majority of patients (n = 51, 63%) had inflammatory bowel disease-related surgery (Crohn's disease n = 19, 58%; ulcerative colitis n = 32, 67%; P = 0.49). There was a markedly increased risk of surgery in patients with primary infliximab treatment failure as compared to initial responders: odds ratio 6.3 (3.8-10.6), P < 0.0001. Among 30 patients handled by medical therapies, 16 (53%) still had active disease 1 year after primary infliximab treatment failure. Primary infliximab treatment failure is associated with poor outcome including high risk of surgery or sustained active disease despite medical interventions.


Contemporary radiooncological management of bone metastases from breast cancer: factors associated with prescription of different fractionation regimens (short or long course) in a rural part of North Norway with long travel distance.
The aim of this study was to reduce barriers that prevent implementation of evidence-based recommendations about single-fraction palliative radiotherapy (PRT) and to demonstrate that single-fraction PRT yields similar outcomes as long-course treatment (≥10 fractions) in patients with bone metastases from breast cancer. This retrospective study (2007-2014) included 118 Norwegian female patients. All patients received guideline-conform systemic therapy including bone-targeting agents. Median survival was 12.7 months. Long-course PRT was prescribed in 60% of patients, while 21% had PRT with a single fraction of 8 Gy to at least one target. Reirradiation rate was not significantly higher after 8 Gy (9%, compared to 5% after long-course PRT and 6% after 4 Gy x5). Patients with favorable baseline characteristics such as younger age and good performance status (PS) were significantly more likely to receive long-course PRT. Biological subtype and comorbidity did not correlate with fractionation. Prognosis was influenced by biological subtype, extra-skeletal disease extent, severe anemia and abnormal CRP. The limited need for reirradiation after single fraction PRT might encourage physicians to prescribe this convenient regimen, which would improve resource utilization. Even patients with PS3 had a median survival of 3 months, which indicates that they could experience worthwhile clinical benefit.


Nifedipine versus fenoterol in the management of preterm labor: a randomized, multicenter clinical study.
To compare the efficacy of nifedipine and fenoterol in the management of threatened preterm labor (TPL). A randomized and multicenter study assessing the tocolytic effect of nifedipine versus fenoterol in patients admitted to the participating maternity units with a diagnosis of TPL and a cost-savings study for economic assessment. For a power of 80% and an α error equal to 0.05, 132 consecutive patients were recruited during the study period; 66 patients were assigned to each group. A χ(2) analysis and a mean differences test were performed according to variable types and survival curves per intention-to-treat. Demographics were similar in both groups. The latency period was similar in both groups (26.7 vs. 25.6; p = 0.3). There were no differences in the results obtained. Nifedipine failed more frequently to obtain tocolysis when used as a first-line agent (80 vs. 90%, p = 0.0001). The group treated with fenoterol showed more drug adverse events (57.8 vs. 19.0%, p = 0.0001). The economic assessment did not evidence a significant difference in terms of cost savings between groups treated with either drug. The present study failed to demonstrate either clinical or economic superiority of any of the two drugs used in TPL management. The highest failure percentage of nifedipine when used as a first-line agent should encourage further research.


An equivalent length model of microdialysis sampling.
One of the critical issues in microdialysis sampling is how to predict the extraction fraction (E(d)), based on transport properties of analytes in both tissues and probes. A one-dimensional (1-D) model has been used widely in previous studies to predict E(d) at the steady state. However, this model is valid only for long probes. To this end, an equivalent length (EL) model was developed for probes with any length used in experiments. The key idea in the model was to replace the probe length (L) in the 1-D model with an equivalent length (L(E)) when calculating transport resistance in surrounding tissues. The length difference, (L(E)-L), was assumed to be proportional to the penetration depth of analytes (Gamma). The proportionality constant (lambda) was determined through minimizing the errors in predicted E(d). We found that, the EL model could accurately predict E(d) when lambda=0.369. The maximum error in EL model predictions was <6%, for model constants varying in the same ranges as those in microdialysis experiments. This error was one order of magnitude smaller than that in 1-D model predictions.