Effects of Tween 80 on the removal, sorption and biodegradation of pyrene by Klebsiella oxytoca PYR-1.
The sorption and biodegradation of pyrene by Klebsiella oxytoca PYR-1 (PYR-1) in the presence of nonionic surfactant Tween 80 were investigated toward a better understanding that how surfactants can affect biodegradation of hydrophobic organic compounds. The results indicated that Tween 80 can promote the removal, sorption and biodegradation of pyrene depending on the surfactant concentration, of which the most significant promotion of biodegradation was achieved at critical micelle concentration of Tween 80 with an improvement of 22.4%. A highly positive correlation (P<0.0001) was observed between the biodegradation and sorption of pyrene with the presence of Tween 80. Biosorption experiments showed the same trends as biodegradation and further illustrated the improved biodegradation of pyrene was mainly due to surfactant-facilitated sorption. The regularly changes of cell surface hydrophobicity suggested formation of more hydrophobic surface caused by surfactant sorption lead to stimulation of pyrene sorption.


Immune suppression in cancer: effects on immune cells, mechanisms and future therapeutic intervention.
Evidence indicates that the healthy immune system is necessary for control of malignant disease and that immune suppression associated with cancer contributes to its progression. Tumors have developed strategies to successfully evade the host immune system, and various molecular and cellular mechanisms responsible for tumor evasion have been identified. Certain of these mechanisms target immune anti-tumor effector cells. Dysfunction and apoptosis of these cells in the tumor-bearing host creates an immune imbalance that cannot be corrected by immunotherapies aimed only at activation of anti-tumor immune responses. Reversal of existing immune dysfunction(s) and normalization of lymphocyte homeostasis in patients with cancer needs to be a part of future cancer immunotherapy. Therapeutic strategies are being designed to correct the immune imbalance, deliver adequate in vivo stimulation, transfer effector T cells capable of in vivo expansion and provide protection for the immune effector cells re-populating the host. Survival of these cells and long-term memory development in patients with malignancy are necessary for improving clinical benefits of cancer immunotherapies.


Antigenic changes in Vibrio cholerae biotype eltor serotype Ogawa after bacteriophage infection.
Vibrio cholerae biotype eltor serotype Ogawa cultures infected with temperate bacteriophage from lysogens of biotype eltor serotype Hikojima yielded types with altered agglutination reactions.


Mycophenolate mofetil is a highly effective and safe immunosuppressive agent for the treatment of uveitis : a retrospective analysis of 106 patients.
We evaluated the outcomes of patients with different forms of chronic uveitis treated with mycophenolate mofetil (MMF) as an immunomodulatory and steroid-sparing agent. The multi-system side effects that arise after long-term treatment with corticosteroids and other immunosuppressants prompted us to use MMF. MMF is a selective inhibitor of inosine monophosphate dehydrogenase, thus blocking purine synthesis via the de novo pathway preferentially used by T and B lymphocytes. Between 1998 and 2003, 106 patients were treated for uveitis (anterior n=26, intermediate n=51, posterior n=23, panuveitis n=6) with MMF at a dose of 1g twice daily. Treatment duration was at least 6 months (n=10), in most cases greater than 12 months (n=77) and in 25 cases between 24 months and 41 months, when the present retrospective evaluation was undertaken. Patient charts were analysed according to a standardized evaluation protocol. In 95 patients MMF was combined with prednisolone at a dosage of 2.5-10 mg per day. In 8 patients MMF was used as a monotherapy, and in 3 cases one further systemic immunosuppressant was required. The number of recurrences during MMF treatment was none or one in 92 patients, two in 6 cases and three or more in 8 patients. In none of the patients had MMF been stopped at the time of data analysis. The most frequently observed side effects were gastrointestinal upset (15%), followed by headache (9.3%), fatigue (5.7%), eczema (5%), and hair loss (3.5%). Other side effects were sporadic. Most of these phenomena were transitory. Forty-two patients experienced no side effects at all. In 4 patients MMF was judged ineffective due to failure to reduce the number of recurrences of severe inflammation compared with the previous therapeutic regime, or indeed occurrence of persistent macular oedema. Our results show that MMF is an effective immunosuppressant in patients with uveitis. We provide evidence that MMF controls the disease in the majority of patients with an acceptable profile of side effects.


Oral Anticoagulation Use in High-Risk Patients Is Improved by Elimination of False-Positive and Inactive Atrial Fibrillation Cases.
Multiple registries have reported that >40% of high-risk atrial fibrillation patients are not taking oral anticoagulants. The purpose of our study was to determine the presence or absence of active atrial fibrillation and CHA2DS2-VASc (Congestive heart failure, Hypertension, Age ≥75 y, Diabetes mellitus, prior Stroke [or transient ischemic attack or thromboembolism], Vascular disease, Age 65-74 y, Sex category) risk factors to accurately identify high-risk atrial fibrillation (CHA2DS2-VASc ≥2) patients requiring oral anticoagulants and the magnitude of the anticoagulant treatment gap. We retrospectively adjudicated 6514 patients with atrial fibrillation documented by at least one of: billing diagnosis, electronic medical record encounter diagnosis, electronic medical record problem list, or electrocardiogram interpretation. After review, 4555/6514 (69.9%) had active atrial fibrillation, while 1201 had no documented history of atrial fibrillation and 758 had a history of atrial fibrillation that was no longer active. After removing the 1201 patients without a confirmed atrial fibrillation diagnosis, oral anticoagulant use in high-risk patients increased to 71.1% (P < .0001 compared with 62.9% at baseline). Oral anticoagulant use increased to 79.7% when the 758 inactive atrial fibrillation patients were also eliminated from the analysis (P < .0001 compared with baseline). In the active high-risk atrial fibrillation group, there was no significant difference in the use of oral anticoagulants between men (80.7%) and women (78.8%) with a CHA2DS2-VASc ≥2, or in women with a CHA2DS2-VASc ≥3 (79.9%). Current registries and health system health records with unadjudicated diagnoses over-report the number of high-risk atrial fibrillation patients not taking oral anticoagulants. Expert adjudication identifies a smaller treatment gap than previously described.


Specific TP53 subtype as biomarker for immune checkpoint inhibitors in lung adenocarcinoma.
Although TP53 co-mutation with KRAS/ATM/EGFR/STK11 have been proved to have predictive value for response to immune checkpoint inhibitors (ICIs), not all TP53 mutations are equal in this context. As the main part of TP53 mutant types, Missense and Nonsense alternations in TP53 as independent factors to predict the response to ICIs within Lung Adenocarcinoma (LUAD) patients have not yet been reported. An integrated analysis based on multiple-dimensional data types including genomic, transcriptomic, proteomic and clinical data from published lung adenocarcinoma data and local database of LUAD taking immune checkpoint inhibitors. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups. Single-sample GSEA (GSVA) is conducted to calculate the score for enrichment of a set of genes regulating DNA damage repair (DDR) pathway. The TP53-missense-mutation group showed increased PD-L1 (CD274) level and enriched IFN-γ signatures compared with the TP53-wild-type subgroup, but no differences were noted in patients with nonsense-mutant vs wild-type p53. Furthermore, a group of suppressor Immune cells like M2 Macrophage and Neutrophils are found enriched in nonsense group. On the other-side, both TP53 missense and nonsense mutations are associated with elevated TMB and neoantigen levels and contribute equally to DNA damage repair deficiency. The distribution regarding to multi-dimensional factors determining the efficacy of ICIs finally transformed into diverse clinical benefits for LUAD. TP53 missense but not -nonsense Mutants are associated with better clinical benefits taking antiPD-1/1L. However, all such TP53 subgroups responds well to nivolumab (antiPD-L1) plus ipilimumab (antiCTLA-4) therapy. Our study demonstrated that not all TP53 mutations are equal in predicting efficacy in patients with LUAD treated with ICIs. Multi-center data showed that TP53 missense and nonsense mutations were significantly different in terms of associations with PD-L1 expression, IFN-γ signatures and TME composition. Special attention should be paid to potential TP53 mutation heterogeneity when evaluating TP53 status as biomarker for ICIs. The study was supported by Key Lab System Project of Guangdong Science and Technology Department - Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2017B030314120, to Yi-Long WU).


Minimal association of alleles of human leukocyte antigen class II gene and long-term antibody response to hepatitis B vaccine vaccinated during infancy.
The human leukocyte antigen (HLA) system plays critical roles in regulating immune responses to various vaccines. This study aimed to evaluate the association of HLA class II gene polymorphisms and the long-term duration of anti-HBs response in children vaccinated against hepatitis B during infancy. Totally 297 children 5-7years after the completion of primary vaccination against hepatitis B in infancy, without booster immunization or natural resolved infection, were enrolled. Of them, 86 children with anti-HBs <10mIU/ml were considered as long-term non- or hypo-responders, and 211 others with anti-HBs ≥10mIU/ml were defined as long-term responders. Ten alleles in HLA-DR and -DQ subregions were detected by polymerase chain reaction with sequence-specific primers. The frequency of HLA-DQB1∗0401 was 15.1% in the long-term non- or hypo-responder group, relatively higher than 7.6% in the long-term responder group (OR=2.17, 95% CI 1.01-4.73), however, the difference had no statistical significance after Bonferroni correction (P=0.470). The frequencies of seven HLA-DRB1 alleles, including ∗01, ∗03, ∗04, ∗07, ∗08, ∗11, and ∗1301/1302, and two HLA-DQB1 alleles, including ∗0201 and ∗0501, were each similarly distributed in the long-term non- or hypo-responders and responders respectively. None of the ten HLA class II gene alleles previously reported to be related with short-term antibody response to hepatitis B vaccine is associated with the long-term antibody response after vaccination during infantile.


Tumor necrosis can facilitate the appearance of metastases.
The non-metastatic murine mammary adenocarcinoma M3 and its metastatic variant MM3 were used to evaluate the role of intratumoral necrosis in cell detachment and metastasis. Accelular extracts from necrotic areas of both tumors increased in vitro cellular detachment from M3 but not from MM3 fragments. Furthermore, the in vivo inoculation of the necrotic extracts within non-metastatic M3 tumors gave rise to pulmonary metastases. Histological studies revealed in M3 a central necrosis limited by an uninterrupted peripheral ring of well preserved cells, while in MM3 necrotic and non-necrotic areas alternated. It is concluded that the distribution of necrosis within the primary tumor by facilitating cell detachment is, at least in part, responsible for the development of metastases.


Double-blind, placebo-controlled study of nicergoline in the treatment of pruritus in patients receiving maintenance hemodialysis.
Pruritus is a common symptom among patients undergoing long-term hemodialysis. The effect of nicergoline, an ergoline, on pruritus was studied in products released during dialysis. In a first experiment series, 20 age-matched normal individuals, 25 patients receiving hemodialysis without pruritus, and 15 patients receiving hemodialysis with pruritus had intradermal tests with 500 micrograms of papaverine. All patients with pruritus had a small papaverine skin test response, and mean values were significantly (p less than 0.0001, Mann-Whitney U test) smaller in patients with pruritus. All patients with pruritus entered in a crossover, double-blind trial with nicergoline. In a first period of six dialyses, they received either nicergoline (daily oral dose, 30 mg, and intravenous dose during dialyses, 5 mg) or placebo. In the second period of six dialyses, patients received the crossover treatment. Nicergoline was effective in 13/15 patients, eight of these patients having a complete remission of pruritus. When nicergoline was stopped, patients relapsed within 24 to 48 hours. All patients who improved during the trial were then treated with a daily dose of 30 mg of nicergoline for 6 months. Seven patients had a complete remission, five had moderate symptoms, and one patient relapsed. This study demonstrated that some hemodialyzed patients with pruritus of unknown etiology had improvement with nicergoline.


Effect of centrifugation and sugar supplementation on the semen cryopreservation of captive collared peccaries (Tayassu tajacu).
The present study is aimed at evaluating the effect of centrifugation for seminal plasma removal and the supplementation of fructose or glucose to the Tris-based extender on the kinematic patterns of the motility parameters of frozen-thawed semen obtained from captive collared peccaries (Tayassu tajacu). Semen samples (n = 14) were collected from 10 sexually mature male collared peccaries by electroejaculation. These samples were further evaluated for parameters such as motility, vigor, sperm viability, membrane integrity, and sperm morphology. The samples were divided into four aliquots, and only two of these aliquots were centrifuged. The semen aliquots (centrifuged and raw semen samples) were diluted in Tris-based extenders supplemented with fructose or glucose. Egg yolk (20%) and glycerol (3%) were added to all the samples which were cryopreserved in liquid nitrogen and thawed at 37 °C/1 min. The frozen-thawed semen was evaluated for the same parameters described for the fresh semen. On the other hand, the kinematic motility patterns were evaluated by a computer-aided system. After thawing, it was observed that the values for the total sperm motility were around 30% for all the samples. A negative effect of centrifugation was verified for parameters such as sperm morphology, linearity, straightness, and beat cross frequency (P < 0.05). However, no differences between fructose and glucose were verified for any semen end point (P > 0.05). In conclusion, it is not recommended to centrifuge the ejaculates from collared peccaries prior to conducting the cryopreservative procedures using a Tris-based extender supplemented with fructose or glucose.


Genetic variants of TCF7L2 are associated with type 2 diabetes in a northeastern Chinese population.
Variants in the gene encoding transcription factor 7-like 2 (TCF7L2) are associated with type 2 diabetes mellitus (T2D) in several ethnic groups. Two intronic variants, rs290487 and rs11196218, were originally identified as T2D modifiers in Hong Kong Chinese and Taiwan Chinese populations, respectively. However, discrepancies were noted in subsequent replicated studies. In this study, an association of these two loci with T2D was investigated in a Harbin Chinese population. Whereas the two populations in the initial studies were southern Han Chinese, Harbin Chinese are from northeastern China. The SNPs rs290487 and rs11196218 were genotyped by ligase detection reactions in 700 T2D patients and 570 unrelated non-diabetic controls. Association analyses, which were carried out using the case-control sample set, yielded a significant association between rs290487 and T2D, with a trend opposite to that described in a previous report. Specifically, rs290487T was found to be significantly associated with disease susceptibility (p=0.039), and the allelic OR of rs290487T carriers was 1.184 (95% CI 1.008-1.391). There was no significant association between rs11196218 and T2D. Taken together, TCF7L2 may be an important susceptibility gene for T2D in some Chinese populations. The discrepancies in the allelic associations determined for northern vs. southern Chinese allude to the presence of genetic variation among the Han Chinese.


Impact of geochemical stressors on shallow groundwater quality.
Groundwater monitoring wells (about 70 wells) were extensively installed in 28 sites surrounding Lake Texoma, located on the border of Oklahoma and Texas, to assess the impact of geochemical stressors to shallow groundwater quality. The monitoring wells were classified into three groups (residential area, agricultural area, and oil field area) depending on their land uses. During a 2-year period from 1999 to 2001 the monitoring wells were sampled every 3 months on a seasonal basis. Water quality assay consisted of 25 parameters including field parameters, nutrients, major ions, and trace elements. Occurrence and level of inorganics in groundwater samples were related to the land use and temporal change. Groundwater of the agricultural area showed lower levels of ferrous iron and nitrate than the residential area. The summer season data revealed more distinct differences in inorganic profiles of the two land use groundwater samples. There is a possible trend that nitrate concentrations in groundwater increased as the proportions of cultivated area increased. Water-soluble ferrous iron occurred primarily in water samples with a low dissolved oxygen concentration and/or a negative redox potential. The presence of brine waste in shallow groundwater was detected by chloride and conductivity in oil field area. Dissolved trace metals and volatile organic carbons were not in a form of concentration to be stressors. This study showed that the quality of shallow ground water could be related to regional geochemical stressors surrounding the lake.


Hypothalamic-pituitary function and radiographic evaluation of women with hyperprolactinemia and an "empty" sella turcica.
A primary "empty" sella may be associated with significant hypothalamic-pituitary dysfunction. This report characterizes the endocrinologic and radiographic findings in six patients with hyperprolactinemia (range 34.3 to 1,170 ng/ml) ultimately found to have an enlarged empty sella. Lateral skull x-ray films and thin-section tomograms were suggestive of pituitary tumors in all patients. Four patients underwent transphenoidal sellar exploration after pneumoencephalography (PEG) failed to demonstrate air within the sella. The inability of PEG to demonstrate an empty sella in two patients was explainable on the basis of an intact diaphragma sellae with previous transient intrasellar pathology responsible for the sellar enlargement. Dynamic hypothalamic-pituitary testing yielded no consistent pattern of response. These studies suggest that an empty sella: (1) may be associated with hyperprolactinemia, regardless of etiology, (2) is not diagnosable by dynamic hormonal testing, and (3) may be indistinguishable from a pituitary tumor by current radiographic techniques.


β-Indolyloxy Functionalized Aspartate Analogs as Inhibitors of the Excitatory Amino Acid Transporters (EAATs).
The excitatory amino acid transporters (EAATs) mediate uptake of the major excitatory neurotransmitter l-glutamate (Glu). The essential functions governed by these transporters in regulating the central Glu level make them interesting therapeutic targets in a wide range of neurodegenerative and psychiatric disorders. l-Aspartate (Asp), another EAAT substrate, has served as a privileged scaffold for the development of EAAT inhibitors. In this study, we designed and synthesized the first β-indolyloxy Asp analogs 15a-d with the aim to probe a hitherto unexplored adjacent pocket to the substrate binding site. The pharmacological properties of 15a-d were characterized at hEAAT1-3 and rEAAT4 in a conventional [3H]-d-Asp uptake assay. Notably, thiophene analog 15b and the para-trifluoromethyl phenyl analog 15d were found to be hEAAT1,2-preferring inhibitors exhibiting IC50 values in the high nanomolar range (0.21-0.71 μM) at these two transporters versus IC50 values in the low micromolar range at EAAT3,4 (1.6-8.9 μM). In summary, the results presented herein open up for further structure-activity relationship studies of this new scaffold.


Peroxide-inducible Ets-1 mediates platelet-derived growth factor receptor-alpha gene transcription in vascular smooth muscle cells.
Platelet-derived growth factor (PDGF) has been implicated in the pathogenesis of vascular occlusive disorders such as atherosclerosis and restenosis in part due to its regulation of smooth muscle cell phenotype. The molecular mechanisms regulating the expression of PDGF-Ralpha, which binds all known dimeric forms of PDGF except PDGF-DD, are poorly understood. Here we demonstrate that the winged helix-turn-helix proto-oncogene Ets-1 controls PDGF-Ralpha transcription and mRNA expression in smooth muscle cells. Mutational analysis, electrophoretic mobility shift assay, and chromatin immunoprecipitation revealed the existence of a reverse Ets binding motif (-45TTCC-42) in the proximal region of the PDGF-Ralpha promoter, which bound both recombinant and endogenous Ets-1. Ets-1-inducible PDGF-Ralpha expression depended on the integrity of both the -45TTCC-42 motif and the -61G10(-52) element, which resides upstream of -45TTCC-42 and mediates Sp1 induction. Hydrogen peroxide (H2O2) at nanomolar concentrations stimulated levels of Ets-1 and increased PDGF-Ralpha transcription and mRNA expression without affecting Sp1 expression. H2O2 activation of the PDGF-Ralpha promoter was abolished by disrupting -45TTCC-42 or -61G10(-52). These studies identify a functional Ets motif in the PDGF-Ralpha promoter that plays a pivotal role in agonist-inducible PDGF-Ralpha transcription.


Metal distribution and bioavailability in surface sediments from the Huaihe River, Anhui, China.
This study presents the total concentrations and chemical fractionations of metals (Cu, Pb, Zn, Ni, Fe, and Mn) in 54 surface sediment samples collected from the Huaihe River (Anhui Province) in eastern China. Compared with the average shale values, Zn and Pb exhibited the most substantial anthropogenic enrichment, especially in Fengtai and Huainan areas, the main industrial districts along the Huaihe River (Anhui Province). Low levels of Cu and Ni were observed in the sediments. Based on risk assessment code (RAC), the metals associated with weak acid soluble (F1) in the Huaihe River sediments followed the order: Mn > Zn > Cu > Pb > Ni > Fe. Manganese presented the most potential for releasing into the aqueous environment and can easily enter the food chain. Copper, zinc, nickel, and iron were found dominant in the residual fraction, implying that these four metals were strongly bound to the sediments. Lead showed a different partitioning pattern from that of other metals studied, with a large percentage in Fe-Mn oxide fraction, indicating that slight redox potential changes may make significant influence on the removability of Pb. Moreover, Cu in oxidizable (F3) and residual (F4) fractions presented high positive correlation with organic matter, which can explain the high percentage of Cu in these two fractions.


Video-otoscopy in children and patient-centered care: A randomized, controlled study.
Medicine today is moving towards patient centered care and patient empowerment. This enhances patient autonomy, allows shared decision making and increases satisfaction. Current technology enables the caregiver to share visual data with the patients, making them more active participants in a medical encounter. It has been shown that higher patient satisfaction rate has a positive effect on outcome and patient compliance. Otoscopic examination is one of the most common procedures performed in the pediatric population. Video-otoscopy uses endoscopic technology to project the image of the tympanic membrane onto a monitor visible to both the physician and the patient. The objective of this study is to assess whether video-otoscopy used in a pediatric emergency department can improve patient-centeredness and parental satisfaction with treatment. A randomized, controlled study comparing video-otoscopy with conventional otoscopy was performed. Patients were randomized into 2 groups. In one, ear examination was performed by video-otoscopy and in the other by conventional otoscopy. Following examination, parents in both groups were asked to fill a questionnaire regarding their satisfaction with the otoscopic examination and the patient-centeredness of the encounter. 60 children were recruited and were randomized into two groups: 30 in the video-otoscopy group and 30 in the conventional otoscopy group. Parental satisfaction was significantly higher in the video-otoscopy group. The level of patient-centeredness was significantly higher in the video-otoscopy group. There was a positive correlation between patient-centeredness and parental satisfaction in both groups, with a significantly higher correlation in the video-otoscopy group. Video-otoscopy was found to encourage patient-centered care and increase parental satisfaction with otoscopy. There is a significantly higher positive correlation between patient-centeredness and parental satisfaction when video-otoscopy is used.


Umbilical metastasis as the presenting symptom of cecal carcinoma.
Umbilical metastases were encountered as the initial presentation of cecal adenocarcinoma in a 62-year-old woman. Intravenous infusion of 5-fluorouracil, along with intralesional injections of 10% 5-fluorouracil, resulted in regression of the tumor masses on the abdominal wall. Although umbilical metastasis is rare, its significance in diagnosing an otherwise silent colorectal cancer warrants the physician's awareness.


Mycotoxins produced by Fusarium species associated with annual legume pastures and 'sheep feed refusal disorders' in Western Australia.
Sheep grazing in Western Australia can partially or completely refuse to consume annual Medicago pods contaminated with a number of different Fusarium species. Many Fusarium species are known to produce trichothecenes as part of their array of toxigenic secondary metabolites, which are known to cause feed refusal in animals. This study reports the identity of Fusarium species using species-specific PCR primers and a characterization of the toxigenic secondary metabolites produced by 24 Fusarium isolates associated with annual legume-based pastures and particularly those associated with sheep feed refusal disorders in Western Australia. Purification of the fungal extracts was facilitated by a bioassay-guided fractionation using brine shrimp. A number of trichothecenes (3-acetyldeoxynivalenol, deoxynivalenol, fusarenon-X, monoacetoxyscirpenols, diacetoxyscirpenol, scirpentriol, HT-2 toxin and T-2 toxin), enniatins (A, A1, B, and B1), chlamydosporol and zearalenone were identified using GC/MS and/or NMR spectroscopy. Some of the crude extracts and fractions showed significant activity against brine shrimp at concentrations as low as 5 μg ml(-1), and are likely to be involved in the sheep feed refusal disorders. This is the first report of chlamydosporol production by confirmed Fusarium spp.; of the incidence of F. brachygibbosum and F. venenatum in Australia and of F. tricinctum in Western Australia; and of mycotoxin production by Fusarium species from Western Australia.


Towards chronic non-invasive stimulation: what can you learn from pain research?
This scientific commentary refers to 'Long-term analgesic effect of trans-spinal direct current stimulation compared to non-invasive motor cortex stimulation in complex regional pain syndrome, by Hodaj et al. (https://doi.org/10.1093/braincomms/fcad191).


[Treatment of hypercorrection after surgical procedure on hallux valgus. Medial osteoplastic ridge (author's transl)].
Hallux varus hypercorrection is reduced and maintained by a medial osteoplastic ridge fixed by screws in the head of the first metacarpal bone. It can be indicated to associate an extensor Hallucis longus lengthening.


Visualizing the conversion of carbamazepine in aqueous suspension with and without the presence of excipients: a single crystal study using SEM and Raman microscopy.
Visual observations of the hydration process of single carbamazepine (CBZ) crystals in water and in various excipient solutions [(1% w/v) - hydroxypropyl cellulose (HPC), poly(vinyl pyrrolidone) (PVP), sodium carboxymethylcellulose (CMC) at pH 7.5 and 3.0, and polyethylene glycol (PEG)] using scanning electron microscopy (SEM) are reported in this paper. Raman microscopy was used to confirm the chemical structures of the unconverted CBZ and the CBZ dihydrate (DH) needles. It was found that defect structures were a more important driving force than the nature of crystal faces for the initiation of the hydration, but face differences became obvious after 6 h immersion. The biggest crystal face grown from methanol, (100), was the slowest one to be covered with DH needles. A comparison of the molecular arrangements along the three crystal faces [(100), (010) and (001)] was carried out using crystal structure visualization software, and fewer polar groups exposed on the (100) face than on the (001) and (010) faces were found, explaining the comparatively weak interaction of the (100) face with water during hydration. Furthermore, investigation of the influence of excipients on the hydration of CBZ showed that both HPC and PVP strongly inhibited conversion, and no conversion of CBZ to DH was found after 18 h immersion in water. PEG and CMC (pH 7.5) were less potent inhibitors than HPC and PVP, and DH needles were observed on all the faces except the (100) face after 18 h immersion. No conversion was detected for the crystal immersed in CMC solution at pH 3.0. This is likely to be caused by the decreased polarity of CMC in water at pH 3.0 (pKa,cmc = 4.3), and thus a higher surface adsorption of CMC to the CBZ crystals in dispersion. The influence of excipients on the conversion of CBZ observed in this study agreed well with our previous quantitative studies using Raman spectroscopy. In this study, visual observation using electron microscopy has been demonstrated to be a unique and powerful tool to improve our understanding of polymorphic conversions of CBZ in aqueous suspension.


Nutritional status, acute phase response and depression in metastatic lung cancer patients: correlations and association prognosis.
Cancer cachexia is a metabolic syndrome related with poor outcome. Cytokines play a key role in the pathophysiology of that syndrome. The aim of this study was to investigate the potential correlations between nutritional status, systemic inflammation, and psychological distress in cancer patients. The prognostic significance of the recorded parameters was also assessed. Patients with metastatic lung cancer were eligible. Mini Nutritional Assessment (MNA) was used for the evaluation of nutritional status, Glasgow Prognostic Score (GPS) for the estimation of systemic inflammation, and Hospital Anxiety and Depression Scale (HADS) for psychological assessment. Totally, 122 patients were enrolled (71.3% with NSCLC and 28.7% with SCLC). The following correlations were observed: MNA and GPS (r = 0.289, p = 0.001), MNA and HADS (depression scale) (r = 0.275, p = 0.002), GPS and HADS (depression scale) (r = 0.256, p = 0.004), and GPS and HADS (anxiety scale) (r =0.194, p =0.033). In univariate analysis, GPS (p = 0.002) and MNA (p = 0.010) emerged as significant predictors of survival. In multivariate analysis, both MNA (p = 0.032) and GPS (p = 0.020) retained their importance. This study highlights the associations between nutritional status, systemic inflammation, and psychological distress, supporting their common underlying pathophysiological mechanisms and further suggesting the necessity of a holistic anti-cachectic approach.


[Nd: YAG laser clearance of the anterior surface of intraocular lenses].
To assess the efficacy and safety of Nd: YAG laser in clearing the anterior fibrinous membrane of posterior chamber intraocular lens (IOL). Twenty-four eyes with the anterior fibrinous membrane of posterior chamber IOL were treated by Nd: YAG laser with the principle of "Low energy and de-focus" from 1997 to 1999 in Peking Union Medical College Hospital. Visual acuity, intraocular pressure (IOP) and anterior segment of the eye were followed after the laser treatment. Nd: YAG laser successfully cleared the anterior fibrinous membrane of IOL and IOLs were not damaged in all 24 eyes. The visual acuity was improved in 83.3% of the eyes. The IOP temporarily raised to above 21 mm Hg in 37.5% of the eyes. Topical steroids were used for the control of the intraocular inflammation in anterior segment after laser treatment. The anterior membrane of IOL can successfully and safely be cleared by Nd: YAG laser with the principle of "low energy and de focus".


High prevalence of plasma hypertonicity among community-dwelling older adults: results from NHANES III.
Recent data suggest that as many as 50% of older adults may have hypertonic plasma, an indicator of cell dehydration that predicts a range of adverse outcomes. To determine if a prevalence of this magnitude could be real, this study used nationally representative data to estimate the prevalence of hypertonicity, and to test for biologically plausible associations between hypertonicity, older age, glucose dysregulation, hemoconcentration, reduced bioelectrical impedance, and water intake. Cross-sectional. Community-dwelling adults (aged 20 to 90 years) who gave blood as part of the Third National Health and Nutrition Examination Survey (N = 14,855). Plasma tonicity was estimated from glucose, sodium, and potassium values. The weighted prevalences of mild (295 to 300 mmol/L) and overt hypertonicity (> or = 300 mmol/L) were estimated by age, sex, race/ethnicity, fasting, and glycemic status. Hyper- and normotonic (285 to 295 mmol/L) groups were compared with respect to elevated blood chemistry values, bioelectrical impedance analysis parameters, as well as total water intake (grams, % Adequate Intake, and grams per kilogram body weight), using multivariable models that adjusted for age, sex, race/ethnicity, and survey design. Mild and overt hypertonicity were observed in 40% and 20% of the sample, respectively. Hypertonicity was positively associated with older age, Hispanic and African-American race, impaired glucose tolerance, diabetes, and hemoconcentration, and inversely associated with bioelectrical impedance analysis parameters. Hypertonicity was associated with greater total water intake in younger adults, but decreased intake in older adults. Clinicians and researchers should be alert to hypertonicity and its causes in older adults.


Interaction of osteogenic cells with hydroxylapatite implant materials in vitro and in vivo.
In a series of scanning electron microscopic studies, the reaction of osteogenic cells to hydroxylapatite (HA) implant materials was investigated in culture and following implantation. Tissue components as found in normal rat and dog bone were identified at the interface in both test systems. In vivo, implant bed cells showed an intimate contact with the HA surfaces. Osteoblasts deposited organic matrix and bone mineral in direct apposition to HA, with no evidence of encapsulation or granulation tissue. The development of such a direct spatial relationship appears to involve mechanisms more encompassing than epitaxis.


Biodiesel and activated carbon from arabica spent coffee grounds.
This study aims to analyze the potential and characteristics of biodiesel and activated carbon from spent coffee grounds (SCG).•Biodiesel was obtained by extracting oil from SCG using Soxhlet extraction method with n-hexane solvent with an oil yield of 18.14% w/w of dry SCG. Furthermore, the coffee oil was esterified and transesterified to produce biodiesel with 57.32 % yield of coffee oil and higher heating value of 36.69 MJ/kg, density (15°C) of 0.89 g/mL, kinematic viscosity (40°C) of 7.67 mm2/s, acid number of 1.19 mg KOH/g oil.•The residue in form of grounds after oil extraction process was turned into activated carbon using two step activation process. Carbonization process was carried out at 500, 600, 700, and 800°C for 30 minutes and then chemically activated using potassium hydroxide (KOH) at 750°C for 2 hours. As the comparison, activated carbon was also made from SCG without oil extraction process. This study shows that the adsorption capacity of activated carbon made from SCG with oil extraction was better than without oil extraction. The best adsorption of activated carbon was obtained from SCG with oil extraction and carbonized at 700°C with iodine value of 1,224.59 mg/g and methylene blue value of 153.08 mg/g.


Relation of attention deficit and conduct disorder to vigilance and reading lag.
The relationship between DSM-III Axis I diagnoses 'attention deficit disorder with hyperactivity' (ADDH), 'conduct disorder' (CD) and 'anxiety disorder' (AD) and measures of attention and reading were studied in 158 children. Children diagnosed as having severe or moderate ADDH were found to be younger at referral and to have a lower IQ than were children with CD and AD. When age, IQ, social class and sex were controlled, children with severe ADDH were found to perform significantly worse than other diagnostic groups on some tests of vigilance and reading age. The data suggest that children with severe ADDH form a distinct group, and those with mild ADDH overlap symptomatically and on tests of vigilance with children with CD.


Seizures and epilepsy in the elderly.
Recent data indicate that the incidence and prevalence of seizures and epilepsy rise substantially in the elderly. Little well-founded information is available on which to base treatment decisions. This article discusses cause, diagnostic evaluation, and antiepileptic drug pharmacology. Tentative treatment suggestions are offered, emphasizing the limits of available knowledge.


Readability of patient information can be improved.
The number of participants in medical experiments has declined and consent often rests on perilous ground because the participant information sheet (PIS) on which informed consent rests preserves identification with the expert environment. This study explores to which extent research ethics committee (REC) members appreciate this problem. A retrospective analysis of ten REC applications were subjected to a naïve reading followed by structural analysis to generate themes and subthemes to guide structured REC member focusgroup interviews. This analysis informed a prospective survey where REC members registered terms and phrases posing comprehension barriers to lay receivers. Main barriers of comprehension were aspects of contents presentation and specialised terminology. Problematic terms centred mainly on epidemiology, design, descriptive and topographic anatomy and physiology, diagnostic procedures and medicines. Contents problems centred on irrelevant and superfluous information and poor presentation. The language, structure and format of the PIS should be improved. Avoiding technical jargon or explaining it when it is used, using more common words when they are available and a clearer structure were identified as potential targets of intervention. not relevant. not relevant.


An Atypical Parvovirus Drives Chronic Tubulointerstitial Nephropathy and Kidney Fibrosis.
The occurrence of a spontaneous nephropathy with intranuclear inclusions in laboratory mice has puzzled pathologists for over 4 decades, because its etiology remains elusive. The condition is more severe in immunodeficient animals, suggesting an infectious cause. Using metagenomics, we identify the causative agent as an atypical virus, termed "mouse kidney parvovirus" (MKPV), belonging to a divergent genus of Parvoviridae. MKPV was identified in animal facilities in Australia and North America, is transmitted via a fecal-oral or urinary-oral route, and is controlled by the adaptive immune system. Detailed analysis of the clinical course and histopathological features demonstrated a stepwise progression of pathology ranging from sporadic tubular inclusions to tubular degeneration and interstitial fibrosis and culminating in renal failure. In summary, we identify a widely distributed pathogen in laboratory mice and establish MKPV-induced nephropathy as a new tool for elucidating mechanisms of tubulointerstitial fibrosis that shares molecular features with chronic kidney disease in humans.


Median of patient results as a tool for assessment of analytical stability.
In spite of the well-established external quality assessment and proficiency testing surveys of analytical quality performance in laboratory medicine, a simple tool to monitor the long-term analytical stability as a supplement to the internal control procedures is often needed. Patient data from daily internal control schemes was used for monthly appraisal of the analytical stability. This was accomplished by using the monthly medians of patient results to disclose deviations from analytical stability, and by comparing divergences with the quality specifications for allowable analytical bias based on biological variation. Seventy five percent of the twenty analytes achieved on two COBASs INTEGRA 800 instruments performed in accordance with the optimum and with the desirable specifications for bias. Patient results applied in analytical quality performance control procedures are the most reliable sources of material as they represent the genuine substance of the measurements and therefore circumvent the problems associated with non-commutable materials in external assessment. Patient medians in the monthly monitoring of analytical stability in laboratory medicine are an inexpensive, simple and reliable tool to monitor the steadiness of the analytical practice.


RASopathy mutations provide functional insight into the BRAF cysteine-rich domain and reveal the importance of autoinhibition in BRAF regulation.
BRAF is frequently mutated in human cancer and the RASopathy syndromes, with RASopathy mutations often observed in the cysteine-rich domain (CRD). Although the CRD participates in phosphatidylserine (PS) binding, the RAS-RAF interaction, and RAF autoinhibition, the impact of these activities on RAF function in normal and disease states is not well characterized. Here, we analyze a panel of CRD mutations and show that they increase BRAF activity by relieving autoinhibition and/or enhancing PS binding, with relief of autoinhibition being the major factor determining mutation severity. Further, we show that CRD-mediated autoinhibition prevents the constitutive plasma membrane localization of BRAF that causes increased RAS-dependent and RAS-independent function. Comparison of the BRAF- and CRAF-CRDs also indicates that the BRAF-CRD is a stronger mediator of autoinhibition and PS binding, and given the increased catalytic activity of BRAF, our studies reveal a more critical role for CRD-mediated autoinhibition in BRAF regulation.


Juvenile angiofibroma: a review of the literature and a case series report.
Juvenile angiofibroma is a rare, histologically benign tumor which occurs almost exclusively in adolescent boys. The morbidity and mortality associated with this tumor are related to its prominent vascularity and its propensity for aggressive local growth. From 1974 through 1988, 21 male patients with a diagnosis of juvenile angiofibroma were managed at the Toronto General Hospital or the Hospital for Sick Children, Toronto. Preoperative computed tomography was performed on 20 patients, selective angiography on 21 patients, and preoperative embolization on 15 patients. Primary surgery was performed on 67% of these patients, with radiation therapy used for advanced stage II and stage III disease or in response to patient preference. Pterygopalatine fossa involvement was demonstrated in 90% of the patients; as a result, the lateral rhinotomy approach was most commonly used in the surgical cases. A successful outcome was achieved in 86% of patients treated with surgery alone. Two patients underwent radiotherapy for salvage following postoperative recurrence. There were no treatment-related deaths and no major surgical complications. The value of computed tomography is discussed, the authors' treatment protocol is outlined, and the case series results are presented.


Treatment and prognosis in sinonasal mucosal melanoma: A retrospective analysis of 65 patients from a single cancer center.
The purpose of this study was to evaluate the outcome in sinonasal mucosal melanoma (SMM). A retrospective analysis of clinicopathological data from January 1976 to December 2005 was performed. Survival curve, univariate, and multivariate analyses were undertaken. Sixty-eight patients with SMM were enrolled; 3 patients refused treatment. The 3-year and 5-year overall survival (OS) rates in the remaining 65 cases of SMM were 36.5% and 29.7%, respectively. Patients who underwent surgery had better 3-year and 5-year OS rates than those treated without surgery (40.7% and 34.1% vs 21.4% and 14.3%, respectively), and the same was true for patients treated with and without biotherapy (58.2% and 50.9% vs 30.0% and 23.4%, respectively). Distant metastasis at presentation was associated with a worse prognosis. Those patients managed with multimodality treatment had better OS rates. The prognosis in SMM is poor, particularly for those with distant metastasis or without surgery. Multimodality treatment may improve survival.


Lung cancer screening adherence among people living with and without HIV: An analysis of an integrated health system in Florida, United States (2012-2021).
Although lung cancer is a leading cause of death among people living with HIV (PLWH), limited research exists characterizing real-world lung cancer screening adherence among PLWH. Our objective was to compare low-dose computed tomography (LDCT) adherence among PLWH to those without HIV treated at one integrated health system. Using the University of Florida's Health Integrated Data Repository (01/01/2012-10/31/2021), we identified PLWH with at least one LDCT procedure, using Current Procedural Terminology codes(S8032/G0297/71271). Lung cancer screening adherence was defined as a second LDCT based on the Lung Imaging Reporting and Data System (Lung-RADS®). Lung-RADS categories were extracted from radiology reports using a natural language processing system. PLWH were matched with 4 randomly selected HIV-negative patients based on (+/- 1 year) age, Lung-RADS category, and calendar year. Seventy-three PLWH and 292 matched HIV-negative adults with at least one LDCT were identified. PLWH were more likely to be male (66% vs.52%,p < 0.04), non-Hispanic Black (53% vs.23%,p < 0.001), and live in an area of high poverty (45% vs.31%,p < 0.001). PLWH were more likely to be diagnosed with lung cancer after first LDCT (8% vs.0%,p < 0.001). Seventeen percent of HIV-negative and 12% of PLWH were adherent to LDCT screenings. Only 25% of PLWH diagnosed with category 4A were adherent compared to 44% of HIV-negative. On multivariable analyses, those with older age (66-80 vs.50-64 years) and with either Medicaid, charity-based, or other government insurance (vs. Medicare) were less likely to be adherent to LDCT screenings. PLWH may have poorer adherence to LDCT compared to their HIV-negative counterparts.


Population genomics and evidence of clonal replacement of Plasmodium falciparum in the Peruvian Amazon.
Previous studies have shown that P. falciparum parasites in South America have undergone population bottlenecks resulting in clonal lineages that are differentially distributed and that have been responsible for several outbreaks different endemic regions. In this study, we explored the genomic profile of 18 P. falciparum samples collected in the Peruvian Amazon Basin (Loreto) and 6 from the Peruvian North Coast (Tumbes). Our results showed the presence of three subpopulations that matched previously typed lineages in Peru: Bv1 (n = 17), Clonet D (n = 4) and Acre-Loreto type (n = 3). Gene coverage analysis showed that none of the Bv1 samples presented coverage for pfhrp2 and pfhrp3. Genotyping of drug resistance markers showed a high prevalence of Chloroquine resistance mutations S1034C/N1042D/D1246Y in pfmdr1 (62.5%) and K45T in pfcrt (87.5%). Mutations associated with sulfadoxine and pyrimethamine treatment failure were found on 88.8% of the Bv1 samples which were triple mutants for pfdhfr (50R/51I/108N) and pfdhps (437G/540E/581G). Analysis of the pfS47 gene that allows P. falciparum to evade mosquito immune responses showed that the Bv1 lineage presented one pfS47 haplotype exclusive to Loreto and another haplotype that was present in both Loreto and Tumbes. Furthermore, a possible expansion of Bv1 was detected since 2011 in Loreto. This replacement could be a result of the high prevalence of CQ resistance polymorphisms in Bv1, which could have provided a selective advantage to the indirect selection pressures driven by the use of CQ for P. vivax treatment.


Ubiquitin-proteasome inhibitor enhances tumour necrosis factor-alpha-induced apoptosis in rat gastric epithelial cells.
Tumour necrosis factor (TNF-alpha) is a candidate factor for involvement in inflammation-mediated gastric mucosal injury. However, the effect of this cytokine on gastric epithelial cells has been poorly investigated. In the present study, we examined whether gastric epithelial cells are resistant to TNF-alpha-induced apoptosis, and whether this resistance is related to ubiquitin-proteasome-associated nuclear factor-kappaB (NF-kappaB) activation. The rat gastric mucosal cell line RGM-1 was grown in DMEM/F12 medium supplemented with 10% FCS. Confluent monolayers of cells were pretreated or not for 60 min with PSI, a peptide aldehyde known to specifically inhibit the chymotrypsin-like activity of 26S proteasome. Cells were subsequently stimulated with recombinant rat TNF-alpha and their viability was determined by WST-1 assay. Apoptosis was confirmed by fluorescence microscopy after staining with Hoechst 33342 and propidium iodide, and DNA fragmentation was determined by flow cytometry using an APO-BRDU kit. IkappaB-alpha and the p65 binding subunit of NF-kappaB were detected by Western blots. Twenty-four-hour incubation with TNF-alpha alone or PSI alone did not affect the cell viability of RGM-1 cells. Pretreatment with PSI significantly enhanced the level of apoptosis induced by TNF-alpha. In RGM-1 cells treated with TNF-alpha, cytoplasmic IkappaB-alpha decreased and p65 in nuclear extracts increased markedly 30 min after cytokine stimulation. Pretreatment with PSI at 12.5 micromol/L blocked these TNF-alpha-induced changes. PSI enhances TNF-alpha-induced apoptosis through inhibition of NF-kappaB activation in RGM-1 cells.


The SOD7/DPA4-GIF1 module coordinates organ growth and iron uptake in Arabidopsis.
Organ growth is controlled by both intrinsic genetic factors and external environmental signals. However, the molecular mechanisms that coordinate plant organ growth and nutrient supply remain largely unknown. We have previously reported that the B3 domain transcriptional repressor SOD7 (NGAL2) and its closest homologue DPA4 (NGAL3) act redundantly to limit organ and seed growth in Arabidopsis. Here we report that SOD7 represses the interaction between the transcriptional coactivator GRF-INTERACTING FACTOR 1 (GIF1) and growth-regulating factors (GRFs) by competitively interacting with GIF1, thereby limiting organ and seed growth. We further reveal that GIF1 physically interacts with FER-LIKE IRON DEFICIENCY-INDUCED TRANSCRIPTION FACTOR (FIT), which acts as a central regulator of iron uptake and homeostasis. SOD7 can competitively repress the interaction of GIF1 with FIT to influence iron uptake and responses. The sod7-2 dpa4-3 mutant enhances the expression of genes involved in iron uptake and displays high iron accumulation. Genetic analyses support that GIF1 functions downstream of SOD7 to regulate organ and seed growth as well as iron uptake and responses. Thus, our findings define a previously unrecognized mechanism that the SOD7/DPA4-GIF1 module coordinates organ growth and iron uptake by targeting key regulators of growth and iron uptake.


The Pediatric Cardiac Care Consortium: a physician-managed clinical review program.
A voluntary physician-initiated and physician-managed clinical review program for pediatric cardiology uses clinical practice data and expected outcome to influence physicians to change their clinical behavior. The program offers a model for clinical review in situations where disease incidence is relatively low and physician performance is difficult to assess and evaluate. The program's major accomplishment is a collective pooling of data across cardiac centers that allows for statistical analysis and comparison not routinely possible at a single center because of sample size; a forum for comparison of different practice styles; and feedback to participants of actual, in contrast to anecdotal, results. The principles, structure, and format of the program can be applied to other specialty areas.


Using Multiple Scale Space-Time Patterns in Variance-Based Global Sensitivity Analysis for Spatially Explicit Agent-Based Models.
Sensitivity analysis (SA) in spatially explicit agent-based models (ABMs) has emerged to address some of the challenges associated with model specification and parameterization. For spatially explicit ABMs, the comparison of spatial or spatio-temporal patterns has been advocated to evaluate models. Nevertheless, less attention has been paid to understanding the extent to which parameter values in ABMs are responsible for mismatch between model outcomes and observations. In this paper, we propose the use of multiple scale space-time patterns in variance-based global sensitivity analysis (GSA). A vector-borne disease transmission model was used as the case study. Input factors used in GSA include one related to the environment (introduction rates), two related to interactions between agents and environment (level of herd immunity, mosquito population density), and one that defines agent state transition (mosquito extrinsic incubation period). The results show parameters related to interactions between agents and the environment have great impact on the ability of a model to reproduce observed patterns, although the magnitudes of such impacts vary by space-time scales. Additionally, the results highlight the time-dependent sensitivity to parameter values in spatially explicit ABMs. The GSA performed in this study helps in identifying the input factors that need to be carefully parameterized in the model to implement ABMs that well reproduce observed patterns at multiple space-time scales.


Characteristics of a shared idiotype by two IgM anti-herpes simplex virus monoclonal antibodies that recognize different determinants.
Two IgM monoclonal antibodies (McAb) that recognized distinct antigenic determinants of herpes simplex virus type 2 (HSV2) were shown to share idiotypes. Seven other IgM McAb generated to either HSV2 or the major envelope glycoprotein of HSV2, VP119, did not express this shared idiotype. The idiotypic determinants were associated with the antibody-combining site, because HSV2 inhibited the idiotype-anti-idiotype reactions. Anti-HSV2 sera raised in BALB/c mice also expressed the idiotype shared by the two anti-HSV2 McAb.


Pancreatic parenchymal changes seen on endoscopic ultrasound are dynamic in the setting of fatty pancreas: A short-term follow-up study.
The impact of fatty pancreas on pancreatic parenchymal changes is unclear. The aim of this study is to assess parenchymal alterations over time in patients with fatty pancreas (FP). This is a retrospective study (2014-2021) of patients with FP identified on endoscopic ultrasound (EUS). Subjects with follow up imaging studies including Computed Tomography (CT) scan, Magnetic Resonance Imaging (MRI), and EUS at least two years after the initial EUS were included. A total of 39 patients with a mean age of 51.21 ± 12.34 years were included. Mean initial weight was 80.17 ± 17.75 kg. Diabetes, hepatic steatosis, and EPI were present in 15%, 46% and 33% of the patients at baseline, respectively. In 25 patients with available follow up EUS over 2.4 ± 0.76 years, 16% progressed to chronic pancreatitis (CP) and 24% had progressive parenchymal changes without meeting the criteria for CP. One patient progressed from focal to diffuse FP, while one patient had resolution of FP. In multivariate analysis, progressive parenchymal changes on EUS were associated with an increase in weight over time (p-value 0.04), independent of the effects of gender, alcohol, or tobacco. Progressive parenchymal changes were noted in 44%. Our result suggests that FP is a dynamic process with the possibility of progression or regression over time.


Temperature dependence of the survival of human erythrocytes frozen slowly in various concentrations of glycerol.
One widely accepted explanation of injury from slow freezing is that damage results when the concentration of electrolyte reaches a critical level in partly frozen solutions during freezing. We have conducted experiments on human red cells to further test this hypothesis. Cells were suspended in phosphate-buffered saline containing 0-3 M glycerol, held for 30 min at 20 degrees C to permit solute permeation, and frozen at 0.5 or 1.7 degrees C/min to various temperatures between -2 and -100 degrees C. Upon reaching the desired minimum temperature, the samples were warmed at rates ranging from 1 to 550 degrees C/min and the percent hemolysis was determined. The results for a cooling rate of 1.7 degrees C/min indicate the following: (a) Between 0.5 and 1.85 M glycerol, the temperature yielding 50% hemolysis (LT50) drops slowly from -18 to -35 degrees C. (b) The LT50's over this range of concentrations are relatively independent of warming rate. (c) With glycerol concentrations of 1.95 and 2.0 M, the LT50 drops abruptly to -60 degrees C and to below -100 degrees C, respectively, and becomes dependent on warming rate. The LT50 is lower with slow warming at 1 degree C/min than with rapid. With still higher concentrations (2.5 and 3.0 M), there is no LT50, i.e., more than 50% of the cells survive freezing to-100 degrees C. Results for cooling at 0.5 degrees C/min in 2 M glycerol were similar except that the LT50s were some 10-20 degrees C higher. A companion paper (Rall et al., Biophys. J. 23:101-120, 1978) examines the relation between survival and the concentrations of salts produced during freezing.


CTLA-4 gene polymorphisms associate with efficacy of postoperative radioiodine-131 for differentiated thyroid carcinoma.
To investigate the association of CTLA-4 polymorphisms with efficacy of postoperative radioiodine-131 (I-131) treatment for differentiated thyroid carcinoma (DTC). A total of 324 DTC patients and 350 healthy individuals were enrolled in our study. Patients received I-131 remnant ablation following surgical resection. Based on the treatment efficacy, patients were divided into the effective (n = 183) and ineffective groups (n = 141). CTLA-4 polymorphisms (+49A>G, CT60A>G and -318C>T) were genotyped by polymerase chain reaction-restriction fragment length polymorphism. AG + AA genotype distribution and A allele frequency of +49A>G and CT60A>G polymorphisms were higher in the effective group than the ineffective group. +49A>G and CT60A>G polymorphisms were associated with the efficacy of postoperative I-131 treatment for DTC; and they might be bioindicators related to the prognosis of I-131 treatment.


Cross-facial nerve graft: a report of chronically paralyzed facial muscle neurotization by a nerve graft.
A 21-year-old housewife with long-standing hemifacial paralysis on the left side decided to undergo the classic two-stage cross-facial nerve graft with muscle transfer. The first stage of the operation was performed successfully with the use of a sural nerve graft. After the appearance of Tinel's sign 8 months later, gain of function in the muscles of the paralyzed side was observed and negated the need for the second-stage muscle transfer.


Blooming of Microcystis aeruginosa in the reservoir of the reclaimed land and discharge of microcystins to Isahaya Bay (Japan).
In the reservoir created in the reclaimed land in Isahaya Bay, Japan, Microcystis aeruginosa, which produces microcystins (MCs), bloomed every year, and the water with high levels of MCs in the reservoir has been often drained to Isahaya Bay to adjust the water level. The principal aims of this study are to clarify the water conditions suitable for blooming of M. aeruginosa in the reservoir, to follow the amount of distribution of MCs inside and outside the reservoir, and to discuss how blooming of M. aeruginosa is controlled in the reservoir and how MCs produced by Microcystis spread or accumulate in the aquatic environment. We monitored the water quality (temperature, salinity, dissolved inorganic nitrogen (DIN), and dissolved inorganic phosphorus) in the reservoir with seasonal blooming of microalgae including phytoplankton and M. aeruginosa using the concentrations of chlorophyll α and MCs, respectively, and collected the surface sediment in the reservoir and the bay to determine the MC content using the ELISA method. M. aeruginosa bloomed in extremely low DIN conditions of the water in warm seasons (spring and late summer to autumn). The year-mean standing stock of MCs was approximately 34.5 kg in the water and 8.4 kg in the surface sediment in the reservoir. Approximately 64.5 kg of MCs was discharged with the effluent to the bay in a year. Since a large amount of MCs always suspends in the water in the reservoir and it has been discharged to the bay, suspension-feeding animals are exposed most seriously to the high levels of MCs occurring in these areas. We need to pay attention to the danger of widespread dispersal of MCs and biological concentration of MCs by fish and clam inside and outside the reservoir.


Anatomy of glycosynthesis: structure and kinetics of the Humicola insolens Cel7B E197A and E197S glycosynthase mutants.
The formation of glycoconjugates and oligosaccharides remains one of the most challenging chemical syntheses. Chemo-enzymatic routes using retaining glycosidases have been successfully harnessed but require tight kinetic or thermodynamic control. "Glycosynthases," specifically engineered glycosidases that catalyze the formation of glycosidic bonds from glycosyl donor and acceptor alcohol, are an emerging range of synthetic tools in which catalytic nucleophile mutants are harnessed together with glycosyl fluoride donors to generate powerful and versatile catalysts. Here we present the structural and kinetic dissection of the Humicola insolens Cel7B glycosynthases in which the nucleophile of the wild-type enzyme is mutated to alanine and serine (E197A and E197S). 3-D structures reveal the acceptor and donor subsites and the basis for substrate inhibition. Kinetic analysis shows that the E197S mutant is considerably more active than the corresponding alanine mutant due to a 40-fold increase in k(cat).


Consultation on the medical frontier. A preliminary survey of the attitudes of infant intensive care nurses.
Advancing medical technology presents problems to medical professionals previously unforeseen. Psychiatric consultants are frequently called upon to assist staff, patients, and families in addressing these issues. The nursing staff of an infant intensive care unit was surveyed as to their perceptions of their work and their coping strategies. The results confirmed that in this technologically novel environment, staff were still attempting to acquire coping strategies to effectively meet demands placed upon them. The present study indicates that consultants need to be cognizant of such concerns to effectively assist such staff.


The colour-matching functions and visual research.
The following points are examined: the problem of how to define the colour of a stimulus used in visual research; the limited relation of the colour-matching functions to the spectral sensitivity curves of the individual colour receptors in the retina; and the case for abandoning luminance as a colorimetric variable and lightness as a colour appearance variable.


Synthesis and Characterization of a Novel γ-Aminobutyric Acid Type A (GABAA) Receptor Ligand That Combines Outstanding Metabolic Stability, Pharmacokinetics, and Anxiolytic Efficacy.
1,4-Benzodiazepines are used in the treatment of anxiety disorders but have limited long-term use due to adverse effects. HZ-166 (2) has been shown to have anxiolytic-like effects with reduced sedative/ataxic liabilities. A 1,3-oxazole KRM-II-81 (9) was discovered from a series of six bioisosteres with significantly improved pharmacokinetic and pharmacodynamic properties as compared to 2. Oxazole 9 was further characterized and exhibited improved anxiolytic-like effects in a mouse marble burying assay and a rat Vogel conflict test.


[Shared-housing arrangements for care-dependent people in Germany. A literature overview of structures, outcomes and quality management].
A main factor for the development of shared-housing arrangements (SHA) was the wish of more self-determination in old age. Since January 2013 SHA is government-funded through the "Pflege-Neuausrichtungs-Gesetz" (PNG). Yet, an overview of the situation of SHA in Germany is not available. Therefore, a systematic literature search (databases CareLit, CINAHL, GeroLit, PubMed) was conducted in order to identify publications regarding resident- and care-specific characteristics, resident-related health outcomes and setting-specific quality management systems. The currently available knowledge in these fields is not exhaustive and further research is needed. The results indicate that care in SHA is not more efficient regarding residents' quality of life than in institutional care settings. Valid studies regarding the quality of care provision in SHA and conceptual basics concerning quality assessment are widely lacking. Thus, the goal of expanding SHA within the framework of the PNG has to be accompanied by in-depth health services research.


The beta-lactam antibiotic ceftriaxone inhibits physical dependence and abstinence-induced withdrawal from cocaine, amphetamine, methamphetamine, and clorazepate in planarians.
Ceftriaxone (a beta-lactam antibiotic) has recently been identified as having the rare ability to increase the expression and functional activity of the glutamate transporter subtype 1 (GLT-1) in rat spinal cord cultures. GLT-1 has been implicated in diverse neurological disorders and in opioid dependence and withdrawal. It has been speculated that it might also be involved in the physical dependence and withdrawal of other abused drugs, but demonstration of this property can be difficult in mammalian models. Here, we demonstrate for the first time using a planarian model that ceftriaxone attenuates both the development of physical dependence and abstinence-induced withdrawal from cocaine, amphetamine, methamphetamine, and a benzodiazepine (clorazepate) in a concentration-related manner. These results suggest that physical dependence and withdrawal from several drugs involve a common - beta-lactam-sensitive - mechanism in planarians. If these findings can be shown to extend to mammals, beta-lactam antibiotics might represent a novel pharmacotherapy or adjunct approach for treating drug abuse or serve as a template for drug discovery efforts aimed at treating drug abuse, recovery from drug abuse, or ameliorating the withdrawal from chronic use of therapeutic medications.


Mindful with your baby for mothers of infants with (parental) stress in a non-clinical setting: a wait-list controlled pilot trial.
Because of the far-reaching negative consequences of high levels of (parental) stress for the mother, infant, the mother-infant relationship, and family functioning, psychological support for young mothers is important. Mindful with Your Baby is a mindfulness-based intervention, originally developed and evaluated in a clinical population of mothers with mental health issues and/or babies with regulation problems. The current pilot examines whether Mindful with Your Baby for mothers with symptoms of (parental) stress offered in a non-clinical setting is also effective and acceptable. In this pilot waitlist-controlled trial, 17 mothers with infants (2-15 months) admitted themselves for a Mindful with Your Baby training in a non-clinical setting because of (parental) stress. Mindful with Your Baby was offered in groups of three to six mother-infant dyads and consisted of eight weekly 2-h sessions. Participants completed questionnaires on symptoms of parental stress, general stress, depression, anxiety, mindfulness and self-compassion at 8-week waitlist, pretest, posttest and 8-week follow-up. There were no training drop-outs, attendance rate was 92.5%, and the training was evaluated positively: all mothers (100%) felt they got something of lasting importance as a result of taking the training, and reported becoming more conscious as a parent, and 93% reported changing their lifestyle or parenting as a result of the training. Multilevel analyses showed no significant changes between waitlist and pretest. At posttest, a significant improvement occurred in all outcome measures compared to pretest, of moderate to large effect sizes. At follow-up, a significant improvement was seen compared to pretest in all outcomes except anxiety compared to pretest, of small to moderate effect sizes. Mindful with Your Baby appears an acceptable and effective intervention for mothers with a baby who experience (parental) stress but who have not been referred to specialized mental health care. A low threshold access to Mindful with Your Baby in non-clinical settings could provide a timely and positive interference in (parental) stress.


Health food stores investigation.
In accordance with the New York City Department of Consumer Affairs' mandate to educate consumers and to prevent fraud and deception in the marketplace, the agency conducted a three-month investigation of city health food stores. Twenty-three health food businesses located throughout the five boroughs were visited from September through November 1982 in order to ascertain what those stores sold and how their merchandise compared, in quality and price, with items sold by other businesses.


Differential effects of buprenorphine and morphine on immune and neuroendocrine functions following acute administration in the rat mesencephalon periaqueductal gray.
The effects of the mu-opioid receptor agonists buprenorphine and morphine on immune and neuroendocrine functions through acute action in the rat mesencephalon periaqueductal gray (PAG) were evaluated. Buprenorphine is an analgesic recently approved for the treatment of drug dependency. In this study, it was shown that injection of an equianalgesic dose of buprenorphine (related to morphine) into the ventral-caudal PAG did not alter splenic NK cell, T cell, and macrophage functions, whereas morphine significantly (p<0.001) suppressed splenic NK cell cytotoxic activity (14-50% reduction), splenic and thymic T cell proliferation to concanavalin A (Con A, 43-76% reduction), antiTCR (T cell receptor) (85% reduction) and IL-2 (36-48% reduction), and macrophage functions including nitric oxide (36-41% reduction) and TNF-alpha production (26%), and phagocytosis of Candida albicans (39%). In addition, buprenorphine was associated with significant (p<0.0001) reductions in adrenocorticotropic hormone (ACTH) and corticosterone (CSO) plasma levels, without altering norepinephrine (NE) and serotonin splenic dialysate levels. In contrast, morphine significantly (p<0.0001) increased glucocorticoid and catecholamine levels in plasma and spleen dialysates, respectively. These results indicated that buprenorphine did not activate either the hypothalamic-pituitary-adrenal (HPA) axis with glucocorticoid release, or the sympathetic nerve (SNS) activity with bioamine production, and was not associated with immunosuppression. The lack of effects of buprenorphine on neuroendocrine systems may be related to its partial agonist properties, the absence of effects on immune system function, and may be associated with the reduction in craving observed in addictive disorders.


Hepatic miR-33a/miR-144 and their target gene ABCA1 are associated with steatohepatitis in morbidly obese subjects.
Abnormal cholesterol metabolism may contribute to the pathogenesis of non-alcoholic steatohepatitis (NASH) and fibrosis. miR-33 and miR-144 regulate adenosine triphosphate binding cassette transporter (ABCA1) and other target genes involved in cholesterol efflux, fatty acid oxidation and inflammation. We explored relationships between non-alcoholic fatty liver disease (NAFLD) and the hepatic expression of ABCA1/ABCG1, as well as other target genes regulated by miR-33 (carnitine O-octanoyltransferase, CROT and hydroxyacyl-CoA-dehydrogenase β-subunit, HADHB) and miR-144 (toll-like receptor-2, TLR2). Moreover, we evaluated whether the expression of these genes is correlated with miR-33a/b and miR-144 expression in Mexican individuals with morbid obesity. Eighty-four morbidly obese subjects undergoing bariatric surgery were included in this study. Liver biopsies were obtained to measure hepatic triglyceride and free cholesterol contents, as well as ABCA1, ABCG1, CROT, HADHB, TLR2, miR-33a/b and miR-144 expression. Hepatic free cholesterol content was significantly increased in NASH as compared to non-NASH subjects, while ABCA1 and ABCG1 protein levels significantly decreased with NASH and fibrosis progression. The relative expression of miR-33a and miR-144 correlated inversely with ABCA1 but not with ABCG1 protein levels. Moreover, both miRNAs increased significantly in NASH individuals. miR-33 target genes CROT and HADHB correlated inversely with miR-33a. However, the expression of these genes was not associated with NASH. miR-33a/144 and their target gene ABCA1 may contribute to the pathogenesis of NASH in morbidly obese subjects.


Authentication of documents using polypropylene immobilized with rare-earth doped aluminate nanoparticles.
Anticounterfeiting of commercial products has been improved using photochromism as an intriguing approach. In order to develop a mechanically reliable nanocomposite, the engineering procedure of the anticounterfeiting nanocomposite must be improved. Rare-earth doped aluminate/polypropylene (REA/PP) hybrid nanofibers were successfully made by electrospinning, and they were shown to be mechanically stable and highly photoluminescent, making them ideal for anticounterfeiting applications. UV-induced photochromic anticounterfeiting properties were monitored in the synthesized nanocomposite films. In order to ensure that the REA-PP film is completely transparent, REA must be embedded into the polypropylene nanofibers in nano-sized particle shape to facilitate a better dispersion without agglomeration of REA particles in polypropylene matrix. The morphology and structure of REA were studied by transmission electron microscopy and X-ray diffraction. The morphologies and chemical contents of the polypropylene nanofibrous films were studied by scanning electron microscopy, X-ray fluorescence, and energy-dispersive X-ray spectroscopy. The REA-PP nanofibrous film showed absorbance and emission maxima at 365 and 517 nm, respectively. When exposed to UV light, the photochromic activity of the transparent nanofibrous substrates to greenish-yellow was rapid and reversible without fatigue. Hydrophobicity of REA-PP films increased without affecting their original look or mechanical properties, while increasing the REA content. It was possible to produce ultraviolet-induced photochromic nanofibrous films that were transparent, flexible, and cost-effective. As a result of this method, numerous anticounterfeiting materials could be developed toward a better marketplace with both economy and community values. HIGHLIGHTS: Rare-earth aluminate/polypropylene (REA/PP) electrospun nanofibers were prepared. The photochromic transparent nanofibers displayed green emission under UV light. The nanofibrous films were flexible, mechanically stable and highly luminescent. Films showed absorbance and emission maxima at 365 and 517 nm, respectively. Hydrophobicity was improved without affecting the films original properties.


Protection from hypoxemia-induced renal dysfunction by the thiophosphate WR-2721.
The acute renal effects of hypoxemia-reoxygenation and the putative protective action of WR-2721 [S-, 2-(3-aminopropyl-amino)-, etylphosphosphorothioic acid], a drug with specific properties such as PTH-secretion inhibiting, calcium lowering and free radical scavenging activities, were investigated in anesthetized-ventilated rabbits. Glomerular filtration rate (GFR) and renal blood flow (RBF) were assessed by the clearance of inulin and para-aminohippuric acid, respectively. Each animal acted as its own control. Normoxemic control rabbits showed no changes in renal hemodynamics and function during 150 minutes. The administration of WR-2721 (75 mg/kg body wt i.v.) to normoxemic animals induced a significant decrease in MBP, RBF and diuresis, without affecting GFR. It significantly reduced plasma levels of PTH, decreased calcemia and increased urinary calcium excretion. In untreated hypoxemic-reoxygenated rabbits, 45 minutes of severe hypoxemia (PO2 around 35 mm Hg) induced a significant fall in MBP, GFR, RBF and diuresis, which persisted during the 60-minute reoxygenation period. The administration of WR-2721 before hypoxemia or reoxygenation prevented the hypoxemia-induced decrease in GFR and diuresis. Filtration fraction increased significantly. The renal functional improvement observed in hypoxemic rabbits administered WR-2721 could be mediated by its effect on calcium metabolism and/or its oxygen free radical scavenging properties.


ReCANVo: A database of real-world communicative and affective nonverbal vocalizations.
Nonverbal vocalizations, such as sighs, grunts, and yells, are informative expressions within typical verbal speech. Likewise, individuals who produce 0-10 spoken words or word approximations ("minimally speaking" individuals) convey rich affective and communicative information through nonverbal vocalizations even without verbal speech. Yet, despite their rich content, little to no data exists on the vocal expressions of this population. Here, we present ReCANVo: Real-World Communicative and Affective Nonverbal Vocalizations - a novel dataset of non-speech vocalizations labeled by function from minimally speaking individuals. The ReCANVo database contains over 7000 vocalizations spanning communicative and affective functions from eight minimally speaking individuals, along with communication profiles for each participant. Vocalizations were recorded in real-world settings and labeled in real-time by a close family member who knew the communicator well and had access to contextual information while labeling. ReCANVo is a novel database of nonverbal vocalizations from minimally speaking individuals, the largest available dataset of nonverbal vocalizations, and one of the only affective speech datasets collected amidst daily life across contexts.


Peripapillary and optic nerve head vessel density of glaucoma and healthy subjects from Afro-Caribbean and European descent: A pilot study.
To compare the peripapillary and optic nerve head vessel density (PP-ONH VD) between glaucoma patients (all, early, moderated, and advanced) and healthy subjects of Afro-Caribbean descent (AD) and European descent (ED). This was a cross-sectional study. One eye was evaluated in 90 subjects, including 66 glaucoma patients and 24 healthy subjects, who underwent PP-ONH VD imaging using SPECTRALIS® Optical Coherence Tomography Angiography (OCT-A). We analysed the superficial vascular complex using the AngioTool version 0.6a software. The correlation between the PP-ONH VD and visual field mean deviation (MD) was evaluated using a scatter plot and Spearman's rho correlation coefficient. Among the healthy subjects, the AD group had a lower superficial PP-ONH VD [43.29±3.25% (mean±standard deviation)] than the ED group (46.06±1.75%) (P=0.016). Overall, superficial PP-ONH VD did not show any significant differences between the total AD and ED glaucoma patients or in the subgroup analyses (early/moderate/advanced) (AD: 32.73±6.70%, 37.11±5.72%, 32.48±5.73%, 27.76±4.74%, respectively; ED: 33.94±6.89%, 38.52±3.82%, 35.56±4.18%; 27.65±6.31%, respectively) (P>0.05 for all). A strong, statistically significant correlation was established between vessel density and mean deviation among AD and ED glaucoma patients (r=0.709 and r=0.704, respectively) (P<0.001 for both). This pilot study shows that healthy subjects of AD had lower peripapillary and optic nerve head superficial vessel density than healthy subjects of ED, but no significant differences were found between AD and ED glaucoma groups (all, early, moderate, or advanced).


Morphological changes to endothelial and interstitial cells and to the extra-cellular matrix in canine myxomatous mitral valve disease (endocardiosis).
Morphological and functional changes in endothelial and interstitial cells are considered central to myxomatous degeneration of the canine mitral valve (endocardiosis). The aim of this study was to describe and quantify changes in valve endothelial cells (VECs), interstitial cells (VICs) and the extra-cellular matrix (ECM) of the sub-endothelial zone of diseased valves using a combination of transmission electron microscopy, stereology and computer-aided image analysis. Marked degradation of the endothelium was evident in diseased valves, which coincided with significant degradation of the local ECM (P<0.001). There were decreases and increases in the numbers of VECs and VICs, respectively, in diseased valves, with particular accumulation of VICs subjacent to the valve surface (P<0.01). Overall, VICs were more pleomorphic than VECs in both normal and diseased valves, but for VECs, the degree of pleomorphism was significantly different in diseased valves (P<0.0001). The findings of the study confirm that canine myxomatous mitral valve disease is associated with marked endothelial damage, with attendant proliferation of subjacent activated myofibroblasts. The fact that similar endothelial changes are present in normal valves suggests these processes not only contribute to valve pathology, but may also represent life-long valve remodelling.


Tumour-induced rickets: a case report and review of the literature.
Hypophosphataemic rickets was diagnosed in a 6-year-old boy with a negative family history. After 16 years of medical treatment he developed a malignant sarcoma of the right distal thigh. Removal of the tumour by high amputation of the leg resulted in disappearance of the phosphate leak. In spite of surgery and chemotherapy, the patient died due to extensive lung metastases. Retrospective analysis of the initial X-ray films showed a benign lesion on the lateral side of the right distal femur. This lesion is believed to be at the origin of the rickets. This is the first paediatric case reported with malignant degeneration of a benign tumour causing rickets. Patients with the classical hallmarks of X-linked, familial hypophosphataemic rickets but no affected family members should have a careful periodic search for a tumour, even years after onset of the disorder.


[Study of the surface self-fluorescence of rat kidneys using the perfusion method].
A method for the measurement of tissue surface fluorescence is described. It allows determination of the biochemical state and properties of superficial cells under influence of test-substances. As example for the suitability of this technique we present the results of self-fluorescence measurements on rat kidneys in vitro after ischaemia and under different conditions of superficial oxygenation.


A novel polymer-conjugated human IL-15 improves efficacy of CD19-targeted CAR T-cell immunotherapy.
Chimeric antigen receptor (CAR)-modified T-cell therapies targeting CD19 represent a new treatment option for patients with relapsed/refractory (R/R) B-cell malignancies. However, CAR T-cell therapy fails to elicit durable responses in a significant fraction of patients. Limited in vivo proliferation and survival of infused CAR T cells are key causes of failure. In a phase 1/2 clinical trial of CD19 CAR T cells for B-cell malignancies (#NCT01865617), low serum interleukin 15 (IL-15) concentration after CAR T-cell infusion was associated with inferior CAR T-cell kinetics. IL-15 supports T-cell proliferation and survival, and therefore, supplementation with IL-15 may enhance CAR T-cell therapy. However, the clinical use of native IL-15 is challenging because of its unfavorable pharmacokinetic (PK) and toxicity. NKTR-255 is a polymer-conjugated IL-15 that engages the entire IL-15 receptor complex (IL-15Rα/IL-2Rβγ) and exhibits reduced clearance, providing sustained pharmacodynamic (PD) responses. We investigated the PK and immune cell PDs in nonhuman primates treated with NKTR-255 and found that NKTR-255 enhanced the in vivo proliferation of T cells and natural killer cells. In vitro, NKTR-255 induced dose-dependent proliferation and accumulation of human CD19 CAR T cells, especially at low target cell abundance. In vivo studies in lymphoma-bearing immunodeficient mice demonstrated enhanced antitumor efficacy of human CD19 CAR T cells. In contrast to mice treated with CAR T cells alone, those that received CAR T cells and NKTR-255 had markedly higher CAR T-cell counts in the blood and marrow that were sustained after tumor clearance, without evidence of persistent proliferation or ongoing activation/exhaustion as assessed by Ki-67 and inhibitory receptor coexpression. These data support an ongoing phase 1 clinical trial of combined therapy with CD19 CAR T cells and NKTR-255 for R/R B-cell malignancies.


Protecting group-free, selective cross-coupling of alkyltrifluoroborates with borylated aryl bromides via photoredox/nickel dual catalysis.
Orthogonal reactivity modes offer substantial opportunities for rapid construction of complex small molecules. However, most strategies for imparting orthogonality to cross-coupling reactions rely on differential protection of reactive sites, greatly reducing both atom and step economies. Reported here is a strategy for orthogonal cross-coupling wherein a mechanistically distinct activation mode for transmetalation of sp(3)-hybridized organoboron reagents enables C-C bond formation in the presence of various protected and unprotected sp(2)-hybridized organoborons. This manifold has the potential for broad application, because orthogonality is inherent to the activation mode itself. The diversification potential of this platform is shown in the rapid elaboration of a trifunctional lynchpin through various transition metal-catalyzed processes without nonproductive deprotection or functional group manipulation steps.


Active Metabolites from Endolichenic Fungus Talaromyces sp.
The active metabolites investigation of Talaromyces sp. (strain No. MH551540) associated with Xanthoparmelia angustiphylla afforded one new δ-lactone, talaromycin A (1), together with six known compounds, clearanol A (2), 6-methylbiphenyl-3,3',4,5'-tetraol (3), desmethylaltenusin (4), ergone (5), ergosterol (6), and palmitic acid (7). The structures of these compounds were elucidated by a combination of spectroscopic-data interpretation and single-crystal X-ray diffraction analysis. The cytotoxicities of 1-7 and the antioxidant activities of 3 and 4 were also evaluated.


Association of IL-13, S100B, and TLR-7 Gene Polymorphisms with Enterovirus 71 Infection in Hand, Foot, and Mouth Disease in China.
This study was conducted to determine if single nucleotide polymorphisms within the interleukin (IL)-13 (rs20541 locus), the S100B (rs9722 locus), and the toll-like receptor (TLR)-7 (rs179019 and rs3853839 loci) genes are associated with the clinical severity of disease caused by enterovirus 71 (EV71) in children suffering from hand, foot, and mouth disease (HFMD). A total of 355 children, diagnosed with HFMD, were divided into two groups: severe (totaling 162 cases) and mild (totaling 193 cases). Three hundred healthy children were recruited as a control group. The gene polymorphisms of the rs20541 locus in the IL-13 gene; the rs9722 locus in the S100B gene; and the rs179019 and the rs3853839 loci in the TLR-7 gene were analyzed with Sanger sequencing. The expression levels of IL-13, S100B, interferon (IFN)-α, IL-6 and the relative expression level of TLR-7 were calculated for each genotype. This study demonstrated that the T allele at the rs9722 locus of the S100B gene was a significant risk factor for severe HFMD. The rs3853839 C allele of the TLR-7 gene was also a risk factor for severe HFMD in both male and female patients. The G allele at the rs20541 locus of IL-13 gene and the A allele at the rs179019 locus of the TLR-7 gene were not risk factors for severe HFMD in either male or female patients. The T allele at the rs9722 locus of S100B gene is a risk factor for the severe HFMD caused by EV71 infection, of which the mechanism may be due to the promotion of S100B protein secretion. The allele C at TLR-7 rs3853839 locus is a risk factor for the severe HFMD caused by EV71 infection, which may be related to a reduction of the relative expression of TLR-7, IFN-α, and IL-6.


Use of marine debris as nest material by ospreys.
The use of anthropogenic debris as nest-building materials may affect nest function. We study ospreys (Pandion haliaetus) on an island with scarce vegetation and high availability of beached marine debris. We describe the anthropogenic debris in osprey nests, evaluate the factors affecting its prevalence and abundance, and test its potential effects on breeding parameters. We also quantify plastic entanglements among adults and nestlings. Of the 36 studied nests, 92 % included non-natural items, with plastic being the most frequent material (88.9 %). Nests that were bigger and closer to the coast had more anthropogenic items. The abundance of anthropogenic items in nests did not correlate with osprey breeding parameters. We recorded two live entangled adult females, which represent 3.9 % of the adult population. Monitoring the abundance of anthropogenic debris and its effects on wildlife is necessary to guarantee long-term viability of coastal wildlife.


Colonic diaphragm disease without significant non-steroidal anti-inflammatory drug use: a case report.
Colonic diaphragm disease is an uncommon condition usually associated with the long-term use of non-steroidal anti-inflammatory drugs. A 48-year-old woman presented as an emergency patient with abdominal pain and vomiting. Past medical history included inflammatory bowel disease of ulcerative colitis type for which she was taking azathioprine and prednisolone. On examination, she was shocked with signs of peritonism. Following resuscitation, she was taken for a laparotomy upon which a small amount of turbid fluid was identified but there was no direct evidence of an intra-abdominal perforation. A peritoneal lavage was performed and she was taken to the intensive care unit. A repeat laparotomy was performed on the sixth postoperative day, following a clinical deterioration and again no leak was identified. Given the history of ulcerative colitis, the perforation was presumed to be of colonic origin and a total colectomy and ileostomy was performed. Histopathological examination of the colectomy specimen revealed extensive colonic diaphragm disease with 30 thin-walled diaphragms, one of which reduced the lumen to a pin-hole. No perforation was identified. To the best of the our knowledge, this is the first report of the development of colonic diaphragm disease in the absence of a history of non-steroidal anti-inflammatory drug ingestion. Given the history of ulcerative colitis we believe that the disease may have arisen as a result of the healing of the underlying inflamed colon rather than as a direct effect of non-steroidal anti-inflammatory drugs.


Congenital adrenal hyperplasia: surgical considerations required to repair a 46,XX patient raised as a boy.
21-hydroxylase deficiency (P450 CYP21) accounts for 90% of cases of congenital adrenal hyperplasia (CAH), which is associated with abnormally low cortisol and high production of androgen precursors and is the most common cause of ambiguous genitalia. Increased androgen causes in utero virilization of the fetus, consisting of clitoral enlargement, an urogenital sinus, and labioscrotal enlargement and fusion. This is the first case in an experience covering more than 30 years, of a 46,XX patient raised as a boy. The authors report a case of a Pakistani patient born of a consanguineous union, who came to medical attention at age 3 because of severe genital ambiguity; genetic analyses showed that the child was a compound heterozygote for CAH. The surgical management of this patient consisted of (1) staged hypospadias repairs preceded by testosterone therapy, (2) creation of a bladder graft neourethra, (3) removal of müllerian structures, (4) correction of bifid prepenile scrotum, and (5) insertion of testicular prostheses. The commitment to raise a 46,XX child as a boy is a very rare event. With a series of staged complex surgical procedures and careful steroid replacement, normal secondary sexual characteristics can be achieved in these children.


Care of the pediatric solid organ transplant recipient. The primary care perspective.
Although transplantation is an effective therapy for many end-stage organ diseases, this treatment cannot be totally successful without continued careful medical management, monitoring, and psychosocial support. Transplantation is a lifelong commitment. Primary care physicians can lay the foundation for ongoing care by providing medical intervention when appropriate and maintaining close communication with the transplant center, but perhaps more importantly by developing a relationship with these children and their families that impacts adherence to care will promote an optimal quality of life.


Impact of CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers.
Glyburide (INN, glibenclamide) is a second-generation sulfonylurea antidiabetic agent with high potency. We hypothesized that glyburide may be a substrate of cytochrome P450 2C9 (CYP2C9), an enzyme that has two low-activity amino acid variants-Arg144Cys (CYP2C9*2) and Ile359Leu (CYP2C9*3). We explored the impact of these polymorphisms on glyburide pharmacokinetics and the effects on insulin and glucose concentrations. Twenty-one healthy volunteers who represented all possible combinations of the two variant alleles were studied (genotypes CYP2C9*1/*1, *1/*2, *2/*2, *1/*3, *2/*3, and *3/*3 ). They received a single oral dose of 3.5 mg glyburide followed by 75 g glucose at 1, 4.5, and 8 hours after administration of glyburide. Glyburide was quantified in plasma by reversed-phase HPLC. Venous blood concentrations of glyburide, insulin, and glucose were analyzed with a population pharmacokinetic-pharmacodynamic model by use of NONMEM statistical software. Pharmacokinetics of glyburide depended significantly on CYP2C9 genotypes. In homozygous carriers of the genotype *3/*3, total oral clearance was less than half of that of the wild-type genotype *1/*1 (P <.001). Correspondingly, insulin secretion measured within 12 hours after glyburide ingestion was higher in carriers of the genotype *3/*3 compared with the other genotypes (P =.028), whereas the differences in glucose concentrations were not significant. Carriers of the CYP2C9 variant *3 had decreased oral clearances of glyburide. This confirms that glyburide is metabolized by CYP2C9. Corresponding differences in insulin plasma levels indicated that dose adjustment based on CYP2C9 genotype may improve antidiabetic treatment.


Influence of long-term obesity on myocardial gene expression.
Several authors have shown that deterioration of cardiac function is associated with the degree and duration of obesity. It is necessary to establish the gene expression patterns after prolonged periods of obesity. This study tested the hypothesis that increased duration of exposure to obesity leads to a reduction in the mRNA levels of proteins involved in regulation of myocardial Ca2+ homeostasis. In addition, this study verified whether the decrease in mRNA expression was caused by a reduction in thyroid hormone. Thirty-day-old male Wistar rats were distributed in two groups: control (C) and obese (Ob). The C group was fed a standard diet and the Ob was fed with high-fat diets for 15, 30 and 45 weeks. Obesity was defined by adiposity index. The gene expression was assessed by quantitative real-time PCR. The adiposity index was higher in the Ob compared to the C after all periods. While obesity at 15 and 45 weeks resulted in a reduction in mRNA of sarcoplasmic reticulum Ca2+- ATPase (SERCA2a), Na+/Ca2+ exchanger (NCX), and calsequestrin (CSQ), L-type Ca2+ channels, ryanodine receptor, SERCA2a, phospholamban (PLB), NCX, and CSQ expression were increased compared to the C after 30 weeks. There was no significant association between T3 levels and mRNA expression. Our data indicate that obesity over the short and long periods of time may promote alteration in gene expression of Ca2+ homeostasis regulatory proteins without influence by thyroid hormone.


exo-FISH: Protocol for detecting DNA breaks in repetitive regions of mammalian genomes.
Detecting DNA breaks in defined regions of the genome is critical to advancing our understanding of genome stability maintenance. Here, we present exo-FISH, a protocol to label exposed single-stranded DNA in defined repetitive regions of mammalian genomes by combining in vitro restriction enzyme digestion on fixed cells with fluorescence in situ hybridization (FISH). We describe steps for cell harvesting and fixation, slide treatments, and FISH probe hybridization. We then detail procedures for imaging and analysis. For complete details on the use and execution of this protocol, please refer to Saayman et al. (2023).1.